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Early life events may predispose to the development of chronic lung disease in adulthood.,To provide an update on current knowledge of early nongenetic origins of COPD.,Systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,A total of 16 studies, comprising 69,365 individuals, met the predefined criteria and were included in the present review.,Studies have shown that in utero tobacco exposure, low birth weight, preterm birth, and respiratory diseases, primarily asthma and pneumonia, in early childhood are associated with lung function impairment later in childhood, and by that predispose to subsequent development of COPD, although the causal association between childhood respiratory diseases and COPD has been questioned in one study.,Environmental tobacco exposure has also been shown to have negative impact on lung function in childhood possibly leading to COPD in adulthood, although it is at present not possible to clearly distinguish between the impact of active and the environmental tobacco exposure on subsequent development of COPD.,Tobacco exposure in utero and early life is a risk factor for subsequent development of COPD.,Furthermore, low birth weight, lower respiratory tract infections and asthma, including wheezy bronchitis, in childhood also seem to be important determinants for later development of COPD.,Early life insults may, therefore, be crucial to COPD development. | 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 |
Incidental CT findings may provide an opportunity for early detection of chronic obstructive pulmonary disease (COPD), which may prove important in CT-based lung cancer screening setting.,We aimed to determine the diagnostic performance of human observers to visually evaluate COPD presence on CT images, in comparison to automated evaluation using quantitative CT measures.,This study was approved by the Dutch Ministry of Health and the institutional review board.,All participants provided written informed consent.,We studied 266 heavy smokers enrolled in a lung cancer screening trial.,All subjects underwent volumetric inspiratory and expiratory chest computed tomography (CT).,Pulmonary function testing was used as the reference standard for COPD.,We evaluated the diagnostic performance of eight observers and one automated model based on quantitative CT measures.,The prevalence of COPD in the study population was 44% (118/266), of whom 62% (73/118) had mild disease.,The diagnostic accuracy was 74.1% in the automated evaluation, and ranged between 58.3% and 74.3% for the visual evaluation of CT images.,The positive predictive value was 74.3% in the automated evaluation, and ranged between 52.9% and 74.7% for the visual evaluation.,Interobserver variation was substantial, even within the subgroup of experienced observers.,Agreement within observers yielded kappa values between 0.28 and 0.68, regardless of the level of expertise.,The agreement between the observers and the automated CT model showed kappa values of 0.12-0.35.,Visual evaluation of COPD presence on chest CT images provides at best modest accuracy and is associated with substantial interobserver variation.,Automated evaluation of COPD subjects using quantitative CT measures appears superior to visual evaluation by human observers. | Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by chronic airflow limitation.,Unraveling of this heterogeneity is challenging but important, because it might enable more accurate diagnosis and treatment.,Because spirometry cannot distinguish between the different contributing pathways of airflow limitation, and visual scoring is time-consuming and prone to observer variability, other techniques are sought to start this phenotyping process.,Quantitative computed tomography (CT) is a promising technique, because current CT technology is able to quantify emphysema, air trapping, and large airway wall dimensions.,This review focuses on CT quantification techniques of COPD disease components and their current status and role in phenotyping COPD. | 1 |
A high percentage of patients with COPD report chronic nasal symptoms.,The study aims to evaluate the clinical impact of a 2-month treatment with inhaled nasal budesonide (100 µg per nostril twice daily) in patients affected by COPD with chronic rhinitis comorbidity.,Fifty-three stable COPD patients in therapy according to the Global initiative for chronic Obstructive Lung Disease recommendations were enrolled; 49 completed the study.,At enrollment (visit 0), patients underwent skin prick test and rhinoscopy.,At visit 0 and after 1 month (visit 1) and 2 months (visit 2) of therapy with nasal budesonide, patients underwent spirometry, and COPD assessment test (CAT), Sinonasal Outcome Test (SNOT 22), and modified Medical Research Council dyspnea scale were administered.,Differences in continuous variables, after 2 months of treatment with nasal budesonide, were evaluated using a paired t-test or Wilcoxon matched-pairs signed-ranks test.,Two months of treatment with nasal budesonide showed a significant statistical improvement in the total scores of CAT, SNOT 22, and modified Medical Research Council (p<0.001).,A significant relationship between CAT and SNOT 22 total scores at baseline and after treatment was observed.,The results of the present study indicate the importance of careful evaluation of the presence of chronic nasal symptoms in all COPD patients and suggest beneficial clinical effect from treatment with nasal budesonide in terms of COPD symptoms and quality of life. | The Continuing to Confront COPD International Patient Survey aimed to estimate the prevalence and burden of COPD globally and to update findings from the Confronting COPD International Survey conducted in 1999-2000.,Chronic obstructive pulmonary disease (COPD) patients in 12 countries worldwide were identified through systematic screening of population samples.,Telephone and face-to-face interviews were conducted between November 2012 and May 2013 using a structured survey that incorporated validated patient-reported outcome instruments.,Eligible patients were adults aged 40 years and older who were taking regular respiratory medications or suffered with chronic respiratory symptoms and reported either 1) a physician diagnosis of COPD/emphysema, 2) a physician diagnosis of chronic bronchitis, or 3) a symptom-based definition of chronic bronchitis.,The burden of COPD was measured with the COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) Dyspnea Scale.,Of 106,876 households with at least one person aged ≥40 years, 4,343 respondents fulfilled the case definition of COPD and completed the full survey.,COPD prevalence ranged from 7% to 12%, with most countries falling within the range of 7%-9%.,In all countries, prevalence increased with age, and in all countries except the US was greater among men (range 6%-14%) than among women (range 5%-11%).,A significant disease burden was observed when considering COPD symptoms or health status, and showed wide variations across countries.,Prevalence of moderate-to-severe dyspnea (mMRC scale ≥2) ranged from 27% to 61%, and mean CAT score ranged from 16.0 to 24.8, indicating medium-to-high impairment.,This survey, representing 12 countries, showed similar rates of estimated COPD prevalence across countries that were higher than those reported a decade ago in the original Confronting COPD International Survey.,A significant burden of COPD was demonstrated by symptoms and health care-resource use, similar to that reported in the original survey. | 1 |
Although chronic obstructive pulmonary disease (COPD) and asthma are well-characterized diseases, they can coexist in a given patient.,The term asthma-COPD overlap (ACO) was introduced to describe patients that have clinical features of both diseases and may represent around 25% of COPD patients and around 20% of asthma patients.,Despite the increasing interest in ACO, there are still substantial controversies regarding its definition and its position within clinical guidelines for patients with obstructive lung disease.,In general, most definitions indicate that ACO patients must present with non-reversible airflow limitation, significant exposure to smoking or other noxious particles or gases, together with features of asthma.,In patients with a primary diagnosis of COPD, the identification of ACO has therapeutic implication because the asthmatic component should be treated with inhaled corticosteroids and some studies suggest that the most severe patients may respond to biological agents indicated for severe asthma.,This manuscript aims to summarize the current state-of-the-art of ACO.,The definitions, prevalence, and clinical manifestations will be reviewed and some innovative aspects, such as genetics, epigenetics, and biomarkers will be addressed.,Lastly, the management and prognosis will be outlined as well as the position of ACO in the COPD and asthma guidelines. | Although elevated blood or sputum eosinophils are present in many patients with COPD, uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils.,Basophils have remained virtually unexplored in COPD.,This study mapped tissue-infiltrating eosinophils, basophils and eosinophil-promoting immune mechanisms in COPD-affected lungs.,Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades Global Initiative for Chronic Obstructive Lung Disease stages I-IV; never-smokers/smokers served as controls.,Automated immunohistochemistry and in situ hybridisation identified immune cells, the type 2 immunity marker GATA3 and eotaxins (CCL11, CCL24).,Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD.,The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3+ cells, including type 2 helper T-cell lymphocytes and type 2 innate lymphoid cells.,A similarly localised and interleukin-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice.,Both mice and patients displayed spatially confined eotaxin signatures with CCL11+ fibroblasts and CCL24+ macrophages.,In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that is likely to have implications for personalised treatment.,Highly localised Th2- and eosinophil-rich pockets were identified in COPD-affected lungs, which increased in number with increasing disease severity and included basophils.,This exemplifies a novel type of heterogeneity in the immunopathology of COPD.http://bit.ly/2HexTco | 1 |
Nasal Highflow (NHF) delivers a humidified and heated airflow via nasal prongs.,Current data provide evidence for efficacy of NHF in patients with hypoxemic respiratory failure.,Preliminary data suggest that NHF may decrease hypercapnia in hypercapnic respiratory failure.,The aim of this study was to evaluate the mechanism of NHF mediated PCO2 reduction in patients with chronic obstructive pulmonary disease (COPD).,In 36 hypercapnic COPD patients (PCO2 > 45 mmHg), hypercapnia was evaluated by capillary gas sampling 1 h after NHF breathing under four conditions A to D with different flow rates and different degrees of leakage (A = 20 L/min, low leakage, two prongs, both inside; B = 40 L/min, low leakage, two prongs, both inside; C = 40 L/min, high leakage, two prongs, one outside and open; D = 40 L/min, high leakage, two prongs, one outside and closed).,Under identical conditions, mean airway pressure was measured in the hypopharynx of 10 COPD patients.,Hypercapnia significantly decreased in all patients.,In patients with capillary PCO2 > 55 mmHg (n = 26), PCO2 additionally decreased significantly by increased leakage and/or flow rate in comparison to lower leakage/ flow rate conditions (A = 94.2 ± 8.2%; B = 93.5 ± 4.4%; C = 90.5 ± 7.2%; D = 86.8 ± 3.8%).,The highest mean airway pressure was observed in patients breathing under condition B (2.3 ± 1.6 mbar; p < 0.05).,This study demonstrates effective PCO2 reduction with NHF therapy in stable hypercapnic COPD patients.,This effect does not correlate with an increase in mean airway pressure but with increased leakage and airflow, indicating airway wash out and reduction of functional dead space as important mechanisms of NHF therapy.,These results may be useful when considering NHF treatment in hypercapnic COPD patients.,Clinical Trials: NCT02504814; First posted July 22, 2015. | Nasal highflow (NHF) provides a warmed and humidified air stream up to 60 L/min.,Recent data demonstrated a positive effect in patients with acute hypoxemic respiratory failure, especially when caused by pneumonia.,Preliminary data show a decrease in hypercapnia in patients with COPD.,Therefore, NHF should be evaluated as a new ventilatory support device.,This study was conducted to assess the impact of different flow rates on ventilatory parameters in patients with COPD.,This interventional clinical study was performed with patients suffering from severe COPD.,The aim was to characterize flow-dependent changes in mean airway pressure, breathing volumes, breathing frequency, and decrease in partial pressure of CO2 (pCO2).,Mean airway pressure was measured in the nasopharyngeal space (19 patients).,To evaluate breathing volumes, we used a polysomnographic device (18 patients).,All patients received 20 L/min, 30 L/min, 40 L/min, and 50 L/min and - to illustrate the effects - nasal continuous positive airway pressure and nasal bilevel positive airway pressure.,Capillary blood gas analyses were performed in 54 patients with hypercapnic COPD before and two hours after the use of NHF.,We compared the extent of decrease in pCO2 when using 20 L/min and 30 L/min.,Additionally, comfort and dyspnea during the use of NHF were surveyed.,NHF resulted in a minor flow dependent increase in mean airway pressure.,Tidal volume increased, and breathing rate decreased.,The calculated minute volume decreased under NHF breathing.,In spite of this fact, hypercapnia decreased with increasing flow (20 L/min vs 30 L/min).,Additionally, an improvement in dyspnea was observed.,The rapid shallow breathing index shows a decrease when using NHF.,NHF leads to a flow-dependent reduction in pCO2.,This is most likely achieved by a washout of the respiratory tract and a functional reduction in dead space.,In summary, NHF enhances effectiveness of breathing in patients with COPD, reduces pCO2, the work of breathing, and rapid shallow breathing index as an indicator of respiratory work load. | 1 |
Exacerbations of COPD represent an important medical and health care problem.,Certain susceptible patients suffer recurrent exacerbations and as a consequence have a poorer prognosis.,The effects of bronchial infection, either acute or chronic, and of the inflammation characteristic of the disease itself raise the question of the possible role of antibiotics and anti-inflammatory agents in modulating the course of the disease.,However, clinical guidelines base their recommendations on clinical trials that usually exclude more severe patients and patients with more comorbidities, and thus often fail to reflect the reality of clinicians attending more severe patients.,In order to discuss aspects of clinical practice of relevance to pulmonologists in the treatment and prevention of recurrent exacerbations in patients with severe COPD, a panel discussion was organized involving expert pulmonologists who devote most of their professional activity to day hospital care.,This article summarizes the scientific evidence currently available and the debate generated in relation to the following aspects: bacterial and viral infections, chronic bronchial infection and its treatment with cyclic oral or inhaled antibiotics, inflammatory mechanisms and their treatment, and the role of computerized tomography as a diagnostic tool in patients with severe COPD and frequent exacerbations. | Chronic obstructive pulmonary disease (COPD) and asthma may overlap and converge in older people (overlap syndrome).,It was hypothesized that patients with overlap syndrome may have different clinical characteristics such as sputum eosinophilia, and better responsiveness to treatment with inhaled corticosteroid (ICS).,Sixty-three patients with stable COPD (forced expiratory volume in 1 second [FEV1] ≤80%) underwent pulmonary function tests, including reversibility of airflow limitation, arterial blood gas analysis, analysis of inflammatory cells in induced sputum, and chest high-resolution computed tomography.,The inclusion criteria for COPD patients with asthmatic symptoms included having asthmatic symptoms such as episodic breathlessness, wheezing, cough, and chest tightness worsening at night or in the early morning (COPD with asthma group).,The clinical features of COPD patients with asthmatic symptoms were compared with those of COPD patients without asthmatic symptoms (COPD without asthma group).,The increases in FEV1 in response to treatment with ICS were significantly higher in the COPD with asthma group.,The peripheral eosinophil counts and sputum eosinophil counts were significantly higher.,The prevalence of patients with bronchial wall thickening on chest high-resolution computed tomography was significantly higher.,A significant correlation was observed between the increases in FEV1 in response to treatment with ICS and sputum eosinophil counts, and between the increases in FEV1 in response to treatment with ICS and the grade of bronchial wall thickening.,Receiver operating characteristic curve analysis revealed 82.4% sensitivity and 84.8% specificity of sputum eosinophil count for detecting COPD with asthma, using 2.5% as the cutoff value.,COPD patients with asthmatic symptoms had some clinical features.,ICS should be considered earlier as a potential treatment in such patients.,High sputum eosinophil counts and bronchial wall thickening on chest high-resolution computed tomography might therefore be a good predictor of response to ICS. | 1 |
To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility).,Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations.,Global.,3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year.,FF/VI 50/25 µg, 100/25 µg or 200/25 µg, or VI 25 µg; all one time per day.,Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy.,Three clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58).,Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility.,In patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations.,In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation.,NCT01009463; NCT01017952; Post-results. | 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 |
Acute Exacerbations of COPD (AECOPD) identified from electronic healthcare records (EHR) are important for research, public health and to inform healthcare utilisation and service provision.,However, there is no standardised method of identifying AECOPD in UK EHR.,We aimed to validate the recording of AECOPD in UK EHR.,We randomly selected 1385 patients with COPD from the Clinical Practice Research Datalink.,We selected dates of possible AECOPD based on 15 different algorithms between January 2004 and August 2013.,Questionnaires were sent to GPs asking for confirmation of their patients’ AECOPD on the dates identified and for any additional relevant information.,Responses were reviewed independently by two respiratory physicians.,Positive predictive value (PPV) and sensitivity were calculated.,The response rate was 71.3%.,AECOPD diagnostic codes, lower respiratory tract infection (LRTI) codes, and prescriptions of antibiotics and oral corticosteroids (OCS) together for 5-14 days had a high PPV (>75%) for identifying AECOPD.,Symptom-based algorithms and prescription of antibiotics or OCS alone had lower PPVs (60-75%).,A combined strategy of antibiotic and OCS prescriptions for 5-14 days, or LRTI or AECOPD code resulted in a PPV of 85.5% (95% CI, 82.7-88.3%) and a sensitivity of 62.9% (55.4-70.4%).,Using a combination of diagnostic and therapy codes, the validity of AECOPD identified from EHR can be high.,These strategies are useful for understanding health-care utilisation for AECOPD, informing service provision and for researchers.,These results highlight the need for common coding strategies to be adopted in primary care to allow easy and accurate identification of events. | Current guidelines for the management of chronic obstructive pulmonary disease (COPD) recommend limiting the use of inhaled corticosteroids (ICS) to patients with more severe disease and/or increased exacerbation risk.,However, there are discrepancies between guidelines and real-life practice, as ICS are being overprescribed.,In light of the increasing concerns about the clinical benefit and long-term risks associated with ICS use, therapy needs to be carefully weighed on a case-by-case basis, including in patients already on ICS.,Several studies sought out to determine the effects of withdrawing ICS in patients with COPD.,Early studies have deterred clinicians from reducing ICS in patients with COPD as they reported that an abrupt withdrawal of ICS precipitates exacerbations, and results in a deterioration in lung function and symptoms.,However, these studies were fraught with numerous methodological limitations.,Recently, two randomized controlled trials and a real-life prospective study revealed that ICS can be safely withdrawn in certain patients.,Of these, the WISDOM (Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management) trial was the largest and first to examine stepwise withdrawal of ICS in patients with COPD receiving maintenance therapy of long-acting bronchodilators (ie, tiotropium and salmeterol).,Even with therapy being in line with the current guidelines, the findings of the WISDOM trial indicate that not all patients benefit from including ICS in their treatment regimen.,Indeed, only certain COPD phenotypes seem to benefit from ICS therapy, and validated markers that predict ICS response are urgently warranted in clinical practice.,Furthermore, we are now better equipped with a larger armamentarium of novel and more effective long-acting β2-agonist/long-acting muscarinic antagonist combinations that can be considered by clinicians to optimize bronchodilation and allow for safer ICS withdrawal.,In addition to providing a review of the aforementioned, this perspective article proposes an algorithm for the stepwise withdrawal of ICS in real-life clinical practice. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) show systemic consequences, such as chronic systemic inflammation leading to changes in the airway, airway penetrability, and endothelial function.,Endothelial dysfunction is characterized by a list of alterations of endothelium towards reduced vasodilation, proinflammatory state, detachment and apoptosis of endothelial cells, and development of atherosclerosis.,COPD-induced endothelial dysfunction is associated with elevated cardiovascular risk.,The increment of physical activities such as pulmonary rehabilitation (PR) training have a significant effect on COPD, thus, PR can be an integrative part of COPD treatment.,In this narrative review the focus is on the function of endothelial inflammatory mediators [cytokines, chemokines, and cellular proteases] and pulmonary endothelial cells and endothelial dysfunction in COPD as well as the effects of dysfunction of the endothelium may play in COPD-related pulmonary hypertension.,The relationship between smoking and endothelial dysfunction is also discussed.,The connection between different pulmonary rehabilitation programs, arterial stiffness and pulse wave velocity (PWV) is presented.,Endothelial dysfunction is a significant prognostic factor of COPD, which can be characterized by PWV.,We discuss future considerations, like training programs, as an important part of the treatment that has a favorable impact on the endothelial function. | Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and loss of lung function, and is currently the third largest cause of death in the world.,It is now well established that cardiovascular-related comorbidities such as stroke contribute to morbidity and mortality in COPD.,The mechanisms linking COPD and stroke remain to be fully defined but are likely to be interconnected.,The association between COPD and stroke may be largely dependent on shared risk factors such as aging and smoking, or the association of COPD with traditional stroke risk factors.,In addition, we propose that COPD-related systemic inflammation and oxidative stress may play important roles by promoting cerebral vascular dysfunction and platelet hyperactivity.,In this review, we briefly discuss the pathogenesis of COPD, acute exacerbations of COPD (AECOPD) and cardiovascular comorbidities associated with COPD, in particular stroke.,We also highlight and discuss the potential mechanisms underpinning the link between COPD and stroke, with a particular focus on the roles of systemic inflammation and oxidative stress. | 1 |
The contribution to airflow obstruction by the remodeling of the peripheral airways in chronic obstructive pulmonary disease (COPD) patients has been well documented, but less is known about the role played by the large airways.,Few studies have investigated the presence of histopathological changes due to remodeling in the large airways of COPD patients.,The aim of this study was to verify the presence of airway remodeling in the central airways of COPD patients, quantifying the airway smooth muscle (ASM) area and the extracellular matrix (ECM) protein deposition, both in the subepithelial region and in the ASM, and to verify the possible contribution to airflow obstruction by the above mentioned histopathological changes.,Biopsies of segmental bronchi spurs were performed in COPD patients and control smoker subjects and immunostained for collagen type I, versican, decorin, biglycan, and alpha-smooth muscle actin.,ECM protein deposition was measured at both subepithelial, and ASM layers.,The staining for collagen I and versican was greater in the subepithelial layer of COPD patients than in control subjects.,An inverse correlation was found between collagen I in the subepithelial layer and both forced expiratory volume in 1 second and ratio between forced expiratory volume in 1 second and forced vital capacity.,A statistically significant increase of the ASM area was observed in the central airways of COPD patients versus controls.,These findings indicate that airway remodeling also affects the large airways in COPD patients who have greater deposition of ECM proteins in the subepithelial layer and a larger smooth muscle area than control smoker subjects.,These changes may contribute to chronic airflow obstruction in COPD patients. | Fibulin-1 (FBLN-1) is a secreted glycoprotein that is associated with extracellular matrix (ECM) formation and rebuilding.,Abnormal and exaggerated deposition of ECM proteins is a hallmark of many fibrotic diseases, such as chronic obstructive pulmonary disease (COPD) where small airway fibrosis occurs.,The aim of this study was to investigate the regulation of FBLN-1 by transforming growth factor beta 1 (TGF-β1) (a pro-fibrotic stimulus) in primary human airway smooth muscle (ASM) cells from volunteers with and without COPD.,Human ASM cells were seeded at a density of 1×104 cells/cm2, and stimulated with or without TGF-β1 (10 ng/ml) for 72 hours before FBLN-1 deposition and soluble FBLN-1 were measured.,Fold change in FBLN-1 mRNA was measured at 4, 8, 24, 48, 72 hours.,In some experiments, cycloheximide (0.5 µg/ml) was used to assess the regulation of FBLN-1 production.,TGF-β1 decreased the amount of soluble FBLN-1 both from COPD and non-COPD ASM cells.,In contrast, the deposition of FBLN-1 into the ECM was increased in ASM cells obtained from both groups.,TGF-β1 did not increase FBLN-1 gene expression at any of the time points.,There were no differences in the TGF-β1 induced FBLN-1 levels between cells from people with or without COPD.,Cycloheximide treatment, which inhibits protein synthesis, decreased both the constitutive release of soluble FBLN-1, and TGF-β1 induced ECM FBLN-1 deposition.,Furthermore, in cycloheximide treated cells addition of soluble FBLN-1 resulted in incorporation of FBLN-1 into the ECM.,Therefore the increased deposition of FBLN-1 by ASM cells into the ECM following treatment with TGF-β1 is likely due to incorporation of soluble FBLN-1 rather than de-novo synthesis. | 1 |
The prevalence of chronic obstructive pulmonary disease (COPD) in females appears to be increasing.,Recent studies have revealed that the percentage of women with COPD in Greece is approximately 12.5%.,To evaluate the burden of COPD among males and females in Greece through a nationwide cross-sectional survey and to explore sex differences regarding functional characteristics and exacerbation frequency.,Data collection was completed in a 6-month period.,The present study followed a nationwide sampling approach of respiratory medicine physicians.,The sampling approach included three steps: 1) estimation of expected incidence and prevalence of COPD cases in each prefecture of Greece and in total; 2) estimation of expected incidence of COPD cases per physician in each prefecture; and 3) creation of a frame of three different sampling zones.,Following this sampling, data were provided by 199 respiratory physicians.,The participating physicians provided data from 6,125 COPD patients.,Female patients represented 28.7% of the study participants.,Female COPD patients were, on average, 5 years younger than male COPD patients.,Never smokers accounted for 9.4% within female patients, compared to 2.7% of males (P<0.001).,Female patients were characterized by milder forms of the disease.,Comorbidities were more prevalent in men, with the exception of gastroesophageal reflux (14.6% versus 17.1% for men and women, respectively, P=0.013).,Female COPD patients had a higher expected number of outpatient visits per year (by 8.9%) than males (P<0.001), although hospital admissions did not differ significantly between sexes (P=0.116).,Females had fewer absences from work due to COPD per year, by 19.0% (P<0.001), compared to males.,The differences observed between male and female COPD patients provide valuable information which could aid the prevention and management of COPD in Greece. | 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 |
Combined pulmonary fibrosis and emphysema (CPFE) patients visit hospitals frequently due to acute exacerbations (AEs); however, the predictors of CPFE AE have not been comprehensively described in literature.,Thus, we investigated the predicting factors of AE in CPFE patients.,We retrospectively reviewed medical records from the past 12 years at Korea University Guro Hospital.,We selected CPFE patients by computed tomography findings.,Rapid deterioration (RD) was defined as acute worsening of dyspnea requiring hospitalization and the presence of newly developed radiologic abnormalities.,AE was defined as RD with newly acquired bilateral pulmonary infiltrates without evidence of pulmonary infection or other known causes.,We evaluated the following variables in CPFE patients: age, sex, smoking history and amount, body mass index, past medical history, pulmonary function test, gender, age, and physiology (GAP) score, and the presence of lung cancer.,Among 227 CPFE patients, 108 had RD and 31 developed AE.,The most common cause of RD was infection (n = 60, 55.6%) and 28.7% (n = 31) developed AE.,Lung cancer [hazard ratio (HR), 3.274; 95% confidence interval (95% CI) 1.444-7.425; P < .01] and GAP score (HR, 1.434; 95% CI 1.072-1.918; P = .02) were significant predictors of AE.,The presence of lung cancer and AE were significant predictors of mortality.,In conclusion, CPFE patients with lung cancer and high GAP scores should be carefully observed for AE. | In large cohort studies comorbidities are usually self-reported by the patients.,This way to collect health information only represents conditions known, memorized and openly reported by the patients.,Several studies addressed the relationship between self-reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation.,We thus developed a detailed procedure to compare self-reported comorbidities with information on comorbidities derived from medication inspection.,This was applied to the data of the German COPD cohort COSYCONET.,Approach I was based solely on ICD10-Codes for the diseases and the indications of medications.,To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease.,The relationship between reported comorbidities and medication was expressed by a four-level concordance score.,Approaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data.,On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication.,The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs.,The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma.,Both approaches represent feasible strategies to confirm self-reported diagnoses via medication.,Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity.,Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores.,The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data. | 1 |
Arformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD.,This was a multicenter, double-blind, randomized, placebo-controlled study.,Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year.,The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization.,Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively).,Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events.,Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively).,Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study.,Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003).,Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different.,Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively).,Significant improvements in quality of life (overall St.,George’s Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05).,Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo.,Arformoterol was well-tolerated and improved lung function vs placebo.,ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov | Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact.,Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations.,The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events.,Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy.,GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β2-agonists (LABAs), such as formoterol and salmeterol.,Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present.,Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components.,This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease. | 1 |
Chronic obstructive pulmonary disease (COPD) and asthma are common diseases with a heterogeneous distribution worldwide.,Here, we present methods and disease and risk estimates for COPD and asthma from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 study.,The GBD study provides annual updates on estimates of deaths, prevalence, and disability-adjusted life years (DALYs), a summary measure of fatal and non-fatal disease outcomes, for over 300 diseases and injuries, for 188 countries from 1990 to the most recent year.,We estimated numbers of deaths due to COPD and asthma using the GBD Cause of Death Ensemble modelling (CODEm) tool.,First, we analysed data from vital registration and verbal autopsy for the aggregate category of all chronic respiratory diseases.,Subsequently, models were run for asthma and COPD relying on covariates to predict rates in countries that have incomplete or no vital registration data.,Disease estimates for COPD and asthma were based on systematic reviews of published papers, unpublished reports, surveys, and health service encounter data from the USA.,We used the Global Initiative of Chronic Obstructive Lung Disease spirometry-based definition as the reference for COPD and a reported diagnosis of asthma with current wheeze as the definition of asthma.,We used a Bayesian meta-regression tool, DisMod-MR 2.1, to derive estimates of prevalence and incidence.,We estimated population-attributable fractions for risk factors for COPD and asthma from exposure data, relative risks, and a theoretical minimum exposure level.,Results were stratified by Socio-demographic Index (SDI), a composite measure of income per capita, mean years of education over the age of 15 years, and total fertility rate.,In 2015, 3·2 million people (95% uncertainty interval [UI] 3·1 million to 3·3 million) died from COPD worldwide, an increase of 11·6% (95% UI 5·3 to 19·8) compared with 1990.,There was a decrease in age-standardised death rate of 41·9% (37·7 to 45·1) but this was counteracted by population growth and ageing of the global population.,From 1990 to 2015, the prevalence of COPD increased by 44·2% (41·7 to 46·6), whereas age-standardised prevalence decreased by 14·7% (13·5 to 15·9).,In 2015, 0·40 million people (0·36 million to 0·44 million) died from asthma, a decrease of 26·7% (−7·2 to 43·7) from 1990, and the age-standardised death rate decreased by 58·8% (39·0 to 69·0).,The prevalence of asthma increased by 12·6% (9·0 to 16·4), whereas the age-standardised prevalence decreased by 17·7% (15·1 to 19·9).,Age-standardised DALY rates due to COPD increased until the middle range of the SDI before reducing sharply.,Age-standardised DALY rates due to asthma in both sexes decreased monotonically with rising SDI.,The relation between with SDI and DALY rates due to asthma was attributed to variation in years of life lost (YLLs), whereas DALY rates due to COPD varied similarly for YLLs and years lived with disability across the SDI continuum.,Smoking and ambient particulate matter were the main risk factors for COPD followed by household air pollution, occupational particulates, ozone, and secondhand smoke.,Together, these risks explained 73·3% (95% UI 65·8 to 80·1) of DALYs due to COPD.,Smoking and occupational asthmagens were the only risks quantified for asthma in GBD, accounting for 16·5% (14·6 to 18·7) of DALYs due to asthma.,Asthma was the most prevalent chronic respiratory disease worldwide in 2015, with twice the number of cases of COPD.,Deaths from COPD were eight times more common than deaths from asthma.,In 2015, COPD caused 2·6% of global DALYs and asthma 1·1% of global DALYs.,Although there are laudable international collaborative efforts to make surveys of asthma and COPD more comparable, no consensus exists on case definitions and how to measure disease severity for population health measurements like GBD.,Comparisons between countries and over time are important, as much of the chronic respiratory burden is either preventable or treatable with affordable interventions.,Bill & Melinda Gates Foundation. | The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high.,We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases.,We conducted a systematic search of Medline, EMBASE and Global Health for original, population-based studies providing spirometry-based prevalence rates of COPD across the world from January 1990 to December 2014.,Random effects meta-analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta-estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural).,We developed a meta-regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more.,Our search returned 37 472 publications.,A total of 123 studies based on a spirometry-defined prevalence were retained for the review.,From the meta-regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%-14.0%) in this age group.,The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%-15.0%).,This increase of 68.9% was mainly driven by global demographic changes.,Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010).,The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%).,In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%).,In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%).,The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%-15.3%) compared to 7.6% (95% CI 7.0%-8.2%) in women.,Our findings suggest a high and growing prevalence of COPD, both globally and regionally.,There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region.,There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally. | 1 |
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM).,Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs.,During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes.,The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study.,The COPDGene study recruited 10,300 COPD patients in 21 centers.,A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE).,Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed.,The circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05).,EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%.,C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = −0.344, p = 0.001), as was EL-NE (r = −0.302, p = 0.004) and Pro-C6 (r = −0.259, p = 0.015).,In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36.,C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively).,These data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema.,Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials. | 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 |
H. haemolyticus is often misidentified as NTHi due to their close phylogenetic relationship.,Differentiating between the two is important for correct identification and appropriate treatment of infective organism and to ensure any role of H. haemolyticus in disease is not being overlooked.,Speciation however is not completely reliable by culture and PCR methods due to the loss of haemolysis by H. haemolyticus and the heterogeneity of NTHi.,Haemophilus isolates from COPD as part of the AERIS study (ClinicalTrials - NCT01360398) were speciated by analysing sequence data for the presence of molecular markers.,Further investigation into the genomic relationship was carried out using average nucleotide identity and phylogeny of allelic and genome alignments.,Only 6.3% were identified as H. haemolyticus.,Multiple in silico methods were able to distinguish H. haemolyticus from NTHi.,However, no single gene target was found to be 100% accurate.,A group of omp2 negative NTHi were observed to be phylogenetically divergent from H. haemolyticus and remaining NTHi.,The presence of an atypical group from a geographically and disease limited set of isolates supports the theory that the heterogeneity of NTHi may provide a genetic continuum between NTHi and H. haemolyticus. | 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. | 1 |
Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality worldwide.,COPD rarely occurs in isolation and is often combined with various diseases.,It is considered that systemic inflammation underlies the comorbid course of COPD.,The data obtained in recent years have shown the importance of violations of the cross-links of lipid metabolism and the immune response, which are links in the pathogenesis of both COPD and atherosclerosis.,The role of lipid metabolism disorders in the pathogenesis of the comorbid course of COPD and atherosclerosis and the participation of ATP-binding cassette (ABC) transporters in these processes is discussed in this article.,It is known that about 20 representatives of a large family of ABC transporters provide lipid homeostasis of cells by moving lipids inside the cell and in its plasma membrane, as well as removing lipids from the cell.,It was shown that some representatives of the ABC-transporter family are involved in various links of the pathogenesis of COPD and atherosclerosis, which can determine their comorbid course. | Inhaled corticosteroids (ICSs) are recommended for patients with frequent exacerbation of chronic obstructive pulmonary disease (COPD).,However, accumulating evidence has indicated the risk of pneumonia from the use of ICS.,This study aimed to investigate the association between ICS and pneumonia in the real-world clinical setting.,A retrospective cohort study was performed using nationwide population data from the Korea National Health Insurance Service.,Subjects who had a new diagnosis of COPD and who received inhaled bronchodilators without a diagnosis of pneumonia before the initiation of bronchodilators were identified.,Subjects were followed up until their first diagnosis of pneumonia.,The risk of pneumonia in ICS users was compared to that in non-ICS users.,A total of 87,594 subjects were identified and 1:1 matched to 22,161 ICS users and non-ICS users.,More ICS users were diagnosed with pneumonia compared to non-ICS users (33.73% versus 24.51%, P<0.0001).,The incidence rate per 100,000 person-years was 8904.98 for ICS users and 6206.79 for non-ICS users.,The hazard ratio (HR) of pneumonia for ICS users was 1.62 (95% CI 1.54-1.70).,The HR of subjects prescribed with the lowest ICS cumulative dose was 1.35 (1.27-1.43).,The HR increased to 1.51 (1.42-1.60), 1.96 (1.85-2.09), and 2.03 (1.89-2.18) as the cumulative dose increased.,Pneumonia was strongly associated with fluticasone propionate (1.79 (1.70-1.89)) and fluticasone furoate (1.80 (1.61-2.01)) use, compared to the use of other types of ICS.,ICS increases the risk of pneumonia in patients with COPD.,Hence, ICS should be carefully prescribed in patients with risk factors for pneumonia while considering the cumulative doses and subtypes of ICS. | 1 |
Oxidative stress has been implicated in the pathogenesis and progression of COPD.,Both reactive oxidant species from inhaled cigarette smoke and those endogenously formed by inflammatory cells constitute an increased intrapulmonary oxidant burden.,Structural changes to essential components of the lung are caused by oxidative stress, contributing to irreversible damage of both parenchyma and airway walls.,The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been applied in these patients to reduce symptoms, exacerbations, and the accelerated lung function decline.,This article reviews the available experimental and clinical data on the antioxidative effects of NAC in COPD, with emphasis on the role of exhaled biomarkers. | Oxidative stress is associated with the pathogenesis of cigarette smoke related lung diseases, but longitudinal effects of smoking cessation on oxidant markers in the airways are unknown.,This study included 61 smokers; 21 with chronic bronchitis or COPD, 15 asthmatics and 25 asymptomatic smokers followed up for 3 months after smoking cessation.,Fractional exhaled nitric oxide (FeNO), sputum neutrophil counts, sputum 8-isoprostane, nitrotyrosine and matrix metalloproteinase-8 (MMP-8) were investigated at baseline and 1 and 3 months after smoking cessation.,After 3 months 15 subjects had succeeded in quitting of smoking and in these subjects symptoms improved significantly.,Unexpectedly, however, sputum neutrophils increased (p = 0.046) after smoking cessation in patients with chronic bronchitis/COPD.,At baseline, the other markers did not differ between the three groups so these results were combined for further analysis.,Sputum 8-isoprostane declined significantly during the follow-up at 3 months (p = 0.035), but levels still remained significantly higher than in non-smokers.,The levels of FeNO, nitrotyrosine and MMP-8 did not change significantly during the 3 months after smoking cessation.,Whilst symptoms improve after smoking cessation, the oxidant and protease burden in the airways continues for months. | 1 |
Cytokines are key players in the initiation and propagation of inflammation in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and allergic asthma.,This makes them attractive targets for specific novel anti-inflammatory treatment strategies.,Recently, both interleukin-1 (IL-1) and IL-6 have been associated with negative health outcomes, mortality and a pro-inflammatory phenotype in COPD.,IL-6 in COPD was shown to correlate negatively with lung function, and IL-1beta was induced by cigarette smoke in the bronchial epithelium, causing airway inflammation.,Furthermore, IL-8 has been shown to be a pro-inflammatory marker in bronchiectasis, COPD and allergic asthma.,Clinical trials using specific cytokine blockade therapies are currently emerging and have contributed to reduce exacerbations and steroid use in COPD.,Here, we present a review of the current understanding of the roles of cytokines in the pathophysiology of chronic inflammatory airway diseases.,Furthermore, outcomes of clinical trials in cytokine blockade as novel treatment strategies for selected patient populations with those diseases will be discussed. | Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory disease and one of the leading causes of morbidity and mortality worldwide.,It is characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the lower airway following consistent exposure to noxious particles or gases.,Acute exacerbations of COPD (AECOPD) are characterized by increased cough, purulent sputum production, and dyspnea.,The AECOPD is mostly associated with infection caused by common cold viruses or bacteria, or co-infections.,Chronic and persistent infection by non-typeable Haemophilus influenzae (NTHi), a Gram-negative coccobacillus, contributes to almost half of the infective exacerbations caused by bacteria.,This is supported by reports that NTHi is commonly isolated in the sputum from COPD patients during exacerbations.,Persistent colonization of NTHi in the lower airway requires a plethora of phenotypic adaptation and virulent mechanisms that are developed over time to cope with changing environmental pressures in the airway such as host immuno-inflammatory response.,Chronic inhalation of noxious irritants in COPD causes a changed balance in the lung microbiome, abnormal inflammatory response, and an impaired airway immune system.,These conditions significantly provide an opportunistic platform for NTHi colonization and infection resulting in a “vicious circle.”,Episodes of large inflammation as the consequences of multiple interactions between airway immune cells and NTHi, accumulatively contribute to COPD exacerbations and may result in worsening of the clinical status.,In this review, we discuss in detail the interplay and crosstalk between airway immune residents and NTHi, and their effect in AECOPD for better understanding of NTHi pathogenesis in COPD patients. | 1 |
Currently, several studies assessed the role of Tai Chi (TC) in management of chronic obstructive pulmonary disease, but these studies have wide variation of sample and convey inconclusive results.,We therefore undertook a meta-analysis to assess the effects of TC.,A computerized search through electronic databases was performed to obtain sample studies.,The primary outcomes were 6-min walking distance (6MWD) and dyspnea.,Secondary outcomes included health-related quality of life and pre-bronchodilator spirometry.,Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with the I2 test.,A random-effects meta-analysis model was applied.,Eight randomized controlled trials involving 544 patients met the inclusion criteria.,The pooled WMDs were 34.22 m (95% CI 21.25-47.20, P<0.00001) for 6 MWD, -0.86 units (95% CI -1.44--0.28, P = 0.004) for dyspnea, 70 ml (95% CI 0.02-0.13, P = 0.01) for FEV1, 120 ml (95% CI 0.00-0.23, P = 0.04) for FVC.,TC significantly improved the Chronic Respiratory Disease Questionnaire total score, and the St George’s Respiratory Questionnaire score except impact score.,Findings suggest that TC may provide an effective alternative means to achieve results similar to those reported following participation in pulmonary rehabilitation programs.,Further studies are needed to substantiate the preliminary findings and investigate the long-term effects of TC. | Pulmonary Rehabilitation for moderate Chronic Obstructive Pulmonary Disease in primary care could improve patients’ quality of life.,This study aimed to assess the efficacy of a 3-month Pulmonary Rehabilitation (PR) program with a further 9 months of maintenance (RHBM group) compared with both PR for 3 months without further maintenance (RHB group) and usual care in improving the quality of life of patients with moderate COPD.,We conducted a parallel-group, randomized clinical trial in Majorca primary health care in which 97 patients with moderate COPD were assigned to the 3 groups.,Health outcomes were quality of life, exercise capacity, pulmonary function and exacerbations.,We found statistically and clinically significant differences in the three groups at 3 months in the emotion dimension (0.53; 95%CI0.06-1.01) in the usual care group, (0.72; 95%CI0.26-1.18) the RHB group (0.87; 95%CI 0.44-1.30) and the RHBM group as well as in fatigue (0.47; 95%CI 0.17-0.78) in the RHBM group.,After 1 year, these differences favored the long-term rehabilitation group in the domains of fatigue (0.56; 95%CI 0.22-0.91), mastery (0.79; 95%CI 0.03-1.55) and emotion (0.75; 95%CI 0.17-1.33).,Between-group analysis only showed statistically and clinically significant differences between the RHB group and control group in the dyspnea dimension (0.79 95%CI 0.05-1.52).,No differences were found for exacerbations, pulmonary function or exercise capacity.,We found that patients with moderate COPD and low level of impairment did not show meaningful changes in QoL, exercise tolerance, pulmonary function or exacerbation after a one-year, community based rehabilitation program.,However, long-term improvements in the emotional, fatigue and mastery dimensions (within intervention groups) were identified.,ISRCTN94514482 | 1 |
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the leading causes of hospitalization and is associated with considerable mortality, for which clinicians are seeking useful and easily obtained biomarkers for prognostic evaluation.,This study aimed to determine the potential role of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) as prognostic makers for hospital mortality in patients with AECOPD.,We included 303 patients with AECOPD in this retrospective study.,Clinical characteristics, NLR, PLR, and serum levels of C-reactive protein (CRP) and other data were collected.,Relationships between NLR/PLR and CRP were evaluated by Pearson’s correlation test.,Receiver operating characteristics curve and the area under the curve (AUC) were used to assess the ability of NLR and PLR to predict hospital mortality in patients with AECOPD.,Mean levels of NLR and PLR of all patients with AECOPD were 7.92±8.79 and 207.21±148.47, respectively.,NLR levels correlated with serum CRP levels (r=0.281, P<0.05).,The overall hospital mortality rate was 12.21% (37/303).,Levels of NLR and PLR were signifi-cantly higher among non-survivors compared to survivors of AECOPD (both P<0.05).,At a cut-off value of 6.24, the sensitivity and specificity of the NLR in predicting hospital mortality were 81.08% and 69.17%, respectively, with an AUC of 0.803.,At a cut-off of 182.68, the corresponding sensitivity, specificity and AUC of PLR were 64.86%, 58.27%, and 0.639.,The combination of NLR, PLR, and CRP increased the prognostic sensitivity.,NLR and PLR levels were increased in non-survivor patients with AECOPD, and the NLR may be simple and useful prognostic marker for hospital mortality in patients with AECOPD.,More studies should be carried out to confirm our findings. | The Continuing to Confront COPD International Patient Survey estimated the prevalence and burden of COPD across 12 countries.,Using data from this survey we evaluated the economic impact of COPD.,This cross-sectional, population-based survey questioned 4,343 subjects aged 40 years and older, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology.,Direct cost measures were based on exacerbations of COPD (treated and those requiring emergency department visits and/or hospitalisation), contacts with healthcare professionals, and COPD medications.,Indirect costs were calculated from work loss values using the Work Productivity and Activity Impairment scale.,Combined direct and indirect costs estimated the total societal costs per patient.,The annual direct costs of COPD ranged from $504 (South Korea) to $9,981 (USA), with inpatient hospitalisations (5 countries) and home oxygen therapy (3 countries) being the key drivers of direct costs.,The proportion of patients completely prevented from working due to their COPD ranged from 6% (Italy) to 52% (USA and UK) with 8 countries reporting this to be ≥20%.,Total societal costs per patient varied widely from $1,721 (Russia) to $30,826 (USA) but a consistent pattern across countries showed greater costs among those with increased burden of COPD (symptoms, health status and more severe disease) and a greater number of comorbidities.,The economic burden of COPD is considerable across countries, and requires targeted resources to optimise COPD management encompassing the control of symptoms, prevention of exacerbations and effective treatment of comorbidities.,Strategies to allow COPD patients to remain in work are important for addressing the substantial wider societal costs. | 1 |
In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression.,The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections.,We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions.,The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD.,Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline.KEY MESSAGEBacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients.The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung.The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.,Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients.,The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung.,The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients. | The chronic obstructive pulmonary disease (COPD) assessment test (CAT) was recently introduced for use in assessing disease-specific quality of life and follow-up of patients with COPD.,The purpose of this study was to evaluate the effect of the dyspnea on disease-specific quality of life detected by CAT score in patients with COPD.,In this study, 90 stable patients with COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria were included.,The level of dyspnea was assessed with the Medical Research Council (MRC) dyspnea scale, and disease-specific quality of life was assessed with CAT score.,The mean±SD age was 68.5±10.9 (range 41-97) years.,A significant relationship was established between CAT score, MRC dyspnea scale score and GOLD stage in patients with COPD.,There was also a positive correlation between dyspnea scale scores and GOLD stage in the patients (p<0.001), as well as positive correlation between CAT score and dyspnea scale score (p<0.001).,CAT score showed a significant correlation with hospitalization and exacerbations (p<0.05).,Dyspnea is an important symptom that may impact quality of life in patients with COPD.,CAT was shown to be a simple, fast and intelligible measurement of disease-specific quality of life, and was correlated with levels of dyspnea in patients with COPD. | 1 |
To estimate the prevalence of both cardiometabolic and other co‐morbidities in patients with COVID‐19, and to estimate the increased risk of severity of disease and mortality in people with co‐morbidities.,Medline, Scopus and the World Health Organization website were searched for global research on COVID‐19 conducted from January 2019 up to 23 April 2020.,Study inclusion was restricted to English language publications, original articles that reported the prevalence of co‐morbidities in individuals with COVID‐19, and case series including more than 10 patients.,Eighteen studies were selected for inclusion.,Data were analysed using random effects meta‐analysis models.,Eighteen studies with a total of 14 558 individuals were identified.,The pooled prevalence for co‐morbidities in patients with COVID‐19 disease was 22.9% (95% CI: 15.8 to 29.9) for hypertension, 11.5% (9.7 to 13.4) for diabetes, and 9.7% (6.8 to 12.6) for cardiovascular disease (CVD).,For chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cerebrovascular disease and cancer, the pooled prevalences were all less than 4%.,With the exception of cerebrovascular disease, all the other co‐morbidities presented a significantly increased risk for having severe COVID‐19.,In addition, the risk of mortality was significantly increased in individuals with CVD, COPD, CKD, cerebrovascular disease and cancer.,In individuals with COVID‐19, the presence of co‐morbidities (both cardiometabolic and other) is associated with a higher risk of severe COVID‐19 and mortality.,These findings have important implications for public health with regard to risk stratification and future planning. | Coronavirus disease 2019 (COVID-19) is an evolving infectious disease that dramatically spread all over the world in the early part of 2020.,No studies have yet summarized the potential severity and mortality risks caused by COVID-19 in patients with chronic obstructive pulmonary disease (COPD), and we update information in smokers.,We systematically searched electronic databases from inception to March 24, 2020.,Data were extracted by two independent authors in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,Study quality was assessed using a modified version of the Newcastle-Ottawa Scale.,We synthesized a narrative from eligible studies and conducted a meta-analysis using a random-effects model to calculate pooled prevalence rates and 95% confidence intervals (95%CI).,In total, 123 abstracts were screened and 61 full-text manuscripts were reviewed.,A total of 15 studies met the inclusion criteria, which included a total of 2473 confirmed COVID-19 patients.,All studies were included in the meta-analysis.,The crude case fatality rate of COVID-19 was 7.4%.,The pooled prevalence rates of COPD patients and smokers in COVID-19 cases were 2% (95% CI, 1%-3%) and 9% (95% CI, 4%-14%) respectively.,COPD patients were at a higher risk of more severe disease (risk of severity = 63%, (22/35) compared to patients without COPD 33.4% (409/1224) [calculated RR, 1.88 (95% CI, 1.4-2.4)].,This was associated with higher mortality (60%).,Our results showed that 22% (31/139) of current smokers and 46% (13/28) of ex-smokers had severe complications.,The calculated RR showed that current smokers were 1.45 times more likely [95% CI: 1.03-2.04] to have severe complications compared to former and never smokers.,Current smokers also had a higher mortality rate of 38.5%.,Although COPD prevalence in COVID-19 cases was low in current reports, COVID-19 infection was associated with substantial severity and mortality rates in COPD.,Compared to former and never smokers, current smokers were at greater risk of severe complications and higher mortality rate.,Effective preventive measures are required to reduce COVID-19 risk in COPD patients and current smokers. | 1 |
Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications.,They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury.,However, much less is known about their function in lung disease.,In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease. | Diabetes mellitus can reinforce the small airway dysfunction of chronic obstructive pulmonary disease (COPD) patients.,The epithelial-mesenchymal transition (EMT) that is associated with small airway remodeling is activated in the airway epithelial cells (AECs) of both COPD patients and diabetic patients.,Transforming growth factor β (TGF-β) can induce EMT via the TGF-β/Smad pathway.,We found that the small airway dysfunction and airflow limitations were worse in COPD patients with a history of smoking or diabetes than in simple COPD patients, and were even worse in COPD patients with both histories.,Pulmonary ventilation tests in rats confirmed these findings.,EMT and the TGF-β/Smad pathway were activated in the AECs of rats with COPD or diabetes, and the combination of COPD and diabetes amplified those effects, as indicated by downregulation of Zo1 and upregulation of vimentin, TGF-β and Smad4 in immunohistochemical experiments.,Twenty-four-hour treatment with 25 mM glucose and/or 1% cigarette smoke extract upregulated vimentin, TGF-β, Smad2/3/4 and p-Smad2/3, but downregulated Zo1 in AECs.,Suppressing the TGF-β/Smad pathway prevented EMT activation and small airway remodeling following cigarette smoke exposure and hyperglycemia.,Thus, cigarette smoke and high glucose exposure induces EMT via the TGF-β/Smad pathway in AECs. | 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. | 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 |
Dysregulated lipid metabolism plays crucial roles in various diseases, including diabetes mellitus, cancer, and neurodegeneration.,Recent studies suggest that alterations in major lipid metabolic pathways contribute to pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD).,These changes allow lung tissue to meet the energy needs and trigger anabolic pathways that initiate the synthesis of active molecules directly involved in the inflammation.,In this review, we summarize the changes of catabolism and anabolism of lipids, lipid molecules including lipid mediators, lipid synthesis transcription factors, cholesterol, and phospholipids, and how those lipid molecules participate in the initiation and resolution of inflammation in COPD. | The aim of this study is to summarize the evidence on the dose-response relationship between body mass index (BMI) and mortality in patients with chronic obstructive pulmonary disease (COPD).,We performed a systemic literature search in PubMed, Embase, and Web of Science for relevant studies that were published until June 2015.,A random effects meta-analysis was used to estimate the pooled relative risks (RRs) of all-cause mortality in COPD patients with normal weight compared with those who were underweight, overweight, or obese.,In addition, a dose-response meta-analysis was conducted to explore the dose-response relationship between BMI and all-cause mortality in COPD patients.,A total of 17 observational studies involving 30,182 COPD patients among 285,960 participants were included.,Compared with the reference category, the RRs of underweight, overweight, and obese individuals were 1.40 (95% confidence interval (CI), 1.20-1.63), 0.80 (95% CI, 0.67-0.96), and 0.77 (95% CI, 0.62-0.95), respectively.,A significant nonlinear relationship between BMI and mortality of COPD patients was found by using a random effects model.,COPD patients with BMI of <21.75 kg/m2 had a higher risk of death.,Moreover, an increase in the BMI resulted in a decrease in the risk of death.,The risk of death was lowest when BMI was 30 kg/m2 (RR = 0.69; 95% CI, 0.53-0.89).,The BMI was not associated with all-cause mortality when BMI was >32 kg/m2.,Our findings indicate that overweight is associated with a lower risk of all-cause mortality among patients with COPD whereas underweight is associated with a higher risk of all-cause mortality in these patients.,However, there is limited evidence to support the association between obesity and the risk of all-cause mortality in patients with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF) frequently require admission to the intensive care unit (ICU) for application of mechanical ventilation (MV).,We aimed to determine whether comorbidities and clinical variables present at ICU admission are predictive of ICU mortality.,A retrospective, observational cohort study was performed in a tertiary teaching hospital’s respiratory ICU using data collected between January 2008 and December 2012.,Previously diagnosed COPD patients who were admitted to the ICU with ARF were included.,Patients’ demographics, comorbidities, body mass index (BMI), ICU admission data, application of noninvasive and invasive MV (NIV and IMV, respectively), cause of ARF, length of ICU and hospital stay, and mortality were recorded from their files.,Patients were grouped according to mortality (survival versus non-survival), and all the variables were compared between the two groups.,During the study period, a total of 1,013 COPD patients (749 male) with a mean age (standard deviation) of 70±10 years met the inclusion criteria.,Comorbidities of the non-survival group (female/male, 40/131) were significantly higher compared with the survival group (female/male, 224/618): arrhythmia (24% vs 11%), hypertension (42% vs 34%), coronary artery disease (28% vs 11%), and depression (7% vs 3%) (P<0.001, P<0.035, P<0.001, and P<0.007, respectively).,Logistic regression revealed the following mortality risk factors: need of IMV, BMI <20 kg/m2, pneumonia, coronary artery disease, arrhythmia, hypertension, chronic hypoxia, and higher acute physiology and chronic health evaluation II (APACHE II) scores.,The respective odds ratios, confidence intervals, and P-values for each of these were as follows: 27.7, 15.7-49.0, P<0.001; 6.6, 3.5-412.7, P<0.001; 5.1, 2.9-8.8, P<0.001; 2.9, 1.5-5.6, P<0.001; 2.7, 1.4-5.2, P<0.003; 2.6, 1.5-4.4, P<0.001; 2.2, 1.2-3.9, P<0.008; and 1.1, 1.03-1.11, P<0.001.,Patients with severe COPD and cardiac comorbidities and cachexia should be closely monitored in ICU due to their high risk of ICU mortality. | Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD).,We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke.,The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema.,Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages.,We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12.,Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice.,AMs with projected pseudopods were decreased in DN-MafB Tg mice.,The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice.,Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice.,Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression. | 1 |
Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.,Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint.,Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment.,A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.,In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators.,Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses.,Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers.,The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.,The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.,NCT00563381; Study identifier: BI 205.389. | Objective To assess the long term effects of two different modes of disease management (comprehensive self management and routine monitoring) on quality of life (primary objective), frequency and patients’ management of exacerbations, and self efficacy (secondary objectives) in patients with chronic obstructive pulmonary disease (COPD) in general practice.,Design 24 month, multicentre, investigator blinded, three arm, pragmatic, randomised controlled trial.,Setting 15 general practices in the eastern part of the Netherlands.,Participants Patients with COPD confirmed by spirometry and treated in general practice.,Patients with very severe COPD or treated by a respiratory physician were excluded.,Interventions A comprehensive self management programme as an adjunct to usual care, consisting of four tailored sessions with ongoing telephone support by a practice nurse; routine monitoring as an adjunct to usual care, consisting of 2-4 structured consultations a year with a practice nurse; or usual care alone (contacts with the general practitioner at the patients’ own initiative).,Outcome measures The primary outcome was the change in COPD specific quality of life at 24 months as measured with the chronic respiratory questionnaire total score.,Secondary outcomes were chronic respiratory questionnaire domain scores, frequency and patients’ management of exacerbations measured with the Nijmegen telephonic exacerbation assessment system, and self efficacy measured with the COPD self-efficacy scale.,Results 165 patients were allocated to self management (n=55), routine monitoring (n=55), or usual care alone (n=55).,At 24 months, adjusted treatment differences between the three groups in mean chronic respiratory questionnaire total score were not significant.,Secondary outcomes did not differ, except for exacerbation management.,Compared with usual care, more exacerbations in the self management group were managed with bronchodilators (odds ratio 2.81, 95% confidence interval 1.16 to 6.82) and with prednisolone, antibiotics, or both (3.98, 1.10 to 15.58).,Conclusions Comprehensive self management or routine monitoring did not show long term benefits in terms of quality of life or self efficacy over usual care alone in COPD patients in general practice.,Patients in the self management group seemed to be more capable of appropriately managing exacerbations than did those in the usual care group.,Trial registration Clinical trials NCT00128765. | 1 |
Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline.,Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear.,This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.,Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients.,Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA.,Sputum bacterial colonisation was measured by PCR.,Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs.,2.5 × 103 RFU, p < 0.01).,There was no correlation for S. pneumoniae.,There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators.,Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation.,In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state.,Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression.,Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.,The online version contains supplementary material available at 10.1186/s12931-021-01718-8. | Several inhaled drugs are dependent on organic cation transporters to cross cell membranes.,To further evaluate their potential to impact on inhaled drug disposition, the localization of MATE1, P-gp, OCTN1 and OCTN2 were investigated in human lung.,Transporter proteins were analysed by immunohistochemistry in lung tissue from healthy subjects and COPD patients.,Transporter mRNA was analysed by qPCR in lung tissue and in bronchoalveolar lavage (BAL) cells from smokers and non-smokers.,We demonstrate for the first time MATE1 protein expression in the lung with localization to the apical side of bronchial and bronchiolar epithelial cells.,Interestingly, MATE1 was strongly expressed in alveolar macrophages as demonstrated both in lung tissue and in BAL cells, and in inflammatory cells including CD3 positive T cells.,P-gp, OCTN1 and OCTN2 were also expressed in the alveolar epithelial cells and in inflammatory cells including alveolar macrophages.,In BAL cells from smokers, MATE1 and P-gp mRNA expression was significantly lower compared to cells from non-smokers whereas no difference was observed between COPD patients and healthy subjects.,THP-1 cells were evaluated as a model for alveolar macrophages but did not reflect the transporter expression observed in BAL cells.,We conclude that MATE1, P-gp, OCTN1 and OCTN2 are expressed in pulmonary lung epithelium, in alveolar macrophages and in other inflammatory cells.,This is important to consider in the development of drugs treating pulmonary disease as the transporters may impact drug disposition in the lung and consequently affect pharmacological efficacy and toxicity.,The online version of this article (10.1186/s12931-018-0760-9) contains supplementary material, which is available to authorized users. | 1 |
The increasing trend of Chronic Obstructive Pulmonary Disease (COPD) in becoming the third leading cause of deaths by 2020 is of great concern, globally as well as in India.,Dysregulation of protease/anti-protease balance in COPD has been reported to cause tissue destruction, inflammation and airway remodelling; which are peculiar characteristics of COPD.,Therefore, it is imperative to explore various serum proteases involved in COPD pathogenesis, as candidate biomarkers.,COPD and Asthma often have overlapping symptoms and therefore involvement of certain proteases in their pathogenesis would render accurate diagnosis of COPD to be difficult.,Serum samples from controls, COPD and Asthma patients were collected after requisite institutional ethics committee approvals.,The preliminary analysis qualitatively and quantitatively analyzed various serum proteases by ELISA and mass spectrometry techniques.,In order to identify a distinct biomarker of COPD, serum neutrophil elastase (NE) and matrix metalloprotease-2 (MMP-2) from COPD and Asthma patients were compared; as these proteases tend to have overlapping activities in both the diseases.,A quantitative analysis of the reactive oxygen species (ROS) in the serum of controls and COPD patients was also performed.,Statistical analysis for estimation of p-values was performed using unpaired t-test with 95% confidence interval.,Amongst the significantly elevated proteases in COPD patients vs the controls- neutrophil elastase (NE) [P < 0.0241], caspase-7 [P < 0.0001] and matrix metalloprotease-2 (MMP-2) [P < 0.0001] were observed, along with increased levels of reactive oxygen species (ROS) [P < 0.0001].,The serum dipeptidyl peptidase-IV (DPP-IV) [P < 0.0010) concentration was found to be decreased in COPD patients as compared to controls.,Interestingly, a distinct elevation of MMP-2 was observed only in COPD patients, but not in Asthma, as compared to controls.,Mass spectrometry analysis further identified significant alterations (fold-change) in various proteases (carboxy peptidase, MMP-2 and human leukocyte elastase), anti-proteases (Preg. zone protein, α-2 macroglobulin, peptidase inhibitor) and signalling mediators (cytokine suppressor- SOCS-3).,The preliminary study of various serum proteases in stable COPD patients distinctly identified elevated MMP-2 as a candidate biomarker for COPD, subject to its validation in large cohort studies. | Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by different phenotypes with either bronchial airways alterations or emphysema prevailing.,As blood biomarkers could be clinically useful for COPD stratification, we aimed at investigating the levels of blood biomarkers in COPD patients differentiated by phenotype: prevalent chronic airway disease versus emphysema.,In 23 COPD patients with prevalent airway disease (COPD-B), 22 COPD patients with prevalent emphysema (COPD-E), 9 control smokers (CSs), and 18 control nonsmokers (CNSs), we analyzed the expression levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, epidermal growth factor (EGF), monocyte chemotactic protein (MCP)-1, and vascular endothelial growth factor by enzyme-linked immunosorbent assay in plasma/serum; glutathione peroxidase and superoxide dismutase (SOD)-1 by immunochemical kits in plasma; and free F2-isoprostanes (F2-IsoPs) by gas chromatography in plasma.,F2-IsoPs level was increased in COPD-B and COPD-E compared with CSs and CNSs; in addition, CS showed higher levels than CNSs; SOD1 level was lower in COPD-B and COPD-E than that in CNSs.,Interestingly, MCP-1 level was higher only in COPD-E versus CSs and CNSs; EGF and IL-8 levels were higher in COPD-B and COPD-E versus CNSs; IL-6 level was increased in all three smoking groups (COPD-B, COPD-E, and CSs) versus CNS; IFN-γ and IL-1α levels were higher in CSs than in CNSs; and IL-1α level was also higher in CSs versus COPD-B and COPD-E.,In all subjects, F2-IsoPs level correlated positively and significantly with MCP-1, IL-2, IL-1β, IFN-γ, and TNF-α and negatively with SOD1.,When correlations were restricted to COPD-E and COPD-B groups, F2-IsoPs maintained the positive associations with IFN-γ, TNF-α, and IL-2.,We did not find any specific blood biomarkers that could differentiate COPD patients with prevalent airway disease from those with prevalent emphysema.,The MCP-1 increase in COPD-E, associated with the imbalance of oxidant/antioxidant markers, may play a role in inducing emphysema. | 1 |
Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD).,We used UK Biobank data to study the genetic causes of smoking behaviour and lung health.,We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers.,We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population.,We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1.,We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease.,We set genome-wide significance at p<5 × 10−8.,UK Biobank participants were recruited from March 15, 2006, to July 7, 2010.,Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012.,We selected 50 008 unique samples: 10 002 individuals with low FEV1, 10 000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups.,We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2·29 × 10−16) and between individuals with and without doctor-diagnosed asthma (p=6·06 × 10−11).,We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2).,These variants also showed association with COPD, including in individuals with no history of smoking.,The number of copies of a 150 kb region containing the 5′ end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1.,We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue.,By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour.,These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease.,Medical Research Council. | The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable.,We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value.,Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction.,Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09).,One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04).,The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels.,Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers.,The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript.,The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung.,Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation. | 1 |
The burden of asthma and COPD among patients is high and people affected are frequently hospitalized due to exacerbations.,There are numerous reasons for the lack of disease control in asthma and COPD patients.,It is associated with non-adherence to guidelines on the part of the health care provider and with poor inhalation technique and/or non-adherence to the prescribed treatment plan by the patient.,This study aims to present data on inhaler technique and its impact on quality of life (QoL) and symptom control in a typical population of patients with chronic lung disease from a randomized controlled trial on medication adherence.,For this cross-sectional analysis, 165 asthma and COPD patients were analyzed.,Correct application of inhaler devices was tested using pre-defined checklists for each inhaler type.,QoL and symptom control were investigated using COPD Assessment Test (CAT) and Asthma Control Test (ACT).,Spirometry was used to measure forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).,Overall, incorrect inhalation technique ranged from 0 to 53% depending on the type of inhaler.,COPD patients with incorrect device application had a higher CAT sum score compared to those with a correct device application (P = .02).,Moreover, COPD patients with incorrect device application were more likely to suffer from cough (P = .03) and were more breathless while walking uphill or a flight of stairs (P = .02).,While there was no significance found in asthma patients, COPD patients who used their devices correctly had a significantly better mean FEV1% predicted at baseline compared to those who applied their devices incorrectly (P = .04).,Correct inhalation of prescribed medication is associated with improved health status and lung function.,These findings should encourage health professionals to provide instructions on correct inhalation technique and to regularly re-evaluate the patients’ inhalation technique.,ClinicalTrials.gov: NCT0238672, Registered 14 February 2014. | Umeclidinium/vilanterol (UMEC/VI) is a novel fixed dose combination of a long-acting muscarinic receptor antagonist (LAMA) and a long-acting beta 2 receptor antagonist (LABA) agent.,This analysis evaluated the incremental cost-effectiveness ratio (ICER) of UMEC/VI compared with tiotropium (TIO), from the Spanish National Health System (NHS) perspective.,A previously published linked equations cohort model based on the epidemiological longitudinal study ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) was used.,Patients included were COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% and the presence of respiratory symptoms measured with the modified Medical Research Council dyspnea scale (modified Medical Research Council ≥2).,Treatment effect, expressed as change in FEV1 from baseline, was estimated from a 24-week head-to-head phase III clinical trial comparing once-daily UMEC/VI with once-daily TIO and was assumed to last 52 weeks following treatment initiation (maximum duration of UMEC/VI clinical trials).,Spanish utility values were derived from a published local observational study.,Unitary health care costs (€2015) were obtained from local sources.,A 3-year time horizon was selected, and 3% discount was applied to effects and costs.,Results were expressed as cost/quality-adjusted life years (QALYs).,Univariate and probabilistic sensitivity analysis (PSA) was performed.,UMEC/VI produced additional 0.03 QALY and €590 vs TIO, leading to an ICER of €21,475/QALY.,According to PSA, the probability of UMEC/VI being cost-effective was 80.3% at a willingness-to-pay of €30,000/QALY.,UMEC/VI could be considered as a cost-effective treatment alternative compared with TIO in symptomatic COPD patients from the Spanish NHS perspective. | 1 |
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. | The fractal dimension characterizing the cumulative size distribution of low attenuation area (LAA) clusters, identified with a fixed threshold such as − 950 Hounsfield Units (HU), on computed tomography (CT) sensitively detects parenchymal destruction in chronic obstructive pulmonary disease (COPD) even when the percent LAA (LAA%), a standard emphysema index, is unchanged.,This study examines whether the cumulative size distribution of LAA clusters, defined with thresholds of the 15th, 25th, and 35th percentiles of a CT density histogram instead of the fixed-threshold of − 950 HU, exhibits a fractal property and whether its fractal dimension (D’15, D’25, and D’35, respectively) provides additional structural information in emphysematous lungs that is difficult to detect with the conventional − 950-HU-based fractal dimension (D950).,Chest inspiratory CT scans and pulmonary functions were cross-sectionally examined in 170 COPD subjects.,A proxy for the inspiration level at CT scan was obtained by dividing CT-measured total lung volume (CT-TLV) by physiologically measured total lung capacity.,Moreover, long-term (> 5 years) changes in D950 and the new fractal dimensions were longitudinally evaluated in 17 current and 42 former smokers with COPD.,D950, but not D’15, D’25, or D’35 was weakly correlated with the proxy for the inspiration.,D950, D’25, and D’35 but not D’15 correlated with LAA% and diffusion capacity.,In the long-term longitudinal study, LAA% was increased and D950 and D’35 were decreased in both current and former smokers, while D’25 was decreased only in current smokers and D’15 was not changed in either group.,The longitudinal changes in D’25 but not those in LAA%, D950, D’15, and D’35 were greater in current smokers than in former smokers.,This greater change in D’25 in current smokers was confirmed after adjusting the change in CT-TLV and the baseline D’25.,D’25 reflects diffusion capacity in emphysematous lungs and is robust against inspiration levels during CT scans.,This new fractal dimension might provide additional structural information that is difficult to detect with the conventional D950 and LAA% and allow for more sensitive evaluation of emphysema progression over time.,The online version of this article (10.1186/s12890-018-0714-5) contains supplementary material, which is available to authorized users. | 1 |
Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD).,Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology.,We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.,Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined.,Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD.,Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.,Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression.,Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR.,ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased.,Healthy smokers were intermediate between healthy nonsmokers and patients with COPD.,Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects.,MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release.,Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation.,Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. | Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation.,In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers.,Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues.,Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease. | 1 |
The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals’ lives may be substantial, yet clinical practice often focuses only on symptoms.,We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals.,Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database.,Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group).,A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment).,Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18).,“Shortness of breath” was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone.,Reported physical impacts included the inability to sleep and socialize, while emotional impacts included “embarrassment, stigma, and/or self-consciousness”, “fear and/or panic”, and “sadness, anxiety, and/or depression”.,Coping mechanisms for normal activities included continuing at reduced pace and avoidance.,Treatment preferences centered on resolving impacts; improved sleep, “speed of action”, and “length of relief” were the most frequently reported ideal treatment factors.,Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se.,Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey.,GSK funded study (H0-15-15502/204821).,The online version of this article (doi:10.1007/s12325-017-0557-0) contains supplementary material, which is available to authorized users. | Guideline recommendations for chronic obstructive pulmonary disease (COPD) are based on the results of large pharmaceutically-sponsored COPD studies (LPCS).,There is a paucity of data on disease characteristics at the primary care level, while the majority of COPD patients are treated in primary care.,We aimed to evaluate the external validity of six LPCS (ISOLDE, TRISTAN, TORCH, UPLIFT, ECLIPSE, POET-COPD) on which current guidelines are based, in relation to primary care COPD patients, in order to inform future clinical practice guidelines and trials.,Baseline data of seven primary care databases (n = 3508) from Europe were compared to baseline data of the LPCS.,In addition, we examined the proportion of primary care patients eligible to participate in the LPCS, based on inclusion criteria.,Overall, patients included in the LPCS were younger (mean difference (MD)-2.4; p = 0.03), predominantly male (MD 12.4; p = 0.1) with worse lung function (FEV1% MD -16.4; p<0.01) and worse quality of life scores (SGRQ MD 15.8; p = 0.01).,There were large differences in GOLD stage distribution compared to primary care patients.,Mean exacerbation rates were higher in LPCS, with an overrepresentation of patients with ≥1 and ≥2 exacerbations, although results were not statistically significant.,Our findings add to the literature, as we revealed hitherto unknown GOLD I exacerbation characteristics, showing 34% of mild patients had ≥1 exacerbations per year and 12% had ≥2 exacerbations per year.,The proportion of primary care patients eligible for inclusion in LPCS ranged from 17% (TRISTAN) to 42% (ECLIPSE, UPLIFT).,Primary care COPD patients stand out from patients enrolled in LPCS in terms of gender, lung function, quality of life and exacerbations.,More research is needed to determine the effect of pharmacological treatment in mild to moderate patients.,We encourage future guideline makers to involve primary care populations in their recommendations. | 1 |
Studies have shown that vasodilators such as iloprost can be useful for treating pulmonary hypertension (PH).,However, in patients with COPD, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange.,The efficacy and safety of iloprost inhalation was assessed in 67 patients with PH associated with COPD (COPD-PH), diagnosed by right heart catheterization.,Of these, 37 patients had severe PH (mean pulmonary arterial pressure [mPAP] >35 mmHg or mPAP 25-35 mmHg with low cardiac index [<2.0 L⋅min−1⋅m−2]).,All patients received a single 20 µg dose of iloprost via a nebulizer (4.4 µg delivered at the mouthpiece).,No serious adverse events were reported.,Hemodynamic and gas exchange parameters (arterial blood gas and shunt fraction [Qs/Qt]) were measured or calculated at baseline and 10 min after iloprost inhalation. mPAP decreased by 2.1 mmHg (95% CI, −3.3 to −1.0), pulmonary vascular resistance (PVR) decreased by 62.4 dyn⋅s⋅cm−5 (95% CI, −92.9 to −31.8), and cardiac output increased by 0.4 L⋅min−1 (95% CI, 0.2-0.5).,There was a more significant decline in PVR in patients with severe COPD-PH than in those with nonsevere COPD-PH.,Hypoxemia and intrapulmonary shunt were more extreme in patients with severe COPD-PH.,However, there were no significant differences in arterial blood gas and Qs/Qt between patients with nonsevere and severe forms of COPD-PH.,In conclusion, iloprost improved pulmonary hemodynamics without detrimental effects on arterial oxygenation in patients with COPD-PH, even in those with severe PH.,These findings suggest that the short-term use of iloprost in patients with COPD-PH is effective and well tolerated. | Background.,Long-term home noninvasive mechanical ventilation (NIV) is beneficial in COPD but its impact on inflammation is unknown.,We assessed the hypothesis that NIV modulates systemic and pulmonary inflammatory biomarkers in stable COPD.,Methods.,Among 610 patients referred for NIV, we shortlisted those undergoing NIV versus oxygen therapy alone, excluding subjects with comorbidities or non-COPD conditions.,Sputum and blood samples were collected after 3 months of clinical stability and analyzed for levels of human neutrophil peptides (HNP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha).,Patients underwent a two-year follow-up.,Unadjusted, propensity-matched, and pH-stratified analyses were performed.,Results.,Ninety-three patients were included (48 NIV, 45 oxygen), with analogous baseline features.,Sputum analysis showed similar HNP, IL-6, IL-10, and TNF-alpha levels (P > 0.5).,Conversely, NIV group exhibited higher HNP and IL-6 systemic levels (P < 0.001) and lower IL-10 concentrations (P < 0.001).,Subjects undergoing NIV had a significant reduction of rehospitalizations during follow-up compared to oxygen group (P = 0.005).,These findings were confirmed after propensity matching and pH stratification.,Conclusions.,These findings challenge prior paradigms based on the assumption that pulmonary inflammation is per se detrimental.,NIV beneficial impact on lung mechanics may overcome the potential unfavorable effects of an increased inflammatory state. | 1 |
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. | Chronic obstructive pulmonary disease (COPD) is a common and deadly disease.,One of the hallmarks of COPD is an accelerated decline in lung function, as measured by spirometry.,Inflammation, oxidative stress and other pathways are hypothesized to be important in this deterioration.,Because progressive airflow obstruction is associated with considerable morbidity and mortality, a major goal of COPD treatment has been to slow or prevent the accelerated decline in lung function.,Until recently, the only known effective intervention was smoking cessation.,However, newly reported large clinical trials have shown that commonly used medications may help slow the rate of lung function decline.,The effect of these medications is modest (and thus required such large, expensive trials) and to be of clinical benefit, therapy would likely need to start early in the course of disease and be prolonged.,Such a treatment strategy aimed at preservation of lung function would need to be balanced against the side effects and costs of prolonged therapy.,A variety of newer classes of medications may help target other pathophysiologically important pathways, and could be used in the future to prevent lung function decline in COPD. | 1 |
After the development of the COPD Strategy of the National Health Service in Spain, all scientific societies, patient organisations, and central and regional governments formed a partnership to enhance care and research in COPD.,At the same time, the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) took the initiative to convene the various scientific societies involved in the National COPD Strategy and invited them to participate in the development of the new Spanish guidelines for COPD (Guía Española de la EPOC; GesEPOC).,Probably the more innovative approach of GesEPOC is to base treatment of stable COPD on clinical phenotypes, a term which has become increasingly used in recent years to refer to the different clinical forms of COPD with different prognostic implications.,The proposed phenotypes are: (A) infrequent exacerbators with either chronic bronchitis or emphysema; (B) overlap COPD-asthma; (C) frequent exacerbators with emphysema predominant; and (D) frequent exacerbators with chronic bronchitis predominant.,The assessment of severity has also been updated with the incorporation of multidimensional indices.,The severity of the obstruction, as measured by forced expiratory volume in 1 second, is essential but not sufficient.,Multidimensional indices such as the BODE index have shown excellent prognostic value.,If the 6-minute walking test is not performed routinely, its substitution by the frequency of exacerbations (BODEx index) provides similar prognostic properties.,This proposal aims to achieve a more personalised management of COPD according to the clinical characteristics and multidimensional assessment of severity. | Patients with severe chronic obstructive pulmonary disease (COPD) are at increased risk of infection by P. aeruginosa.,The specific role of bronchiectasis in both infection and chronic colonization by this microorganism in COPD, however, remains ill defined.,To evaluate the prevalence and risk factors for P. aeruginosa recovery from sputum in outpatients with severe COPD, characterizing P. aeruginosa isolates by pulsed-field gel electrophoresis (PFGE) and focusing on the influence of bronchiectasis on chronic colonization in these patients.,A case-cohort study of 118 patients with severe COPD attended at a Respiratory Day Unit for an acute infectious exacerbation and followed up over one year.,High-resolution CT scans were performed during stability for bronchiectasis assessment and sputum cultures were obtained during exacerbation and stability in all patients.,P. aeruginosa isolates were genotyped by PFGE.,Determinants of the recovery of P. aeruginosa in sputum and chronic colonization by this microorganism were assessed by multivariate analysis.,P. aeruginosa was isolated from 41 of the 118 patients studied (34.7%).,Five of these 41 patients (12.2%) with P. aeruginosa recovery fulfilled criteria for chronic colonization.,In the multivariate analysis, the extent of bronchiectasis (OR 9.8, 95% CI: 1.7 to 54.8) and the number of antibiotic courses (OR 1.7, 95% CI: 1.1 to 2.5) were independently associated with an increased risk of P. aeruginosa isolation.,Chronic colonization was unrelated to the presence of bronchiectasis (p=0.75).,In patients with chronic colonization the isolates of P. aeruginosa retrieved corresponded to the same clones during the follow-up, and most of the multidrug resistant isolates (19/21) were harbored by these patients.,The main risk factors for P. aeruginosa isolation in severe COPD were the extent of bronchiectasis and exposure to antibiotics.,Over 10% of these patients fulfilled criteria for chronic colonization by P. aeruginosa and showed clonal persistence, independently of the presence of bronchiectasis. | 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 |
Self-management interventions for chronic obstructive pulmonary disease (COPD) can improve quality of life, reduce hospital admissions, and improve symptoms.,However, many factors impede engagement for patients and practitioners.,Qualitative research, with its focus on subjective experience, can provide invaluable insights into such factors.,Therefore, a systematic review and synthesis of qualitative evidence on COPD self-management from the perspective of patients, carers, and practitioners was conducted.,Following a systematic search and screening, 31 studies were appraised and data extracted for analysis.,This review found that patients can adapt to COPD; however, learning to self-manage is often a protracted process.,Emotional needs are considerable; frustration, depression, and anxiety are common.,In addition, patients can face an assortment of losses and limitations on their lifestyle and social interaction.,Over time, COPD can consume their existence, reducing motivation.,Support from family can prove vital, yet tinged with ambivalence and burden.,Practitioners may not have sufficient time, resources, or appropriate skills or confidence to provide effective self-management support, particularly in regard to patients’ psychosocial needs.,This can compound patients’ capability to engage in self-management.,For COPD self-management to be effective, patients’ psychosocial needs must be prioritised alongside medication and exacerbation management.,In addition, patients’ personal beliefs regarding COPD and its management should be reviewed periodically to avoid problematic behaviours and enhance positive adaptions to the disease.,Patients with COPD are not a homogenous group and no one intervention will prove effective for all.,Finally, practitioners require greater education, training, and support to successfully assist patients. | Objective To assess the effect of second generation, home based telehealth on health related quality of life, anxiety, and depressive symptoms over 12 months in patients with long term conditions.,Design A study of patient reported outcomes (the Whole Systems Demonstrator telehealth questionnaire study; baseline n=1573) was nested in a pragmatic, cluster randomised trial of telehealth (the Whole Systems Demonstrator telehealth trial, n=3230).,General practice was the unit of randomisation, and telehealth was compared with usual care.,Data were collected at baseline, four months (short term), and 12 months (long term).,Primary intention to treat analyses tested treatment effectiveness; multilevel models controlled for clustering by general practice and a range of covariates.,Analyses were conducted for 759 participants who completed questionnaire measures at all three time points (complete case cohort) and 1201 who completed the baseline assessment plus at least one other assessment (available case cohort).,Secondary per protocol analyses tested treatment efficacy and included 633 and 1108 participants in the complete case and available case cohorts, respectively.,Setting Provision of primary and secondary care via general practices, specialist nurses, and hospital clinics in three diverse regions of England (Cornwall, Kent, and Newham), with established integrated health and social care systems.,Participants Patients with chronic obstructive pulmonary disease (COPD), diabetes, or heart failure recruited between May 2008 and December 2009.,Main outcome measures Generic, health related quality of life (assessed by physical and mental health component scores of the SF-12, and the EQ-5D), anxiety (assessed by the six item Brief State-Trait Anxiety Inventory), and depressive symptoms (assessed by the 10 item Centre for Epidemiological Studies Depression Scale).,Results In the intention to treat analyses, differences between treatment groups were small and non-significant for all outcomes in the complete case (0.480≤P≤0.904) or available case (0.181≤P≤0.905) cohorts.,The magnitude of differences between trial arms did not reach the trial defined, minimal clinically important difference (0.3 standardised mean difference) for any outcome in either cohort at four or 12 months.,Per protocol analyses replicated the primary analyses; the main effect of trial arm (telehealth v usual care) was non-significant for any outcome (complete case cohort 0.273≤P≤0.761; available case cohort 0.145≤P≤0.696).,Conclusions Second generation, home based telehealth as implemented in the Whole Systems Demonstrator Evaluation was not effective or efficacious compared with usual care only.,Telehealth did not improve quality of life or psychological outcomes for patients with chronic obstructive pulmonary disease, diabetes, or heart failure over 12 months.,The findings suggest that concerns about potentially deleterious effect of telehealth are unfounded for most patients.,Trial Registration ISRCTN43002091. | 1 |
Determine the effect of twice-daily chlorhexidine oral rinses on oral and lung microbiota biomass and respiratory symptoms.,Single centre.,Participants were aged 40-85 with chronic obstructive pulmonary disease (COPD) and chronic productive cough or COPD exacerbation within the last year.,Exclusions included antibiotics in the previous 2 months and/or those with less than four teeth.,Forty-four participants were recruited and 40 completed the study.,Participants were randomised 1:1 to twice-daily 0.12% chlorhexidine oral rinses versus placebo for 2 months along with daily diaries.,St.,George’s Respiratory Questionnaire (SGRQ), blood tests, oral rinse and induced sputum were collected at randomisation and the final visit.,Primary outcome was a change in oral and sputum microbiota biomass.,Secondary outcomes included: sputum and oral microbiota Shannon and Simpson diversity and taxonomy; inflammatory markers; Breathlessness, Cough and Sputum Scale and SGRQ scores.,Neither the oral microbiota nor the sputum microbiota biomass decreased significantly in those using chlorhexidine compared with placebo (oral microbiota mean log10 difference (SE)=−0.103 (0.23), 95% CI −0.59 to 0.38, p=0.665; sputum microbiota 0.80 (0.46), 95% CI −0.15 to 1.75, p=0.096).,Chlorhexidine decreased both oral and sputum microbiota alpha (Shannon) diversity (linear regression estimate (SE) oral: −0.349 (0.091), p=0.001; sputum −0.622 (0.169), p=0.001).,Chlorhexidine use did not decrease systemic inflammatory markers compared with placebo (C reactive protein (chlorhexidine 1.8±7.5 vs placebo 0.4±6.8, p=0.467), fibrinogen (22.5±77.8 vs 10.0±77.0, p=0.406) or leucocytes (0.2±1.8 vs 0.5±1.8, p=0.560)).,Chlorhexidine use decreased SGRQ scores compared with placebo (chlorhexidine −4.7±8.0 vs placebo 1.7±8.9, p=0.032).,We did not detect a significant difference in microbiota biomass due to chlorhexidine use.,Chlorhexidine decreased oral and sputum microbiota alpha diversity and improved respiratory health-related quality of life compared with placebo.,NCT02252588. | Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage.,Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking.,Two-hundred severe COPD patients from Europe and North America were followed longitudinally for 3 years.,We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits.,Similar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates.,Virus infection was strongly associated with exacerbation events (P < 5E-20).,Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation.,Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event.,Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung.,This study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations.,It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications. | 1 |
To develop reference equations for the Glittre Activities of Daily Living test (Glittre ADL-test) on the basis of anthropometric and demographic variables in apparently healthy individuals.,A secondary objective was to determine the reliability of the equations in a sample of COPD patients.,This was a cross-sectional study including 190 apparently healthy individuals (95 males; median age, 54.5 years [range, 42-65]; median FEV1 = 97% [range, 91-105.2]; and median FVC = 96% [range, 88.5-102]) recruited from the general community and 74 COPD patients (55 males; mean age, 65 ± 8 years; body mass index [BMI] = 25.9 ± 4.7 kg/m2; FEV1 = 36.1 ± 14.1%; and FVC = 62.7 ± 16.1%) recruited from a pulmonary rehabilitation center.,The mean time to complete the Glittre ADL-test was 2.84 ± 0.45 min.,In the stepwise multiple linear regression analysis, age and height were selected as Glittre ADL-test performance predictors, explaining 32.1% (p < 0.01) of the total variance.,Equation 1 was as follows: Glittre ADL-testpredicted = 3.049 + (0.015 × ageyears) + (−0.006 × heightcm).,Equation 2 included age and BMI and explained 32.3% of the variance in the test, the equation being as follows: Glittre ADL-testpredicted = 1.558 + (0.018 × BMI) + (0.016 × ageyears).,The reference equations for the time to complete the Glittre ADL-test were based on age, BMI, and height as independent variables and can be useful for predicting the performance of adult individuals.,The predicted values appear to be reliable when applied to COPD patients. | Impaired physical performance is common in chronic obstructive pulmonary disease (COPD), but its assessment can be difficult in routine clinical practice.,We compared the timed up and go (TUG) test and other easily applied assessments of physical performance with the 6-minute walk distance (6MWD).,In a longitudinal study of comorbidities in COPD, submaximal physical performance was determined in 520 patients and 150 controls using the TUG test and 6MWD.,Spirometry, body composition, handgrip strength, the COPD assessment test, St George’s Respiratory Questionnaire (SGRQ), and the modified Medical Research Council dyspnoea scale were also determined.,Patients and controls were similar in age, body mass index, and sex proportions.,The TUG in the patients was greater than that in the control group, P=0.001, and was inversely related to 6MWD (r=−0.71, P<0.001) and forced expiratory volume in one second predicted (r=−0.19, P<0.01) and was directly related to the SGRQ activity (r=0.39, P<0.001), SGRQ total (r=0.37, P<0.001), and total COPD assessment test scores (r=0.37, P<0.001).,The TUG identified the difference in physical performance between patients and controls.,The TUG test and validated questionnaires provide a measure of physical performance, which is rapid and could be used in clinical practice. | 1 |
Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system.,Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity.,They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases.,However, the pathological mechanism of neutrophils remains complex and obscure.,The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed.,With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases.,We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases. | There has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients.,We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort.,We prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012.,Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test.,Airway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p < 0.001, p = 0.049 and p = 0.261, respectively).,Increasing total bacterial load was associated with increasing airway (p < 0.01) but not systemic inflammation (p > 0.05).,Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads.,Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p < 0.05), and was significantly greater than with other PPMs.,No association was observed between inflammation and health status (p > 0.05).,Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique.,The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae.,However, discordance between inflammation and health status was observed.,The online version of this article (doi:10.1186/s12931-014-0114-1) contains supplementary material, which is available to authorized users. | 1 |
Lung macrophages (LMs) are essential immune effector cells that are pivotal in both innate and adaptive immune responses to inhaled foreign matter.,They either reside within the airways and lung tissues (from early life) or are derived from blood monocytes.,Similar to macrophages in other organs and tissues, LMs have natural plasticity and can change phenotype and function depending largely on the microenvironment they reside in.,Phenotype changes in lung tissue macrophages have been implicated in chronic inflammatory responses and disease progression of various chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD).,LMs have a wide variety of functional properties that include phagocytosis (inorganic particulate matter and organic particles, such as viruses/bacteria/fungi), the processing of phagocytosed material, and the production of signaling mediators.,Functioning as janitors of the airways, they also play a key role in removing dead and dying cells, as well as cell debris (efferocytic functions).,We herein review changes in LM phenotypes during chronic lung disease, focusing on COPD, as well as changes in their functional properties as a result of such shifts.,Targeting molecular pathways involved in LM phenotypic shifts could potentially allow for future targeted therapeutic interventions in several diseases, such as COPD. | It is known that tissue macrophages derive not only from blood monocytes but also from yolk sac or fetal liver, and the tissue of residence guides their function.,When isolated, they lose tissue specific signatures, hence studies of human macrophages should be ideally done directly in the tissue.,The aim of this study was to investigate directly in human lung tissue the polarization of alveolar macrophage (AM), classic (M1) or alternative (M2), in health and disease, using COPD as a model.,Surgical lungs from 53 subjects were studied: 36 smokers whose FEV1 varied from normal to severe COPD, 11 non-smokers and 6 normal donors. iNOS and CD206 immunohistochemistry was used to quantify the percentage of AM polarized as M1 or M2 in lung sections.,The percentage of M1 and M2 increased progressively with smoking and COPD severity, from 26% to 84% for M1 and from 7% to 78% for M2.,In donors 74% of AM were negative for M1 and 93% for M2.,Confocal microscopy showed co-localization of M1 and M2 in the same AM in severe COPD.,In normal lungs alveolar macrophages were mostly non-polarized.,With smoking and COPD severity, M1 and M2 polarization increased significantly and so did the co-expression of M1 and M2 in the same alveolar macrophage.,The online version of this article (doi:10.1186/s12931-017-0522-0) contains supplementary material, which is available to authorized users. | 1 |
Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism.,We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smokers with preserved lung function and COPD subjects.,PBMCs were isolated from healthy non-smokers (HNS), healthy smokers (HS) and COPD subjects, cultured and the mitochondrial respiration while utilizing glucose (glycolysis), fatty acids (β-oxidation) or pyruvate (direct Krebs’ cycle substrate) was measured using the XFp Extracellular Flux Analyzer.,Plasma levels of inflammatory cytokines IFN-γ, IL-17, TNF-α, IL-5, IL-9 and IFN-α were measured using flow cytometry.,RAW264.7 cells were exposed to cigarette smoke condensate (CSC) for 1 h and its effect on cell viability, cellular metabolism and phagocytosis ability were also studied.,Patient’s data was analyzed using the Mann Whitney U test, whereas Student’s t test was performed to analyze the in-vitro data.,PBMCs from COPD subjects showed a significant decrease in extracellular acidification rate (ECAR) while utilizing glucose as compared to HNS (151.9 Vs 215%).,Mitochondrial oxygen consumption rate (OCR) on palmitate or pyruvate was also found to be significantly lower in COPD subjects as compared to HS and a strong positive correlation between palmitate OCR in PBMCs and FEV1 (r = 0.74, p < 0.05) and FVC (r = 0.79, p < 0.05) values in HS was observed.,The metabolic shift towards fatty acid metabolism in healthy smokers promoted an inflammatory cytokine response with a greater increase in the levels of IL-5, IL-9 and IFN-α as compared to IFN-γ, IL-17 and TNF-α.,In-vitro experiments with RAW 264.7 cells showed similar metabolic alterations and a reduced ability to phagocytose Streptococcus pneumonia and Haemophilus influenza after cigarette smoke exposure in the presence of glucose or palmitate.,These findings indicate a metabolic basis for the inflammatory response in COPD and could suggest a new therapeutic target for controlling the immune response and delaying the onset of disease.,This observational study was retrospectively registered in the Clinical Trails Registry - India (ICMR - NIMS) on 19th January 2018 with the registration number CTRI/2018/01/011441.,The online version of this article (10.1186/s12931-019-1139-2) contains supplementary material, which is available to authorized users. | Tobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD), though the mechanisms of its toxicity are still unclear.,The ABC transporters multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp/MDR1) extrude a wide variety of toxic substances across cellular membranes and are highly expressed in bronchial epithelium.,Their impaired function may contribute to COPD development by diminished detoxification of noxious compounds in cigarette smoke.,We examined whether triple knock-out (TKO) mice lacking the genes for Mrp1 and Mdr1a/1b are more susceptible to develop COPD features than their wild-type (WT) littermates.,TKO and WT mice (six per group) were exposed to 2 cigarettes twice daily by nose-only exposure or room air for 6 months.,Inflammatory infiltrates were analyzed in lung sections, cytokines and chemokines in whole lung homogenates, emphysema by mean linear intercept.,Multiple linear regression analysis with an interaction term was used to establish the statistical significances of differences.,TKO mice had lower levels of interleukin (IL)-7, KC (mouse IL-8), IL-12p70, IL-17, TNF-alpha, G-CSF, GM-CSF and MIP-1-alpha than WT mice independent of smoke exposure (P < 0.05).,IL-1-alpha, IL-6, IL-8, IL-13, IL-17, TNF-alpha, G-CSF, GM-CSF and MCP-1 increased after smoke exposure in both groups, but the increase in IL-8 was lower in TKO than WT mice (P < 0.05) with a same trend for G-CSF (P < 0.10).,Smoke-induced increase in pulmonary inflammatory cells in WT mice was almost absent in TKO mice.,The mean linear intercept was not different between groups.,Mrp1/Mdr1a/1b knock-out mice have a reduced inflammatory response to cigarette smoke.,In addition, the expression levels of several cytokines and chemokines were also lower in lungs of Mrp1/Mdr1a/1b knock-out mice independent of smoke exposure.,Further studies are required to determine whether dysfunction of MRP1 and/or P-gp contribute to the pathogenesis of COPD. | 1 |
The EQ-5D, a generic health status questionnaire that is widely used in health economic evaluation, was recently expanded to the EQ-5D-5L to address criticisms of unresponsiveness and ceiling effect.,To describe the validity, responsiveness and minimum important difference of the EQ-5D-5L in COPD.,Study 1: The validity of the EQ-5D-5L utility index and visual analogue scale (EQ-VAS) was compared with four established disease-specific health status questionnaires and other measures of disease severity in 616 stable outpatients with COPD.,Study 2: The EQ-5D-5L utility index and EQ-VAS were measured in 324 patients with COPD before and after 8 weeks of pulmonary rehabilitation.,Distribution and anchor-based approaches were used to estimate the minimum important difference.,There were moderate-to-strong correlations between utility index and EQ-VAS with disease-specific questionnaires (Pearson's r=0.47-0.72).,A ceiling effect was seen in 7% and 2.6% of utility index and EQ-VAS.,Utility index decreased (worsening health status) with indices of worsening disease severity.,With rehabilitation, mean (95% CI) changes in utility index and EQ-VAS were 0.065 (0.047 to 0.083) and 8.6 (6.5 to 10.7), respectively, with standardised response means of 0.39 and 0.44.,The mean (range) anchor estimates of the minimum important difference for utility index and EQ-VAS were 0.051 (0.037 to 0.063) and 6.9 (6.5 to 8.0), respectively.,The EQ-5D-5L is a valid and responsive measure of health status in COPD and may provide useful additional cost-effectiveness data in clinical trials. | COPD exerts a substantial burden on health and health care systems globally and will continue to do so for the foreseeable future.,Treatment however can be costly and health care providers are interested in both whether treatments can offer improvements in disease burden and whether they represent value for money.,Economic evaluations seek to resolve this issue by producing results that can be used to inform and assist the decision maker in allocating scarce health care resources.,In this paper we introduce economic evaluation and then use these themes to review and critically appraise the existing COPD economic evaluations, in order to assess quality in light of today’s standards.,The use of existing economic evaluations in informing the decision maker is then discussed.,Ten out of the fifteen studies were clinical trial or observational study based, and the remaining five on a decision analytic model.,Study design, interventions, outcome measures and the use of uncertainty varied considerably; consequentially the results are difficult to compare in any consistent manner.,Efforts for future studies to harmonize study design and methodology, particularly towards adopting a modeling framework, using current treatment as comparator and adopting a common effectiveness measure, such as the QALY, should be made in order to produce results that are comparable and useful to a decision maker. | 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. | Dual bronchodilator maintenance therapy may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) versus long-acting muscarinic antagonist (LAMA) monotherapy.,The efficacy and safety of US-approved LAMA/long-acting beta-agonist (LABA) combinations versus tiotropium (TIO), a LAMA, were assessed.,This systematic review and meta-analysis (GSK: 206938), conducted in MEDLINE, MEDLINE In-process, and EMBASE following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, identified randomized clinical trials (>8 weeks) in moderate-to-severe COPD (per Global Initiative for Chronic Obstructive Lung Disease guidelines), receiving LAMA/LABA or TIO.,Endpoints: difference in change from baseline in lung function (forced expiratory volume in 1 s [FEV1]; trough, peak, area under the curve 0-3 h post-dose (AUC0-3), St George’s Respiratory Questionnaire (SGRQ) responder rate (≥4-unit improvement), SGRQ total score, and rescue medication use at 12 and 24 weeks.,Safety was also assessed.,From 5683 citations, the meta-analysis included eight clinical trials.,LAMA/LABA significantly improved FEV1 trough (Week 12: 63.0 mL, 95% confidence intervals [CI]: 39.2, 86.8; Week 24: 66.1 mL, 95% CI: 40.0, 92.3), peak (Week 12: 91.5 mL, 95% CI: 70.5, 112.4; Week 24: 92.4 mL, 95% CI: 72.9, 111.9), AUC0-3 (Week 12: 126.8 mL, 95% CI: 108.1, 145.4), SGRQ responder rate at Week 12 (risk ratio: 1.19; 95% CI: 1.09, 1.28), mean SGRQ total score (Week 12: −1.87, 95% CI: −2.72, −1.02; Week 24: −1.05, 95% CI: −2.02, −0.09), and rescue medication use (Week 24: −0.47 puffs/day, 95% CI: −0.64, −0.30) versus TIO (all p ≤ 0.03).,The SGRQ responder rate at 24 weeks and adverse events were not significantly different between treatments.,US-approved LAMA/LABA therapies improved lung function, SGR,Q and rescue medication use versus TIO, without compromising safety.,Dual maintenance therapies combining two types of long-acting bronchodilator appear to be effective and safe for treating moderate-to-severe chronic obstructive pulmonary disease (COPD).,Given that patients with COPD often have poor quality of life and, in the US, incur substantial healthcare costs, it is vital to provide optimal symptom management to improve lung function and limit exacerbations over time.,Beth Hahn at GSK, North Carolina, and co-workers carried out a literature review and meta-analysis of 8 clinical trials, which indicates that combined long-acting muscarinic antagonist (LAMA)/long-acting beta-agonist (LABA) treatments-currently prescribed in the US-are an effective and safe way of tackling COPD symptoms.,The team compared patients using LAMA/LABA for 12 weeks with those on single LAMA (tiotropium) treatment and found LAMA/LABA significantly improved lung function and reduced exacerbation risk. | 1 |
Existing data on COPD prevalence are limited or totally lacking in many regions of Europe.,The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be an effective tool in spatial distribution estimation of epidemiological variables, when real data are few and widely separated.,Therefore, in order to represent cartographically the prevalence of COPD in Europe, an IDW interpolation mapping was performed.,The point prevalence data provided by 62 studies from 19 countries (21 from 5 Northern European countries, 11 from 3 Western European countries, 14 from 5 Central European countries, and 16 from 6 Southern European countries) were identified using validated spirometric criteria.,Despite the lack of data in many areas (including all regions of the eastern part of the continent), the IDW mapping predicted the COPD prevalence in the whole territory, even in extensive areas lacking real data.,Although the quality of the data obtained from some studies may have some limitations related to different confounding factors, this methodology may be a suitable tool for obtaining epidemiological estimates that can enable us to better address this major public health problem. | Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant inherited disease that is significantly underdiagnosed.,We have previously shown that the combination of an awareness campaign with the offer of free diagnostic testing results in the detection of a relevant number of severely deficient AATD patients.,The present study provides an update on the results of our targeted screening program (German AAT laboratory, University of Marburg) covering a period from August 2003 to May 2015.,Diagnostic AATD detection test kits were offered free of charge.,Dried blood samples were sent to our laboratory and used for the semiquantitative measurement of the AAT-level (nephelometry) and the detection of the S- or Z-allele (PCR).,Isoelectric focusing was performed when either of the initial tests was indicative for at least one mutation.,Besides, we evaluated the impact of additional screening efforts and the changes of the detection rate over time, and analysed the relevance of clinical parameters in the prediction of severe AATD.,Between 2003 and 2015, 18,638 testing kits were analysed.,6919 (37.12 %) carried at least one mutation.,Of those, we identified 1835 patients with severe AATD (9.82 % of the total test population) including 194 individuals with rare genotypes.,Test initiatives offered to an unselected population resulted in a dramatically decreased detection rate.,Among clinical characteristics, a history of COPD, emphysema, and bronchiectasis were significant predictors for Pi*ZZ, whereas a history of asthma, cough and phlegm were predictors of not carrying the genotype Pi*ZZ.,A targeted screening program, combining measures to increase awareness with cost-free diagnostic testing, resulted in a high rate of AATD detection.,The clinical data suggest that testing should be primarily offered to patients with COPD, emphysema, and/or bronchiectasis.,The online version of this article (doi:10.1186/s13023-016-0453-8) contains supplementary material, which is available to authorized users. | 1 |
The morbidity and mortality associated with COPD exacts a considerable economic burden.,Comorbidities in COPD are associated with poor health outcomes and increased costs.,Our objective was to assess the impact of comorbidities on COPD-associated costs in a large administrative claims dataset.,This was a retrospective observational study of data from the Truven Health MarketScan Commercial Claims and Encounters and the MarketScan Medicare Supplemental Databases from January 1, 2009, to September 30, 2012.,Resource consumption was measured from the index date (date of first occurrence of non-rule-out COPD diagnosis) to 360 days after the index date.,Resource use (all-cause and disease-specific [ie, COPD- or asthma-related] ED visits, hospitalizations, office visits, other outpatient visits, and total length of hospital stay) and health-care costs (all-cause and disease-specific costs for ED visits, hospitalizations, office visits, and other outpatient visits and medical, prescription, and total health-care costs) were assessed.,Generalized linear models were used to evaluate the impact of comorbidities on total health-care costs, adjusting for age, sex, geographic location, baseline health-care use, employment status, and index COPD medication.,Among 183,681 patients with COPD, the most common comorbidities were cardiovascular disease (34.8%), diabetes (22.8%), asthma (14.7%), and anemia (14.2%).,Most patients (52.8%) had one or two comorbidities of interest.,The average all-cause total health-care costs from the index date to 360 days after the index date were highest for patients with chronic kidney disease ($41,288) and anemia ($38,870).,The impact on total health-care costs was greatest for anemia ($10,762 more, on average, than a patient with COPD without anemia).,Our analysis demonstrated that high resource use and costs were associated with COPD and multiple comorbidities. | Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.,Comorbidities are often reported in patients with COPD and may influence the cost of care.,Yet, the extent by which comorbidities affect costs remains to be determined.,To review, quantify and evaluate excess costs of comorbidities in COPD.,Using a systematic review approach, Pubmed and Embase were searched for studies analyzing excess costs of comorbidities in COPD.,Resulting studies were evaluated according to study characteristics, comorbidity measurement and cost indicators.,Mark-up factors were calculated for respective excess costs.,Furthermore, a checklist of quality criteria was applied.,Twelve studies were included.,Nine evaluated comorbidity specific costs; three examined index-based results.,Pneumonia, cardiovascular disease and diabetes were associated with the highest excess costs.,The mark-up factors for respective excess costs ranged between 1.5 and 2.5 in the majority of cases.,On average the factors constituted a doubling of respective costs in the comorbid case.,The main cost driver, among all studies, was inpatient cost.,Indirect costs were not accounted for by the majority of studies.,Study heterogeneity was high.,The reviewed studies clearly show that comorbidities are associated with significant excess costs in COPD.,The inclusion of comorbid costs and effects in future health economic evaluations of preventive or therapeutic COPD interventions seems highly advisable. | 1 |
There are only scarce data regarding the evolution of the chronic obstructive pulmonary disease (COPD) assessment test (CAT) over time.,Our aim was to investigate the evolution of the CAT in a telehealthcare (THC) cohort and to evaluate its potential to predict exacerbations.,The CAT was measured weekly over up to 1 year in 40 COPD patients undergoing a THC intervention.,The evolution of the CAT was analyzed using linear regression.,The association between this evolution and the occurrence of exacerbations was evaluated using the Andersen-Gill formulation of the Cox proportional hazards model for the analysis of recurrent time-to-event data with time-varying predictors.,The median CAT at inclusion was 17 (interquartile range 13-22) points.,During the study, 25% of patients had a significant negative slope (median −7 points per year [ppy]), 38% were stable (median +0 ppy) and 38% had a significant positive slope (median +6 ppy).,The median slope of the CAT in the overall cohort was +1 (interquartile range −3 to +6) ppy.,A significant positive association was found between the change in CAT scores and the risk of exacerbations (hazard ratio =1.08, 95% CI: 1.03-1.13; p<0.001).,There was an 8% increase of the risk of exacerbation per unit increase in CAT.,We detected a significant learning effect in filling out the CAT in 18.4% of patients with a median learning phase of five filled questionnaires.,Sixty-three percent of the COPD patients monitored by THC experienced a stable or improved CAT during 1-year follow-up.,We found a significant positive association between the evolution of the CAT over time and the risk of exacerbations.,In about one-fifth of patients, there was a significant learning effect in filling out the CAT, before reliable results could be obtained.,The evolution of the CAT could help to assess the risk for future exacerbations. | COPD is a highly complex disease to manage as patients show great variation in symptoms and limitations in daily life.,In the last decade self-management support of COPD has been introduced as an effective method to improve quality and efficiency of care, and to reduce healthcare costs.,Despite the urge to change the organisation of health care and the potential of eHealth to support this, large-scale implementation in daily practice remains behind, especially in the Netherlands.,We designed a multilevel study, called e-Vita, to investigate different organisational implementation methods of a self-management web portal to support and empower patients with COPD in three different primary care settings.,Using a parallel cohort design, the clinical effects of the web portal will be assessed using an interrupted times series (ITS) study design and measured according to changes in health status with the Clinical COPD Questionnaire (CCQ).,The different implementations and net benefits of self-management through eHealth on clinical outcomes will be evaluated from human, organisational, and technical perspectives.,To our knowledge this is the first study to combine different study designs that enable simultaneous investigation of clinical effects, as well as effects of different organisational implementation methods whilst controlling for confounding effects of the organisational characteristics.,We hypothesize that an implementation with higher levels of personal assistance, and integrated in an existing care program will result in increased use of and satisfaction with the platform, thereby increasing health status and diminishing exacerbation and hospitalisation.,NTR4098 (31-07-2013) | 1 |
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by chronic airflow limitation.,Unraveling of this heterogeneity is challenging but important, because it might enable more accurate diagnosis and treatment.,Because spirometry cannot distinguish between the different contributing pathways of airflow limitation, and visual scoring is time-consuming and prone to observer variability, other techniques are sought to start this phenotyping process.,Quantitative computed tomography (CT) is a promising technique, because current CT technology is able to quantify emphysema, air trapping, and large airway wall dimensions.,This review focuses on CT quantification techniques of COPD disease components and their current status and role in phenotyping COPD. | Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum.,The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population.,The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ.,The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others.,Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life.,Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition.,Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs.,Cirrhotic liver failure may occur around age 50.,In very rare cases, necrotizing panniculitis and secondary vasculitis may occur.,AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait.,The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing.,Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis.,For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended.,Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids.,The end-stage liver and lung disease can be treated by organ transplantation.,In AATD patients with cirrhosis, prognosis is generally grave. | 1 |
COPD patients have increased numbers of macrophages and neutrophils in the lungs.,Interleukin-6 (IL-6) trans-signaling via its soluble receptor sIL-6R, governs the influx of innate immune cells to inflammatory foci through regulation of the chemokine CCL3.,We hypothesized that there would be enhanced levels of IL-6, sIL-6R and CCL3 in COPD sputum.,59 COPD patients, 15 HNS and 15 S underwent sputum induction and processing with phosphate buffered saline to obtain supernatants for IL-6, sIL-6R and CCL3 analysis.,Cytoslides were produced for differential cell counting and immunocytochemistry (COPD; n = 3) to determine cell type surface expression of the CCL3 receptors CCR5 and CCR1.,COPD patients expressed higher levels (p < 0.05) of sIL-6R and CCL3 compared to controls (sIL-6R medians pg/ml: COPD 166.4 vs S 101.1 vs HNS 96.4; CCL3 medians pg/ml: COPD 117.9 vs S 0 vs HNS 2.7).,COPD sIL-6R levels were significantly correlated with sputum neutrophil (r = 0.5, p < 0.0001) and macrophage (r = 0.3, p = 0.01) counts.,Immunocytochemical analysis revealed that CCR5 and CCR1 were exclusively expressed on airway macrophages.,Enhanced airway generation of sIL-6R may promote IL-6 trans-signaling in COPD.,Associated upregulation of CCL3 may facilitate the recruitment of macrophages into the airways by ligation of CCR1 and CCR5.,The online version of this article (doi:10.1186/s12931-014-0103-4) contains supplementary material, which is available to authorized users. | The incidence of chronic obstructive pulmonary disease (COPD) in China is very high.,This study aimed to assess the vulnerability of COPD patients in rural areas outside Xuzhou City, Jiangsu province, in order to provide helpful guidance for future research and public policies.,The vulnerability of 8,217 COPD patients was evaluated using a face-to-face questionnaire to obtain information on general characteristics, awareness, beliefs, medication usage, acute exacerbation of the disease, and economic burdens.,Direct economic burdens were calculated based on the questionnaire, and indirect economic burdens were estimated using local per capita income and life expectancy in 2008.,The years of potential life lost were calculated using loss of life years for each age group and multiplying by the number of deaths in a given age group.,Of the 8,217 patients, 7,921 (96.4%) had not heard of COPD, and 2,638 (32.1%) did not understand that smoking was a risk factor for COPD.,No patients had used inhalers, nebulizer drugs or oxygen therapy, either regularly or sporadically.,No patients had undergone pulmonary rehabilitation or surgical treatment, while 4,215 (51.3%) took theophylline to relieve dyspnea, and 3,418 (41.6%) used antibiotics to treat exacerbations.,A total of 2,925 (35.6%) patients had been admitted to hospital during the past year because of respiratory symptoms.,The average direct and indirect economic burdens on COPD patients were 1,090 and 20,605 yuan, respectively.,The vulnerability of patients in rural Xuzhou to COPD was high.,Their awareness of COPD was poor, their treatment during both the stable and acute exacerbation stages did not meet standards, and the economic burdens were large.,Interventions are therefore needed to improve the prevention and management of COPD in this population.,Further studies are required to verify these findings. | 1 |
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments.,In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression.,The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology.,The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription.,Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression).,However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling.,Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD.,Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression.,This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD. | Chronic Obstructive Pulmonary disease (COPD) is an inflammatory syndrome that represents an increasing health problem, especially in the elderly population.,Drug therapies are symptomatic and inadequate to contrast disease progression and mortality.,Thus, there is an urgent need to clarify the molecular mechanisms responsible for this condition in order to identify new biomarkers and therapeutic targets.,Processes including oxidant/antioxidant, protease/antiprotease, and proliferative/antiproliferative balance and control of inflammatory response become dysfunctional during aging as well as in COPD.,Recently it was suggested that Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to oxidative stress and chronic inflammation, is implicated in both development and progression of COPD.,The present review focuses on the involvement of SIRT1 in the regulation of redox state, inflammation, and premature senescence, all crucial characteristics of COPD phenotypes.,Recent evidence corroborating the statement of the “aging theory for COPD” was also discussed. | 1 |
Patients with COPD often have multiple comorbidities requiring use of multiple medications, and adherence rates for maintenance COPD (mCOPD) medications are already known to be suboptimal.,Presence of comorbidities in COPD patients, and use of medications used to treat those comorbidities (non-COPD medications), may have an adverse impact on adherence to mCOPD medications.,The objective of the study was to evaluate the association between non-adherence to mCOPD medications and non-COPD medications in COPD patients.,COPD patients were identified using a large administrative claims database.,Selected patients were 40-89 years old and continuously enrolled for 12 months prior to and 24 months after the first identified COPD diagnosis (index date) during January 1, 2009 to December 31, 2010.,Patients were required to have ≥1 prescription for a mCOPD medication within 365 days of the index date and ≥1 prescription for one of 12 non-COPD medication classes within ±30 days of the first COPD prescription.,Adherence (proportion of days covered [PDC]) was measured during 365 days following the first COPD prescription.,The association between non-adherence (PDC <0.8) to mCOPD and non-adherence to non-COPD medications was determined using logistic regression, controlling for baseline patient characteristics.,A total of 14,117 patients, with a mean age of 69.9 years, met study criteria.,Of these, 40.9% were males and 79.2% were non-adherent to mCOPD medications with a mean PDC of 0.47.,Non-adherence to mCOPD medications was associated with non-adherence to 10 of 12 non-COPD medication classes (odds ratio 1.38-1.78, all P<0.01).,Adherence to mCOPD medications is low.,Non-adherence (or adherence) to mCOPD medications is positively related to non-adherence (or adherence) to non-COPD medications, implying that the need to take medications prescribed for comorbid conditions does not adversely impact adherence to mCOPD medications. | Dementia increases the risk of morbidity and mortality in hospitalized patients.,However, information on the potential effects of dementia on the risks of acute organ dysfunction, severe sepsis and in-hospital mortality, specifically among inpatients with chronic obstructive pulmonary disease (COPD), is limited.,The observational analytic study was inpatient claims during the period from 2000 to 2010 for 1 million people who were randomly selected from all of the beneficiaries of the Taiwan National Health Insurance in 2000.,In total, 1406 patients with COPD and dementia were admitted during the study period.,Hospitalized patients with COPD and free from a history of dementia were randomly selected and served as control subjects (n = 5334).,The patient groups were matched according to age (±3 years), gender, and the year of admission, with a control/dementia ratio of 4.,Only the first-time hospitalization data for each subject was analyzed.,Logistic regression models were used to calculate the odds ratio (OR) of outcome measures (acute organ dysfunction, severe sepsis, and mortality), controlling for confounding factors (age, sex, comorbidity, infection site, hospital level, and length of stay).,In COPD patients with dementia, the incidence rate of severe sepsis and hospital mortality was 17.1% and 4.8%, respectively, which were higher than the controls (10.6% and 2.3%).,After controlling for potential confounding factors, dementia was found to significantly increase the odds of severe sepsis and hospital mortality with an adjusted OR (OR) of 1.38 (95% confidence interval [CI] 1.10-1.72) and 1.69 (95% CI 1.18-2.43), respectively.,Dementia was also significantly associated with an increased OR of acute respiratory dysfunction (adjusted OR 1.39, 95% CI 1.09-1.77).,In hospitalized COPD patients, the presence of dementia may increase the risks of acute respiratory dysfunction, severe sepsis, and hospital mortality, which warrants the attention of health care professionals. | 1 |
The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high.,We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases.,We conducted a systematic search of Medline, EMBASE and Global Health for original, population-based studies providing spirometry-based prevalence rates of COPD across the world from January 1990 to December 2014.,Random effects meta-analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta-estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural).,We developed a meta-regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more.,Our search returned 37 472 publications.,A total of 123 studies based on a spirometry-defined prevalence were retained for the review.,From the meta-regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%-14.0%) in this age group.,The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%-15.0%).,This increase of 68.9% was mainly driven by global demographic changes.,Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010).,The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%).,In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%).,In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%).,The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%-15.3%) compared to 7.6% (95% CI 7.0%-8.2%) in women.,Our findings suggest a high and growing prevalence of COPD, both globally and regionally.,There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region.,There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally. | Objective To determine whether supported self management in chronic obstructive pulmonary disease (COPD) can reduce hospital readmissions in the United Kingdom.,Design Randomised controlled trial.,Setting Community based intervention in the west of Scotland.,Participants Patients admitted to hospital with acute exacerbation of COPD.,Intervention Participants in the intervention group were trained to detect and treat exacerbations promptly, with ongoing support for 12 months.,Main outcome measures The primary outcome was hospital readmissions and deaths due to COPD assessed by record linkage of Scottish Morbidity Records; health related quality of life measures were secondary outcomes.,Results 464 patients were randomised, stratified by age, sex, per cent predicted forced expiratory volume in 1 second, recent pulmonary rehabilitation attendance, smoking status, deprivation category of area of residence, and previous COPD admissions.,No difference was found in COPD admissions or death (111/232 (48%) v 108/232 (47%); hazard ratio 1.05, 95% confidence interval 0.80 to 1.38).,Return of health related quality of life questionnaires was poor (n=265; 57%), so that no useful conclusions could be made from these data.,Pre-planned subgroup analysis showed no differential benefit in the primary outcome relating to disease severity or demographic variables.,In an exploratory analysis, 42% (75/150) of patients in the intervention group were classified as successful self managers at study exit, from review of appropriateness of use of self management therapy.,Predictors of successful self management on stepwise regression were younger age (P=0.012) and living with others (P=0.010).,COPD readmissions/deaths were reduced in successful self managers compared with unsuccessful self managers (20/75 (27%) v 51/105 (49%); hazard ratio 0.44, 0.25 to 0.76; P=0.003).,Conclusion Supported self management had no effect on time to first readmission or death with COPD.,Exploratory subgroup analysis identified a minority of participants who learnt to self manage; this group had a significantly reduced risk of COPD readmission, were younger, and were more likely to be living with others.,Trial registration Clinical trials NCT 00706303. | 1 |
Asthma-COPD overlap (ACO) refers to a group of poorly studied and characterised patients reporting with disease presentations of both asthma and COPD, thereby making both diagnosis and treatment challenging for the clinicians.,They exhibit a higher burden in terms of both mortality and morbidity in comparison to patients with only asthma or COPD.,The pathophysiology of the disease and its existence as a unique disease entity remains unclear.,The present study aims to determine whether ACO has a distinct metabolic and immunological mediator profile in comparison to asthma and COPD.,Global metabolomic profiling using two different groups of patients [discovery (D) and validation (V)] were conducted.,Serum samples obtained from moderate and severe asthma [n = 34(D); n = 32(V)], moderate and severe COPD [n = 30(D); 32(V)], ACO patients [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using gas chromatography mass spectrometry (GC-MS).,Multiplexed analysis of 25 immunological markers (IFN-γ (interferon gamma), TNF-α (tumor necrosis factor alpha), IL-12p70 (interleukin 12p70), IL-2, IL-4, IL-5, IL-13, IL-10, IL-1α, IL-1β, TGF-β (transforming growth factor), IL-6, IL-17E, IL-21, IL-23, eotaxin, GM-CSF (granulocyte macrophage-colony stimulating factor), IFN-α (interferon alpha), IL-18, NGAL (neutrophil gelatinase-associated lipocalin), periostin, TSLP (thymic stromal lymphopoietin), MCP-1 (monocyte chemoattractant protein- 1), YKL-40 (chitinase 3 like 1) and IL-8) was also performed in the discovery cohort.,Eleven metabolites [serine, threonine, ethanolamine, glucose, cholesterol, 2-palmitoylglycerol, stearic acid, lactic acid, linoleic acid, D-mannose and succinic acid] were found to be significantly altered in ACO as compared with asthma and COPD.,The levels and expression trends were successfully validated in a fresh cohort of subjects.,Thirteen immunological mediators including TNFα, IL-1β, IL-17E, GM-CSF, IL-18, NGAL, IL-5, IL-10, MCP-1, YKL-40, IFN-γ, IL-6 and TGF-β showed distinct expression patterns in ACO.,These markers and metabolites exhibited significant correlation with each other and also with lung function parameters.,The energy metabolites, cholesterol and fatty acids correlated significantly with the immunological mediators, suggesting existence of a possible link between the inflammatory status of these patients and impaired metabolism.,The present findings could be possibly extended to better define the ACO diagnostic criteria, management and tailoring therapies exclusively for the disease. | 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. | 1 |
The inflammatory responses and associated clinical severity of COPD exacerbations are greatly variable, and the determinants of these factors are poorly understood.,We examined the hypothesis that bacteria and viruses may modulate this heterogeneity and that interactions between bacterial and viral infection may affect changes in airway bacterial load and the clinical features and inflammatory responses of exacerbations in patients with COPD.,Prospective cohort study.,Outpatient Department, London Chest Hospital, London, UK.,Thirty-nine patients with COPD.,We prospectively studied 56 COPD exacerbations, obtaining clinical data and paired sputum and serum samples at baseline and exacerbation.,Qualitative and quantitative microbiology, polymerase chain reaction detection for rhinovirus, and estimation of cytokine levels by enzyme-linked immunosorbent assay were performed.,A total of 69.6% of exacerbations were associated with a bacterial pathogen, most commonly Haemophilus influenzae.,Rhinovirus was identified in 19.6% of exacerbations.,The rise in bacterial load at exacerbation correlated with the rise in sputum interleukin (IL)-8 (r = 0.37, p = 0.022) and fall in FEV1 (r = 0.35, p = 0.048).,Exacerbations with both rhinovirus and H influenzae had higher bacterial loads (108.56 cfu/mL vs 108.05cfu/mL, p = 0.018) and serum IL-6 (13.75 pg/mL vs 6.29 pg/mL, p = 0.028) than exacerbations without both pathogens.,In exacerbations with both cold symptoms (a marker of putative viral infection) and a bacterial pathogen, the FEV1 fall was greater (20.3% vs 3.6%, p = 0.026) and symptom count was higher (p = 0.019) than those with a bacterial pathogen alone.,The clinical severity and inflammatory responses in COPD exacerbations are modulated by the nature of the infecting organism: bacterial and viral pathogens interact to cause additional rises in inflammatory markers and greater exacerbation severity. | Biomass smoke is the leading cause of COPD in developing countries such as Turkey.,In rural areas of Turkey, females are more exposed to biomass smoke because of traditional lifestyles.,The aim of this study was to determine the adverse effects of biomass smoke on pulmonary functions and define the relationship between duration in years and an index (cumulative exposure index) with altered pulmonary function test results.,A total of 115 females who lived in the village of Kağizman (a borough of Kars located in the eastern part of Turkey) and were exposed to biomass smoke were included in the study.,The control group was generated with 73 individuals living in the same area who were never exposed to biomass smoke.,Twenty-seven (23.8%) females in the study group and four (5.5%) in the control group had small airway disease (P=0.038).,Twenty-two (19.1%) females in the study group and ten (13.7%) in the control group had obstruction (P=0.223).,Twenty (17.3%) females in the study group who were exposed to biomass smoke had restriction compared with ten (13%) in the control group (P=0.189).,The duration needed for the existence of small airway disease was 16 years, for obstructive airway disease was 17 years, and for restrictive airway disease was 17 years.,The intensity of biomass smoke was defined in terms of cumulative exposure index; it was calculated by multiplying hours per day, weeks per month, and total years of smoke exposure and dividing the result by three.,Exposure to biomass smoke is a serious public health problem, especially in rural areas of developing countries, because of its negative effects on pulmonary functions.,As the duration and the intensity of exposure increase, the probability of having altered pulmonary function test results is higher. | 1 |
No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD).,Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.,Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors.,Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.,236 COPD patients from five European centres were included.,Results indicated the concept of physical activity in COPD had two domains, labelled “amount” and “difficulty”.,After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14.,Both demonstrated good model fit (person separation index >0.7).,Confirmatory factor analysis supported the bidimensional structure.,Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.,Daily and clinical visit “PROactive physical activity in COPD” instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.,Both PROactive hybrid tools are simple, valid, and reliable measures of physical activity in COPD patientshttp://ow.ly/LJqP8 | The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed.,Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD.,We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012.,Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence.,86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both.,Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence.,Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low.,As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence.,Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence.,Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment. | 1 |
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.,Comorbidities are often reported in patients with COPD and may influence the cost of care.,Yet, the extent by which comorbidities affect costs remains to be determined.,To review, quantify and evaluate excess costs of comorbidities in COPD.,Using a systematic review approach, Pubmed and Embase were searched for studies analyzing excess costs of comorbidities in COPD.,Resulting studies were evaluated according to study characteristics, comorbidity measurement and cost indicators.,Mark-up factors were calculated for respective excess costs.,Furthermore, a checklist of quality criteria was applied.,Twelve studies were included.,Nine evaluated comorbidity specific costs; three examined index-based results.,Pneumonia, cardiovascular disease and diabetes were associated with the highest excess costs.,The mark-up factors for respective excess costs ranged between 1.5 and 2.5 in the majority of cases.,On average the factors constituted a doubling of respective costs in the comorbid case.,The main cost driver, among all studies, was inpatient cost.,Indirect costs were not accounted for by the majority of studies.,Study heterogeneity was high.,The reviewed studies clearly show that comorbidities are associated with significant excess costs in COPD.,The inclusion of comorbid costs and effects in future health economic evaluations of preventive or therapeutic COPD interventions seems highly advisable. | The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.,The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990-2005, using the healthcare databases from the province of Quebec, Canada.,Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified.,The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.,The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively.,The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th.,The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first.,Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.,The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation.,Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality. | 1 |
Chronic obstructive pulmonary disease is associated with significant morbidity and mortality.,Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status.,Our aim was to investigate the effects of tiotropium + olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy.,Two pairs of replicate, phase III studies of 12 (OTEMTO 1 + 2) and 52 weeks’ (TONADO 1 + 2) duration were evaluated, in which patients received either tiotropium + olodaterol 2.5/5 or 5/5 μg, tiotropium 2.5 or 5 μg, olodaterol 5 μg or placebo, all delivered once daily via Respimat inhaler.,Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George’s Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks.,Outcomes from the pooled study data are reported.,Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively.,Significantly larger improvements in St George’s Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George’s Respiratory Questionnaire and transition dyspnoea index) with tiotropium + olodaterol compared to either monotherapy or to placebo.,Tiotropium + olodaterol 5/5 µg significantly reduced night-time rescue medication usage.,Results from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease.,Alleviating the symptoms of chronic obstructive pulmonary disease (COPD), particularly sleep disturbance, is crucial to enhancing patients’ quality of life.,Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan, together with other scientists across the USA and Germany, analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat, a combination of two bronchodilators-tiotropium, and olodaterol, which tackle airway obstruction and breathlessness, improving long-term lung function.,They found that the new drug combination triggered significant improvements in patients’ quality of life and levels of breathlessness.,Use of night-time rescue medication in patients on STIOLTO Respimat was considerably reduced.,A greater number of patients responded positively to the combined inhaler than to monotherapy. | 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. | 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. | Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation.,Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood.,Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists.,We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients.,We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II).,Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage.,All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage.,These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1.,There were no severe exacerbations or other adverse events.,Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation. | 1 |
COPD is underdiagnosed and its early assessment is problematic.,It has been suggested that symptomatic smokers with normal FEV1/FVC (Stage 0 COPD, GOLD criteria) can develop COPD in the future.,Potential early biomarkers in COPD include the matrix metallo-proteinases (MMPs).,It is not yet known, whether alterations in MMP expression are associated with smoking alone or with the risk of developing COPD.,In this cross-sectional study MMP-8, MMP-9 and MMP-12 were determined from induced sputum and plasma by ELISA, immunocytochemistry, zymography, and/or Western blot in non-smokers (n = 32), smokers with symptoms (Stage 0, GOLD criteria) (n = 23) or without symptoms (n = 23).,Only MMP-8 differentiated Stage 0 COPD from non-symptomatic smokers (p = 0.02).,MMP-9 levels were significantly elevated in the induced sputum of non-symptomatic smokers and Stage 0 COPD (p = 0.01, p < 0.001) compared to non-smokers, but did not differ between the two subgroups of smokers.,MMP-12 was higher only at Stage 0 compared to non-smokers (p = 0.04).,MMP-8, MMP-9 and MMP-12 immunoreactivity was localized in macrophages and neutrophils, especially in smokers.,MMP-8 levels correlated significantly with the small airway flow parameters (MEF50, MEF25) (p = 0.005 and p = 0.0004) and markers of neutrophil activation (myeloperoxidase, lactoferrin).,In conclusion MMP-8 may differentiate Stage 0 from healthy smokers. | Smoking activates and recruits inflammatory cells and proteases to the airways.,Matrix metalloproteinase (MMP)-12 may be a key mediator in smoke induced emphysema.,However, the influence of smoking and its cessation on airway inflammation and MMP-12 expression during COPD is still unknown.,We aimed to analyse airway inflammatory cell patterns in induced sputum (IS) and bronchoalveolar lavage (BAL) from COPD patients who are active smokers and who have ceased smoking >2 years ago.,39 COPD outpatients - smokers (n = 22) and ex-smokers (n = 17) were studied. 8 'healthy' smokers and 11 healthy never-smokers were tested as the control groups.,IS and BAL samples were obtained for differential and MMP-12+-macrophages count analysis.,The number of IS neutrophils was higher in both COPD groups compared to both controls.,The amount of BAL neutrophils was higher in COPD smokers compared to healthy never-smokers.,The number of BAL MMP-12+-macrophages was higher in COPD smokers (1.6 ± 0.3 × 106/ml) compared to COPD ex-smokers, 'healthy' smokers and healthy never-smokers (0.9 ± 0.4, 0.4 ± 0.2, 0.2 ± 0.1 × 106/ml respectively, p < 0.05).,The lower amount of BAL neutrophils in COPD ex-smokers, compared to COPD smokers, suggests positive alterations in alveolar compartment after smoking cessation.,Smoking and disease itself may stimulate MMP-12 expression in airway compartments (IS and BAL) from COPD patients. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from acute exacerbations (AECOPD) and display varying disease severity.,However, there is no available biomarker for the classification of AECOPD.,This study is aimed at investigating the sputum cellular profiles to classify patients with AECOPD.,A total of 83 patients with AECOPD and 26 healthy controls were recruited.,Their demographic and clinical characteristics were recorded, and their lung function was examined.,The phenotypes of sputum inflammatory cells were characterised, and the concentrations of sputum and serum amyloid-A (SAA), C-reactive protein (CRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) were measured.,Based on the sputum inflammatory cell profiles, individual patients were categorized into one of the four subgroups with inflammatory eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic AECOPD.,Most AECOPD patients were reevaluated within 12-14 months after discharge.,There were 10 (12%) eosinophilic, 36 (43%) neutrophilic, 5 (6%) mixed granulocytic, and 32 (39%) paucigranulocytic AECOPD patients.,The patients with mixed granulocytic or neutrophilic AECOPD had a higher BODE score, more sputum inflammatory cells, lower lung function, and longer hospital stay, accompanied by higher concentrations of sputum MMP-9, IL-6 and CRP, and serum SAA, IL-6 and CRP.,Notably, 83% of patients with neutrophilic AECOPD displayed evidence of bacterial infection and many of them responded poorly to standard therapies.,In addition, patients with mixed granulocytic or neutrophilic stable COPD remained at lower lung functions and higher levels of inflammation.,Patients with AECOPD display heterogeneous inflammation, and the profiles of sputum inflammatory cells may be used as valuable biomarkers for the classification of AECOPD patients. | Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma.,Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation.,This study was undertaken to investigate relationship between apoptosis of peripheral blood lymphocytes during exacerbation of COPD and inflammatory response that characterizes this condition.,Seventeen patients with COPD exacerbation, 21 stable COPD, and 12 control subjects were included.,T lymphocytes were isolated from peripheral blood using MACS.,Apoptosis of T lymphocytes was assessed with FACS using annexin V and 7-aminoactinomycin.,Serum levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α were determined by an immunoassay technique.,There was significantly increased percentage of apoptotic lymphocytes, CD 4+, and CD 8+ T cells in the peripheral blood of patients with exacerbation of COPD compared with stable COPD.,Serum levels of IL-6, IL-8, and TNF-α were significantly increased in patients with exacerbation of COPD compared with stable COPD.,Only TNF-α presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD.,Increased apoptotic lymphocytes may be associated with upregulation of TNF-α in the peripheral blood of patients with acute exacerbation of COPD. | 1 |
TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.,In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219).,Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4).,Time to first and rate of moderate/severe exacerbations were assessed.,BFF MDI 320/10 µg improved pre-dose trough FEV1 versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4 versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24.,BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI.,Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.,BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.,TELOS: co-suspension delivery technology budesonide/formoterol fumarate dihydrate in a metered dose inhaler improved lung function and time to first and rate of exacerbations versus monocomponents in patients with moderate to very severe COPDhttp://ow.ly/ffWo30lrJL6 | 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 |
Exposure to noxious gases and particles contained in both tobacco smoking (TS) and biomass smoke (BS) are well recognized environmental risk factors for chronic obstructive pulmonary disease (COPD).,COPD is characterized by an abnormal inflammatory response, both in the pulmonary and systemic compartments.,The differential effects of TS, BS or their combined exposure have not been well characterized yet.,This study sought to compare the lung function characteristics and systemic inflammatory response in COPD patients exposed to TS, BS or their combination.,Sociodemographic, clinical and lung functional parameters were compared across 49 COPD patients with a history of smoking and no BS exposure (TS COPD), 31 never-smoker COPD patients with BS exposure (BS COPD), 46 COPD patients with a combined exposure (TS + BS COPD) and 52 healthy controls (HC) who have never been exposed neither to TS or BS.,Blood cell counts, C-reactive protein (CRP), fibrinogen and immunoglobulin E (IgE) levels were quantified in all four groups.,TS + BS COPD patients exhibited significantly lower oxygen saturation than the rest of groups (p < 0.01).,Spirometry and diffusing capacity were significantly higher in BS than in TS or TS + BS patients.,CRP levels were significantly higher in TS COPD patients than in BS COPD group (p < 0.05), whereas fibrinogen was raised in COPD patients with a history of smoking (TS and TS + BS) when compared to control subjects (p < 0.01).,Finally, COPD patients with BS exposure (BS and BS + TS groups) showed higher IgE levels than TS and HC (p < 0.05).,There are significant physiological and inflammatory differences between COPD patients with TS, BS and TS + BS exposures.,The latter had worse blood oxygenation, whereas the raised levels of IgE in BS exposed patients suggests a differential Th2 systemic inflammatory pattern triggered by this pollutant. | Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year.,To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort.,We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105).,We classified participants according to yearly exacerbation frequency.,Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none.,During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none.,Only 2·1% had ≥2 AECOPD in each year.,An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%).,In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8).,Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year.,Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year.,In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8. | 1 |
Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression.,A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs).,PQTLs consistently replicated between the two cohorts.,Features of pQTLs were compared to previously reported expression QTLs (eQTLs).,Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests.,We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested.,Most pQTL SNPs were novel with low overlap to eQTL SNPs.,The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC).,Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes.,Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins.,The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates.,Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema.,In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms.,Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group. | COPD (chronic obstructive pulmonary disease) is defined by a fixed expiratory airflow obstruction associated with disordered airways and alveolar destruction.,COPD is caused by cigarette smoking and is the third greatest cause of mortality in the US.,Forced expiratory volume in 1 second (FEV1) is the only validated clinical marker of COPD, but it correlates poorly with clinical features and is not sensitive enough to predict the early onset of disease.,Using LC/MS global untargeted metabolite profiling of serum samples from a well-defined cohort of healthy smokers (n = 37), COPD smokers (n = 41) and non-smokers (n = 37), we sought to discover serum metabolic markers with known and/or unknown molecular identities that are associated with early-onset COPD.,A total of 1,181 distinct molecular ions were detected in 95% of sera from all study subjects and 23 were found to be differentially-expressed in COPD-smokers vs. healthy-smokers.,These 23 putative biomarkers were differentially-correlated with lung function parameters and used to generate a COPD prediction model possessing 87.8% sensitivity and 86.5% specificity.,In an independent validation set, this model correctly predicted COPD in 8/10 individuals.,These serum biomarkers included myoinositol, glycerophopshoinositol, fumarate, cysteinesulfonic acid, a modified version of fibrinogen peptide B (mFBP), and three doubly-charged peptides with undefined sequence that significantly and positively correlate with mFBP levels.,Together, elevated levels of serum mFBP and additional disease-associated biomarkers point to a role for chronic inflammation, thrombosis, and oxidative stress in remodeling of the COPD airways.,Serum metabolite biomarkers offer a promising and accessible window for recognition of early-stage COPD. | 1 |
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD.,We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.,PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458).,Patients received 24 weeks’ treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily.,GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization).,Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs).,The pooled intent-to-treat population comprised 729 GOLD category A patients.,GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p<0.0001).,Improvements over 24 weeks were comparable to at Week 24.,The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI.,GFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings. | To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD.,In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days.,The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0-12) on Day 7.,Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7.,Safety was assessed.,All 185 randomized patients received treatment.,All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P≤0.0137).,For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg.,No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints.,The incidence of adverse events was similar between treatments.,While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed.,All treatments were well tolerated with no unexpected safety findings. | 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. | Twenty per cent of chronic obstructive pulmonary disease (COPD) patients are readmitted for acute exacerbation (AECOPD) within 30 days of discharge.,The prognostic significance of early readmission is not fully understood.,The objective of our study was to estimate the mortality risk associated with readmission for acute exacerbation within 30 days of discharge in COPD patients.,The cohort (n = 378) was divided into patients readmitted (n = 68) and not readmitted (n = 310) within 30 days of discharge.,Clinical, laboratory, microbiological, and severity data were evaluated at admission and during hospital stay, and mortality data were recorded at four time points during follow-up: 30 days, 6 months, 1 year and 3 years.,Patients readmitted within 30 days had poorer lung function, worse dyspnea perception and higher clinical severity.,Two or more prior AECOPD (HR, 2.47; 95% CI, 1.51-4.05) was the only variable independently associated with 30-day readmission.,The mortality risk during the follow-up period showed a progressive increase in patients readmitted within 30 days in comparison to patients not readmitted; moreover, 30-day readmission was an independent risk factor for mortality at 1 year (HR, 2.48; 95% CI, 1.10-5.59).,In patients readmitted within 30 days, the estimated absolute increase in the mortality risk was 4% at 30 days (number needed to harm NNH, 25), 17% at 6-months (NNH, 6), 19% at 1-year (NNH, 6) and 24% at 3 years (NNH, 5).,In conclusion a readmission for AECOPD within 30 days is associated with a progressive increased long-term risk of death. | 1 |
Using a mobile health (mHealth) intervention, consisting of a smartphone and compatible medical device, has the potential to enhance chronic obstructive pulmonary disease (COPD) treatment outcomes while mitigating health care costs.,The aim of this study was to explore the potential facilitators and barriers among health care providers (HCPs) regarding the use of mHealth interventions for COPD management.,This was a qualitative study.,Semistructured individual interviews were conducted with HCPs, including nurses, pharmacists, and physicians who work directly with patients with COPD.,A flexible prompts guide was used to facilitate discussions.,Interview topics included the following: demographics, mHealth usage, perceptions toward challenges of mHealth adoption, factors facilitating mHealth adoption, and preferences regarding features of the mHealth intervention for COPD management.,Interviews were conversational in nature, and items were not asked verbatim or in the order presented.,The interviews were transcribed verbatim and compared against the digital recordings to ensure the accuracy of the content.,After creating a codebook for analysis, 2 researchers independently coded the remaining interview data using pattern coding.,They discussed commonalities and differences in coding until a consensus was reached.,A total of 30 nurses, physicians, and pharmacists participated.,The main facilitators to mHealth adoption are possible health benefits for patients, ease of use, educating patients and their HCPs, credibility, and reducing cost to the health care system.,Alternatively, the barriers to adoption are technical issues, privacy and confidentiality issues, lack of awareness, potential limited uptake from the elderly, potential limited connection between patients and HCPs, and finances.,It is important to understand the perceptions of HCPs regarding the adoption of innovative mHealth interventions for COPD management.,This study identifies some potential facilitators and barriers that may inform the successful development and implementation of mHealth interventions for COPD management. | Remote patient monitoring should reduce mortality rates, improve care, and reduce costs.,We present an overview of the available technologies for the remote monitoring of chronic obstructive pulmonary disease (COPD) patients, together with the most important medical information regarding COPD in a language that is adapted for engineers.,Our aim is to bridge the gap between the technical and medical worlds and to facilitate and motivate future research in the field.,We also present a justification, motivation, and explanation of how to monitor the most important parameters for COPD patients, together with pointers for the challenges that remain.,Additionally, we propose and justify the importance of electrocardiograms (ECGs) and the arterial carbon dioxide partial pressure (PaCO2) as two crucial physiological parameters that have not been used so far to any great extent in the monitoring of COPD patients.,We cover four possibilities for the remote monitoring of COPD patients: continuous monitoring during normal daily activities for the prediction and early detection of exacerbations and life-threatening events, monitoring during the home treatment of mild exacerbations, monitoring oxygen therapy applications, and monitoring exercise.,We also present and discuss the current approaches to decision support at remote locations and list the normal and pathological values/ranges for all the relevant physiological parameters.,The paper concludes with our insights into the future developments and remaining challenges for improvements to continuous remote monitoring systems.,Graphical abstractᅟ,ᅟ | 1 |
Patients with COPD and other chronic respiratory diseases are especially vulnerable to viral and bacterial pulmonary infections, which are major causes of exacerbations, hospitalization, disease progression, and mortality in COPD patients.,Effective vaccines could reduce the burden of respiratory infections and acute exacerbations in COPD patients, but what is the evidence for this?,This article reviews and discusses the existing evidence for pneumococcal vaccination efficacy and its changing role in patients with chronic respiratory diseases, especially COPD.,Specifically, the recent Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) showed the efficacy of pneumococcal conjugate vaccine in older adults, many of whom had additional risk factors for pneumococcal disease, including chronic lung diseases.,Taken together, the evidence suggests that pneumococcal and influenza vaccinations can prevent community-acquired pneumonia and acute exacerbations in COPD patients, while pneumococcal vaccination early in the course of COPD could help maintain stable health status.,Despite the need to prevent pulmonary infections in patients with chronic respiratory diseases and evidence for the efficacy of pneumococcal conjugate vaccine, pneumococcal vaccine coverage and awareness are low and need to be improved.,Respiratory physicians need to communicate the benefits of vaccination more effectively to their patients who suffer from chronic respiratory diseases. | Several fixed-dose combinations (FDCs) of long-acting bronchodilators (a long-acting muscarinic antagonist [LAMA] plus a long-acting β2-agonist [LABA]) are available for the treatment of COPD.,Studies of these FDCs have demonstrated substantial improvements in lung function (forced expiratory volume in 1 second) in comparison with their respective constituent monocomponents.,Improvements in patient-reported outcomes (PROs), such as symptoms and health status, as well as exacerbation rates, have been reported compared with a LABA or LAMA alone, but results are less consistent.,The inconsistencies may in part be owing to differences in study design, methods used to assess study end points, and patient populations.,Nevertheless, these observations tend to support an association between improvements in forced expiratory volume in 1 second and improvements in symptom-based outcomes.,In order to assess the effects of FDCs on PROs and evaluate relationships between PROs and changes in lung function, we performed a systematic literature search of publications reporting randomized controlled trials of FDCs.,Results of this literature search were independently assessed by two reviewers, with a third reviewer resolving any conflicting results.,In total, 22 Phase III randomized controlled trials of FDC bronchodilators in COPD were identified, with an additional study including a post-literature search (ten for indacaterol-glycopyrronium once daily, eight for umeclidinium-vilanterol once daily, three for tiotropium-olodaterol once daily, and two for aclidinium-formoterol twice daily).,Results from these studies demonstrated that the LAMA-LABA FDCs significantly improved lung function compared with their component monotherapies or other single-agent treatments.,Furthermore, LABA-LAMA combinations also generally improved symptoms and health status versus monotherapies, although some discrepancies between lung function and PROs were observed.,Overall, the safety profiles of the FDCs were similar to placebo.,Further research is required to examine more closely any relationship between lung function and PROs in patients receiving LABA-LAMA combinations. | 1 |
The benefits of pharmacotherapy with tiotropium HandiHaler 18 μg for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated.,However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).,To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.,A randomised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily (via HandiHaler) was performed in maintenance therapy-naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ⩾50 and <80%.,A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93 l (66% predicted)).,Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h (AUC0-3h) at week 24 (primary endpoint): 0.19 vs.,−0.03 l (least-squares mean difference 0.23 l, P<0.001).,FVC AUC0-3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001).,Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS).,Physician’s Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24.,The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.,Tiotropium improved lung function and patient-reported outcomes in maintenance therapy-naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early. | 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 |
Inappropriate use of an inhaled corticosteroid (ICS) for COPD has clinical and economic disadvantages.,This retrospective analysis of The UK Health Improvement Network (THIN) database identified factors influencing treatment escalation (step-up) from a long-acting muscarinic antagonist (LAMA) to triple therapy (LAMA + long-acting β-agonist-ICS).,Secondary objectives included time to step up from first LAMA prescription, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grouping (2011/2013, 2017), and Medical Research Council (MRC) grade prior to treatment escalation.,Data were included from 14,866 people ≥35 years old with a COPD diagnosis (June 1, 2010-May 10, 2015) and initiated on LAMA monotherapy.,The most commonly used LAMA at baseline was tiotropium (92%).,Multivariate analysis (10,492 patients) revealed that COPD exacerbations, lower forced expiratory volume in 1 second (FEV1), “asthma”, MRC grade, proactive and reactive COPD primary care, elective secondary-care contact, cough, and number of short-acting bronchodilator prescriptions were positively associated with treatment escalation (P<0.05).,Being older, a current/ex-smoker, or having increased sputum symptom codes were negatively associated with treatment escalation (P<0.05).,Median MRC score was 2 at baseline and 3 prior to treatment escalation.,Using the last MRC reading and exacerbation history in the year prior to escalation, GOLD 2017 groupings were A 27.4%, B 37.3%, C 15.3%, and D 20%.,In patients with available FEV1 measures, exacerbations, and MRC code (n=1,064), GOLD 2011/2013 groupings were A 20.4%, B 19.2%, C 24.8%, and D 35.6%.,While the presence of COPD exacerbations seems to be the main driver for treatment escalation, according to the 2017 GOLD strategy many patients appear to be overtreated, as they would not be recommended for treatment escalation.,Reviewing patients’ treatment in the light of the new GOLD strategy has the potential to reduce inappropriate use of triple therapy. | 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. | 1 |
The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 μg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD.,Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair® dry powder inhaler for 8 weeks.,From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals).,The primary end point was trough functional residual capacity (FRC) at Week 4.,Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI).,Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise.,After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690).,However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001).,AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively).,AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo.,Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo.,AB/FF 400/12 μg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI.,A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF. | The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed.,Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD.,We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012.,Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence.,86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both.,Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence.,Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low.,As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence.,Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence.,Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment. | 1 |
The diagnosis of COPD is not always consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy in daily clinical practice, especially in primary care.,This study aimed to estimate the overall COPD prevalence and severity, to identify differences between newly and previously diagnosed patients, and to evaluate the potential COPD overtreatment in a smoking population attending a primary care spirometry surveillance program.,A study was conducted in 10 primary health care centers of Central Greece during a 7-month period.,Eligible participants were aged ≥40 years and were either current smokers or exsmokers.,A total of 186 subjects were included (68% males, mean age 62.3±12.6 years, mean life-time tobacco exposure 50 pack-years).,COPD prevalence was 17.8%, identified to be higher in elderly males.,Forty-two percent of the COPD group were newly diagnosed patients, who were of younger age, current smokers, presented with less dyspnea and better health status, and mainly appeared with mild-to-moderate disease.,Interestingly, 61.4% of non-COPD and 85.7% of newly diagnosed COPD individuals had been using inhaled medication under primary care provider’s prescription without ever undergoing spirometry or further evaluation by a pulmonologist; thus, the phenomena of COPD overdiagnosis and missed diagnosis came into the spotlight.,Moreover, only 26.3% of known COPD patients were properly medicated according to GOLD guidelines, while half of them were inappropriately treated with triple inhaled therapy.,We reported a significant prevalence of COPD in smoking population attending this spirometry program.,A remarkable proportion of COPD patients were undiagnosed and made case finding worthwhile.,Underutilization of spirometry in the diagnosis and management of COPD as well as general practitioners’ nonadherence to the GOLD treatment guidelines was confirmed by our data.,These findings highlight the need for a major overhaul and culture change in primary care settings of Central Greece. | The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7.,Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative.,We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis.,In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years.,Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated.,The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography.,Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively.,The GOLD classification led to more false positives, the LLNs to more false negative diagnoses.,The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC).,Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses.,The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN.,GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis.,Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice. | 1 |
Changes in sputum microbiology following antibiotic treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), including patterns of bacteriological relapse and superinfection are not well understood.,Sputum microbiology at exacerbation is not routinely performed, but pathogen presence and species are determinants of outcomes.,Therefore, we determined whether baseline clinical factors could predict the presence of bacterial pathogens at exacerbation.,Bacterial eradication at end of treatment (EOT) is associated with clinical resolution of exacerbation.,We determined the clinical, microbiological and therapeutic factors that were associated with bacteriological eradication in AECOPD at EOT and in the following 8 weeks.,Sputum bacteriological outcomes (i.e., eradication, persistence, superinfection, reinfection) from AECOPD patients (N = 1352) who were randomized to receive moxifloxacin or amoxicillin/clavulanate in the MAESTRAL study were compared.,Independent predictors of bacterial presence in sputum at exacerbation and determinants for bacteriological eradication were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.,Significantly greater bacteriological eradication with moxifloxacin was mainly driven by superior Haemophilus influenzae eradication (P = 0.002, EOT).,Baseline clinical factors were a weak predictor of the presence of pathogens in sputum (AUCROC = 0.593).,On multivariate analysis, poorer bacterial eradication was associated with antibiotic resistance (P = 0.0001), systemic steroid use (P = 0.0024) and presence of P. aeruginosa (P = 0.0282).,Since clinical prediction of bacterial presence in sputum at AECOPD is poor, sputum microbiological analysis should be considered for guiding antibiotic therapy in moderate-to-severe AECOPD, particularly in those who received concomitant systemic corticosteroids or are at risk for infection with antibiotic-resistant bacteria.,The online version of this article (doi:10.1007/s15010-015-0833-3) contains supplementary material, which is available to authorized users. | Sputum induction is a non-invasive method for obtaining measurements of inflammation in the airways.,Whether spontaneously sampled sputum can be a valid surrogate is unknown.,The aim of this study was to compare levels of six inflammatory markers in sputum pairs consisting of induced and spontaneous sputum sampled on the same consultation either in a stable state or during exacerbations of chronic obstructive pulmonary disease (COPD).,433 COPD patients aged 40-76, Global initiative for chronic Obstructive Lung Disease (GOLD) stage II-IV were enrolled in 2006/07 and followed every six months for three years. 356 patients were followed for potential exacerbations.,Interleukin-6, interleukin-8, interleukin-18, interferon gamma-inducible protein-10, monokine induced by gamma interferon and tumor necrosis factor-alpha (IL-6, IL-8, IL-18, IP-10, MIG and TNF-α) were measured by bead based multiplex immunoassay in 60 paired sputum samples from 45 patients.,Albumin was measured by enzyme immunoassay, for concentration correction.,Culturing for bacterial growth was performed on 24 samples.,Bland-Altman plots were used to assess agreement.,The paired non-parametric Wilcoxon signed-rank test, the non-parametric Spearman’s rank correlation test and Kruskal-Wallis test were used for statistical analyses.,For all analyses, a p-value < 0.05 was considered significant.,Agreement between the two measurements was generally low for all six markers.,TNF-α was significantly higher in spontaneous sputum at exacerbations (p = 0.002) and trending higher at the steady state (p = 0.06).,Correlation coefficients between the levels of markers in induced and spontaneous sputum varied between 0.58 (IL-18) to 0.83 (IP-10).,In spontaneous sputum IL-18 and MIG were higher in ex-smokers (p < 0.05).,The levels of all markers were higher in GOLD stage III & IV except for IL-6 in spontaneous sputum and IL-18 in induced sputum, compared with GOLD stage II, although not statistically significant.,In spontaneous sputum the levels of IL-6 were significantly higher if Haemophilus influenzae (HI) was not cultured.,We observed a low agreement and significant differences in inflammatory markers between induced and spontaneous sputum, both at steady state and exacerbations.,We recommend considering sampling method when reporting on inflammatory markers in sputum. | 1 |
The risk of dying of lung cancer is up to eightfold higher in patients with COPD than in age- and gender-matched controls.,The aim of this study was to investigate the factors associated with lung cancer in a large cohort of COPD patients from primary care centers.,To analyze whether age, gender, socioeconomic factors, comorbidity, and medication affect the risk of lung cancer in COPD, we used a COPD cohort of primary care patients.,Data from primary care medical records and mandatory Swedish national registers were collected and linked in this population-based, retrospective observational registry study (NCT01146392).,Of the total cohort, 19,894 patients were included in the study.,Five hundred and ninety-four lung cancer cases were diagnosed, corresponding to 3.0% of the studied population.,In a multivariate analysis, the risk of lung cancer was lower if the COPD patients had a concurrent asthma diagnosis (HR: 0.54, CI: 0.41-0.71), while the risk of lung cancer increased with increasing age.,A decreased lung cancer risk was observed in an exposure-dependent manner in patients who were prescribed inhaled corticosteroids (HR: 0.52, CI: 0.37-0.73), while the opposite was found for the use of acetylsalicylic acid (HR: 1.58, CI: 1.15-2.16).,In this large population-based cohort, a concurrent asthma diagnosis and use of inhaled corticosteroids were independently related to decreased risk of lung cancer in COPD patients, while the use of acetylsalicylic acid was associated with an increased risk.,The findings of the present study should be seen as hypothesis generating and need to be confirmed in prospective studies. | Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist.,Design Observational retrospective pairwise cohort study matched (1:1) for propensity score.,Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.,Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.,Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.,Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each.,In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up.,Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively.,The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6).,The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003).,All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).,Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.,Trial registration Clinical Trials.gov NCT01146392. | 1 |
Cognitive impairment has been found in chronic obstructive pulmonary disease (COPD) patients.,However, the structural alteration of the brain and underlying mechanisms are poorly understood.,Thirty-seven mild-to-moderate COPD patients, forty-eight severe COPD patients, and thirty-one control subjects were recruited for cognitive test and neuroimaging studies.,Serum levels of S100B,pulmonary function and arterial blood gas levels were also evaluated in each subject.,The hippocampal volume was significantly smaller in COPD patients compared to the control group.,It is positively correlated with a mini mental state examination (MMSE) score, SaO2 in mild-to-moderate COPD patients, the levels of PaO2 in both mild-to-moderate and severe COPD patients.,Higher S100B concentrations were observed in mild-to-moderate COPD patients, while the highest S100B level was found in severe COPD patients when compared to the control subjects.,S100B levels are negatively associated with MMSE in both mild-to-moderate and severe COPD patients and also negatively associated with the hippocampal volume in the total COPD patients.,Hippocampal atrophy based on quantitative assessment by magnetic resonance imaging does occur in COPD patients, which may be associated with cognitive dysfunction and the most prevalent mechanism accountable for hippocampal atrophy is chronic hypoxemia in COPD.,Higher serum S100B levels may be peripheral biochemical marker for cognitive impairment in COPD. | Several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment.,These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group.,This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD.,In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy.,We used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD.,Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points.,Disease severity was using Forced Expiratory Volume in one second (FEV1); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index.,Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking.,COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043-6.64).,Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases).,Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation ≤88% (OR 5.45; 95% CI 1.014-29.2; P = 0.048).,Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07-0.27; P < 0.0001).,COPD is a major risk factor for cognitive impairment.,Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective.,Health care providers should consider screening their COPD patients for cognitive impairment. | 1 |
Treatment of chronic diseases such as chronic obstructive pulmonary disease (COPD) is complicated by the presence of comorbidities.,The objective of this analysis was to estimate the prevalence of comorbidity in COPD using nationally-representative data.,This study draws from a multi-year analytic sample of 14,828 subjects aged 45+, including 995 with COPD, from the National Health and Nutrition Examination Survey (NHANES), 1999-2008.,COPD was defined by self-reported physician diagnosis of chronic bronchitis or emphysema; patients who reported a diagnosis of asthma were excluded.,Using population weights, we estimated the age-and-gender-stratified prevalence of 22 comorbid conditions that may influence COPD and its treatment.,Subjects 45+ with physician-diagnosed COPD were more likely than subjects without physician-diagnosed COPD to have coexisting arthritis (54.6% vs.,36.9%), depression (20.6% vs.,12.5%), osteoporosis (16.9% vs.,8.5%), cancer (16.5% vs.,9.9%), coronary heart disease (12.7% vs.,6.1%), congestive heart failure (12.1% vs.,3.9%), and stroke (8.9% vs.,4.6%).,Subjects with COPD were also more likely to report mobility difficulty (55.6% vs.,32.5%), use of >4 prescription medications (51.8% vs.,32.1), dizziness/balance problems (41.1% vs.,23.8%), urinary incontinence (34.9% vs.,27.3%), memory problems (18.5% vs.,8.8%), low glomerular filtration rate (16.2% vs.,10.5%), and visual impairment (14.0% vs.,9.6%).,All reported comparisons have p < 0.05.,Our study indicates that COPD management may need to take into account a complex spectrum of comorbidities.,This work identifies which conditions are most common in a nationally-representative set of COPD patients (physician-diagnosed), a necessary step for setting research priorities and developing clinical practice guidelines that address COPD within the context of comorbidity. | Recent studies described association between chronic obstructive pulmonary disease (COPD) and increased risk of cardiovascular diseases (CVD).,In their analysis none of these studies accounted for sociodemographic factors, health behaviors, and patient comorbidities simultaneously.,To study whether COPD diagnosis is an independent risk factor for CVD.,Subjects aged 40 years and older (N = 18,342) from the sample adult file of the 2002 National Health Interview Survey (NHIS) were included in the analysis.,Chi-squared tests and odds ratios (OR) were utilized to compare the data.,Multiple logistic regression was employed to analyze the association between COPD and CVD with simultaneous control for sociodemographic factors (age, gender, race, marital status, education, income), health behaviors (tobacco use, alcohol consumption, physical activity), and patient comorbidities (diabetes, hypertension, high cholesterol, and obesity).,The analysis employed NHIS sampling weights to generate data representative of the entire US population.,The COPD population had increased prevalence of CVD (56.5% vs 25.6%; P < 0.0001).,Adjusted logistic regression showed that COPD patients (N = 958) were at higher risk of having coronary heart disease (OR = 2.0, 95% CI: 1.5-2.5), angina (OR = 2.1, 95% CI: 1.6-2.7), myocardial infarction (OR = 2.2, 95% CI: 1.7-2.8), stroke (OR = 1.5, 95% CI: 1.1-2.1), congestive heart failure (OR = 3.9, 95% CI: 2.8-5.5), poor circulation in lower extremities (OR = 2.5, 95% CI: 2.0-3.0), and arrhythmia (OR = 2.4, 95% CI: 2.0-2.8).,Overall, the presence of COPD increased the odds of having CVD by a factor of 2.7 (95% CI: 2.3-3.2).,These findings support the conclusion that COPD is an independent risk factor for CVD. | 1 |
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is associated with infective triggers including bacterial or viral in many cases, and pneumonia is a major contributor to hospitalization for AECOPD and has a close relationship with poor outcomes.,Increased delta neutrophil index (DNI) can be useful in the detection of COPD patients with pneumonia.,A retrospective cohort study was performed to investigate the mortality rate of the patients who were re-admitted within 6 months after discharge from the hospital due to AECOPD with or without CAP.,We analyzed the difference of cumulative survival rate according to serum DNI level and readmission duration.,Finally, 140 AECOPD patients with community-acquired pneumonia (CAP) and 174 AECOPD patients without CAP were enrolled during 6 months, respectively.,The mean age was 72.2 ± 9.4 year-old, and 240 patients (76.4%) were male.,When comparing the cumulative survival rate according to readmission duration (≤ 30 vs > 30 days) and DNI level (< 3.5 vs ≥ 3.5%), AECOPD patients with readmission ≤30 days and DNI ≥ 3.5% showed the lowest cumulative survival rate compared to other groups (P < 0.001).,Multivariate analysis revealed readmission duration ≤30 days (HR 7.879, 95% CI 4.554-13.632, P < 0.001); and serum DNI level (HR 1.086, 95% CI 1.043-1.131, P < 0.001) were significantly associated with the mortality of AECOPD patients during 6 months.,The area under the curve for readmission (≤ 30 days) + DNI level (≥ 3.5%) was 0.753 (95% CI 0.676-0.830, P < 0.001) with a sensitivity of 73.7% and a specificity of 67.3%.,AECOPD patients who were readmitted ≤30 days and DNI ≥ 3.5% showed higher mortality.,DNI level can be used as a predictor of prognosis in AECOPD patients who were readmitted after discharge. | The association between N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations and in-hospital and 1-year mortality in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients is largely unknown.,Our objective was to explore the usefulness of NT-proBNP concentrations in AECOPD patients as a prognostic marker for in-hospital and 1-year mortality.,NT-proBNP levels were measured in patients upon admission and laboratory and clinical data were also recorded.,The cut-point for the NT-proBNP concentration level for in-hospital death was obtained using the receiver operating characteristic (ROC) curve.,Univariate and multivariate logistic regression and Cox regression were used in the analyses of factors of in-hospital and 1-year mortality.,A total of 429 patients were enrolled.,Twenty-nine patients died during hospitalization and 59 patients died during the 1-year follow-up.,Patients who died in-hospital compared with those in-hospital survivors were older (80.14±6.56 vs 75.93±9.45 years, p=0.003), had a higher percentage of congestive heart failure (65.52% vs 33.75%, p<0.001), had higher NT-proBNP levels (5767.00 (1372.50-12,887.00) vs 236.25 (80.03-1074.75) ng/L, p<0.001), higher neutrophil counts (10.52±5.82 vs 7.70±4.31, p=0.016), higher D-dimer levels (1231.62±1921.29 vs 490.11±830.19, p=0.048), higher blood urea nitrogen levels (9.91±6.33 vs 6.51±4.01 mmol/L, p=0.001), a lower body mass index (19.49±3.57 vs 22.19±4.76, p=0.003), and higher hemoglobin levels (122.34±25.36 vs 130.57±19.63, p=0.034).,The area under the ROC curve (AUC) for NT-proBNP concentration was 0.88 (95% confidence interval [CI], 0.84-0.93).,NT-proBNP concentrations ≥551.35 ng/L were an independent prognostic factor for both in-hospital and 1-year mortality after adjustment for relative risk (RR) (RR=29.54, 95% CI 3.04-286.63, p=0.004 for the multivariate logistic regression analysis) and hazard ratio (HR) (HR=4.47, 95% CI, 2.38-8.41, p <0.001 for the multivariate cox regression analysis).,NT-proBNP was a strong and independent predictor of in-hospital and 1-year mortality in AECOPD patients. | 1 |
Comprehensive multidisciplinary pulmonary rehabilitation is vital in the management of chronic obstructive pulmonary disease (COPD) and is considered for any stage of the disease.,Rehabilitation programmes are often centre-based and organised in groups.,However, the distance from the patient’s home to the centre and lack of transportation may hinder participation.,Rehabilitation at home can improve access to care for patients regardless of disease severity.,We had previously studied the technology usability and acceptability of a comprehensive home rehabilitation programme designed for patients with very severe COPD receiving long-term oxygen therapy.,The acceptability of such comprehensive home programmes for those with less severe COPD, who may be less homebound, is not known.,The aims of this feasibility study were to assess patient acceptability of the delivery mode and components of a comprehensive pulmonary rehabilitation programme for any stage of COPD, as well as the technology usability, patient outcomes and economic aspects.,Ten participants with COPD in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade I-IV were enrolled in a 9-week home programme and divided into two rehabilitation groups, with five patients in each group.,The programme included exercise training and self-management education in online groups of patients, and individual online consultations.,The patients also kept a digital health diary.,To assess the acceptability of the programme, the patients were interviewed after the intervention using a semi-structured interview guide.,In addition the number of sessions attended was observed.,The usability of the technology was assessed using interviews and the System Usability Scale questionnaire.,The St George’s Respiratory Questionnaire (SGRQ) was used to measure health-related quality of life.,The mode of delivery and the components of the programme were well accepted by the patients.,The programme provided an environment for learning from both healthcare professionals and peers, for asking questions and discussing disease-related issues and for group exercising.,The patients considered that it facilitated health-enhancing behaviours and social interactions with a social group formed among the participants.,Even participants who were potentially less homebound appreciated the home group and social aspects of the programme.,The participants found the technology easy to learn and use.,The acceptability and usability results were consistent with those in our previous study of patients with very severe COPD.,Only the mean change in the SGRQ total score of −6.53 (CI 95 % −0.38 to −12.68, p = 0.04) indicates a probable clinically significant effect.,Economic calculations indicated that the cost of the programme was feasible.,The results of this study indicate that comprehensive pulmonary rehabilitation delivered in home-based online groups may be feasible in COPD.,The mode of delivery and components of the programme appeared to be acceptable across patients with different disease severity.,The results in terms of patient outcomes are inconclusive, and further assessment is needed. | Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality.,Effective self-management support interventions are needed to improve the health and functional status of people with COPD or at risk for COPD.,Computer-tailored technology could be an effective way to provide this support.,This paper presents the protocol of a randomised controlled trial testing the effectiveness of a web-based, computer-tailored self-management intervention to change health behaviours of people with or at risk for COPD.,An intervention group will be compared to a usual care control group, in which the intervention group will receive a web-based, computer-tailored self-management intervention.,Participants will be recruited from an online panel and through general practices.,Outcomes will be measured at baseline and at 6 months.,The primary outcomes will be smoking behaviour, measuring the 7-day point prevalence abstinence and physical activity, measured in minutes.,Secondary outcomes will include dyspnoea score, quality of life, stages of change, intention to change behaviour and alternative smoking behaviour measures, including current smoking behaviour, 24-hour point prevalence abstinence, prolonged abstinence, continued abstinence and number of quit attempts.,To the best of our knowledge, this will be the first randomised controlled trial to test the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPD.,The results will be important to explore the possible benefits of computer-tailored interventions for the self-management of people with or at risk for COPD and potentially other chronic health conditions.,NTR3421 | 1 |
The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) gene regulates transcription of enzymes involved in cellular detoxification and lipids homeostasis.,NFE2L2 is associated with pathophysiology of atherosclerosis and chronic obstructive pulmonary disease (COPD).,Therefore we studied the relation between NFE2L2 and all-cause, cardiovascular, and COPD mortality and its associations with triglyceride and cholesterol levels.,We genotyped five tagging single nucleotide polymorphisms (SNPs) (rs4243387, rs2364723, rs13001694, rs1806649, and rs6726395) in NFE2L2 in 1,390 subjects from the Vlagtwedde-Vlaardingen cohort.,Participants were examined in 1989/1990 and followed up till the vital status evaluation on December 31st, 2008.,Associations between SNPs and mortality were estimated by Cox proportional hazards regression, and associations between SNPs and triglyceride and cholesterol levels were tested with linear regression.,After 18 yr, 284 (20.4%) subjects had died, 107 from cardiovascular disease and 20 from COPD.,Minor allele carriers of rs13001694 had a significantly reduced risk of all-cause mortality compared with wild types: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.6 to 1.0].,Minor allele carriers of rs2364723 had significantly reduced risk of cardiovascular mortality: HR = 0.5 (95% CI: 0.3-0.7).,This result was consistent in stratified analyses: females 0.4 (0.2-0.7), males 0.6 (0.3-0.9), never smokers 0.5 (0.2-1.1), ever smokers 0.5 (0.3-0.8).,Minor allele carriers of rs1806649 had a markedly reduced COPD mortality: HR = 0.3 (95% CI: 0.1-0.9).,Rs2364723 was associated with lower triglyceride levels.,None of the SNPs was associated with cholesterol levels.,This study shows for the first time that NFE2L2 is associated with reduced risk of all-cause, cardiovascular and COPD mortality in humans. | Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD).,To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function.,We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11). | 1 |
Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases.,Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.,We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality.,A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes.,A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.,Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4-11.7%) of them were diagnosed with AATD.,Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8-13.3), asthma (OR 2.0, 95% CI 1.4-3.0), bronchiectasis (OR 7.3, 95%CI 3.2-16.8), pneumonia (OR 2.7, 95% CI 1.5-4.9) and cirrhosis (OR 7.8, 95% CI 2.5-24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2-4.6), compared to PI*MM (wildtype) (n=398 424).,These associations were stronger among smokers.,PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis.,Polygenic risk score and PI*ZZ were independently associated with FEV1/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4-1.5 and OR 4.5, 95% CI 3.0-6.9, respectively).,The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.,Only 6.4% of those with genotype-defined alpha-1 antitrypsin deficiency had been diagnosed with this serious disease in UK Biobank.,Genotype-guided diagnosis could help to identify the thousands of people in the UK with this partially preventable disease. https://bit.ly/3dMu5Ng | A decrease in bone mineral density (BMD) is a systemic consequence of chronic obstructive pulmonary disease (COPD).,Past reports have rarely examined any correlation between sarcopenia and BMD.,We investigated the relationship cross-sectionally between the presence of sarcopenia and BMD reduction in COPD patients.,COPD patients aged 50 or older with qualifying spirometry and dual-energy X-ray absorptiometry data were from participants in the Korean National Health and Nutrition Examination Surveys IV and V (2008-2011).,There were 286 (33.3%) subjects in the sarcopenia group and 572 (66.7%) in the non-sarcopenia group.,The sarcopenia group had lower T-scores than the non-sarcopenia group (femur: -0.73±0.88 vs. -0.18±0.97, p < 0.001; femur neck: -1.44±0.98 vs. -0.99±1.06, p < 0.001; lumbar: -1.38±1.36 vs. -0.84±1.38, p < 0.001).,The prevalences of osteopenia and osteoporosis were 60.8% and 22.0%, respectively, in the sarcopenia group and 45.6% and 13.3% in the non-sarcopenia group (both p < 0.001).,After adjusting for multiple variables, the presence of sarcopenia associated with increased the risk of osteopenia, osteoporosis, and a low BMD (OR = 3.227, 95% CI = 2.125-4.899, p < 0.001, OR = 6.952, 95% CI = 3.418-14.139, p < 0.001, and OR = 3.495, 95% CI = 2.315-5.278, p < 0.001, respectively).,In a subgroup analysis, similar OR changes were confirmed in the high-body-weight group (n = 493) (OR = 2.248, 95% CI = 1.084-4.665, p = 0.030, OR = 4.621, 95% CI = 1.167-18.291, p = 0.029, and OR = 2.376, 95% CI = 1.158-4.877, p = 0.018, respectively).,The presence of sarcopenia was associated with increased the risk for decreased BMD in COPD. | 1 |
Natriuretic peptides (NPs) are a family of prognostic biomarkers in patients with heart failure (HF).,HF is one of the most frequent comorbidities in patients with chronic obstructive pulmonary disease (COPD).,However, the prognostic role of NP in COPD patients remains unclear.,The aim of this meta-analysis was to evaluate the relation between NP and all-cause mortality in COPD patients.,We performed a systematic review and meta-analysis of observational studies assessing prognostic implications of elevated NP levels on all-cause mortality in COPD patients.,Nine studies were considered for qualitative analysis for a total of 2788 patients.,Only two studies focused on Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and brain natriuretic peptide (BNP), respectively, but seven studies focused on pro-BNP (NT-proBNP) and were included in the quantitative analysis.,Elevated NT-proBNP values were related to increased risk of all-cause mortality in COPD patients both with and without exacerbation (hazard ratio (HR): 2.87, p < 0.0001 and HR: 3.34, p = 0.04, respectively).,The results were confirmed also after meta-regression analysis for confounding factors (previous cardiovascular history, hypertension, HF, forced expiratory volume at 1 second and mean age).,NT-proBNP may be considered a reliable predictive biomarker of poor prognosis in patients with COPD. | Elevated plasma B-type natriuretic peptide (BNP) levels and their association with heart failure have been reported in subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).,To examine and compare plasma BNP levels and diastolic and systolic dysfunction in subjects with AECOPD and stable chronic obstructive pulmonary disease (COPD).,In all, 87 unselected consecutive hospitalizations due to AECOPD in 61 subjects and a total of 190 consecutive subjects with stable COPD were recruited.,Plasma BNP levels were compared cross-sectionally and longitudinally.,Transthoracic echocardiographic examinations were also performed in the hospitalized subjects.,In the hospitalized subjects, the median plasma BNP level (interquartile range) was 55.4 (26.9-129.3) pg/mL and was higher than that of patients with stable COPD: 18.3 (10.0-45.3) for Global Initiative for Chronic Obstructive Lung Disease grade I; 25.8 (11.0-53.7) for grade II; 22.1 (9.1-52.6) for grade III; and 17.2 (9.6-22.9) pg/mL for grade I V, all P<0.001.,In 15 subjects studied prospectively, the median plasma BNP level was 19.4 (9.8-32.2) pg/mL before AECOPD, 72.7 (27.7-146.3) pg/mL during AECOPD, and 14.6 (12.9-39.0) pg/mL after AECOPD (P<0.0033 and P<0.0013, respectively).,Median plasma BNP levels during AECOPD were significantly higher in ten unsuccessfully discharged subjects 260.5 (59.4-555.0) than in 48 successfully discharged subjects 48.5 (24.2-104.0) pg/mL (P=0.0066).,Only 5.6% of AECOPD subjects were associated with systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <50%; a further 7.4% were considered to have impaired relaxation defined as an E/A wave velocity ratio <0.8 and a deceleration time of E >240 ms.,BNP levels were weakly correlated with the E/peak early diastolic velocity of the mitral annulus (Ea) ratio (Spearman’s rank correlation coefficient =0.353, P=0.018), but they were not correlated with the LVEF (Spearman’s rank correlation coefficient =−0.221, P=0.108).,A modest elevation of plasma BNP is observed during AECOPD.,It appears that AECOPD may have an impact on plasma BNP levels that is not attributable to heart failure. | 1 |
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease of the lungs that is currently the fourth leading cause of death worldwide.,Genetic factors account for only a small amount of COPD risk, but epigenetic mechanisms, including DNA methylation, have the potential to mediate the interactions between an individual’s genetics and environmental exposure.,DNA methylation is highly cell type-specific, and individual cell type studies of DNA methylation in COPD are sparse.,Fibroblasts are present within the airway and parenchyma of the lung and contribute to the aberrant deposition of extracellular matrix in COPD.,No assessment or comparison of genome-wide DNA methylation profiles in the airway and parenchymal fibroblasts from individuals with and without COPD has been undertaken.,These data provide valuable insight into the molecular mechanisms contributing to COPD and the differing pathologies of small airways disease and emphysema in COPD.,Genome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in the airway (non-COPD n = 8, COPD n = 7) and parenchymal fibroblasts (non-COPD n = 17, COPD n = 29) isolated from individuals with and without COPD.,Targeted gene expression was assessed by qPCR in matched RNA samples.,Differentially methylated DNA regions were identified between cells isolated from individuals with and without COPD in both airway and parenchymal fibroblasts.,Only in parenchymal fibroblasts was differential DNA methylation associated with differential gene expression.,A second analysis of differential DNA methylation variability identified 359 individual differentially variable CpG sites in parenchymal fibroblasts.,No differentially variable CpG sites were identified in the airway fibroblasts.,Five differentially variable-methylated CpG sites, associated with three genes, were subsequently assessed for gene expression differences.,Two genes (OAT and GRIK2) displayed significantly increased gene expression in cells isolated from individuals with COPD.,Differential and variable DNA methylation was associated with COPD status in the parenchymal fibroblasts but not airway fibroblasts.,Aberrant DNA methylation was associated with altered gene expression imparting biological function to DNA methylation changes.,Changes in DNA methylation are therefore implicated in the molecular mechanisms underlying COPD pathogenesis and may represent novel therapeutic targets.,The online version of this article (10.1186/s13148-018-0464-5) contains supplementary material, which is available to authorized users. | Goblet cell metaplasia, a common feature of chronic obstructive pulmonary disease (COPD), is associated with mucus hypersecretion which contributes to the morbidity and mortality among patients.,Transcription factors SAM-pointed domain-containing Ets-like factor (SPDEF) and forkhead box protein A2 (FOXA2) regulate goblet cell differentiation.,This study aimed to (1) investigate DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation and (2) compare this in airway epithelial cells from patients with COPD and controls during mucociliary differentiation.,To assess DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation, primary airway epithelial cells, isolated from trachea (non-COPD controls) and bronchial tissue (patients with COPD), were differentiated by culture at the air-liquid interface (ALI) in the presence of cytokine interleukin (IL)-13 to promote goblet cell differentiation.,We found that SPDEF expression was induced during goblet cell differentiation, while FOXA2 expression was decreased.,Importantly, CpG number 8 in the SPDEF promoter was hypermethylated upon differentiation, whereas DNA methylation of FOXA2 promoter was not changed.,In the absence of IL-13, COPD-derived ALI-cultured cells displayed higher SPDEF expression than control-derived ALI cultures, whereas no difference was found for FOXA2 expression.,This was accompanied with hypomethylation of CpG number 6 in the SPDEF promoter and also hypomethylation of CpG numbers 10 and 11 in the FOXA2 promoter.,These findings suggest that aberrant DNA methylation of SPDEF and FOXA2 is one of the factors underlying mucus hypersecretion in COPD, opening new avenues for epigenetic-based inhibition of mucus hypersecretion.,The online version of this article (doi:10.1186/s13148-017-0341-7) contains supplementary material, which is available to authorized users. | 1 |
Reduced physical activity is an important feature of Chronic Obstructive Pulmonary Disease (COPD).,Various activity monitors are available but their validity is poorly established.,The aim was to evaluate the validity of six monitors in patients with COPD.,We hypothesized triaxial monitors to be more valid compared to uniaxial monitors.,Thirty-nine patients (age 68±7years, FEV1 54±18%predicted) performed a one-hour standardized activity protocol.,Patients wore 6 monitors (Kenz Lifecorder (Kenz), Actiwatch, RT3, Actigraph GT3X (Actigraph), Dynaport MiniMod (MiniMod), and SenseWear Armband (SenseWear)) as well as a portable metabolic system (Oxycon Mobile).,Validity was evaluated by correlation analysis between indirect calorimetry (VO2) and the monitor outputs: Metabolic Equivalent of Task [METs] (SenseWear, MiniMod), activity counts (Actiwatch), vector magnitude units (Actigraph, RT3) and arbitrary units (Kenz) over the whole protocol and slow versus fast walking.,Minute-by-minute correlations were highest for the MiniMod (r = 0.82), Actigraph (r = 0.79), SenseWear (r = 0.73) and RT3 (r = 0.73).,Over the whole protocol, the mean correlations were best for the SenseWear (r = 0.76), Kenz (r = 0.52), Actigraph (r = 0.49) and MiniMod (r = 0.45).,The MiniMod (r = 0.94) and Actigraph (r = 0.88) performed better in detecting different walking speeds.,The Dynaport MiniMod, Actigraph GT3X and SenseWear Armband (all triaxial monitors) are the most valid monitors during standardized physical activities.,The Dynaport MiniMod and Actigraph GT3X discriminate best between different walking speeds. | Fatigue is a distressing, complex, multidimensional sensation common in individuals with chronic obstructive pulmonary disease (COPD).,While fatigue negatively impacts functional performance and quality of life, there has been little study of the fatigue that affects participants in pulmonary rehabilitation programs.,The purpose of this study was to examine the emotional, behavioral, cognitive, and physical dimensions of fatigue and their relationships to dyspnea, mental health, sleep, and physiologic factors.,A convenience sample of 42 pulmonary rehabilitation participants with COPD completed self-report questionnaires which measured dimensions of fatigue using the Multidimensional Fatigue Inventory, anxiety and depression using the Hospital Anxiety and Depression Scale, and sleep quality using the Pittsburgh Sleep Quality Index.,Data on other clinical variables were abstracted from pulmonary rehabilitation program health records.,Almost all (95.3%) participants experienced high levels of physical fatigue.,High levels of fatigue were also reported for the dimensions of reduced activity (88.1%), reduced motivation (83.3%), mental fatigue (69.9%), and general fatigue (54.5%).,Close to half (42.9%) of participants reported symptoms of anxiety, while almost one quarter (21.4%) reported depressive symptoms.,Age was related to the fatigue dimensions of reduced activity (ρ = 0.43, P < 0.01) and reduced motivation (ρ = 0.31, P < 0.05).,Anxiety was related to reduced motivation (ρ = −0.47, P < 0.01).,Fatigue was not associated with symptoms of depression, sleep quality, gender, supplemental oxygen use, smoking status, or Medical Research Council dyspnea scores.,Fatigue (particularly the physical and reduced motivation dimensions of fatigue) was experienced by almost all participants with COPD attending this pulmonary rehabilitation program.,Fatigue affected greater proportions of participants than either anxiety or depression.,The high prevalence of fatigue may impact on enrolment, participation, and attrition in pulmonary rehabilitation programs.,Further investigation of the nature, correlates, and impact of fatigue in this population is required. | 1 |
Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD).,However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD.,We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium.,In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera.,Haemophilus formed only 3% of the healthy microbiome.,In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively.,There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history.,Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001).,The healthy and COPD sputum microbiomes are distinct and independent of smoking history.,Our results underline the important role for Gammaproteobacteria in COPD. | Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.,We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations.,Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center.,Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation.,Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators.,Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters.,The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology.,Three exacerbation biologic clusters were identified.,Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria.,Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes.,Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes.,A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD.,The sputum mediator and microbiome profiles were distinct between clusters. | 1 |
Treatment of chronic diseases such as chronic obstructive pulmonary disease (COPD) is complicated by the presence of comorbidities.,The objective of this analysis was to estimate the prevalence of comorbidity in COPD using nationally-representative data.,This study draws from a multi-year analytic sample of 14,828 subjects aged 45+, including 995 with COPD, from the National Health and Nutrition Examination Survey (NHANES), 1999-2008.,COPD was defined by self-reported physician diagnosis of chronic bronchitis or emphysema; patients who reported a diagnosis of asthma were excluded.,Using population weights, we estimated the age-and-gender-stratified prevalence of 22 comorbid conditions that may influence COPD and its treatment.,Subjects 45+ with physician-diagnosed COPD were more likely than subjects without physician-diagnosed COPD to have coexisting arthritis (54.6% vs.,36.9%), depression (20.6% vs.,12.5%), osteoporosis (16.9% vs.,8.5%), cancer (16.5% vs.,9.9%), coronary heart disease (12.7% vs.,6.1%), congestive heart failure (12.1% vs.,3.9%), and stroke (8.9% vs.,4.6%).,Subjects with COPD were also more likely to report mobility difficulty (55.6% vs.,32.5%), use of >4 prescription medications (51.8% vs.,32.1), dizziness/balance problems (41.1% vs.,23.8%), urinary incontinence (34.9% vs.,27.3%), memory problems (18.5% vs.,8.8%), low glomerular filtration rate (16.2% vs.,10.5%), and visual impairment (14.0% vs.,9.6%).,All reported comparisons have p < 0.05.,Our study indicates that COPD management may need to take into account a complex spectrum of comorbidities.,This work identifies which conditions are most common in a nationally-representative set of COPD patients (physician-diagnosed), a necessary step for setting research priorities and developing clinical practice guidelines that address COPD within the context of comorbidity. | COPD is currently the fourth cause of morbidity and mortality in the developed world.,Patients with COPD experience a progressive deterioration and disability, which lead to a worsening in their health-related quality of life (HRQoL).,The aim of this work is to assess the Health-Related Quality of Life (HRQoL) of patients with stable COPD followed in primary care and to identify possible predictors of disease.,It is a multicenter, epidemiological, observational, descriptive study.,Subjects of both sexes, older than 40 years and diagnosed of COPD at least 12 months before starting the study were included.,Sociodemographic data, severity of disease, comorbidity, and use of health resources in the previous 12 months were collected.,All patients were administered a generic quality-of-life questionnaire, the SF-12, that enables to calculate two scores, the physical (PCS-12) and the mental (MCS-12) component summary scores.,10,711 patients were evaluated (75.6% men, 24.4% women), with a mean age of 67.1 years (SD 9.66).,The mean value of FEV1 was 35.9 ± 10.0%.,Mean PCS-12 and MCS-12 scores were 36.0 ± 9.9 and 48.3 ± 10.9, respectively.,Compared to the reference population, patients with COPD had a reduction of PCS-12, even in mild stages of the disease.,The correlation with FEV1 was higher for PCS-12 (r = 0.38) than for MCS-12 (r = 0.12).,Predictors for both HRQoL components were sex, FEV1, use of oxygen therapy, and number of visits to emergency rooms and hospital admissions.,Other independent predictors of PCS-12 were age, body mass index and educational level.,Patients with stable COPD show a reduction of their HRQoL, even in mild stages of the disease.,The factors determining the HRQoL include sex, FEV1, use of oxygen therapy, and number of visits to emergency rooms and hospital admissions. | 1 |
Care guidelines for people with chronic obstructive pulmonary disease (COPD) recommend an integrated approach for holistic, flexible, and tailored interventions.,Continuity of care is also emphasised.,However, many patients with COPD experience fragmented care.,Discontinuities in healthcare and related social services are likely to result in disjointed rather than integrated care which can negatively affect patient health outcomes.,The purpose of this qualitative study was to improve our understanding of, and how, contextual features pertaining to structures and processes of COPD integrated care influence delivery of care within patients’ healthcare networks.,We conducted individual interviews with 28 participants (9 patients, 16 healthcare professionals, and 3 spousal caregivers).,Participants were recruited through the lung clinic at a city hospital in western Canada.,We employed a social network paradigm to analyse and interpret the data.,The analysis revealed an overarching theme of fragmented COPD care with two sub-themes: (1) Funding shortfalls and availability of resources, and (2) Dis(mis)connected communication pathways.,The overarching theme depicts variations, delays, and discontinuities in patient care.,The sub-themes describe how macro level influences and meso level shortfalls were perceived to influence the availability of respiratory care resources that contributed to fragmented COPD care.,Employing a social network lens drew particular attention to family physicians’ pivotal role in delivering community-based COPD care.,While an integrated approach to care is recommended by care guidelines, institutional and organizational structures and processes, such as financial and communication structures, may inhibit delivery of integrated care.,Thus, macro and meso level structures and processes have the potential to shape patient care by constraining family physicians’ purposive and communication actions necessary for facilitating an integrated distributed approach to care.,We propose a context of care which fosters a context for family physicians’ delivery of patient-centered care.,Integrated care delivery may improve patients’ wellbeing and alleviate financial constraints on the healthcare system. | Chronic obstructive pulmonary disease (COPD) is a public health problem.,Interprofessional collaboration and health promotion interventions such as exercise training, education, and behaviour change are cost effective, have a good effect on health status, and are recommended in COPD treatment guidelines.,There is a gap between the guidelines and the healthcare available to people with COPD.,The aim of this study was to increase the understanding of what shapes the provision of primary care services to people with COPD and what healthcare is offered to them from the perspective of healthcare professionals and managers.,The study was conducted in primary care in a Swedish county council during January to June 2015.,A qualitatively driven mixed methods design was applied.,Qualitative and quantitative findings were merged into a joint analysis.,Interviews for the qualitative component were performed with healthcare professionals (n = 14) from two primary care centres and analysed with qualitative content analysis.,Two questionnaires were used for the quantitative component; one was answered by senior managers or COPD nurses at primary care centres (n = 26) in the county council and the other was answered by healthcare professionals (n = 18) at two primary care centres.,The questionnaire data were analysed with descriptive statistics.,The analysis gave rise to the overarching theme building COPD care on shaky ground.,This represents professionals driven to build a supportive COPD care on ‘shaky’ organisational ground in a fragmented and non-compliant healthcare organisation.,The shaky ground is further represented by uninformed patients with a complex disease, which is surrounded with shame.,The professionals are autonomous and pragmatic, used to taking responsibility for their work, and with limited involvement of the management.,They wish to provide high quality COPD care with interprofessional collaboration, but they lack competence and are hindered by inadequate routines and lack of resources.,There is a gap between COPD treatment guidelines and the healthcare that is provided in primary care.,To facilitate implementation of the guidelines several actions are needed, such as further training for professionals, additional resources, and improved organisational structure for interprofessional collaboration and patient education.,The online version of this article (doi:10.1186/s12913-017-2393-y) contains supplementary material, which is available to authorized users. | 1 |
Myeloid-derived suppressor cells (MDSCs) are present in the human lung microenvironment, and they may be involved in the local inflammatory process in chronic obstructive pulmonary disease (COPD).,Chronic inflammation in COPD may induce immunogenic cell death of structural airway cells, causing the release of damage-associated molecular patterns (DAMPs).,DAMPs may activate the innate and adaptive immune system.,The relationship between MDSCs and DAMPs in COPD is poorly described in the available literature.,Objectives.,(1) Assessment of MDSC percentage and DAMP concentration in bronchoalveolar lavage fluid (BALF) and peripheral blood.,(2) Analysis of the relationship between MDSC percentage and chosen DAMPs.,Patients and Methods.,30 COPD patients were included.,Using monoclonal antibodies directly conjugated with fluorochromes in flow cytometry, MDSCs were assessed in BALF and peripheral blood.,The concentration of DAMPs was estimated using sandwich ELISA.,Using the Bradford method, the total protein concentrations were evaluated.,Results.,The percentage of MDSCs among MC in BALF correlated well with the concentration of defensin and heat shock protein 27.,Assessing the percentage of MDSCs among all leukocytes in BALF, we revealed a significant correlation with the concentration of defensin, hyaluronic acid, and surfactant protein A.,No dependencies occurred between DAMPs and MDSCs in peripheral blood.,Conclusion.,MDSCs and DAMPs occur in the COPD patient lung microenvironment.,Significant correlations between them found in BALF may indicate their influence on the local inflammatory process in COPD.,These relationships allow better understanding of the inflammatory process in COPD. | Transforming growth factor-beta1 (TGF-β1) is a multipotential cytokine with angiogenic activity.,There are only limited data about its role in airway remodeling in COPD.,We have previously shown that the reticular basement membrane (Rbm) is hypervascular in the airways of current smokers either with or without chronic obstructive pulmonary disease (COPD).,This study evaluated TGF-β1 immunostaining in the Rbm and its relationship to vascularity in smokers with or without COPD.,Bronchial biopsies from 15 smokers with normal lung function, 19 current and 14 ex-smokers with COPD were immunostained for TGF-β1 antibody and compared to 17 healthy controls.,The percentage area of tissue and also number and area of vessels staining positively for TGF-β1 were measured and compared between groups.,Some bronchial biopsies from current smoking COPD subjects were also stained for phosphorylated (active) Smad2/3.,Epithelial TGF- β1 staining was not different between COPD current smokers and normal controls.,TGF-β1 stained vessels in the Rbm were increased in smokers with normal lung function, current smoking COPD and ex-smokers with COPD compared to controls [median (range) for number of vessels/mm Rbm 2.5 (0.0-12.7), 3.4 (0.0-8.1) and 1.0 (0.0-6.3) vs.,0.0 (0.0-7.0), p<0.05].,Percentage of vessels stained was also increased in these clinical groups.,Preliminary data suggest that in current smoking COPD subjects endothelial cells and cells in the Rbm stain positively for phosphorylated Smad2/3 suggesting TGF-β1 is functionally active in this situation.,Vessel-associated TGF-β1 activity is increased in the bronchial Rbm in smokers and especially those with COPD. | 1 |
NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD).,The GLycopyrronium bromide in COPD airWays clinical Study 2 (GLOW2) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks.,Patients were randomised 2:1:1 to NVA237 50 μg, placebo or open-label tiotropium 18 μg for 52 weeks.,Primary end-point was trough forced expiratory volume in 1 s (FEV1) at 12 weeks.,1,066 patients were randomised, 810 completed the study.,At week 12, trough FEV1 increased significantly by 97 mL with NVA237 (95% CI 64.6-130.2; p<0.001) and 83 mL with tiotropium (95% CI 45.6-121.4; p<0.001).,Compared with placebo, NVA237 produced significant improvements in dyspnoea (Transition Dyspnoea Index at week 26; p=0.002) and health status (St George's Respiratory Questionnaire at week 52; p<0.001).,NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34% (p=0.001) and the use of rescue medication (p=0.039), versus placebo.,NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes.,Safety profiles were similar across groups.,NVA237 50 μg provided significant improvements in lung function, dyspnoea, health status, exacerbations and rescue medication use, versus placebo, and was comparable to tiotropium.,NVA237 can potentially be an alternative choice of LAMA for COPD patients. | NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD).,The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.,Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled.,Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry.,The primary outcome measure was trough FEV1 at Week 12.,A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270).,Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001).,Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26.,FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints.,Transition dyspnoea index focal scores and St.,George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and-2.81 (p = 0.004), respectively.,NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo.,NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.,Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.,ClinicalTrials.gov: NCT01005901 | 1 |
Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD).,To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function.,We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11). | There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD).,The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1-2% of individuals with COPD.,We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study.,The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population.,Logistic regression models with adjustments of covariates were used to analyze the case-control populations.,Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations.,Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study.,They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730).,Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations.,The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%.,The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels.,Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429).,The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD.,CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer. | 1 |
Stenotrophomonas maltophilia is an emerging Gram-negative MDR bacteria.,In patients with chronic obstructive pulmonary disease (COPD), it is mostly found in those with severe exacerbation of COPD requiring mechanical ventilation.,The significance of S. maltophilia when detected in the sputum of ambulatory patients with COPD is uncertain.,To access the prevalence and the risk factors of the presence of S. maltophilia in the sputum of ambulatory patients with COPD and to determine whether it was associated with prognosis.,All consecutive unselected ambulatory patients with GOLD 2-4 COPD were recruited between January 2017 and September 2019 from the COPD clinic of a tertiary care hospital.,Presence of S. maltophilia was defined by a positive sputum culture for S. maltophilia.,Demographics, COPD characteristics, comorbidities and known predisposing risk factors associated with S. maltophilia were collected from medical records.,S. maltophilia was detected in the sputum of 41/393 (10%) of study participants.,Comorbidities, exacerbation, use of oral steroids and carbapenems in the previous year were risk factors for the presence of S. maltophilia.,After adjusting on confounding factors associated with mortality including age, Charlson comorbidity index and FEV1, S. maltophilia was significantly associated with mortality (adjusted hazard ratio 2.3; 95% CI 1.1-4.9).,In the current study, we found that 10% of ambulatory patients with GOLD 2-4 COPD had S. maltophilia detected in their sputum.,In addition, S. maltophilia may represent a marker of overall morbidity in patients with COPD. | Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD.,To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes.,We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene.,We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes.,The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies.,Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated.,We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis.,Subtypes of COPD have distinct bacterial compositions and stabilities over time.,Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future.,This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient.,Results, NCT01360398. | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the most common chronic illnesses in the world.,The disease encompasses emphysema, chronic bronchitis, and small airway obstruction and can be caused by environmental exposures, primarily cigarette smoking.,Since only a small subset of smokers develop COPD, it is believed that host factors interact with the environment to increase the propensity to develop disease.,The major pathogenic factors causing disease include infection and inflammation, protease and antiprotease imbalance, and oxidative stress overwhelming antioxidant defenses.,In this review, we will discuss the major environmental and host sources for oxidative stress; discuss how oxidative stress regulates chronic bronchitis; review the latest information on genetic predisposition to COPD, specifically focusing on oxidant/antioxidant imbalance; and review future antioxidant therapeutic options for COPD.,The complexity of COPD will necessitate a multi-target therapeutic approach.,It is likely that antioxidant supplementation and dietary antioxidants will have a place in these future combination therapies. | Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages.,The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.,19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods.,Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP.,The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of α-actin and desmin.,Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically.,The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.,Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta.,Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure.,Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure.,Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces.,Lung expression of eNOS was decreased in animals exposed to cigarette smoke.,In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS.,These changes appear after 3 months of exposure and precede the development of pulmonary emphysema. | 1 |
The present study has shown that the bronchodilator effectiveness of β-adrenoceptor agonists is diminished in CS and influenza A virus-induced lung disease and has identified the need for the development of novel bronchodilators for these diseases.,β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited.,In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A.,Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1).,CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression.,This impaired relaxation was restored by day 12 in the absence of further CS exposure.,In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained.,CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered.,The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms.,In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators. | 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). | 1 |
COPD has been identified as an etiology or related disease of bronchiectasis, and bronchiectasis has been classified as a comorbidity of COPD.,In this study, we investigated the prevalence of bronchiectasis in different phenotypes of COPD subjects and the correlation between bronchiectasis and different phenotypes, especially emphysema.,COPD patients were recruited from April 2012 to December 2015.,The presence of bronchiectasis and related information were statistically analyzed.,COPD subjects were separated into subgroups in two ways: COPD with and without bronchiectasis groups and emphysema-predominant (emphysema index, EI≥9.9%) and non-emphysema-predominant (EI<9.9%) groups.,In total, 1,739 COPD patients were incorporated into the study, among which 140 cases (8.1%) were accompanied with radiological bronchiectasis.,COPD patients with concomitant bronchiectasis presented worse pulmonary function (FEV1% predicted, P<0.001), higher EI (15.0% vs 13.4%, P<0.001), and higher proportion of pulmonary hypertension and cor pulmonale (6.4% vs 2.4%, P=0.005 and 23.6% vs 16.1%, P=0.022) than patients without bronchiectasis.,Of all the COPD patients, 787 with EI data were divided into emphysema-predominant (n=369) and non-emphysema-predominant groups (n=418).,The proportion of bronchiectasis was 16.5% and 10.3% (P=0.01), respectively.,Severity of bronchiectasis increased as the degree of airflow limitation (r=−0.371, P<0.001) and emphysema increased (r=0.226, P=0.021).,After adjusting confounding factors, FEV1% predicted (OR, 1.636; 95% CI, 1.219-2.197; P=0.001) and EI (OR, 1.993; 95% CI, 1.199-3.313; P=0.008) were significantly related with the presence of bronchiectasis in COPD patients.,The proportion of bronchiectasis is higher in emphysema-predominant COPD subjects.,Emphysema measured by EI and FEV1% predicted are independent predictors for bronchiectasis in COPD subjects, while the underlying mechanism deserves further investigation. | 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. | 1 |
Symptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk still have disease instability, which can be improved with better bronchodilation.,We evaluated two long-acting bronchodilators individually and in combination on reducing exacerbation risk and the potential impact of concurrent medication in these patients.,Integrated post hoc intent-to-treat (ITT) analysis of data from two large 24-week, randomized placebo (PBO)-controlled trials (NCT01313637, NCT01313650).,Symptomatic patients with moderate-to-very-severe COPD with/without an exacerbation history were randomized (2:3:3:3) to once-daily: PBO, umeclidinium/vilanterol (UMEC/VI 62.5/25 μg [NCT01313650] or 125/25 μg [NCT01313637]), UMEC (62.5 [NCT01313650] or 125 μg [NCT01313637]) or VI (25 μg) via the ELLIPTA inhaler.,Medication subgroups were segmented by treatment status at screening: a) maintenance-naïve or on maintenance medications, b) inhaled corticosteroid [ICS]-free or ICS-treated, c) low or high albuterol use based on median run-in use (< 3.6 or ≥ 3.6 puffs/day).,Time to first moderate/severe exacerbation (Cox proportional hazard model) and change from baseline in trough forced expiratory volume in 1 s (FEV1; mixed model repeated measures) were analyzed.,Safety was also assessed.,Of 3021 patients (ITT population; UMEC/VI: n = 816; UMEC: n = 825; VI: n = 825; PBO: n = 555), 36% had a recent exacerbation history, 33% were maintenance-naïve, 51% were ICS-free.,Mean baseline albuterol use was 5.1 puffs/day.,In the ITT population, UMEC/VI, UMEC, and VI reduced the risk of a first exacerbation versus PBO by 58, 44, and 39%, respectively (all p < 0.05).,UMEC/VI provided significant risk reductions versus PBO in all subgroups.,VI had no benefit versus PBO in maintenance-naïve, ICS-free, and low rescue use patients and was significantly less effective than UMEC/VI in these subgroups.,UMEC had no significant benefit versus PBO in maintenance-naïve and ICS-free patients.,All bronchodilators improved FEV1 versus PBO, and UMEC/VI significantly improved FEV1 versus both monotherapies across all populations studied (p < 0.05).,All bronchodilators were similarly well tolerated.,Results suggest that UMEC/VI reduces exacerbation risk versus PBO more consistently across medication subgroups than UMEC or VI, particularly in patients with no/low concurrent medication use.,Confirmed prospectively, these findings may support first-line use of dual bronchodilation therapy in symptomatic low-risk patients.,The online version of this article (10.1186/s12931-019-1027-9) contains supplementary material, which is available to authorized users. | Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD.,In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients.,Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC).,Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD.,Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George’s Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation.,In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1.,Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001).,With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036).,These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD.,Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting β2-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population. | 1 |
The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication.,Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD.,Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients.,Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers.,The effects of disease severity, age and gender on PIF rate were also evaluated.,This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years.,No active drug or placebo was administered during the study.,The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece.,For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis.,A paired t-test was performed to compare mean PIFs between each combination of devices.,In total, 97 COPD patients were enrolled and completed the study.,The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population.,A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders.,Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers.,These results were similar irrespective of patients’ COPD severity, age or gender.,The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.,The online version of this article (10.1186/s12890-018-0662-0) contains supplementary material, which is available to authorized users. | Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent.,Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function.,The factors affecting their inspiratory flows through inhalers are unclear.,To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity.,Flow-volume spirometry was performed in 93 COPD patients.,Maximum PIF rates were recorded through an empty Easyhaler® (PIFEH; Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher.,The mean PIFEH was 54 L/min (range 26-95 L/min) with a coefficient of variation of 7%.,All but two patients were able to generate a flow of ≥28 L/min.,In a general linear model, the independent determinants for PIFEH were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV1) expressed as percent predicted was not a significant factor.,The regression model accounted only for 18% of the variation in PIFEH.,In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction.,Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways. | 1 |
Pulmonary rehabilitation (PR) may improve respiratory symptoms and skeletal muscle strength in patients with COPD.,We aimed to evaluate changes in ultrasound (US) measurements of diaphragmatic mobility and thickness after PR in COPD patients and to test its correlation with PR outcomes.,Twenty-five COPD patients were enrolled and underwent a diaphragm US assessment before and after a 12-week PR program.,We found a correlation between the intraindividual percentage of change in the diaphragmatic length of zone of apposition at functional residual capacity (ΔLzapp%) and the change in 6-minute walking distance (6MWD) after PR (rho=0.49, P=0.02).,ΔLzapp% was significantly higher in patients with improved 6MWD and COPD Assessment Test (CAT) score (mean rank=12.03±2.57 vs 6.88±4.37; P=0.02).,A ΔLzapp% of ≥10% was able to discriminate among patients with improved 6MWD, with a sensitivity of 83% and a specificity of 74%.,The area under the receiver operating characteristic curve for ΔLzapp% was 0.83.,A cutoff value of ≥9% of ΔLzapp% had a positive predictive value in discriminating a reduction in ≥2 points of CAT score after PR, with a sensitivity and a specificity of 80% and 62%, respectively.,Diaphragm US assessment represents a useful prognostic marker of PR outcomes in COPD patients. | The use of noninvasive intermittent positive pressure ventilation (NIPPV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure remains controversial as long-term data are almost lacking.,The aim was to compare the outcome of 2-year home-based nocturnal NIPPV in addition to rehabilitation (NIPPV + PR) with rehabilitation alone (PR) in COPD patients with chronic hypercapnic respiratory failure.,Sixty-six patients could be analyzed for the two-year home-based follow-up period.,Differences in change between the NIPPV + PR and PR group were assessed by a linear mixed effects model with a random effect on the intercept, and adjustment for baseline values.,The primary outcome was health-related quality of life (HRQoL); secondary outcomes were mood state, dyspnea, gas exchange, functional status, pulmonary function, and exacerbation frequency.,Although the addition of NIPPV did not significantly improve the Chronic Respiratory Questionnaire compared to rehabilitation alone (mean difference in change between groups -1.3 points (95% CI: -9.7 to 7.4)), the addition of NIPPV did improve HRQoL assessed with the Maugeri Respiratory Failure questionnaire (-13.4% (-22.7 to -4.2; p = 0.005)), mood state (Hospital Anxiety and Depression scale -4.0 points (-7.8 to 0.0; p = 0.05)), dyspnea (Medical Research Council -0.4 points (-0.8 to -0.0; p = 0.05)), daytime arterial blood gases (PaCO2 -0.4 kPa (-0.8 to -0.2; p = 0.01); PaO2 0.8 kPa (0.0 to 1.5; p = 0.03)), 6-minute walking distance (77.3 m (46.4 to 108.0; p < 0.001)), Groningen Activity and Restriction scale (-3.8 points (-7.4 to -0.4; p = 0.03)), and forced expiratory volume in 1 second (115 ml (19 to 211; p = 0.019)).,Exacerbation frequency was not changed.,The addition of NIPPV to pulmonary rehabilitation for 2 years in severe COPD patients with chronic hypercapnic respiratory failure improves HRQoL, mood, dyspnea, gas exchange, exercise tolerance and lung function decline.,The benefits increase further with time.,ClinicalTrials.Gov (ID NCT00135538). | 1 |
COPD-related deaths are increasing in Japan, with ~5.3 million people at risk.,The SHINE was a 26-week, multicenter, randomized, double-blind, parallel-group study that evaluated safety and efficacy of indacaterol (IND)/glycopyrronium (GLY) 110/50 μg once daily (od) compared with GLY 50 μg od, IND 150 μg od, open-label tiotropium (TIO) 18 μg od, and placebo.,The primary end point was trough forced expiratory volume in 1 second (FEV1) at Week 26.,Other key end points included peak FEV1, area under the curve for FEV1 from 5 minutes to 4 hours (FEV1 AUC5 min-4 h), Transition Dyspnea Index focal score, St George’s Respiratory Questionnaire total score, and safety.,Here, we present efficacy and safety of IND/GLY in the Japanese subgroup.,Of 2,144 patients from the SHINE study, 182 (8.5%) were Japanese and randomized to IND/GLY (n=42), IND (n=41), GLY (n=40), TIO (n=40), or placebo (n=19).,Improvement in trough FEV1 from baseline was 190 mL with IND/GLY and treatment differences versus IND (90 mL), GLY (100 mL), TIO (90 mL), and placebo (280 mL) along with a rapid onset of action at Week 26.,IND/GLY showed an improvement in FEV1 AUC5 min-4 h versus all comparators (all P<0.05).,All the treatments were well tolerated and showed comparable effect on Transition Dyspnea Index focal score and St George’s Respiratory Questionnaire total score.,The effect of IND/GLY in the Japanese subgroup was consistent to overall SHINE study population.,IND/GLY demonstrated superior efficacy and comparable safety compared with its monocomponents, open-label TIO, and placebo and may be used as a treatment option for the management of moderate-to-severe COPD in Japanese patients. | In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors.,The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD) continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines.,COPD is a complex condition that has pulmonary and extrapulmonary manifestations.,These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies.,The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease.,Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient’s characteristics, together with his or her genotype, will be key to choosing the best treatment option.,At present in Japan, fixed combinations of inhaled corticosteroids (ICSs) and LABAs are frequently prescribed in the earlier stages of COPD.,However, ICSs increase the risk of pneumonia.,Notably, 10%-30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids.,Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that benefits from ICSs.,In this review, I propose one plausible approach to position ICSs and LABAs/LAMAs in clinical practice, based on both the extent of airflow obstruction and the presence of an asthma component or airway eosinophilic inflammation.,This approach is a tentative move toward personalized treatment for COPD patients, and with progress in knowledge and developments in physiology, lung imaging, medical biology, and genetics, identification of COPD phenotypes that provide prognostic and therapeutic information that can affect clinically meaningful outcomes is an urgent medical need. | 1 |
The aim of this study was to evaluate the cost-effectiveness of the long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator indacaterol/glycopyrronium (IND/GLY) as a maintenance treatment for COPD patients from the perspective of health care payer in Taiwan.,We adopted a patient-level simulation model, which included a cohort of COPD patients aged ≥40 years.,The intervention used in the study was the treatment using IND/GLY, and comparators were tiotropium or salmeterol/fluticasone combination (SFC).,Data related to the efficacy of drugs, incidence of exacerbation, and utility were obtained from clinical studies.,Direct costs were estimated from claims data based on the severity of COPD.,The cycle length was 6 months (to match forced expiratory volume in 1 second [FEV1] data), and the time horizons included 1, 3, 5, 10 years, and lifetime.,Deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the model results.,Costs were expressed in US dollars with a discount rate of 3.0%.,Compared to tiotropium and SFC, the incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY) gained of patients treated with IND/GLY were US$5,987 and US$14,990, respectively.,One-way sensitivity analysis revealed that the improvement in FEV1 provided by IND/GLY, the distribution of patients with regard to the severity of COPD, and acute exacerbation rate ratio were the key drivers behind cost-effectiveness.,Adopting a willingness to pay of US$60,000 per QALY gained as the threshold, there was a 98.7% probability that IND/GLY was cost-effective compared to tiotropium.,Similarly, there was a 99.9% probability that IND/GLY was cost-effective compared to SFC.,As a maintenance treatment for COPD, we consider the dual bronchodilator IND/GLY as a cost-effective strategy when compared to either tiotropium or SFC. | Nonadherence to medication and incorrect use of inhalers represent significant barriers to optimal disease management of patients with chronic obstructive pulmonary disease (COPD).,Thus, health care professionals (HCPs) play a critical role in educating their patients on appropriate inhaler use and in ensuring medication adherence.,However, many patients do not receive appropriate inhaler training or have not had their inhaler technique checked.,The Real-life Experience and Accuracy of inhaLer use (REAL) survey was a computer-assisted, telephonic survey consisting of 23 questions gathering real-world information on correct inhaler use, inhalation technique, device attributes, adherence, dosing accuracy, training, correct device use, ease of use, and factors that influence patient adherence in commercially available inhalers delivering COPD maintenance therapy.,All results are based on patient-reported data.,The survey was conducted between January 4, 2016 and February 2, 2016.,A total of 764 patients using various inhalers (Breezhaler® =186; Ellipta® =191; Genuair® =194; Respimat® =201) with mild to very severe COPD, with a mean ± SD age 56±9.8 years, completed the survey.,Patient self-reported adherence was significantly lower in younger patients compared to older patients (p=0.020).,Eighty-three percent of patients indicated that a demonstration (in-person) was “very helpful” versus 58% for video.,Patient preferences for training methods were as follows: demonstration of inhaler use (83%), video (58%), instructions for use (51%), and leaflet (34%).,Twenty-nine percent of patients had not been checked to see if they were using their device correctly by a HCP within the last two years.,Patients who were checked were significantly more adherent than unchecked patients (p=0.020).,The majority of the patients using Breezhaler reported either being very confident or confident of having taken a full dose, which was higher than those using Genuair, Ellipta (α=0.05), and Respimat (α=0.05).,Treatment adherence in the last 30 days was highest with Breezhaler followed by Respimat, Ellipta, and Genuair.,The REAL survey identified attributes that influenced patient adherence and optimal inhaler use.,Predictive attributes that influence patient adherence which HCPs should be aware of include age and disease severity.,Modifiable attributes which the HCP can influence include correct inhaler use training, choice of training methods, checking patient inhaler technique at subsequent visits, and device selection.,Inhalers are integral in the effective management of patients with COPD; it is therefore important that patients use the inhaler correctly and have full confidence in the dosage. | 1 |
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