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c-Kit + lung stem cells have been described in the human healthy lung.,Their potential relation with smoking and/or chronic obstructive pulmonary disease (COPD) is unknown.,We characterized and compared c-Kit+ cells in lung tissue of 12 never smokers (NS), 15 smokers with normal spirometry (S) and 44 COPD patients who required lung resectional surgery.,Flow cytometry (FACS) was used to characterize c-Kit+ cells in fresh lung tissue disaggregates, and immunofluorescence (IF) for further characterization and to determine their location in OCT- embedded lung tissue.,We identified 4 c-Kit+ cell populations, with similar proportions in NS, S and COPD: (1) By FACS, c-Kithigh/CD45+ cells (4.03 ± 2.97% (NS), 3.96 ± 5.30% (S), and 5.20 ± 3.44% (COPD)).,By IF, these cells were tryptase+ (hence, mast cells) and located around the airways; (2) By IF, c-Kitlow/CD45+/triptase- (0.07 ± 0.06 (NS), 0.03 ± 0.02 (S), and 0.06 ± 0.07 (COPD) cells/field), which likely correspond to innate lymphoid cells; (3) By FACS, c-Kitlow/CD45-/CD34+ (0.95 ± 0.84% (NS), 1.14 ± 0.94% (S) and 0.95 ± 1.38% (COPD)).,By IF these cells were c-Kitlow/CD45-/CD31+, suggesting an endothelial lineage, and were predominantly located in the alveolar wall; and, (4) by FACS, an infrequent c-Kitlow/CD45-/CD34- population (0.09 ± 0.14% (NS), 0.08 ± 0.09% (S) and 0.08 ± 0.11% (COPD)) compatible with a putative lung stem cell population.,Yet, IF failed to detect them and we could not isolate or grow them, thus questioning the existence of c-Kit+ lung stem-cells.,The adult human lung contains a mixture of c-Kit+ cells, unlikely to be lung stem cells, which are independent of smoking status and/or presence of COPD.,The online version of this article (10.1186/s12890-018-0688-3) contains supplementary material, which is available to authorized users. | Alveolar macrophages (AMs) are equipped with innate immune receptors such as toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4).,In primary bronchial epithelial cells, exposure of toll-like receptor (TLR) ligands or tumor necrosis factor-alpha (TNF-α) increased TLR2 mRNA expression and reduced interleukin-8 (IL-8) release when coincubated with glucocorticosteroids.,The aim of this study was to compare TLR2 and TLR4 expression levels and the effect of a glucocorticosteroid after stimulation with TLR ligands on AMs from smokers with and without COPD compared with the healthy controls.,Bronchoalveolar lavage was performed, and AMs were isolated from smokers with (n=10) and without COPD (n=11) and healthy controls (n=10) and stimulated ex vivo with peptidoglycan (PGN), lipopolysaccharide (LPS), or TNF-α ± budesonide (Bud).,Blocking antibodies to TLR2 or TLR4 were added before stimulation with LPS or PGN ± Bud, respectively.,The release of proinflammatory cytokine (TNF-α), chemoattractant (CXCL8), and TLR expression was analyzed by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction.,LPS, PGN, and TNF-α induced an increased release of IL-8 and TNF-α in the AMs in all the groups independent of smoking or disease.,These responses were inhibited by a glucocorticosteroid (Bud) in all the three groups, except PGN-induced IL-8 secretion in smokers without COPD.,Bud increased TLR2 expression in the healthy controls and smokers without COPD.,Costimulation of TLR ligands and Bud significantly enhanced TLR2 mRNA expression in both groups of smokers compared with TLR ligands alone.,In smokers, costimulation with PGN and Bud significantly increased TLR2 expression when compared with Bud alone.,On stimulation with the TLR4 agonist, LPS downregulated TLR4 mRNA expression in all the three groups.,The combination of glucocorticosteroids with TLR ligands can increase TLR2 expression, thereby improving host defense in smokers.,Also this combination can decrease the secretion of proinflammatory cytokines and chemokines as an anti-inflammatory response.,Our findings indicate that glucocorticosteroid therapy strengthens immune defense pathways, which may have implication during exacerbation caused by microorganisms. | 1 |
It is unclear whether procalcitonin (PCT) is correlated with noninvasive ventilation (NIV) failure.,This retrospective case-control study aimed to compare PCT levels, C-reactive protein (CRP) levels, and PaCO2 in patients (05/2014-03/2015 at the Harrison International Peace Hospital, China) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and NIV failure/success.,This was a retrospective case-control study of patients with AECOPD who required NIV between May 2014 and March 2015.,All consecutive patients with AECOPD admitted at the Department of Critical Care Medicine and transferred from the general ward were included in the study.,Hemogram, PCT, erythrocyte sedimentation rate (ESR), arterial blood gas (ABG), and CRP levels were measured ≤1 hour before NIV was used.,NIV was considered to have failed if at least one of the following criteria was met: cardiac arrest or severe hemodynamic instability; respiratory arrest or gasping; mask intolerance; difficulty in clearing bronchial secretions; or worsening of ABGs or sensorium level during NIV.,The factors associated with NIV failure were determined.,A total of 376 patients were included: 286 with successful NIV and 90 wither NIV failure.,The multivariate analysis showed that PCT (OR = 2.0, 95%CI: 1.2-3.2, P = .006), CRP (OR = 1.2, 95%CI: 1.1-1.3, P < .001), and PaCO2 (OR = 1.1, 95%CI: 1.1-1.2, P < .001) ≤1 hour before NIV were independently associated with NIV failure.,The optimal cutoff were 0.31 ng/mL for PCT (sensitivity, 83.3%; specificity, 83.7%), 15.0 mg/mL for CRP (sensitivity, 75.6%; specificity, 93.0%), and 73.5 mm Hg for PaCO2 (sensitivity, 71.1%; specificity, 100%).,The area under the curve (AUC) was 0.854 for PCT, 0.849 for CRP, and 0.828 for PaCO2.,PCT, CRP, and PaCO2 were used to obtain a combined prediction factor, which achieved an AUC of 0.978 (95%CI: 0.961-0.995).,High serum PCT, CRP, and PaCO2 levels predict NIV failure for patients with AECOPD.,The combination of these three parameters might enable even more accurate prediction. | Noninvasive ventilation (NIV) reduces the rate of endotracheal intubation (ETI) and overall mortality in severe acute exacerbation of COPD (AECOPD) with acute respiratory failure and is increasingly applied in respiratory intermediate care units.,However, inadequate patient selection and incorrect management of NIV increase mortality.,We aimed to identify factors that predict the outcome of NIV in AECOPD.,Also, we looked for factors that influence ventilator settings and duration.,A prospective cohort study was undertaken in a respiratory intermediate care unit in an academic medical center between 2016 and 2017.,Age, BMI, lung function, arterial pH and pCO2 at admission (t0), at 1-2 h (t1) and 4-6 h (t2) after admission, creatinine clearance, echocardiographic data (that defined left heart dysfunction), mean inspiratory pressure during the first 72 h (mIPAP-72 h) and hours of NIV during the first 72 h (dNIV-72 h) were recorded.,Main outcome was NIV failure (i.e., ETI or in-hospital death).,Secondary outcomes were in-hospital mortality, length of stay (LOS), duration of NIV (days), mIPAP-72 h, and dNIV-72 h.,We included 89 patients (45 male, mean age 67.6 years) with AECOPD that required NIV.,NIV failure was 12.4%, and in-hospital mortality was 11.2%.,NIV failure was correlated with days of NIV, LOS, in-hospital mortality (p < 0.01), and kidney dysfunction (p < 0.05).,In-hospital mortality was strongly associated with days of NIV (OR 1.27, 95%CI: 1.07-1.5, p < 0.01) and with FEV1 (p < 0.05).,All other investigated parameters (including left heart dysfunction, dNIV-72 h, mIPAP-72 h, pH, etc.) did not influence NIV failure or mortality. dNIV-72 h and days of NIV were independent predictors of LOS (p < 0.01).,Regarding the secondary outcomes, left heart dysfunction and pH at 1-2 h independently predicted NIV duration (dNIV-72 h, p < 0.01), while BMI and baseline pCO2 predicted NIV settings (mIPAP-72 h, p < 0.01).,In-hospital mortality and NIV failure were not influenced by BMI, left heart dysfunction, age, nor by arterial blood gas values in the first 6 h of NIV.,Patients with severe acidosis and left heart dysfunction required prolonged use of NIV.,BMI and pCO2 levels influence the NIV settings in AECOPD regardless of lung function. | 1 |
Chronic obstructive pulmonary disease (COPD) and heart failure (HF) often coexist in patients.,Many studies have explored the short-term and long-term outcomes of patients with comorbid COPD and HF; however, there have been discrepancies in their findings.,In this systematic review, MEDLINE and Embase will be searched using a prespecified search strategy.,Randomised controlled trials and studies conducted in the general population that employ analytical or descriptive (longitudinal or case-control) study designs that report odds ratios (ORs), hazard ratios (HRs), or risk ratios (RRs) of mortality or hospitalisation, comparing patients with comorbid COPD and HF with patients with just COPD, will be selected.,Screening by title and abstract, then full-text screening will be conducted by two reviewers.,The Population, Exposure, Comparator, Outcomes, Study (PECOS) characteristics framework will be used to systemise the data extraction from selected studies.,Study quality will be assessed using an adapted version of the Newcastle-Ottawa risk of bias tool.,Data extraction and the risk of bias will also be conducted by two reviewers.,Given sufficient homogeneity of selected studies, a meta-analysis will be conducted.,Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria will be used to assess the quality of cumulative evidence.,With this review, we hope to improve the understanding of clinical outcomes of patients with comorbid COPD and HF.,We intend to publish the results of our review in a peer-reviewed journal and to present our findings at national and international meetings and conferences.,CRD42018089534 | Non-cardiovascular comorbidities are recognised as independent prognostic factors in selected heart failure (HF) populations, but the evidence on non-selected HF and how comorbid disease severity and change impacts on outcomes has not been synthesised.,We identified primary HF comorbidity follow-up studies to compare the impact of non-cardiovascular comorbidity, severity and change on the outcomes of quality of life, all-cause hospital admissions and all-cause mortality.,Literature databases (Jan 1990-May 2013) were screened using validated strategies and quality appraisal (QUIPS tool).,Adjusted hazard ratios for the main HF outcomes were combined using random effects meta-analysis and inclusion of comorbidity in prognostic models was described.,There were 68 primary HF studies covering nine non-cardiovascular comorbidities.,Most were on diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and renal dysfunction (RD) for the outcome of mortality (93%) and hospital admissions (16%), median follow-up of 4 years.,The adjusted associations between HF comorbidity and mortality were DM (HR 1.34; 95% CI 1.2, 1.5), COPD (1.39; 1.2, 1.6) and RD (1.52; 1.3, 1.7).,Comorbidity severity increased mortality from moderate to severe disease by an estimated 78%, 42% and 80% respectively.,The risk of hospital admissions increased up to 50% for each disease.,Few studies or prognostic models included comorbidity change.,Non-cardiovascular comorbidity and severity significantly increases the prognostic risk of poor outcomes in non-selected HF populations but there is a major gap in investigating change in comorbid status over time.,The evidence supports a step-change for the inclusion of comorbidity severity in new HF interventions to improve prognostic outcomes.,•We synthesise the prognosis evidence on non-CVD comorbidity and severity in non-selected HF•Most studies focused on three comorbid diseases for mortality and admissions and none for QoL•COPD, diabetes and CKD increased mortality and admission risk in non-selected HF•Severity studies were few but where available, risk increased with disease severity•Comorbidity severity is important but has yet to be included in HF prognostic models,We synthesise the prognosis evidence on non-CVD comorbidity and severity in non-selected HF,Most studies focused on three comorbid diseases for mortality and admissions and none for QoL,COPD, diabetes and CKD increased mortality and admission risk in non-selected HF,Severity studies were few but where available, risk increased with disease severity,Comorbidity severity is important but has yet to be included in HF prognostic models | 1 |
While the health effects of air pollution have been an international public health concern since at least the 1950s, recent research has focused on two broad sources of air pollution, namely, biomass fuel (BMF) and motor vehicle exhaust (MVE).,Many studies have shown associations between air pollution PM and exacerbations of pre-existing COPD, but the role of air pollution PM in the development and progression of COPD is still uncertain.,The current study indicates that rats can develop pronounced COPD following chronic exposure to air pollution PM (BMF and MVE), as characterized by lung function reduction, mucus metaplasia, lung and systemic inflammation, emphysema, and small airway remodeling.,Comparative analyses demonstrate that both BMF and MVE activate similar pathogenesis that are linked to the development of COPD.,These findings also show that some differences are found in the lungs of rats exposed to BMF or MVE, which might result in different phenotypes of COPD. | Baarsma et al. report increased expression and posttranslational modification of the noncanonical ligand WNT-5A in COPD.,Fibroblast-derived WNT-5A inhibits canonical WNT-β-catenin-driven alveolar epithelial cell-mediated wound healing and transdifferentiation, and thus contributes to impaired lung regeneration and COPD pathogenesis.,Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide.,One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined.,Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated.,Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis.,We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens.,WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence.,Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro.,Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo.,Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD.,We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy. | 1 |
Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD.,We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center.,Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants.,We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2.,We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease.,We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures.,We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance.,The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data.,We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes.,We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes.,However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking.,In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies.,Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology.,These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis.,The online version of this article (10.1186/s12931-019-1032-z) contains supplementary material, which is available to authorized users. | Cigarette smoke (CS) induces lung cellular senescence that plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD).,How aging influences cellular senescence and other molecular hallmarks, and increases the risk of CS-induced damage remains unknown.,We hypothesized that aging-associated changes in lungs worsen the COPD/emphysema by CS exposure.,Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls.,CS caused a decline in lung function and affected the lung structure of both groups of mice.,No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation.,Aging per se increased lung cellular senescence and significant changes in damage-associated molecular patterns marker S100A8.,Gene transcript analysis using the nanoString nCounter showed a significant upregulation of key pro-senescence targets by CS (Mmp12, Ccl2, Cdkn2a, Tert, Wrn, and Bub1b).,Aging independently influenced lung function and structure, as well as increased susceptibility to CS-induced inflammation in emphysema, but had a negligible effect on cellular senescence.,Thus, aging solely does not contribute to the induction of cellular senescence by CS in a mouse model of COPD/emphysema. | 1 |
The underlying biological mechanisms of the frequent exacerbator phenotype of COPD remain unclear.,We compared systemic neutrophil function in COPD patients with or without frequent exacerbations.,Whole blood from COPD frequent exacerbators (defined as ≥2 moderate-severe exacerbations in the previous 2 years) and non-exacerbators (no exacerbations in the preceding 2 years) was assayed for neutrophil function.,Neutrophil function in healthy ex-smoking volunteers was also measured as a control (reference) group.,A total of 52 subjects were included in this study: 26 frequent exacerbators, 18 non-exacerbators and 8 healthy controls.,COPD frequent exacerbators had blunted blood neutrophil fMLP-stimulated oxidative burst compared to both non-exacerbators (p < 0.01) and healthy controls (p < 0.001).,There were no differences between COPD frequent exacerbators and non-exacerbators in blood neutrophil PMA-stimulated oxidative burst, but both COPD groups had reduced responses compared to healthy controls (p < 0.001).,Bacterial-stimulated neutrophil degranulation was greater in frequent exacerbators than non-exacerbators (p < 0.05).,This study is the first to report aberrant receptor-mediated blood neutrophil function in the frequent exacerbator of COPD. | To examine the association between exacerbation frequency and mortality following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,Cohort study using medical databases.,Northern Denmark.,On 1 January 2005, we identified all patients with prevalent hospital-diagnosed chronic obstructive pulmonary disease (COPD) who had at least one AECOPD during 1 January 2005 to 31 December 2009.,We followed patients from the first AECOPD during this period until death, emigration or 31 December 2009, whichever came first.,We flagged all AECOPD events during follow-up and characterised each by the exacerbation frequency (0, 1, 2 or 3+) in the prior 12-month period.,Using Cox regression, we computed 0-30-day and 31-365-day age-adjusted, sex-adjusted, and comorbidity-adjusted mortality rate ratios (MRRs) with 95% CIs entering exacerbation frequency as a time-varying exposure.,We identified 16 647 eligible patients with prevalent COPD, of whom 6664 (40%) developed an AECOPD and were thus included in the study cohort.,The 0-30-day MRRs were 0.97 (95% CI 0.80 to 1.18), 0.90 (95% CI 0.70 to 1.15) and 1.03 (95% CI 0.81 to 1.32) among patients with AECOPD with 1, 2 and 3+ AECOPDs versus no AECOPD within the past 12 months, respectively.,The corresponding MRRs were 1.47 (95% CI 1.30 to 1.66), 1.89 (95% CI 1.59 to 2.25) and 1.59 (95% CI 1.23 to 2.05) for days 31-365.,Among patients with AECOPD, one or more exacerbations in the previous year were not associated with 30-day mortality but were associated with an increased 31-365-day mortality. | 1 |
Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD).,The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation.,Data were collected from the National Health Insurance Database of Korea.,The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009.,Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors.,The prevalence of GERD in COPD patients was 28% (39,987/141,057).,Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD.,Most of COPD medications except inhaled muscarinic antagonists were associated with GERD.,The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001).,The prevalence of GERD in patients with COPD was high.,Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD.,The presence of GERD was associated with COPD exacerbation. | Salmeterol and fluticasone combination (SFC) has anti-inflammatory effects and improves clinical symptoms in patients with chronic obstructive pulmonary disease (COPD).,However, the anti-inflammatory mechanism of SFC remains unclear.,In this study, we investigated the inflammatory responses of COPD, as well as the relationship of the inflammatory factors with the levels of CD4+CD25+Foxp3+ regulatory T cells (Foxp3+Tregs) after SFC therapy.,Twenty-one patients with moderate or severe COPD received treatment with 50/500 μg of SFC twice a day for 12 weeks.,Before and after treatment, the patients were evaluated using the Modified Medical Research Council (MMRC) dyspnea scale and by conducting a 6-min walk test.,The number of neutrophils, monocytes and lymphocytes in induced sputum were counted.,Levels of cytokines, including pre-inflammatory IL-8, TNF-α, IL-17A and cytokine IL-10, in the sputum supernatant and peripheral blood were measured by ELISA.,The proportion of Foxp3+Tregs in the total CD4+ T cell of the peripheral blood was determined by flow cytometry.,The relationship between IL-17A levels and the percentage of Foxp3+Tregs was analyzed by statistical analysis.,After treatment with SFC, the forced expiratory volume in 1 s as a percentage of predicted values (FEV1%) and the 6-min walk distance in the COPD patients significantly increased, while dyspnea scores decreased.,The total number of cells, neutrophils, and the percentage of neutrophils in induced sputum reduced notably, while the proportion of monocytes was significantly increased.,Levels of the inflammatory cytokines IL-8, TNF-α, and IL-17A in the sputum supernatant and in the blood were markedly lowered, while IL-10 levels were unchanged.,The proportion of Foxp3+Tregs in the total CD4+T cell population in the peripheral blood was drastically higher than that before treatment.,The level of IL-17A was negatively correlated with the proportion of Foxp3+Tregs in CD4+T cells.,SFC can reduce the levels of inflammatory factors and improve symptoms of COPD.,The levels of inflammatory factors are associated with the variation of Foxp3+Tregs in COPD.,This study was registered with http://www.chictr.org (Chinese Clinical Trial Register) as follows: ChiCTR-TNC-10001270 | 1 |
Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year.,To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort.,We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105).,We classified participants according to yearly exacerbation frequency.,Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none.,During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none.,Only 2·1% had ≥2 AECOPD in each year.,An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%).,In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8).,Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year.,Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year.,In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8. | Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting β2-agonist combinations in patients with chronic obstructive pulmonary disease (COPD).,It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity.,Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very-severe COPD.,Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 μg or placebo, twice daily; in one study, tiotropium 18 μg once daily was also given.,Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with ≥1 exacerbation, respectively).,This was true in each COPD severity group.,Compared with placebo, B/F treatment led to significantly lower 3-month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD.,Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity.,B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo.,Treatment with B/F decreased exacerbations in patients with moderate-to-very-severe COPD within 3 months of commencing treatment.,This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity. | 1 |
The expression of CCAAT/enhancer-binding protein (C/EBP)β in the small airway epithelium of COPD is unknown.,C/EBPβ was assessed in peripheral lung tissue of non-smoking/smoking controls and patients with GOLD I-IV COPD by quantitative immunohistochemistry.,The expression of C/EBPβ was decreased in smokers compared to never smokers.,Furthermore, C/EBPβ was significantly elevated in advanced COPD vs. asymptomatic smokers, and the expression correlated to lung function decline.,As C/EBPβ exerts pro-inflammatory effects in the context of cigarette smoke, the elevated C/EBPβ in advanced COPD may be an indication of a breakdown of regulatory mechanisms and excessive inflammation. | Epithelial-to-mesenchymal transition (EMT), which involves changes in cellular morphology of highly polarized epithelial cells and the gain of mesenchymal cell phenotype with migratory and invasive capacities, is implicated in smoking-related chronic obstructive pulmonary disease (COPD).,However, the interactions of fibroblasts and epithelial cells and the participation of fibroblasts in the EMT processes in COPD are poorly understood.,Here, we investigated the hypothesis that EMT is active in human bronchial epithelial (HBE) cells of COPD patients, and that mediators secreted by lung fibroblasts from COPD patients induce EMT.,Primary HBE cells from normal subjects and COPD patients were purchased from LONZA.,HLFs were derived from resected lung obtained from normal (N) and COPD (D) subjects and their conditioned medium (CM) was collected after 2-day culture in serum-free medium.,The expression of epithelial and mesenchymal markers as well as EMT-related transcription factors in lung biopsies, and in HBE cells following stimulation with CM from both normal human lung fibroblasts (NHLF) and COPD human lung fibroblasts (DHLF) was evaluated by immunohistochemistry, qRT-PCR and western blot.,Basal mRNA expression of mesenchymal markers and EMT-related transcription factors were increased in DHBE cells compared to normal human bronchial epithelial cells (NHBE) cells as well as in COPD lungs.,CM from NHLF significantly induced vimentin expression in both NHBE and COPD human bronchial epithelial cells (DHBE) cells, but only increased N-cadherin expression in DHBE cells.,CM from NHLF significantly induced Twist1 and Twist2 expression in NHBE cells and increased Snai2 (Slug) expression in DHBE cells.,While CM from NHLF had no effect on such EMT markers, CM from DHLF significantly increased the protein expression of E-cadherin and vimentin in NHBE cells compared to control.,N-cadherin expression was upregulated to a greater degree in NHBE cells than DHBE cells.,Only CM from DHLF significantly increased E-/N-cadherin ratio in DHBE cells.,Our results suggest that DHBE cells have partially undergone EMT under baseline conditions.,DHLF-CM promoted EMT in NHBE, suggesting that interactions between fibroblast and epithelial cells may play an important role in the EMT process in COPD. | 1 |
Bronchiectasis revealed by chest computed tomography in COPD patients and its comorbid effect on prognosis have not been addressed by large-sized studies.,Understanding the presence of bronchiectasis in COPD is important for future intervention and preventing disease progression.,Observational studies were identified from electronic literature searches in Cochrane library, PubMed, ScienceDirect databases, American Thoracic Society and European Respiratory Society meeting abstracts.,A systematic review and meta-analysis of studies was performed to summarize the factors associated with bronchiectasis in COPD patients.,Primary outcomes included the risks for exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality.,Odds ratios (ORs) were pooled by random effects models.,Fourteen observational studies were eligible for the study.,Compared with COPD without bronchiectasis, comorbid bronchiectasis in COPD increased the risk of exacerbation (1.97, 95% CI, 1.29-3.00), isolation of a potentially pathogenic microorganism (4.11, 95%CI, 2.16-7.82), severe airway obstruction (1.31, 95% CI, 1.09-1.58) and mortality (1.96, 95% CI, 1.04-3.70).,The presence of bronchiectasis in patients with COPD was associated with exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality. | Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria.,The optimum antibiotic choice remains unknown.,We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo.,This was a single-centre, single-blind, randomised placebo-controlled trial.,Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks.,The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance.,99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed.,After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI −0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (−0.33 to 0.55, p=0.62) with doxycycline and 0.08 (−0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively.,There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation.,More treatment-related adverse events occurred with moxifloxacin.,Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms.,Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy.,Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies.,clinicaltrials.gov (NCT01398072). | 1 |
The term asthma-COPD overlap syndrome (ACOS) is one of multiple terms used to describe patients with characteristics of both COPD and asthma, representing ~20% of patients with obstructive airway diseases.,The recognition of both sets of morbidities in patients is important to guide practical treatment decisions.,It is widely recognized that patients with COPD and coexisting asthma present with a higher disease burden, despite the conceptual expectation that the “reversible” or “treatable” component of asthma would allow for more effective management and better outcomes.,However, subcategorization into terms such as ACOS is complicated by the vast spectrum of heterogeneity that is encapsulated by asthma and COPD, resulting in different clinical clusters.,In this review, we discuss the possibility that these different clusters are suboptimally described by the umbrella term “ACOS”, as this additional categorization may lead to clinical confusion and potential inappropriate use of resources.,We suggest that a more clinically relevant approach would be to recognize the extreme variability and the numerous phenotypes encompassed within obstructive airway diseases, with various degrees of overlapping in individual patients.,In addition, we discuss some of the evidence to be considered when making practical decisions on the treatment of patients with overlapping characteristics between COPD and asthma, as well as the potential options for phenotype and biomarker-driven management of airway disease with the aim of providing more personalized treatment for patients.,Finally, we highlight the need for more evidence in patients with overlapping disease characteristics and to facilitate better characterization of potential treatment responders. | Exercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD).,We assessed the effects of glycopyrronium bromide (NVA237), a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD.,Patients were randomized to a cross-over design of once-daily NVA237 50 μg or placebo for 3 weeks, with a 14-day washout.,Exercise endurance, inspiratory capacity (IC) during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales), and transition dyspnea index were measured on Days 1 and 21 of treatment.,The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21.,A total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted).,Ninety-five patients completed the study.,On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001); the effect was also significant from Day 1, with an increase of 10%.,Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study.,This was accompanied by inverse decreases in residual volume and functional residual capacity.,NVA237 was superior to placebo (P < 0.05) in decreasing leg discomfort (Borg CR10 scale) on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime).,The safety profile of NVA237 was similar to that of the placebo.,NVA237 50 μg once daily produced immediate and significant improvement in exercise tolerance from Day 1.,This was accompanied by sustained reductions in lung hyperinflation (indicated by sustained and significant improvements in IC at isotime), and meaningful improvements in trough FEV1 and dyspnea.,Improvements in exercise endurance increased over time, suggesting that mechanisms beyond improved lung function may be involved in enhanced exercise tolerance.,(ClinicalTrials.gov Identifier: NCT01154127). | 1 |
Supplemental Digital Content is available in the text,Nowadays, there is growing recognition that chronic obstructive pulmonary disease (COPD) may have influence on lung cancer.,However, coexisted COPD related to prognosis of lung cancer is still elusive.,We conducted this meta-analysis to examine the association between COPD and 5-year overall survival (OS) and postoperative pulmonary complications of patients with lung cancer.,A comprehensive computer-based online search was conducted using PubMed, Embase, Medline, and the Cochrane Library for articles published before September 30, 2017.,We identified 29 eligible studies, which included 70,111 patients in the related literature.,Twenty-two of the 29 studies provided hazard ratio for OS (1.18, 95% confidence interval: 1.11-1.25; P < .001), it suggested that the presence of COPD indicated poor survival for the patients with lung cancer.,In subgroup analysis, the relationship between COPD and OS occurrence remained statistically prominent in the subgroups stratified by study designs, COPD diagnosis timing, lung cancer surgery, cancer stage, and origins of patients.,The presence of COPD increased the risk of bronchopleural fistula, pneumonia, prolonged air leakage, and prolonged mechanical ventilation.,The present meta-analysis suggested that coexisting COPD is associated with poor survival outcomes in patients with lung cancer and higher rates of postoperative pulmonary complications. | Cardiovascular diseases (CVDs) are arguably the most important comorbidities in chronic obstructive pulmonary disease (COPD).,CVDs are common in people with COPD, and their presence is associated with increased risk for hospitalization, longer length of stay and all-cause and CVD-related mortality.,The economic burden associated with CVD in this population is considerable and the cumulative cost of treating comorbidities may even exceed that of treating COPD itself.,Our understanding of the biological mechanisms that link COPD and various forms of CVD has improved significantly over the past decade.,But despite broad acceptance of the prognostic significance of CVDs in COPD, there remains widespread under-recognition and undertreatment of comorbid CVD in this population.,The reasons for this are unclear; however institutional barriers and a lack of evidence-based guidelines for the management of CVD in people with COPD may be contributory factors.,In this review, we summarize current knowledge relating to the prevalence and incidence of CVD in people with COPD and the mechanisms that underlie their coexistence.,We discuss the implications for clinical practice and highlight opportunities for improved prevention and treatment of CVD in people with COPD.,While we advocate more active assessment for signs of cardiovascular conditions across all age groups and all stages of COPD severity, we suggest targeting those aged under 65 years.,Evidence indicates that the increased risks for CVD are particularly pronounced in COPD patients in mid-to-late-middle-age and thus it is in this age group that the benefits of early intervention may prove to be the most effective. | 1 |
A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo.,This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study.,Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks.,Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed.,In all, 277 symptomatic patients were included in this post hoc analysis.,Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo.,In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P<0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P<0.05).,Aclidinium improved trough FEV1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P<0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P<0.05).,Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks.,Tolerability showed similar incidence of AEs in each arm.,In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity. | The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one’s ability to perform even simple activities.,Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD.,A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials.,A qualitative interview study was conducted among a sample of symptomatic adults with COPD.,Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD).,All interview transcript data were coded using ATLAS.ti software for content analysis.,Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively.,The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement.,During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %).,A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD.,Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand.,The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary.,This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing. | 1 |
The association between exposure to ambient particles with a median aerodynamic diameter less than 10/2.5 µm (particulate matter, PM10/2.5) and COPD remains unclear.,Our study objective was to examine the association between ambient PM10/2.5 concentrations and lung functions in adults.,A cross-sectional study was conducted in southern China.,Seven clusters were randomly selected from four cities across Guangdong province.,Residents aged ≥20 years in the participating clusters were randomly recruited; all eligible participants were examined with a standardised questionnaire and spirometry.,COPD was defined as a post-bronchodilator FEV1/FVC less than 70%.,Atmosphere PM sampling was conducted across the clusters along with our survey.,Of the subjects initially recruited, 84.4% (n=5993) were included for analysis.,COPD prevalence and atmosphere PM concentration varied significantly among the seven clusters.,COPD prevalence was significantly associated with elevated PM concentration levels: adjusted OR 2.416 (95% CI 1.417 to 4.118) for >35 and ≤75 µg/m3 and 2.530 (1.280 to 5.001) for >75 µg/m3 compared with the level of ≤35 µg/m3 for PM2.5; adjusted OR 2.442 (95% CI 1.449 to 4.117) for >50 and ≤150 µg/m3 compared with the level of ≤50 µg/m3 for PM1.,A 10 µg/m3 increase in PM2.5 concentrations was associated with a 26 mL (95% CI −43 to −9) decrease in FEV1, a 28 mL (−49 to −8) decrease in FVC and a 0.09% decrease (−0.170 to −0.010) in FEV1/FVC ratio.,The associations of COPD with PM10 were consistent with PM2.5 but slightly weaker.,Exposure to higher PM concentrations was strongly associated with increased COPD prevalence and declined respiratory function.,ChiCTR-OO-14004264; Post-results. | While the health effects of air pollution have been an international public health concern since at least the 1950s, recent research has focused on two broad sources of air pollution, namely, biomass fuel (BMF) and motor vehicle exhaust (MVE).,Many studies have shown associations between air pollution PM and exacerbations of pre-existing COPD, but the role of air pollution PM in the development and progression of COPD is still uncertain.,The current study indicates that rats can develop pronounced COPD following chronic exposure to air pollution PM (BMF and MVE), as characterized by lung function reduction, mucus metaplasia, lung and systemic inflammation, emphysema, and small airway remodeling.,Comparative analyses demonstrate that both BMF and MVE activate similar pathogenesis that are linked to the development of COPD.,These findings also show that some differences are found in the lungs of rats exposed to BMF or MVE, which might result in different phenotypes of COPD. | 1 |
Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]).,Roflumilast is approved to treat severe COPD in patients with chronic bronchitis - and a history of frequent exacerbations - as an add-on to bronchodilators.,The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials. gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.,REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination.,A concomitant long-acting muscarinic antagonist will be allowed at stable doses.,The primary outcome is the rate of moderate or severe COPD exacerbations.,Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power.,COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.,It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators.,REACT will be important to determine the role of roflumilast in COPD management.,Here, the design and rationale for this important study is described. | Frequent exacerbations which are both costly and potentially life-threatening are a major concern to patients with chronic obstructive pulmonary disease (COPD), despite the availability of several treatment options.,This study aimed to assess the lifetime costs and outcomes associated with alternative treatment regimens for patients with severe COPD in the UK setting.,A Markov cohort model was developed to predict lifetime costs, outcomes, and cost-effectiveness of various combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), an inhaled corticosteroid (ICS), and roflumilast in a fully incremental analysis.,Patients willing and able to take ICS, and those refusing or intolerant to ICS were analyzed separately.,Efficacy was expressed as relative rate ratios of COPD exacerbation associated with alternative treatment regimens, taken from a mixed treatment comparison.,The analysis was conducted from the UK National Health Service (NHS) perspective.,Parameter uncertainty was explored using one-way and probabilistic sensitivity analysis.,Based on the results of the fully incremental analysis a cost-effectiveness frontier was determined, indicating those treatment regimens which represent the most cost-effective use of NHS resources.,For ICS-tolerant patients the cost-effectiveness frontier suggested LAMA as initial treatment.,Where patients continue to exacerbate and additional therapy is required, LAMA + LABA/ICS can be a cost-effective option, followed by LAMA + LABA/ICS + roflumilast (incremental cost-effectiveness ratio [ICER] versus LAMA + LABA/ICS: £16,566 per quality-adjusted life-year [QALY] gained).,The ICER in ICS-intolerant patients, comparing LAMA + LABA + roflumilast versus LAMA + LABA, was £13,764/QALY gained.,The relative rate ratio of exacerbations was identified as the primary driver of cost-effectiveness.,The treatment algorithm recommended in UK clinical practice represents a costeffective approach for the management of COPD.,The addition of roflumilast to the standard of care regimens is a clinical and cost-effective treatment option for patients with severe COPD, who continue to exacerbate despite existing bronchodilator therapy. | 1 |
Objective To investigate the long term effectiveness of integrated disease management delivered in primary care on quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with usual care.,Design 24 month, multicentre, pragmatic cluster randomised controlled trial,Setting 40 general practices in the western part of the Netherlands,Participants Patients with COPD according to GOLD (Global Initiative for COPD) criteria.,Exclusion criteria were terminal illness, cognitive impairment, alcohol or drug misuse, and inability to fill in Dutch questionnaires.,Practices were included if they were willing to create a multidisciplinary COPD team.,Intervention General practitioners, practice nurses, and specialised physiotherapists in the intervention group received a two day training course on incorporating integrated disease management in practice, including early recognition of exacerbations and self management, smoking cessation, physiotherapeutic reactivation, optimal diagnosis, and drug adherence.,Additionally, the course served as a network platform and collaborating healthcare providers designed an individual practice plan to integrate integrated disease management into daily practice.,The control group continued usual care (based on international guidelines).,Main outcome measures The primary outcome was difference in health status at 12 months, measured by the Clinical COPD Questionnaire (CCQ); quality of life, Medical Research Council dyspnoea, exacerbation related outcomes, self management, physical activity, and level of integrated care (PACIC) were also assessed as secondary outcomes.,Results Of a total of 1086 patients from 40 clusters, 20 practices (554 patients) were randomly assigned to the intervention group and 20 clusters (532 patients) to the usual care group.,No difference was seen between groups in the CCQ at 12 months (mean difference -0.01, 95% confidence interval -0.10 to 0.08; P=0.8).,After 12 months, no differences were seen in secondary outcomes between groups, except for the PACIC domain “follow-up/coordination” (indicating improved integration of care) and proportion of physically active patients.,Exacerbation rates as well as number of days in hospital did not differ between groups.,After 24 months, no differences were seen in outcomes, except for the PACIC follow-up/coordination domain.,Conclusion In this pragmatic study, an integrated disease management approach delivered in primary care showed no additional benefit compared with usual care, except improved level of integrated care and a self reported higher degree of daily activities.,The contradictory findings to earlier positive studies could be explained by differences between interventions (provider versus patient targeted), selective reporting of positive trials, or little room for improvement in the already well developed Dutch healthcare system.,Trial registration Netherlands Trial Register NTR2268. | There is insufficient evidence of the cost-effectiveness of Chronic Obstructive Pulmonary Disease (COPD) Disease Management (COPD-DM) programs.,The aim of this review is to evaluate the economic impact of COPD-DM programs and investigate the relation between the impact on healthcare costs and health outcomes.,We also investigated the impact of patient-, intervention, and study-characteristics.,We conducted a systematic literature review to identify cost-effectiveness studies of COPD-DM.,Where feasible, results were pooled using random-effects meta-analysis and explorative subgroup analyses were performed.,Sixteen papers describing 11 studies were included (7 randomized control trials (RCT), 2 pre-post, 2 case-control).,Meta-analysis showed that COPD-DM led to hospitalization savings of €1060 (95% CI: €2040 to €80) per patient per year and savings in total healthcare utilization of €898 (95% CI: €1566 to €231) (excl. operating costs).,In these health economic studies small but positive results on health outcomes were found, such as the St Georges Respiratory Questionnaire (SGRQ) score, which decreased with 1.7 points (95% CI: 0.5-2.9).,There was great variability in DM interventions-, study- and patient-characteristics.,There were indications that DM showed greater savings in studies with: severe COPD patients, patients with a history of exacerbations, RCT study design, high methodological quality, few different professions involved in the program, and study setting outside Europe.,COPD-DM programs were found to have favourable effects on both health outcomes and costs, but there is considerable heterogeneity depending on patient-, intervention-, and study-characteristics. | 1 |
Endocan is thought to be a novel inflammatory marker that is associated with a variety of inflammatory diseases.,However, its role in the pathogenesis of COPD remains unclear.,This study aims to explore the potential role of endocan in COPD.,In total, 27 healthy volunteers, 55 COPD patients and 36 acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients were included in the study.,Basic demographic characteristics, clinical features and blood samples were collected.,Magnetic luminex screening assays were used to detect the concentration of endocan, Fas and Fas ligand (Fas-L) in plasma.,Differences between groups were compared using an Independent sample t-test, Welch’s t-test, chi-squared test and Wilcoxon rank sum test.,The correlations of plasma endocan with lung function parameters, Fas and Fas-L were analyzed by Pearson’s partial correlation test (adjusted for age, gender, body mass index and smoking history) and multiple linear regression.,Plasma endocan levels in COPD patients were significantly higher than those in healthy volunteers (509.7±18.25 pg/mL vs 434.8±18.98 pg/mL (P=0.0124)), and AECOPD patients had the highest levels of endocan (524.7±27.18 pg/mL).,Correlation analysis showed that circulating endocan had a negative correlation to FEV1/FVC, FEV1/predictive and FVC (adjusted r=−0.213, P=0.03; adjusted r=−0.209, P=0.034; and adjusted r=−0.300, P=0.002, respectively), and had a positive correlation to Fas (adjusted r=0.280, P=0.004).,Our study shows that elevated circulating endocan levels are associated with reduced lung ventilation function in COPD and AECOPD patients.,In addition, endocan may influence apoptosis in COPD, suggesting that endocan may play a role in COPD pathogenesis. | Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) carries a poor prognosis, therefore a non-invasive marker of this process could be useful.,Reduced expression of muscle-specific microRNA (myomiRs) in quadriceps muscle in patients with COPD is associated with skeletal muscle weakness and changes in muscle fibre composition.,Circulating exosomal miRNAs can be measured in blood, making them candidate biomarkers of biopsy phenotype.,To determine whether plasma myomiR levels were associated with fibre size or fibre proportion, we measured myomiRs in plasma from patients with COPD and healthy controls.,103 patients with COPD and 25 age-matched controls were studied.,Muscle-specific miRNA was elevated in the plasma of patients with COPD and showed distinct patterns.,Specifically, miR-1 was inversely associated with fat-free mass in the cohort, whereas levels of miR-499 were more directly associated with strength and quadriceps type I fibre proportion.,Two miRs not restricted to muscle in origin (miR-16 and miR-122) did not differ between patients and controls.,Plasma miR-499 was also associated with muscle nuclear factor κB p50 but not p65 in patients with early COPD whereas plasma inflammatory cytokines were associated with miR-206 in patients with more advanced disease.,Plasma levels of individual myomiRs are altered in patients with COPD but alone do not predict muscle fibre size or proportion.,Our findings are consistent with an increase in muscle wasting and turnover associated with the development of skeletal muscle dysfunction and fibre-type shift in patients with stable COPD. | 1 |
Smoking and aberrant epithelial responses are risk factors for lung cancer as well as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.,In these conditions, disease progression is associated with epithelial damage and fragility, airway remodelling and sub-epithelial fibrosis.,The aim of this study was to assess the acute effects of cigarette smoke on epithelial cell phenotype and pro-fibrotic responses in vitro and in vivo.,Apoptosis was significantly greater in unstimulated cells from COPD patients compared to control, but proliferation and CXCL8 release were not different.,Cigarette smoke dose-dependently induced apoptosis, proliferation and CXCL8 release with normal epithelial cells being more responsive than COPD patient derived cells.,Cigarette smoke did not induce epithelial-mesenchymal transition.,In vivo, cigarette smoke exposure promoted epithelial apoptosis and proliferation.,Moreover, mimicking a virus-induced exacerbation by exposing to mice to poly I:C, exaggerated the inflammatory responses, whereas expression of remodelling genes was similar in both.,Collectively, these data indicate that cigarette smoke promotes epithelial cell activation and hyperplasia, but a secondary stimulus is required for the remodelling phenotype associated with COPD.,The online version of this article (doi:10.1186/s12931-017-0565-2) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations.,Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD.,We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists.,Lung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15).,TLR3 expression was measured in lung tissue and in HBECs.,IL-8 secretion was measured in cell cultures after TLR3 stimulation with poly I:C 10 μg/mL.,We found that TLR3 expression was increased by 1.95 fold (protein) and 2.5 fold (mRNA) in lung tissues from smokers with COPD and inversely correlated with lung function.,The TLR3 agonist poly I:C 10 μg/mL increased the IL-8 release in HBECs that was poorly inhibited by dexamethasone in smokers (24.5%) and smokers with COPD (21.6%).,In contrast, roflumilast showed similar inhibitory effects on IL-8 release in healthy (58.8%), smokers (56.6%) and smokers with COPD (50.5%).,The combination of roflumilast N-oxide and dexamethasone showed additive inhibitory effects.,Mechanistically, roflumilast N-oxide when combined with dexamethasone increased the expression of MKP1, and enhanced the inhibitory effects on phospho-p38, AP1 and NFκB activities which may explain the additive anti-inflammatory effects.,Altogether, our data provide in vitro evidence for a possible clinical utility to add roflumilast on top of inhaled corticosteroid in COPD. | 1 |
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. | Guidelines recommend inhaled corticosteroids (ICS) for patients with severe chronic obstructive pulmonary disease (COPD).,Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity.,The effect of withdrawing ICS from COPD patients in primary care is unknown.,In a pragmatic randomised, double-blind, placebo-controlled trial in 31 practices, 260 COPD patients stopped their usual ICS (median duration of use 8 years) and were allocated to 500 mcg fluticasone propionate twice daily (n = 128), or placebo (n = 132).,Follow-up assessments took place at three monthly intervals for a year at the patients' practice.,Our primary outcome was COPD exacerbation frequency.,Secondary outcomes were time to first COPD exacerbation, reported symptoms, peak expiratory flow rate and reliever inhaler use, and lung function and health related quality of life.,In patients randomised to placebo, COPD exacerbation risk over one year was RR: 1.11 (CI: 0.91-1.36).,Patients taking placebo were more likely to return to their usual ICS following exacerbation, placebo: 61/128 (48%); fluticasone: 34/132 (26%), OR: 2.35 (CI: 1.38-4.05).,Exacerbation risk whilst taking randomised treatment was significantly raised in the placebo group 1.48 (CI: 1.17-1.86).,Patients taking placebo exacerbated earlier (median time to first exacerbation: placebo (days): 44 (CI: 29-59); fluticasone: 63 (CI: 53-74), log rank 3.81, P = 0.05) and reported increased wheeze.,In a post-hoc analysis, patients with mild COPD taking placebo had increased exacerbation risk RR: 1.94 (CI: 1.20-3.14).,Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration.,Patients with mild COPD may be at increased risk of exacerbation after withdrawal.,ClinicalTrials.gov NCT00440687 | 1 |
Inhaled corticosteroids (ICS) might lower the risk of coronary heart disease (CHD) in patients with chronic obstructive pulmonary disease (COPD).,This study aimed to assess the association of ICS with the development of CHD in COPD patients by using data from the Korean Nationwide study.,Patients who were newly diagnosed with COPD between 2004 and 2013 and who were not diagnosed with coronary heart disease before their diagnosis of COPD were included.,Exposure of ICS was incorporated into multivariable Cox regression models using time-dependent methods.,To accurately estimate ICS-exposure accumulation, a washout period of 2 years from 2002 to 2003 was applied.,Among a total of 4,400 newly diagnosed COPD patients, 771 patients were diagnosed as CHD incident cases during a median follow-up of one year (interquartile range 0.1-2.9).,The cumulative dose of ICS was associated with a reduced risk of CHD (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.52-0.89).,When the cumulative exposure dose of ICS was divided into quartiles, the aHR for CHD incidence was 0.70 (95% CI, 0.55-0.88) in the highest quartile ICS dose use.,The effect of ICS on reducing CHD incidence was pronounced in adults over 55 years, men under 55 years, and former smokers.,Our findings demonstrate the role of ICS for the prevention of CHD in COPD patients without a history of CHD.,Further research is needed to determine whether a certain amount of ICS exposure in COPD patients is protective against CHD. | The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD).,However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear.,We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation.,We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6).,In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation.,Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition.,Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD. | 1 |
Recent telehealth studies have demonstrated minor impact on patients affected by long-term conditions.,The use of technology does not guarantee the compliance required for sustained collection of high-quality symptom and physiological data.,Remote monitoring alone is not sufficient for successful disease management.,A patient-centred design approach is needed in order to allow the personalisation of interventions and encourage the completion of daily self-management tasks.,A digital health system was designed to support patients suffering from chronic obstructive pulmonary disease in self-managing their condition.,The system includes a mobile application running on a consumer tablet personal computer and a secure backend server accessible to the health professionals in charge of patient management.,The patient daily routine included the completion of an adaptive, electronic symptom diary on the tablet, and the measurement of oxygen saturation via a wireless pulse oximeter.,The design of the system was based on a patient-centred design approach, informed by patient workshops.,One hundred and ten patients in the intervention arm of a randomised controlled trial were subsequently given the tablet computer and pulse oximeter for a 12-month period.,Patients were encouraged, but not mandated, to use the digital health system daily.,The average used was 6.0 times a week by all those who participated in the full trial.,Three months after enrolment, patients were able to complete their symptom diary and oxygen saturation measurement in less than 1 m 40s (96% of symptom diaries).,Custom algorithms, based on the self-monitoring data collected during the first 50 days of use, were developed to personalise alert thresholds.,Strategies and tools aimed at refining a digital health intervention require iterative use to enable convergence on an optimal, usable design.,‘Continuous improvement’ allowed feedback from users to have an immediate impact on the design of the system (e.g., collection of quality data), resulting in high compliance with self-monitoring over a prolonged period of time (12-month).,Health professionals were prompted by prioritisation algorithms to review patient data, which led to their regular use of the remote monitoring website throughout the trial.,Trial registration: ISRCTN40367841.,Registered 17/10/2012. | Altered cardiac repolarization and increased dispersion of repolarization have been identified as risk factors for sudden cardiac death (SCD).,The prevalence of and the mechanisms contributing to altered cardiac repolarization are currently unknown in COPD.,In 91 COPD patients, 32 controls matched for age, cardiovascular risk and medication, and 41 healthy subjects, measures of cardiac repolarization and dispersion of repolarization (QTc interval, QT dispersion) were derived from 12-lead electrocardiography (ECG).,Prevalence rates of heart rate corrected QT (QTc) >450ms and QT dispersion >60ms were determined to assess the number of subjects at risk for SCD.,Univariate and multivariate analyses were used to identify possible factors contributing to altered cardiac repolarization.,QTc was found to be prolonged in 31.9% and QT dispersion in 24.2% of the COPD patients compared to 12.5% in matched controls and 0% in healthy subjects.,The QTc interval was longer in COPD patients compared to matched and healthy controls respectively (437.9 ± 29.5 vs.,420.1 ± 25.3 ms, p = 0.001 and vs.,413.4 ± 18.2 ms, p < 0.001).,QT dispersion was significantly increased in COPD patients compared to healthy subjects (45.4 (34.8 , 59.5) vs.,39.7 (29.3 , 54.8) ms, p = 0.049).,Only oxygen saturation was independently associated with QTc duration in multivariate analysis (β = -0.29, p = 0.015).,One third of a typical COPD population has altered cardiac repolarization and increased dispersion of repolarization, which may be related to hypoxia.,Altered cardiac repolarization may expose these patients to an increased risk for malignant ventricular arrhythmias and SCD. | 1 |
The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms.,The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.,In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks.,The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26.,Overall, 676 patients completed the study.,The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met.,QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001).,QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001).,QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use.,However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.,Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%).,The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%).,These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year. | Few estimates of health care costs related to chronic obstructive pulmonary disease (COPD) are available regarding commercially insured patients in the United States.,The aims of this retrospective observational analysis of administrative data were to describe and compare health care resource use and costs related to COPD in the United States for patients with commercial insurance or Medicare Advantage with Part D benefits, and to assess cost trends over time.,Patient-level and visit-level health care costs in the calendar years 2006, 2007, 2008, and 2009 were assessed for patients with evidence of COPD.,Generalized linear models adjusting for sex, age category, and geographic region were used to investigate cost trends over time for patients with Medicare or commercial insurance.,Medical costs, which ranged from an annual mean of US$2382 (Medicare 2007) to US$3339 (commercial 2009) per patient, comprised the majority of total costs in all years for patients with either type of insurance.,COPD-related costs were less for Medicare than commercial cohorts.,In the multivariate analysis, total costs increased by approximately 6% per year for commercial insurance patients (cost ratio 1.06; 95% confidence interval [CI] 1.04-1.07; P < 0.001) and 5% per year for Medicare patients (cost ratio 1.05; 95% CI 1.03-1.07; P < 0.001).,Costs for outpatient and emergency department visits increased significantly over time in both populations.,Standard admission costs increased significantly for Medicare patients (cost ratio 1.03; 95% CI 1.00-1.05; P = 0.03), but not commercial patients, and costs for intensive care unit visits remained stable for both populations.,COPD imposed a substantial economic burden on patients and the health care system, with costs increasing significantly in both the Medicare and commercial populations. | 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. | Understanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety.,Our goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes.,Our study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same period.,We utilized SPIROMICS participants (n = 98) that returned to their clinical center within 6 weeks of their baseline visit to repeat complete baseline assessments.,Demographics, spirometry, questionnaires, complete blood cell counts (CBC), medical history, and emphysema status by computerized tomography (CT) imaging were obtained.,Pulmonary function tests (PFTs) were highly repeatable (ICC’s >0.9) but the 6 minute walk (6MW) was less so (ICC = 0.79).,Among questionnaires, the Saint George’s Respiratory Questionnaire (SGRQ) was most repeatable.,Self-reported clinical features, such as exacerbation history, and features of chronic bronchitis, often produced kappa values <0.6.,Reported age at starting smoking and average number of cigarettes smoked were modestly repeatable (kappa = 0.76 and 0.79).,Complete blood counts (CBC) variables produced intraclass correlation coefficients (ICC) values between 0.6 and 0.8.,PFTs were highly repeatable, while subjective measures and subject recall were more variable.,Analyses using features with poor repeatability could lead to misclassification and outcome errors.,Hence, care should be taken when interpreting change in clinical features based on measures with low repeatability.,Efforts to improve repeatability of key clinical features such as exacerbation history and chronic bronchitis are warranted. | 1 |
The respiratory microbiome is altered in COPD patients but its relationship with core components of the disease, such as the severity of airflow limitation, the frequency of exacerbations or the circulating levels of eosinophils, is unclear.,Cross-sectional study comprising 72 clinically stable COPD patients (mean age 68 [SD 7.9] years; FEV1 48.7 [SD 20.1]% of reference) who provided spontaneous sputum samples for 16S rRNA gene amplification and sequencing.,The microbiome composition was analysed with QIIME.,We observed that: (1) more severe airflow limitation was associated with reduced relative abundance (RA) of Treponema and an increase in Pseudomonas; (2) patients with ≥2 exacerbations the previous year showed a significantly different bacterial community with respect to non-exacerbators (p = 0.014), with changes in 13 genera, including an increase of Pseudomonas, and finally, (3) peripheral eosinophils levels ≥2% were associated with more diverse microbiome [Chao1 224.51 (74.88) vs 277.39 (78.92) p = 0.006; Shannon 3.94 (1.05) vs 4.54 (1.06) p = 0.020], and a significant increase in the RAs of 20 genera.,The respiratory microbiome in clinically stable COPD patients varies significantly according to the severity of airflow limitation, previous history of exacerbations and circulating eosinophils levels.,The online version of this article (10.1186/s12890-019-0867-x) contains supplementary material, which is available to authorized users. | Bacterial colonisation in chronic obstructive pulmonary disease (COPD) contributes to airway inflammation and modulates exacerbations.,We assessed risk factors for bacterial colonisation in COPD.,Patients with stable COPD consecutively recruited over 1 year gave consent to provide a sputum sample for microbiologic analysis.,Bronchial colonisation by potentially pathogenic microorganisms (PPMs) was defined as the isolation of PPMs at concentrations of ≥102 colony-forming units (CFU)/mL on quantitative bacterial culture.,Colonised patients were divided into high (>105 CFU/mL) or low (<105 CFU/mL) bacterial load.,A total of 119 patients (92.5% men, mean age 68 years, mean forced expiratory volume in one second [FEV1] [% predicted] 46.4%) were evaluated.,Bacterial colonisation was demonstrated in 58 (48.7%) patients.,Patients with and without bacterial colonisation showed significant differences in smoking history, cough, dyspnoea, COPD exacerbations and hospitalisations in the previous year, and sputum colour.,Thirty-six patients (62% of those colonised) had a high bacterial load.,More than 80% of the sputum samples with a dark yellow or greenish colour yielded PPMs in culture.,In contrast, only 5.9% of white and 44.7% of light yellow sputum samples were positive (P < 0.001).,Multivariate analysis showed an increased degree of dyspnoea (odds ratio [OR] = 2.63, 95% confidence interval [CI] 1.53-5.09, P = 0.004) and a darker sputum colour (OR = 4.11, 95% CI 2.30-7.29, P < 0.001) as factors associated with the presence of PPMs in sputum.,Almost half of our population of ambulatory moderate to very severe COPD patients were colonised with PPMs.,Patients colonised present more severe dyspnoea, and a darker colour of sputum allows identification of individuals more likely to be colonised. | 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. | 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. | 1 |
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. | Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology.,We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression.,A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry.,Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression.,Physiological and CT measures indicated disease progression in the whole group.,In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37).,LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38).,The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice. | 1 |
Pulse oximetry could potentially contribute to self-monitoring.,NHS Lothian’s ‘Light Touch’ service provided COPD patients with a self-management plan based on symptoms and oximetry.,The service was overseen (though not actively monitored) by respiratory-trained community teams who were contactable by a telephone helpline.,We aimed to assess the feasibility, perceived utility and impact of the ‘Light Touch’ service.,A before-and-after assessment of St George’s Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS) and use of healthcare resources during the 6-month feasibility study compared to the previous corresponding 6-months.,Paired semi-structured interviews with patients at baseline and 6-months, interviews with managers and a focus group of professionals explored perceptions of the service and self-management.,Transcripts were coded, and analysed thematically.,We recruited 51 participants (mean age 69.7 years (SD 8.4); 21 (46 %) male). 46 participants completed quantitative follow up (2 died, 2 were unwell, 1 refused).,SGRQ: 21 (46 %) participants improved by 4 or more (the minimum important difference); 12 (26 %) deteriorated by 4 or more.,HADS: more participants had normal scores for anxiety (65 %) and depression (80 %) at 6-months than at baseline (51 and 64 %).,More emergency therapy was prescribed during the study period compared to the previous year.,Only 18 participants (39 %) contacted the Light Touch Helpline during the 6-month study.,Twenty patients provided a total of 36 interviews, 8 clinicians contributed to a focus group and 6 managers were interviewed.,Patients considered that the oximetry readings heightened awareness of their condition and gave them confidence to make self-management decisions.,Healthcare professionals valued oximetry as a tool for teaching people self-management skills, but were concerned that patients rarely contacted the teams for help or advice during the study.,‘Light Touch’ shows promise as a low-cost strategy for empowering patients’ self-management skills and reducing reliance on clinical supervision.,The online version of this article (doi:10.1186/s12913-015-1135-2) contains supplementary material, which is available to authorized users. | Objective To test the effectiveness of telemonitoring integrated into existing clinical services such that intervention and control groups have access to the same clinical care.,Design Researcher blind, multicentre, randomised controlled trial.,Setting UK primary care (Lothian, Scotland).,Participants Adults with at least one admission for chronic obstructive pulmonary disease (COPD) in the year before randomisation.,We excluded people who had other significant lung disease, who were unable to provide informed consent or complete the study, or who had other significant social or clinical problems.,Interventions Participants were recruited between 21 May 2009 and 28 March 2011, and centrally randomised to receive telemonitoring or conventional self monitoring.,Using a touch screen, telemonitoring participants recorded a daily questionnaire about symptoms and treatment use, and monitored oxygen saturation using linked instruments.,Algorithms, based on the symptom score, generated alerts if readings were omitted or breached thresholds.,Both groups received similar care from existing clinical services.,Main outcome measures The primary outcome was time to hospital admission due to COPD exacerbation up to one year after randomisation.,Other outcomes included number and duration of admissions, and validated questionnaire assessments of health related quality of life (using St George’s respiratory questionnaire (SGRQ)), anxiety or depression (or both), self efficacy, knowledge, and adherence to treatment.,Analysis was intention to treat.,Results Of 256 patients completing the study, 128 patients were randomised to telemonitoring and 128 to usual care; baseline characteristics of each group were similar.,The number of days to admission did not differ significantly between groups (adjusted hazard ratio 0.98, 95% confidence interval 0.66 to 1.44).,Over one year, the mean number of COPD admissions was similar in both groups (telemonitoring 1.2 admissions per person (standard deviation 1.9) v control 1.1 (1.6); P=0.59).,Mean duration of COPD admissions over one year was also similar between groups (9.5 days per person (standard deviation 19.1) v 8.8 days (15.9); P=0.88).,The intervention had no significant effect on SGRQ scores between groups (68.2 (standard deviation 16.3) v 67.3 (17.3); adjusted mean difference 1.39 (95% confidence interval −1.57 to 4.35)), or on other questionnaire outcomes.,Conclusions In participants with a history of admission for exacerbations of COPD, telemonitoring was not effective in postponing admissions and did not improve quality of life.,The positive effect of telemonitoring seen in previous trials could be due to enhancement of the underpinning clinical service rather than the telemonitoring communication.,Trial registration ISRCTN96634935.,Funding: The trial was funded by an NHS applied research programme grant from the Chief Scientist Office of the Scottish government (ARPG/07/03).,The funder had no role in study design and the collection, analysis, and interpretation of data and the writing of the article and the decision to submit it for publication.,NHS Lothian supported the telemonitoring service and the clinical services. | 1 |
Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic respiratory disease, characterized by an obstructive pattern.,Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens.,MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that modulate the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules.,Emerging evidences demonstrated the potential use of miRNAs as a disease biomarker.,This pilot study aimed to investigate the association of the MIR-196a2 rs11614913 (C/T) polymorphism with COPD susceptibility, the clinical outcome and bronchodilator response to short-acting β2-agonist.,Genotyping of rs11614913 polymorphism was determined in 108 COPD male patients and 116 unrelated controls using real-time polymerase chain reaction technology.,In silico target prediction and network core analysis were performed.,COPD patients did not show significant differences in the genotype distribution (p = 0.415) and allele frequencies (p = 0.306) of the studied miRNA when compared with controls.,There were also no associations with GOLD stage, dyspnea grade, disease exacerbations, COPD assessment test for estimating impact on health status score, or the frequency of intensive care unit admission.,However, COPD patients with CC genotype corresponded to the smallest bronchodilator response after Salbutamol inhalation, the heterozygotes (CT) had an intermediate response, while those with the TT genotype showed the highest response (p < 0.001).,In conclusion MIR-196a2 rs11614913 polymorphism is associated with the bronchodilator response of COPD in our sample of the Egyptian population, generating hypothesis of the potential use of MIR-196a2 variant as a pharmacogenetic marker for COPD. | Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain.,We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable.,During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids.,We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants.,Of 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data.,Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations.,No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased.,During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased.,The decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues.,GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD.,These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute.,NCT00281216, ClinicalTrials.gov.,The online version of this article (doi:10.1186/s12931-015-0251-1) contains supplementary material, which is available to authorized users. | 1 |
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. | Familial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees.,The aim was to determine whether the familial transmission of COPD is related to disease in biological and/or adoptive parents.,Historic cohort study.,80 214 (50% females).,The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born in 1932-2004 (n=80 214) between 1 January 1964 and 31 December 2010 for COPD (n=1978).,The risk of COPD was estimated in adoptees with at least one biological parent with COPD but no adoptive parent with COPD (n=162) compared with adoptees without a biological or adoptive parent with COPD.,The risk of COPD was also determined in adoptees with at least one adoptive parent but no biological parent with COPD (n=110), and in adoptees with both affected biological and adoptive parents (n=162).,COPD in adoptees.,Adoptees with COPD in at least one biological parent but no adoptive parent were more likely to have COPD than adoptees without a biological or adoptive parent with COPD (standardised incidence ratio, SIR=1.98 (95% CI 1.69 to 2.31)).,The familial SIR for adoptees with both a biological parent and an adoptive parent with COPD was 1.68 (95% CI 1.39 to 2.00).,Adoptees with at least one adoptive parent with COPD but no biological parent with COPD were not at an increased risk of COPD (SIR=1.12 (95% CI 0.92 to 1.35)).,The findings of the study show that the familial transmission of COPD is associated with COPD in biological but not adoptive parents, suggesting that genetic or early life factors are important in the familial transmission of COPD. | 1 |
Inhaled medications are the cornerstone of treatment and management of asthma and COPD.,However, inhaler device errors are common among patients and have been linked with reduced symptom control, an increased risk of exacerbations, and increased healthcare utilisation.,These observations have prompted GINA (Global INitiative for Asthma) and GOLD (Global initiative for chronic Obstructive Lung Disease) to recommend regular assessment of inhaler technique in a bid to improve therapeutic outcomes.,To better define the relationship between device errors and health outcomes (clinical outcomes, quality of life, and healthcare utilisation) in asthma and COPD, we conducted a systematic review of the literature, with a particular focus on the methods used to assess the relationship between device errors and outcomes.,Sixteen studies were identified (12 in patients with asthma, one in patients with COPD, and three in both asthma and COPD) with varying study designs, endpoints, and patient populations.,Most of the studies reported that inhalation errors were associated with worse disease outcomes in patients with asthma or COPD.,Patients who had a reduction in errors over time had improved outcomes.,These findings suggest that time invested by healthcare professionals is vital to improving inhalation technique in asthma and COPD patients to improve health outcomes. | 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. | 1 |
COPD is characterized by chronic bronchitis, chronic airway obstruction, and emphysema, leading to a progressive and irreversible decline in lung function.,Inflammation is central for the development of COPD.,Chronic inflammation in COPD mainly involves the infiltration of neutrophils, macrophages, lymphocytes, and other inflammatory cells into the small airways.,The contribution of resident airway structural cells to the inflammatory process is also important in COPD.,Airway remodeling consists of detrimental changes in structural tissues and cells including airway wall thickening, epithelial metaplasia, goblet cell hypertrophy, and smooth muscle hyperplasia.,Persistent airway inflammation might contribute to airway remodeling and small airway obstruction.,However, the underlying mechanisms remain unclear.,In this review, we will provide an overview of recent insights into the role of major immunoinflammatory cells in COPD airway remodeling. | Baarsma et al. report increased expression and posttranslational modification of the noncanonical ligand WNT-5A in COPD.,Fibroblast-derived WNT-5A inhibits canonical WNT-β-catenin-driven alveolar epithelial cell-mediated wound healing and transdifferentiation, and thus contributes to impaired lung regeneration and COPD pathogenesis.,Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide.,One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined.,Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated.,Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis.,We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens.,WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence.,Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro.,Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo.,Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD.,We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy. | 1 |
We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.,This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy.,Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa.,The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population.,The incidence of adverse events was also assessed.,In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population.,UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001].,Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14).,Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.,In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD.,Both treatments had similar safety profiles.,These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.,ClinicalTrials.gov identifier NCT02799784.,GlaxoSmithKline.,The online version of this article (doi:10.1007/s12325-017-0626-4) contains supplementary material, which is available to authorized users. | Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD.,Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk.,This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.,The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.,This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks.,The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.,Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively).,Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).,Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate.,Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. | 1 |
Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD.,We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.,Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans.,Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT.,Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.,In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema.,The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema.,Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema.,In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.,Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans. | The percentage of neutrophils in sputum are increased in COPD patients, and may therefore be a biomarker of airway inflammation.,We studied the relationships between sputum neutrophils and FEV1, health status, exacerbation rates, systemic inflammation and emphysema, and long term variability at 1 year.,Sputum samples were obtained from 488 COPD patients within the ECLIPSE cohort. 359 samples were obtained at baseline, and 297 after 1 year. 168 subjects provided samples at both visits.,Serum interleukin-6 (IL-6), IL-8, surfactant protein D and C-reactive protein levels were measured by immunoassays.,Low-dose CT scans evaluated emphysema.,Sputum neutrophil % increased with GOLD stage.,There was a weak association between % sputum neutrophils and FEV1 % predicted (univariate r2 = 0.025 and 0.094 at baseline and year 1 respectively, p < 0.05 after multivariate regression).,Similar weak but significant associations were observed between neutrophil % and health status measured using the St Georges Respiratory Questionairre.,There were no associations between neutrophils and exacerbation rates or emphysema.,Associations between sputum neutrophils and systemic biomarkers were non-significant or similarly weak.,The mean change over 1 year in neutrophil % was an increase of 3.5%.,Sputum neutrophil measurements in COPD are associated weakly with FEV1 % predicted and health status.,Sputum neutrophil measurements were dissociated from exacerbation rates, emphysema and systemic inflammation. | 1 |
Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year.,To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort.,We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105).,We classified participants according to yearly exacerbation frequency.,Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none.,During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none.,Only 2·1% had ≥2 AECOPD in each year.,An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%).,In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8).,Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year.,Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year.,In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8. | The Spanish Guidelines for COPD (GesEPOC) describe four clinical phenotypes: non-exacerbator (NE), asthma-COPD overlap syndrome (ACO), frequent exacerbator with emphysema (EE), and exacerbator with chronic bronchitis (ECB).,The objective of this study was to determine the frequency of COPD phenotypes, their clinical characteristics, and the availability of diagnostic tools to classify COPD phenotypes in clinical practice.,This study was an epidemiological, cross-sectional, and multi-centered study.,Patients ≥40 years old with a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio of <0.7 and who were smokers or former smokers (with at least 10 pack-years) were included.,The availability of diagnostic tools to classify COPD phenotypes was assessed by an ad hoc questionnaire.,A total of 647 patients (294 primary care [PC], 353 pulmonology centers) were included.,Most patients were male (80.8%), with a mean age (SD) of 68.2 (9.2) years, mean post-bronchodilator FEV1 was 53.2% (18.9%) and they suffered a mean of 2.2 (2.1) exacerbations in the last year.,NE was the most frequent phenotype (47.5%) found, followed by ECB (29.1%), EE (17.0%), and ACO (6.5%).,Significant differences between the four phenotypes were found regarding age; sex; body mass index; FEV1; body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE)/body mass index, airflow obstruction, dyspnea and exacerbations (BODEx) index; modified Medical Research Council dyspnea scale; respiratory symptoms; comorbidi-ties; hospitalizations; and exacerbations in the last year.,Physicians considered that >80% of the diagnostic tools needed to classify COPD phenotypes were available, with the exception of computed tomography (26.9%) and carbon monoxide transfer test (13.5%) in PC, and sputum eosinophilia count in PC and pulmonology centers (40.4% and 49.4%, respectively).,In Spanish clinical practice, almost half of the patients with COPD presented with NE phenotype.,The prevalence of ACO according to the Spanish consensus definition was very low.,In general, physicians indicated that they had the necessary tools for diagnosing COPD phenotypes. | 1 |
Chronic obstructive pulmonary disease (COPD) represents a major health problem in Central and Eastern European (CEE) countries; however, there are no data regarding clinical phenotypes of these patients in this region.,Participation in the Phenotypes of COPD in Central and Eastern Europe (POPE) study was offered to stable patients with COPD in a real-life setting.,The primary aim of this study was to assess the prevalence of phenotypes according to predefined criteria.,Secondary aims included analysis of differences in symptom load, comorbidities and pharmacological treatment.,3362 patients with COPD were recruited in 10 CEE countries. 63% of the population were nonexacerbators, 20.4% frequent exacerbators with chronic bronchitis, 9.5% frequent exacerbators without chronic bronchitis and 6.9% were classified as asthma-COPD overlap.,Differences in the distribution of phenotypes between countries were observed, with the highest heterogeneity observed in the nonexacerbator cohort and the lowest heterogeneity observed in the asthma-COPD cohort.,There were statistically significant differences in symptom load, lung function, comorbidities and treatment between these phenotypes.,The majority of patients with stable COPD in CEE are nonexacerbators; however, there are distinct differences in surrogates of disease severity and therapy between predefined COPD phenotypes.,Distinct phenotypes of COPD in Central and Eastern Europe have differences in symptoms, comorbidities and treatmenthttp://ow.ly/oMZI307ndr5 | The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components.,Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown.,The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands.,A cost-utility study was performed, using an individual-level Markov model.,To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial.,In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium.,Cost-utility analysis was performed from the Dutch health care payer’s perspective using a 15-year time horizon in the base-case analysis.,The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%).,Both univariate and probabilistic sensitivity analyses were performed.,Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence.,As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY.,Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY.,Results were robust in univariate and probabilistic sensitivity analyses.,Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence.,Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively.,Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD) are the third largest cause of emergency hospital admissions in the UK.,This systematic literature review explored the relationship between the hospitalization rates and the COPD comorbidities, anxiety, and depression.,The Centre for Research Dissemination’s framework for systematic reviews was followed using search terms relating to COPD, anxiety, depression, and hospital admission.,Papers identified were assessed for relevance and quality, using a suitable Critical Appraisal Skills Programme tool and Mixed Methods Assessment Tool.,Twenty quantitative studies indicated that anxiety and depression led to a statistically significant increase in the likelihood of COPD patients being hospitalized.,These comorbidities also led to an increased length of stay and a greater risk of mortality postdischarge.,Other significant factors included lower Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise scores, female gender, lower socioeconomic status, poorer patient perceived quality of life, increased severity of lung function, and less improvement in dyspnea from admission to discharge.,It was also highlighted that only 27%-33% of those with depression were being treated for it.,Four qualitative studies revealed that patients saw anxiety and depression as a major factor that affected their ability to cope with and self-manage their condition.,Findings from the systematic review have highlighted a need for better recognition and treatment of anxiety and depression amongst individuals with COPD.,Ongoing research will develop and test strategies for promoting better management and self-management as a means of reducing hospital admissions. | 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. | 1 |
Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.,The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40-80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III.,Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months.,The primary outcome was the number of acute exacerbations during the study.,In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus.,1.13 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.002).,No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group.,Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023).,Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.,In patients with COPD, erdosteine can reduce both the rate and duration of exacerbations.,The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.,RESTORE study: erdosteine reduces both rate and duration of COPD exacerbations with a placebo-like safety profilehttp://ow.ly/BbGI30dRdEt | COPD is characterized by progressive airflow obstruction which does not fully reverse to inhaled or oral pharmacotherapy.,The management of patients with COPD has taken a totally new direction over the past 20 years, thank to the use of novel therapies aimed to improve and modify the natural history of COPD.,Long-acting bronchodilators, including long-acting β2-agonists (LABAs), were introduced several years ago in order to enhance improvements in lung function, health status related quality of life, and reduce the rate of exacerbations.,These effects can be boosted by the combination of LABAs with long-acting anticholinergic, and/or with inhaled corticosteroids.,Inhaled LABAs are commonly well tolerated although adverse effects such as tremor and palpitations are occasionally troublesome. | 1 |
COPD-associated mortality was examined using a novel approach of phenotyping COPD based on computed tomography (CT)-emphysema index from quantitative CT (QCT) and post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) in a local Malaysian cohort.,Prospectively collected data of 112 eligible COPD subjects (mean age, 67 years; male, 93%; mean post-BD FEV1, 45.7%) was available for mortality analysis.,Median follow-up time was 1,000 days (range, 60-1,400).,QCT and clinicodemographic data were collected at study entry.,Based on CT-emphysema index and post-BD FEV1% predicted, subjects were categorized into “emphysema-dominant,” “airway-dominant,” “mild mixed airway-emphysema,” and “severe mixed airway-emphysema” diseases.,Sixteen patients (14.2%) died of COPD-associated causes.,There were 29 (25.9%) “mild mixed,” 23 (20.5%) “airway-dominant,” 15 (13.4%) “emphysema-dominant,” and 45 (40.2%) “severe mixed” cases.,“Mild mixed” disease was proportionately more in Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group A, while “severe mixed” disease was proportionately more in GOLD Groups B and D.,Kaplan-Meier survival estimates showed increased mortality risk with “severe mixed” disease (log rank test, p=0.03) but not with GOLD groups (p=0.08).,Univariate Cox proportionate hazard analysis showed that age, body mass index, long-term oxygen therapy, FEV1, forced volume capacity, COPD Assessment Test score, modified Medical Research Council score, St Georges’ Respiratory Questionnaire score, CT-emphysema index, and “severe mixed” disease (vs “mild mixed” disease) were associated with mortality.,Multivariate Cox analysis showed that age, body mass index, and COPD Assessment Test score remain independently associated with mortality.,“Severe mixed airway-emphysema” disease may predict COPD-associated mortality.,Age, body mass index, and COPD Assessment Test score remain as key mortality risk factors in our cohort. | Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology.,Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome.,We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype.,We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study.,PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity.,PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location.,PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques. | 1 |
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. | 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 |
Few studies have evaluated the contribution of multiple virus and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease.,This study estimated the burden of multiple viral and bacterial respiratory infections in moderate to very severe chronic obstructive pulmonary disease patients that were prospectively followed‐up during a 12‐month pilot study.,Clinical data were collected monthly and sputum was collected at the time of each acute exacerbation event.,Classical culture techniques for bacteria and multiplex polymerase chain reaction (PCR) and microarray detection assays were performed to identify viral and atypical bacterial pathogens in the sputum.,Overall, 51 patients were included and 45 acute exacerbation events were investigated clinically and microbiologically.,Among the 45 acute exacerbation events, 44% had evidence of viral infection involving human rhinovirus (HRV) and metapneumovirus (hMPV) in 20% and 18%, respectively.,Intracellular bacteria were not found in sputum by PCR.,Common bacterial pathogens were identified in 42% of acute exacerbation patients, most frequently Branhamella catarrhalis, Streptococcus pneumoniae and Haemophilus influenzae.,Viral or virus and bacteria co‐infections were detected in 27% of acute exacerbation events (n = 12) with HRV and hMPV involved in 92% of cases.,Patients with co‐infections did not present greater clinical severity scores at exacerbation and more recurrence of acute exacerbation events at 3 and 6 months than those with single infections (P > 0.4).,These results suggest that HRV and hMPV may be contributors or cofactors of AECOPD.,These findings indicate that viral or virus and bacterial co‐infections do not impact significantly on the clinical severity of acute exacerbation of chronic obstructive pulmonary disease and recurrence at 3 and 6 months.,J.,Med.,Virol.,85:866-873, 2013.,© 2013 Wiley Periodicals, Inc. | The role of viruses in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) needs further elucidation.,The aim of the present study was to evaluate the molecular epidemiology of viral pathogens in AECOPD.,Patients presenting to the Emergency Room with AECOPD needing hospitalization were recruited.,Oropharyngeal and sputum samples were collected in order to perform microarrays-based viral testing for the detection of respiratory viruses.,A total of 200 (100%) patients were analyzed and from them in 107 (53.5%) a virus was detected.,The commonest identified viruses were the human Respiratory Syncytial Virus (subtypes A and B) (40.5%), influenza virus (subtypes A, B, C) (11%), rhinovirus (8%) and human Parainfluenza Virus (subtypes A and B) (7.5%).,A bacterial pathogen was isolated in 27 (14%) patients and a dual infection due to a bacterial and a viral pathogen was recognised in 14/107 patients.,Patients with AECOPD and a viral infection had a lengthier hospital stay (9.2 ± 4.6 vs 7.6 ± 4.3, p < 0.01) while the severity of the disease was no related with significant differences among the groups of the study population.,In conclusion, the isolation of a virus was strongly associated with AECOPD in the examined population.,The stage of COPD appeared to have no relation with the frequency of the isolated viruses while dual infection with a viral and a bacterial pathogen was not rare. | 1 |
How well the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification prognosticates for Asian patients with COPD is unknown.,The authors aimed to study the predictive utility of the GOLD 2011 classification for exacerbations and mortality as compared with other multidimensional tools in an Asian population.,In all, 1,110 COPD patients were prospectively followed between March 2008 and March 2013.,They were classified using the 2011 and 2007 GOLD guidelines, modified Medical Research Council score, St.,George’s Respiratory Questionnaire (SGRQ), and Body mass index, Obstruction, Dyspnea (BOD) index.,Outcome measures were exacerbations and mortality.,Multivariable survival analyses and receiver operating characteristic (ROC) curves were used to assess the different classification systems.,Time-to-event analyses demonstrated earlier exacerbations in 2011’s GOLD D when compared with GOLD A (hazard ratio [HR] 0.54, 95% confidence interval [CI]: 0.31-0.95, P=0.032) and GOLD B (HR 0.62, 95% CI: 0.45-0.85, P=0.003) and higher mortality when compared with GOLD A (HR 0.37, 95% CI: 0.16-0.88, P=0.025) and GOLD B (HR 0.46, 95% CI: 0.31-0.70, P<0.001).,The areas under the ROC curve for GOLD 2011, GOLD 2007, modified Medical Research Council, St.,George’s Respiratory Questionnaire, and BOD index were 0.62, 0.59, 0.61, 0.60, and 0.61, respectively, for the prediction of exacerbations and 0.71, 0.70, 0.71, 0.71, and 0.72, respectively, for the prediction of mortality (ROC comparator, P>0.05).,The 2011 GOLD classification predicts exacerbations and mortality moderately well in Asian COPD patients.,Its prognostic utility is similar to that of other multidimensional systems. | Prediction of future exacerbations of chronic obstructive pulmonary disease (COPD) is a major concern for long-term management of this disease.,To determine which of three multidimensional assessment systems (the body mass index, obstruction, dyspnea, and exercise capacity [BODE] index; dyspnea, obstruction, smoking, exacerbations [DOSE] index; or age, dyspnea, obstruction [ADO] index) is superior for predicting exacerbations.,This was a 2-year prospective cohort study of COPD patients.,Pulmonary function tests, the 6-minute walk distance (6MWD), Modified Medical Respiratory Council (MMRC) dyspnea scores, chest computed-tomography measurements, and body composition were analyzed, and predictions of exacerbation by the three assessment systems were compared.,Among 183 patients who completed the study, the mean annual exacerbation rate was 0.57 events per patient year, which correlated significantly with lower predicted forced expiratory volume in 1 second (FEV1) (P < 0.001), lower transfer coefficient of the lung for carbon monoxide (%DLco/VA) (P = 0.021), lesser 6MWD (P = 0.016), higher MMRC dyspnea score (P = 0.001), higher DOSE index (P < 0.001), higher BODE index (P = 0.001), higher ADO index (P = 0.001), and greater extent of emphysema (P = 0.002).,For prediction of exacerbation, the areas under the curves were larger for the DOSE index than for the BODE and ADO indices (P < 0.001).,Adjusted multiple logistic regression identified the DOSE index as a significant predictor of risk of COPD exacerbation.,In this study, the DOSE index was a better predictor of exacerbations of COPD when compared with the BODE and ADO indices. | 1 |
There is a high prevalence of comorbidities among patients with chronic obstructive pulmonary disease (COPD).,Comorbidities are likely common in patients with any COPD degree and are associated with increased mortality.,The aim of this study was to determine the prevalence of thirty-one different COPD comorbidities and to evaluate the association between physical activity (PA) levels in people with COPD residing in Spain.,Cross-sectional data from the Spanish National Health Survey 2017 were analysed.,A total of 601 adults (52.2% females) with COPD aged 15 to 69 participated in this study.,PA (exposure) was measured with the International Physical Activity Questionnaire (IPAQ) short form and comorbidities (outcomes) were self-reported in response to the question “Have you ever been diagnosed with…?”,Multivariable logistic regression, in three different models, was used to assess this association.,Results showed a high prevalence of comorbidities (94%), these being chronic lumbar back pain (38.9%), chronic allergy (34.8%), arthrosis (34.1%), chronic cervical back pain (33.3%), asthma (32.9%) and hypertension (32.8%) the most prevalent.,Low PA level was significantly associated with urinary incontinence (2.115[1.213-3.689]), chronic constipation (1.970[1.119-3.459]), cataracts (1.840[1.074-3.153]), chronic anxiety (1.508[1.002-2.269]) and chronic lumbar back pain (1.489[1.044-2.125]).,Therefore, people with COPD should increase their PA levels in order to reduce their risk of comorbidities and increase their quality of life. | Reduced physical activity (PA) in patients with COPD is associated with a poor prognosis.,Increasing PA is a key therapeutic target, but thus far few strategies have been found effective in this patient group.,To investigate the effectiveness of a 12-week semiautomated telecoaching intervention on PA in patients with COPD in a multicentre European randomised controlled trial.,343 patients from six centres, encompassing a wide spectrum of disease severity, were randomly allocated to either a usual care group (UCG) or a telecoaching intervention group (IG) between June and December 2014.,This 12-week intervention included an exercise booklet and a step counter providing feedback both directly and via a dedicated smartphone application.,The latter provided an individualised daily activity goal (steps) revised weekly and text messages as well as allowing occasional telephone contacts with investigators.,PA was measured using accelerometry during 1 week preceding randomisation and during week 12.,Secondary outcomes included exercise capacity and health status.,Analyses were based on modified intention to treat.,Both groups were comparable at baseline in terms of factors influencing PA.,At 12 weeks, the intervention yielded a between-group difference of mean, 95% CI (lower limit - upper limit; ll-ul) +1469, 95% CI (971 to 1965) steps/day and +10.4, 95% CI (6.1 to 14.7) min/day moderate PA; favouring the IG (all p≤0.001).,The change in 6-min walk distance was significantly different (13.4, 95% CI (3.40 to 23.5) m, p<0.01), favouring the IG.,In IG patients, an improvement could be observed in the functional state domain of the clinical COPD questionnaire (p=0.03) compared with UCG.,Other health status outcomes did not differ.,The amount and intensity of PA can be significantly increased in patients with COPD using a 12-week semiautomated telecoaching intervention including a step counter and an application installed on a smartphone.,NCT02158065. | 1 |
Cardiovascular disease is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD).,We aimed to systematically review the evidence for: (1) risk of myocardial infarction (MI) in people with COPD; (2) risk of MI associated with acute exacerbation of COPD (AECOPD); (3) risk of death after MI in people with COPD.,Systematic review and meta-analysis.,MEDLINE, EMBASE and SCI were searched up to January 2015.,Two reviewers screened abstracts and full text records, extracted data and assessed studies for risk of bias.,We used the generic inverse variance method to pool effect estimates, where possible.,Evidence was synthesised in a narrative review where meta-analysis was not possible.,Searches yielded 8362 records, and 24 observational studies were included.,Meta-analysis showed increased risk of MI associated with COPD (HR 1.72, 95% CI 1.22 to 2.42) for cohort analyses, but not in case-control studies: OR 1.18 (0.80 to 1.76).,Both included studies that investigated the risk of MI associated with AECOPD found an increased risk of MI after AECOPD (incidence rate ratios, IRR 2.27, 1.10 to 4.70, and IRR 13.04, 1.71 to 99.7).,Meta-analysis showed weak evidence for increased risk of death for patients with COPD in hospital after MI (OR 1.13, 0.97 to 1.31).,However, meta-analysis showed an increased risk of death after MI for patients with COPD during follow-up (HR 1.26, 1.13 to 1.40).,There is good evidence that COPD is associated with increased risk of MI; however, it is unclear to what extent this association is due to smoking status.,There is some evidence that the risk of MI is higher during AECOPD than stable periods.,There is poor evidence that COPD is associated with increased in hospital mortality after an MI, and good evidence that longer term mortality is higher for patients with COPD after an MI. | Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler® (18 μg once daily) or Respimat® Soft Mist™ inhaler (5 μg once daily).,The recent TIOtropium Safety and Performance In Respimat® (TIOSPIR™) study demonstrated that both exhibit similar safety profiles.,This analysis provides an updated comprehensive safety evaluation of tiotropium® using data from placebo-controlled HandiHaler® and Respimat® trials.,Pooled analysis of adverse event (AE) data from tiotropium HandiHaler® 18 μg and Respimat® 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks).,Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler® and Respimat® trials, both together and separately.,In the 28 HandiHaler® and 7 Respimat® trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler®; 2,440 with Respimat®) patient-years of tiotropium exposure.,Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted).,The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler® and Respimat® pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]).,The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group.,Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium.,Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.,This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler® or Respimat® (overall and separately) in patients with COPD. | 1 |
The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.,The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990-2005, using the healthcare databases from the province of Quebec, Canada.,Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified.,The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.,The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively.,The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th.,The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first.,Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.,The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation.,Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality. | Tobacco-related lung diseases, including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide.,Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory tract viral infections and can result in respiratory failure in those with advanced lung disease.,We sought to determine the mechanism underlying COPD exacerbation and host response to pathogen-derived factors.,Over a 24-month period, we assessed the viral causes for upper and lower respiratory tract infections in patients with COPD (n = 155) and control subjects (n = 103).,We collected nasal and bronchoalveolar lavage fluid and peripheral blood under baseline and exacerbated conditions.,We determined the effect of human rhinovirus (HRV) proteinases on T-cell activation in human subjects and mice.,HRVs are isolated from nasal and lung fluid from subjects with AE-COPD.,Bronchoalveolar lavage fluid and CD4 T cells from patients with COPD exhibited a TH1 and TH2 cell cytokine phenotype during acute infection.,HRV-encoded proteinase 2A activated monocyte-derived dendritic cells in vitro and induced strong TH1 and TH2 immune responses from CD4 T cells.,Intranasal administration of recombinant rhinovirus proteinase 2A in mice resulted in an increase in airway hyperreactivity, lung inflammation, and IL-4 and IFN-γ production from CD4 T cells.,Our findings suggest that patients with severe COPD show TH1- and TH2-biased responses during AE-COPD.,HRV-encoded proteinase 2A, like other microbial proteinases, could provide a TH1- and TH2-biasing adjuvant factor during upper and lower respiratory tract infection in patients with severe COPD.,Alteration of the immune response to secreted viral proteinases might contribute to worsening of dyspnea and respiratory failure in patients with COPD. | 1 |
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. | Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis.,We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD.,The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.,This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations.,Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.,In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%).,The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001).,In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%).,UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).,This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods.,UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy. | 1 |
This study investigated patient perceptions, experiences and management of COPD throughout the SLS COPD study.,Follow-up interviews were conducted with 400 patients who completed SLS COPD; a mixed-methods approach was used to collect quantitative and qualitative information.,Structured interviews using closed-ended questions were conducted with 360 patients, detailing aspects of background/lifestyle information and COPD.,Extended interviews containing open-ended questions on perceptions of COPD and quality of life (QoL) in addition to the closed-ended questions were completed by 40 further patients.,Participants also completed the Adherence Starts with Knowledge-12 (ASK-12) and the COPD and Asthma Sleep Impact Scale (CASIS) questionnaire.,Quantitative data were analysed descriptively; qualitative data were analysed using qualitative description.,The participants (n = 400) were reasonably representative of the SLS COPD population; mean age was 66.2 years.,Breathlessness was the most commonly recalled symptom of/associated with COPD (88.5% of patients) and was the symptom that changed the most (improved, 26.8%/worsened, 20.9%) throughout the study.,Participants’ daily functioning and activities were most affected by symptoms of/associated with COPD, followed by relationships and psychological issues.,66.5% of participants experienced exacerbations, 60.5% of whom reported self-management as their first treatment strategy (taking antibiotics, resting and/or corticosteroids).,Qualitative analysis revealed COPD symptoms, breathlessness in particular, to have a significant impact on mobility and in turn QoL.,In conclusion, breathlessness was cited in these interviews as the COPD symptom with the greatest impact on participants’ daily functioning, activities and self-care.,The findings provided significant additional knowledge to the SLS COPD study findings.,Interviews with patients undergoing a clinical trial for chronic lung disease highlights the impact of breathlessness on quality of life.,Henrik Svedsater at GlaxoSmithKline in the UK, and co-workers, wanted to dig deeper into patient perceptions of COPD during the Salford Lung Study in Chronic Obstructive Pulmonary Disease (SLS COPD) clinical trial, which trialed an alternative self-administered inhaler treatment.,To this end, Svedsater’s team administered questionnaires and interviewed 400 patients involved in SLS COPD, to examine disease impacts on their quality of life.,The patients cited breathlessness as having the greatest bearing on daily life, particularly on their ability to carry out physical tasks and continue a self-care regime.,Investigations of disease impact should be incorporated into future clinical trials, particularly to assess how improving lung function affects patient perceptions and quality of life. | Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted).,Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes.,Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity.,In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified.,The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients.,Strengths and weaknesses of these statistical approaches are briefly described.,Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases).,Finally, gaps in current knowledge are described, leading to proposals for future studies. | 1 |
Asthma and chronic obstructive pulmonary disease are inflammatory lung disorders responsible for significant morbidity and mortality worldwide.,While the importance of allergic responses in asthma is well known, respiratory viral and bacterial infections and pollutants especially cigarette smoke are important factors in the pathogenesis of both diseases.,Corticosteroid treatment remains the first preference of treatment in either disease, however these therapies are not always completely effective, and are associated with side effects and steroid resistance.,Due to such limitations, development of new treatments represents a major goal for both the pharmaceutical industry and academic researchers.,There are now excellent reasons to promote NF-κB signalling intermediates and Rel family proteins as potential therapeutic targets for both asthma and chronic obstructive pulmonary disease.,This notion is supported by the fact that much of the underlying inflammation of both diseases independent of stimuli, is mediated at least in part, by NF-κB mediated signalling events in several cell types.,Also, a range of inhibitors of NF-κB signalling intermediates are now available, including DNA oligonucleotides and DNA-peptide molecules that act as NF-κB decoy sequences, small molecule inhibitors such as IKK-β inhibitors, and proteasome inhibitors affecting NF-κB signalling, that have either shown promise in animal models or have begun clinical trials in other disorders.,This review will focus on the role of NF-κB in both diseases, will discuss its suitability as a target, and will highlight recent key studies that support the potential of NF-κB as a therapeutic target in these two important inflammatory lung diseases. | 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. | 1 |
We assessed direct and indirect costs associated with COPD in Sweden and examined how these costs vary across time, age, and disease stage in a cohort of patients with COPD and matched controls in a real-world, primary care (PC) setting.,Data from electronic medical records linked to the mandatory national health registers were collected for COPD patients and a matched reference population in 52 PC centers from 2000 to 2014.,Direct health care costs (drug, outpatient or inpatient, PC, both COPD related and not COPD related) and indirect health care costs (loss of income, absenteeism, loss of productivity) were assessed.,A total of 17,479 patients with COPD and 84,514 reference controls were analyzed.,During 2013, direct costs were considerably higher among the COPD patient population (€13,179) versus the reference population (€2,716), largely due to hospital nights unrelated to COPD.,Direct costs increased with increasing disease severity and increasing age and were driven by higher respiratory drug costs and non-COPD-related hospital nights.,Indirect costs (~€28,000 per patient) were the largest economic burden in COPD patients of working age during 2013.,As non-COPD-related hospital nights represent the largest direct cost, management of comorbidities in COPD would offer clinical benefits and relieve the financial burden of disease. | This study assessed the adherence profiles to inhaled therapies and the agreement between two patient self-report adherence methods in stable COPD lpatients from seven Latin American countries.,This observational, cross-sectional, multinational, multicenter study involved 795 COPD patients (post-bronchodilator forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] <0.70).,Adherence to inhaled therapy was assessed using the specific Test of Adherence to Inhalers (10-item TAI) and the generic 8-item Morisky Medication Adherence Scale (MMAS-8) questionnaires.,The percentage agreement and the kappa index were used to compare findings.,59.6% of patients were male (69.5±8.7 years); post-bronchodilator FEV1 percent predicted was 50.0±18.6%.,Mean values for 10-item TAI and MMAS-8 questionnaires were 47.4±4.9 and 6.8±1.6, respectively.,Based on the TAI questionnaire, 54.1% of patients had good, 26.5% intermediate, and 19.4% poor adherence.,Using the MMAS-8 questionnaire, 51% had high, 29.1% medium, and 19.9% low adherence.,According to both questionnaires, patients with poor adherence had lower smoking history, schooling but higher COPD Assessment Test score, exacerbations in the past-year and post-bronchodilator FEV1.,The agreement between 10-item TAI and MMAS-8 questionnaires was moderate (Kappa index: 0.42; agreement: 64.7%).,Suboptimal adherence to medication was frequent in COPD patients from Latin America.,Low adherence was associated with worse health status impairment and more exacerbations.,There was inadequate agreement between the two questionnaires.,Greater effort should be made to improve COPD patients’ adherence to treatment, and assessment of adherence with more specific instruments, such as the TAI questionnaire, would be more convenient in these patients.,NCT02789540 | 1 |
Patients with chronic obstructive pulmonary disease (COPD) exhibit poor sleep quality and consider morning as the worst time of day for their symptoms.,While work has been done to characterize nighttime (NT) and early morning (EM) symptoms in various populations, the impact and factors associated with NT/EM symptoms among patients with COPD in the United States is not well understood.,Commercially insured patients aged ≥40 years with one or more medical claim for COPD and one or more pharmacy claim for COPD maintenance medication were identified from the HealthCore Integrated Research Database between September 1, 2010 and August 31, 2011.,Consenting respondents were asked whether they had COPD symptoms on at least three nights or at least three mornings during the past week.,Respondents were then either assigned to one of three symptom groups to complete the survey or excluded if their predefined group quota limit had been met.,Survey completers completed the survey with questions about COPD symptoms and other commonly used patient-reported outcome measures.,Respondents with NT/EM symptoms were asked about the frequency, severity, and impact of the symptoms on sleep, morning activities, and anxiety levels.,Among respondents with symptoms, 73.1% of respondents with NT symptoms (N=376) and 83% of respondents with EM symptoms (N=506) experienced at least three distinct types of symptoms over the past week, with cough being the most frequently reported symptom.,Approximately half of respondents with NT or EM symptoms perceived their symptoms as moderate to very severe, with a majority reporting their symptoms affected their NT sleep and morning activities, and more than half felt anxious due to their symptoms.,Multinomial logistic regression showed COPD patients with both or either NT/EM symptoms were associated with poorer health status compared to those without.,Improved disease management may reduce NT/EM symptoms and improve health status in patients with COPD. | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
The World Health Organization has projected that by 2030, chronic obstructive pulmonary disease (COPD) will be the third-leading cause of mortality and the seventh-leading cause of morbidity worldwide.,Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with an accelerated decline in lung function, diminished quality of life, and higher mortality.,Accurate early detection of acute exacerbations will enable early management and reduce mortality.,The aim of this study was to develop a prediction system using lifestyle data, environmental factors, and patient symptoms for the early detection of AECOPD in the upcoming 7 days.,This prospective study was performed at National Taiwan University Hospital.,Patients with COPD that did not have a pacemaker and were not pregnant were invited for enrollment.,Data on lifestyle, temperature, humidity, and fine particulate matter were collected using wearable devices (Fitbit Versa), a home air quality-sensing device (EDIMAX Airbox), and a smartphone app.,AECOPD episodes were evaluated via standardized questionnaires.,With these input features, we evaluated the prediction performance of machine learning models, including random forest, decision trees, k-nearest neighbor, linear discriminant analysis, and adaptive boosting, and a deep neural network model.,The continuous real-time monitoring of lifestyle and indoor environment factors was implemented by integrating home air quality-sensing devices, a smartphone app, and wearable devices.,All data from 67 COPD patients were collected prospectively during a mean 4-month follow-up period, resulting in the detection of 25 AECOPD episodes.,For 7-day AECOPD prediction, the proposed AECOPD predictive model achieved an accuracy of 92.1%, sensitivity of 94%, and specificity of 90.4%.,Receiver operating characteristic curve analysis showed that the area under the curve of the model in predicting AECOPD was greater than 0.9.,The most important variables in the model were daily steps walked, stairs climbed, and daily distance moved.,Using wearable devices, home air quality-sensing devices, a smartphone app, and supervised prediction algorithms, we achieved excellent power to predict whether a patient would experience AECOPD within the upcoming 7 days.,The AECOPD prediction system provided an effective way to collect lifestyle and environmental data, and yielded reliable predictions of future AECOPD events.,Compared with previous studies, we have comprehensively improved the performance of the AECOPD prediction model by adding objective lifestyle and environmental data.,This model could yield more accurate prediction results for COPD patients than using only questionnaire data. | 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 |
This retrospective, observational cohort study investigated the association of blood eosinophil counts within 1 week of hospitalization for acute exacerbation of COPD (AECOPD) with subsequent risk of all-cause and COPD-related readmission from a large integrated health system.,Electronic medical records were extracted for index hospitalization for AECOPD at all Intermountain Healthcare hospitals.,The primary outcome was the relationship of blood eosinophil count to 30-day all-cause readmission; secondary outcomes were 60-day, 90-day, and 12-month all-cause readmission, COPD-related readmission, and empiric derivation of the eosinophil count with the highest area under the curve (AUC) for predicting 30-day all-cause readmission.,Of 2445 included patients, 1935 (79%) had a blood eosinophil count <300 cells/µL and 510 (21%) had a count ≥300 cells/µL.,Using a 300-cells/μL threshold, there was no significant difference between high and low eosinophil groups in 30-day (odds ratio [OR]=1.05, 95% confidence interval [CI]=0.75-1.47) or 60-day (OR=1.15, 95% CI=0.88-1.51) all-cause readmissions.,However, patients with greater (versus lesser) eosinophil counts had increased 90-day and 12-month all-cause readmissions (OR=1.35, 95% CI=1.06-1.72, and OR=1.32, 95% CI=1.07-1.62).,COPD-related readmission rates were significantly greater for patients with greater (versus lesser) eosinophil counts at 30, 60, and 90 days and 12 months (OR range=1.52-1.97).,A total of 70 cells/µL had the most discriminatory power to predict 30-day all-cause readmission (highest AUC).,Eosinophil counts in patients with COPD were not associated with a difference in 30-day all-cause readmissions.,However, greater eosinophil counts were associated with increased risk of all-cause readmission at 90 days and 12 months and COPD-related readmission at 30, 60, and 90 days and 12 months.,Patients with eosinophils <70 cells/μL had the lowest risk for 30-day all-cause readmission.,Blood eosinophils in patients hospitalized with AECOPD may be a useful biomarker for the risk of hospital readmission. | The use of a severity score to help orientation decisions could improve the efficiency of care for acute exacerbations of COPD (AECOPD).,We previously developed a score (‘2008 score’, based on age, dyspnea grade at steady state and number of clinical signs of severity) predicting in-hospital mortality in patients with AECOPD visiting emergency departments (EDs).,External validity of this score remained to be assessed.,To test the predictive properties of the ‘2008 score’ in a population of patients hospitalized in medical respiratory wards for AECOPD, and determine whether a new score specifically derived from this population would differ from the previous score in terms of components or predictive performance.,Data from a cohort study in 1824 patients hospitalized in a medical ward for an AECOPD were analyzed.,Patients were categorized using the 2008 score and its predictive characteristics for in-hospital mortality rates were assessed.,A new score was developed using multivariate logistic regression modeling in a randomly selected derivation population sample followed by testing in the remaining population (validation sample).,Robustness of results was assessed by case-by-case validation.,The 2008 score was characterized by a c-statistic at 0.77, a sensitivity of 69% and a specificity of 76% for prediction of in-hospital mortality.,The new score comprised the same variables plus major cardiac comorbidities and was characterized by a c-statistic of 0.78, a sensitivity of 77% and specificity of 66%.,A score using simple clinical variables has robust properties for predicting the risk of in-hospital death in patients hospitalized for AECOPD.,Adding cardiac comorbidities to the original score increased its sensitivity while decreasing its specificity.,The online version of this article (doi:10.1186/s12931-014-0099-9) contains supplementary material, which is available to authorized users. | 1 |
Particulate matter with an aerodynamic diameter equal or less than 2.5 micrometers (PM2.5) is associated with the development of chronic obstructive pulmonary disease (COPD).,The mechanisms by which PM2.5 accelerates disease progression in COPD are poorly understood.,In this study, we aimed to investigate the effect of PM2.5 on lung injury in rats with hallmark features of COPD.,Cardinal features of human COPD were induced in a rat model by repeated cigarette smoke inhalation and bacterial infection for 8 weeks.,Then, from week 9 to week 16, some of these rats with COPD were subjected to real-time concentrated atmospheric PM2.5.,Lung function, pathology, inflammatory cytokines, oxidative stress, and mucus and collagen production were measured.,As expected, the COPD rats had developed emphysema, inflammation, and deterioration in lung function.,PM2.5 exposure resulted in greater lung function decline and histopathological changes, as reflected by increased Mucin (MUC) 5ac, MUC5b, Collagen I, Collagen III, and the profibrotic cytokine α-smooth muscle-actin (SMA), transforming growth factor- (TGF-) β1 in lung tissues.,PM2.5 also aggravated inflammation, increasing neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF) and cytokines including Interleukin- (IL-) 1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4.,The likely mechanism is through oxidative stress as antioxidants levels were decreased, whereas oxidants were increased, indicating a detrimental shift in the oxidant-antioxidant balance.,Altogether, these results suggest that PM2.5 exposure could promote the development of COPD by impairing lung function and exacerbating pulmonary injury, and the potential mechanisms are related to inflammatory response and oxidative stress. | Exposure to air pollution is associated with chronic obstructive pulmonary disease (COPD).,However, findings on the effects of air pollution on lung function and systemic inflammation in Chinese COPD patients are inconsistent and scarce.,This study aims to evaluate the effects of ambient air pollution on lung function parameters and serum cytokine levels in a COPD cohort in Beijing, China.,We enrolled COPD participants on a rolling basis from December 2015 to September 2017 in Beijing, China.,Follow-ups were performed every 3 months for each participant.,Serum levels of 20 cytokines were detected every 6 months.,Hourly ambient pollutant levels over the same periods were obtained from 35 monitoring stations across Beijing.,Geocoded residential addresses of the participants were used to estimate daily mean pollution exposures.,A linear mixed-effect model was applied to explore the effects of air pollutants on health in the first-year of follow-up.,A total of 84 COPD patients were enrolled at baseline.,Of those, 75 COPD patients completed the first-year of follow-up.,We found adverse cumulative effects of particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO) on the forced vital capacity % predicted (FVC % pred) in patients with COPD.,Further analyses illustrated that among COPD patients, air pollution exposure was associated with reduced levels of serum eotaxin, interleukin 4 (IL-4) and IL-13 and was correlated with increased serum IL-2, IL-12, IL-17A, interferon γ (IFNγ), monocyte displacing protein 1 (MCP-1) and soluble CD40 ligand (sCD40L).,Acute exposures to PM2.5, NO2, SO2 and CO were associated with a reduction in FVC % pred in COPD patients.,Furthermore, short-term exposure to air pollutants increased systemic inflammation in COPD patients; this may be attributed to increased Th1 and Th17 cytokines and decreased Th2 cytokines. | 1 |
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD).,We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals.,We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2.,Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. | The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4.,These cells are also present in the basal epithelium.,Such changes are likely hallmarks of epithelial mesenchymal transition (EMT).,We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells.,Endobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells).,The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope".,Slides were double stained for S100A4 and cytokeratin(s).,In the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p < 0.003.,Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p < 0.003.,Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4.,These data provide additional support for active EMT in COPD airways. | 1 |
Background: Inhaled corticosteroid (ICS)-containing medications slow rate of decline of FEV1.,Blood eosinophil (EOS) levels are associated with the degree of exacerbation reduction with ICS.,Purpose: We investigated whether FEV1 decline differs between patients with and without ICS, stratified by blood EOS level.,Patients and methods: The UK Clinical Practice Research Datalink (primary care records) and Hospital Episode Statistics (hospital records) were used to identify COPD patients aged 35 years or older, who were current or ex-smokers with ≥2 FEV1 measurements ≥6 months apart.,Prevalent ICS use and the nearest EOS count to start of follow-up were identified.,Patients were classified at baseline as higher stratum EOS (≥150 cell/µL) on ICS; higher stratum EOS not on ICS; lower stratum EOS (<150 cells/µL) on ICS; and lower stratum EOS not on ICS.,In addition, an incident ICS cohort was used to investigate the rate of FEV1 change by EOS and incident ICS use.,Mixed-effects linear regression was used to compare rates of FEV1 change in mL/year.,Results: A total of 26,675 COPD patients met our inclusion criteria (median age 69, 46% female).,The median duration of follow up was 4.2 years.,The rate of FEV1 change in prevalent ICS users was slower than non-ICS users (−12.6 mL/year vs −21.1 mL/year; P =0.001).,The rate of FEV1 change was not significantly different when stratified by EOS level.,The rate of FEV1 change in incident ICS users increased (+4.2 mL/year) vs −21.2 mL/year loss in non-ICS users; P<0.001.,In patients with high EOS, incident ICS patients showed an increase in FEV1 (+12 mL/year) compared to non-ICS users whose FEV1 decreased (−20.8 mL/year); P<0.001.,No statistical difference was seen in low EOS patients.,Incident ICS use is associated with an improvement in FEV1 change, however, over time this association is lost.,Conclusion: Regardless of blood EOS level, prevalent ICS use is associated with slower rates of FEV1 decline in COPD. | COPD is characterized by chronic bronchitis, chronic airway obstruction, and emphysema, leading to a progressive and irreversible decline in lung function.,Inflammation is central for the development of COPD.,Chronic inflammation in COPD mainly involves the infiltration of neutrophils, macrophages, lymphocytes, and other inflammatory cells into the small airways.,The contribution of resident airway structural cells to the inflammatory process is also important in COPD.,Airway remodeling consists of detrimental changes in structural tissues and cells including airway wall thickening, epithelial metaplasia, goblet cell hypertrophy, and smooth muscle hyperplasia.,Persistent airway inflammation might contribute to airway remodeling and small airway obstruction.,However, the underlying mechanisms remain unclear.,In this review, we will provide an overview of recent insights into the role of major immunoinflammatory cells in COPD airway remodeling. | 1 |
CD8 cells may contribute towards an autoimmune process in COPD.,Down regulation of T cell receptor (TCR) signalling molecules occurs in autoimmune diseases with consequent T cell dysfunction.,We hypothesise that TCR signalling is abnormal in COPD pulmonary CD8 cells.,Micro-array gene expression analysis of blood and pulmonary COPD CD8 samples was performed and compared to pulmonary CD8 cells from smoker controls (S).,We focused on the TCR signalling pathway, with validation of key findings using polymerase chain reaction and immunofluorescence.,TCR signalling molecules in COPD pulmonary CD8 cells were down regulated compared to blood CD8 cells (CD247: fold change (FC) −2.43, Q = 0.001; LCK: FC −2.25, Q = 0.01).,Micro-array analysis revealed no significant differences between COPD and S pulmonary CD8 cells.,However, PCR revealed significantly lower gene expression levels of CD247 (FC −1.79, p = 0.04) and LCK (FC −1.77, p = 0.01) in COPD compared to S pulmonary CD8 cells.,CD247 down regulation in COPD CD8 cells was confirmed by immunofluorescent staining of bronchoalveolar lavage cells: Significantly fewer COPD CD8 cells co-expressed CD247 compared to healthy non-smoker CD8 cells (mean 88.9 vs 75.2%, p<0.05) There is down regulation of TCR signalling molecules in COPD pulmonary CD8 cells.,This may cause T cell dysfunction. | Tobacco-related lung diseases, including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide.,Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory tract viral infections and can result in respiratory failure in those with advanced lung disease.,We sought to determine the mechanism underlying COPD exacerbation and host response to pathogen-derived factors.,Over a 24-month period, we assessed the viral causes for upper and lower respiratory tract infections in patients with COPD (n = 155) and control subjects (n = 103).,We collected nasal and bronchoalveolar lavage fluid and peripheral blood under baseline and exacerbated conditions.,We determined the effect of human rhinovirus (HRV) proteinases on T-cell activation in human subjects and mice.,HRVs are isolated from nasal and lung fluid from subjects with AE-COPD.,Bronchoalveolar lavage fluid and CD4 T cells from patients with COPD exhibited a TH1 and TH2 cell cytokine phenotype during acute infection.,HRV-encoded proteinase 2A activated monocyte-derived dendritic cells in vitro and induced strong TH1 and TH2 immune responses from CD4 T cells.,Intranasal administration of recombinant rhinovirus proteinase 2A in mice resulted in an increase in airway hyperreactivity, lung inflammation, and IL-4 and IFN-γ production from CD4 T cells.,Our findings suggest that patients with severe COPD show TH1- and TH2-biased responses during AE-COPD.,HRV-encoded proteinase 2A, like other microbial proteinases, could provide a TH1- and TH2-biasing adjuvant factor during upper and lower respiratory tract infection in patients with severe COPD.,Alteration of the immune response to secreted viral proteinases might contribute to worsening of dyspnea and respiratory failure in patients with COPD. | 1 |
Several studies have reported an association between chronic obstructive pulmonary disease (COPD) and periodontal diseases.,However, a large-scale population-based cohort study was previously absent from the literature.,Therefore, we evaluated the risk of periodontal diseases in patients with COPD in a nationwide population.,From the National Health Insurance claims data of Taiwan, we identified 22,332 patients with COPD who were newly diagnosed during 2000 to 2010.,For each case, two individuals without COPD were randomly selected and frequency matched by age, sex, and diagnosis year.,Both groups were followed up till the end of 2011.,The overall incidence of periodontal diseases was 1.19-fold greater in the COPD group than in the comparison group (32.2 vs 26.4 per 1000 person-years; 95% confidence interval [CI] 1.15-1.24).,Compared with non-COPD patients, the adjusted hazard ratios of patients with COPD increased with the number of emergency room visits (from 1.14 [95% CI 1.10-1.19] to 5.09 [95% CI 4.53-5.72]) and admissions (from 1.15 [95% CI 1.10-1.20] to 3.17 [95% CI 2.81-3.57]).,In addition, the adjusted hazard ratios of patients with COPD treated with inhaled corticosteroids (1.22, 95% CI 1.11-1.34) and systemic corticosteroids (1.15, 95% CI 1.07-1.23) were significantly higher than those of patients not treated with corticosteroids.,Patient with COPD are at a higher risk of developing periodontal diseases than the general population.,Our results also support that the risk of periodontal diseases is proportional to COPD control.,In addition, patients who receive corticosteroid treatment are at a higher risk of developing periodontal diseases. | The possible relationship between chronic inflammatory diseases and their co-morbidities has become an increasing focus of research.,Both chronic periodontitis and chronic obstructive pulmonary disease are neutrophilic, inflammatory conditions characterized by the loss of local connective tissue.,Evidence suggests an association and perhaps a causal link between the two diseases.,However, the nature of any relationship between them is unclear, but if pathophysiologically established may have wide-reaching implications for targeted treatments to improve outcomes and prognosis.,There have been a number of epidemiological studies undertaken demonstrating an independent association between chronic periodontitis and chronic obstructive pulmonary disease.,However, many of them have significant limitations, and drawing firm conclusions regarding causality may be premature.,Although the pathology of both these diseases is complex and involves many cell types, such as CD8 positive cells and macrophages, both conditions are predominantly characterized by neutrophilic inflammation.,Increasingly, there is evidence that the two conditions are underpinned by similar pathophysiological processes, especially centered on the functions of the neutrophil.,These include a disturbance in protease/anti-protease and redox state balance.,The association demonstrated by epidemiological studies, as well as emerging similarities in pathogenesis at the level of the neutrophil, suggest a basis for testing the effects of treatment for one condition upon the severity of the other.,Although the evidence of an independent association between chronic periodontitis and chronic obstructive pulmonary disease grows stronger, there remains a lack of definitive studies designed to establish causality and treatment effects.,There is a need for future research to be focused on answering these questions. | 1 |
Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD.,Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk.,This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.,The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.,This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks.,The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.,Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively).,Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).,Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate.,Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. | Umeclidinium (UMEC; long-acting muscarinic antagonist) plus vilanterol (VI; long-acting beta2 agonist [LABA]) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol (FP/SAL) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD).,This 12-week, multicentre, double-blind, parallel-group, double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment.,Patients (n = 717) were randomised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg.,Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, symptoms, quality of life (QoL) and safety.,Improvements with UMEC/VI versus FP/SAL were 0.080 L (95 % confidence interval: 0.046-0.113; wmFEV1) and 0.090 L (0.055-0.125; trough FEV1) (both p < 0.001).,UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL.,Both treatments demonstrated a clinically meaningful improvement in symptoms (Transition Dyspnoea Index ≥1 unit) and QoL (St George’s Respiratory Questionnaire Total score ≥4 unit decrease from baseline) over 12 weeks.,The incidence of adverse events was 28 % (UMEC/VI) and 29 % (FP/SAL); nasopharyngitis and headache were most common.,Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment.,NCT01822899 Registration date: March 28, 2013,The online version of this article (doi:10.1186/s12890-015-0092-1) contains supplementary material, which is available to authorized users. | 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. | There is a gap between prescribed asthma medication and diagnosed asthma in children and adolescents.,However, few studies have explored this issue among adults, where asthma medication is also used for the treatment of chronic obstructive pulmonary disease (COPD).,The aim of this study was to examine the relationship between prescribing of medications indicated for asthma and COPD and the recorded diagnosis for these conditions.,In a register-based study, individuals prescribed a medication indicated for asthma and COPD during 2004-2005 (Group A; n = 14 101) and patients with diagnoses of asthma or COPD recorded during 2000-2005 (Group B; n = 12 328) were identified from primary health care centers in Skaraborg, Sweden.,From a 5% random sample of the medication users (n = 670), the written medical records were accessed.,Primary outcomes: prevalence of medication and diagnoses, reasons for prescription.,Secondary outcomes: type and number of prescribed drugs and performance of peak expiratory flow or spirometry.,Medications indicated for asthma and COPD was prescribed to 5.6% of the population in primary care (n = 14 101).,Among them, an asthma diagnosis was recorded for 5876 individuals (42%), 1116 (8%) were diagnosed with COPD and 545 (4%) had both diagnoses.,The remaining 6564 individuals (46%) were lacking a recorded diagnosis.,The gap between diagnosis and medication was present in all age-groups.,Medication was used as a diagnostic tool among 30% of the undiagnosed patients and prescribed off-label for 54%.,Missed recording of ICD-codes for existing asthma or COPD accounted for 16%.,There was a large discrepancy between prescribing of medication and the prevalence of diagnosed asthma and COPD.,Consequently, the prevalence of prescriptions of medications indicated for asthma and COPD should not be used to estimate the prevalence of these conditions.,Medication was used both as a diagnostic tool and in an off-label manner.,Therefore, the prescribing of medications for asthma and COPD does not adhere to national clinical guidelines.,More efforts should be made to improve the prescribing of medication indicated for asthma and COPD so that they align with current guidelines. | 1 |
To systematically investigate the prevalence of pain, factors related with pain and pain management interventions in patients with chronic obstructive pulmonary disease (COPD).,Systematic review and meta-analysis.,PubMed (MEDLINE), EMBASE, CINAHL and PsychINFO from 1966 to December 2013.,Studies were included if they presented clinical data on pain or symptom burden in patients with COPD, or pain as a domain of quality of life (QoL).,All types of study designs were included.,Of the 1571 articles that were identified, 39 met the inclusion criteria and were included in this review.,Fourteen studies focused on pain and symptom burden (including pain) in patients with COPD and 25 studies focused on QoL using a questionnaire that included a separate pain domain.,Reported pain prevalence in high-quality studies ranged from 32 to 60%.,Included studies report that pain is more prevalent in patients with COPD compared to participants from the general population.,Comorbidity, nutritional status, QoL and several symptoms were related to pain.,None of the included studies reported a significant relationship between lung function and pain prevalence or severity.,However, studies investigating pain in patients with moderate COPD reported higher pain prevalence compared to studies in patients with severe of very severe COPD.,Although literature on this topic is limited and shows substantial heterogeneity, pain seems to be a significant problem in patients with COPD and is related to several other symptoms, comorbidity and QoL.,Data synthesis suggests that pain is more prevalent in patients with moderate COPD compared to patients with severe or very severe COPD.,Further research is needed and should focus on determining a more accurate pain prevalence, investigating the relationship between pain prevalence, disease severity and comorbidity and explore implementation and efficacy of pain management interventions in patients with COPD. | Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients.,Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype.,This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes.,These patients are therefore a priority for research and treatment.,The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection.,Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment.,Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype.,This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.,The online version of this article (doi:10.1186/1741-7015-11-181) contains supplementary material, which is available to authorized users. | 1 |
Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.,For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler.,Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).,295 and 291 patients were treated in MORACTO 1 and 2, respectively.,Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001).,Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).,Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies.,Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.,T/O reduces lung hyperinflation in COPD versus T, O or placebo and increases exercise endurance versus placebohttp://ow.ly/ml3G307XW6a | Exercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD).,We assessed the effects of glycopyrronium bromide (NVA237), a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD.,Patients were randomized to a cross-over design of once-daily NVA237 50 μg or placebo for 3 weeks, with a 14-day washout.,Exercise endurance, inspiratory capacity (IC) during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales), and transition dyspnea index were measured on Days 1 and 21 of treatment.,The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21.,A total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted).,Ninety-five patients completed the study.,On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001); the effect was also significant from Day 1, with an increase of 10%.,Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study.,This was accompanied by inverse decreases in residual volume and functional residual capacity.,NVA237 was superior to placebo (P < 0.05) in decreasing leg discomfort (Borg CR10 scale) on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime).,The safety profile of NVA237 was similar to that of the placebo.,NVA237 50 μg once daily produced immediate and significant improvement in exercise tolerance from Day 1.,This was accompanied by sustained reductions in lung hyperinflation (indicated by sustained and significant improvements in IC at isotime), and meaningful improvements in trough FEV1 and dyspnea.,Improvements in exercise endurance increased over time, suggesting that mechanisms beyond improved lung function may be involved in enhanced exercise tolerance.,(ClinicalTrials.gov Identifier: NCT01154127). | 1 |
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC).,Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047).,We identified three novel loci not previously associated with pulmonary function.,SNPs in or near DNER (smallest P JMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest P JMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest P JMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction.,The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated.,We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue.,DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers.,Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects. | 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 |
Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in chronic obstructive pulmonary disease (COPD).,Recent investigations suggest the participation of the inflammasome in the pathomechanism of airway inflammation.,The inflammasome is a cytosolic protein complex important for early inflammatory responses, by processing Interleukin-1β (IL-1β) to its active form.,Since inflammasome activation has been described for a variety of inflammatory diseases, we investigated whether this pathway plays a role in NTHi infection of the airways.,A murine macrophage cell line (RAW 264.7), human alveolar macrophages and human lung tissue (HLT) were stimulated with viable or non-viable NTHi and/or nigericin, a potassium ionophore.,Secreted cytokines were measured with ELISA and participating proteins detected via Western Blot or immunohistochemistry.,Western Blot analysis of cells and immunohistochemistry of lung tissue detected the inflammasome key components NLRP3 and caspase-1 after stimulation, leading to a significant induction of IL-1β expression (RAW: control at the lower detection limit vs.,NTHi 505±111pg/ml, p<0.01).,Inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1β and IL-18 levels (IL-1β: NTHi 24 h 17423±3198pg/ml vs.,NTHi+Z-YVAD-FMK 6961±1751pg/ml, p<0.01).,Our data demonstrate the upregulation of the NRLP3-inflammasome during NTHi-induced inflammation in respiratory cells and tissues.,Our findings concerning caspase-1 dependent IL-1β release suggest a role for the inflammasome in respiratory tract infections with NTHi which may be relevant for the pathogenesis of bacterial exacerbations in COPD. | Due to the rapid urbanization of the world population, a better understanding of the detrimental effects of exposure to urban air pollution on chronic lung disease is necessary.,Strong epidemiological evidence suggests that exposure to particulate matter (PM) air pollution causes exacerbations of pre-existing lung conditions, such as, chronic obstructive pulmonary disease (COPD) resulting in increased morbidity and mortality.,However, little is known whether a chronic, low-grade exposure to ambient PM can cause the development and progression of COPD.,The deposition of PM in the respiratory tract depends predominantly on the size of the particles, with larger particles deposited in the upper and larger airways and smaller particles penetrating deep into the alveolar spaces.,Ineffective clearance of this PM from the airways could cause particle retention in lung tissues, resulting in a chronic, low-grade inflammatory response that may be pathogenetically important in both the exacerbation, as well as, the progression of lung disease.,This review focuses on the adverse effects of exposure to ambient PM air pollution on the exacerbation, progression, and development of COPD. | 1 |
The aim of this study was to investigate the vascular alteration of the whole lung and individual lobes in patients with COPD, and assess the association between pulmonary vessels and the extent and distribution of emphysema as well as pulmonary function by a 3-dimensional automated approach.,A total of 83 computed tomography images from COPD patients were analyzed.,Automated computerized approach was used to measure the total number of vessels at the fifth generation.,The extent of emphysema (%LAA-950) in the whole lung and individual lobes were also calculated automatically.,The association between the vascular number and the extent and distribution of emphysema, as well as the pulmonary function were assessed.,Both the vascular number of fifth generation in the upper lobe and in the lower lobe were significantly negatively correlated with %LAA-950 (P < 0.05).,Furthermore, there were significant, yet weak correlations between the vascular number and FEV1% predicted (R = 0.556, P = 0.039) and FEV1/FVC (R = 0.538, P = 0.047).,In contrast, the vascular numbers were strongly correlated with DLco (R = 0.770, P = 0.003).,Finally, the vascular number correlated closer with %LAA-950 of upper lobes than with %LAA-950 of lower lobes.,Pulmonary vessel alteration can be measured; it is related to the extent of emphysema rather than the distribution of emphysema. | The Wnt pathway mediates differentiation of epithelial tissues; depending on the tissue types, Wnt can either drive or inhibit the differentiation process.,We hypothesized that key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the epithelial differentiated state.,Microarrays were used to assess the expression of Wnt-related genes in the small airway epithelium (SAE) obtained via bronchoscopy and brushing of healthy nonsmokers, healthy smokers, and smokers with COPD.,Thirty-three of 56 known Wnt-related genes were expressed in the SAE.,Wnt pathway downstream mediators β-catenin and the transcription factor 7-like 1 were down-regulated in healthy smokers and smokers with COPD, as were many Wnt target genes.,Among the extracellular regulators that suppress the Wnt pathway, secreted frizzled-related protein 2 (SFRP2), was up-regulated 4.3-fold in healthy smokers and 4.9-fold in COPD smokers, an observation confirmed by TaqMan Real-time PCR, Western analysis and immunohistochemistry.,Finally, cigarette smoke extract mediated up-regulation of SFRP2 and down-regulation of Wnt target genes in airway epithelial cells in vitro.,Smoking down-regulates the Wnt pathway in the human airway epithelium.,In the context that Wnt pathway plays an important role in differentiation of epithelial tissues, the down-regulation of Wnt pathway may contribute to the dysregulation of airway epithelium differentiation observed in smoking-related airway disorders. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD) are an important measure of disease severity in terms of impaired disease progression, increased recovery time, healthcare resource utilization, overall morbidity and mortality.,We aimed to quantify exacerbation and healthcare resource utilization rates among COPD patients in Sweden with respect to baseline treatments, exacerbation history, and comorbidities.,Patients with a COPD or chronic bronchitis (CB) diagnosis in secondary care at age of ≥40 years on 1.7.2009 were identified and followed until 1.7.2010 or death.,Severe exacerbations were defined as hospitalizations due to respiratory disease, and healthcare resource utilization was measured by all-cause hospitalizations and secondary care visits.,Poisson regression was used adjusting for age, gender, time since COPD/CB diagnosis, and Charlson comorbidity index.,In 88,548 patients (54% females, mean age 72 years), previous respiratory hospitalizations and current high use of COPD medication (double or triple therapy) predicted an 8.3-fold increase in severe exacerbation rates and 1.8-fold increase in healthcare resource utilization rates in the following year, compared to patients without combination treatment and/or history of severe exacerbations.,COPD/CB patients with history of severe exacerbations and high use of COPD medication experienced a significantly increased rate of severe exacerbations and healthcare resource utilization during the one-year follow-up.,The online version of this article (10.1186/s12890-018-0573-0) contains supplementary material, which is available to authorized users. | COPD often coexists with chronic conditions that may influence disease prognosis.,We investigated associations between chronic (co)morbidities and exacerbations in primary care COPD patients.,Retrospective cohort study based on 2012-2013 electronic health records from 179 Dutch general practices.,Comorbidities from patients with physician-diagnosed COPD were categorized according to International Classification of Primary Care (ICPC) codes.,Chi-squared tests, uni- and multivariable logistic, and Cox regression analyses were used to study associations with exacerbations, defined as oral corticosteroid prescriptions.,Fourteen thousand six hundred three patients with COPD could be studied (mean age 67 (SD 12) years, 53% male) for two years.,At baseline 12,826 (88%) suffered from ≥1 comorbidities, 3263 (22%) from ≥5.,The most prevalent comorbidities were hypertension (35%), coronary heart disease (19%), and osteoarthritis (18%).,Several comorbidities showed statistically significant associations with frequent (i.e., ≥2/year) exacerbations: heart failure (odds ratio [OR], 95% confidence interval: 1.72; 1.38-2.14), blindness & low vision (OR 1.46; 1.21-1.75), pulmonary cancer (OR 1.85; 1.28-2.67), depression 1.48; 1.14-1.91), prostate disorders (OR 1.50; 1.13-1.98), asthma (OR 1.36; 1.11-1.70), osteoporosis (OR 1.41; 1.11-1.80), diabetes (OR 0.80; 0.66-0.97), dyspepsia (OR 1.25; 1.03-1.50), and peripheral vascular disease (OR 1.20; 1.00-1.45).,From all comorbidity categories, having another chronic respiratory disease beside COPD showed the highest risk for developing a new exacerbation (Cox hazard ratio 1.26; 1.17-1.36).,Chronic comorbidities are highly prevalent in primary care COPD patients.,Several chronic comorbidities were associated with having frequent exacerbations and increased exacerbation risk. | 1 |
Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event.,To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD.,In this double-blind, placebo-controlled study, COPD patients (40-80 years, ≥10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 µg, 50 µg, 100 µg, 250 µg, 500 µg, or 750 µg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period.,The primary endpoint was change from baseline in post-bronchodilator FEV1 at week 12.,Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George's Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability.,There was no difference in change from baseline FEV1 at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 µg and placebo: −0.004L (95% CrI: −0.051L to 0.042L)).,Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations.,Plasma PK increased in a dose proportional manner.,The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related.,The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD.,However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted. | We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).,Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo.,Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days.,Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sGaw) were measured.,In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively).,The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001).,In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo.,The average FEV1(0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009).,In both studies, lung volumes and sGaw showed greater RPL554 combination treatment effects versus monotherapy.,RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.,The dual PDE3 and PDE4 inhibitor RPL554 causes additional bronchodilation when combined with commonly used short- or long-acting bronchodilatorshttp://ow.ly/CUYi30lDcYW | 1 |
MiR‐148 is a negative regulator of autophagy 16‐like 1 (ATG16L1), a gene implicated in the pathogenesis of ventilator‐associated pneumonia (VAP).,Therefore, the role of miR‐148 polymorphism in the pathogenesis of VAP was studied here.,The expression of miR‐148, ATG16L1, Beclin‐I, LC3‐II, TNF‐α and IL‐6 in serum and peripheral blood mononuclear cells (PBMCs) of VAP patients was detected to study their relationship in the pathogenesis of VAP.,Chronic obstructive pulmonary disease patients carrying the AA/AG genotypes of miR‐148 rs4719839 single nucleotide polymorphism (SNP) were more prone to VAP due to the higher expression of miR‐148, TNF‐α and IL‐6 along with suppressed expression of ATG16L1, Beclin‐I and LC3‐II in their serum and PBMCs.,Transfection of miR‐148 mimics to primary PBMCs genotyped as GG and AA decreased the expression of ATG16L1, Beclin‐I and LC3‐II.,Finally, cells carrying the AA genotype of rs4719839 SNP were more sensitive to the role of LPS stimulation in suppressing ATG16L1, Beclin‐I and LC3‐II expression while activating TNF‐α and IL‐6 expression.,Our work presented detailed evidence, suggesting that the rs4719839 polymorphism can affect the risk of VAP. | Chronic obstructive pulmonary disease (COPD) is related to endothelial dysfunction and the impaired generation of nitric oxide (NO) from L-arginine by the endothelial NO synthase (eNOS).,The relationship between eNOS dysfunctionality and airway inflammation is unknown.,We assessed serum asymmetric and symmetric dimethylarginine (ADMA and SDMA) and nitrite/nitrate concentrations, indicators of eNOS function, in patients with COPD and correlated them with markers of inflammation.,We recruited 15 control smokers, 29 patients with stable and 32 patients with exacerbated COPD requiring hospitalization (20 of them were measured both at admission and discharge).,Serum L-arginine, ADMA, SDMA, nitrite and nitrate were measured and correlated with airway inflammatory markers (fractional exhaled nitric oxide concentration - FENO, sputum nitrite and nitrate, sputum cellularity), serum C-reactive protein - CRP, white blood cell count, lung function and blood gases.,ANOVA, t-tests and Pearson correlation were used (mean ± SD or geometric mean ± geometric SD for nitrite/nitrate).,Serum L-arginine/ADMA, a marker of substrate availability for eNOS, was lower in stable (214 ± 58, p < 0.01) and exacerbated COPD (231 ± 68, p < 0.05) than in controls (287 ± 64).,The serum concentration of SDMA, a competitor of L-arginine transport, was elevated during an exacerbation (0.78 ± 0.39 μM) compared to stable patients (0.53 ± 0.14 μM, p < 0.01) and controls (0.45 ± 0.14 μM, p < 0.001).,ADMA correlated with blood neutrophil percentage (r = 0.36, p < 0.01), FENO (r = 0.42, p < 0.01) and a tendency for positive association was observed to sputum neutrophil count (r = 0.33, p = 0.07).,SDMA correlated with total sputum inflammatory cell count (r = 0.61, p < 0.01) and sputum neutrophil count (r = 0.62, p < 0.01).,Markers were not related to lung function, blood gases or CRP.,L-arginine/ADMA was unchanged, but serum SDMA level decreased (0.57 ± 0.42 μM, p < 0.05) after systemic steroid treatment of the exacerbation.,Serum nitrite level increased in stable and exacerbated disease (4.11 ± 2.12 and 4.03 ± 1.77 vs. control: 1.61 ± 1.84 μM, both p < 0.001).,Our data suggest impaired eNOS function in stable COPD, which is transiently aggravated during an exacerbation and partly reversed by systemic steroid treatment.,Serum ADMA and SDMA correlate with airway inflammatory markers implying a possible effect of anti-inflammatory therapy on endothelial dysfunction.,Serum nitrite can serve as a compensatory pool for impaired endothelial NO generation. | 1 |
Increasing availability of therapeutic options for COPD may drive new treatment pathways.,This study describes COPD treatment in France, focusing on identifying initial treatment modifications in patients with COPD who either initiated long-acting bronchodilator (LABD)-based therapy or escalated to triple therapy (long-acting muscarinic antagonist [LAMA] + long-acting β2-agonist [LABA] + inhaled corticosteroid [ICS]).,This retrospective analysis of patients with COPD in a large general practitioner database (IQVIA Longitudinal Patient Database) in France included two cohorts: Cohort 1 - new initiators of LABD-based therapy (LAMA, LABA, LAMA + LABA, LAMA + ICS, LABA + ICS or LAMA + LABA + ICS); Cohort 2 - patients escalating to triple therapy from mono- or dual-bronchodilator-based maintenance treatment.,Both cohorts were indexed on the date of initiation/escalation (January 2008-December 2013), and the first treatment modification (at class level) within the 18-month post-index observational period was described.,Five mutually exclusive outcomes were defined: continuous use (no modification), discontinuation (permanent [≥91 days with no restart] or temporary [≥91 days with subsequent restart]), switch, and augmentation (Cohort 1 only).,Exploratory analysis of Cohort 1 explored potential drivers of treatment initiation.,Overall, 5,065 patients initiated LABD-based therapy (Cohort 1), and 501 escalated to triple therapy (Cohort 2).,In Cohort 1, 7.0% of patients were continuous users, 46.5% discontinued permanently, 28.5% discontinued temporarily, 2.8% augmented (added LAMA and/or LABA and/or ICS), and 15.2% switched therapy.,In Cohort 2, 18.2% of patients were continuous users, 7.2% discontinued permanently, 27.9% discontinued temporarily, and 46.7% switched therapy.,Exploratory analyses showed that time since COPD diagnosis was first recorded, pre-index exacerbation events, and concomitant medical conditions were potential drivers of initial maintenance treatment choices.,Discontinuation among new initiators of LABD-based therapy was high in France, whereas few switched or augmented treatment.,In comparison, permanent discontinuation within 18 months was low in patients escalating to triple therapy. | 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. | 1 |
Non-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future.,Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes.,We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD) and clinically relevant disease phenotypes.,Breath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of-flight mass spectrometry.,Subjects with COPD also underwent sputum induction.,Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis.,Comparing COPD versus healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance.,Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%.,The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74.,Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy.,Models were constructed which classified subjects with ≥2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95.,Potential biomarkers correlated to clinical variables were identified in each subgroup.,The exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups.,If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease. | Airway inflammation in COPD can be measured using biomarkers such as induced sputum and FeNO.,This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA).,In 127 COPD patients (mean FEV1 61%), pulmonary function, FeNO, plasma CRP and TNF-α, sputum differential cell counts and sputum IL8 (pg/ml) were measured.,Principal components analysis as well as multivariate analysis was performed.,PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-α (20.2%), (2) Sputum eosinophils % and FeNO (18.2%), (3) Bronchodilator reversibility, FEV1 and IC (15.1%) and (4) CRP (11.4%).,These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2.,COPD is a multi dimensional disease.,Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased FeNO.,We confirm dissociation between airway inflammation and lung function in this cohort of patients. | 1 |
Cigarette smoking causes Chronic Obstructive Pulmonary Disease (COPD), the 3rd leading cause of death in the U.S.,CFTR ion transport dysfunction has been implicated in COPD pathogenesis, and is associated with chronic bronchitis.,However, susceptibility to smoke induced lung injury is variable and the underlying genetic contributors remain unclear.,We hypothesized that presence of CFTR mutation heterozygosity may alter susceptibility to cigarette smoke induced CFTR dysfunction.,Consequently, COPD patients with chronic bronchitis may have a higher rate of CFTR mutations compared to the general population.,Primary human bronchial epithelial cells derived from F508del CFTR heterozygotes and mice with (CFTR+/-) and without (CFTR+/+) CFTR heterozygosity were exposed to whole cigarette smoke (WCS); CFTR-dependent ion transport was assessed by Ussing chamber electrophysiology and nasal potential difference measurements, respectively.,Caucasians with COPD and chronic bronchitis, age 40 to 80 with FEV1/FVC < 0.70 and FEV1 < 60% predicted, were selected for genetic analysis from participants in the NIH COPD Clinical Research Network’s Azithromycin for Prevention of Exacerbations of COPD in comparison to 32,900 Caucasian women who underwent prenatal genetic testing.,Genetic analysis involved an allele-specific genotyping of 89 CFTR mutations.,Exposure to WCS caused a pronounced reduction in CFTR activity in both CFTR (+/+) cells and F508del CFTR (+/-) cells; however, neither the degree of decrement (44.7% wild-type vs.,53.5% F508del heterozygous, P = NS) nor the residual CFTR activity were altered by CFTR heterozygosity.,Similarly, WCS caused a marked reduction in CFTR activity measured by NPD in both wild type and CFTR heterozygous mice, but the severity of decrement (91.1% wild type vs.,47.7% CF heterozygous, P = NS) and the residual activity were not significantly affected by CFTR genetic status.,Five of 127 (3.9%) COPD patients with chronic bronchitis were heterozygous for CFTR mutations which was not significantly different from controls (4.5%) (P = NS).,The magnitude of WCS induced reductions in CFTR activity was not affected by the presence of CFTR mutation heterozygosity.,CFTR mutations do not increase the risk of COPD with chronic bronchitis.,CFTR dysfunction due to smoking is primarily an acquired phenomenon and is not affected by the presence of congenital CFTR mutations. | Given the relative abundance and toxic potential of acrolein in inhaled cigarette smoke, it is surprising how little is known about the pulmonary and systemic effects of acrolein.,Here we test the hypothesis whether systemic administration of acrolein could cause endoplasmic reticulum (ER) stress, and lung cell apoptosis, leading to the enlargement of the alveolar air spaces in rats.,Acute and chronic effects of intraperitoneally administered acrolein were tested.,Mean alveolar airspace area was measured by using light microscopy and imaging system software.,TUNEL staining and immunohistochemistry (IHC) for active caspase 3 and Western blot analysis for active caspase 3, and caspase 12 were performed to detect apoptosis.,The ER-stress related gene expression in the lungs was determined by Quantitative real-time PCR analysis.,Acrolein-protein adducts in the lung tissue were detected by IHC.,Acute administration of acrolein caused a significant elevation of activated caspase 3, upregulation of VEGF expression and induced ER stress proteins in the lung tissue.,The chronic administration of acrolein in rats led to emphysematous lung tissue remodeling.,TUNEL staining and IHC for cleaved caspase 3 showed a large number of apoptotic septal cells in the acrolein-treated rat lungs.,Chronic acrolein administration cause the endoplasmic reticulum stress response manifested by significant upregulation of ATF4, CHOP and GADd34 expression.,In smokers with COPD there was a considerable accumulation of acrolein-protein adducts in the inflammatory, airway and vascular cells.,Systemic administration of acrolein causes endoplasmic reticulum stress response, lung cell apoptosis, and chronic administration leads to the enlargement of the alveolar air spaces and emphysema in rats.,The substantial accumulation of acrolein-protein adducts in the lungs of COPD patients suggest a role of acrolein in the pathogenesis of emphysema. | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the main contributors to the global burden of disease.,The aim of this systematic review was to quantify the disease burden of COPD in China and to determine the risk factors of the disease.,The number of studies included in the review was 47 with an average quality assessment score of 7.70 out of 10.,Reported COPD prevalence varied between 1.20% and 8.87% in different provinces/cities across China.,The prevalence rate of COPD was higher among men (7.76%) than women (4.07%).,The disease was more prevalent in rural areas (7.62%) than in urban areas (6.09%).,The diagnostic rate of COPD patients in China varied from 23.61% to 30.00%.,The percentage of COPD patients receiving outpatient treatment was around 50%, while the admission rate ranged between 8.78% and 35.60%.,Tobacco exposure and biomass fuel/solid fuel usage were documented as two important risk factors of COPD.,COPD ranked among the top three leading causes of death in China.,The direct medical cost of COPD ranged from 72 to 3,565 USD per capita per year, accounting for 33.33% to 118.09% of local average annual income.,The most commonly used scales for the assessment of quality of life (QoL) included Saint George Respiratory Questionnaire, Airways Questionnaire 20, SF-36, and their revised versions.,The status of QoL was worse among COPD patients than in non-COPD patients, and COPD patients were at higher risks of depression.,The COPD burden in China was high in terms of economic burden and QoL.,In view of the high smoking rate and considerable concerns related to air pollution and smog in China, countermeasures need to be taken to improve disease prevention and management to reduce disease burdens raised by COPD. | Different definitions used for chronic obstructive pulmonary disease (COPD) preclude getting reliable prevalence estimates.,Study objective was to find the prevalence of COPD as per standard Global Initiative for Chronic Obstructive Lung Disease definition, risk factors associated, and treatment seeking in adults >30 years.,Community-based cross-sectional study was conducted in Delhi, among 1200 adults, selected by systematic random sampling.,Pretested questionnaire was used to interview all subjects and screen for symptoms of COPD.,Postbronchodilator spirometry was done to confirm COPD.,Adjusted odds ratio (aOR) was calculated by multivariable analysis to examine the association of risk factors with COPD.,Receiver operating characteristic (ROC) curve was developed to assess predictability.,Results: The prevalence of COPD was 10.1% (95% confidence interval [CI] 8.5, 11.9%).,Tobacco smoking was the strongest risk factor associated (aOR 9.48; 95% CI 4.22, 14.13) followed by environmental tobacco smoke (ETS), occupational exposure, age, and biomass fuel.,Each pack-year of smoking increased 15% risk of COPD.,Ex-smokers had 63% lesser risk compared to current smokers.,Clinical allergy seems to preclude COPD (aOR 0.06; 95% CI 0.02, 0.37).,ROC analysis showed 94.38% of the COPD variability can be assessed by this model (sensitivity 57.4%; positive predictive value 93.3%).,Only 48% patients were on treatment.,Treatment continuation was impeded by its cost.,COPD prevalence in the region of Delhi, India, is high, and our case-finding population study identified a high rate of patients who were not on any treatment.,Our study adds to creating awareness on the importance of smoking cessation, early diagnosis of COPD, and the need for regular treatment. | 1 |
‘Clinically important deterioration’ (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations.,ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 μg/formoterol fumarate (FF) 12 μg.,This pooled post-hoc analysis assessed the effects of AB/FF 400/12 μg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD.,A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV1; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George’s Respiratory Questionnaire (SGRQ) total score (≥4 units).,A ‘sustained’ CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time.,CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18.,AB/FF 400/12 μg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 μg (HR 0.82, p < 0.01), and 15% versus AB 400 μg (HR 0.85, p < 0.05).,Similarly, AB/FF 400/12 μg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 μg (HR 0.78, p < 0.01).,AB/FF 400/12 μg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV1 and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 μg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 μg (first CID, p < 0.05).,AB/FF 400/12 μg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies.,Clinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011.,Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.,The online version of this article (doi:10.1186/s12931-017-0583-0) contains supplementary material, which is available to authorized users. | The 2013 GOLD classification system for COPD distinguishes four stages: A (low symptoms, low exacerbation risk), B (high symptoms, low risk), C (low symptoms, high risk) and D (high symptoms, high risk).,Assessment of risk is based on exacerbation history and airflow obstruction, whatever results in a higher risk grouping.,The previous system was solely based on airflow obstruction.,Earlier studies compared the predictive performance of new and old classification systems with regards to mortality and exacerbations.,The objective of this study was to compare the ability of both classifications to predict the number of future (total and severe) exacerbations and mortality in a different patient population, and to add an outcome measure to the comparison: lung function decline.,Patient-level data from the UPLIFT trial were used to analyze 4-year survival in a Weibull model, with GOLD stages at baseline as covariates.,A generalized linear model was used to compare the numbers of exacerbations (total and severe) per stage.,Analyses were repeated with stages C and D divided into substages depending on lung function and exacerbation history.,Lung function decline was analysed in a repeated measures model.,Mortality increased from A to D, but there was no difference between B and C.,For the previous GOLD stages 2-4, survival curves were clearly separated.,Yearly exacerbation rates were: 0.53, 0.72 and 0.80 for stages 2-4; and 0.35, 0.45, 0.58 and 0.74 for A-D.,Annual rates of lung function decline were: 47, 38 and 26 ml for stages 2-4 and 44, 48, 38 and 39 for stages A-D.,With regards to model fit, the new system performed worse at predicting mortality and lung function decline, and better at predicting exacerbations.,Distinguishing between the sub-stages of high-risk led to substantial improvements.,The new classification system is a modest step towards a phenotype approach.,It is probably an improvement for the prediction of exacerbations, but a deterioration for predicting mortality and lung function decline.,ClinicalTrials.gov NCT00144339 (September 2, 2005).,The online version of this article (doi:10.1186/1471-2466-14-163) contains supplementary material, which is available to authorized users. | 1 |
Cardiovascular diseases (CVDs) are arguably the most important comorbidities in chronic obstructive pulmonary disease (COPD).,CVDs are common in people with COPD, and their presence is associated with increased risk for hospitalization, longer length of stay and all-cause and CVD-related mortality.,The economic burden associated with CVD in this population is considerable and the cumulative cost of treating comorbidities may even exceed that of treating COPD itself.,Our understanding of the biological mechanisms that link COPD and various forms of CVD has improved significantly over the past decade.,But despite broad acceptance of the prognostic significance of CVDs in COPD, there remains widespread under-recognition and undertreatment of comorbid CVD in this population.,The reasons for this are unclear; however institutional barriers and a lack of evidence-based guidelines for the management of CVD in people with COPD may be contributory factors.,In this review, we summarize current knowledge relating to the prevalence and incidence of CVD in people with COPD and the mechanisms that underlie their coexistence.,We discuss the implications for clinical practice and highlight opportunities for improved prevention and treatment of CVD in people with COPD.,While we advocate more active assessment for signs of cardiovascular conditions across all age groups and all stages of COPD severity, we suggest targeting those aged under 65 years.,Evidence indicates that the increased risks for CVD are particularly pronounced in COPD patients in mid-to-late-middle-age and thus it is in this age group that the benefits of early intervention may prove to be the most effective. | Exacerbations of chronic obstructive pulmonary disease (COPD) are an important measure of disease severity in terms of impaired disease progression, increased recovery time, healthcare resource utilization, overall morbidity and mortality.,We aimed to quantify exacerbation and healthcare resource utilization rates among COPD patients in Sweden with respect to baseline treatments, exacerbation history, and comorbidities.,Patients with a COPD or chronic bronchitis (CB) diagnosis in secondary care at age of ≥40 years on 1.7.2009 were identified and followed until 1.7.2010 or death.,Severe exacerbations were defined as hospitalizations due to respiratory disease, and healthcare resource utilization was measured by all-cause hospitalizations and secondary care visits.,Poisson regression was used adjusting for age, gender, time since COPD/CB diagnosis, and Charlson comorbidity index.,In 88,548 patients (54% females, mean age 72 years), previous respiratory hospitalizations and current high use of COPD medication (double or triple therapy) predicted an 8.3-fold increase in severe exacerbation rates and 1.8-fold increase in healthcare resource utilization rates in the following year, compared to patients without combination treatment and/or history of severe exacerbations.,COPD/CB patients with history of severe exacerbations and high use of COPD medication experienced a significantly increased rate of severe exacerbations and healthcare resource utilization during the one-year follow-up.,The online version of this article (10.1186/s12890-018-0573-0) contains supplementary material, which is available to authorized users. | 1 |
COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal.,Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD.,Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases.,Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS)-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L) mice.,Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study.,Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study) or in week 14, 16, 18 and 20 (chronic study).,Inflammatory parameters were measured in bronchoalveolar lavage (BAL) and lung tissue.,Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study.,In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment.,Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers.,In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis.,Emphysema and atherosclerosis development were unaffected after MSC treatment.,These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study. | In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD).,The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models.,A systematic search of electronic databases was performed.,Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3).,The pooled Hedges’s g with 95% confidence intervals (95% CIs) was adopted to assess the effect size.,Random effect model was used due to the heterogeneity between the studies.,A total of 20 eligible studies were included in the current systematic review.,The overall meta-analysis showed that MSC administration was significantly in favor of attenuating acute lung injury (Hedges’s g = -2.325 ± 0.145 with 95% CI: -2.609 ~ -2.040, P < 0.001 for mean linear intercept, MLI; Hedges’s g = -3.488 ± 0.504 with 95% CI: -4.476 ~ -2.501, P < 0.001 for TUNEL staining), stimulating lung tissue repair (Hedges’s g = 3.249 ± 0.586 with 95% CI: 2.103~ 4.394, P < 0.001) and improving lung function (Hedges’s g = 2.053 ± 0.408 with 95% CI: 1.253 ~ 2.854, P< 0.001).,The mechanism of MSC therapy in COPD is through ameliorating airway inflammation (Hedges’s g = -2.956 ± 0.371 with 95% CI: -3.683 ~ -2.229, P< 0.001) and stimulating cytokine synthesis that involves lung tissue repair (Hedges’s g = 3.103 ± 0.734 with 95% CI: 1.664 ~ 4.541, P< 0.001).,This systematic review and meta-analysis suggest a promising role for MSCs in COPD treatment.,Although the COPD models may not truly mimic COPD patients, these pre-clinical studies demonstrate that MSC hold promise in the treatment of chronic lung diseases including COPD.,The mechanisms of MSCs role in preclinical COPD treatment may be associated with attenuating airway inflammation as well as stimulating lung tissue repair. | 1 |
Diverse risk factors intercede the outcomes of coronavirus disease 2019 (COVID-19).,We conducted this retrospective cohort study with a cohort of 1016 COVID-19 patients diagnosed in May 2020 to identify the risk factors associated with morbidity and mortality outcomes.,Data were collected by telephone-interview and reviewing records using a questionnaire and checklist.,The study identified morbidity and mortality risk factors on the 28th day of the disease course.,The majority of the patients were male (64.1%) and belonged to the age group 25-39 years (39.4%).,Urban patients were higher in proportion than rural (69.3% vs.,30.7%).,Major comorbidities included 35.0% diabetes mellitus (DM), 28.4% hypertension (HTN), 16.6% chronic obstructive pulmonary disease (COPD), and 7.8% coronary heart disease (CHD).,The morbidity rate (not-cured) was 6.0%, and the mortality rate (non-survivor) was 2.5%.,Morbidity risk factors included elderly (AOR = 2.56, 95% CI = 1.31-4.99), having comorbidity (AOR = 1.43, 95% CI = 0.83-2.47), and smokeless tobacco use (AOR = 2.17, 95% CI = 0.84-5.61).,The morbidity risk was higher with COPD (RR = 2.68), chronic kidney disease (CKD) (RR = 3.33) and chronic liver disease (CLD) (RR = 3.99).,Mortality risk factors included elderly (AOR = 7.56, 95% CI = 3.19-17.92), having comorbidity (AOR = 5.27, 95% CI = 1.88-14.79) and SLT use (AOR = 1.93, 95% CI = 0.50-7.46).,The mortality risk was higher with COPD (RR = 7.30), DM (RR = 2.63), CHD (RR = 4.65), HTN (RR = 3.38), CKD (RR = 9.03), CLD (RR = 10.52) and malignant diseases (RR = 9.73).,We must espouse programme interventions considering the morbidity and mortality risk factors to condense the aggressive outcomes of COVID-19. | 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 |
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. | Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α).,Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH).,The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD).,The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.,We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls.,COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema).,Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.,Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001).,A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001).,Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).,Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD.,Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later. | 1 |
Saliva is increasingly promoted as an alternative diagnostic bio-sample to blood; however its role in respiratory disease requires elucidation.,Our aim was to investigate whether C-reactive protein (CRP), procalcitonin (PCT) and neutrophil elastase (NE) could be measured in unstimulated whole saliva, and to explore differences between COPD patients and controls with normal lung function.,We also determined the relationship between these salivary biomarkers and self-reported COPD-relevant metrics.,Salivary CRP, PCT and NE levels were measured at each of 3 visits over a 14-day period alongside spirometry and a daily self-assessment dairy in 143 subjects: 20 never-smokers and 25 smokers with normal spirometry; 98 COPD patients [GOLD Stage I, 16; Stage II, 32; Stage III, 39; Stage IV, 11].,Twenty-two randomly selected subjects provided simultaneous blood samples.,Levels of each salivary biomarker could distinguish between the above cohorts.,Significant differences remained for salivary CRP and NE (p < 0.05) following adjustment for age, gender, sampling time, gum disease and total co-morbidities; but not for BMI except for salivary NE, which remained higher in smokers compared to non-smokers and stable COPD subjects (p < 0.001).,Patients with acute COPD exacerbations had a median increase in all 3 salivary biomarkers (p < 0.001); CRP: median 5.74 ng/ml, [interquartile range (IQR) 2.86-12.25], PCT 0.38 ng/ml, [IQR 0.22-0.94], and NE 539 ng/ml, [IQR 112.25-1264].,In COPD patients, only salivary CRP and PCT levels correlated with breathing scores (r = 0.14, p < 0.02; r = 0.13, p < 0.03 respectively) and sputum features but not with activities of daily living.,Salivary CRP and PCT concentrations strongly correlated with serum counterparts [r = 0.82, (95 % CI: 0.72-0.87), p < 0.001 by Spearman’s; and r = 0.53, (95 % CI: 0.33-0.69), p < 0.006 respectively]; salivary NE did not.,CRP, PCT and NE were reliably and reproducibly measured in saliva, providing clinically-relevant information on health status in COPD; additionally NE distinguished smoking status.,All 3 salivary biomarkers increased during COPD exacerbations, with CRP and PCT correlating well with patient-derived clinical metrics.,These results provide the conceptual basis for further development of saliva as a viable bio-sample in COPD monitoring and exacerbation management.,The online version of this article (doi:10.1186/s12931-015-0219-1) contains supplementary material, which is available to authorized users. | Reports regarding gender-related differences in COPD expression have provided conflicting results.,In the French Initiatives BPCO real-world cohort, which contained 688 patients (146 women) when data were extracted, women were matched with men (1:3 ratio: n = 107:275) on age (5-year intervals) and FEV1 (5% predicted intervals) and comparisons were performed using univariate logistic regressions.,For a given age and level of airflow obstruction, women with COPD had higher BOD scores due to more pronounced dyspnea and lower BMI, suggesting worse prognosis, and were more likely to exhibit anxiety, suggesting the need for specific assessment and care. | 1 |
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated.,The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung.,We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort.,Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]).,Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]).,In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers.,Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab.,In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells.,However, we were unable to identify evidence for an association between Asp358Ala and COPD. | Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period.,However, longer period follow-up studies are still lacking.,Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.,A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV1, 56% predicted) were included in the prospective study.,We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years.,Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.,IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance.,In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02].,CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.,The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.,No.:NCT00605540 | 1 |
Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient’s health-related quality of life (HRQL).,While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health.,This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George’s Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments.,Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions.,Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences.,In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease.,Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions.,The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions.,For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL.,All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities.,Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.,The online version of this article (doi:10.1186/s12890-016-0238-9) contains supplementary material, which is available to authorized users. | Acute exacerbations may cause deteriorations in the health status of subjects with chronic obstructive pulmonary disease (COPD).,The present study prospectively evaluated the effects of such exacerbations on the health status and pulmonary function of subjects with COPD over a 6-month period, and examined whether those subjects showed a steeper decline in their health status versus those subjects without exacerbations.,A total of 156 subjects with COPD (mean age 71.4 ± 6.3 years) were included in the analysis.,At baseline and after 6 months, their pulmonary function and health status were evaluated using the Chronic Respiratory Disease Questionnaire (CRQ) and the St.,George's Respiratory Questionnaire (SGRQ).,An acute exacerbation was defined as a worsening of respiratory symptoms requiring the administration of systemic corticosteroids or antibiotics, or both.,Forty-eight subjects experienced one or more exacerbations during the 6-month study period, and showed a statistically and clinically significant decline in Symptom scores on the SGRQ, whereas subjects without exacerbations did not show a clinically significant decline.,Logistic multiple regression analyses confirmed that the exacerbations significantly influenced the Fatigue and Mastery domains of the CRQ, and the Symptoms in the SGRQ.,Twelve subjects with frequent exacerbations demonstrated a more apparent decline in health status.,Although pulmonary function did not significantly decline during the 6-month period, acute exacerbations were responsible for a decline in health status.,To minimize deteriorations in health status, one must prevent recurrent acute exacerbations and reduce the exacerbation frequencies in COPD subjects. | 1 |
Pulmonary rehabilitation is a highly effective treatment for people with chronic lung disease but remains underused across the world.,Recent years have seen the emergence of new program models that aim to improve access and uptake, including telerehabilitation and low-cost, home-based models.,This workshop was convened to achieve consensus on the essential components of pulmonary rehabilitation and to identify requirements for successful implementation of emerging program models.,A Delphi process involving experts from across the world identified 13 essential components of pulmonary rehabilitation that must be delivered in any program model, encompassing patient assessment, program content, method of delivery, and quality assurance, as well as 27 desirable components.,Only those models of pulmonary rehabilitation that have been tested in clinical trials are currently considered as ready for implementation.,The characteristics of patients most likely to succeed in each program model are not yet known, and research is needed in this area.,Health professionals should use clinical judgment to determine those patients who are best served by a center-based, multidisciplinary rehabilitation program.,A comprehensive patient assessment is critical for personalization of pulmonary rehabilitation and for effectively addressing individual patient goals.,Robust quality-assurance processes are important to ensure that any pulmonary rehabilitation service delivers optimal outcomes for patients and health services.,Workforce capacity-building and training should consider the skills necessary for emerging models, many of which are delivered remotely.,The success of all pulmonary rehabilitation models will be judged on whether the essential components are delivered and on whether the expected patient outcomes, including improved exercise capacity, reduced dyspnea, enhanced health-related quality of life, and reduced hospital admissions, are achieved. | 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 |
BACKGROUND.,Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation.,This inflammation may persist even after smoking cessation and responds variably to corticosteroids.,Personalizing treatment to biologically similar “molecular phenotypes” may improve therapeutic efficacy in COPD.,IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype.,METHODS.,We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis.,This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids.,RESULTS.,The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages.,In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT.,In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation.,CONCLUSION.,These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.,TRIAL REGISTRATION.,ClinicalTrials.gov NCT01969344.,FUNDING.,Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C. | Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin.,NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity.,In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs.,NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells.,Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA.,The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s.,NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.,•NRP1+ ILC3s are present in lymphoid tissues, but not in the peripheral blood or skin•NRP1+ ILC3s express CD45RO and produce higher amounts of cytokines than NRP1− ILC3s•NRP1 is a marker for human ILC3s with LTi phenotype and in vitro LTi activity•NRP1+ ILC3s are present in lung tissues from smokers and COPD patients,NRP1+ ILC3s are present in lymphoid tissues, but not in the peripheral blood or skin,NRP1+ ILC3s express CD45RO and produce higher amounts of cytokines than NRP1− ILC3s,NRP1 is a marker for human ILC3s with LTi phenotype and in vitro LTi activity,NRP1+ ILC3s are present in lung tissues from smokers and COPD patients,Shikhagaie et al. find that NRP1 expressing human ILC3s are LTi-like cells, which are present in fetal tissues and adult lymphoid tissues, but not in peripheral blood or skin.,NRP1+ ILC3s cells are primed and migrate in response to VEGF-A.,In addition, their presence in the lungs of smokers and COPD patients provides insight into the formation of ectopic lymphoid aggregates. | 1 |
The pulmonary rehabilitation (PR) is beneficial for COPD patients.,Due to the poor rate of adherence, we evaluate the factors which will predict the nonadherence of PR.,We analyzed the data from a retrospective study of COPD patients who were enrolled to attend the PR program.,Patients were classified as the adherence group and the nonadherence group according to completion of over 50% sessions during the 8-week PR program.,Demographic characteristics, 6-minute walking distance (6MWD), COPD assessment test (CAT), modified Medical Research Council scale (mMRC), and emotional function were compared between two groups.,Univariate and multivariable analyses were performed to determine the factors of poor adherence of PR.,Among 418 patients, 170 patients (40.7%) who completed less than 50% sessions of the PR program were categorized as “nonadherence.”,Compared to completers, “nonadherence” patients had more cigarette consumption, higher emotional score, less 6MWD, more exacerbation, using nebulizer frequently, and higher rate of smoking at enrollment.,On multivariate analysis, more exacerbation frequency (odds ratio (OR) = 1.434, 95% confidence interval (CI): 1.191∼1.796, P=0.046) and smoking at enrollment (OR = 3.349, 95% CI: 1.194∼6.302, P=0.012) were predict factors associated with nonadherence of PR.,COPD patients with frequent exacerbation and smoking currently were more likely to be nonadherence during PR. | 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. | 1 |
COPD is a disease associated with significant economic burden.,It was reported that Global initiative for chronic Obstructive Lung Disease (GOLD) guideline-oriented pharmacotherapy improves airflow limitation and reduces health care costs.,However, several studies showed a significant dissociation between international recommendations and clinicians’ practices.,The consequent reduced diagnostic and therapeutic inappropriateness has proved to be associated with an increase in costs and a waste of economic resources in the health sector.,The aim of the study was to evaluate COPD management in the Puglia region.,The study was performed in collaboration with the pulmonology centers and the Regional Health Agency (AReS Puglia).,An IT platform allowed the pulmonologists to enter data via the Internet.,All COPD patients who visited a pneumological outpatient clinic for the first time or for regular follow-ups or were admitted to a pneumological department for an exacerbation were considered eligible for the study.,COPD’s diagnosis was confirmed by a pulmonologist at the moment of the visit.,The project lasted 18 months and involved 17 centers located in the Puglia region.,Six hundred ninety-three patients were enrolled, evenly distributed throughout the region.,The mean age was 71±9 years, and 85% of them were males.,Approximately 23% were current smokers, 63% former smokers and 13.5% never smokers.,The mean post-bronchodilator forced expiratory volume in 1 second was 59%±20% predicted.,The platform allowed the classification of patients according to the GOLD guidelines (Group A: 20.6%, Group B: 32.3%, Group C: 5.9% and Group D: 39.2%), assessed the presence and severity of exacerbations (20% of the patients had an exacerbation defined as mild [13%], moderate [37%] and severe [49%]) and evaluated the appropriateness of inhalation therapy at the time of the visit.,Forty-nine percent of Group A patients were following inappropriate therapy; in Group B, 45.8% were following a therapy in contrast with the guidelines.,Among Group C patients, 41.46% resulted in triple combination therapy, whilê14% of Group D patients did not have a therapy or were following an inappropriate therapy.,In conclusion, 30% of all patients evaluated had been following an inadequate therapy.,Subsequently, an online survey was developed to inquire about the reasons for the results obtained.,In particular, we investigated the reasons why 30% of our population did not follow the therapy suggested by the GOLD guidelines: 1) why was there an excessive use of inhaled corticosteroids, 2) why a significantly high percentage was inappropriately treated with triple therapy and 3) why a consistent percentage (11%) of Group D patients were not treated at all.,The data provides an overview on the management of COPD in the region of Puglia (Italy) and represents a resource in order to improve appropriateness and reduce the waste of health resources. | Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.,Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face.,Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.,Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P<0.001) to diagnose COPD and frequently included validated patient-reported outcome measures (PCPs 67%, respiratory specialists 81%; P<0.001).,Respiratory specialists were more likely than PCPs to report awareness of the GOLD global strategy (93% versus 58%, P<0.001); however, when presented with patient scenarios, they did not always perform better than PCPs with regard to recommending GOLD-concordant treatment options.,The proportion of PCPs and respiratory specialists providing first- or second-choice treatment options concordant with GOLD strategy for a GOLD B-type patient was 38% versus 67%, respectively.,For GOLD C and D-type patients, the concordant proportions for PCPs and respiratory specialists were 40% versus 38%, and 57% versus 58%, respectively.,This survey of physicians in 12 countries practicing in the primary care and respiratory specialty settings showed high awareness of COPD-management guidelines.,Frequent use of guideline-recommended COPD diagnostic practices was reported; however, gaps in the application of COPD-treatment recommendations were observed, warranting further evaluation to understand potential barriers to adopt guideline recommendations. | 1 |
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with variable clinical manifestations, structural changes, and treatment responses.,In a cohort study, we performed a baseline cluster analysis to identify the subgroups of COPD and to assess the clinical outcomes of each subgroup during a 1-year follow-up.,We analyzed dusty areas cohort comprising 272 patients with COPD.,The main factors with the highest loading in 15 variables were selected using principal component analysis (PCA) at baseline.,The COPD patients were classified by hierarchical cluster analysis using clinical, physiological, and imaging data based on PCA-transformed data.,The clinical parameters and outcomes during the 1-year follow-up were evaluated among the subgroups.,PCA revealed that six independent components accounted for 77.3% of variance.,Three distinct subgroups were identified through the cluster analysis.,Subgroup 1 included younger subjects with fewer symptoms and mild airflow obstruction, and they had fewer exacerbations during the 1-year follow-up.,Subgroup 2 comprised subjects with additional symptoms and moderate airflow obstruction, and they most frequently experienced exacerbations requiring hospitalization during the 1-year follow-up.,Subgroup 3 included subjects with additional symptoms and mild airflow obstruction; this group had more female patients and a modest frequency of exacerbations requiring hospitalization.,Cluster analysis using the baseline data of a COPD cohort identified three distinct subgroups with different clinical parameters and outcomes.,These findings suggest that the identified subgroups represent clinically meaningful subtypes of COPD.,The online version of this article (10.1186/s12890-017-0553-9) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology.,Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome.,We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype.,We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study.,PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity.,PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location.,PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques. | 1 |
Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.,Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks.,Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.,In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment.,Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies.,Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg.,Incidence of adverse events was comparable between the FDCs and the mono-components.,These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.,Lung function and symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate to very severe COPDhttp://ow.ly/DIKiY | Chronic obstructive pulmonary disease (COPD) 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 |
Events of the past decade have stimulated development of new drug formulations and delivery devices that have improved the efficiency, ease of use, and environmental impact of inhaled drug therapy.,Respimat® Soft Mist™ Inhaler is a novel, multidose, propellant-free, hand-held, liquid inhaler that represents a new category of inhaler devices.,The aerosol cloud generated by Respimat contains a higher fraction of fine particles than most pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), and the aerosol spray exits the inhaler more slowly and for a longer duration than with pMDIs.,This translates into higher lung drug deposition and lower oropharyngeal deposition, making it possible to give lower nominal doses of delivered drugs without lowering efficacy.,In clinical trials in patients with COPD, bronchodilator drugs delivered from Respimat were equally effective at half of the dose delivered from a pMDI.,In one study of inhaler preference, Respimat was preferred over the pMDI by patients with COPD and other obstructive lung diseases.,Respimat is a valuable addition to the range of inhaler devices available to the patient with COPD. | Aerosols delivered by Respimat® Soft Mist™ Inhaler (SMI) are slower-moving and longer-lasting than those from pressurized metered-dose inhalers (pMDIs), improving the efficiency of pulmonary drug delivery to patients.,In this four-way cross-over study, adults with chronic obstructive pulmonary disease (COPD) and with poor pMDI technique received radiolabelled Berodual® (fenoterol hydrobromide 50 μg/ipratropium bromide 20 μg) via Respimat® SMI or hydrofluoroalkane (HFA)-MDI (randomized order) on test days 1 and 2, with no inhaler technique training.,The procedure was repeated on test days 3 and 4 after training.,Deposition was measured by gamma scintigraphy.,All 13 patients entered (9 males, mean age 62 years; FEV1 46% of predicted) inhaled too fast at screening (peak inspiratory flow rate [IF]: 69-161 L/min).,Whole lung deposition was higher with Respimat® SMI than with pMDI for untrained (37% of delivered dose vs 21% of metered dose) and trained patients (53% of delivered vs 21% of metered dose) (pSign-Test].15; pANOVA < = 0.05).,Training also improved inhalation profiles (slower average and peak IF as well as longer breath-hold time).,Drug delivery to the lungs with Respimat® SMI is more efficient than with pMDI, even with poor inhaler technique.,Teaching patients to hold their breath as well as to inhale slowly and deeply increased further lung deposition using Respimat® SMI. | 1 |
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. | To explore the change and its significance of cytokines in patients with pulmonary tuberculosis complicated with COPD.,The immune function of 152 cases of pulmonary tuberculosis with COPD was detected to compare with 150 cases of patients with pulmonary tuberculosis, 157 cases of patients with COPD and 50 cases of healthy volunteers who were in the hospital during the same period.,T lymphocyte cell population in peripheral blood was detected by flow cytometry.,The serum levels of sIL-2R, IL-6, IFN-γ, TNF-α were measured using ELISA.,The percentage of CD4+ T cells in TB patients with or without COPD and COPD patients without TB was significantly lower than that in control group.,The percentage of CD4+ T cells in patients with TB and COPD was significantly lower than that in the non-COPD TB patients.,The percentage of CD8+ T cells was higher in the TB patients group than that in control group.,The CD4+/CD8+ ratio in the TB patients group was significantly lower than that in control group.,The concentrations of sIL-2R, IL-6, TNF-α, IFN-γ in TB patients with or without COPD and COPD patients without TB were significantly higher than those in control group.,In addition, sIL-2R, IL-6, TNF-α concentrations in the patients with TB and COPD were higher than those in the non-COPD TB patients.,The concentrations of sIL-2R, IL-6, TNF-α, IFN-γ in COPD patients with TB were significantly higher than those in COPD patients without TB.,There was a significant negative correlation between serum levels of TNF-α, IL-6 and FEV1 (%, predicted) in COPD without TB group.,The patients with pulmonary tuberculosis complicated with COPD were impaired in cellular immunity, and its extent of immune impairment is more serious than those of the patients with pulmonary tuberculosis and the patients with COPD. | 1 |
Respiratory viral infections, particularly those caused by rhinovirus, exacerbate chronic respiratory inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD).,Airway epithelial cells are the primary site of rhinovirus replication and responsible of initiating the host immune response to infection.,Numerous studies have reported that the anti-viral innate immune response (including type I and type III interferon) in asthma is less effective or deficient leading to the conclusion that epithelial innate immunity is a key determinant of disease severity during a rhinovirus induced exacerbation.,However, deficient rhinovirus-induced epithelial interferon production in asthma has not always been observed.,We hypothesized that disparate in vitro airway epithelial infection models using high multiplicity of infection (MOI) and lacking genome-wide, time course analyses have obscured the role of epithelial innate anti-viral immunity in asthma and COPD.,To address this, we developed a low MOI rhinovirus model of differentiated primary epithelial cells obtained from healthy, asthma and COPD donors.,Using genome-wide gene expression following infection, we demonstrated that gene expression patterns are similar across patient groups, but that the kinetics of induction are delayed in cells obtained from asthma and COPD donors.,Rhinovirus-induced innate immune responses were defined by interferons (type-I, II, and III), interferon response factors (IRF1, IRF3, and IRF7), TLR signaling and NF-κB and STAT1 activation.,Induced gene expression was evident at 24 h and peaked at 48 h post-infection in cells from healthy subjects.,In contrast, in cells from donors with asthma or COPD induction was maximal at or beyond 72-96 h post-infection.,Thus, we propose that propensity for viral exacerbations of asthma and COPD relate to delayed (rather than deficient) expression of epithelial cell innate anti-viral immune genes which in turns leads to a delayed and ultimately more inflammatory host immune response. | CD8 cells may contribute towards an autoimmune process in COPD.,Down regulation of T cell receptor (TCR) signalling molecules occurs in autoimmune diseases with consequent T cell dysfunction.,We hypothesise that TCR signalling is abnormal in COPD pulmonary CD8 cells.,Micro-array gene expression analysis of blood and pulmonary COPD CD8 samples was performed and compared to pulmonary CD8 cells from smoker controls (S).,We focused on the TCR signalling pathway, with validation of key findings using polymerase chain reaction and immunofluorescence.,TCR signalling molecules in COPD pulmonary CD8 cells were down regulated compared to blood CD8 cells (CD247: fold change (FC) −2.43, Q = 0.001; LCK: FC −2.25, Q = 0.01).,Micro-array analysis revealed no significant differences between COPD and S pulmonary CD8 cells.,However, PCR revealed significantly lower gene expression levels of CD247 (FC −1.79, p = 0.04) and LCK (FC −1.77, p = 0.01) in COPD compared to S pulmonary CD8 cells.,CD247 down regulation in COPD CD8 cells was confirmed by immunofluorescent staining of bronchoalveolar lavage cells: Significantly fewer COPD CD8 cells co-expressed CD247 compared to healthy non-smoker CD8 cells (mean 88.9 vs 75.2%, p<0.05) There is down regulation of TCR signalling molecules in COPD pulmonary CD8 cells.,This may cause T cell dysfunction. | 1 |
Forced expiratory volume in 1s/forced expiratory volume in 6 s ( FEV1/FEV6) assessment with a microspirometer may be useful in the diagnostic work up of subjects who are suspected of having COPD in primary care.,To determine the diagnostic accuracy of a negative pre-bronchodilator (BD) microspirometry test relative to a full diagnostic spirometry test in subjects in whom general practitioners (GPs) suspect airflow obstruction.,Cross-sectional study in which the order of microspirometry and diagnostic spirometry tests was randomised.,Study subjects were (ex-)smokers aged ⩾50 years referred for diagnostic spirometry to a primary care diagnostic centre by their GPs.,A pre-BD FEV1/FEV6 value <0.73 as measured with the PiKo-6 microspirometer was compared with a post-BD FEV1/FVC (forced vital capacity) <0.70 and FEV1/FVC<lower limit of normal (LLN) from diagnostic spirometry.,One hundred and four subjects were analysed (59.6% males, 42.3% current smokers).,Negative predictive values from microspirometry for airflow obstruction based on the fixed and LLN cut-off points were 94.4% (95% confidence interval (CI), 86.4-98.5) and 96.3% (95% CI, 88.2-99.3), respectively.,In all, 18% of positive microspirometry results were not confirmed by a post-BD FEV1/FVC <0.70 and 44% of tests were false positive compared with the LLN criterion for airflow obstruction.,Pre-bronchodilator microspirometry seems to be able to reliably preselect patients for further assessment of airflow obstruction by means of regular diagnostic spirometry.,However, use of microspirometry alone would result in overestimation of airflow obstruction and should not replace regular spirometry when diagnosing COPD in primary care. | Underdiagnosis of chronic obstructive pulmonary disease (COPD) is widespread.,Early detection of COPD may improve the outcome by timely smoking cessation, a change in lifestyle, and treatment with an inhaled bronchodilator (BD).,The objective of this study was to evaluate the diagnostic role of BD reversibility testing in early COPD case finding.,General practitioners (n=241) consecutively recruited subjects aged ≥35 years with relevant exposure (history of smoking, and/or occupational exposure) and at least one respiratory symptom.,Information on age, smoking status, body mass index, dyspnea score (Medical Research Council scale), and spirometry was obtained.,Individuals with airway obstruction (forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] <0.70) underwent a BD test with an inhaled β2 agonist, which was considered positive if ΔFEV1 was >0.20 L and >12%.,Asthma and COPD were, respectively, defined as an FEV1 increase >0.50 L and a post-BD FEV1/FVC <0.70.,In total, 4,049 subjects (51% male) were included (mean age 58 years, body mass index 27, 32 pack-years of smoking).,A significant BD response was found in 143 (15%) of the 937 subjects (23%) with airway obstruction at screening spirometry.,In 59% of these subjects, the post-BD FEV1/FVC remained <0.70.,In 24% of the subjects with pre-BD airway obstruction, the post-BD FEV1/FVC ratio was within the reference range.,In subjects with confirmed COPD, the mean increase in FEV1 following BD was 0.11 L±0.10 L.,The subjects with COPD and a significant BD response were characterized by a higher prevalence of dyspnea (72% versus 57%, P=0.02) but less cough (55% versus 75%, P=0.001) when compared with COPD subjects without BD reversibility.,Administration of a BD in COPD case finding is important in order to determine the post-BD FEV1/FVC ratio.,Exclusion of subjects with a significant BD response may result in underdiagnosis of COPD, and we question the need for the BD reversibility test in the diagnostic screening algorithm in early COPD case finding. | 1 |
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, mainly due to cigarette smoking, which represents the third cause of mortality worldwide.,The mechanisms driving its epithelial salient features remain largely elusive.,We aimed to evaluate the activation and the role of the canonical, β-catenin-dependant WNT pathway in the airway epithelium from COPD patients.,The WNT/β-catenin pathway was first assessed by WNT-targeted RNA sequencing of the air/liquid interface-reconstituted bronchial epithelium from COPD and control patients.,Airway expression of total and active β-catenin was assessed in lung sections, as well as WNT components in laser-microdissected airway epithelium.,Finally, we evaluated the role of WNT at the bronchial epithelial level by modulating the pathway in the reconstituted COPD epithelium.,We show that the WNT/β-catenin pathway is upregulated in the COPD airway epithelium as compared with that of non-smokers and control smokers, in targeted RNA-sequencing of in vitro reconstituted airway epithelium, and in situ in lung tissue and laser-microdissected epithelium.,Extrinsic activation of this pathway in COPD-derived airway epithelium inhibited epithelial differentiation, polarity and barrier function, and induced TGF-β-related epithelial-to-mesenchymal transition (EMT).,Conversely, canonical WNT inhibition increased ciliated cell numbers, epithelial polarity and barrier function, whilst inhibiting EMT, thus reversing COPD features.,In conclusion, the aberrant reactivation of the canonical WNT pathway in the adult airway epithelium recapitulates the diseased phenotype observed in COPD patients, suggesting that this pathway or its downstream effectors could represent a future therapeutic target.,This study was supported by the Fondation Mont-Godinne, the FNRS and the WELBIO. | Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD).,Epithelial-mesenchymal transition (EMT) commonly coexists in lung cancer and COPD.,CS triggers many factors including matrix metalloproteinases (MMPs) production, contributing to EMT progression in the lungs.,Here, how Shp2 signaling regulates the CS-induced MMP-9 production and EMT progression were investigated in mouse lungs and in pulmonary epithelial cell cultures (NCI-H292) found CS induced MMP-9 production, EMT progression (increased vimentin and α-SMA; decreased E-cadherin) and collagen deposition in lung tissues; cigarette smoke extract (CSE) induced MMP-9 production and EMT-related phenotypes in NCI-H292 cells, which were partially prevented by Shp2 KO/KD or Shp2 inhibition.,The CSE exposure induced EMT phenotypes were suppressed by MMP-9 inhibition.,Recombinant MMP-9 induced EMT, which was prevented by MMP-9 inhibition or Shp2 KD/inhibition.,Mechanistically, CS and CSE exposure resulted in ERK1/2, JNK and Smad2/3 phosphorylation, which were suppressed by Shp2 KO/KD/inhibition.,Consequentially, the CSE exposure-induced MMP-9 production and EMT progression were suppressed by ERK1/2, JNK and Smad2/3 inhibitors.,Thus, CS induced MMP-9 production and EMT resulted from activation of Shp2/ERK1/2/JNK/Smad2/3 signaling pathways.,Our study contributes to the underlying mechanisms of pulmonary epithelial structural changes in response to CS, which may provide novel therapeutic solutions for treating associated diseases, such as COPD and lung cancer. | 1 |
Patients with COPD often experience severe exacerbations involving hospitalization, which accelerate lung function decline and reduce quality of life.,This study aimed to develop and validate a predictive model to identify patients at risk of developing severe COPD exacerbations using administrative claims data, to facilitate appropriate disease management programs.,A predictive model was developed using a retrospective cohort of COPD patients aged 55-89 years identified between July 1, 2010 and June 30, 2013 using Humana’s claims data.,The baseline period was 12 months postdiagnosis, and the prediction period covered months 12-24.,Patients with and without severe exacerbations in the prediction period were compared to identify characteristics associated with severe COPD exacerbations.,Models were developed using stepwise logistic regression, and a final model was chosen to optimize sensitivity, specificity, positive predictive value (PPV), and negative PV (NPV).,Of 45,722 patients, 5,317 had severe exacerbations in the prediction period.,Patients with severe exacerbations had significantly higher comorbidity burden, use of respiratory medications, and tobacco-cessation counseling compared to those without severe exacerbations in the baseline period.,The predictive model included 29 variables that were significantly associated with severe exacerbations.,The strongest predictors were prior severe exacerbations and higher Deyo-Charlson comorbidity score (OR 1.50 and 1.47, respectively).,The best-performing predictive model had an area under the curve of 0.77.,A receiver operating characteristic cutoff of 0.4 was chosen to optimize PPV, and the model had sensitivity of 17%, specificity of 98%, PPV of 48%, and NPV of 90%.,This study found that of every two patients identified by the predictive model to be at risk of severe exacerbation, one patient may have a severe exacerbation.,Once at-risk patients are identified, appropriate maintenance medication, implementation of disease-management programs, and education may prevent future exacerbations. | COPD exacerbations are responsible for the morbidity and mortality of this disease.,The relationship between exacerbations and patient-related clinical outcomes is not clearly understood.,A retrospective analysis of two 1-year, placebo-controlled clinical trials with tiotropium 18 μg daily was conducted to examine relationships between exacerbations and other clinical outcomes.,The relationship between FEV1, St.,George’s Respiratory Questionnaire (SGRQ), and the transition dyspnea index (TDI) were examined based on the frequency of exacerbations (0, 1, 2, >2).,921 patients participated in the trials (mean age 65 years, mean FEV1 = 1.02 L (39% predicted).,The percent change from baseline in FEV1 in the tiotropium group was +12.6%, +12.0%, +2.1% and +8.9%; and in the placebo group was −3.4%, −3.4%, −5.7% and −6.7% for exacerbation frequencies of 0, 1, 2, >2, respectively.,Compared with baseline, the largest improvement in SGRQ occurred in patients with no exacerbations.,In the placebo group, there was a significant association between an increased frequency of exacerbations and worsening SGRQ scores.,A reduction in exacerbation rates of 4.4% to 42.0% such as that shown in this study cohort was associated with meaningful changes in questionnaire based instruments.,In the placebo-treated patients increased frequency of exacerbations was associated with larger decrements in FEV1, TDI, and SGRQ.,A reduction in the frequency of exacerbations is associated with changes that are considered meaningful in these clinical outcomes. | 1 |
Little is known about whether there is any sex effect on chronic obstructive lung disease (COPD) exacerbations.,This study is intended to describe the possible sex-associated differences in exacerbation profile in COPD patients.,A total of 384 COPD patients who were hospitalized due to exacerbation were evaluated retrospectively for their demographics and previous and current exacerbation characteristics.,The study was conducted on 109 (28%) female patients and 275 (72%) male patients.,The mean age was 68.30±10.46 years.,Although females had better forced expiratory volume in 1 second and near-normal forced vital capacity, they had much impaired arterial blood gas levels (partial oxygen pressure [PO2] was 36.28 mmHg vs 57.93 mmHg; partial carbon dioxide pressure [PCO2] was 45.97 mmHg vs 42.49 mmHg; P=0.001), indicating severe exacerbation with respiratory failure.,More females had two exacerbations and two hospitalizations, while more men had one exacerbation and one hospitalization.,Low adherence to treatment and pulmonary embolism were more frequent in females.,Females had longer time from the onset of symptoms till the admission and longer hospitalization duration than males.,Comorbidities were less in number and different in women (P<0.05).,Women were undertreated and using more oral corticosteroids.,Current data showed that female COPD patients might be more prone to have severe exacerbations, a higher number of hospitalizations, and prolonged length of stay for hospitalization.,They have a different comorbidity profile and might be undertreated for COPD. | The impact of COPD on patient’s quality of life is well established, but gender differences have received little attention.,To describe factors associated with the health-related quality of life by gender: A cross-sectional observational study (NCT01007734) was conducted in COPD patients followed by pulmonologists.,The first patient included had to be a woman.,Data concerning the patient, COPD and their management were collected by the physician.,The patient had to fill in several questionnaires: Saint-George Hospital respiratory Questionnaire (SGRQ-C), and motivation to quit smoking.,Four hundred and thirty patients were included: mean age 63.9 ± 11.3 years; 57.4% were women.,Women were significantly younger than men (61.9 vs.,66.6) and their tobacco use was lower (37.1 vs.,40.4 PY).,Cardiovascular comorbidities were more frequent in men while osteoporosis, anxiety and depression were frequent in women.,The frequency of cough, sputum and the severity of dyspnea did not differ significantly between genders.,Lung function impairment was less severe in women than in men (mean FEV1 52% predicted normal vs.,47.,8%).,Anxiety score was higher (score 9.8 vs.,7.1) and quality of life (SGRQ-C) more impaired in women (scores 50.6 vs.,45.4; p < 0.02) than in men.,Moreover, in multivariate analysis, chronic sputum was associated with higher SGRQ-C scores in women but not in men.,This study underlines that despite less airflow limitation, quality of life is more impacted by chronic sputum in women than in men. | 1 |
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. | Chronic obstructive pulmonary disease (COPD) imposes a substantial burden on individuals with the disease, which can include a range of symptoms (breathlessness, cough, sputum production, wheeze, chest tightness) of varying severities.,We present an overview of the biomedical literature describing reported relationships between COPD symptoms and disease burden in terms of quality of life, health status, daily activities, physical activity, sleep, comorbid anxiety, and depression, as well as risk of exacerbations and disease prognosis.,In addition, the substantial variability of COPD symptoms encountered (morning, daytime, and nighttime) is addressed and their implications for disease burden considered.,The findings from this narrative review, which mainly focuses on real-world and observational studies, demonstrate the impact of COPD symptoms on the burden of disease and that improved recognition and understanding of their impact is central to alleviating this burden. | 1 |
Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement.,The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT).,Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1) <50% of predicted value from 27 secondary care respiratory units in Sweden.,Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables.,Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments.,Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] −0.07 [−0.13 to −0.02]), EQ-5D VAS (−5.17 [−9.42 to −0.92]), and CAT (3.78 [2.35 to 5.20]).,Musculoskeletal symptoms were significantly associated with worse EQ-5D index (−0.08 [−0.14 to −0.02]), osteoporosis with worse EQ-5D VAS (−4.65 [−9.27 to −0.03]), and depression with worse EQ-5D index (−0.10 [−0.17 to −0.04]).,In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients.,The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD.,Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL.,We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD. | In 5,541 community dwelling men, chronic obstructive pulmonary disease, or asthma was associated with lower bone mineral density (BMD) at the spine and total hip and an increased risk of vertebral and nonvertebral fractures independent of age, body mass index, and smoking.,Men prescribed with corticosteroids had the lowest BMD.,It is unclear whether chronic obstructive pulmonary disease (COPD) is independently associated with BMD and fractures.,In 5,541 men from the Osteoporotic Fractures in Men Study, history of COPD or asthma, current treatment with corticosteroids, BMD, bone loss after 4.5 years and fractures were ascertained.,Seven hundred fourteen (13%) men reported COPD or asthma, of which 103 were prescribed an oral steroid and 177 an inhaled steroid.,Independent of confounders, men prescribed corticosteroids for COPD or asthma had the lowest BMD and a 2-fold increased risk of vertebral osteoporosis compared to men with no history of COPD or asthma (OR 2.13, 95% CI (confidence interval) 1.15-3.93 oral steroids; OR 2.05, 95% CI 1.27-3.31 inhaled steroids).,During follow-up, BMD increased at the spine, but there was no difference in bone loss at the hip.,However, men with COPD or asthma had a 2.6- and 1.4-fold increased risk of vertebral and nonvertebral fractures, respectively.,Chronic obstructive pulmonary disease or asthma was associated with lower BMD at the spine and hip and increased risk of vertebral and nonvertebral fractures independent of age, clinic site, BMI, and smoking.,A history of COPD or asthma may be a useful clinical risk factor to identify patients with osteoporosis. | 1 |
Background: COPD pathology involves not only the lungs but also extrapulmonary abnormalities.,Osteoporosis is one of the most important abnormalities because it may cause vertebral compression fractures and deteriorate pulmonary function.,COPD patients have many risk factors for osteoporosis, such as low BMI, decreased activity, systemic inflammation, and use of corticosteroids.,Some of these factors have been shown to deteriorate with COPD exacerbations.,We previously demonstrated the correlation between emphysema and osteoporosis and between emphysema progression and COPD exacerbations.,Thus, the hypothesis that exacerbation causes osteoporosis progression in COPD patients was investigated.,Methods: Forty-two COPD patients not on osteoporosis treatment for over 2 years were recruited.,During follow-up, exacerbations had been prospectively recorded.,Thoracic vertebral bone mineral density (BMD) was measured using chest CT, and the annual change in BMD was calculated.,The change was compared between patients with and without a history of exacerbations.,Results: The decrease in thoracic vertebral BMD was greater in patients with than in those without a history of exacerbations (median ABMD mg/ml year: −3.78 versus −0.30, p = 0.02).,Moreover, multivariate regression analysis showed that exacerbations and baseline Pa02 were independent predictors of the BMD decrease (R2 = 0.20, p = 0.007, and R2 = 0.09, p = 0.03, respectively) after adjustment for baseline age, smoking status, and airflow limitation.,Conclusions: This is the first longitudinal study to demonstrate that COPD exacerbations are independently associated with osteoporosis progression.,Osteoporosis progression should be evaluated in COPD patients, especially in those with a history of frequent exacerbations. | Little is known about factors that determine health status decline in clinical trials of COPD.,To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo.,St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months.,Data from 4951 patients in 28 countries were available.,SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains.,SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001).,There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women.,Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1.,The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change.,In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors.,Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation.,ClinicalTrials.gov: NCT00268216 | 1 |
The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented.,However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.,TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers).,To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ≥ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).,Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV.,SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage.,Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV.,The rates of adverse events were similar across treatment arms and increased with disease severity.,Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.,In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages.,Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease.,The effects were similar to those reported for the study as a whole.,Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.,Clinicaltrial.gov registration NCT00268216; Study number: SCO30003 | COPD is a leading cause of morbidity and mortality, characterized by a chronic abnormal inflammatory response to noxious agents.,Apoptosis is a physiologic process, critical to cellular homeostasis, in which cell death follows a programmed sequence of events.,Apoptosis has been recognized to play an important role in clinical and experimental models of lung diseases.,Abnormal apoptotic events in smokers’ and in emphysematous lungs have been shown in epithelial and endothelial lung cells, neutrophils, lymphocytes, and myocytes.,Many factors associated with COPD, including cigarette smoke, have the potential to cause apoptosis of alveolar epithelial cells, the main sites of vascular endothelial growth factor (VEGF) production.,The decreased expression of VEGF, a known survival factor for endothelial cells, and its receptor, results in lung septal endothelial cell death, leading perhaps to the emphysema observed in COPD.,In smokers who develop COPD there is an activation of adaptive immunity, with an infiltration of CD4+ and, especially, CD8 + cells.,CD8 + cells are cytotoxic to epithelial cells through the release of granzymes and perforin, which can further induce apoptosis of alveolar cells.,Moreover, any reduction in neutrophil apoptosis or dysregulation of macrophage uptake of apoptotic neutrophils could lead to chronic inflammation and tissue injury.,Increased rates of T-cell apoptosis may lead to a defective immune response to infective organisms, contributing to the high frequency of infections seen in COPD.,Increased apoptosis of skeletal muscle could be responsible for the skeletal muscle atrophy, the main cause of unexplained weight loss in patients with COPD.,This paper is a review of the current knowledge on the apoptotic pathways involved in COPD pathogenesis and their interaction with other known contributing factors. | 1 |
The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases.,The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function.,We conducted a multi-center, cross-sectional study (“COPD Outcomes-based Network for Clinical Effectiveness & Research Translation” [CONCERT]).,We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires.,Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification.,Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered.,Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed.,Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male).,More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L.,Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) correlated.,A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles.,Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients. | 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 |
Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD).,But a fewer smoking cessation measures were conducted in communities for smokers with COPD in China.,The aim of our study was to assess the preventive effects of behavioral interventions for smoking cessation and potential impact factors in smokers with COPD in China.,In a randomised controlled smoking cessation trial 3562 patients with COPD who were current smoker were allocated to intervention group received behavioral intervention and control group received the usual care for two years.,The primary efficacy endpoint was the complete and continuous abstinence from smoking from the beginning of month 24 to the end of month 30.,Participants were followed up at month 48.,Continuous smoking abstinence rates from month 24 to 30 were significantly higher in participants receiving behavioral intervention than in those receiving usual care (46.4% vs 3.4%, p < 0.001).,Continuous abstinence rates from months 24 to 36 (45.8% vs 4.0%) and months 24 to 48 (44.3% vs 5.1%) were also higher in participants receiving behavioral intervention than in those control group.,Family members or family physicians/nurses smoking were first identified to influence smoking cessation.,Behavioral intervention doubled the smoking cessation rate in patients with COPD and was complied well by the general practitioners.,The family members and family physicians/nurses smoking were the main risk factors for smoking cessation.,Chinese Clinical Trials Registration (ChiCTR-TRC-12001958). | Chronic obstructive pulmonary disease (COPD) remains a major public health problem that affects the quality of life of patients, however smoking cessation may emeliorate the functional effects of COPD and alter patient quality of life.,The aim of this study was to validate the Clinical COPD Questionnaire (CCQ) into Greek and with such to evaluate the quality of life in patients with different stages of COPD, as also assess their quality of life before and after smoking cessation.,The internal validity of questionnaire was high (Cronbach's a = 0.92).,The reliability of equivalent types in 16 stabilized patients also was high (ICC = 0.99).,In general the domains within the CCQ were strongly correlated with each other, while each domain in separate was strongly correlated with the overall CCQ score (r2 = 0.953, r2 = 0.915 and r2 = 0.842 in regards to the functional, symptomatic and mental domain, respectively).,The CCQ scores were also correlated with FEV1, (r2 = -0.252, p < 0.001), FEV1/FVC, (r2 = -0.135, p < 0.001) as also with the quality of life questionnaire SF-12 (r2 = -0.384, p < 0.001).,Smoking cessation also lead to a significant reduction in CCQ score and increase in the SF-12 score.,The self administered CCQ indicates satisfactory validity, reliability and responsiveness and may be used in clinical practice to assess patient quality of life.,Moreover the CCQ indicated the health related quality of life gains attributable to smoking cessation among COPD patients, projecting smoking cessation as a key target in COPD patient management. | 1 |
Although step counters are popularly employed for physical rehabilitation in chronic obstructive pulmonary disease (COPD) patients, their effectiveness is inconsistent and even questioned.,This meta-analysis aimed to investigate whether step counter use increases physical activity or improves exercise capacity in COPD patients.,Electronic databases were searched for randomized controlled trials that assessed the efficacy of step counter use in increasing physical activity or in improving exercise capacity.,Data were aggregated using a random-effects model to get the overall effect sizes [standard mean difference (SMD) with 95% confidence interval (CI)], and subgroup analyses were performed.,A total of 15 trials enrolling 1316 patients with moderate to severe COPD were included.,Step counter use increased physical activity compared with controls (SMD = 0.57, 95% CI 0.31-0.84), which is equal to a magnitude of 1026 steps/day in daily steps.,It also enhanced exercise capacity with an effect size of 0.30 (95% CI 0.16-0.45), approximating to a magnitude of 11.6 m in the 6-min walking distance.,Step counter use could augment physical activity (SMD = 0.64, 95% CI 0.19-1.08) and exercise capacity (SMD = 0.32, 95% CI 0.01-0.62) for patients receiving pulmonary rehabilitation.,Yet it cannot enhance physical activity or exercise capacity in patients with severe COPD or among studies with intervention durations ⩾6 months (both p > 0.50).,Step counter use increases physical activity and improves exercise capacity in COPD patients, at least in the short term, which supports the notion of recommending step counter use in COPD management. | To evaluate the ability of COPD patients to perform activities of daily living (ADL); to identify barriers that prevent these individuals from performing ADL; and to correlate those barriers with dyspnea severity, six-minute walk test (6MWT), and an ADL limitation score.,In COPD patients and healthy, age-matched controls, the number of steps, the distance walked, and walking time were recorded with a triaxial accelerometer, for seven consecutive days.,A questionnaire regarding perceived barriers and the London Chest Activity of Daily Living (LCADL) scale were used in order to identify the factors that prevent the performance of ADL.,The severity of dyspnea was assessed with two scales, whereas submaximal exercise capacity was determined on the basis of the 6MWT.,We evaluated 40 COPD patients and 40 controls.,In comparison with the control values, the mean walk time was significantly shorter for COPD patients (68.5 ± 25.8 min/day vs.,105.2 ± 49.4 min/day; p < 0.001), as was the distance walked (3.9 ± 1.9 km/day vs.,6.4 ± 3.2 km/day; p < 0.001).,The COPD patients also walked fewer steps/day.,The most common self-reported barriers to performing ADL were lack of infrastructure, social influences, and lack of willpower.,The 6MWT distance correlated with the results obtained with the accelerometer but not with the LCADL scale results.,Patients with COPD are less active than are healthy adults of a comparable age.,Physical inactivity and the barriers to performing ADL have immediate implications for clinical practice, calling for early intervention measures. | 1 |
The aim of this study was to investigate the effects of high-intensity aerobic training (AT) and high-intensity aerobic training combined with resistance training (ie, combined training [CT]) on cognitive function in patients with COPD.,Twenty-eight Caucasian male patients (68.35±9.64 years; mean ± SD) with COPD were recruited and randomized into two groups, AT and CT.,Both groups performed physical reconditioning for 4 weeks, with a frequency of five training sessions per week.,The CT group completed two daily sessions of 30 minutes: one aerobic session and one strength session, respectively; The AT group performed two 30-minute aerobic endurance exercise sessions on treadmill.,Physical and cognitive function tests were performed before and after the training intervention performances.,Exercise training improved the following cognitive functions: long-term memory, verbal fluency, attentional capacity, apraxia, and reasoning skills (P<0.01).,Moreover, the improvements in the CT group were significantly greater than those in the AT group in long-term memory, apraxia, and reasoning skills (P<0.05).,CT may be a possible strategy to prevent cognitive decline and associated comorbidities in male patients with COPD. | Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α).,Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH).,The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD).,The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.,We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls.,COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema).,Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.,Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001).,A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001).,Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).,Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD.,Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later. | 1 |
Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD).,To identify dysregulation of specific proteins and pathways in bronchoalveolar lavage (BAL) cells associated with smoking, isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun proteomics analyses were performed on BAL cells from healthy never-smokers and smokers with normal lung function from the Karolinska COSMIC cohort.,Multivariate statistical modeling, multivariate correlations with clinical data, and pathway enrichment analysis were performed.,Smoking exerted a significant impact on the BAL cell proteome, with more than 500 proteins representing 15 molecular pathways altered due to smoking.,The majority of these alterations occurred in a gender-independent manner.,The phagosomal- and leukocyte trans endothelial migration (LTM) pathways significantly correlated with FEV1/FVC as well as the percentage of CD8+ T-cells and CD8+CD69+ T-cells in smokers.,The correlations to clinical parameters in healthy never-smokers were minor.,The significant correlations of proteins in the phagosome- and LTM pathways with activated cytotoxic T-cells (CD69+) and the level of airway obstruction (FEV1/FVC) in smokers, both hallmarks of COPD, suggests that these two pathways may play a role in the molecular events preceding the development of COPD in susceptible smokers.,Both pathways were found to be further dysregulated in COPD patients from the same cohort, thereby providing further support to this hypothesis.,Given that not all smokers develop COPD in spite of decades of smoking, it is also plausible that some of the molecular pathways associated with response to smoking exert protective mechanisms to smoking-related pathologies in resilient individuals.,ClinicalTrials.gov identifier NCT02627872; Retrospectively registered on December 9, 2015.,The online version of this article (10.1186/s12931-017-0695-6) contains supplementary material, which is available to authorized users. | Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia.,These features are partially attributed to activation of the epidermal growth factor receptor (EGFR).,Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists.,We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation.,114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted.,Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies.,Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression.,Epithelial features were not different between short-term quitters (<3.5 years) and current smokers.,Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs.,14.4%, p = 0.005; 7.9% vs.,13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs.,18.6%, p < 0.001).,Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years).,NCT00158847 | 1 |
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