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Forced expiratory volume in one second (FEV1) characterizes the pathophysiology of COPD and different trajectories of FEV1 decline have been observed in patients with COPD (e.g. gradual or episodic).,There is limited information about the development of patient-reported health-related quality of life (HRQL) over the full range of the natural history of COPD.,We examined the longitudinal association between change in FEV1 and change in disease-specific and generic HRQL.,We analysed data of 1734 patients with COPD participating in the COSYCONET cohort with up to 3 years of follow-up.,Patients completed the Saint George’s Respiratory Questionnaire (SGRQ) and the EQ-5D Visual Analog Scale (EQ VAS).,Change score models were used to investigate the relationship between HRQL and FEV1 and to calculate mean changes in HRQL per FEV1 change categories [decrease (≤ − 100 ml), no change, increase (≥ 100 ml)] after 3 years.,Applying hierarchical linear models (HLM), we estimated the cross-sectional between-subject difference and the longitudinal within-subject change of HRQL as related to a FEV1 difference or change.,We observed a statistically significant deterioration in SGRQ (total score + 1.3 units) after 3 years, which was completely driven by the activity component (+ 4 units).,No significant change was found for the generic EQ VAS.,Over the same period, 58% of patients experienced a decrease in FEV1, 28% were recorded as no change in FEV1, and 13% experienced an increase.,The relationship between HRQL and FEV1 was found to be approximately linear with decrease in FEV1 being statistically significantly associated with a deterioration in SGRQ (+ 3.20 units).,Increase in FEV1 was associated with improvements in SGRQ (− 3.81 units).,The associations between change in FEV1 and the EQ VAS were similar.,Results of the HLMs were consistent and highly statistically significant, indicating cross-sectional and longitudinal associations.,The largest estimates were found for the association between FEV1 and the SGRQ activity domain.,Difference and change in FEV1 over time correlate with difference and change in disease-specific and generic HRQL.,We conclude, that deterioration of HRQL should induce timely re-examination of physical status and lung function and possibly reassessment of therapeutic regimes.,NCT01245933.,Date of registration: 18 November 2010. | Interactions between spirometry and patient-reported outcomes in COPD are not well understood.,This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy.,Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations.,Mean and standard deviations of treatment effects were extracted for each arm of each study.,Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling.,The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score.,Thirty-six studies (≥3 months) were included.,Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data.,Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ.,The correlation strengthened with increasing study duration from 3 to 12 months.,Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1.,The association between change in FEV1 and other patient-reported outcomes was generally weak.,Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status. | 1 |
Features of the deaths caused by COPD (chronic obstructive pulmonary disease) in cancer patients remained a controversial issue.,This study aimed to characterize the demographic characteristics and mortality rates of the deaths from COPD in patients with cancer.,In total, 7,846,370 cancer patients aged 40 years or older in the United States were identified from the Surveillance, Epidemiology, and End Results database (1975-2016).,Mortality rates and SMRs (standardized mortality ratios) adjusted by age, race, sex, and calendar year were calculated to investigate the risk of COPD deaths in cancer survivors and to compare it with the general population.,A total of 119,228 COPD deaths in patients with cancer were recorded, with a mortality rate of 261.5/100,000 person-years, nearly two-fold that of the general population (SMR, 2.17; 95% CI [confidence interval], 2.16-2.18).,The proportion of cancer survivors dying from COPD increased from 0.9% in 1975 to 3.4% in 2016.,Patients with lung cancer had a higher overall risk (SMR, 9.23; 95% CI, 9.12-9.35) than those with extrapulmonary malignancies.,Among all extrapulmonary sites, laryngeal (SMR, 5.54; 95% CI, 5.34-5.75) and esophageal cancers (SMR, 4.33; 95% CI, 4.04-4.63) had the highest SMR.,The risk of death from COPD increased with follow-up time. | Small airway fibrosis is the main contributor in airflow obstruction in chronic obstructive pulmonary disease.,Epithelial mesenchymal transition (EMT) has been implicated in this process, and in large airways, is associated with angiogenesis, ie, Type-3, which is classically promalignant.,In this study we have investigated whether EMT biomarkers are expressed in small airways compared to large airways in subjects with chronic airflow limitation (CAL) and what type of EMT is present on the basis of vascularity.,We evaluated epithelial activation, reticular basement membrane fragmentation (core structural EMT marker) and EMT-related mesenchymal biomarkers in small and large airways from resected lung tissue from 18 lung cancer patients with CAL and 9 normal controls.,Tissues were immunostained for epidermal growth factor receptor (EGFR; epithelial activation marker), vimentin (mesenchymal marker), and S100A4 (fibroblast epitope).,Type-IV collagen was stained to demonstrate vessels.,There was increased expression of EMT-related markers in CAL small airways compared to controls: EGFR (P<0.001), vimentin (P<0.001), S100A4 (P<0.001), and fragmentation (P<0.001), but this was less than that in large airways.,Notably, there was no hypervascularity in small airway reticular basement membrane as in large airways.,Epithelial activation and S100A4 expression were related to airflow obstruction.,EMT is active in small airways, but less so than in large airways in CAL, and may be relevant to the key pathologies of chronic obstructive pulmonary disease, small airway fibrosis, and airway cancers. | 1 |
Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented.,However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited.,Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons.,We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002).,Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects.,No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA.,Co-occurrence analysis suggests the presence of networks of co-occurring bacteria.,Four communities of positively correlated bacteria were revealed.,The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype.,Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells.,This might result in a changed interplay with the host immune system. | Although culture-independent techniques have shown that the lungs are not sterile, little is known about the lung microbiome in chronic obstructive pulmonary disease (COPD).,We used pyrosequencing of 16S amplicons to analyze the lung microbiome in two ways: first, using bronchoalveolar lavage (BAL) to sample the distal bronchi and air-spaces; and second, by examining multiple discrete tissue sites in the lungs of six subjects removed at the time of transplantation.,We performed BAL on three never-smokers (NS) with normal spirometry, seven smokers with normal spirometry (“heathy smokers”, HS), and four subjects with COPD (CS).,Bacterial 16 s sequences were found in all subjects, without significant quantitative differences between groups.,Both taxonomy-based and taxonomy-independent approaches disclosed heterogeneity in the bacterial communities between HS subjects that was similar to that seen in healthy NS and two mild COPD patients.,The moderate and severe COPD patients had very limited community diversity, which was also noted in 28% of the healthy subjects.,Both approaches revealed extensive membership overlap between the bacterial communities of the three study groups.,No genera were common within a group but unique across groups.,Our data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas.,Most strikingly, there were significant micro-anatomic differences in bacterial communities within the same lung of subjects with advanced COPD.,These studies are further demonstration of the pulmonary microbiome and highlight global and micro-anatomic changes in these bacterial communities in severe COPD patients. | 1 |
Chronic obstructive pulmonary disease (COPD) guidelines recommend early access to palliative care together with optimal, disease-directed therapy for people with advanced disease, however, this occurs infrequently.,This study explored the approaches of respiratory and palliative medicine specialists to palliative care and advance care planning (ACP) in advanced COPD.,An online survey was emailed to all specialists and trainees in respiratory medicine in Australia and New Zealand (ANZ), and to all palliative medicine specialists and trainees in ANZ and the United Kingdom.,Five hundred seventy-seven (33.1%) responses were received, with 440 (25.2%) complete questionnaires included from 177 respiratory and 263 palliative medicine doctors.,Most respiratory doctors (140, 80.9%) were very or quite comfortable providing a palliative approach themselves to people with COPD.,113 (63.8%) respiratory doctors recommended referring people with advanced COPD to specialist palliative care, mainly for access to: psychosocial and spiritual care (105, 59.3%), carer support (104, 58.5%), and end-of-life care (94, 53.1%).,432 (98.2%) participants recommended initiating ACP discussions.,Palliative medicine doctors were more likely to recommend discussing: what palliative care is (p < 0.0001), what death and dying might be like (p < 0.0001) and prognosis (p = 0.004).,Themes highlighted in open responses included: inadequate, fragmented models of care, with limited collaboration or support from palliative care services.,While both specialties recognised the significant palliative care and ACP needs of people with advanced COPD, in reality few patients access these elements of care.,Formal collaboration and bi-directional support between respiratory and palliative medicine, are required to address these unmet needs. | Anticholinergics have been used to treat obstructive respiratory disease for many years from historical preparations of the deadly nightshade genus, to the more recent developments of ipratropium, oxitropium, and tiotropium.,The medical treatment of airways obstruction has focused on achieving maximal airway function through bronchodilators.,Of the two main bronchodilators, beta2-agonists are often the first treatment choice although there is evidence of equivalence and some suggestions of the superiority of anticholinergics in chronic obstructive pulmonary disease (COPD).,The following review looks at the background of anticholinergics, their pharmacological properties, and the evidence for use with suggestions for their place in the treatment of COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening lung disease with increasing prevalence and incidence worldwide.,Increasing evidence suggests that lung microbiomes might play a physiological role in acute exacerbations of COPD.,The objective of this study was to characterize the association of the microbiota and exacerbation risk or airflow limitation in stable COPD patients.,The sputum microbiota from 78 COPD outpatients during periods of clinical stability was investigated using 16S rRNA V3-V4 amplicon sequencing.,The microbiome profiles were compared between patients with different risks of exacerbation, i.e., the low risk exacerbator (LRE) or high risk exacerbator (HRE) groups, and with different airflow limitation severity, i.e., mild to moderate (FEV1 ≥ 50; PFT I) or severe to very severe (FEV1 < 50; PFT II).,The bacterial diversity (Chao1 and observed OTUs) was significantly decreased in the HRE group compared to that in the LRE group.,The top 3 dominant phyla in sputum were Firmicutes, Actinobacteria, and Proteobacteria, which were similar in the HRE and LRE groups.,At the genus level, compared to that in the LRE group (41.24%), the proportion of Streptococcus was slightly decreased in the HRE group (28.68%) (p = 0.007).,However, the bacterial diversity and the proportion of dominant bacteria at the phylum and genus levels were similar between the PFT I and PFT II groups.,Furthermore, the relative abundances of Gemella morbillorum, Prevotella histicola, and Streptococcus gordonii were decreased in the HRE group compared to those in the LRE group according to linear discriminant analysis effect size (LEfSe).,Microbiome network analysis suggested altered bacterial cooperative regulation in different exacerbation phenotypes.,The proportions of Proteobacteria and Neisseria were negatively correlated with the FEV1/FVC value.,According to functional prediction of sputum bacterial communities through Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis, genes involved in lipopolysaccharide biosynthesis and energy metabolism were enriched in the HRE group.,The present study revealed that the sputum microbiome changed in COPD patients with different risks of exacerbation.,Additionally, the bacterial cooperative networks were altered in the HRE patients and may contribute to disease exacerbation.,Our results provide evidence that sputum microbiome community dysbiosis is associated with different COPD phenotypes, and we hope that by understanding the lung microbiome, a potentially modifiable clinical factor, further targets for improved COPD therapies during the clinically stable state may be elucidated.,The online version contains supplementary material available at 10.1186/s12967-021-02788-4. | Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide.,The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes.,These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease.,A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer.,In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent.,In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression.,The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death.,Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks.,Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer.,In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer. | 1 |
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. | Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD).,We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls.,This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD.,To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects.,Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable.,The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects.,Rbm fragmentation correlated with smoking history in COPD but not with age.,There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05).,The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004).,In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02).,Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall.,Rbm fragmentation was also present to as great an extent in ex-smokers with COPD.,These characteristics may have potential physiological consequences. | 1 |
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses a serious threat to healthcare systems worldwide.,Binding of the virus to angiotensin‐converting enzyme 2 (ACE2) is an important step in the infection mechanism.,However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls.,We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS‐CoV‐2 infection.,Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open‐access RNA sequencing datasets.,Immunohistochemical and single‐cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively.,Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme‐linked immunosorbent assay.,In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples.,Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD.,None of these changes were associated with changes in pulmonary hemodynamics.,Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells.,This was confirmed by scRNAseq analysis.,There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control.,In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients.,These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS‐CoV‐2 infection. | To describe the characteristics and prognosis of patients with COPD admitted to the hospital due to SARS-CoV-2 infection.,The SEMI-COVID registry is an ongoing retrospective cohort comprising consecutive COVID-19 patients hospitalized in Spain since the beginning of the pandemic in March 2020.,Data on demographics, clinical characteristics, comorbidities, laboratory tests, radiology, treatment, and progress are collected.,Patients with COPD were selected and compared to patients without COPD.,Factors associated with a poor prognosis were analyzed.,Of the 10,420 patients included in the SEMI-COVID registry as of May 21, 2020, 746 (7.16%) had a diagnosis of COPD.,Patients with COPD are older than those without COPD (77 years vs 68 years) and more frequently male.,They have more comorbidities (hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, ischemic heart disease, peripheral vascular disease, kidney failure) and a higher Charlson Comorbidity Index (2 vs 1, p<0.001).,The mortality rate in COPD patients was 38.3% compared to 19.2% in patients without COPD (p<0.001).,Male sex, a history of hypertension, heart failure, moderate-severe chronic kidney disease, presence of cerebrovascular disease with sequelae, degenerative neurological disease, dementia, functional dependence, and a higher Charlson Comorbidity Index have been associated with increased mortality due to COVID-19 in COPD patients.,Survival was higher among patients with COPD who were treated with hydroxychloroquine (87.1% vs 74.9%, p<0.001) and with macrolides (57.9% vs 50%, p<0.037).,Neither prone positioning nor non-invasive mechanical ventilation, high-flow nasal cannula, or invasive mechanical ventilation were associated with a better prognosis.,COPD patients admitted to the hospital with SARS-CoV-2 infection have more severe disease and a worse prognosis than non-COPD patients. | 1 |
We investigated the association between cognitive impairment and chronic obstructive pulmonary disease (COPD), taking into account demographic and clinical variables evaluated during routine practice.,We performed a post hoc analysis of a cross-sectional study that included subjects with stable COPD.,Sociodemographic and clinical information was recorded using the Body mass index, airflow Obstruction, Dyspnea and Exacerbations index and the Charlson comorbidity index.,Cognitive performance was studied by the mini-mental state examination, with a score less than 27 indicating clinical impairment.,Depressive symptoms, physical activity, and quality of life (EuroQoL-5 dimensions and COPD Assessment Test) were also evaluated.,The analysis included 940 subjects.,The prevalence of cognitive impairment was 39.4%.,Multivariate logistic regression models revealed that cognitive impairment was associated with educational level (odds ratio [OR] =0.096, 95% confidence interval [CI] =0.011-0.447) and poorer quality of life measured by the EuroQoL-5 dimensions social tariff (OR =0.967, 95% CI =0.950-0.983).,When questionnaires were not included in the analysis, cognitive impairment was associated with educational level (OR =0.063, 95% CI =0.010-0.934), number of exacerbations (OR =11.070, 95% CI =1.450-84.534), Body mass index, airflow Obstruction, Dyspnea and Exacerbations index score (OR =1.261, 95% CI =1.049-1.515), and the Charlson comorbidity index (OR =1.412, 95% CI =1.118-1.783).,Cognitive impairment is common in COPD and is associated with low educational level, higher disease severity, and increased comorbidity.,This could have therapeutic implications for this population. | This study was conducted to investigate the association between the chronic obstructive pulmonary disease (COPD) assessment test (CAT) and depression in COPD patients.,The Korean versions of the CAT and patient health questionnaire-9 (PHQ-9) were used to assess COPD symptoms and depressive disorder, respectively.,In total, 803 patients with COPD were enrolled from 32 hospitals and the prevalence of depression was 23.8%.,The CAT score correlated well with the PHQ-9 score (r=0.631; P<0.001) and was significantly associated with the presence of depression (β±standard error, 0.452±0.020; P<0.001).,There was a tendency toward increasing severity of depression in patients with higher CAT scores.,By assessment groups based on the 2011 Global Initiative for Chronic Obstructive Lung Disease guidelines, the prevalence of depression was affected more by current symptoms than by airway limitation.,The area under the receiver operating characteristic curve for the CAT was 0.849 for predicting depression, and CAT scores ≥21 had the highest accuracy rate (80.6%).,Among the eight CAT items, energy score showed the best correlation and highest power of discrimination.,CAT scores are significantly associated with the presence of depression and have good performance for predicting depression in COPD patients. | 1 |
Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis.,We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD.,The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.,This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations.,Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.,In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%).,The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001).,In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%).,UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).,This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods.,UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy. | Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterized by airflow limitation that is not fully reversible.,It is a major cause of morbidity and mortality and represents substantial economic and social burden throughout the world.,A range of interventions has been developed that decrease symptoms and address complications associated with COPD.,However, to date few interventions have been unequivocally demonstrated to modify disease progression.,Assessment of the potential for interventions to modify disease progression is complicated by the lack of a clear definition of disease modification and disagreement over appropriate markers by which modification should be evaluated.,To clarify these issues, a working group of physicians and scientists from the USA, Canada and Europe was convened.,The proposed working definition of disease modification resulting from the group discussions was “an improvement in, or stabilization of, structural or functional parameters as a result of reduction in the rate of progression of these parameters which occurs whilst an intervention is applied and may persist even if the intervention is withdrawn”.,According to this definition, pharmacologic interventions may be considered disease-modifying if they provide consistent and sustained improvements in structural and functional parameters.,Smoking cessation and lung volume reduction surgery would both qualify as disease-modifying interventions. | 1 |
The risk and outcomes of stroke in patients with chronic obstructive pulmonary disease exacerbations (COPDe) remain unclear.,We examined whether patients with COPDe faced increased risk of stroke or post-stroke outcomes.,Using Taiwan’s National Health Insurance Research Database, we identified 1918 adults with COPDe and selected comparison cohorts of 3836 adults with COPD no exacerbations and 7672 adults without COPD who were frequency matched by age and sex in 2000-2008 (Study 1).,Stroke event was identified during 2000-2013 follow-up period.,Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of stroke associated with COPDe were calculated.,In a nested cohort study (Study 2) of 261686 new-diagnosed stroke patients in 2000-2009, we calculated adjusted odds ratios (ORs) and 95% CIs of adverse events after stroke in patients with COPDe.,Patients with COPDe had increased stroke incidence, with an adjusted HR of 1.28 (95% CI, 1.03-1.59).,In the Study 2, COPDe were associated with post-stroke mortality (OR, 1.34, 95% CI 1.20-1.52), epilepsy (OR, 1.43; 95% CI, (1.22-1.67), and pneumonia (OR, 1.50; 95% CI, 1.39-1.62).,Previous intubation for COPD and inpatient admissions due to COPD were factors associated with post-stroke adverse events.,Patients who have had COPDe face increased risks of stroke and post-stroke adverse events. | Exacerbations of chronic obstructive pulmonary disease (COPD) are acute events of worsened respiratory symptoms that may increase the risk of cardiovascular disease (CVD), a leading cause of mortality amongst COPD patients.,The utility of lung-specific inflammatory mediators such as club cell protein-16 (CC-16) and surfactant protein D (SPD) and that of a novel marker of CV outcomes in COPD- RelB- in predicting adverse cardiovascular events during exacerbation is not known.,Thirty-eight subjects with COPD admitted to the hospital for severe exacerbation were included in this analysis.,Clinical, physiological and arterial stiffness measurements were performed within 72 hours of admission; this was followed by measurements taken every 3 days until hospital discharge, then once a week until 30 days after discharge, and then again at 90 and 180 days.,Plasma concentrations of inflammatory mediators were measured from peripheral venous blood taken at admission, and at days 15, 30, 90 and 180.,CC-16 and RelB concentrations were increased at day 15 of exacerbations whereas SPD concentrations were decreased.,The course of change in CC-16 and RelB levels over time was inversely associated with that of carotid-femoral pulse wave velocity, the gold-standard measure of arterial stiffness.,Increases in CC-16 could predict a decreased number of subsequent exacerbations during follow-up.,Lung-specific (CC-16) and novel (RelB) biomarkers are associated with systemic cardiovascular changes over time.,CC-16 can predict subsequent exacerbations in subjects with severe COPD and may be an important biomarker of pulmonary and systemic stress in COPD. | 1 |
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the history of this debilitating lung condition.,Associated health care utilization and morbidity are high, and many patients require supplemental oxygen or ventilatory support.,The last 2 decades have seen a substantial increase in our understanding of the best way to manage the respiratory failure suffered by many patients during this high-risk period.,This review article examines the evidence underlying supplemental oxygen therapy during exacerbations of COPD.,We first discuss the epidemiology and pathophysiology of respiratory failure in COPD during exacerbations.,The rationale and evidence underlying oxygen therapy, including the risks when administered inappropriately, are then discussed, along with further strategies for ventilatory support.,We also review current recommendations for best practice, including methods for improving oxygen provision in the future. | Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations.,This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).,We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers.,In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.,COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function.,Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage.,The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study.,The distribution of these variables within each GOLD stage was wide.,Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation.,The amount of emphysema increased with GOLD severity.,The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage.,Some gender differences were also identified.,The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease. | 1 |
Today, many different tools are developed to execute and visualize physiological models that represent the human physiology.,Most of these tools run models written in very specific programming languages which in turn simplify the communication among models.,Nevertheless, not all of these tools are able to run models written in different programming languages.,In addition, interoperability between such models remains an unresolved issue.,In this paper we present a simulation environment that allows, first, the execution of models developed in different programming languages and second the communication of parameters to interconnect these models.,This simulation environment, developed within the Synergy-COPD project, aims at helping and supporting bio-researchers and medical students understand the internal mechanisms of the human body through the use of physiological models.,This tool is composed of a graphical visualization environment, which is a web interface through which the user can interact with the models, and a simulation workflow management system composed of a control module and a data warehouse manager.,The control module monitors the correct functioning of the whole system.,The data warehouse manager is responsible for managing the stored information and supporting its flow among the different modules.,This simulation environment has been validated with the integration of three models: two deterministic, i.e. based on linear and differential equations, and one probabilistic, i.e., based on probability theory.,These models have been selected based on the disease under study in this project, i.e., chronic obstructive pulmonary disease.,It has been proved that the simulation environment presented here allows the user to research and study the internal mechanisms of the human physiology by the use of models via a graphical visualization environment.,A new tool for bio-researchers is ready for deployment in various use cases scenarios. | Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management.,Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease.,Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.,To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management.,To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.,An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).,Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.,(1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.,The results indicate the high potential of a systems approach to address COPD heterogeneity.,Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD. | 1 |
The objective of this study was to examine the association among the duration of COPD, degree of hypoxemia, and neurological abnormalities including cognitive functioning.,Fifty-four patients with severe COPD and 24 age- and sex-matched controls, were included in the study.,All patients and controls were administered pulmonary function tests, standardized Mini-mental State Examination (MMSE), Blessed Dementia Scale (BDS), Physical Self-maintenance Scale (PSMS), Modified Activities of Daily Living scale (MADL), Instrumental Activities of Daily Living scale (IADL), Cornell Scale for Depression in Dementia (CSDD), Global Deterioration Scale (GDS) and Clinical Dementia Rating (CDR).,In addition, detailed physical and neurological examinations were performed.,Sixty-four percent of patients with COPD showed abnormalities in MMSE, predominantly in recent memory, construction, attention, language, and orientation domains.,Functional abnormalities were correlated with cognitive abnormalities.,Although COPD patients did not show significant depression compared to controls, 77.7%. of the patients showed subjective and objective cognitive disturbance and 72.2% of the patients were classified as questionable or mild dementia.,In conclusion, patients with COPD show significant cognitive and functional impairments that cannot be explained just by coincidence or by depression. | Chronic obstructive pulmonary disease (COPD), especially in severe forms, is commonly associated with multiple cognitive problems.,Montreal Cognitive Assessment test (MoCA) is used to detect cognitive impairment evaluating several areas: visuospatial, memory, attention and fluency.,Our study aim was to evaluate the impact of stable COPD and exacerbation (AECOPD) phases on cognitive status using MoCA questionnaire.,We enrolled 39 patients (pts), smokers with COPD group D (30 stable and 9 in AECOPD) and 13 healthy subjects (control group), having similar level of education and no significant differences regarding the anthropometric measurements.,We analyzed the differences in MoCA score between these three groups and also the correlation between this score and inflammatory markers.,Patients with AECOPD had a significant (p<0.001) decreased MoCA score (14.6±3.4) compared to stable COPD (20.2±2.4) and controls (24.2±5.8).,The differences between groups were more accentuated for the language abstraction and attention (p<0.001) and delayed recall and orientation (p<0.001) sub-topics.,No significant variance of score was observed between groups regarding visuospatial and naming score (p = 0.095).,The MoCA score was significantly correlated with forced expiratory volume (r = 0.28) and reverse correlated with C-reactive protein (CRP) (r = −0.57), fibrinogen (r = −0.58), erythrocyte sedimentation rate (ESR) (r = −0.55) and with the partial pressure of CO2 (r = −0.47).,According to this study, COPD significantly decreases the cognitive status in advanced and acute stages of the disease. | 1 |
Decreased physical activity is associated with higher mortality in subjects with COPD.,The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.,Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV1%) predicted values of 43 ± 16 were included.,The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR).,TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry.,Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics.,Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.,The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary.,The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m2, identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted.,The regression model explained 45.5% (p < 0.001) of the variance in PAL.,The FEV1% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%).,Neither age, gender nor systemic inflammation contributed to the model.,Apart from lung function, walking speed and muscle strength are important correlates of physical activity.,Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted. | The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented.,However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.,TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers).,To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ≥ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).,Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV.,SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage.,Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV.,The rates of adverse events were similar across treatment arms and increased with disease severity.,Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.,In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages.,Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease.,The effects were similar to those reported for the study as a whole.,Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.,Clinicaltrial.gov registration NCT00268216; Study number: SCO30003 | 1 |
In a previous study, we demonstrated that asthma patients with signs of emphysema on quantitative computed tomography (CT) fulfill the diagnosis of asthma-COPD overlap syndrome (ACOS).,However, quantitative CT measurements of emphysema are not routinely available for patients with chronic airway disease, which limits their application.,Spirometry was a widely used examination tool in clinical settings and shows emphysema as a sharp angle in the maximum expiratory flow volume (MEFV) curve, called the “angle of collapse (AC)”.,The aim of this study was to investigate the value of the AC in the diagnosis of emphysema and ACOS.,This study included 716 participants: 151 asthma patients, 173 COPD patients, and 392 normal control subjects.,All the participants underwent pulmonary function tests.,COPD and asthma patients also underwent quantitative CT measurements of emphysema.,The AC was measured using computer models based on Matlab software.,The value of the AC in the diagnosis of emphysema and ACOS was evaluated using receiver-operating characteristic (ROC) curve analysis.,The AC of COPD patients was significantly lower than that of asthma patients and control subjects.,The AC was significantly negatively correlated with emphysema index (EI; r=−0.666, P<0.001), and patients with high EI had a lower AC than those with low EI.,The ROC curve analysis showed that the AC had higher diagnostic efficiency for high EI (area under the curve =0.876) than did other spirometry parameters.,In asthma patients, using the AC ≤137° as a surrogate criterion for the diagnosis of ACOS, the sensitivity and specificity were 62.5% and 89.1%, respectively.,The AC on the MEFV curve quantified by computer models correlates with the extent of emphysema.,The AC may become a surrogate marker for the diagnosis of emphysema and help to diagnose ACOS. | Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway obstruction from emphysema.,We aimed to develop a computer model that quantifies airway collapse on forced expiratory flow-volume loops.,We then explored and validated the relationship of airway collapse with computed tomography (CT) diagnosed emphysema in two large independent cohorts.,A computer model was developed in 513 Caucasian individuals with ≥15 pack-years who performed spirometry, diffusion capacity and CT scans to quantify emphysema presence.,The model computed the two best fitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them.,The collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema.,Findings were validated in an independent group of 340 individuals.,AC in emphysema subjects (N = 251) was significantly lower (131° ± 14°) compared to AC in subjects without emphysema (N = 223), (152° ± 10°) (p < 0.0001).,Multivariate regression analysis revealed AC as best indicator of visually scored emphysema (R2 = 0.505, p < 0.0001) with little significant contribution of KCO, %predicted and FEV1, %predicted to the total model (total R2 = 0.626, p < 0.0001).,Similar associations were obtained when using CT-automated density scores for emphysema assessment.,Receiver operating characteristic (ROC) curves pointed to 131° as the best cut-off for emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity).,Validation in a second group confirmed the significant difference in mean AC between emphysema and non-emphysema subjects.,When applying the 131° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.,Airway collapse on forced expiration quantified by a computer model correlates with emphysema.,An AC below 131° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers. | 1 |
The aim of this investigation was to compare and contrast the use of cross sample entropy (xSE) and cross recurrence quantification analysis (cRQA) measures for the assessment of coupling of rhythmical patterns.,Measures were assessed using simulated signals with regular, chaotic, and random fluctuations in frequency, amplitude, and a combination of both.,Biological data were studied as models of normal and abnormal locomotor-respiratory coupling.,Nine signal types were generated for seven frequency ratios.,Fifteen patients with COPD (abnormal coupling) and twenty-one healthy controls (normal coupling) walked on a treadmill at three speeds while breathing and walking were recorded. xSE and the cRQA measures of percent determinism, maximum line, mean line, and entropy were quantified for both the simulated and experimental data.,In the simulated data, xSE, percent determinism, and entropy were influenced by the frequency manipulation.,The 1 : 1 frequency ratio was different than other frequency ratios for almost all measures and/or manipulations.,The patients with COPD used a 2 : 3 ratio more often and xSE, percent determinism, maximum line, mean line, and cRQA entropy were able to discriminate between the groups.,Analysis of the effects of walking speed indicated that all measures were able to discriminate between speeds. | Chronic obstructive pulmonary disease (COPD) is a disease associated with dyspnea, fatigue, and exercise intolerance.,The degree of functional debility and level of exercise capacity greatly influences quality of life and mortality in patients with COPD, and the measures of exercise capacity are to be an integral part of patient assessment but often not feasible in routine daily practice, resulting in likely suboptimal care.,There is a need for simple ways to identify functional decline in the clinical setting in order to guide resources to preventive interventions or proper care, including palliative care.,Gait speed, or measuring how long it takes for a patient to walk a short distance, takes very little time and space, and can serve as a candidate measure of physical function in COPD.,Gait speed has been shown to be an indicator of disability, health care utilization, and survival in older adults.,It is a simple, reliable, and feasible measure to perform in the clinic and has been promoted as the next vital sign, providing insight into patients’ functional capacity.,Gait speed is mainly determined by exercise capacity but reflects global well-being as it captures many of the multisystemic effects of disease severity in COPD rather than pulmonary impairment alone.,It is an excellent screening measure for exercise capacity and frailty; in COPD, the usual gait speed (4-m course with rolling start) has been very accurate in identifying clinically relevant benchmarks of the 6-minute walk test, poor (<350 m) and very poor (<200 m) 6-minute walk test distances.,A specific cut-off point of 0.8 m · s−1 had a positive predictive value of 69% and negative predictive value of 98% in predicting very poor exercise capacity.,The increasing evidence on gait speed is promising as a simple test that can inform the clinician about many important functional aspects of the COPD patient.,Further work will likely show the strength of gait speed as a predictive marker of hospitalizations, re-admissions, and mortality.,Instead of relying on the “eyeball test” regarding the patient’s frailty or exercise capacity, a gait speed in its simplicity represents a much more solid assessment.,Furthermore, repeat measures over serial clinic visits may show a pattern and further guide a change in therapy, whether it be medications, rehabilitation, or even initiation of palliative care discussions. | 1 |
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. | Interactions between spirometry and patient-reported outcomes in COPD are not well understood.,This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy.,Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations.,Mean and standard deviations of treatment effects were extracted for each arm of each study.,Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling.,The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score.,Thirty-six studies (≥3 months) were included.,Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data.,Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ.,The correlation strengthened with increasing study duration from 3 to 12 months.,Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1.,The association between change in FEV1 and other patient-reported outcomes was generally weak.,Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status. | 1 |
COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow.,It is mainly associated with exposure to cigarette smoke.,In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide.,Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells.,Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways.,The aims of these molecules are differentiation, proliferation and recruitment of neutrophils.,Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight.,In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract.,Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity. | To evaluate differentially expressed long noncoding RNAs (lncRNAs) and the potential role of lncRNA TUG1 in patients with chronic obstructive pulmonary disease (COPD).,Total RNA was extracted from both COPD and non-COPD lung tissues, and microarray analysis was performed with 25,628 lncRNA probes and 20,106 mRNA probes.,In addition, five up-regulated and five down-regulated lncRNAs were selected for identification using quantitative real-time polymerase chain reaction.,COPD cell model was established by transforming growth factor β (TGF-β) treatment.,Cell Counting Kit-8 assay was used to detect BEAS-2B and HFL1 cell proliferation after TUG-siRNA transfection with TGF-β treatment.,In addition, the expression levels of α-SMA and fibronectin proteins were determined using Western blot in BEAS-2B and HFL1 cells after TUG-siRNA transfection with TGF-β treatment.,There were 8,376 (32.7%) differentially expressed lncRNAs and 5,094 (25.3%) differentially expressed mRNAs in COPD lung tissues compared with non-COPD lung tissues.,Five of the analyzed lncRNAs (BC038205, BC130595, TUG1, MEG3, and LOC646329) were markedly increased, while five lncRNAs (LOC729178, PLAC2, LOC339529, LINC00229, and SNHG5) were significantly decreased in COPD lung tissues compared with non-COPD lung tissues (n=20) (***P<0.001).,Knockdown of lncRNA TUG1 promotes BEAS-2B and HFL1 cell proliferation after TGF-β treatment through inhibiting the expression levels of α-SMA and fibronectin.,Abundant, differentially expressed lncRNAs and mRNAs were identified by microarray analysis and these might play a partial or key role in the diagnosis of patients with COPD.,LncRNA TUG1 may become a very important class of biomarker and may act as a potential diagnostic and therapeutic target for patients with COPD. | 1 |
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood.,Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD).,The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.,We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.,Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13.,The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12).,But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants.,Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57).,Extending the analysis to lung function revealed a more complex situation.,Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants.,Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population. | 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. | 1 |
Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD), including the chronic inflammatory process, emphysema, and altered innate immune response.,Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-1β, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP), and growth factors such as transforming growth factor-β.,The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations.,While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable.,In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines.,The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor.,Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in COPD.,The two largest studies that have been reported in the literature involve the use of blocking antibody to TNFα and CXCL8 (IL-8), and neither has provided benefit.,Blocking the actions of CXCL8 through its CXCR2 receptor blockade was not successful either.,Studies of antibodies against IL-17, IL-18, IL-1β, and TSLP are currently either being undertaken or planned.,There is a need to carefully phenotype COPD and discover good biomarkers of drug efficacy for each specific target.,Specific groups of COPD patients should be targeted with specific anticytokine therapy if there is evidence of high expression of that cytokine and there are features of the clinical expression of COPD that will respond. | Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD).,In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP).,The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE).,Here we investigated whether cigarette smoke extract (CSE) stimulates human PMNs to breakdown whole matrix collagen leading to the generation of the chemotactic collagen fragment N-ac-PGP.,Incubating PMNs with CSE led to the release of chemo-attractant CXCL8 and proteases MMP8 and MMP9.,PMNs constitutively expressed PE activity as well as PE protein.,Incubating CSE-primed PMNs with collagen resulted in collagen breakdown and in N-ac-PGP generation.,Incubation of PMNs with the tripeptide N-ac-PGP resulted in the release of CXCL8, MMP8 and MMP9.,Moreover, we tested whether PMNs from COPD patients are different from PMNs from healthy donors.,Here we show that the intracellular basal PE activity of PMNs from COPD patients increased 25-fold compared to PMNs from healthy donors.,Immunohistological staining of human lung tissue for PE showed that besides neutrophils, macrophages and epithelial cells express PE.,This study indicates that neutrophils activated by cigarette smoke extract can breakdown collagen into N-ac-PGP and that this collagen fragment itself can activate neutrophils, which may lead in vivo to a self-propagating cycle of neutrophil infiltration, chronic inflammation and lung emphysema.,MMP-, PE- or PGP-inhibitors can serve as an attractive therapeutic target and may open new avenues towards effective treatment of COPD. | 1 |
Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts.,The evidence for many of these is, however, lacking or old and therefore in need of re-examination.,Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes.,It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages.,We review the evidence, or lack thereof, underlying ten items of inhaler ‘lore’ commonly passed on by health professionals to each other and thence to patients.,The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience.,It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future.,The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group. | Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity.,Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians.,The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids.,There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting.,Patients’ comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use.,This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques.,Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is emphysema and/or chronic bronchitis characterised by long-term breathing problems and poor airflow.,The prevalence of COPD has increased over the last decade and the drugs most commonly used to treat it, such as glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression.,Here we reviewed the pathogenesis and progression of COPD and elaborated on the effects and mechanisms of newly developed molecular targeted COPD therapeutic drugs.,Among these new drugs, we focussed on thioredoxin (Trx).,Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-κB and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways.,The mechanism by which Trx affects COPD is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses.,In addition, Trx also improves the insensitivity of COPD to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (MIF).,Taken together, these findings suggest that Trx may be the ideal drug for treating COPD. | Acute exacerbations of chronic obstructive pulmonary disease (COPD) are associated with a significant mortality, health and economic burden.,Their diagnosis, assessment and management remain suboptimal and unchanged for decades.,Recent clinical and translational studies revealed that the significant heterogeneity in mechanisms and outcomes of exacerbations could be resolved by grouping them etiologically.,This is anticipated to lead to a better understanding of the biological processes that underlie each type of exacerbation and to allow the introduction of precision medicine interventions that could improve outcomes.,This review summarises novel data on the diagnosis, phenotyping, targeted treatment and prevention of COPD exacerbations. | 1 |
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD).,The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.,Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354).,Eligible studies were those of any treatment used in severe AATD.,Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible.,All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months).,Risk of bias was assessed appropriately according to study methodology.,In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation).,Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments.,Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes.,Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02).,Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD.,Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.,Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density.,There is paucity of data around other treatments in AATD.,Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group. | Severe alpha 1-antitrypsin (AAT) deficiency (genotype PiZZ) is a well-known risk factor for COPD.,A cohort of PiZZ and PiSZ individuals was identified by the Swedish national neonatal AAT screening program in 1972-1974 and followed up regularly since birth.,Our aim was to study the lung function, respiratory symptoms and health status at the age of 38 years in comparison with a random sample of control subjects selected from the population registry.,The study group included 120 PiZZ, 46 PiSZ and 164 control subjects (PiMM), who answered a questionnaire on smoking habits and symptoms and the Saint George Respiratory Questionnaire (SGRQ) on quality of life.,A total of 89 PiZZ, 33 PiSZ and 92 PiMM subjects underwent spirometry.,Four percent of the PiZZ, 2% of the PiSZ and 12% of the control subjects were current smokers (P=0.008), and 17% of the PiZZ, 9% of the PiSZ and 21% of the control subjects had stopped smoking.,The PiZZ current smokers had a significantly higher (ie, poorer) median activity score according to the SGRQ than the PiZZ never-smokers (P=0.032).,The PiMM current smokers had significantly higher activity score (P<0.001), symptom score (P<0.001), and total score (P=0.001) according to the SGRQ than the PiMM never-smokers.,The PiZZ current smokers had a significantly lower postbronchodilator forced expiratory volume in 1 second (FEV1)% of predicted value (P=0.019) and FEV1/forced vital capacity (FVC) ratio (P=0.032) than the PiZZ never-smokers.,The proportion of subjects with a FEV1/FVC ratio of <0.70, indicating COPD, was significantly higher in the PiZZ current smokers than in the PiZZ never-smokers (P=0.001).,Among the PiSZ and PiMM subjects, the differences in lung function between the smoking subgroups were insignificant.,PiZZ current smokers were found to have signs of COPD before 40 years of age.,Smoking is less common among the AAT-deficient subjects identified by neonatal screening than among their peers in the general population. | 1 |
Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century.,The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD.,Our understanding of the key molecular mechanisms which drive the pathological changes are not complete.,In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation.,We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations.,We discuss the need to specifically target SAD to attenuate the progression of COPD. | The tissue turnover of unperturbed adult lung is remarkably slow.,However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration.,Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction.,Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis.,Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development.,Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors.,Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs.,With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality.,In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. | 1 |
Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs.,Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases.,Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells.,These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease.,Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1.,MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1.,Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle.,MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6).,Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.-Baker, J.,R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P.,S., Donnelly, L.,E., Ito, K., Barnes, P.,J.,MicroRNA-570 is a novel regulator of cellular senescence and inflammaging. | Blood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers.,We used two MSD multiplex panels to measure 9 cytokines and chemokines in 2123 subjects from COPDGene and 1117 subjects from SPIROMICS.,These biomarkers included: interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, eotaxin/CCL-11, eotaxin-3/CCL-26, and thymus and activation-regulated chemokine (TARC)/CCL-17.,Regression models adjusted for clinical covariates were used to determine which biomarkers were associated with the following COPD phenotypes: airflow obstruction (forced expiratory flow at 1 s (FEV1%) and FEV1/forced vital capacity (FEV1/FVC), chronic bronchitis, COPD exacerbations, and emphysema.,Biomarker-genotype associations were assessed by genome-wide association of single nucleotide polymorphisms (SNPs).,Eotaxin and IL-6 were strongly associated with airflow obstruction and accounted for 3-5% of the measurement variance on top of clinical variables.,IL-6 was associated with progressive airflow obstruction over 5 years and both IL-6 and IL-8 were associated with progressive emphysema over 5 years.,None of the biomarkers were consistently associated with chronic bronchitis or COPD exacerbations.,We identified one novel SNP (rs9302690 SNP) that was associated with CCL17 plasma measurements.,When assessing smoking related pulmonary disease, biomarkers of inflammation such as IL-2, IL-6, IL-8, and eotaxin may add additional modest predictive value on top of clinical variables alone.,COPDGene (ClinicalTrials.gov Identifier: NCT02445183).,Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) (ClinicalTrials.gov Identifier: NCT 01969344).,The online version of this article (10.1186/s12931-017-0662-2) contains supplementary material, which is available to authorized users. | 1 |
Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments.,The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.,This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks’ LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only).,Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.,Eighteen studies (23 trials) were eligible (N=20,185).,LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively).,LABA/LAMA improved transitional dyspnea index and St George’s Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively).,LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]).,Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]).,LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).,The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD.,These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use. | Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD).,The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation.,Data were collected from the National Health Insurance Database of Korea.,The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009.,Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors.,The prevalence of GERD in COPD patients was 28% (39,987/141,057).,Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD.,Most of COPD medications except inhaled muscarinic antagonists were associated with GERD.,The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001).,The prevalence of GERD in patients with COPD was high.,Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD.,The presence of GERD was associated with COPD exacerbation. | 1 |
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. | Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for asthma.,Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction.,Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients.,Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle.,Vagally derived acetylcholine also regulates mucus production in the airways.,A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling.,Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo.,Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways.,Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors.,Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD.,Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the pathophysiology and treatment of asthma and COPD. | 1 |
Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation.,We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis.,We studied changes in mitochondrial morphology and in expression of markers for mitochondrial capacity, damage/biogenesis and fission/fusion in the human bronchial epithelial cell line BEAS-2B upon 6-months from ex-smoking COPD GOLD stage IV patients to age-matched smoking and never-smoking controls.,We observed that long-term CSE exposure induces robust changes in mitochondrial structure, including fragmentation, branching and quantity of cristae.,The majority of these changes were persistent upon CSE depletion.,Furthermore, long-term CSE exposure significantly increased the expression of specific fission/fusion markers (Fis1, Mfn1, Mfn2, Drp1 and Opa1), oxidative phosphorylation (OXPHOS) proteins (Complex II, III and V), and oxidative stress (Mn-SOD) markers.,These changes were accompanied by increased levels of the pro-inflammatory mediators IL-6, IL-8, and IL-1β.,Importantly, COPD primary bronchial epithelial cells (PBECs) displayed similar changes in mitochondrial morphology as observed in long-term CSE-exposure BEAS-2B cells.,Moreover, expression of specific OXPHOS proteins was higher in PBECs from COPD patients than control smokers, as was the expression of mitochondrial stress marker PINK1.,The observed mitochondrial changes in COPD epithelium are potentially the consequence of long-term exposure to cigarette smoke, leading to impaired mitochondrial function and may play a role in the pathogenesis of COPD. | Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking.,Several mechanisms are involved in the development of the disease: influx of inflammatory cells into the lung (leading to chronic inflammation of the airways), imbalance between proteolytic and anti-proteolytic activity (resulting in the destruction of healthy lung tissue) and oxidative stress.,Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD.,There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients.,Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema.,Data from animal models suggest a role for Vascular Endothelial Growth Factor (VEGF) in the induction of apoptosis of structural cells in the lung.,Other mediators of apoptosis, such as caspase-3 and ceramide, could be interesting targets to prevent apoptosis and the development of emphysema.,In this review, recent data on the role of apoptosis in COPD from both animal models as well as from studies on human subjects will be discussed.,The aim is to provide an up to date summary on the increasing knowledge on the role of apoptosis in COPD and pulmonary emphysema. | 1 |
LABA (long-acting β2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD.,Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient.,To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings.,The main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice.,Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended.,Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures.,Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™).,Furthermore, a number of exacerbations and early morning COPD symptoms were documented.,In total, 3653 patients were enrolled.,FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001).,CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001).,Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups.,A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%.,In summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions.,All three treatments were well tolerated. | 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 |
Recent studies that assessed the relevance of the blood eosinophil count as a biomarker in patients with COPD may have overestimated it because they included patients with asthma-COPD overlap syndrome (ACOS).,We investigated the clinical implications of the blood eosinophil count in patients with non-ACOS COPD.,From a Korean COPD Subtype Study (KOCOSS) cohort, we selected patients with non-ACOS COPD after excluding ACOS patients according to Spanish criteria.,Clinical characteristics and the incidence of moderate-to-severe exacerbation were compared among the four groups stratified according to the quartiles of blood eosinophil percent and count.,Of the KOCOSS cohort of 1,132 patients with COPD, 467 non-ACOS COPD patients (41.2%) with data of blood eosinophil count remained after excluding those with ACOS based on the Spanish definition.,There was no difference in clinical characteristics among groups classified according to the quartiles of eosinophil percent and count.,On multivariate logistic regression, eosinophil quartiles in percent and absolute count were not associated with the incidence of moderate-to-severe acute exacerbations of COPD (AECOPD).,The eosinophil count did not affect the risk of AECOPD or forced expiratory volume in 1 second (FEV1) changes according to exposure to inhaled corticosteroid (ICS).,However, by increasing the cutoff value for the eosinophil count from 200/μL to 600/μL, the odds ratio for risk of exacerbation increased serially from 0.82 to 2.96 on trend analysis.,In patients with non-ACOS COPD, the blood eosinophil count and percent were not associated with FEV1 changes, quality of life (QoL), AECOPD frequency, or response to ICS.,The clinical implication of the blood eosinophil count should not be overestimated in patients with non-ACOS COPD. | We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy.,Three studies of ≥1-year duration met the inclusion criteria.,Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%).,At baseline, 57-75% of patients had ≥2% blood eosinophils.,Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level.,For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001).,No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively).,In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo).,No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ.,Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations. | 1 |
Long-acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD).,The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from COPD.,This study comprised a systematic review of randomized controlled trials identified through systematic searches of different databases of published trials.,Nine trials (6,166 participants) were included.,Fixed-dose once-daily indacaterol/glycopyrronium seems to be safe and well tolerated in patients with COPD.,Compared with single therapy with other long-acting bronchodilators (indacaterol, glycopyrronium, and tiotropium) and fixed-combination long-acting β2-agonist/inhaled corticosteroid (salmeterol/fluticasone twice daily), once-daily fixed-dose indacaterol/glycopyrronium has clinically important effects on symptoms, including dyspnea score, health status, level of lung function, and rate of moderate or severe exacerbations in patients with moderate-to-very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] spirometric criteria).,Furthermore, a very recent study has shown that fixed-dose indacaterol/glycopyrronium improves exercise endurance time compared with placebo, although no significant difference was observed between fixed-dose indacaterol/glycopyrronium and tiotropium.,Fixed-dose indacaterol/glycopyrronium has clinically relevant effects on important COPD outcome measures and is, in general, superior to therapy with a single long-acting bronchodilator (with or without inhaled corticosteroid) indicating long-acting dual bronchodilation as a potential important maintenance therapeutic option for patients with symptomatic COPD, possibly also for the treatment of naïve patients. | Indacaterol is a novel, once-daily (od), inhaled, long-acting ß2-agonist bronchodilator for maintenance treatment of airflow limitation in patients with COPD.,The aim of this study was to evaluate the efficacy of indacaterol on dyspnea, using available randomized placebo-controlled trials.,A systematic search was made of MEDLINE, EMBASE, the Cochrane trials databases, and a manual search of journals.,Randomized placebo-controlled trials of 12 weeks or more comparing indacaterol with placebo were reviewed, and eligible studies were included in a meta-analysis.,The odds ratio (OR) for likelihood of achieving TDI score ≥ 1 after 12 weeks of treatment was used as an outcome measure to compare indacaterol to placebo.,Six trials were included in the analysis.,Relative to placebo, the overall ORs for response were: indacaterol 75 μg od 1.784 (95% CI 1.282 to 2.482); indacaterol 150 μg od 2.149 (95% CI 1.746 to 2.645); and indacaterol 300 μg od 2.458 (95% CI 2.010 to 3.006).,Overall OR for response in TDI tended to increase with higher indacaterol doses.,Patients receiving indacaterol had clinically significant improvements in symptoms of dyspnea compared to placebo.,Incremental benefits in TDI were observed with increasing doses.,Indacaterol may provide patients and physicians with a useful treatment option in symptomatic patients with dyspnea. | 1 |
Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe COPD and recurrent exacerbations.,It is not known what impact ICS cause in terms of COVID-19 positivity or disease severity in COPD.,This study examined 27,810 patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th and September 16th, 2020.,Electronic health records were used to determine diagnosis of COPD, ICS use, and clinical outcomes.,Multivariate logistic regression was used to adjust for demographics, month of COVID-19 testing, and comorbidities known to be associated with increased risk for severe COVID-19 disease.,Amongst the COPD patients who were tested for COVID-19, 44.1% of those taking an ICS-containing inhaler tested positive for COVID-19 versus 47.2% who tested negative for COVID-19 (p = 0.033).,Of those who tested positive for COVID-19 (n = 1288), 371 (28.8%) required hospitalization.,In-hospital outcomes were not significantly different when comparing ICS versus no ICS in terms of ICU admission (36.8% [74/201] vs 31.2% [53/170], p = 0.30), endotracheal intubation (21.9% [44/201] vs 16.5% [28/170], p = 0.24), or mortality (18.4% [37/201] vs 20.0% [34/170], p = 0.80).,Multivariate logistic regression demonstrated no significant differences in hospitalization (adj OR 1.12, CI: 0.90-1.38), ICU admission (adj OR: 1.31, CI: 0.82-2.10), need for mechanical ventilation (adj OR 1.65, CI: 0.69-4.02), or mortality (OR: 0.80, CI: 0.43-1.49).,In conclusion, ICS therapy did not increase COVID-19 related healthcare utilization or mortality outcome in patients with COPD followed at the Cleveland Clinic health system.,These findings should encourage clinicians to continue ICS therapy for COPD patients during the COVID-19 pandemic. | Chronic respiratory diseases (CRD) are common among patients with coronavirus disease 2019 (COVID-19).,We sought to determine the association between CRD (including disease overlap) and the clinical outcomes of COVID-19.,Data of diagnoses, comorbidities, medications, laboratory results, and clinical outcomes were extracted from the national COVID-19 reporting system.,CRD was diagnosed based on International Classification of Diseases-10 codes.,The primary endpoint was the composite outcome of needing invasive ventilation, admission to intensive care unit, or death within 30 days after hospitalization.,The secondary endpoint was death within 30 days after hospitalization.,We included 39,420 laboratory-confirmed patients from the electronic medical records as of May 6, 2020.,Any CRD and CRD overlap was present in 2.8% and 0.2% of patients, respectively.,Chronic obstructive pulmonary disease (COPD) was most common (56.6%), followed by bronchiectasis (27.9%) and asthma (21.7%).,COPD-bronchiectasis overlap was the most common combination (50.7%), followed by COPD-asthma (36.2%) and asthma-bronchiectasis overlap (15.9%).,After adjustment for age, sex, and other systemic comorbidities, patients with COPD (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.44-2.03) and asthma (OR: 1.45, 95% CI: 1.05-1.98), but not bronchiectasis, were more likely to reach to the composite endpoint compared with those without at day 30 after hospitalization.,Patients with CRD were not associated with a greater likelihood of dying from COVID-19 compared with those without.,Patients with CRD overlap did not have a greater risk of reaching the composite endpoint compared with those without.,CRD was associated with the risk of reaching the composite endpoint, but not death, of COVID-19. | 1 |
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are associated with a significant mortality, health and economic burden.,Their diagnosis, assessment and management remain suboptimal and unchanged for decades.,Recent clinical and translational studies revealed that the significant heterogeneity in mechanisms and outcomes of exacerbations could be resolved by grouping them etiologically.,This is anticipated to lead to a better understanding of the biological processes that underlie each type of exacerbation and to allow the introduction of precision medicine interventions that could improve outcomes.,This review summarises novel data on the diagnosis, phenotyping, targeted treatment and prevention of COPD exacerbations. | Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide.,Genetic risk loci provide novel insights into disease pathogenesis.,We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.,We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function.,Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium.,Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types.,We found 14 COPD loci shared with either asthma or pulmonary fibrosis.,COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations.,Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD. | 1 |
Physical activity, sedentary and sleep behaviours have strong associations with health.,This systematic review aimed to identify how clinical practice guidelines (CPGs) for the management of chronic obstructive pulmonary disease (COPD) report specific recommendations and strategies for these movement behaviours.,A systematic search of databases (Medline, Scopus, CiNAHL, EMbase, Clinical Guideline), reference lists and websites identified current versions of CPGs published since 2005.,Specific recommendations and strategies concerning physical activity, sedentary behaviour and sleep were extracted verbatim.,The proportions of CPGs providing specific recommendations and strategies were reported.,From 2370 citations identified, 35 CPGs were eligible for inclusion.,Of these, 21 (60%) provided specific recommendations for physical activity, while none provided specific recommendations for sedentary behaviour or sleep.,The most commonly suggested strategies to improve movement behaviours were encouragement from a healthcare provider (physical activity n = 20; sedentary behaviour n = 2) and referral for a diagnostic sleep study (sleep n = 4).,Since optimal physical activity, sedentary behaviour and sleep durations and patterns are likely to be associated with mitigating the effects of COPD, as well as with general health and well-being, there is a need for further COPD-specific research, consensus and incorporation of recommendations and strategies into CPGs. | Persons with Chronic Obstructive Pulmonary Disease (COPD), performing some level of regular physical activity, have a lower risk of both COPD-related hospital admissions and mortality.,COPD patients of all stages seem to benefit from exercise training programs, thereby improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue.,Physical inactivity, which becomes more severe with increasing age, is a point of concern in healthy older adults.,COPD might worsen this scenario, but it is unclear to what degree.,This literature review aims to present the extent of the impact of COPD on objectively-measured daily physical activity (DPA).,The focus is on the extent of the impact that COPD has on duration, intensity, and counts of DPA, as well as whether the severity of the disease has an additional influence on DPA.,A literature review was performed in the databases PubMed [MEDLINE], Picarta, PEDRO, ISI Web of Knowledge and Google scholar.,After screening, 11 studies were identified as being relevant for comparison between COPD patients and healthy controls with respect to duration, intensity, and counts of DPA.,Four more studies were found to be relevant to address the subject of the influence the severity of the disease may have on DPA.,The average percentage of DPA of COPD patients vs. healthy control subjects for duration was 57%, for intensity 75%, and for activity counts 56%.,Correlations of DPA and severity of the disease were low and/or not significant.,From the results of this review, it appears that patients with COPD have a significantly reduced duration, intensity, and counts of DPA when compared to healthy control subjects.,The intensity of DPA seems to be less affected by COPD than duration and counts.,Judging from the results, it seems that severity of COPD is not strongly correlated with level of DPA.,Future research should focus in more detail on the relation between COPD and duration, intensity, and counts of DPA, as well as the effect of disease severity on DPA, so that these relations become more understandable. | 1 |
This study investigated the effect of dual bronchodilation with the long-acting β-receptor agonist/long-acting muscarinic antagonist combination, indacaterol/glycopyrronium (IND/GLY), on nighttime oxygenation, lung function, sleep quality, and symptoms in patients with moderate-to-severe COPD.,This was a 4-week, double-blind, multicenter, placebo-controlled, two-period crossover study.,Patients were randomized in a 1:1 ratio to receive IND/GLY 110/50 µg once daily or matching placebo.,The primary objective was to evaluate the effect of treatment with IND/GLY on mean nighttime oxygenation, compared with placebo.,The secondary objective was to determine the time spent <90% in blood oxygen saturation (SpO2) compared with placebo.,Exploratory objectives were to assess the effect of IND/GLY, compared with placebo, on sleep quality measured by the Medical Outcomes Study (MOS) Sleep Scale and the COPD and Asthma Sleep Impact Scale (CASIS) questionnaires and on symptoms assessed by COPD Assessment Test (CAT) questionnaire.,In total, 38 patients were randomized (n=22, IND/GLY; n=16, placebo).,The change in nighttime oxygenation (SpO2) was similar, and there was a comparable difference in time spent <90% SpO2 between IND/GLY and placebo.,Increases from baseline for the difference between IND/GLY and placebo for trough FEV1, FVC, and inspiratory capacity (P<0.05) were seen, with a corresponding reduction in residual volume and functional residual capacity (P<0.05).,IND/GLY treatment showed an improvement in scores for CAT (P=0.0208), CASIS, and the MOS Sleep Scale measures, Sleep Problems Index I, Sleep Problems Index II (P=0.0315), Sleep Adequacy, Sleep Disturbance Scale, Somnolence Scale, and Short of Breath Scale (P=0.0031).,In this study, IND/GLY 110/50 µg once daily improved symptoms, sleep quality, and lung function, but showed no effect on nighttime oxygenation in patients with moderate-to-severe COPD. | Patients with COPD may show slow, progressive deteriorations in arterial blood gases during the night, particularly during rapid eye movement (REM) sleep.,This is mainly due to hypoventilation, while a deterioration of ventilation/perfusion mismatch plays a minor role.,The severity of gas exchanges alterations is proportional to the degree of impairment of diurnal pulmonary function tests, particularly of partial pressure of oxygen (PaO2) and of carbon dioxide (PaCO2) in arterial blood, but correlations between diurnal and nocturnal blood gas levels are rather loose.,Subjects with diurnal PaO2 of 60-70 mmHg are distinguished in “desaturators” and “nondesaturators” according to nocturnal oxyhemoglobin saturation behavior.,The role of nocturnal hypoxemia as a determinant of alterations in sleep structure observed in COPD is dubious.,Effects of the “desaturator” condition on pulmonary hemodynamics, evolution of diurnal blood gases, and life expectancy are also controversial.,Conversely, it is generally accepted that occurrence of sleep apneas in COPD is associated with a worse evolution of the disease.,Nocturnal polysomnographic monitoring in COPD is usually performed when coexistence of sleep apnea (“overlap syndrome”) is suspected, while in most other cases nocturnal oximetry may be enough.,Nocturnal oxygen attenuates sleep desaturations among stable patients, without increases in PaCO2 of clinical concern.,Nocturnal treatment with positive pressure ventilators may give benefit to some stable hypercapnic subjects and patients with the overlap syndrome. | 1 |
To describe a murine model of emphysema induced by a combination of exposure to cigarette smoke (CS) and instillation of porcine pancreatic elastase (PPE).,A total of 38 C57BL/6 mice were randomly divided into four groups: control (one intranasal instillation of 0.9% saline solution); PPE (two intranasal instillations of PPE); CS (CS exposure for 60 days); and CS + PPE (two intranasal instillations of PPE + CS exposure for 60 days).,At the end of the experimental protocol, all animals were anesthetized and tracheostomized for calculation of respiratory mechanics parameters.,Subsequently, all animals were euthanized and their lungs were removed for measurement of the mean linear intercept (Lm) and determination of the numbers of cells that were immunoreactive to macrophage (MAC)-2 antigen, matrix metalloproteinase (MMP)-12, and glycosylated 91-kDa glycoprotein (gp91phox) in the distal lung parenchyma and peribronchial region.,Although there were no differences among the four groups regarding the respiratory mechanics parameters assessed, there was an increase in the Lm in the CS + PPE group.,The numbers of MAC-2-positive cells in the peribronchial region and distal lung parenchyma were higher in the CS + PPE group than in the other groups, as were the numbers of cells that were positive for MMP-12 and gp91phox, although only in the distal lung parenchyma.,Our model of emphysema induced by a combination of PPE instillation and CS exposure results in a significant degree of parenchymal destruction in a shorter time frame than that employed in other models of CS-induced emphysema, reinforcing the importance of protease-antiprotease imbalance and oxidant-antioxidant imbalance in the pathogenesis of emphysema. | There is a need to identify individuals with COPD at risk for disease progression and mortality.,Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation.,We hypothesized that ECM remodeling was associated with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling.,Biomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort.,Validated immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used.,Multivariate models were used to assess the prognostic value of these biomarkers.,Thirty subjects (3.0 %) died during follow-up.,Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers.,All collagen biomarkers were significantly elevated in non-survivors compared to survivors.,Mortality risk was significantly increased for subjects with collagen remodeling biomarkers in the upper quartile, especially for the degradation fragment of collagen type IV C6M (hazard ratio 6.6 [95 % confidence interval 2.9-15.2], P < 0.0001) after adjusting for relevant confounders.,Serological biomarkers of collagen remodeling were strongly associated with mortality in subjects with COPD indicating that assessment of tissue turnover in the parenchyma and small airways may be useful in the prognosis of COPD.,NCT00292552, GSK Study No.,SCO104960.,The online version of this article (doi:10.1186/s12931-016-0440-6) contains supplementary material, which is available to authorized users. | 1 |
It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation.,We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation.,Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed.,Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation.,The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD.,The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV.,The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21-5.70, P=0.000-0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages.,From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness.,Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%-75.3%) and specificities (70.3%-75.7%).,We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation. | Information about daily physical activity levels (PAL) in subjects with undiagnosed chronic obstructive pulmonary disease (COPD) is scarce.,This study aims to assess PA and to investigate the associations between PA and clinical characteristics in subjects with newly diagnosed COPD.,Fifty-nine subjects with a new spirometry-based diagnosis of mild (n=38) and moderate (n=21) COPD (63±6 years, 68% male) were matched with 65 smoking controls (62±7 years, 75% male).,PA (daily steps, time spent in moderate-to-vigorous intense physical activities (MVPA) and PAL) was measured by accelerometry.,Dyspnoea, complete pulmonary function tests, peripheral muscle strength and exercise capacity served as clinical characteristics.,PA was significantly lower in COPD versus smoking controls (7986±2648 vs 9765±3078 steps, 64 (27-120) vs 110 (55-164) min of MVPA, 1.49±0.21 vs 1.62±0.24 PAL respectively, all p<0.05).,Subjects with COPD with either mild symptoms of dyspnoea (mMRC 1), those with lower diffusion capacity (TL,co), low 6 min walking distance (6MWD) or low maximal oxygen uptake (VO2 peak) had significantly lower PA.,Multiple regression analysis identified 6 MWD and TL,co as independent predictors of PA in COPD.,The reduction in PA starts early in the disease, even when subjects are not yet diagnosed with COPD.,Inactivity is more pronounced in subjects with mild symptoms of dyspnoea, lower levels of diffusion capacity and exercise capacity. | 1 |
Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis.,Frequent co-morbidities with a higher incidence than in idiopathic pulmonary fibrosis or emphysema alone are pulmonary hypertension (WHO group 3) in 47-90% of the patients and lung cancer in 46.8% of the patients.,Review current evidence and knowledge concerning diagnosis, risk factors, disease evolution and treatment options of CPFE.,We searched studies reporting CPFE in original papers, observational studies, case reports, and meta-analyses published between 1990 and August 2020, in the PubMed, Embase, Cochrane Library, Wiley Online Library databases and Google Scholar using the search terms [CPFE], [pulmonary fibrosis] OR [IPF] AND [emphysema].,Bibliographies of retrieved articles were searched as well.,Further inclusion criteria were publications in English, French, German and Italian, with reference to humans.,In vitro data and animal data were not considered unless they were mentioned in studies reporting predominantly human data.,Between May 1, 1990, and September 1, 2020, we found 16 studies on CPFE from the online sources and bibliographies.,A total of 890 patients are described in the literature.,Although male/female ratio was not reported in all studies, the large majority of patients were male (at least 78%), most of them were current or former heavy smokers.,CPFE is a syndrome presenting with dyspnea on exertion followed by disruptive cough and recurrent exacerbations.,The disease may progress rapidly, be aggravated by pulmonary hypertension WHO group 3 and is associated with an increased risk of lung cancer.,Smoking and male sex are important risk factors.,There is a need for more research on CPFE especially relating to etiology, influence of genetics, treatment and prevention options.,Antifibrotic therapy might be an interesting treatment option for these patients. | Previous analyses of combined pulmonary fibrosis and emphysema (CPFE) cohorts have provided conflicting data on the survival of patients with CPFE.,Therefore, the aim of this study was to investigate the clinical prognosis of acute exacerbations (AE) of CPFE.,We retrospectively reviewed the medical records of patients who had been treated at the Shinshu University Hospital (Matsumoto, Japan) between 2003 and 2017.,We identified 21 patients with AE of CPFE and 41 patients with AE of idiopathic pulmonary fibrosis (IPF) and estimated their prognoses using the Kaplan-Meier method.,Treatment content and respiratory management were not significantly different between the two groups before and after exacerbation.,At the time of AE, the median serum Krebs von den Lungen-6 level was significantly lower in the CPFE group (Krebs von den Lungen-6: 966 U/μL; white blood cell count: 8810 /μL) than that in the IPF group (Krebs von den Lungen-6: 2130 U/μL, p < 0.001; white blood cells: 10809/μL, p = 0.0096).,The baseline Gender-Age-Physiology scores were not significantly different between the two groups (CPFE, 4.5 points; IPF, 4.7 points; p = 0.58).,Kaplan-Meier curves revealed that the survival time after AE for patients with CPFE was longer than that for patients with IPF (p < 0.001, log-rank test).,Survival prognoses after AE were significantly better for patients with CPFE than that for those with IPF.,Our findings may improve the medical treatment and respiratory management of patients with AE-CPFE. | 1 |
Skeletal muscle dysfunction leads to reduction in activity in patients with COPD.,As an essential part of the management of COPD, pulmonary rehabilitation (PR) alleviates dyspnea and fatigue, improves exercise tolerance and health-related quality of life, and reduces hospital admissions and mortality for COPD patients.,Exercise is the key component of PR, which is composed of exercise assessment and training therapy.,To evaluate PR’s application in clinical practice, this article summarizes the common methods of exercise measurement and exercise training for patients with COPD.,Exercise assessments should calculate patients’ symptoms, endurance, strength, and health-related quality of life.,After calculation, detailed exercise therapies should be developed, which may involve endurance, strength, and respiratory training.,The detailed exercise training of each modality is mentioned in this review.,Although various methods and therapies of PR have been used in COPD patients, developing an individualized exercise training prescription is the target.,More studies are warranted to support the evidence and examine the effects of long-term benefits of exercise training for patients with COPD in each stage. | This retrospective, observational study of a routine clinical practice reports the feasibility and efficiency of home-based pulmonary rehabilitation (PR), including transcutaneous neuromuscular electrical stimulation (NMES) or usual endurance physical exercise (UEPE), on exercise tolerance, anxiety/depression, and health-related quality of life (HRQoL) in patients with COPD.,Seventy-one patients with COPD participated in home-based PR with NMES (Group NMES [GNMES]), while 117 patients participated in home-based PR with the UEPEs (Group UEPE [GUEPE]).,NMES was applied for 30 minutes twice a day, every day.,The endurance exercises in GUEPE began with a minimum 10-minute session at least 5 days a week, with the goal being 30-45 minutes per session.,Three upper and lower limb muscle strengthening exercises lasting 10-15 minutes were also proposed to both the groups for daily practice.,Moreover, PR in both the groups included a weekly 90-minute session based on an educational needs assessment.,The sessions comprised endurance physical exercise for GUEPE, NMES for GNMES, resumption of physical daily living activities, therapeutic patient education, and psychosocial support to facilitate health behavior changes.,Before and after PR, functional mobility and physical exercise capacity, anxiety, depression, and HRQoL were evaluated at home.,The study revealed that NMES significantly improved functional mobility (−18.8% in GNMES and −20.6% in GUEPE), exercise capacity (+20.8% in GNMES and +21.8% in GUEPE), depression (−15.8% in GNMES and −30.1% in GUEPE), and overall HRQoL (−7.0% in GNMES and −18.5% in GUEPE) in the patients with COPD, regardless of the group (GNMES or GUEPE) or severity of airflow obstruction.,Moreover, no significant difference was observed between the groups with respect to these data (P>0.05).,Home-based PR including self-monitored NMES seems feasible and effective for severely disabled COPD patients with severe exercise intolerance. | 1 |
Many patients suffering from asthma or COPD have overlapping features of both diseases.,However, a phenotypical approach for evaluating asthma-COPD overlap syndrome (ACOS) has not been established.,In this report, we examined the phenotypes in patients with ACOS.,Patients diagnosed with ACOS between 2011 and 2015 were identified and classified into four phenotype groups.,Group A was composed of patients who smoked <10 pack years and had blood eosinophil counts ≥300.,Group B was composed of patients who smoked <10 pack years and had blood eosinophil counts <300.,Group C was composed of patients who smoked ≥10 pack years and had blood eosinophil counts ≥300.,Group D was composed of patients who smoked <10 pack years and had blood eosinophil counts <300.,Clinical characteristics were analyzed and compared among groups.,Comparisons were made among 103 ACOS patients.,Patients in group D were oldest, while patients in group A were youngest.,There were relatively more female patients in groups A and B; the majority of patients in groups C and D were male.,The degree of airflow obstruction was most severe in group C.,The rate of being free of severe exacerbation was significantly lower in group C than in the other groups.,In this study, each ACOS phenotype showed different characteristics.,The proportion of patients free of severe exacerbation differed significantly among groups.,At this time, further studies on the phenotypes of ACOS are required. | Asthma-COPD overlap syndrome (ACOS) is a commonly encountered chronic airway disease.,However, ACOS is still a consensus-based clinical phenotype and the underlying inflammatory mechanisms are inadequately characterized.,To clarify the inflammatory mediatypical for ACOS, five biomarkers, namely interleukin (IL)-13, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-like protein (YKL-40), and IL-6, were selected.,This study hypothesized that sputum biomarkers relevant for airway inflammation in asthma (IL-13), COPD (MPO, NGAL), or in both asthma and COPD (YKL-40, IL-6) could be used to differentiate ACOS from COPD and asthma.,The aim of this study was to characterize the inflammatory profile and improve the recognition of ACOS.,Induced sputum levels of IL-13, MPO, NGAL, YKL-40, and IL-6 were measured by enzyme-linked immunosorbent assay/Luminex assay in a Finnish discovery cohort (n=90) of nonsmokers, smokers, and patients with asthma, COPD, and ACOS and validated in a Japanese cohort (n=135).,The classification accuracy of potential biomarkers was compared with area under the receiver operating characteristic curves.,Only sputum NGAL levels could differentiate ACOS from asthma (P<0.001 and P<0.001) and COPD (P<0.05 and P=0.002) in the discovery and replication cohorts, respectively.,Sputum NGAL levels were independently correlated with the percentage of pre-bronchodilator forced expiratory volume in 1 second predicted in multivariate analysis in the discovery and replication cohorts (P=0.001 and P=0.002, respectively).,In conclusion, sputum biomarkers reflecting both airway inflammation and remodeling of the tissue show potential in differentiation between asthma, COPD, and ACOS. | 1 |
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. | 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 |
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood.,Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD).,The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.,We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.,Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13.,The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12).,But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants.,Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57).,Extending the analysis to lung function revealed a more complex situation.,Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants.,Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population. | Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood.,A number of candidate genes have been proposed on the basis of the pathogenesis of COPD.,These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD.,Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.,To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations.,We used logistic regression to adjust for age, gender, centre and smoking history.,Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.,Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94).,The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129).,This implicates haplotypes of MMP-12 as modifiers of disease severity. | 1 |
The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD.,This study investigated the efficacy and safety of UMEC versus TIO in COPD.,This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study.,Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo.,The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin −50 mL; per-protocol [PP] population).,Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose.,Patient-reported outcomes comprised Transition Dyspnea Index score, St George’s Respiratory Questionnaire total score, and COPD Assessment Test score.,Adverse events were also assessed.,In total, 1,017 patients were randomized to treatment.,In the PP population, 489 and 487 patients received UMEC and TIO, respectively.,In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001).,Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001).,Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015).,Clinically meaningful improvements in Transition Dyspnea Index and St George’s Respiratory Questionnaire were observed with both treatments at all time points.,No differences were observed between UMEC and TIO in patient-reported outcomes.,Overall incidences of adverse events were similar for UMEC and TIO.,UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85.,Safety profiles were similar for both treatments. | Medications for respiratory disorders including asthma and chronic obstructive pulmonary disease (COPD) are typically delivered to the lung by means of a handheld inhaler.,Patient preference for and ability to use the inhaler may influence their adherence to maintenance therapy, and adherence may affect treatment outcomes.,In this study, patient experience of using a dry powder inhaler (DPI), the ELLIPTA™ DPI, in clinical trials of a new maintenance therapy for asthma and COPD was investigated.,The ELLIPTA DPI has been designed to contain two separate blister strips from which inhalation powder can be delivered, and to be simple to use with a large, easy-to-read dose counter.,Semi-structured, in-depth, qualitative interviews were carried out 2-4 weeks after patients had completed one of six phase IIIa clinical trials using the ELLIPTA DPI.,Interview participants were asked about their satisfaction with various attributes of the inhaler and their preference for the ELLIPTA DPI relative to currently-prescribed inhalers, and responses were explored using an inductive content analysis approach.,Participants also rated the performance of the inhaler on several criteria, using a subjective 1-10 scale.,Participants with asthma (n = 33) and COPD (n = 42) reported high levels of satisfaction with the ELLIPTA DPI.,It was frequently described as straightforward to operate and easy to use by interview participants.,Ergonomic design, mouthpiece fit, and dose counter visibility and ease of interpretation emerged as frequently cited drivers of preference for the ELLIPTA DPI compared with their current prescribed inhaler.,Of participants with asthma, 71% preferred the ELLIPTA DPI to DISKUS™ and 60% to metered dose inhalers.,Of participants with COPD, 86% preferred the ELLIPTA DPI to DISKUS, 95% to HandiHaler™, and 85% to metered dose inhalers.,Overall average performance scores were >9 (out of 10) in participants with asthma and COPD.,The ELLIPTA DPI was associated with high patient satisfaction and was preferred to other inhalers by interview participants with asthma and COPD.,The development of an inhaler that is regarded as easy and intuitive to use may have positive implications for adherence to therapy in asthma and COPD.,Asthma: NCT01165138, NCT01431950.,COPD: NCT01053988, NCT01054885, NCT01009463, NCT01017952. | 1 |
Telemonitoring (TM) of patients with COPD has gained much interest, but studies have produced conflicting results.,We aimed to investigate the effect of TM with the option of video consultations on quality of life (QoL) in patients with severe COPD.,COPD patients at high risk of exacerbations were eligible for the 6-month study and a total of 281 patients were equally randomized to either TM (n=141) or usual care (n=140).,TM comprised recording of symptoms, oxygen saturation, spirometry, and video consultations.,Algorithms generated alerts if readings breached thresholds.,Both groups filled in a health-related QoL questionnaire (15D©) and the COPD Assessment Test (CAT) at baseline and at 6 months.,Within-group differences were analyzed by paired t-test.,Most of the enrolled patients had severe COPD (86% with Global Initiative for Chronic Obstructive Lung Disease stage 3 or 4 and 45% with admission for COPD within the last year, respectively).,No difference in drop-out rate and mortality was found between the groups, and likewise there was no difference in 15D or CAT at baseline.,At 6 months, a significant improvement of 0.016 in 15D score (p=0.03; minimal clinically important difference 0.015) was observed in the TM group (compared to baseline), while there was no improvement in the control group −0.003 (p=0.68).,After stratifying 15D score at baseline to <0.75 or ≥0.75, respectively, there was a significant difference in the <0.75 TM group of 0.037 (p=0.001), which is a substantial improvement.,No statistically significant changes were found in CAT score.,Compared to the nonintervention group, TM as an add-on to usual care over a 6-month period improved QoL, as assessed by the 15D questionnaire, in patients with severe COPD, whereas no difference between groups was observed in CAT score. | 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. | 1 |
Evidence from longitudinal studies on the impact of exacerbation symptoms on physical activity in chronic obstructive pulmonary disease (COPD) is lacking.,The aim of this first exploratory study was to assess the association between exacerbation symptoms and physical activity, and to quantify the relative influence of specific symptoms.,We recruited COPD patients at high risk for exacerbations from 2 pulmonary rehabilitation clinics and 1 acute care clinic in Switzerland.,For 3 months after discharge, patients completed a daily symptom diary on a smartphone application, the EXAcerbations of Chronic pulmonary disease Tool (EXACT), and wore a pedometer to measure daily steps.,We used mixed-effects models to determine the association of daily steps with exacerbation symptoms.,A total of 21 patients (Global Initiative for Chronic Obstructive Lung Disease grades 2-4) were enrolled for a mean of 94.4 days (standard deviation 4.2).,The baseline median number of daily steps was 3,264.6 (interquartile range [IQR]: 1,851.3-4,784.1) and EXACT score was 37.0 (IQR: 30.9-41.4).,A 12-point increase in EXACT score (indicating the start of an exacerbation) was statistically significantly associated with a decrease in daily steps of 653.3 (95% CI 969.7-336.9).,Chest symptoms (tightness, discomfort and congestion) were more strongly associated with change in steps than breathlessness, and cough and sputum (z-value −4.5 vs −2.9 and −3.0).,This is the first study to show that, in a small cohort of COPD patients, increases in exacerbation symptoms were associated with a statistically and clinically significant reduction in daily physical activity.,These results underscore the importance for symptom control and exacerbation prevention in COPD patients. | This study was performed to examine acute exacerbation of COPD (AECOPD) during pulmonary rehabilitation (PR) and the usefulness of multidimensional indices (MIs) to predict AECOPD at enrolment in PR.,A 4-week PR program (PRP) was implemented for 125 consecutive patients with COPD.,At baseline and PRP completion, we recorded the FEV1, 6-minute walk test, peak work rate at cardiopulmonary testing, modified Medical Research Council score, and COPD Assessment Test (CAT) score.,The risk of AECOPDs at baseline was assessed using the body mass index, airway obstruction, dyspnea, Exercise capacity (BODE), dyspnea, obstruction, smoking, exacerbation (DOSE), and score to predict short-term risk of COPD exacerbations (SCOPEX) MIs.,Thirty-two episodes of AECOPD occurred.,The COPD status was worse in patients with than without AECOPD at baseline (lower FEV1, 6-minute walk test, and peak work rate; higher modified Medical Research Council and CAT scores).,The sensitivities of the BODE, DOSE, and SCOPEX MIs to predict the occurrence of AECOPD during PRP were 78.1%, 21.9%, and 84.4%, and the specificities were 73.6%, 87.1%, and 51.6%, respectively.,The BODE and SCOPEX MIs help to predict the exacerbation risk during PR. | 1 |
Chronic obstructive pulmonary disease (COPD), a general airway disease, is featured by progressive and chronic immunoreaction in the lung.,Increasing evidences have showed that cigarette smoking is the main reason in the COPD progression, and human pulmonary microvascular endothelial cell (HPMEC) apoptosis often be observed in COPD, while its pathogenesis is not yet fully described.,Upregulation of long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) was observed in COPD patients, but the specific mechanism of lncRNA MEG3 in COPD remains unknown.,The objective of this research was to explore the role of lncRNA MEG3 in cigarette smoke extract (CSE)-induced HPMECs.,HPMECs were induced by a series of concentrations of CSE (0%, 0.1%, 1%, and 10%).,Then cell apoptosis was analyzed by flow cytometry.,Cell apoptosis related proteins were tested using western blot assay.,Finally, we applied knockdown and over-expression system to explore the lncRNA MEG3 functions in CSE-induced HPMECs.,Our results indicated that various concentrations of CSE (0%, 0.1%, 1%, and 10%) significantly promoted cell apoptosis, augmented caspase-3 activity, upregulated Bax expression, decreased Bcl-2 expression, and enhanced lncRNA MEG3 level in HPMECs.,LncRNA MEG3-plasmid transfection resulted in the upregulation of lncRNA MEG3, more apoptotic HPMECs, and higher caspase-3 activity.,While lncRNA MEG3 knockdown presented the opposite effects.,Further investigation suggested that all the effects of CSE treatment on HPMECs were markedly reversed by lncRNA MEG3-shRNA (short hairpin RNA).,Our study illustrated a protective effect of lncRNA MEG3-shRNA on CSE-induced HPMECs, indicting lncRNA MEG3 can be a new therapeutic approach for COPD treatment. | The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD.,Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers.,A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10− 8) and FEV1 (p = 2.1 × 10− 9).,In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10− 4) and severity (OR = 4.1; p = 0.0036).,Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype.,8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P < 2.2 × 10− 16).,This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function.,Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers.,The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity.,Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.,The online version of this article (10.1186/s12881-018-0656-z) contains supplementary material, which is available to authorized users. | 1 |
Severe hyperinflation causes detrimental effects such as dyspnea and reduced exercise capacity and is an independent predictor of mortality in COPD patients.,Static lung volumes are required to diagnose severe hyperinflation, which are not always accessible in primary care.,Several studies have shown that the area under the forced expiratory flow-volume loop (AreaFE) is highly sensitive to bronchodilator response and is correlated with residual volume/total lung capacity (RV/TLC), a common index of air trapping.,In this study, we investigate the role of AreaFE% (AreaFE expressed as a percentage of reference value) and conventional spirometry parameters in indicating severe hyperinflation.,We used a cohort of 215 individuals with COPD.,The presence of severe hyperinflation was defined as elevated air trapping (RV/TLC >60%) or reduced inspiratory fraction (inspiratory capacity [IC]/TLC <25%) measured using body plethysmography.,AreaFE% was calculated by integrating the maximal expiratory flow-volume loop with the trapezoidal rule and expressing it as a percentage of the reference value estimated using predicted values of FVC, peak expiratory flow and forced expiratory flow at 25%, 50% and 75% of FVC.,Receiver operating characteristics (ROC) curve analysis was used to identify cut-offs that were used to indicate severe hyperinflation, which were then validated in a separate group of 104 COPD subjects.,ROC analysis identified cut-offs of 15% and 20% for AreaFE% in indicating RV/TLC >60% and IC/TLC <25%, respectively (N=215).,On validation (N=104), these cut-offs consistently registered the highest accuracy (80% each), sensitivity (68% and 75%) and specificity (83% and 80%) among conventional parameters in both criteria of severe hyperinflation.,AreaFE% consistently provides a superior estimation of severe hyperinflation using different indices, and may provide a convenient way to refer COPD patients for body plethysmography to address static lung volumes. | The traditional classification of COPD, which relies solely on spirometry, fails to account for the complexity and heterogeneity of the disease.,Phenotyping is a method that attempts to derive a single or combination of disease attributes that are associated with clinically meaningful outcomes.,Deriving phenotypes entails the use of cluster analyses, and helps individualize patient management by identifying groups of individuals with similar characteristics.,We aimed to systematically review the literature for studies that had derived such phenotypes using unsupervised methods.,Two independent reviewers systematically searched multiple databases for studies that performed validated statistical analyses, free of definitive pre-determined hypotheses, to derive phenotypes among patients with COPD.,Data were extracted independently.,9156 citations were retrieved, of which, 8 studies were included.,The number of subjects ranged from 213 to 1543.,Most studies appeared to be biased: patients were more likely males, with severe disease, and recruited in tertiary care settings.,Statistical methods used to derive phenotypes varied by study.,The number of phenotypes identified ranged from 2 to 5.,Two phenotypes, with poor longitudinal health outcomes, were common across multiple studies: young patients with severe respiratory disease, few cardiovascular co-morbidities, poor nutritional status and poor health status, and a phenotype of older patients with moderate respiratory disease, obesity, cardiovascular and metabolic co-morbidities.,The recognition that two phenotypes of COPD were often reported may have clinical implications for altering the course of the disease.,This review also provided important information on limitations of phenotype studies in COPD and the need for improvement in future studies.,The online version of this article (doi:10.1186/s12931-015-0208-4) contains supplementary material, which is available to authorized users. | 1 |
Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy.,The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA).,A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD.,Studies were assessed for methodological quality and risk of bias.,A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St.,George’s Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score.,Change from baseline in rescue medication use over weeks 12-24 was also analyzed.,Meta-regression and sensitivity analyses were used to assess heterogeneity across studies.,Eighteen studies (n = 29,232 patients) contributed to the NMA.,ICS/LABA dual combinations were combined as a single treatment group to create a connected network.,Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network.,Results from sensitivity analyses and meta-regression were consistent with the base-case scenario.,This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD.,Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.,The online version of this article (10.1007/s12325-020-01311-3) contains supplementary material, which is available to authorized users. | As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy.,Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive.,This led to the question of whether a responsive subset existed that could be investigated further.,The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.,The pooled analysis included 2686 randomized patients.,Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026).,Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014).,The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).,This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS.,These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.,ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729. | 1 |
Cigarette smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide.,We aimed to elucidate whether mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology.,In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow using alternative oxidase (AOX), which bypasses the cytochrome segment of the respiratory chain.,AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS for 9 months.,It preserved the cell viability of isolated mouse embryonic fibroblasts treated with CS condensate, limited the induction of apoptosis, and decreased the production of reactive oxygen species (ROS).,In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e., infiltration by macrophages and neutrophils and adverse signaling, was unaffected.,The use of AOX allowed us to obtain novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production, and lung remodeling.,Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung.,We propose AOX as a novel tool to study CS-related lung remodeling and potentially to counteract CS-induced ROS production and cell damage. | Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation.,We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis.,We studied changes in mitochondrial morphology and in expression of markers for mitochondrial capacity, damage/biogenesis and fission/fusion in the human bronchial epithelial cell line BEAS-2B upon 6-months from ex-smoking COPD GOLD stage IV patients to age-matched smoking and never-smoking controls.,We observed that long-term CSE exposure induces robust changes in mitochondrial structure, including fragmentation, branching and quantity of cristae.,The majority of these changes were persistent upon CSE depletion.,Furthermore, long-term CSE exposure significantly increased the expression of specific fission/fusion markers (Fis1, Mfn1, Mfn2, Drp1 and Opa1), oxidative phosphorylation (OXPHOS) proteins (Complex II, III and V), and oxidative stress (Mn-SOD) markers.,These changes were accompanied by increased levels of the pro-inflammatory mediators IL-6, IL-8, and IL-1β.,Importantly, COPD primary bronchial epithelial cells (PBECs) displayed similar changes in mitochondrial morphology as observed in long-term CSE-exposure BEAS-2B cells.,Moreover, expression of specific OXPHOS proteins was higher in PBECs from COPD patients than control smokers, as was the expression of mitochondrial stress marker PINK1.,The observed mitochondrial changes in COPD epithelium are potentially the consequence of long-term exposure to cigarette smoke, leading to impaired mitochondrial function and may play a role in the pathogenesis of COPD. | 1 |
Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function.,In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections.,As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients.,To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients.,Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life.,We performed a randomized, double-blind, placebo-controlled pilot trial.,Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months.,Study visits were conducted at baseline, and at 3 and 6 months after randomization.,During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed.,In addition, participants kept a diary card in which they registered respiratory symptoms.,At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group.,Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P<0.001).,Primary outcomes, respiratory muscle strength and physical performance, did not differ between the groups after 6 months.,In addition, no differences were found in the 6-minute walking test results, handgrip strength, pulmonary function, exacerbation rate, or quality of life.,Vitamin D supplementation did not affect (respiratory) muscle strength or physical performance in this pilot trial in vitamin D-deficient COPD patients. | To characterise the pattern of colonisation and serotypes of Streptococcus pneumoniae among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids.,To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort.,A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits.,Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland.,Patients with an established diagnosis of COPD attending a tertiary medical centre.,Colonisation rate of S. pneumoniae in patients with COPD and characterisation of serotypes of S. pneumoniae with correlation to currently available pneumococcal vaccines.,Sputum and oropharyngeal swab samples were collected for the isolation of S. pneumoniae.,Seasonality of colonisation of S. pneumoniae and its relationship with the incidence of exacerbations of COPD.,S. pneumoniae was detected in 16 of 417 samples, a colonisation incident rate of 3.8% and in 11 of 133 (8%) patients at least once during the study.,The majority of S. pneumoniae isolates were identified in spring and were non-vaccine serotypes for either the PPV-23 or PCV-13 (63%).,The colonisation incident rate of S. pneumoniae fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter.,Antibiotic use was highest during periods of low colonisation.,There is seasonal variation in S. pneumoniae colonisation among patients with COPD which may reflect antibiotic use in autumn and winter.,The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23.,NCT02535546; post-results. | 1 |
Previous studies suggested that the prevalence of chronic respiratory disease in patients hospitalised with COVID-19 was lower than its prevalence in the general population.,The aim of this study was to assess whether chronic lung disease or use of inhaled corticosteroids (ICS) affects the risk of contracting severe COVID-19.,In this population cohort study, records from 1205 general practices in England that contribute to the QResearch database were linked to Public Health England's database of SARS-CoV-2 testing and English hospital admissions, intensive care unit (ICU) admissions, and deaths for COVID-19.,All patients aged 20 years and older who were registered with one of the 1205 general practices on Jan 24, 2020, were included in this study.,With Cox regression, we examined the risks of COVID-19-related hospitalisation, admission to ICU, and death in relation to respiratory disease and use of ICS, adjusting for demographic and socioeconomic status and comorbidities associated with severe COVID-19.,Between Jan 24 and April 30, 2020, 8 256 161 people were included in the cohort and observed, of whom 14 479 (0·2%) were admitted to hospital with COVID-19, 1542 (<0·1%) were admitted to ICU, and 5956 (0·1%) died.,People with some respiratory diseases were at an increased risk of hospitalisation (chronic obstructive pulmonary disease [COPD] hazard ratio [HR] 1·54 [95% CI 1·45-1·63], asthma 1·18 [1·13-1·24], severe asthma 1·29 [1·22-1·37; people on three or more current asthma medications], bronchiectasis 1·34 [1·20-1·50], sarcoidosis 1·36 [1·10-1·68], extrinsic allergic alveolitis 1·35 [0·82-2·21], idiopathic pulmonary fibrosis 1·59 [1·30-1·95], other interstitial lung disease 1·66 [1·30-2·12], and lung cancer 2·24 [1·89-2·65]) and death (COPD 1·54 [1·42-1·67], asthma 0·99 [0·91-1·07], severe asthma 1·08 [0·98-1·19], bronchiectasis 1·12 [0·94-1·33], sarcoidosis 1·41 [0·99-1·99), extrinsic allergic alveolitis 1·56 [0·78-3·13], idiopathic pulmonary fibrosis 1·47 [1·12-1·92], other interstitial lung disease 2·05 [1·49-2·81], and lung cancer 1·77 [1·37-2·29]) due to COVID-19 compared with those without these diseases.,Admission to ICU was rare, but the HR for people with asthma was 1·08 (0·93-1·25) and severe asthma was 1·30 (1·08-1·58).,In a post-hoc analysis, relative risks of severe COVID-19 in people with respiratory disease were similar before and after shielding was introduced on March 23, 2020.,In another post-hoc analysis, people with two or more prescriptions for ICS in the 150 days before study start were at a slightly higher risk of severe COVID-19 compared with all other individuals (ie, no or one ICS prescription): HR 1·13 (1·03-1·23) for hospitalisation, 1·63 (1·18-2·24) for ICU admission, and 1·15 (1·01-1·31) for death.,The risk of severe COVID-19 in people with asthma is relatively small.,People with COPD and interstitial lung disease appear to have a modestly increased risk of severe disease, but their risk of death from COVID-19 at the height of the epidemic was mostly far lower than the ordinary risk of death from any cause.,Use of inhaled steroids might be associated with a modestly increased risk of severe COVID-19.,National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust. | To estimate the prevalence of both cardiometabolic and other co‐morbidities in patients with COVID‐19, and to estimate the increased risk of severity of disease and mortality in people with co‐morbidities.,Medline, Scopus and the World Health Organization website were searched for global research on COVID‐19 conducted from January 2019 up to 23 April 2020.,Study inclusion was restricted to English language publications, original articles that reported the prevalence of co‐morbidities in individuals with COVID‐19, and case series including more than 10 patients.,Eighteen studies were selected for inclusion.,Data were analysed using random effects meta‐analysis models.,Eighteen studies with a total of 14 558 individuals were identified.,The pooled prevalence for co‐morbidities in patients with COVID‐19 disease was 22.9% (95% CI: 15.8 to 29.9) for hypertension, 11.5% (9.7 to 13.4) for diabetes, and 9.7% (6.8 to 12.6) for cardiovascular disease (CVD).,For chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cerebrovascular disease and cancer, the pooled prevalences were all less than 4%.,With the exception of cerebrovascular disease, all the other co‐morbidities presented a significantly increased risk for having severe COVID‐19.,In addition, the risk of mortality was significantly increased in individuals with CVD, COPD, CKD, cerebrovascular disease and cancer.,In individuals with COVID‐19, the presence of co‐morbidities (both cardiometabolic and other) is associated with a higher risk of severe COVID‐19 and mortality.,These findings have important implications for public health with regard to risk stratification and future planning. | 1 |
Atherosclerosis and COPD are both systemic inflammatory diseases that may influence each other.,The aim of the present study was to determine the prevalence of COPD in patients with cerebral and/or peripheral artery disease and to assess factors associated with the presence of COPD.,Following the diagnosis of cerebral and/or peripheral artery disease by means of duplex sonography, 166 consecutive patients underwent body plethysmography with capillary blood gas analysis.,Thereafter, blood tests with determination of different parameters such as lipid profile, inflammatory and coagulation markers were conducted in remaining 136 patients who fulfilled inclusion criteria of the study.,Thirty-six out of 136 patients suffered from COPD, mostly in early stages of the disease.,Residual volume indicating emphysema was increased (162.9%±55.9% vs 124.5%±37.0%, p<0.05) and diffusion capacity was decreased (55.1%±19.5% vs 75.3%±18.6%, p<0.05) in COPD patients vs non-COPD group.,In capillary blood gas analysis, COPD patients had lower partial pressure of oxygen (70.9±11.5 vs 75.2±11.0 mmHg, p<0.05) and higher partial pressure of carbon dioxide (36.8±7.5 vs 34.4±4.4 mmHg, p<0.05) compared with non-COPD individuals.,Presence of COPD was associated with predominance of diabetes mellitus, interleukin-8-related systemic neutrophilic inflammation and anemia.,In conclusion, COPD is highly prevalent in patients with atherosclerotic artery disease. | Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD).,MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1β.,We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD.,This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study.,Subjects aged 45-75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks.,The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation).,Secondary endpoints were severe AECOPD rate and St George’s Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation).,Of subjects randomised to placebo (n = 164) and MEDI8968 (n = 160), 79.3% and 75.0%, respectively, completed the study.,There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores.,Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome.,The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar.,The most common TEAE was worsening of COPD.,In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life.,ClinicalTrials.gov, NCT01448850, date of registration: 06 October 2011.,The online version of this article (doi:10.1186/s12931-017-0633-7) contains supplementary material, which is available to authorized users. | 1 |
Tiotropium-olodaterol, formulated in the Respimat soft-mist inhaler, is an inhaled fixed-dose combination (FDC) of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), commercialized under the name of Spiolto or Stiolto.,The efficacy of tiotropium-olodaterol 5-5 μg once daily in adult patients with COPD was documented in eleven large, multicenter trials of up to 52 weeks duration.,Tiotropium-olodaterol 5-5 μg not only improved spirometric values to a significantly greater extent than placebo but also resulted in statistically significant beneficial effects on dyspnea, markers of hyperinflation, use of rescue medication, health-related quality of life, and exercise endurance.,Improvements exceeded the minimal clinically important difference (MCID) for forced expiratory volume in 1 second (FEV1), dyspnea, and quality of life.,Differences between tiotropium-olodaterol 5-5 μg and the respective monocomponents were statistically significant for FEV1, dyspnea, markers of hyperinflation, use of rescue medication, and health-related quality of life, but did not reach the MCID.,However, dual bronchodilatation significantly increased the number of patients who exceeded the MCID for dyspnea and quality of life.,Moreover, tiotropium-olodaterol 5-5 μg was significantly more effective than salmeterol-fluticasone (FDC) twice daily at improving pulmonary function.,Differences between tiotropium-olodaterol and other LAMA/LABA FDCs were not observed for FEV1 or other efficacy markers.,Therefore, tiotropium-olodaterol is a valuable option in the treatment of COPD patients who remain symptomatic under monotherapy. | Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD).,We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.,This retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo.,Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0, >0-1, >1-2, and >2).,Spirometry and the St George’s Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).,In total, 5992 patients (mean age 65 years, 75% male) were randomized.,Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units).,Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium).,Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium).,The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium).,The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.,Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD.,Increasing rates of hospitalized exacerbations are associated with increasing risk of death. | 1 |
Animal model of cigarette smoke (CS) -induced chronic obstructive pulmonary disease (COPD) is the primary testing methodology for drug therapies and studies on pathogenic mechanisms of disease.,However, researchers have rarely run simultaneous or side-by-side tests of whole-body and nose-only CS exposure in building their mouse models of COPD.,We compared and evaluated these two different methods of CS exposure, plus airway Lipopolysaccharides (LPS) inhalation, in building our COPD mouse model.,Compared with the control group, CS exposed mice showed significant increased inspiratory resistance, functional residual capacity, right ventricular hypertrophy index, and total cell count in BALF.,Moreover, histological staining exhibited goblet cell hyperplasia, lung inflammation, thickening of smooth muscle layer on bronchia, and lung angiogenesis in both methods of CS exposure.,Our data indicated that a viable mouse model of COPD can be established by combining the results from whole-body CS exposure, nose-only CS exposure, and airway LPS inhalation testing.,However, in our study, we also found that, given the same amount of particulate intake, changes in right ventricular pressure and intimal thickening of pulmonary small artery are a little more serious in nose-only CS exposure method than changes in the whole-body CS exposure method. | Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease caused predominantly by cigarette smoking.,Smoking cessation is the only intervention in the management of COPD.,However, even after cessation, the airway inflammation may be present.,In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation.,Morphological changes were evaluated by mean linear intercepts (Lm) and destructive index (DI).,The frequencies of CD8+IL-17+(Tc17) and CD4+IL-17+(Th17) cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed.,Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation.,In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions.,More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17.,These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema.,Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema. | 1 |
There is a need to increase and maintain physical activity in patients with chronic obstructive pulmonary disease (COPD).,We assessed 12-month efficacy and effectiveness of the Urban Training intervention on physical activity in COPD patients.,This randomised controlled trial (NCT01897298) allocated 407 COPD patients from primary and hospital settings 1:1 to usual care (n=205) or Urban Training (n=202).,Urban Training consisted of a baseline motivational interview, advice to walk on urban trails designed for COPD patients in outdoor public spaces and other optional components for feedback, motivation, information and support (pedometer, calendar, physical activity brochure, website, phone text messages, walking groups and a phone number).,The primary outcome was 12-month change in steps·day−1 measured by accelerometer.,Efficacy analysis (with per-protocol analysis set, n=233 classified as adherent to the assigned intervention) showed adjusted (95% CI) 12-month difference +957 (184-1731) steps·day−1 between Urban Training and usual care.,Effectiveness analysis (with intention-to-treat analysis set, n=280 patients completing the study at 12 months including unwilling and self-reported non-adherent patients) showed no differences between groups.,Leg muscle pain during walks was more frequently reported in Urban Training than usual care, without differences in any of the other adverse events.,Urban Training, combining behavioural strategies with unsupervised outdoor walking, was efficacious in increasing physical activity after 12 months in COPD patients, with few safety concerns.,However, it was ineffective in the full population including unwilling and self-reported non-adherent patients.,Urban Training in COPD increased physical activity after 12 months but not in self-reported non-adherent patientshttp://ow.ly/dc2C30lnAEs | The six-minute walk test (6MWT) is considered to be a simple and inexpensive tool for the assessment of functional tolerance of submaximal effort.,The aim of this work was 1) to background the nonlinear nature of the energy expenditure process due to physical activity, 2) to compare the results/scores of the submaximal treadmill exercise test and those of 6MWT in pulmonary patients and 3) to develop nonlinear mathematical models relating the two.,The study group included patients with the COPD.,All patients were subjected to a submaximal exercise test and a 6MWT.,To develop an optimal mathematical solution and compare the results of the exercise test and the 6MWT, the least squares and genetic algorithms were employed to estimate parameters of polynomial expansion and piecewise linear models.,Mathematical analysis enabled to construct nonlinear models for estimating the MET result of submaximal exercise test based on average walk velocity (or distance) in the 6MWT.,Submaximal effort tolerance in COPD patients can be effectively estimated from new, rehabilitation-oriented, nonlinear models based on the generalized MET concept and the 6MWT. | 1 |
Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier.,Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity.,In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling.,The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD.,Patients scheduled for lung resection were prospectively recruited.,Demographic, clinical data and pulmonary function tests results were recorded.,Emphysema was visually scored and histological remodeling features were noted.,Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay.,We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding.,In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze.,13 COPD and 7 non COPD patients were included.,The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [−0.77;-0.03] respectively).,Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04).,The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 105 AU in COPD GOLD D vs 12.8 ± 0.13 105 AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]).,Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively).,Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels.,Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).,Our results showed an abnormal bronchial epithelial wound closure process in severe COPD.,Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.,The online version of this article (doi:10.1186/s12931-014-0151-9) contains supplementary material, which is available to authorized users. | Asthma and COPD are characterized by airway dysfunction and inflammation.,Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease.,The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain.,We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects.,Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD.,The median (interquartile range) IL-17A cells/mm2 submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04).,In COPD, IL-17A+ cells/mm2 submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046).,IL-17F+ cells/mm2 submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD.,IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005).,The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV1% predicted (r = −0.5, P = .008) and FEV1/FVC (r = −0.4, P = .04).,Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation. | 1 |
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.,Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities.,COPD exacerbations and comorbidities contribute to the overall severity in individual patients.,Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age.,Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations.,However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide.,This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale.,Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases.,All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases.,In this review, we focus on the major comorbidities that affect COPD patients.,We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs.,We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity. | The Global Initiative for Chronic Obstructive Lung Disease proposed in 2011 a new system to classify chronic obstructive pulmonary disease (COPD) patients into risk groups A-D, which considers symptoms and future exacerbation risk to grade disease severity.,The aim of this study was to investigate the agreement between COPD risk group classifications using COPD assessment test (CAT) or modified Medical Research Council (mMRC) and severity grades or past-year exacerbations.,Furthermore, physical activity across risk groups was examined.,87 patients with stable COPD were classified into risk groups A-D.,CAT and mMRC were completed.,Severity grades I-IV were determined using spirometry and the number of past-year exacerbations was recorded.,To test the interrater agreement, Cohen’s Kappa was calculated.,Daily physical activity was measured by the SenseWear Mini armband.,Using CAT, 65.5% of patients were in high-symptom groups (B and D).,With mMRC, only 37.9% were in B and D.,Using severity grades, 20.7% of patients were in high-exacerbation risk groups (C and D).,With past-year exacerbations, 9.2% were in C and D.,Interrater agreement between CAT and mMRC (κ = 0.21) and between severity grades and past-year exacerbations (κ = 0.31) was fair.,Daily steps were reduced in risk groups B and C + D compared to A (p < 0.01), using either classification.,When classifying COPD patients into risk groups A-D, the use of CAT or mMRC and severity grades or past-year exacerbations does not provide equal results.,Daily steps decreased with increasing COPD risk groups. | 1 |
Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD.,We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.,In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers.,Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases.,All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study.,Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park).,Baseline measurements of participants were taken before the walk in the hospital laboratory.,During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.,Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited.,Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park.,Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park.,In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk.,By contrast, these beneficial responses were attenuated after walking on Oxford Street.,In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles.,In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles.,Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases.,Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease.,Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects.,British Heart Foundation. | Adverse health effects at relatively low levels of ambient air pollution have consistently been reported in the last years.,We conducted a time-series panel study of subjects with chronic obstructive pulmonary disease (COPD), asthma, and ischemic heart disease (IHD) to evaluate whether daily levels of air pollutants have a measurable impact on the lung function of adult subjects with pre-existing lung or heart diseases.,Twenty-nine patients with COPD, asthma, or IHD underwent repeated lung function tests by supervised spirometry in two one-month surveys.,Daily samples of coarse (PM10-2.5) and fine (PM2.5) particulate matter were collected by means of dichotomous samplers, and the dust was gravimetrically analyzed.,The particulate content of selected metals (cadmium, chrome, iron, nickel, lead, platinum, vanadium, and zinc) was determined by atomic absorption spectrometry.,Ambient concentrations of nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and sulphur dioxide (SO2) were obtained from the regional air-quality monitoring network.,The relationships between concentrations of air pollutants and lung function parameters were analyzed by generalized estimating equations (GEE) for panel data.,Decrements in lung function indices (FVC and/or FEV1) associated with increasing concentrations of PM2.5, NO2 and some metals (especially zinc and iron) were observed in COPD cases.,Among the asthmatics, NO2 was associated with a decrease in FEV1.,No association between average ambient concentrations of any air pollutant and lung function was observed among IHD cases.,This study suggests that the short-term negative impact of exposure to air pollutants on respiratory volume and flow is limited to individuals with already impaired respiratory function.,The fine fraction of ambient PM seems responsible for the observed effects among COPD cases, with zinc and iron having a potential role via oxidative stress.,The respiratory function of the relatively young and mild asthmatics included in this study seems to worsen when ambient levels of NO2 increase. | 1 |
Few studies have investigated the 24-hour symptom profile in patients with COPD or how symptoms during the 24-hour day are inter-related.,This observational study assessed the prevalence, severity and relationship between night-time, early morning and daytime COPD symptoms and explored the relationship between 24-hour symptoms and other patient-reported outcomes.,The study enrolled patients with stable COPD in clinical practice.,Baseline night-time, early morning and daytime symptoms (symptom questionnaire), severity of airflow obstruction (FEV1), dyspnoea (modified Medical Research Council Dyspnoea Scale), health status (COPD Assessment Test), anxiety and depression levels (Hospital Anxiety and Depression Scale), sleep quality (COPD and Asthma Sleep Impact Scale) and physical activity level (sedentary, moderately active or active) were recorded.,The full analysis set included 727 patients: 65.8% male, mean ± standard deviation age 67.2 ± 8.8 years, % predicted FEV1 52.8 ± 20.5%.,In each part of the 24-hour day, >60% of patients reported experiencing ≥1 symptom in the week before baseline.,Symptoms were more common in the early morning and daytime versus night-time (81.4%, 82.7% and 63.0%, respectively).,Symptom severity was comparable for each period assessed.,Overall, in the week before baseline, 56.7% of patients had symptoms throughout the whole 24-hour day (3 parts of the day); 79.9% had symptoms in ≥2 parts of the 24-hour day.,Symptoms during each part of the day were inter-related, irrespective of disease severity (all p < 0.001).,Early morning and daytime symptoms were associated with the severity of airflow obstruction (p < 0.05 for both).,Night-time, early morning and daytime symptoms were all associated with worse dyspnoea, health status and sleep quality, and higher anxiety and depression levels (all p < 0.001 versus patients without symptoms in each corresponding period).,In each part of the 24-hour day, there was also an association between symptoms and a patient’s physical activity level (p < 0.05 for each period).,More than half of patients experienced COPD symptoms throughout the whole 24-hour day.,There was a significant relationship between night-time, early morning and daytime symptoms.,In each period, symptoms were associated with worse patient-reported outcomes, suggesting that improving 24-hour symptoms should be an important consideration in the management of COPD.,The online version of this article (doi:10.1186/s12931-014-0122-1) contains supplementary material, which is available to authorized users. | Inhaled corticosteroids (ICS) reduce COPD exacerbation frequency and slow decline in health related quality of life but have little effect on lung function, do not reduce mortality, and increase the risk of pneumonia.,We systematically reviewed trials in which ICS have been withdrawn from patients with COPD, with the aim of determining the effect of withdrawal, understanding the differing results between trials, and making recommendations for improving methodology in future trials where medication is withdrawn.,Trials were identified by two independent reviewers using MEDLINE, EMBASE and CINAHL, citations of identified studies were checked, and experts contacted to identify further studies.,Data extraction was completed independently by two reviewers.,The methodological quality of each trial was determined by assessing possible sources of systematic bias as recommended by the Cochrane collaboration.,We included four trials; the quality of three was adequate.,In all trials, outcomes were generally worse for patients who had had ICS withdrawn, but differences between outcomes for these patients and patients who continued with medication were mostly small and not statistically significant.,Due to data paucity we performed only one meta-analysis; this indicated that patients who had had medication withdrawn were 1.11 (95% CI 0.84 to 1.46) times more likely to have an exacerbation in the following year, but the definition of exacerbations was not consistent between the three trials, and the impact of withdrawal was smaller in recent trials which were also trials conducted under conditions that reflected routine practice.,There is no evidence from this review that withdrawing ICS in routine practice results in important deterioration in patient outcomes.,Furthermore, the extent of increase in exacerbations depends on the way exacerbations are defined and managed and may depend on the use of other medication.,In trials where medication is withdrawn, investigators should report other medication use, definitions of exacerbations and management of patients clearly.,Intention to treat analyses should be used and interpreted appropriately. | 1 |
Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown.,Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands.,We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants.,All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD.,In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells.,Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists.,Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD.,These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1. | Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation.,Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood.,This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation.,Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation.,Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand.,MMP-9 levels increased from 10.5 μg/g [1.2 to 21.1] prior to exacerbation to 17.1 μg/g [9.3 to 48.7] during exacerbation (P < 0.01).,TIMP-1 levels decreased from 3.5 μg/g [0.6 to 7.8] to 1.5 μg/g [0.3 to 4.9] (P = 0.16).,MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05).,Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05).,Macrophage numbers remained level.,MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01).,During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1.,This may suggest a pathway connecting frequent exacerbations with lung function decline. | 1 |
In recent years, the pleiotropic roles of vitamin D have been highlighted in various diseases.,However, the association between serum vitamin D and COPD is not well studied.,This updated systematic review and meta-analysis aimed to assess the relationship between vitamin D and the risk, severity, and exacerbation of COPD.,A systematic literature search was conducted in PubMed, Medline, EMBASE, Chinese National Knowledge Infrastructure, Wanfang, and Weipu databases.,The pooled risk estimates were standardized mean difference (SMD) with 95% confidence interval (CI) for vitamin D levels and odds ratio (OR) with 95% CI for vitamin D deficiency.,Meta-regression and subgroup analyses were performed on latitude, body mass index, and assay method.,A total of 21 studies, including 4,818 COPD patients and 7,175 controls, were included.,Meta-analysis showed that lower serum vitamin D levels were found in COPD patients than in controls (SMD: −0.69, 95% CI: −1.00, −0.38, P<0.001), especially in severe COPD (SMD: −0.87, 95% CI: −1.51, −0.22, P=0.001) and COPD exacerbation (SMD: −0.43, 95% CI: −0.70, −0.15, P=0.002).,Vitamin D deficiency was associated with increased risk of COPD (OR: 1.77, 95% CI: 1.18, 2.64, P=0.006) and with COPD severity (OR: 2.83, 95% CI: 2.00, 4.00, P<0.001) but not with COPD exacerbation (OR: 1.17, 95% CI: 0.86, 1.59, P=0.326).,Assay methods had significant influence on the heterogeneity of vitamin D deficiency and COPD risk.,Serum vitamin D levels were inversely associated with COPD risk, severity, and exacerbation.,Vitamin D deficiency is associated with increased risk of COPD and severe COPD but not with COPD exacerbation.,It is worth considering assay methods in the heterogeneity sources analysis of association between vitamin D deficiency and COPD. | To understand and predict chronic obstructive pulmonary disease (COPD), a biomarker that reflects disease severity is needed.,Data from 10269 adults aged over 40 years of age were retrieved from the Korea National Health and Nutrition Examination Survey (KNHANES), and 1302 patients met the criteria for COPD.,The association between values of vitamin D and parathyroid hormone (PTH), and COPD severity including lung function and quality of life, were analyzed.,In COPD patients, lung function was inversely related to PTH values (P = 0.02 for FVC [% predicted]; P < 0.001 for FEV1 [% predicted]); however, the association of lung function with vitamin D levels was not statistically significant in a multivariable analysis.,Value of PTH was independently associated with EQ5D-index (P = 0.04), but vitamin D level showed no significant relationship with EQ5D-index (P = 0.59) or EQ5D-VAS (P = 0.81).,Elevation of PTH, unlike vitamin D, is independently associated with COPD severity, and may be a better biomarker for COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is the end result of a susceptible individual being exposed to sufficiently deleterious environmental stimuli.,More than 90% of COPD-related deaths occur in low- and middle-income countries (LMICs).,LMICs face unique challenges in managing COPD; for example, deficient primary care systems present challenges for proper diagnosis and management.,Formal diagnosis of COPD requires quality-assured spirometry, which is often limited to urban health centres.,Similarly, standard treatment options for COPD remain limited where few providers are trained to manage COPD.,The Global Excellence in COPD Outcomes (GECo) studies aim to assess the performance of a COPD case-finding questionnaire with and without peak expiratory flow (PEF) to diagnose COPD, and inform the effectiveness and implementation of COPD self-management Action Plans in LMIC settings.,The ultimate goal is to develop simple, low-cost models of care that can be implemented in LMICs.,This study will be carried out in Nepal, Peru and Uganda, three distinct LMIC settings.,We aim to assess the diagnostic accuracy of a simple questionnaire with and without PEF to case-find COPD (GECo1), and examine the effectiveness, cost-effectiveness and implementation of a community-health-worker-supported self-management Action Plan strategy for managing exacerbations of COPD (GECo2).,To achieve the first aim, we will enrol a randomly selected sample of up to 10,500 adults aged ≥ 40 years across our three sites, with the goal to enrol 240 participants with moderate-to-severe COPD in to GECo2.,We will apply two case-finding questionnaires (Lung Function Questionnaire and CAPTURE) with and without PEF and compare performance against spirometry.,We will report ROC areas, sensitivity and specificity.,Individuals who are identified as having COPD grades B-D will be invited to enrol in an effectiveness-implementation hybrid randomised trial of a multi-faceted COPD self-management Action Plan intervention delivered by CHWs.,The intervention group will receive (1) COPD education, (2) facilitated-self management Action Plans for COPD exacerbations and (3) monthly visits by community health workers.,The control group will receive COPD education and standard of care treatment provided by local health providers.,Beginning at baseline, we will measure quality of life with the EuroQol-5D (EQ-5D) and St.,George’s Respiratory Questionnaire (SGRQ) every 3 months over a period of 1 year.,The primary endpoint is SGRQ at 12 months.,Quality-adjusted life years (QALYs) using the Short-Form 36 version 2 will also be calculated.,We will additionally assess the acceptability and feasibility of implementing COPD Action Plans in each setting among providers and individuals with COPD.,This study should provide evidence to inform the use of pragmatic models of COPD diagnosis and management in LMIC settings.,NCT03359915 (GECo1).,Registered on 2 December 2017 and NCT03365713 (GECo2).,Registered on 7 December 2017.,Trial acronym: Global Excellence in COPD Outcomes (GECo1; GECo2).,The online version of this article (10.1186/s13063-018-2909-8) contains supplementary material, which is available to authorized users. | COPD is a leading cause of morbidity and mortality, yet it remains largely under-diagnosed.,Case-finding is encouraged by many professionals, but there is a lack of information on the patients’ views and perspectives.,Semistructured interviews were conducted with adults, aged 40 years or older with a history of smoking, who were eligible and invited for case-finding for COPD as a part of a large UK primary care trial.,Patients, including those who consented or declined participation and those with and without COPD after screening, were interviewed.,Interviews were transcribed and analyzed using the framework method.,The 43 interviews revealed the following two main categories of themes: patients’ views on COPD case-finding and barriers to case-finding.,Overall, case-finding was deemed important and beneficial.,Participants highlighted the need for screening activities to be convenient for patients but perceived that general practitioners (GPs) lacked the time and accessing appointments was difficult.,Desire for a health check among symptomatic patients facilitated participation in case-finding.,Psychological barriers to engagement included denial of ill health or failure to recognize symptoms, fear of the “test”, and lung symptoms being low on the hierarchy of patient health complaints.,Mechanical barriers included providing care for another person (and therefore being too busy), being unable to access GP appointments, and lacking feedback of spirometry results or communication of the diagnosis.,Patient engagement with case-finding may be limited by denial or lack of recognition of symptoms and physical barriers to attendance.,Increasing public awareness of COPD risk factors and early symptoms may enhance case-finding. | 1 |
Sirtuin-1 (SIRT1) and SIRT6, NAD+-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress.,Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD.,Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins.,Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction.,Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible.,Other sirtuin isoforms were not affected by miR-34a.,Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases. | Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction.,COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma.,Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression.,Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology.,Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease-antiprotease imbalance, and oxidative stress.,Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients.,For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status. | 1 |
Information about daily physical activity levels (PAL) in subjects with undiagnosed chronic obstructive pulmonary disease (COPD) is scarce.,This study aims to assess PA and to investigate the associations between PA and clinical characteristics in subjects with newly diagnosed COPD.,Fifty-nine subjects with a new spirometry-based diagnosis of mild (n=38) and moderate (n=21) COPD (63±6 years, 68% male) were matched with 65 smoking controls (62±7 years, 75% male).,PA (daily steps, time spent in moderate-to-vigorous intense physical activities (MVPA) and PAL) was measured by accelerometry.,Dyspnoea, complete pulmonary function tests, peripheral muscle strength and exercise capacity served as clinical characteristics.,PA was significantly lower in COPD versus smoking controls (7986±2648 vs 9765±3078 steps, 64 (27-120) vs 110 (55-164) min of MVPA, 1.49±0.21 vs 1.62±0.24 PAL respectively, all p<0.05).,Subjects with COPD with either mild symptoms of dyspnoea (mMRC 1), those with lower diffusion capacity (TL,co), low 6 min walking distance (6MWD) or low maximal oxygen uptake (VO2 peak) had significantly lower PA.,Multiple regression analysis identified 6 MWD and TL,co as independent predictors of PA in COPD.,The reduction in PA starts early in the disease, even when subjects are not yet diagnosed with COPD.,Inactivity is more pronounced in subjects with mild symptoms of dyspnoea, lower levels of diffusion capacity and exercise capacity. | The GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk.,We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC.,Outpatients with COPD were enrolled from January to June in 2012.,The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively.,Additionally, correlations between mMRC scores and each item of CAT scores were analyzed.,Classification of 257 patients using the CAT score vs mMRC scale was as follows.,By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D.,On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D.,The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510.,The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001).,The classification of COPD produced by the mMRC or CAT score was not identical.,Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document. | 1 |
Managing and preventing disease exacerbations are key goals of COPD care.,Oscillating positive expiratory pressure (OPEP) devices have been shown to improve clinical outcomes when added to COPD standard of care.,This retrospective database study compared real-world resource use and disease exacerbation among patients with COPD or chronic bronchitis prescribed either of two commonly used OPEP devices.,Patients using the Aerobika® (Trudell Medical International, London, ON, Canada) or Acapella® (Smiths Medical, Wampsville, New York, USA) OPEP device for COPD or chronic bronchitis were identified from hospital claims linked to medical and prescription claims between September 2013 and April 2018; the index date was the first hospital visit with an OPEP device.,Severe disease exacerbation, defined as an inpatient visit with a COPD or chronic bronchitis diagnosis, and all-cause healthcare resource utilization over 30 days and 12 months post-discharge were compared in propensity score (PS)-matched Aerobika device and Acapella device users.,In total, 619 Aerobika device and 1857 Acapella device users remained after PS matching.,After discharge from the index visit, Aerobika device users were less likely to have ≥1 severe exacerbation within 30 days (12.0% vs 17.4%, p=0.01) and/or 12 months (39.6% vs 45.3%, p=0.01) and had fewer 12-month severe exacerbations (mean, 0.7 vs 0.9 per patient per year, p=0.01), with significantly longer time to first severe exacerbation than Acapella users (log-rank p=0.01).,Aerobika device users were also less likely to have ≥1 all-cause inpatient visit within 30 days (13.9% vs 20.3%, p<0.001) and 12 months (44.9% vs 51.8%, p=0.003) than Acapella users.,Patients receiving the Aerobika OPEP device, compared to the Acapella device, had lower rates of subsequent severe disease exacerbation and all-cause inpatient admission.,This suggests that Aerobika OPEP device may be a beneficial add-on to usual care and that OPEP devices may vary in clinical effectiveness. | COPD patients suffer from respiratory symptoms and limitations in daily life.,We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients.,We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs).,The St.,George’s Respiratory Questionnaire for COPD patients (SGRQ-C) was used.,Inclusion criteria were a physician’s diagnosis of COPD and age ≥40 years.,Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded.,Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients.,Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV1/FVC <0.7) and 77 were excluded due to missing data.,Finally, 850 patients (62.8% men; mean age 66.2 ± 0.3 (SE) years; mean FEV1%pred.,51.5 ± 0.6 (SE)) were analyzed.,Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation.,Mean SGRQ-C total score was 43.1 ± 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively.,Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do.,In patients with less severe COPD (FEV1pred ≥50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD.,In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations.,Our finding suggests that validated assessment of global health status might decrease these differences of perception. | 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. | Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium.,We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.,We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.,We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups.,Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2.,CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8.,This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor.,Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers.,Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups.,Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers.,Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) often have poor health-related quality of life (HRQoL) that is disproportionate to their degree of airflow limitation.,This study evaluated the association between St George’s Respiratory Questionnaire for COPD (SGRQ-C) score and forced expiratory volume in one second and investigated the factors responsible for high SGRQ-C score according to severity of airflow limitation.,Data from 1,264 COPD patients were obtained from the Korean COPD Subgroup Study (KOCOSS) cohort.,Patients were categorized into two groups according to severity of airflow limitation: mild-to-moderate and severe-to-very severe COPD groups.,We evaluated the clinical factors associated with high SGRQ-C score (≥25) in each COPD patient group.,Of the 1,264 COPD patients, 902 (71.4%) had mild-to-moderate airflow limitation and 362 (28.6%) had severe-to-very severe airflow limitation.,Of the mild-to-moderate COPD patients, 59.2% (534/902) had high SGRQ-C score, while 80.4% (291/362) of the severe-to-very severe COPD patients had high SGRQ-C score.,The association between SGRQ-C score and post-bronchodilator forced expiratory volume in one second (% predicted) was very weak in the mild-to-moderate COPD patients (r=−0.103, p=0.002) and weak in the severe-to-very severe COPD patients (r=−0.219, p<0.001).,Multiple logistic regression analysis revealed that age, being an ex- or current smoker, lower level of education, cough, dyspnea, and number of comorbidities with congestive heart failure, hyperlipidemia, and depression were significantly associated with high SGRQ-C score in mild-to-moderate COPD patients.,In comparison, being an ex-smoker and having respiratory symptoms including sputum and dyspnea were significant factors associated with high SGRQ-C score in severe-to-very severe COPD patients.,In addition to the respiratory symptoms of dyspnea and cough, high SGRQ-C score was associated with extra-pulmonary comorbidities in mild-to-moderate COPD patients.,However, only respiratory symptoms such as sputum and dyspnea were significantly associated with high SGRQ-C score in severe-to-very severe COPD patients.,This indicates the need for an improved management strategy for relieving respiratory symptoms in COPD patients with poor HRQoL.,In addition, attention should be paid to extra-pulmonary comorbidities, especially in mild-to-moderate COPD patients with poor HRQoL. | Little is known about iron deficiency (ID) and anemia in Chronic Obstructive Pulmonary Disease (COPD).,The purposes of this study were: (i) To study the prevalence and treatment of anemia and ID in patients hospitalized with an exacerbation of COPD. (ii) to study the hematological responses and degree of dyspnea before and after correction of anemia with subcutaneous Erythropoiesis Stimulating Agents (ESAs) and intravenous (IV) iron therapy, in ambulatory anemic patients with both COPD and chronic kidney disease.,(i) We examined the hospital records of all patients with an acute exacerbation of COPD (AECOPD) to assess the investigation, prevalence, and treatment of anemia and ID. (ii) We treated 12 anemic COPD outpatients with the combination of ESAs and IV-iron, given once weekly for 5 weeks.,One week later we measured the hematological response and the severity of dyspnea by Visual Analogue Scale (VAS).,(i) Anemia and iron deficiency in hospitalized COPD patients: Of 107 consecutive patients hospitalized with an AECOPD, 47 (43.9%) were found to be anemic on admission.,Two (3.3%) of the 60 non-anemic patients and 18 (38.3%) of the 47 anemic patients had serum iron, percent transferrin saturation (%Tsat) and serum ferritin measured.,All 18 (100%) anemic patients had ID, yet none had oral or IV iron subscribed before or during hospitalization, or at discharge. (ii) Intervention outpatient study: ID was found in 11 (91.7%) of the 12 anemic ambulatory patients.,Hemoglobin (Hb), Hematocrit (Hct) and the VAS scale scores increased significantly with the ESAs and IV-iron treatment.,There was a highly significant correlation between the ∆Hb and ∆VAS; rs = 0.71 p = 0.009 and between the ∆Hct and ∆VAS; rs = 0.8 p = 0.0014.,ID is common in COPD patients but is rarely looked for or treated.,Yet correction of the ID in COPD patients with ESAs and IV iron can improve the anemia, the ID, and may improve the dyspnea. | 1 |
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. | Symptomatic relief is an important treatment goal for patients with COPD.,To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines.,The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need.,The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation.,The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.,This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international).,Subjects completed the E-RS as part of a daily eDiary.,Tests of reliability, validity, and responsiveness were conducted in each dataset.,In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74).,RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p < 0.01, all comparisons listed here): FEV1% predicted (−0.19, −0.14, −0.15); St.,George’s Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (−0.30, −0.14) and incremental shuttle walk (ISWT) (−0.18) tests.,Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity.,RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001).,RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001).,Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.,Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.,MPEX: NCT00739648; AZ1: NCT00949975; AZ 2: NCT01023516,The online version of this article (doi:10.1186/s12931-014-0124-z) contains supplementary material, which is available to authorized users. | 1 |
COPD is associated with a relevant burden of disease and a high mortality worldwide.,Only recently, the importance of comorbidities of COPD has been recognized.,Studies postulated an association with inflammatory conditions potentially sharing pathogenic pathways and worsening overall prognosis.,More evidence is required to estimate the role of comorbidities of COPD.,Our aim was to investigate the prevalence and clustering of comorbidities associated with COPD, and to estimate their impact on clinically relevant outcomes.,In this population-based case-control study, a nation-wide database provided by the Swiss Federal Office for Statistics enclosing every hospital entry covering the years 2002-2010 (n = 12′888′075) was analyzed using MySQL and R statistical software.,Statistical methods included non-parametric hypothesis testing by means of Fisher’s exact test and Wilcoxon rank sum test, as well as linear models with generalized estimating equation to account for intra-patient variability.,Exploratory multivariate approaches were also used for the identification of clusters of comorbidities in COPD patients.,In 2.6% (6.3% in patients aged >70 years) of all hospitalization cases an active diagnosis of COPD was recorded.,In 21% of these cases, COPD was the main reason for hospitalization.,Patients with a diagnosis of COPD had more comorbidities (7 [IQR 4-9] vs.,3 [IQR 1-6]; ), were more frequently rehospitalized (annual hospitalization rate 0.33 [IQR 0.20-0.67] vs.,0.25 [IQR 0.14-0.43]/year; ), had a longer hospital stay (9 [IQR 4-15] vs.,5 [IQR 2-11] days; ), and had higher in-hospital mortality (5.9% [95% CI 5.8%-5.9%] vs.,3.4% [95% CI 3.3%-3.5%]; ) compared to matched controls.,A set of comorbidities was associated with worse outcome.,We could identify COPD-related clusters of COPD-comorbidities. | To evaluate the influence of heart disease on clinical characteristics, quality of life, use of health resources, and costs of patients with COPD followed at primary care settings under common clinical practice conditions.,Epidemiologic, observational, and descriptive study (EPIDEPOC study).,Patients ≥ 40 years of age with stable COPD attending primary care settings were included.,Demographic, clinical characteristics, quality of life (SF-12), seriousness of the disease, and treatment data were collected.,Results were compared between patients with or without associated heart disease.,A total of 9,390 patients with COPD were examined of whom 1,770 (18.8%) had heart disease and 78% were males.,When comparing both patient groups, significant differences were found in the socio-demographic characteristics, health profile, comorbidities, and severity of the airway obstruction, which was greater in patients with heart disease.,Differences were also found in both components of quality of life, physical and mental, with lower scores among those patients with heart disease.,Higher frequency of primary care and pneumologist visits, emergency-room visits and number of hospital admissions were observed among patients with heart diseases.,The annual total cost per patient was significantly higher in patients with heart disease; 2,937 ± 2,957 vs. 1,749 ± 2,120, p < 0.05.,Variables that were showed to be independently associated to COPD in subjects with hearth conditions were age, being inactive, ex-smokers, moderate physical exercise, body mass index, concomitant blood hypertension, diabetes, anxiety, the SF-12 physical and mental components and per patient per year total cost.,Patients with COPD plus heart disease had greater disease severity and worse quality of life, used more healthcare resources and were associated with greater costs compared to COPD patients without known hearth disease. | 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. | We investigated a large population of patients with chronic obstructive pulmonary disease (COPD) to determine their frequency of medication use and patterns of pharmacotherapy.,Medical and pharmacy claims data were retrospectively analyzed from 19 health plans (>7.79 million members) across the US.,Eligible patients were aged ≥40 years, continuously enrolled during July 2004 to June 2005, and had at least one inpatient or at least two outpatient claims coded for COPD.,As a surrogate for severity of illness, COPD patients were stratified by complexity of illness using predefined International Classification of Diseases, Ninth Revision, Clinical Modification, Current Procedural Terminology, Fourth Edition, and Healthcare Common Procedure Coding System codes.,A total of 42,565 patients with commercial insurance and 8507 Medicare patients were identified.,Their mean age was 54.7 years and 74.8 years, and 48.7% and 46.9% were male, respectively.,In total, 66.3% of commercial patients (n = 28,206) were not prescribed any maintenance COPD pharmacotherapy (59.1% no medication; 7.2% inhaled short-acting β2-agonist only).,In the Medicare population, 70.9% (n = 6031) were not prescribed any maintenance COPD pharmacotherapy (66.0% no medication; 4.9% short-acting β2-agonist only).,A subset of patients classified as high-complexity were similarly undertreated, with 58.7% (5358/9121) of commercial and 68.8% (1616/2350) of Medicare patients not prescribed maintenance COPD pharmacotherapy.,Only 18.0% and 9.8% of diagnosed smokers in the commercial and Medicare cohorts had a claim for a smoking cessation intervention and just 16.6% and 23.5%, respectively, had claims for an influenza vaccination.,This study highlights a high degree of undertreatment of COPD in both commercial and Medicare patients, with most patients receiving no maintenance pharmacotherapy or influenza vaccination. | 1 |
Chronic obstructive pulmonary disease (COPD) has become a major cause of morbidity and mortality worldwide.,Increasing evidence indicates that aberrantly expressed microRNAs (miRNAs) are involved in the pathogenesis of COPD.,However, an integrative exploration of miRNA-mRNA regulatory network in COPD plasma remains lacking.,The microarray datasets GSE24709, GSE61741, and GSE31568 were downloaded from the GEO database and analyzed using GEO2R tool to identify differentially expressed miRNAs (DEMs) between COPD and normal plasma.,The consistently changing miRNAs in the three datasets were screened out as candidate DEMs.,Potential upstream transcription factors and downstream target genes of candidate DEMs were predicted by FunRich and miRNet, respectively.,Next, GO annotation and KEGG pathway enrichment analysis for target genes were performed using DAVID.,Then, PPI and DEM-hub gene network were constructed using the STRING database and Cytoscape software.,Finally, GSE56768 was used to evaluate the hub gene expressions.,A total of nine (six upregulated and three downregulated) DEMs were screened out in the above three datasets.,SP1 was predicted to potentially regulate most of the downregulated DEMs, while YY1 and E2F1 could regulate both upregulated and downregulated DEMs. 1139 target genes were then predicted, including 596 upregulated DEM target genes and 543 downregulated DEM target genes.,Target genes of DEMs were mainly enriched in PI3K/Akt signaling pathway, mTOR signaling pathway, and autophagy.,Through the DEM-hub gene network construction, most of the hub genes were found to be potentially modulated by miR-497-5p, miR-130b-5p, and miR-126-5p.,Among the top 12 hub genes, MYC and FOXO1 expressions were consistent with that in the GSE56768 dataset.,In the study, potential miRNA-mRNA regulatory network was firstly constructed in COPD plasma, which may provide a new insight into the pathogenesis and treatment of COPD. | The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) a pandemic [1].,COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,COVID-19 displays symptoms ranging from mild to severe (pneumonia) that can lead to death in some individuals [2-4].,As of 18 April 2020, there have been 2 280 945 cases of COVID-19 worldwide and 156 354 deaths [5].,SARS-CoV-2 uses the angiotensin-converting enzyme II (ACE-2) as the cellular entry receptor [6].,While the virus can infect individuals of any age, to date, most of the severe cases have been described in those >55 years of age and with significant comorbidities, such as COPD [7].,Here, we determined whether patients with COPD have increased expression of ACE-2 in bronchial epithelial cells in the lower respiratory tract.,Smokers and those with COPD have increased airway expression of ACE-2, which is the entry receptor for the COVID-19 virus.,This may explain the increased risk of severe COVID-19 in these subpopulations and highlight the importance of smoking cessation.https://bit.ly/3bC29es | 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. | In China, the burden of chronic obstructive disease (COPD) is high in never-smokers but little is known about its causes in this group.,We analysed data on 287 000 female and 30 000 male never-smokers aged 30-79 years from 10 regions in China, who participated in the China Kadoorie Biobank baseline survey (2004-2008).,Prevalence of airflow obstruction (AFO) (pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and below the lower limit of normal (LLN)) was estimated, by age and region.,Cross-sectional associations of AFO (FEV1/FVC <0.7), adjusted for confounding, were examined.,AFO prevalence defined as FEV1/FVC <0.7 was 4.0% in females and 5.1% in males (mean ages 51 and 54 years, respectively).,AFO prevalence defined as FEV1/FVC <LLN was 5.9% and 5.2%, respectively.,In females, odds ratios of AFO were positively associated with lower household income (1.63, 95% CI 1.55-1.72 for lowest versus highest income groups), prior tuberculosis (2.36, 95% CI 2.06-2.71), less education (1.17, 95% CI 1.12-1.23 for no schooling versus college education), rural region and lower body mass index.,AFO was positively associated with cooking with coal but not with other sources of household air pollution.,Associations were similar for males.,AFO is prevalent in Chinese never-smokers, particularly among those with low socioeconomic status or prior tuberculosis, and in rural males.,Airflow obstruction is prevalent in Chinese never-smokers and particularly associated with low socioeconomic statushttp://ow.ly/sG481 | 1 |
Little is known about the interactions between the lung microbiome and host response in chronic obstructive pulmonary disease (COPD).,We performed a longitudinal 16S ribosomal RNA gene-based microbiome survey on 101 sputum samples from 16 healthy subjects and 43 COPD patients, along with characterization of host sputum transcriptome and proteome in COPD patients.,Dysbiosis of sputum microbiome was observed with significantly increased relative abundance of Moraxella in COPD versus healthy subjects and during COPD exacerbations, and Haemophilus in COPD ex-smokers versus current smokers.,Multivariate modeling on sputum microbiome, host transcriptome and proteome profiles revealed that significant associations between Moraxella and Haemophilus, host interferon and pro-inflammatory signaling pathways and neutrophilic inflammation predominated among airway host-microbiome interactions in COPD.,While neutrophilia was positively correlated with Haemophilus, interferon signaling was more strongly linked to Moraxella.,Moreover, while Haemophilus was significantly associated with host factors both in stable state and during exacerbations, Moraxella-associated host responses were primarily related to exacerbations.,Our study highlights a significant airway host-microbiome interplay associated with COPD inflammation and exacerbations.,These findings indicate that Haemophilus and Moraxella influence different components of host immune response in COPD, and that novel therapeutic strategies should consider targeting these bacteria and their associated host pathways in COPD.,The online version of this article (10.1186/s12931-019-1085-z) contains supplementary material, which is available to authorized users. | Antimicrobial treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains controversial.,In some cases AECOPD are caused by microorganisms that are resistant to treatments recommended by guidelines.,Our aims were: 1) identify the risk factors associated with infection by microorganisms resistant to conventional treatment (MRCT), 2) Compare the clinical characteristics and outcomes of patients with AECOPD resulting from MRCT against those with AECOPD from other causes.,We prospective analysed a cohort of patients admitted with severe AECOPD (2009 to 2015) who were assigned to three groups: patients with MRCT (those patients with germs resistant to antibiotics recommended in guidelines), patients with microorganisms sensitive to conventional antimicrobial treatment (MSCT), and patients with negative microbiology results who had not previously received antibiotics.,Multinomial logistic regression analyses were used to examine the associations between microbial aetiology groups and risk factors.,The association between LOS and risk factors was also tested in simple and multiple analyses, and similar inclusion criteria were applied for the linear regression analysis.,Of the 451 patients admitted, 195 patients (43%) were included.,Respiratory cultures were positive in 86(44%) and negative in 109(56%).,MRCT were isolated in 34 cases (40%) and MSCT in 52 (60%).,Patients with MRCT had more AECOPD in the previous year, received more antibiotic treatment in the previous three months, had more severe disease, higher dyspnoea and a positive respiratory culture in the previous year (mainly for Pseudomonas aeruginosa).,The following conditions were independent factors for MRCT isolation: non-current smoker (odds ratio [OR] 4.19 [95% confidence interval [CI] 1.29-13.67], p = 0.017), ≥ 2 AECOPD or ≥ 1 admission for AECOPD in the previous year (OR 4.13 [95% CI 1.52-11.17], p = 0.005), C-reactive protein < 5 mg/dL; (OR 3.58 [95% CI 1.41-9.07], p = 0.007).,Mortality rates were comparable at 30-days, one year and 3 years; however, patients in the MRCT group had longer hospital stays.,In conclusion, there are risk factors for resistant germs in AECOPD; however, the presence of these germs does not increase mortality.,Patients with isolation of MRCT had longer length of stay.,The online version of this article (10.1186/s12931-018-0820-1) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is a debilitating disease affecting patients in daily life, both physically and emotionally.,Symptoms such as dyspnea and muscle fatigue, lead to exercise intolerance, which, together with behavioral issues, trigger physical inactivity, a key feature of COPD.,Physical inactivity is associated with adverse clinical outcomes, including hospitalization and all-cause mortality.,Increasing activity levels is crucial for effective management strategies and could lead to improved long-term outcomes.,In this review we summarize objective and subjective instruments for evaluating physical activity and focus on interventions such as pulmonary rehabilitation or bronchodilators aimed at increasing activity levels.,To date, only limited evidence exists to support the effectiveness of these interventions.,We suggest that a multimodal approach comprising pulmonary rehabilitation, pharmacotherapy, and counselling programs aimed at addressing emotional and behavioural aspects of COPD may be an effective way to increase physical activity and improve health status in the long term. | Pulmonary Rehabilitation for moderate Chronic Obstructive Pulmonary Disease in primary care could improve patients’ quality of life.,This study aimed to assess the efficacy of a 3-month Pulmonary Rehabilitation (PR) program with a further 9 months of maintenance (RHBM group) compared with both PR for 3 months without further maintenance (RHB group) and usual care in improving the quality of life of patients with moderate COPD.,We conducted a parallel-group, randomized clinical trial in Majorca primary health care in which 97 patients with moderate COPD were assigned to the 3 groups.,Health outcomes were quality of life, exercise capacity, pulmonary function and exacerbations.,We found statistically and clinically significant differences in the three groups at 3 months in the emotion dimension (0.53; 95%CI0.06-1.01) in the usual care group, (0.72; 95%CI0.26-1.18) the RHB group (0.87; 95%CI 0.44-1.30) and the RHBM group as well as in fatigue (0.47; 95%CI 0.17-0.78) in the RHBM group.,After 1 year, these differences favored the long-term rehabilitation group in the domains of fatigue (0.56; 95%CI 0.22-0.91), mastery (0.79; 95%CI 0.03-1.55) and emotion (0.75; 95%CI 0.17-1.33).,Between-group analysis only showed statistically and clinically significant differences between the RHB group and control group in the dyspnea dimension (0.79 95%CI 0.05-1.52).,No differences were found for exacerbations, pulmonary function or exercise capacity.,We found that patients with moderate COPD and low level of impairment did not show meaningful changes in QoL, exercise tolerance, pulmonary function or exacerbation after a one-year, community based rehabilitation program.,However, long-term improvements in the emotional, fatigue and mastery dimensions (within intervention groups) were identified.,ISRCTN94514482 | 1 |
Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from comorbidities.,COPD severity may be evaluated by the Global initiative for chronic Obstructive Lung Disease (GOLD) combined risk assessment score (GOLD score).,Spirometry, body plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO), and high-resolution computed tomography (HR-CT) measure lung function and elucidate pulmonary pathology.,This study assesses associations between GOLD score and measurements of lung function in COPD patients with and without (≤1) comorbidities.,It evaluates whether the presence of comorbidities influences evaluation by GOLD score of COPD severity, and questions whether GOLD score describes morbidity rather than COPD severity.,In this prospective study, 106 patients with stable COPD were included.,Patients treated for lung cancer were excluded.,Demographics, oxygen saturation (SpO2), modified Medical Research Council Dyspnea Scale, COPD exacerbations, and comorbidities were recorded.,Body plethysmography and DLCO were measured, and HR-CT performed and evaluated for emphysema and airways disease.,COPD severity was stratified by the GOLD score.,Correlation analyses: 1) GOLD score, 2) emphysema grade, and 3) airways disease and lung function parameters, described by: forced expiratory volume in the first second in percent of expected value (FEV1%), inspiratory capacity (IC%), total lung volume (TLC%), IC/TLC, and SpO2.,Correlation analyses between subgroups and hierarchical cluster analysis were performed.,Significant associations were found between GOLD score and both emphysema grade (correlation coefficients [cc]: −0.2, P=0.03) and lung function parameters (cc: −0.5 to −0.7, P-values all <0.001) weakened in patients with >1 comorbidity (cc: −0.4 to −0.5, P-values all 0.001).,Significant differences between subgroups were found in GOLD score and both FEV1% (cc: −0.2, P=0.02) and IC/TLC (cc: −0.2, P=0.02).,Comorbidities were associated with GOLD score and composite measures in hierarchical cluster analysis.,The presence of comorbidities influences the relationship between GOLD score and lung function measurements.,GOLD score may be more representative of morbidity than of COPD severity. | In Tunisia, there is a paucity of population-based data on Chronic Obstructive Pulmonary Disease (COPD) prevalence.,To address this problem, we estimated the prevalence of COPD following the Burden of Lung Disease Initiative.,We surveyed 807 adults aged 40+ years and have collected information on respiratory history and symptoms, risk factors for COPD and quality of life.,Post-bronchodilator spirometry was performed and COPD and its stages were defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.,Six hundred and sixty one (661) subjects were included in the final analysis.,The prevalence of GOLD Stage I and II or higher COPD were 7.8% and 4.2%, respectively (Lower Limit of Normal modified stage I and II or higher COPD prevalence were 5.3% and 3.8%, respectively).,COPD was more common in subjects aged 70+ years and in those with a BMI < 20 kg/m2.,Prevalence of stage I+ COPD was 2.3% in <10 pack years smoked and 16.1% in 20+ pack years smoked.,Only 3.5% of participants reported doctor-diagnosed COPD.,In this Tunisian population, the prevalence of COPD is higher than reported before and higher than self-reported doctor-diagnosed COPD.,In subjects with COPD, age is a much more powerful predictor of lung function than smoking. | 1 |
Racial disparities in influenza vaccination among underserved minority older adults are a public health problem.,Understanding the factors that impact influenza vaccination behaviors among underserved older African-Americans could lead to more effective communication and delivery strategies.,We aimed to investigate rate and factors associated with seasonal influenza vaccination among underserved African-American older adults.,We were particularly interested in the roles of demographic factors, socioeconomic status, and continuity and patient satisfaction with medical care, as well as physical and mental health status.,This community-based cross-sectional study recruited 620 African-American older adults residing in South Los Angeles, one of the most under-resources areas within Los Angeles County, with a population of over one million.,Bivariate and multiple regression analyses were performed to document independent correlates of influenza vaccination.,One out of three underserved African-American older adults aged 65 years and older residing in South Los Angeles had never been vaccinated against the influenza.,Only 49% of participants reported being vaccinated within the 12 months prior to the interview.,One out of five participants admitted that their health care provider recommended influenza vaccination.,However, only 45% followed their provider's recommendations.,Multivariate logistic regression shows that old-old (≥75 years), participants who lived alone, those with a lower level of continuity of care and satisfaction with the accessibility, availability, and quality of care, and participants with a higher number of depression symptoms were less likely to be vaccinated.,As expected, participants who indicated that their physician had advised them to obtain a flu vaccination were more likely to be vaccinated.,Our data shows that only gender was associated with self-report of being advised to have a flu shot.,Discussion.,One of the most striking aspects of this study is that no association between influenza vaccination and being diagnosed with chronic obstructive pulmonary disease or other major chronic condition was detected.,Our study confirmed that both continuity of care and satisfaction with access, availability, and quality of medical care are strongly associated with current influenza vaccinations.,We documented that participants with a higher number of depression symptoms were less likely to be vaccinated.,These findings highlight the role that culturally acceptable and accessible usual source of care van play as a gatekeeper to facilitate and implement flu vaccination among underserved minority older adults.,Consistent disparities in influenza vaccine uptake among underserved African-American older adults, coupled with a disproportionate burden of chronic diseases, places them at high risk for undesired outcomes associated with influenza.,As depression is more chronic/disabling and is less likely to be treated in African-Americans, there is a need to screen and treat depression as a strategy to enhance preventive care management such as vaccination of underserved African-American older adults.,Quantification of associations between lower vaccine uptake and both depression symptoms as well as living alone should enable health professionals target underserved African-American older adults who are isolated and suffer from depression to reduce vaccine-related inequalities. | Influenza vaccination rates are low in adults with chronic obstructive pulmonary disease (COPD).,A diagnostic breathing test in adults with COPD may increase vaccination rates; however, research has not demonstrated this relationship.,The purpose of this research was to determine if adults with COPD diagnosed by a breathing test were more likely to have had an influenza vaccination during the past 12 months when compared to those with COPD diagnosed without a breathing test.,This was a cross-sectional study using data from the 2011 Behavioral Risk Factor Surveillance System.,Logistic regression examined the relationship between influenza vaccination among adults with COPD diagnosed with a breathing test (n = 13,201) compared to those diagnosed without a breathing test (n = 3,108), after controlling for all potential confounders.,Overall, 49% of respondents with COPD received an influenza vaccination within the past 12 months and 78% reported their COPD was diagnosed by a breathing test.,The prevalence of influenza vaccination in the past 12 months was greater in those with COPD diagnosed by a breathing test (53%) compared to those diagnosed without a breathing test (36%).,In adjusted analysis, adults with COPD who had a breathing test were 31% (confidence interval 1.1, 1.6) more likely to have received an influenza vaccination in the past 12 months compared to those without a breathing test.,A diagnostic breathing test for COPD was associated with increased likelihood of having had an influenza vaccination in the past 12 months.,This may be an indicator of the relationship between knowledge of lung function and the need for preventative care, a sign of quality healthcare, or good health-seeking behaviors in patients with COPD.,This research is the first to use a nationally representative sample to suggest that spirometry diagnosis of COPD may increase rates of influenza vaccination. | 1 |
Chronic obstructive pulmonary disease (COPD) is associated with changes in the composition and function of peripheral and respiratory muscles, which can negatively impact quality of life.,Ultrasonography can provide a non-invasive evaluation of the integrity of both peripheral muscles and diaphragm, but its use in patients with COPD is still being investigated.,We aimed at evaluating the relationship between quadriceps size, using ultrasonography and symptoms, lung function and diaphragm contractility in a cohort of patients with COPD.,COPD patients were prospectively recruited and ultrasonography of the dominant quadriceps and of the diaphragm was performed.,Quadriceps size was evaluated using three measurements: 1) cross-sectional area of the rectus femoris (Qcsa), 2) thickness (Qthick) and 3) contractile index (Qci), defined as the ratio of quadriceps thickness/total anterior thigh thickness.,Diaphragm contractility was evaluated using thickening fraction (TFdi).,Clinical characteristics and number of moderate-to-severe exacerbations in the previous year were retrieved from medical files.,Dyspnea (mMRC scale) and disease impact on health status (COPD Assessment Test (CAT)) were measured at inclusion.,Fat-free mass index (FFMI) was assessed using bioelectrical impedance.,Forty patients were recruited (20 males, mean age and FEV1 66±6 years and 49±17%predicted, respectively).,Mean Qcsa, Qthick and Qci were 336±145 mm2, 1.55±0.53 cm and 64±16%, respectively, and mean TFdi was 91±36%.,Qci was significantly correlated with FFMI (rho=0.59, p=0.001), TFdi (rho=0.41, p=0.008), FEV1 (rho=0.43, p=0.001) but not with age (rho=0.18, p=0.28).,Qci was significantly correlated to CAT score (rho=−0.47, p=0.002), even when controlled for FEV1, and was lower in patients with an mMRC score ≥2 (55±15 vs 70±14%, p=0.002).,Qcsa and Qci were significantly lower in patients with frequent exacerbations.,In a multiple linear regression analysis that included age, gender, FFMI, FEV1 and TFdi, only FFMI and TFdi were found to be significantly related to lower Qci values.,In patients with COPD, ultrasound evaluation of the quadriceps contractile index is feasible and related to disease severity, clinical symptoms, exacerbation history and diaphragm contractility.,As such, it may provide a novel tool for the evaluation of the severity and burden of the disease in this population.,Further studies are required to better delineate its potential role as a prognostic marker in this population. | The diaphragmatic rapid shallow breathing index (D-RSBI), which is the ratio between respiratory rate (RR) and the ultrasonographic evaluation of diaphragmatic displacement (DD), is a new and promising tool to predict weaning outcome.,Its accuracy in predicting weaning failure, in ready-to-wean acute exacerbation COPD (AECOPD) patients, needs to be evaluated.,A prospective observational study was carried out on ready-to-wean AECOPD patients.,During a T-tube spontaneous breathing trial (SBT) evaluation of the right hemidiaphragm displacement (ie, DD), M-mode ultrasonography to calculate the D-RSBI, as well as the RSBI (RR/tidal volume [VT]) were carried out simultaneously.,Outcome of the weaning trial was recorded.,Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of D-RSBI and RSBI.,A total of 50 AECOPD patients requiring mechanical ventilation for more than 48 h who were ready to perform a SBT were included.,Of these, 37 (74%) were successfully liberated from mechanical ventilation.,Among the 13 patients who failed the weaning trial, 8 (62%) failed the SBT and reconnected to the ventilator, 2 (15%) were reintubated within 48 h of extubation and 3 (23%) required NIV support within 48 h of extubation.,The areas under the ROC curves for D-RSBI and RSBI were 0.97 (p<0.001) and 0.67 (p<0.06), respectively.,D-RSBI (RR/DD) is superior to the traditional RSBI (RR/VT) in predicting weaning outcome in AECOPD patients. | 1 |
We examined the influence of overweight and obesity on pulmonary function, exercise tolerance, quality of life and response to pulmonary rehabilitation in COPD.,261 patients with COPD were divided into three groups: normal body mass index (BMI), overweight and obese.,Baseline and post rehabilitation pulmonary function, 6-min walking test (6MWT), endurance time during a constant workrate exercise test (CET) and St.,George's Respiratory Questionnaire (SGRQ) scores were compared between all three classes of BMI.,At baseline, obese and overweight patients had less severe airflow obstruction compared to normal BMI patients.,There was no baseline difference in CET performance or SGRQ scores across BMI classes and 6MWT was reduced in the presence of obesity (p < 0.01).,Compared to baseline, post-rehabilitation 6MWT, CET performance and SGRQ scores improved significantly in each group (p < 0.01), but 6MWT was still significantly lower in the presence of obesity.,Walking, but not cycling performance was worse in obese patients.,This difference was maintained post rehabilitation despite significant improvements.,Weight excess may counterbalance the effect of a better preserved respiratory function in the performance of daily activities such as walking.,However, obesity and overweight did not influence the magnitude of improvement after pulmonary rehabilitation. | Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations.,This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).,We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers.,In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.,COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function.,Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage.,The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study.,The distribution of these variables within each GOLD stage was wide.,Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation.,The amount of emphysema increased with GOLD severity.,The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage.,Some gender differences were also identified.,The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease. | 1 |
Chronic obstructive pulmonary disease (COPD) has traditionally been considered an inexorably progressive disease, associated with a constant increase of symptoms that occur as the forced expiratory volume in 1 second (FEV1) worsens, only intermittently interrupted by exacerbations.,However, this paradigm has been challenged in recent decades by the available evidence.,Recent studies have pointed out that COPD-related symptoms are not consistently perceived by patients in the same way, showing not only seasonal variation, but also changes in symptom perception during a week or even within a single day.,According to the available data, patients experience the biggest increase in respiratory symptoms during the first hours of the early morning, followed by the nighttime.,This variation over time is of considerable importance, since it impacts on daily life activities and health-related quality of life, as measured by a recently developed ad hoc questionnaire.,Additionally, recent clinical trials have suggested that the use of rapid-onset long-acting bronchodilators may have an impact on morning symptoms, despite their current use as maintenance treatment for a determined period.,Although this hypothesis is to be validated in future long-term clinical trials comparing fast-onset versus slow-onset inhaled drugs in COPD, it may bring forward a new concept of long-term bronchodilator therapy.,At the present time, the two available long-acting, fast-onset bronchodilators used in the treatment of COPD are formoterol and the recently marketed indacaterol.,Newer drugs have also been shown to have a rapid onset of action in preclinical studies.,Health care professionals caring for COPD patients should consider this variation in the perception of symptoms during their clinical interview as a potential new target in the long-term treatment plan. | Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL).,The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL.,The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects.,Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.,Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted.,Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93).,Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52).,The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD.,Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD.,Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD.,These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge.,Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults [1-3].,Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common.,The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35% [1].,In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms [4,5].,Respiratory symptoms are important markers of the risk of having or developing disease.,Respiratory symptoms have been shown to be predictors for lung function decline [6-8], asthma [9,10], and even all-cause mortality in a general population study [11].,In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL) [12-15].,The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases [16-18].,Thus, the high prevalence of respipratory symptoms may mirror undiagnosed and untreated disease.,The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease.,Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies [6,19], but no study of respiratory sypmtoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health.,The ECRHS is a randomly sampled, multi-cultural, population based cohort study.,The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.,In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR. | 1 |
As of 11 July, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic has infected over 12.7 million people around the world and caused more than 560,000 deaths [1].,Given the devastating impact that COVID-19 can have on the lung, it is natural to fear for patients with underlying COPD.,Estimating their excess risk for contracting COVID-19 and, in particular, its more severe respiratory manifestations has been a challenging exercise in this pandemic for various reasons.,First, the reporting on cases has concentrated on hospitalised and intensive care unit (ICU) patients, rather than on mild, outpatient cases.,This is in part also due to the variability in testing strategies across the world, where some nations with stricter testing requirements and scarce testing resources have focused on testing only those requiring hospitalisation.,COPD patients have increased risk of severe pneumonia and poor outcomes when they develop COVID-19.,This may be related to poor underlying lung reserves or increased expression of ACE-2 receptor in small airways.https://bit.ly/37dSB8l | 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. | 1 |
Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD).,It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.,We formed a new-user cohort of patients with COPD treated during 1990-2005.,Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia.,A nested case-control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.,The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year).,Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75).,The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17).,The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).,ICS use by patients with COPD increases the risk of serious pneumonia.,The risk is particularly elevated and dose related with fluticasone.,While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials. | Bronchodilators provide the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and anticholinergic bronchodilators, in particular, appear to be the most effective.,There are currently two anticholinergic agents available in the US for the treatment of COPD (ipratropium bromide and tiotropium bromide), but several others are in various stages of development.,Aclidinium bromide, a novel, long-acting, anticholinergic bronchodilator, is currently in Phase III trials for the management of COPD.,Available evidence suggests that aclidinium is a safe and well tolerated drug with a relatively rapid onset and a sufficient duration of action to provide once-daily dosing.,This article will provide a pharmacologic profile of aclidinium bromide and review the preclinical and clinical studies evaluating its safety and efficacy in the treatment of COPD. | 1 |
Pulmonary rehabilitation is an important treatment for patients with Chronic Obstructive Pulmonary Disease, who are often vitamin D deficient.,As vitamin D status is linked to skeletal muscle function, we aimed to explore if high dose vitamin D supplementation can improve the outcomes of rehabilitation in Chronic Obstructive Pulmonary Disease.,This study is a post-hoc subgroup analysis of a larger randomized trial comparing a monthly dose of 100.000 IU of vitamin D with placebo to reduce exacerbations.,50 Subjects who followed a rehabilitation program during the trial are included in this analysis.,We report changes from baseline in muscle strength and exercise performance between both study arms after 3 months of rehabilitation.,Vitamin D intervention resulted in significantly higher median vitamin D levels compared to placebo (51 [44-62] ng/ml vs 15 [13-30] ng/ml; p < 0.001).,Patients receiving vitamin D had significantly larger improvements in inspiratory muscle strength (-11±12 cmH2O vs 0±14 cmH2O; p = 0.004) and maximal oxygen uptake (110±211 ml/min vs -20±187 ml/min; p = 0.029).,Improvements in quadriceps strength (15±16 Nm) or six minutes walking distance (40±55 meter) were not significantly different from the effects in the placebo group (7±19 Nm and 11±74 meter; p>0.050).,High dose vitamin D supplementation during rehabilitation may have mild additional benefits to training. | COPD patients may be at increased risk for vitamin D (25(OH)D) deficiency, but risk factors for deficiency among COPD patients have not been extensively reported.,Serum 25(OH)D levels were measured by liquid chromatography double mass spectrometry in subjects aged 40-76 years from Western Norway, including 433 COPD patients (GOLD stage II-IV) and 325 controls.,Levels <20 ng/mL defined deficiency.,Season, sex, age, body mass index (BMI), smoking, GOLD stage, exacerbation frequency, arterial oxygen tension (PaO2), respiratory symptoms, depression (CES-D score≥16), comorbidities (Charlson score), treatment for osteoporosis, use of inhaled steroids, and total white blood count were examined for associations with 25(OH)D in both linear and logistic regression models.,COPD patients had an increased risk for vitamin D deficiency compared to controls after adjustment for seasonality, age, smoking and BMI.,Variables associated with lower 25(OH)D levels in COPD patients were obesity ( = −6.63), current smoking ( = −4.02), GOLD stage III- IV ( = −4.71, = −5.64), and depression ( = −3.29).,Summertime decreased the risk of vitamin D deficiency (OR = 0.22).,COPD was associated with an increased risk of vitamin D deficiency, and important disease characteristics were significantly related to 25(OH)D levels. | 1 |
Triple combination therapy involving long-acting muscarinic antagonists long-acting β2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD.,Some add-on clinical trials have reported the benefits of these combinations.,However, the process to step up to triple therapy varies for individual cases.,Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD.,Their prescription history and clinical course were retrospectively analyzed based on the physicians’ medical records and patient questionnaires.,This study was registered with UMIN (UMIN000003470, April 10, 2010).,A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting β2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading.,For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma.,In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%).,Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe.,To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan. | The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.,Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD.,Physician-diagnosed GERD was ascertained by questionnaire.,Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD.,We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models.,Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs).,To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.,GERD was reported by 29% of subjects with female predominance.,Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs.,13.4.0%, p < 0.0001).,Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs.,1.8, p < 0.0001), and poorer quality of life (QOL) scores (St.,George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs.,34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs.,41.4, p < 0.0001).,In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006).,During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included.,PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.,In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up.,These associations are maintained after controlling for PPI use.,The PPI-exacerbations association could result from confounding-by-indication. | 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. | Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear.,We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes.,Sputum was collected from 174 stable COPD subjects longitudinally over 12 months.,Microbial sampling using culture and qPCR was performed.,Spirometry and sputum measures of airway inflammation were assessed.,Sputum was qPCR-positive (>106 copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]).,Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >106 copies/mL.,Samples that had qPCR copy numbers >106/mL, whether culture-positive or not, had increased sputum neutrophil counts.,H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P<0.001), were repeatable within subjects, and were >106/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive.,Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life.,qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods. | 1 |
Attention to COPD is increasing worldwide because its high prevalence, morbidity, and mortality present a challenging problem for all healthcare systems.,The burden of COPD, which is usually measured in terms of progressive lung function decline, impact on patients’ symptoms, patient’s disability, and quality of life, together with the corresponding use of health care resources, is still a major aspect of the disease.,Recommendations to treat COPD according to the most accepted guidelines have expanded in recent years even though COPD still remains unacceptably under-diagnosed and under-treated worldwide.,Obviously, more severe degrees of COPD receive major attention both in terms of monitoring of clinical outcomes and of assessing the economic value of therapeutic interventions.,The role of different strategies against COPD should be valued on the basis of their effectiveness in outcome optimization, which primarily depends on the efficacy of prevention activities and of early diagnosis programs.,It is generally agreed that the main proportion of COPD burden still depends on the clinically uncontrolled disease and on its high exacerbation rate, which frequently leads to the patient hospitalization.,In COPD, the effects of guideline recommendations have been only sporadically investigated in pharmaoeconomic terms, even though symptoms and disability have declined substantially; the corresponding improvement in quality of life, and a significant decrease in both direct and indirect costs have been proved to depend on appropriate rehabilitative and pharmacological long-term treatment of the disease.,At present, more precise indices and more fitting outcomes are continuously sought and found in order to assess more effective strategies for controlling COPD. | Several studies have demonstrated that long-acting β2-agonists such as salmeterol are beneficial in chronic obstructive pulmonary disease (COPD).,A meta-analysis was therefore conducted to review studies in COPD to provide pooled estimates of the effect of salmeterol 50 mcg taken twice daily in addition to usual therapy on several clinically relevant endpoints, when compared with placebo/usual therapy.,An extensive search of literature and clinical trial databases was conducted using the terms salmeterol, COPD, chronic, obstructive, bronchitis and emphysema.,Nine randomized, double-blind, parallel-group, placebo-controlled trials of ≥12 week duration with salmeterol 50 mcg bid treatment in COPD were included (>3500 patients), with a further 14 trials excluded due to study design or reporting timelines.,All patients were included, and a sub-group of subjects (84%) with poorly reversible COPD were considered separately.,Statistical testing was carried out at the 5% level, except for interaction testing which was carried out at the 10% level.,Patients treated with salmeterol over 12 months were less likely to withdraw early from the studies (19% patients compared with 25% on their current usual therapy, p < 0.001), less likely to suffer a moderate/severe exacerbation (34% compared with 39%, p < 0.0001) and had a greater increase in average FEV1 (73 mL difference vs placebo/usual therapy, p < 0.0001).,Similar differences were found at 3 and 6 months.,At all time points, more patients experienced an improvement in health status and also a greater change with salmeterol than with placebo/usual therapy (p < 0.002).,There was no evidence of tachyphylaxis to salmeterol over 12 months.,The meta-analysis confirmed clinically and statistically significant, sustained and consistent superiority of salmeterol 50 mcg bid over placebo/usual therapy on a broad range of outcome measures. | 1 |
To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility).,Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations.,Global.,3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year.,FF/VI 50/25 µg, 100/25 µg or 200/25 µg, or VI 25 µg; all one time per day.,Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy.,Three clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58).,Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility.,In patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations.,In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation.,NCT01009463; NCT01017952; Post-results. | 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 |
Induced and spontaneous sputum are used to evaluate the airways microbiota.,Whether the sputum types can be used interchangeably in microbiota research is unknown.,Our aim was to compare microbiota in induced and spontaneous sputum from COPD patients sampled during the same consultation.,COPD patients from Bergen, Norway, were followed between 2006/2010, examined during the stable state and exacerbations. 30 patients delivered 36 sample pairs.,DNA was extracted by enzymatic and mechanical lysis methods.,The V3-V4 region of the 16S rRNA gene was PCR-amplified and prepared for paired-end sequencing.,Illumina Miseq System was used for sequencing, and Quantitative Insights Into Microbial Ecology (QIIME) and Stata were used for bioinformatics and statistical analyses.,Approximately 4 million sequences were sorted into 1004 different OTUs and further assigned to 106 different taxa.,Pair-wise comparison of both taxonomic composition and beta-diversity revealed significant differences in one or both parameters in 1/3 of sample pairs.,Alpha-diversity did not differ.,Comparing abundances for each taxa identified, showed statistically significant differences between the mean abundances in induced versus spontaneous samples for 15 taxa when disease state was considered.,This included potential pathogens like Haemophilus and Moraxella.,When studying microbiota in sputum samples one should take into consideration how samples are collected and avoid the usage of both induced and spontaneous sputum in the same study. | Some patients with chronic obstructive pulmonary disease (COPD) show increased airway inflammation and bacterial colonization during stable phase.,The aim of this study was to follow COPD patients and investigate chronic colonization with pathogenic bacteria during stable disease phase, and relate these findings to clinical parameters, inflammatory pattern, lung function, and exacerbations.,Forty-three patients with COPD were included while in a stable state and followed up monthly until exacerbation or for a maximum of 6 months.,The patients completed the Clinical COPD Questionnaire and Medical Research Council dyspnea scale questionnaires, and exhaled breath condensate was collected, followed by spirometry, impulse oscillometry, and sputum induction.,Ten patients were chronically colonized (ie, colonized at all visits) with Haemophilus influenzae during stable phase.,These patients had higher sputum levels of leukotriene B4 (P<0.001), 8-isoprostane (P=0.002), myeloperoxidase activity (P=0.028), and interleukin-8 (P=0.02) during stable phase when compared with other patients.,In addition, they had lower forced vital capacity (P=0.035) and reactance at 5 Hz (P=0.034), but there was no difference in forced expiratory volume in 1 second (FEV1), FEV1 % predicted, forced vital capacity % predicted, exhaled breath condensate biomarkers, C-reactive protein, or Clinical COPD Questionnaire and Medical Research Council dyspnea scale results.,Three patients had intermittent colonization (colonized at only some visits) of H. influenzae during stable phase, and had lower levels of inflammatory biomarkers in sputum when compared with the chronically colonized patients.,The difference in airway inflammation seen during stable phase in patients chronically colonized with H. influenzae was not observed during exacerbations.,Some COPD patients who were chronically colonized with H. influenzae during stable phase showed increased airway inflammation and reduced lung volumes when compared with non-chronically colonized patients. | 1 |
Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease.,Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.,To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.,We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality.,Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC.,Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation.,Few studies examined associations with musculoskeletal measures.,Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD.,Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.,CRD42016052075. | Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality.,Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.,Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed.,To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD.,To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS).,To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.,The prevalence of PRISm in COPDGene is 12.3%.,Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models.,Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001).,Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.,PRISm subjects are clinically and genetically heterogeneous.,Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.,Clinicaltrials.gov Identifier: NCT000608764.,The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users. | 1 |
More than one third of individuals with chronic obstructive pulmonary disease (COPD) experience comorbid symptoms of depression and anxiety.,This review aims to provide an overview of the burden of depression and anxiety in those with COPD and to outline the contemporary advances and challenges in the management of depression and anxiety in COPD.,Symptoms of depression and anxiety in COPD lead to worse health outcomes, including impaired health-related quality of life and increased mortality risk.,Depression and anxiety also increase health care utilization rates and costs.,Although the quality of the data varies considerably, the cumulative evidence shows that complex interventions consisting of pulmonary rehabilitation interventions with or without psychological components improve symptoms of depression and anxiety in COPD.,Cognitive behavioral therapy is also an effective intervention for managing depression in COPD, but treatment effects are small.,Cognitive behavioral therapy could potentially lead to greater benefits in depression and anxiety in people with COPD if embedded in multidisciplinary collaborative care frameworks, but this hypothesis has not yet been empirically assessed.,Mindfulness-based treatments are an alternative option for the management of depression and anxiety in people with long-term conditions, but their efficacy is unproven in COPD.,Beyond pulmonary rehabilitation, the evidence about optimal approaches for managing depression and anxiety in COPD remains unclear and largely speculative.,Future research to evaluate the effectiveness of novel and integrated care approaches for the management of depression and anxiety in COPD is warranted. | During our medical training, we learned that oxygen administration in patients with chronic obstructive pulmonary disease (COPD) induces hypercapnia through the 'hypoxic drive' mechanism and can be dangerous.,This mindset frequently results in the reluctance of clinicians to administer oxygen to hypoxemic patients with COPD.,However, this fear is not based on evidence in the literature.,Here, we will review the impact and pathophysiology of oxygen-induced hypercapnia in patients with acute exacerbation of COPD and recommend a titrated oxygen management. | 1 |
Community-acquired pneumonia (CAP) is more common in patients with COPD than in the adult general population, with studies of hospitalized CAP patients consistently reporting COPD as a frequent comorbidity.,However, despite an increasing recognition of its importance, large studies evaluating the incidence patterns over time, risk factors and burden of CAP in COPD are currently lacking.,A retrospective observational study using a large UK-based database of linked primary and secondary care records was conducted.,Patients with a diagnosis of COPD aged ≥40 years were followed up for 5 years from January 1, 2010.,CAP and exacerbation episodes were identified from hospital discharge data and primary care coding records, and rates were calculated per month, adjusting for mortality, and displayed over time.,In addition, baseline factors predicting future risk of CAP and hospital admission with CAP were identified.,A total of 14,513 COPD patients were identified: 13.4% (n=1,938) had ≥1 CAP episode, of whom 18.8% suffered from recurrent (≥2) CAP.,Highest rates of both CAP and exacerbations were seen in winter.,A greater proportion of frequent, compared to infrequent, exacerbators experienced recurrent CAP (5.1% versus 2.0%, respectively, P<0.001); 75.6% of CAP episodes were associated with hospital admission compared to 22.1% of exacerbations.,Older age and increasing grade of airflow limitation were independently associated with increased odds of CAP and hospital admission with CAP.,Other independent predictors of future CAP included lower body mass index, inhaled corticosteroid use, prior frequent exacerbations and comorbidities, including ischemic heart disease and diabetes.,CAP in COPD demonstrates clear seasonal patterns, with patient characteristics predictive of the odds of future CAP and hospital admission with CAP.,Highlighting this burden of COPD-associated CAP during the winter period informs us of the likely triggers and the need for more effective preventive strategies. | The aim of this study is to summarize the evidence on the dose-response relationship between body mass index (BMI) and mortality in patients with chronic obstructive pulmonary disease (COPD).,We performed a systemic literature search in PubMed, Embase, and Web of Science for relevant studies that were published until June 2015.,A random effects meta-analysis was used to estimate the pooled relative risks (RRs) of all-cause mortality in COPD patients with normal weight compared with those who were underweight, overweight, or obese.,In addition, a dose-response meta-analysis was conducted to explore the dose-response relationship between BMI and all-cause mortality in COPD patients.,A total of 17 observational studies involving 30,182 COPD patients among 285,960 participants were included.,Compared with the reference category, the RRs of underweight, overweight, and obese individuals were 1.40 (95% confidence interval (CI), 1.20-1.63), 0.80 (95% CI, 0.67-0.96), and 0.77 (95% CI, 0.62-0.95), respectively.,A significant nonlinear relationship between BMI and mortality of COPD patients was found by using a random effects model.,COPD patients with BMI of <21.75 kg/m2 had a higher risk of death.,Moreover, an increase in the BMI resulted in a decrease in the risk of death.,The risk of death was lowest when BMI was 30 kg/m2 (RR = 0.69; 95% CI, 0.53-0.89).,The BMI was not associated with all-cause mortality when BMI was >32 kg/m2.,Our findings indicate that overweight is associated with a lower risk of all-cause mortality among patients with COPD whereas underweight is associated with a higher risk of all-cause mortality in these patients.,However, there is limited evidence to support the association between obesity and the risk of all-cause mortality in patients with COPD. | 1 |
Clinical evidence indicates that patients with severe chronic obstructive pulmonary disease (COPD) are more susceptible to Aspergillus.,However, the exact mechanisms underlying this effect are not known.,In this study, we used cigarette smoke exposure to generate COPD rat model. colony-forming units (CFU) count assessment and phagocytosis were applied to evaluate the defense function of COPD rats against Aspergillus challenge.,ELISA, western blotting, and GST-Rac1 pull-down assays were conducted to determine the expressions of cytokines and TLR2-associated signaling pathway.,Our data showed that Aspergillus burdens increased, phagocytosis of Aspergillus as well as the expressions of inflammatory cytokines from alveolar macrophages (AMs) were impaired in COPD rats compared with normal rats.,Though TLR2 signaling-related proteins were induced in response to the stimulation of Aspergillus or Pam3csk4 (TLR2 agonist), the activation of TLR2-associated signaling pathway was apparently interfered in rats with COPD, compared to that in normal rats.,Taken together, our study demonstrated that COPD caused the deficiency of AMs function and impaired the activation of TLR2/PI3K/Rac 1 signaling pathway, leading to invasion of Aspergillus infection, which also provides a future basis for the infection control in COPD patients. | The incidence of chronic obstructive pulmonary disease (COPD) in China is very high.,This study aimed to assess the vulnerability of COPD patients in rural areas outside Xuzhou City, Jiangsu province, in order to provide helpful guidance for future research and public policies.,The vulnerability of 8,217 COPD patients was evaluated using a face-to-face questionnaire to obtain information on general characteristics, awareness, beliefs, medication usage, acute exacerbation of the disease, and economic burdens.,Direct economic burdens were calculated based on the questionnaire, and indirect economic burdens were estimated using local per capita income and life expectancy in 2008.,The years of potential life lost were calculated using loss of life years for each age group and multiplying by the number of deaths in a given age group.,Of the 8,217 patients, 7,921 (96.4%) had not heard of COPD, and 2,638 (32.1%) did not understand that smoking was a risk factor for COPD.,No patients had used inhalers, nebulizer drugs or oxygen therapy, either regularly or sporadically.,No patients had undergone pulmonary rehabilitation or surgical treatment, while 4,215 (51.3%) took theophylline to relieve dyspnea, and 3,418 (41.6%) used antibiotics to treat exacerbations.,A total of 2,925 (35.6%) patients had been admitted to hospital during the past year because of respiratory symptoms.,The average direct and indirect economic burdens on COPD patients were 1,090 and 20,605 yuan, respectively.,The vulnerability of patients in rural Xuzhou to COPD was high.,Their awareness of COPD was poor, their treatment during both the stable and acute exacerbation stages did not meet standards, and the economic burdens were large.,Interventions are therefore needed to improve the prevention and management of COPD in this population.,Further studies are required to verify these findings. | 1 |
A large proportion of people with COPD are not referred to pulmonary rehabilitation (PR) despite its proven benefits.,No previous studies have examined predictors of referral to PR.,To determine the characteristics of people with COPD associated with referral to PR.,Cross-sectional analysis of a primary care cohort of 82,696 Welsh people with COPD generated as part of a UK national audit of COPD care.,Data represent care received by patients as of 31/03/2017.,Referral to PR was defined as any code in the patient record indicating referral to PR in the last 3 years.,Potential predictors of referral to PR were chosen based on clinical judgement and data availability.,Independent predictors of PR referral were determined using backward stepwise mixed-effects logistic regression with a random effect for practice.,Variables assessed were: age, gender, deprivation, MRC recorded in past year, MRC grade, smoking status recorded in past year, smoking status, number of exacerbations in past year, inhaled therapy prescription, influenza vaccination, and comorbidities of diabetes, hypertension, coronary heart disease, stroke, heart failure, lung cancer, asthma, bronchiectasis, depression, anxiety, severe mental illness, osteoporosis, and painful condition.,A total of 13,297 people (16%) with COPD were referred from primary care for PR.,Patients with a comorbidity of bronchiectasis or depression, MRC recorded in the last year, higher MRC grade, more exacerbations in the last year, a greater level of inhaled therapy, an influenza vaccination, or were an ex-smoker had significantly higher odds of referral to PR.,Patients that were older, female, more deprived, or had a comorbidity of diabetes, asthma, or painful condition had significantly lower odds of referral to PR.,Generally appropriate patients are being prioritised for PR referral; however, it is concerning that women, current smokers, and more deprived patients appear to have lower odds of referral. | Singing group participation may benefit patients with chronic obstructive pulmonary disease (COPD).,Previous studies are limited by small numbers of participants and short duration of generally hospital-based singing group intervention.,This study examines the feasibility of long-term participation in a community singing group for patients with COPD who had completed pulmonary rehabilitation (PR).,This was a feasibility cohort study.,Patients with COPD who had completed PR and were enrolled in a weekly community exercise group were recruited to a new community-based singing group which met weekly for over 1 year.,Measurements at baseline, 4 months and 1 year comprised comprehensive pulmonary function tests including lung volumes, 6 min walk test (6MWT), Clinical COPD Questionnaire (CCQ), Hospital Anxiety and Depression Scale (HADS) and hospital admission days for acute exacerbation of COPD (AECOPD) for 1 year before and after the first singing group session.,There were 28 participants with chronic lung disease recruited from 140 people approached.,Five withdrew in the first month. 21 participants meeting Global Initiative for Chronic Obstructive Lung Disease criteria for COPD completed 4-month and 18 completed 1-year assessments.,The mean attendance was 85%.,For the prespecified primary outcome measure, total HADS score, difference between baseline and 12 months was −0.9, 95% CI −3.0 to 1.2, p=0.37.,Of the secondary measures, a significant reduction was observed for HADS anxiety score after 1 year of −0.9 (95% CI −1.8 to −0.1) points, p=0.038 and an increase in the 6MWT at 1 year, of 65 (95% CI 35 to 99) m compared with baseline p<0.001.,Our findings support the feasibility of long-term participation in a community singing group for adults with COPD who have completed PR and are enrolled in a weekly community exercise group and provide evidence of improved exercise capacity and a reduction in anxiety.,ACTRN12615000736549; Results. | 1 |
Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19).,Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown.,We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection.,We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects.,ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = − 0.28, p = 0.0090).,ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049).,Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and − 0.40, (p = 0.0010), respectively.,However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051).,Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES.,Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD.,However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E−06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively).,This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung.,Further studies to understand the impact on clinical course of disease are now required.,The online version contains supplementary material available at 10.1186/s12931-021-01755-3. | The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) a pandemic [1].,COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,COVID-19 displays symptoms ranging from mild to severe (pneumonia) that can lead to death in some individuals [2-4].,As of 18 April 2020, there have been 2 280 945 cases of COVID-19 worldwide and 156 354 deaths [5].,SARS-CoV-2 uses the angiotensin-converting enzyme II (ACE-2) as the cellular entry receptor [6].,While the virus can infect individuals of any age, to date, most of the severe cases have been described in those >55 years of age and with significant comorbidities, such as COPD [7].,Here, we determined whether patients with COPD have increased expression of ACE-2 in bronchial epithelial cells in the lower respiratory tract.,Smokers and those with COPD have increased airway expression of ACE-2, which is the entry receptor for the COVID-19 virus.,This may explain the increased risk of severe COVID-19 in these subpopulations and highlight the importance of smoking cessation.https://bit.ly/3bC29es | 1 |
Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control.,We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.,Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only).,Lung function was assessed over 24 h on day 29 of each treatment period.,The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0-24).,Other outcomes included change from baseline in average daily rescue medication use over the treatment period.,In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.,GFF MDI treatment significantly increased FEV1AUC0-24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0-12 and 12-24.,In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12-24 compared to 0-12 h.,GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p<0.0001] and −1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [p=0.017] puffs/day).,A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29).,There were no significant safety/tolerability findings.,GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.,Pearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085.,Registered 21 January 2015. | NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD).,The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.,Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled.,Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry.,The primary outcome measure was trough FEV1 at Week 12.,A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270).,Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001).,Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26.,FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints.,Transition dyspnoea index focal scores and St.,George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and-2.81 (p = 0.004), respectively.,NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo.,NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.,Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.,ClinicalTrials.gov: NCT01005901 | 1 |
The best method for expressing lung function impairment is undecided.,We tested in a population of patients with chronic obstructive pulmonary disease (COPD) whether forced expiratory volume in 1 second (FEV1) or FEV1 divided by height squared (FEV1/ht2) was better than FEV1 percent predicted (FEV1PP) for predicting survival.,FEV1, FEV1PP, and FEV1/ht2 recorded post bronchodilator were compared as predictors of survival in 1095 COPD patients followed for 15 years.,A staging system for severity of COPD was defined from FEV1/ht2 and compared with the Global Initiative for Obstructive Lung Disease (GOLD) staging system.,FEV1/ht2 was a better univariate predictor of survival in COPD than FEV1 and both were better than FEV1PP.,The best multivariate model for predicting survival included FEV1/ht2, age and sex.,Comparing the GOLD stages with the FEV1/ht2 groups found that survival was more coherent within each FEV1/ht group than it was within each GOLD stage.,FEV1/ht2 had 60% more people in its most severe group than the severest GOLD stage with these extra subjects having equivalently poor survival and had 155% more in the least severe group with equivalent survival.,GOLD staging misclassified 51% of subjects with regard to survival.,We conclude that GOLD criteria using FEV1PP do not optimally stage COPD with regard to survival.,An alternative strategy using FEV1/ht2 improves the staging of this disease.,Studies which stratify COPD patients to determine the effect of interventions such as drug trials, rehabilitation, or management guidelines should consider alternatives to the GOLD classification. | The aim of this study was to evaluate the association between health-related quality of life (HRQL) and disease severity using lung function measures.,A survey was performed in subjects with COPD in Sweden. 168 subjects (70 women, mean age 64.3 years) completed the generic HRQL questionnaire, the Short Form 36 (SF-36), the disease-specific HRQL questionnaire; the St George's Respiratory Questionnaire (SGRQ), and the utility measure, the EQ-5D.,The subjects were divided into four severity groups according to FEV1 per cent of predicted normal using two clinical guidelines: GOLD and BTS.,Age, gender, smoking status and socio-economic group were regarded as confounders.,The COPD severity grades affected the SGRQ Total scores, varying from 25 to 53 (GOLD p = 0.0005) and from 25 to 45 (BTS p = 0.0023).,The scores for SF-36 Physical were significantly associated with COPD severity (GOLD p = 0.0059, BTS p = 0.032).,No significant association were noticed for the SF-36, Mental Component Summary scores and COPD severity.,Scores for EQ-5D VAS varied from 73 to 37 (GOLD I-IV p = 0.0001) and from 73 to 50 (BTS 0-III p = 0.0007).,The SGRQ Total score was significant between age groups (p = 0.0047).,No significant differences in HRQL with regard to gender, smoking status or socio-economic group were noticed.,The results show that HRQL in COPD deteriorates with disease severity and with age.,These data show a relationship between HRQL and disease severity obtained by lung function. | 1 |
Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century.,The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD.,Our understanding of the key molecular mechanisms which drive the pathological changes are not complete.,In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation.,We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations.,We discuss the need to specifically target SAD to attenuate the progression of COPD. | This study assessed the effects of inhaled corticosteroid (ICS) on airway vascular remodeling in chronic obstructive pulmonary disease (COPD).,Thirty-four subjects with mild-to-moderate COPD were randomly allocated 2:1 to ICS or placebo treatment in a double-blinded clinical trial over 6 months.,Available tissue was compared before and after treatment for vessel density, and expression of VEGF, TGF-β1, and TGF-β1-related phosphorylated transcription factors p-SMAD 2/3.,This clinical trial has been registered and allocated with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 17/10/2012 with reference number ACTRN12612001111864.,There were no significant baseline differences between treatment groups.,With ICS, vessels and angiogenic factors did not change in hypervascular reticular basement membrane, but in the hypovascular lamina propria (LP), vessels increased and this had a proportionate effect on lung air trapping.,There was modest evidence for a reduction in LP vessels staining for VEGF with ICS treatment, but a marked and significant reduction in p-SMAD 2/3 expression.,Six-month high-dose ICS treatment had little effect on hypervascularity or angiogenic growth factors in the reticular basement membrane in COPD, but normalized hypovascularity in the LP, and this was physiologically relevant, though accompanied by a paradoxical reduction in growth factor expression. | 1 |
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 economic burden of chronic obstructive pulmonary disease (COPD) exacerbations is significant, but the impact of other sources on the overall cost of COPD management is largely unknown.,We aimed to estimate overall costs for patients experiencing none, one, or two or more exacerbations per year in the UK.,A retrospective cohort of prevalent COPD patients was identified in the Clinical Practice Research Datalink UK database.,Patients with information recorded for at least 12 months before and after cohort entry date were included (first prevalent COPD diagnosis confirmed by spirometry on/after April 1, 2009).,Patients were categorized as having none, one, or two or more moderate-to-severe COPD exacerbations in the 12 months after cohort entry and further classified by the Global initiative for chronic Obstructive Lung Disease (GOLD) category of airflow obstruction and the Medical Research Council dyspnea scale.,Study outcomes included counts of general practitioner interactions, moderate-severe COPD exacerbations, and non-COPD hospitalizations.,Estimated resource use costs were calculated using National Health Service reference costs for 2010-2011.,The cohort comprised 58,589 patients (mean age 69.5 years, mean dyspnea grade 2.5, females 46.6%, current smokers 33.1%).,The average total annual per patient cost of COPD management, excluding medications, was £2,108 for all patients and £1,523, £2,405, and £3,396 for patients experiencing no, one, or two or more moderate-to-severe exacerbations, respectively.,General practitioner interactions contributed most to these annual costs, accounting for £1,062 (69.7%), £1,313 (54.6%), and £1,592 (46.9%) in patients with no, one, or two or more moderate-to-severe exacerbations, respectively.,Disease management strategies focused on reducing costs in primary care may help reduce total COPD costs significantly. | 1 |
Rationale: In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.,Objectives: To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.,Methods: Exacerbations and change from baseline in trough FEV1 and St.,George’s Respiratory Questionnaire results were analyzed by prior ICS use.,Exacerbations were also analyzed while excluding data from the first 30 days.,Measurements and Main Results: FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction; P < 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction; P = 0.115).,To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%; P < 0.001) compared with UMEC/VI.,The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction; P < 0.001; non-ICS users, 35% reduction; P = 0.018), and overall when excluding the first 30 days (29%; P < 0.001).,Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV1 and St.,George’s Respiratory Questionnaire, regardless of prior ICS use.,Conclusions: These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.,Clinical trial registered with www.clinicaltrials.gov (NCT 02164513). | There is controversy regarding the significance of radiological consolidation in the context of COPD exacerbation (eCOPD).,While some studies into eCOPD exclude these cases, consolidation is a common feature of eCOPD admissions in real practice.,This study aims to address the question of whether consolidation in eCOPD is a distinct clinical phenotype with implications for management decisions and outcomes.,The European COPD Audit was carried out in 384 hospitals from 13 European countries between 2010 and 2011 to analyze guideline adherence in eCOPD.,In this analysis, admissions were split according to the presence or not of consolidation on the admission chest radiograph.,Groups were compared in terms of clinical and epidemiological features, existing treatment, clinical care utilized and mortality.,14,111 cases were included comprising 2,714 (19.2%) with consolidation and 11,397 (80.8%) without.,The risk of radiographic consolidation increased with age, female gender, cardiovascular diseases, having had two or more admissions in the previous year, and sputum color change.,Previous treatment with inhaled steroids was not associated.,Patients with radiographic consolidation were significantly more likely to receive antibiotics, oxygen and non-invasive ventilation during the admission and had a lower survival from admission to 90-day follow-up.,Patients admitted for COPD exacerbation who have radiological consolidation have a more severe illness course, are treated more intensively by clinicians and have a poorer prognosis.,We recommend that these patients be considered a distinct subset in COPD exacerbation. | 1 |
Chronic Obstructive Pulmonary Disease (COPD) is a growing worldwide problem that imposes a great burden on the daily life of patients.,Since there is no cure, the goal of treating COPD is to maintain or improve quality of life.,We have developed a new tool, the Assessment of Burden of COPD (ABC) tool, to assess and visualize the integrated health status of patients with COPD, and to provide patients and healthcare providers with a treatment algorithm.,This tool may be used during consultations to monitor the burden of COPD and to adjust treatment if necessary.,The aim of the current study is to analyse the effectiveness of the ABC tool compared with usual care on health related quality of life among COPD patients over a period of 18 months.,A cluster randomised controlled trial will be conducted in COPD patients in both primary and secondary care throughout the Netherlands.,An intervention group, receiving care based on the ABC tool, will be compared with a control group receiving usual care.,The primary outcome will be the change in score on a disease-specific-quality-of-life questionnaire, the Saint George Respiratory Questionnaire.,Secondary outcomes will be a different questionnaire (the COPD Assessment Test), lung function and number of exacerbations.,During the 18 months follow-up, seven measurements will be conducted, including a baseline and final measurement.,Patients will receive questionnaires to be completed at home.,Additional data, such as number of exacerbations, will be recorded by the patients’ healthcare providers.,A total of 360 patients will be recruited by 40 general practitioners and 20 pulmonologists.,Additionally, a process evaluation will be performed among patients and healthcare providers.,The new ABC tool complies with the 2014 Global Initiative for Chronic Obstructive Lung Disease guidelines, which describe the necessity to classify patients on both their airway obstruction and a comprehensive symptom assessment.,It has been developed to classify patients, but also to provide visual insight into the burden of COPD and to provide treatment advice.,Netherlands Trial Register, NTR3788. | Health status provides valuable information, complementary to spirometry and improvement of health status has become an important treatment goal in COPD management.,We compared the usefulness and validity of the COPD Assessment Test (CAT) and the Clinical COPD Questionnaire (CCQ), two simple questionnaires, in comparison with the St.,George Respiratory Questionnaire (SGRQ).,We administered the CAT, CCQ and SGRQ in patients with COPD stage I-IV during three visits.,Spirometry, 6 MWT, MRC scale, BODE index, and patients perspectives on questionnaires were recorded in all visits.,Standard Error of Measurement (SEM) was used to calculate the Minimal Clinical Important Difference (MCID) of all questionnaires.,We enrolled 90 COPD patients.,Cronbach's alpha for both CAT and CCQ was high (0.86 and 0.89, respectively).,Patients with severe COPD reported worse health status compared to milder subgroups.,CAT and CCQ correlated significantly (rho =0.64, p < 0.01) and both with the SGRQ (rho = 0.65; CAT and rho = 0.77; CCQ, p < 0.01).,Both questionnaires exhibited a weak correlation with lung function (rho = −0.35;CAT and rho = −0.41; CCQ, p < 0.01).,Their reproducibility was high; CAT: ICC = 0.94 (CI 0.92-0.96), total CCQ ICC = 0.95 (0.92-0.96) and SGRQ = 0.97 (CI 0.95-0.98).,The MCID calculated using the SEM method showed results similar to previous studies of 3.76 for the CAT, 0.41 for the CCQ and 4.84 for SGRQ.,Patients suggested both CAT and CCQ as easier tools than SGRQ in terms of complexity and time considerations.,More than half of patients preferred CCQ instead of CAT.,The CAT and CCQ have similar psychometric properties with a slight advantage for CCQ based mainly on patients’ preference and are both valid and reliable questionnaires to assess health status in COPD patients. | 1 |
Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia.,However, evidence for clinical efficacy and optimal management of therapy is limited.,Target Audience: Patients with COPD, clinicians who care for them, and policy makers.,Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions.,The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations.,Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.,Recommendations:1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).,Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure. | Acute hypercapnic respiratory failure (AHRF) treated with non-invasive ventilation in the ICU is frequently caused by chronic obstructive pulmonary disease (COPD) exacerbations and obesity-hypoventilation syndrome, the latter being most often associated with obstructive sleep apnea.,Overlap syndrome (a combination of COPD and obstructive sleep apnea) may represent a major burden in this population, and specific diagnostic pathways are needed to improve its detection early after ICU discharge.,To evaluate whether pulmonary function tests can identify a high probability of obstructive sleep apnea in AHRF survivors and outperform common screening questionnaires to identify the disorder.,Fifty-three patients surviving AHRF (31 males; median age 67 years (interquartile range: 62-74) participated in the study.,Anthropometric data were recorded and body plethysmography was performed 15 days after ICU discharge.,A sleep study was performed 3 months after ICU discharge.,The apnea-hypopnea index was negatively associated with static hyperinflation as measured by the residual volume to total lung capacity ratio in the % of predicted (coefficient = -0.64; standard error 0.17; 95% CI -0.97 to -0.31; p<0.001).,A similar association was observed in COPD patients only: coefficient = -0.65; standard error 0.19; 95% CI -1.03 to -0.26; p = 0.002.,Multivariate analysis with penalized maximum likelihood confirmed that the residual volume to total lung capacity ratio was the main contributor for apnea-hypopnea index variance in addition to classic predictors.,Screening questionnaires to select patients at risk for sleep-disordered breathing did not perform well.,In AHRF survivors, static hyperinflation is negatively associated with the apnea-hypopnea index in both COPD and non-COPD patients.,Measuring static hyperinflation in addition to classic predictors may help to increase the recognition of obstructive sleep apnea as common screening tools are of limited value in this specific population. | 1 |
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