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Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function.,Additionally, CS can induce autophagy which contributes to COPD.,Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy.,For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo.,Adult male wild-type (WT) C57BL/6J and Ephx2−/− mice were exposed to air or CS for 12 weeks, and lung inflammatory responses, air space enlargement (emphysema), lung function, and autophagy were assessed.,Lungs of Ephx2−/− mice had a less pronounced inflammatory response and less autophagy with mild distal airspace enlargement accompanied by restored lung function and steady weight gain.,These findings support the idea that Ephx2 may hold promise as a therapeutic target for COPD induced by CS, and it may be protective property by inhibiting autophagy. | Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers.,The causal mechanism(s) linking these illnesses is unknown.,We hypothesized autoimmune responses may be involved in both disorders.,To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.,Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers.,Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG.,Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays.,Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects.,Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7-5.7, p = 0.003).,Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7-13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006).,Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03).,Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively).,Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis.,These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders. | 1 |
Despite optimal pharmacological therapy and pulmonary rehabilitation, patients with COPD continue to be breathless.,There is a need to develop additional strategies to alleviate symptoms.,Learning to sing requires control of breathing and posture and might have benefits that translate into daily life.,To test this hypothesis we performed a randomised controlled trial, comparing a six week course of twice weekly singing classes to usual care, in 28 COPD patients.,The experience of singing was assessed in a qualitative fashion, through interviews with a psychologist.,In addition, we surveyed patients with chronic respiratory conditions who participated in a series of open singing workshops.,In the RCT, the physical component score of the SF36 improved in the singers (n = 15) compared to the controls (n = 13); +7.5(14.6) vs. -3.8(8.4) p = 0.02.,Singers also had a significant fall in HAD anxiety score; -1.1(2.7) vs.,+0.8(1.7) p = 0.03.,Singing did not improve single breath counting, breath hold time or shuttle walk distance.,In the qualitative element, 8 patients from the singing group were interviewed.,Positive effects on physical sensation, general well-being, community/social support and achievement/efficacy emerged as common themes. 150 participants in open workshops completed a questionnaire. 96% rated the workshops as "very enjoyable" and 98% thought the workshop had taught them something about breathing in a different way. 81% of attendees felt a "marked physical difference" after the workshop.,Singing classes can improve quality of life measures and anxiety and are viewed as a very positive experience by patients with respiratory disease; no adverse consequences of participation were observed.,Current Controlled Trials - ISRCTN17544114. | This study aimed to investigate the effects of weekly singings classes on pulmonary function parameters and quality of life (QoL) of COPD patients.,Forty-three patients were randomized to weekly classes of singing practice, or handcraft work.,They performed spirometry and completed maximal respiratory pressure measurements, evaluations of dyspnea, and the Saint George’s Respiratory Questionnaire, before and after 24 training classes.,A functional evaluation, immediately after 10 minutes of singing practice, was also performed at the end of the study.,Fifteen subjects completed the study in each group.,In comparison to controls the singing group exhibited transitory elevations on the dyspnea Borg scale (p = 0.02), and inspiratory capacity (p = 0.01), and decreases of expiratory reserve volume (p = 0.03), just after a short session of singing.,There was a significant difference on changes of maximal expiratory pressures in the comparison between groups at the end of training.,While the control group showed deterioration of maximal expiratory pressure, the singing group exhibited a small improvement (p = 0.05).,Both groups showed significant improvements of QoL in within group comparisons.,We have concluded that singing classes are a well tolerated activity for selected subjects with COPD.,Regular practice of singing may improve QoL, and preserve the maximal expiratory pressure of these patients. | 1 |
Non-invasive mechanical ventilation (NIV) in patients with acute respiratory failure has been traditionally determined based on clinical assessment and changes in blood gases, with NIV support pressures manually adjusted by an operator.,Bilevel positive airway pressure-spontaneous/timed (BiPAP S/T) with average volume assured pressure support (AVAPS) uses a fixed tidal volume that automatically adjusts to a patient’s needs.,Our study assessed the use of BiPAP S/T with AVAPS in patients with chronic obstructive pulmonary disease (COPD) and hypercapnic encephalopathy as compared to BiPAP S/T alone, upon immediate arrival in the Emergency-ICU.,We carried out a prospective interventional match-controlled study in Guayaquil, Ecuador.,A total of 22 patients were analyzed.,Eleven with COPD exacerbations and hypercapnic encephalopathy with a Glasgow Coma Scale (GCS) <10 and a pH of 7.25-7.35 were assigned to receive NIV via BiPAP S/T with AVAPS.,Eleven patients were selected as paired controls for the initial group by physicians who were unfamiliar with our study, and these patients were administered BiPAP S/T.,Arterial blood gases, GCS, vital signs, and ventilatory parameters were then measured and compared between the two groups.,We observed statistically significant differences in favor of the BiPAP S/T + AVAPS group in GCS (P = .00001), pCO2 (P = .03) and maximum inspiratory positive airway pressure (IPAP) (P = .005), among others.,However, no significant differences in terms of length of stay or days on NIV were observed.,BiPAP S/T with AVAPS facilitates rapid recovery of consciousness when compared to traditional BiPAP S/T in patients with chronic obstructive pulmonary disease and hypercapnic encephalopathy.,Current Controlled Trials application ref is ISRCTN05135218 | Inefficient clearance of copious respiratory secretion is a cause of non-invasive positive pressure ventilation (NPPV) failure, especially in chronic respiratory patients with community-acquired-pneumonia (CAP) and impaired consciousness.,We postulated that in such a clinical scenario, when intubation and conventional mechanical ventilation (CMV) are strongly recommended, the suction of secretions with fiberoptic bronchoscopy (FBO) may increase the chance of NPPV success.,The objective of this pilot study was, firstly, to verify the safety and effectiveness of early FBO during NPPV and, secondly, to compare the hospital outcomes of this strategy versus a CMV-based strategy in patients with decompensated chronic obstructive pulmonary disease (COPD) due to CAP who are not appropriate candidates for NPPV because of inefficient mucous clearance and hypercapnic encephalopathy (HE).,This is a 12-month prospective matched case-control study performed in one respiratory semi-intensive care unit (RSICU) with expertise in NPPV and in one intensive care unit (ICU).,Fifteen acutely decompensated COPD patients with copious secretion retention and HE due to CAP undergoing NPPV in RSICU, and 15 controls (matched for arterial blood gases, acute physiology and chronic health evaluation score III, Kelly-Matthay scale, pneumonia extension and severity) receiving CMV in the ICU were studied.,Two hours of NPPV significantly improved arterial blood gases, Kelly and cough efficiency scores without FBO-related complications.,NPPV avoided intubation in 12/15 patients (80%).,Improvement in arterial blood gases was similar in the two groups, except for a greater PaO2/fraction of inspired oxygen ratio with CMV.,The rates of overall and septic complications, and of tracheostomy were lower in the NPPV group (20%, 20%, and 0%) versus the CMV group (80%, 60%, and 40%; P < 0.05).,Hospital mortality, duration of hospitalisation and duration of ventilation were similar in the two groups.,In patients with decompensated COPD due to CAP who are candidates for CMV because of HE and inability to clear copious secretions, NPPV with early therapeutic FBO performed by an experienced team is a feasible, safe and effective alternative strategy. | 1 |
Nebulized heparin has been effectively used in the management of many pulmonary diseases.,However, its effect on mechanically ventilated patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD) has never been studied.,This study aimed to assess the efficacy of nebulized heparin and salbutamol to increase ventilator-free days (VFD) in mechanically ventilated AECOPD patients and the effect of nebulized heparin on respiratory and coagulation functions.,In this double-blind controlled study, 60 mechanically ventilated adult patients with AECOPD were randomly allocated into two groups; heparin and salbutamol (HS) group and salbutamol only (S) group.,In the Group HS, patients received nebulized heparin (25,000 IU) and salbutamol (5 mg) every 6 hours.,Patients in the Group S received nebulized salbutamol only (5 mg).,The treatment was continued while patients remained ventilated for a maximum of 14 days.,The primary outcome was VFDs at day 14.,PaCO2, PaO2/FiO2 ratio, number of nebulizations withheld, C-reactive protein (CRP) titer and activated partial thromboplastin time (APTT) were secondary outcomes.,Patients in the Group HS had significantly more VFDs (4.7 ± 3.3) compared with those in the Group S (2.4 ± 2.6), P = 0.007.,PaCO2 levels, PaO2/FiO2, the decrease in the CRP level and the increase in the APTT from the baseline showed no evidence of difference in both groups.,The co-administration of nebulized heparin and salbutamol, compared with salbutamol alone, significantly increased (VFDs) among mechanically ventilated AECOPD patients without increasing bleeding risks. | Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma.,In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017.,Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex.,Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases.,We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs.,In 2017, 544·9 million people (95% uncertainty interval [UI] 506·9-584·8) worldwide had a chronic respiratory disease, representing an increase of 39·8% compared with 1990.,Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia.,The age-sex-specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically.,Chronic respiratory diseases were the third leading cause of death in 2017 (7·0% [95% UI 6·8-7·2] of all deaths), behind cardiovascular diseases and neoplasms.,Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578-4 044 819) in 2017, an increase of 18·0% since 1990, while total DALYs increased by 13·3%.,However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14·3% decrease), age-standardised death rates (42·6%), and age-standardised DALY rates (38·2%).,In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD.,In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes.,Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world.,Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions.,Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men.,Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region.,Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.,Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis.,Bill & Melinda Gates Foundation. | 1 |
Beta (β)-blockers are under-prescribed in patients with heart failure (HF) and concurrent chronic obstructive pulmonary disease (COPD) due to concerns about adverse pulmonary effects and a poor understanding of the effects of these drugs.,We aimed to evaluate the survival effects of β-blockers in patients with coexistent HF and COPD.,Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study.,Patients with coexistent HF and COPD diagnosed between 2000 and 2009 were enrolled.,Doses of the 3 β-blockers proven to be beneficial to HF (carvedilol, bisoprolol, and metoprolol) during the study period were extracted.,The primary endpoint was cumulative survival.,Patients were followed until December 31, 2009.,The study included 11,558 subjects, with a mean follow-up period of 4.07 years.,After adjustment for age, sex, comorbidities, and severity of HF and COPD, bisoprolol use showed a dose-response survival benefit [low dose: adjusted hazard ratio (HR) = 0.76, 95% confidence interval (CI) = 0.59-0.97, P = 0.030; high dose: adjusted HR = 0.40, 95% CI = 0.26-0.63, P < 0.001] compared with nonusers, whereas no survival difference was observed for carvedilol or metoprolol.,Compared with patients with HF alone, this special HF + COPD cohort received significantly fewer targeted β-blockers (108.8 vs 137.3 defined daily doses (DDDs)/person-year, P < 0.001) and bisoprolol (57.9 vs 70.8 DDDs/person-year, P < 0.001).,In patients with coexisting HF and COPD, this study demonstrated a dose-response survival benefit of bisoprolol use, but not of carvedilol or metoprolol use. | Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial.,Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD.,We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD.,Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies.,Publication bias was assessed using a funnel plot.,Our search identified nine retrospective cohort studies that met the study inclusion criteria.,The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%).,The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality.,Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded.,The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials. | 1 |
The choice between lower limit of normal or fixed value of forced expiratory volume in one second/forced vital capacity ratio (FEV1/FVC) < 0.70 as the criterion for confirming airway obstruction is an open issue.,In this study, we compared the criteria of lower limit of normal and fixed FEV1/FVC for diagnosis of airway obstruction, with a focus on healthy elderly people.,We selected 367 healthy nonsmoking subjects aged 65-93 years from 1971 participants in the population-based SARA (Salute Respiratoria nell’Anziano, Italian for “Respiratory Health in the Elderly”) study, analyzed their spirometric data, and tested the relationship between spirometric indices and anthropometric variables.,The lower limit of normal for FEV1/FVC was calculated as the fifth percentile of the normal distribution for selected subjects.,While FEV1 and FVC decreased significantly with aging, the relationship between FEV1/FVC and age was not statistically significant in men or women.,The lower limit of normal for FEV1/FVC was 0.65 in men and 0.67 in women.,Fifty-five participants (15%) had FEV1/FVC < 0.70 and would have been inappropriately classified as obstructed according to the Global Initiative for Obstructive Lung Disease, American Thoracic Society/European Respiratory Society, and Canadian guidelines on chronic obstructive pulmonary disease.,By applying different FEV1/FVC thresholds for the different age groups, as previously proposed in the literature, (0.70 for <70 years, 0.65 for 70-80 years, and 0.60 for >80 years) the percentage of patients classified as obstructed decreased to 6%.,No subjects older than 80 years had an FEV1/FVC < 0.60.,The present results confirm the inadequacy of FEV1/FVC < 0.70 as a diagnostic criterion for airway obstruction after the age of 65 years.,FEV1/FVC < 0.65 and <0.67 (for men and women, respectively) could identify subjects with airway obstruction in such a population.,Further reduction of the threshold after 80 years is not justified. | Forced expiratory volume in one second (FEV1) is used to diagnose and establish a prognosis in chronic obstructive pulmonary disease (COPD).,Using multi-dimensional scores improves this predictive capacity.Two instruments, the BODE-index (Body mass index, Obstruction, Dyspnea, Exercise capacity) and the HADO-score (Health, Activity, Dyspnea, Obstruction), were compared in the prediction of mortality among COPD patients.,This is a prospective longitudinal study.,During one year (2003 to 2004), 543 consecutively COPD patients were recruited in five outpatient clinics and followed for three years.,The endpoints were all-causes and respiratory mortality.,In the multivariate analysis of patients with FEV1 < 50%, no significant differences were observed in all-cause or respiratory mortality across HADO categories, while significant differences were observed between patients with a lower BODE (less severe disease) and those with a higher BODE (greater severity).,Among patients with FEV1 ≥ 50%, statistically significant differences were observed across HADO categories for all-cause and respiratory mortality, while differences were observed across BODE categories only in all-cause mortality.,HADO-score and BODE-index were good predictors of all-cause and respiratory mortality in the entire cohort.,In patients with severe COPD (FEV1 < 50%) the BODE index was a better predictor of mortality whereas in patients with mild or moderate COPD (FEV1 ≥ 50%), the HADO-score was as good a predictor of respiratory mortality as the BODE-index.,These differences suggest that the HADO-score and BODE-index could be used for different patient populations and at different healthcare levels, but can be used complementarily. | 1 |
Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown.,This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity.,Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene).,Cross-sectional associations of thrombocytosis (platelet count ≥350 × 109/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score ≥ 2), COPD Assessment Test (CAT) score ≥ 10, six-minute-walk distance (6MWD), and St.,George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression.,A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies.,Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants.,In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1-2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1-2.2), dyspnea (mMRC ≥ 2 aOR 1.4; 95% CI: 1.0-1.9), respiratory symptoms (CAT ≥ 10 aOR 1.6; 95% CI: 1.1-2.4), and higher SGRQ score (β 2.7; 95% CI: 0.5, 5).,Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2-2.4).,Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms.,Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment.,Future longitudinal studies investigating the role of platelets in COPD progression may be warranted.,ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). | To demonstrate three‐dimensional (3D) multiple b‐value diffusion‐weighted (DW) MRI of hyperpolarized 3He gas for whole lung morphometry with compressed sensing (CS).,A fully‐sampled, two b‐value, 3D hyperpolarized 3He DW‐MRI dataset was acquired from the lungs of a healthy volunteer and retrospectively undersampled in the k y and k z phase‐encoding directions for CS simulations.,Optimal k‐space undersampling patterns were determined by minimizing the mean absolute error between reconstructed and fully‐sampled 3He apparent diffusion coefficient (ADC) maps.,Prospective three‐fold, undersampled, 3D multiple b‐value 3He DW‐MRI datasets were acquired from five healthy volunteers and one chronic obstructive pulmonary disease (COPD) patient, and the mean values of maps of ADC and mean alveolar dimension (Lm D) were validated against two‐dimensional (2D) and 3D fully‐sampled 3He DW‐MRI experiments.,Reconstructed undersampled datasets showed no visual artifacts and good preservation of the main image features and quantitative information.,A good agreement between fully‐sampled and prospective undersampled datasets was found, with a mean difference of +3.4% and +5.1% observed in mean global ADC and Lm D values, respectively.,These differences were within the standard deviation range and consistent with values reported from healthy and COPD lungs.,Accelerated CS acquisition has facilitated 3D multiple b‐value 3He DW‐MRI scans in a single breath‐hold, enabling whole lung morphometry mapping.,Magn Reson Med 77:1916-1925, 2017.,© 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.,This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | 1 |
TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.,In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219).,Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4).,Time to first and rate of moderate/severe exacerbations were assessed.,BFF MDI 320/10 µg improved pre-dose trough FEV1 versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4 versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24.,BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI.,Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.,BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.,TELOS: co-suspension delivery technology budesonide/formoterol fumarate dihydrate in a metered dose inhaler improved lung function and time to first and rate of exacerbations versus monocomponents in patients with moderate to very severe COPDhttp://ow.ly/ffWo30lrJL6 | Inhaled corticosteroids (ICSs) treatment combined with long-acting β2-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia.,There are indications that this association is stronger for fluticasone propionate than for budesonide.,We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy.,Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%-78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide.,We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs.,These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid. | 1 |
Whole-body vibration training (WBV) performed on a vibration platform can significantly improve physical performance in patients with chronic obstructive pulmonary disease.,It has been suggested that an important mechanism of this improvement is based on an improvement in balance.,Therefore, the aim of this study was to investigate the effects of WBV compared to conventional balance training.,48 patients with severe COPD (FEV1: 37 ± 7%predicted) and low exercise performance (6 min walk distance (6MWD): 55 ± 10%predicted) were included in this randomized controlled trial during a 3 week inpatient pulmonary rehabilitation.,All patients completed a standardized endurance and strength training program.,Additionally, patients performed 4 different balance exercises 3x/week for 2 sets of 1 min each, either on a vibration platform (Galileo) at varying frequencies (5-26 Hz) (WBV) or on a conventional balance board (BAL).,The primary outcome parameter was the change in balance performance during a semi tandem stance with closed eyes assessed on a force measurement platform.,Muscular power during a countermovement jump, the 6MWD, and 4 m gait speed test (4MGST) were secondary outcomes.,Non-parametric tests were used for statistical analyses.,Static balance performance improved significantly more (p = 0.032) in favor of WBV (path length during semi-tandem stand: − 168 ± 231 mm vs. + 1 ± 234 mm).,Muscular power also increased significantly more (p = 0.001) in the WBV group (+ 2.3 ± 2.5 W/kg vs.,− 0.1 ± 2.0 W/kg).,6MWD improved to a similar extent in both groups (WBV: 48 ± 46 m, p < 0.001 vs.,BAL: 38 ± 32 m; p < 0.001) whereas the 4MGST increased significantly only in the WBV-group (0.08 ± 0.14 m/s2, p = 0.018 vs.,0.01 ± 0.11 m/s2, p = 0.71).,WBV can improve balance performance and muscular power significantly more compared to conventional balance training.,Trial registration: Clinical-Trials registration number: NCT03157986; date of registration: May 17, 2017. https://clinicaltrials.gov/ct2/results?,cond=&term=NCT03157986&cntry=&state=&city=&dist =,The online version contains supplementary material available at 10.1186/s12931-021-01688-x. | Pulmonary rehabilitation is a highly effective treatment for people with chronic lung disease but remains underused across the world.,Recent years have seen the emergence of new program models that aim to improve access and uptake, including telerehabilitation and low-cost, home-based models.,This workshop was convened to achieve consensus on the essential components of pulmonary rehabilitation and to identify requirements for successful implementation of emerging program models.,A Delphi process involving experts from across the world identified 13 essential components of pulmonary rehabilitation that must be delivered in any program model, encompassing patient assessment, program content, method of delivery, and quality assurance, as well as 27 desirable components.,Only those models of pulmonary rehabilitation that have been tested in clinical trials are currently considered as ready for implementation.,The characteristics of patients most likely to succeed in each program model are not yet known, and research is needed in this area.,Health professionals should use clinical judgment to determine those patients who are best served by a center-based, multidisciplinary rehabilitation program.,A comprehensive patient assessment is critical for personalization of pulmonary rehabilitation and for effectively addressing individual patient goals.,Robust quality-assurance processes are important to ensure that any pulmonary rehabilitation service delivers optimal outcomes for patients and health services.,Workforce capacity-building and training should consider the skills necessary for emerging models, many of which are delivered remotely.,The success of all pulmonary rehabilitation models will be judged on whether the essential components are delivered and on whether the expected patient outcomes, including improved exercise capacity, reduced dyspnea, enhanced health-related quality of life, and reduced hospital admissions, are achieved. | 1 |
Self-management (SM) is defined as the provision of interventions to increase patients’ skills and confidence, empowering the individual to take an active part in their disease management.,There is uncertainty regarding the optimal format and the short- and long-term benefits of chronic obstructive pulmonary disease (COPD) SM interventions in adults.,Therefore, a high-quality overview of reviews was updated to examine their clinical effectiveness.,Sixteen reviews were identified, interventions were broadly classified as education or action plans, complex interventions with an SM focus, pulmonary rehabilitation (PR), telehealth and outreach nursing.,Systematic review and meta-analysis quality and the risk of bias of underlying primary studies were assessed.,Strong evidence was found that PR is associated with significant improvements in health-related quality of life (HRQoL).,Limited to moderate evidence for complex interventions (SM focus) with limited evidence for education, action plans, telehealth interventions and outreach nursing for HRQoL was found.,There was strong evidence that education is associated with a significant reduction in COPD-related hospital admissions, moderate to strong evidence that telehealth interventions and moderate evidence that complex interventions (SM focus) are associated with reduced health care utilization.,These findings from a large body of evidence suggesting that SM, through education or as a component of PR, confers significant health gains in people with COPD in terms of HRQoL.,SM supported by telehealth confers significant reductions in healthcare utilization, including hospitalization and emergency department visits. | Self-management support is one mechanism by which telehealth interventions have been proposed to facilitate management of long-term conditions.,The objectives of this metareview were to (1) assess the impact of telehealth interventions to support self-management on disease control and health care utilization, and (2) identify components of telehealth support and their impact on disease control and the process of self-management.,Our goal was to synthesise evidence for telehealth-supported self-management of diabetes (types 1 and 2), heart failure, asthma, chronic obstructive pulmonary disease (COPD) and cancer to identify components of effective self-management support.,We performed a metareview (a systematic review of systematic reviews) of randomized controlled trials (RCTs) of telehealth interventions to support self-management in 6 exemplar long-term conditions.,We searched 7 databases for reviews published from January 2000 to May 2016 and screened identified studies against eligibility criteria.,We weighted reviews by quality (revised A Measurement Tool to Assess Systematic Reviews), size, and relevance.,We then combined our results in a narrative synthesis and using harvest plots.,We included 53 systematic reviews, comprising 232 unique RCTs.,Reviews concerned diabetes (type 1: n=6; type 2, n=11; mixed, n=19), heart failure (n=9), asthma (n=8), COPD (n=8), and cancer (n=3).,Findings varied between and within disease areas.,The highest-weighted reviews showed that blood glucose telemonitoring with feedback and some educational and lifestyle interventions improved glycemic control in type 2, but not type 1, diabetes, and that telemonitoring and telephone interventions reduced mortality and hospital admissions in heart failure, but these findings were not consistent in all reviews.,Results for the other conditions were mixed, although no reviews showed evidence of harm.,Analysis of the mediating role of self-management, and of components of successful interventions, was limited and inconclusive.,More intensive and multifaceted interventions were associated with greater improvements in diabetes, heart failure, and asthma.,While telehealth-mediated self-management was not consistently superior to usual care, none of the reviews reported any negative effects, suggesting that telehealth is a safe option for delivery of self-management support, particularly in conditions such as heart failure and type 2 diabetes, where the evidence base is more developed.,Larger-scale trials of telehealth-supported self-management, based on explicit self-management theory, are needed before the extent to which telehealth technologies may be harnessed to support self-management can be established. | 1 |
The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes.,FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations.,In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50 μg once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use.,This post-hoc analysis included 2557 men and 805 women.,Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ≥2 exacerbations in the previous year.,Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively).,Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively).,Results were similar for all (mild/moderate/severe) exacerbations.,Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women.,The smaller sample size for women may account for some observed discrepancies in treatment responses.,Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC.,Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis.,Post hoc analysis of the FLAME study.,ClinicalTrials.gov number: NCT01782326.,Registered 1 February 2013. | A substantial proportion of patients with chronic obstructive pulmonary disease (COPD) develops various degree of intrathoracic tracheal collapsibility.,We studied whether the magnitude of intrathoracic tracheal collapsibility could be different across clinical phenotypes and sex in COPD.,Intrathoracic tracheal collapsibility measured at paired inspiratory-expiratory low dose computed tomography (CT) and its correlation with clinical, functional, and CT-densitometric data were investigated in 69 patients with COPD according to their predominant conductive airway or emphysema phenotypes and according to sex.,Intrathoracic tracheal collapsibility was higher in patients with predominant conductive airway disease (n=28) and in females (n=27).,Women with a predominant conductive airway phenotype (n=10) showed a significantly greater degree of collapsibility than women with predominant emphysema (28.9%±4% versus 11.6%±2%; P<0.001).,Intrathoracic tracheal collapsibility was directly correlated with inspiratory-expiratory volume variation at CT and with forced expiratory volume (1 second), and inversely correlated with reduced CT lung density and functional residual capacity.,Intrathoracic tracheal collapsibility was not correlated with cough and wheezing; however, intrathoracic tracheal collapsibility and clinical phenotypes of COPD are closely correlated.,In patients with a predominant emphysematous phenotype, a reduced collapsibility may reflect the mechanical properties of the stiff hyperinflated emphysematous lung.,The high collapsibility in patients with predominant airway disease, mild airway obstruction, and in women with this phenotype may reflect chronic airway inflammation.,The lack of relationship with such symptoms as wheezing, cough, and dyspnea could indicate that intrathoracic tracheal collapsibility itself should be considered neither an abnormal feature of COPD nor a relevant clinical finding. | 1 |
Patients with COPD might not report mild exacerbation.,The frequency, risk factors, and impact of mild exacerbation on COPD status are unknown.,The present study was performed to compare features between mild exacerbation and moderate or severe exacerbation in Japanese patients with COPD.,An observational COPD cohort was designed at Keio University and affiliated hospitals to prospectively investigate the management of COPD comorbidities.,This study analyzes data only from patients with COPD who had completed annual examinations and questionnaires over a period of 2 years (n=311).,Among 59 patients with mild exacerbations during the first year, 32.2% also experienced only mild exacerbations in the second year.,Among 60 patients with moderate or severe exacerbations during the first year, 40% also had the same severity of exacerbation during the second year.,Findings of the COPD assessment test and the symptom component of the St George’s Respiratory Questionnaire at steady state were worse in patients with mild exacerbations than in those who were exacerbation free during the 2-year study period, although the severity of the ratio of predicted forced expiratory volume in 1 second did not differ between them.,Severe airflow limitation (the ratio of predicted forced expiratory volume in 1 second <50%) and experience of mild exacerbations independently advanced the likelihood of an elevated COPD assessment test score to ≥2 per year.,The severity of COPD exacerbation seemed to be temporally stable over 2 years, and even mild exacerbations adversely impacted the health-related quality of life of patients with COPD. | 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. | 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. | Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic respiratory disease, characterized by an obstructive pattern.,Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens.,MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that modulate the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules.,Emerging evidences demonstrated the potential use of miRNAs as a disease biomarker.,This pilot study aimed to investigate the association of the MIR-196a2 rs11614913 (C/T) polymorphism with COPD susceptibility, the clinical outcome and bronchodilator response to short-acting β2-agonist.,Genotyping of rs11614913 polymorphism was determined in 108 COPD male patients and 116 unrelated controls using real-time polymerase chain reaction technology.,In silico target prediction and network core analysis were performed.,COPD patients did not show significant differences in the genotype distribution (p = 0.415) and allele frequencies (p = 0.306) of the studied miRNA when compared with controls.,There were also no associations with GOLD stage, dyspnea grade, disease exacerbations, COPD assessment test for estimating impact on health status score, or the frequency of intensive care unit admission.,However, COPD patients with CC genotype corresponded to the smallest bronchodilator response after Salbutamol inhalation, the heterozygotes (CT) had an intermediate response, while those with the TT genotype showed the highest response (p < 0.001).,In conclusion MIR-196a2 rs11614913 polymorphism is associated with the bronchodilator response of COPD in our sample of the Egyptian population, generating hypothesis of the potential use of MIR-196a2 variant as a pharmacogenetic marker for COPD. | 1 |
Previous studies have investigated the effects of air pollution on chronic obstructive pulmonary disease (COPD) patients using either fixed-site measurements or a limited number of personal measurements, usually for one pollutant and a short time period.,These limitations may introduce bias and distort the epidemiological associations as they do not account for all the potential sources or the temporal variability of pollution.,We used detailed information on individuals’ exposure to various pollutants measured at fine spatiotemporal scale to obtain more reliable effect estimates.,A panel of 115 patients was followed up for an average continuous period of 128 days carrying a personal monitor specifically designed for this project that measured temperature, nitrogen dioxide (NO2), ozone (O3), nitric oxide (NO), carbon monoxide (CO), and particulate matter with aerodynamic diameter <2.5 and <10 μm at 1-min time resolution.,Each patient recorded daily information on respiratory symptoms and measured peak expiratory flow (PEF).,A pulmonologist combined related data to define a binary variable denoting an “exacerbation”.,The exposure-response associations were assessed with mixed effects models.,We found that gaseous pollutants were associated with a deterioration in patients’ health.,We observed an increase of 16.4% (95% CI 8.6-24.6%), 9.4% (95% CI 5.4-13.6%) and 7.6% (95% CI 3.0-12.4%) in the odds of exacerbation for an interquartile range increase in NO2, NO and CO, respectively.,Similar results were obtained for cough and sputum.,O3 was found to have adverse associations with PEF and breathlessness.,No association was observed between particulate matter and any outcome.,Our findings suggest that, when considering total personal exposure to air pollutants, mainly the gaseous pollutants affect COPD patients’ health.,Significant adverse associations were found between the respiratory health of COPD patients and their personal exposure to gaseous pollutants measured using portable sensors over 6 months.,No significant associations were found for particulate pollutants.https://bit.ly/3aqMT6O | While the health effects of air pollution have been an international public health concern since at least the 1950s, recent research has focused on two broad sources of air pollution, namely, biomass fuel (BMF) and motor vehicle exhaust (MVE).,Many studies have shown associations between air pollution PM and exacerbations of pre-existing COPD, but the role of air pollution PM in the development and progression of COPD is still uncertain.,The current study indicates that rats can develop pronounced COPD following chronic exposure to air pollution PM (BMF and MVE), as characterized by lung function reduction, mucus metaplasia, lung and systemic inflammation, emphysema, and small airway remodeling.,Comparative analyses demonstrate that both BMF and MVE activate similar pathogenesis that are linked to the development of COPD.,These findings also show that some differences are found in the lungs of rats exposed to BMF or MVE, which might result in different phenotypes of COPD. | 1 |
Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma.,In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017.,Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex.,Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases.,We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs.,In 2017, 544·9 million people (95% uncertainty interval [UI] 506·9-584·8) worldwide had a chronic respiratory disease, representing an increase of 39·8% compared with 1990.,Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia.,The age-sex-specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically.,Chronic respiratory diseases were the third leading cause of death in 2017 (7·0% [95% UI 6·8-7·2] of all deaths), behind cardiovascular diseases and neoplasms.,Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578-4 044 819) in 2017, an increase of 18·0% since 1990, while total DALYs increased by 13·3%.,However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14·3% decrease), age-standardised death rates (42·6%), and age-standardised DALY rates (38·2%).,In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD.,In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes.,Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world.,Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions.,Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men.,Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region.,Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.,Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis.,Bill & Melinda Gates Foundation. | Fractional exhaled nitric oxide (FENO) is a useful and noninvasive biomarker for eosinophilic airway inflammation, particularly in asthma.,However, its utility in chronic obstructive pulmonary disease (COPD) remains controversial.,In this study, we performed a systematic review and meta-analysis to evaluate FENO levels in COPD.,A search of PubMed, Embase, Cochrane Library, and clinical trial registry was conducted from inception to January 2018.,Studies were included if they reported FENO levels in patients with COPD and healthy controls.,We then extracted relevant information and analyzed data.,Standard mean difference (SMD) with 95% confidence interval (CI) was applied in this meta-analysis.,A total of 2,073 studies were reviewed for eligibility, with 24 studies pooled for analysis.,The FENO levels in patients with COPD were elevated mildly compared with healthy controls (SMD 1.28, 95% CI 0.60-1.96).,A similar result was also observed in stable COPD, with an SMD of 1.21 (95% CI 0.47-1.96).,On the other hand, we found no association between FENO levels and exacerbated COPD.,Additionally, for patients with COPD, ex-smokers had higher levels of FENO than current smokers (SMD 2.05, 95% CI 1.13-2.97).,Our studies demonstrated a mild elevation of FENO in COPD, and the association between exacerbated COPD and FENO levels needs to be further explored.,The potential mechanism is still unknown and conflicting. | 1 |
Background and objective: There are few data on the short‐term natural history of airway inflammation during severe episodes of acute exacerbation of COPD (AECOPD).,An observational study was performed to determine how rapidly conventional treatment improves airway inflammation in patients admitted to hospital with AECOPD.,Methods: Twenty‐four consecutive patients with AECOPD were recruited and changes in sputum inflammatory indices were assessed after 2 and 4 days of treatment.,The primary end‐points included presence of bacteria and viruses, changes in sputum total cell counts (TCC) and polymorphonuclear leukocyte (PMN) differential counts, and levels of secretory leukocyte protease inhibitor (SLPI), IL‐8 and TNF‐α.,Results: All patients received oral corticosteroids and 17 (71%) were also treated with oral antibiotics.,A bacterial or viral pathogen was isolated from 12 patients (50%), and Aspergillus fumigatus was isolated from one.,A positive bacterial culture was associated with increased sputum TCC and PMN count (P < 0.05), as well as higher levels of IL‐8 and TNF‐α (P < 0.05), and a trend towards lower sputum SLPI levels (P = 0.06).,Sputum PMN numbers fell by 70% within the first 48 h of admission (P < 0.05), accompanied by an increase in sputum SLPI (P < 0.001) and reductions in the levels of TNF‐α (P < 0.005) and IL‐8 (P = 0.06), with no further significant change at 4 days.,Conclusions: Conventional treatment for severe AECOPD is associated with rapid reduction of neutrophilic inflammation and improvement in anti‐protease defences. | COPD exacerbations are responsible for the morbidity and mortality of this disease.,The relationship between exacerbations and patient-related clinical outcomes is not clearly understood.,A retrospective analysis of two 1-year, placebo-controlled clinical trials with tiotropium 18 μg daily was conducted to examine relationships between exacerbations and other clinical outcomes.,The relationship between FEV1, St.,George’s Respiratory Questionnaire (SGRQ), and the transition dyspnea index (TDI) were examined based on the frequency of exacerbations (0, 1, 2, >2).,921 patients participated in the trials (mean age 65 years, mean FEV1 = 1.02 L (39% predicted).,The percent change from baseline in FEV1 in the tiotropium group was +12.6%, +12.0%, +2.1% and +8.9%; and in the placebo group was −3.4%, −3.4%, −5.7% and −6.7% for exacerbation frequencies of 0, 1, 2, >2, respectively.,Compared with baseline, the largest improvement in SGRQ occurred in patients with no exacerbations.,In the placebo group, there was a significant association between an increased frequency of exacerbations and worsening SGRQ scores.,A reduction in exacerbation rates of 4.4% to 42.0% such as that shown in this study cohort was associated with meaningful changes in questionnaire based instruments.,In the placebo-treated patients increased frequency of exacerbations was associated with larger decrements in FEV1, TDI, and SGRQ.,A reduction in the frequency of exacerbations is associated with changes that are considered meaningful in these clinical outcomes. | 1 |
Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent.,Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function.,The factors affecting their inspiratory flows through inhalers are unclear.,To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity.,Flow-volume spirometry was performed in 93 COPD patients.,Maximum PIF rates were recorded through an empty Easyhaler® (PIFEH; Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher.,The mean PIFEH was 54 L/min (range 26-95 L/min) with a coefficient of variation of 7%.,All but two patients were able to generate a flow of ≥28 L/min.,In a general linear model, the independent determinants for PIFEH were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV1) expressed as percent predicted was not a significant factor.,The regression model accounted only for 18% of the variation in PIFEH.,In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction.,Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways. | This review summarizes the long-term clinical outcomes associated with β-agonist and anticholinergic bronchodilator use in patients with chronic obstructive pulmonary disease (COPD).,Pooled data from randomized placebo-controlled trials of at least three months duration were used to evaluate the risk for COPD hospitalizations, respiratory mortality, and total mortality.,The results show that anticholinergic use is associated with a 30% reduction in COPD hospitalizations, a 70% reduction in respiratory mortality, and without a significant effect on total mortality.,In contrast, β-agonist use had no effect on COPD hospitalizations and was associated with a two-fold increased risk for respiratory death compared with placebo.,When the two bronchodilators were directly compared with each other, β-agonists were associated with a two-fold increased risk for COPD hospitalization and a five-fold increased risk for total mortality compared with anticholinergics.,When β-agonists were added to either anticholinergic use or inhaled corticosteroid use alone, there was no significant improvement in any long-term clinical outcome.,These results indicate that anticholinergics should be the bronchodilator of choice in COPD, while β-agonists may be associated with poorer disease control. | 1 |
Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids.,Novel treatment options are needed for these patients.,Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects.,This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD.,This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 40-80% predicted and FEV1/forced vital capacity ratio ≤ 0.7.,Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily.,Primary outcome: placebo-adjusted difference in peak FEV1 (assessed over 3 h) at Week 4.,The study took place between July 2017 and February 2018.,Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study.,For peak FEV1 at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively.,Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4.,Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo.,In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated.,The study supports the continuing development of ensifentrine in COPD.,EudraCT 2016-005205-40, registered 30 May 2017. | We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).,Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo.,Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days.,Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sGaw) were measured.,In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively).,The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001).,In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo.,The average FEV1(0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009).,In both studies, lung volumes and sGaw showed greater RPL554 combination treatment effects versus monotherapy.,RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.,The dual PDE3 and PDE4 inhibitor RPL554 causes additional bronchodilation when combined with commonly used short- or long-acting bronchodilatorshttp://ow.ly/CUYi30lDcYW | 1 |
The increasing prevalence and associated cost of treating chronic obstructive pulmonary disease (COPD) is unsustainable, and focus is needed on self-management and prevention of hospital admissions.,Telehealth monitoring of patients’ vital signs allows clinicians to prioritise their workload and enables patients to take more responsibility for their health.,This paper reports the results of a pilot randomised controlled trial (RCT) of Telehealth-supported care within a community-based COPD supported-discharge service.,A two-arm pragmatic pilot RCT was conducted comparing the standard service with a Telehealth-supported service and assessed the potential for progressing into a full RCT.,The co-primary outcome measures were the proportion of COPD patients readmitted to hospital and changes in patients’ self-reported quality of life.,The objectives were to assess the suitability of the methodology, produce a sample size calculation for a full RCT, and to give an indication of cost-effectiveness for both pathways.,Sixty three participants were recruited (n = 31 Standard; n = 32 Telehealth); 15 participants were excluded from analysis due to inadequate data completion or withdrawal from the Telehealth arm.,Recruitment was slow with significant gaps in data collection, due predominantly to an unanticipated 60% reduction of staff capacity within the clinical team.,The sample size calculation was guided by estimates of clinically important effects and COPD readmission rates derived from the literature.,Descriptive analyses showed that the standard service group had a lower proportion of patients with hospital readmissions and a greater increase in self-reported quality of life compared to the Telehealth-supported group.,Telehealth was cost-effective only if hospital admissions data were excluded.,Slow recruitment rates and service reconfigurations prevented progression to a full RCT.,Although there are advantages to conducting an RCT with data collection conducted by a frontline clinical team, in this case, challenges arose when resources within the team were reduced by external events.,Gaps in data collection were resolved by recruiting a research nurse.,This study reinforces previous findings regarding the difficulty of undertaking evaluation of complex interventions, and provides recommendations for the introduction and evaluation of complex interventions within clinical settings, such as prioritisation of research within the clinical remit.,Current Controlled Trials ISRCTN68856013, registered Nov 2010. | People with chronic obstructive pulmonary disease (COPD) continue to experience dyspnea with activities of daily living (ADL) despite optimal medical management.,Information and communication technologies may facilitate collaborative symptom management and could potentially increase the reach of such interventions to those who are unable to attend face-to-face pulmonary rehabilitation or self-management programs.,The purpose of this randomized study was to test the efficacy of two 6-month dyspnea self-management programs, Internet-based (eDSMP) and face-to-face (fDSMP), on dyspnea with ADL in people living with COPD.,We randomly assigned 50 participants with moderate to severe COPD who were current Internet users to either the eDSMP (n = 26) or fDSMP (n = 24) group.,The content of the two programs was similar, focusing on education, skills training, and ongoing support for dyspnea self-management, including independent exercise.,The only difference was the mode (Internet/personal digital assistant [PDA] or face-to-face) in which the education sessions, reinforcement contacts, and peer interactions took place.,Participants returned to one of two academic clinical sites for evaluation at 3 and 6 months.,The primary outcome of dyspnea with ADL was measured with the Chronic Respiratory Questionnaire.,Secondary outcomes of exercise behavior, exercise performance, COPD exacerbations, and mediators, such as self-efficacy and social support, were also measured.,A satisfaction survey was administered and a semistructured exit interview was conducted at the final visit.,The study was stopped early due to multiple technical challenges with the eDSMP, but follow-up was completed on all enrolled participants.,Data were available for 39 participants who completed the study (female: 44%; age: 69.5 ± 8.5 years; percent predicted forced expiratory volume in 1 s: 49.6 ± 17.0%).,The fDSMP and eDSMP showed similar clinically meaningful changes in dyspnea with ADL from baseline to 3 months (fDSMP: + 3.3 points; eDSMP: + 3.5 points) and sustained these improvements at 6 months (fDSMP: + 4.0 points; eDSMP: + 2.5 points; time effects P < .001; group by time P = .51).,Self-reported endurance exercise time (P = .001), physical functioning (P = .04), and self-efficacy for managing dyspnea (P = .02) also showed positive improvements over time in both groups with no significant differences with respect to program modality.,Participants who completed the study reported favorable satisfaction with the programs.,Although there were numerous technical challenges with the eDSMP, both dyspnea self-management programs were effective in reducing dyspnea with ADL in the short term.,Our findings will need to be confirmed in a larger randomized trial with more mature Web and personal digital assistant tools, use of a control group, and longer follow-up.,clinicaltrials.gov NCT00102401, http://www.webcitation.org/5X8CX4gLC | 1 |
It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations.,The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations.,914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited.,Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients).,FEV1, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period.,816 patients (89.3%) concluded the study.,FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6.,We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6.,We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. | 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 |
To review and summarize existing literature on the indirect burden of chronic obstructive pulmonary disease (COPD) in the US.,Medline, Scopus, and OvidSP databases were searched using defined search terms to identify relevant studies.,Eligible studies were published in English between January 2000 and April 2012 and calculated the indirect burden of COPD in a US population in terms of prevalence, incidence or costs of productivity loss, disability, morbidity, or mortality.,Of 53 studies identified, eleven met eligibility criteria, with data years spanning 1987-2009.,Estimates of workforce participation range from 56% to 69% among individuals with COPD and from 65% to 77% among individuals without COPD.,Approximately 13%-18% of those with COPD are limited in the amount or type of work they can do and one-third or more experience general activity limitation.,Estimates of restricted activity days range from 27-63 days per year.,Estimates of mean annual sick leave and/or disability days among employed individuals with COPD range from 1.3-19.4 days.,Estimates of bed confinement range from 13-32 days per year.,Estimated mean annual indirect costs were $893-$2,234/person (US dollars) with COPD ($1,521-$3,348 in 2010 [US dollars]) and varied with the population studied, specific cost outcomes, and economic inputs.,In studies that assessed total (direct and indirect) costs, indirect costs accounted for 27%-61% of total costs, depending on the population studied.,COPD is associated with substantial indirect costs.,The disease places a burden on employers in terms of lost productivity and associated costs and on individuals in terms of lost income related to absenteeism, activity limitation, and disability.,Consideration of indirect as well as direct costs is necessary to gain a more complete view of the societal burden of COPD. | 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 |
Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).,Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation.,To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.,The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=−2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group.,Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=−5.368, P<0.001).,Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024).,Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029).,The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication.,The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy.,FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease.,Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations. | Salbutamol and ipratropium bromide improve lung function in patients with chronic obstructive pulmonary disease (COPD).,However, their bronchodilating effect has not yet been compared in the central and distal airways.,Functional imaging using computational fluid dynamics offers the possibility of making such a comparison.,The objective of this study was to assess the effects of salbutamol and ipratropium bromide on the geometry and computational fluid dynamics-based resistance of the central and distal airways.,Five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner with a 1-week interval between treatments.,Patients underwent lung function testing and a multislice computed tomography scan of the thorax that was used for functional imaging.,Two hours after dosing, the patients again underwent lung function tests and repeat computed tomography.,Lung function parameters, including forced expiratory volume in 1 second, vital capacity, overall airway resistance, and specific airway resistance, changed significantly after administration of each product.,On functional imaging, the bronchodilating effect was greater in the distal airways, with a corresponding drop in airway resistance, compared with the central airways.,Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient.,Salbutamol was more effective in the other patients.,This pilot study gives an innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD, using the new techniques of functional imaging and computational fluid dynamics. | 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. | To analyze the role of the capsular type in pneumococci causing relapse and reinfection episodes of acute exacerbation in COPD patients.,A total of 79 patients with 116 recurrent episodes of acute exacerbations caused by S. pneumoniae were included into this study (1995-2010).,A relapse episode was considered when two consecutive episodes were caused by the same strain (identical serotype and genotype); otherwise it was considered reinfection.,Antimicrobial susceptibility testing (microdilution), serotyping (PCR, Quellung) and molecular typing (PFGE/MLST) were performed.,Among 116 recurrent episodes, 81 (69.8%) were reinfections, caused by the acquisition of a new pneumococcus, and 35 (30.2%) were relapses, caused by a pre-existing strain.,Four serotypes (9V, 19F, 15A and 11A) caused the majority (60.0%) of relapses.,When serotypes causing relapses and reinfection were compared, only two serotypes were associated with relapses: 9V (OR 8.0; 95% CI, 1.34-85.59) and 19F (OR 16.1; 95% CI, 1.84-767.20).,Pneumococci isolated from relapses were more resistant to antimicrobials than those isolated from the reinfection episodes: penicillin (74.3% vs.,34.6%, p<0.001), ciprofloxacin (25.7% vs.,9.9%, p<0.027), levofloxacin (22.9% vs.,7.4%, p = 0.029), and co-trimoxazole (54.3% vs.,25.9%, p<0.001).,Although the acquisition of a new S. pneumoniae strain was the most frequent cause of recurrences, a third of the recurrent episodes were caused by a pre-existing strain.,These relapse episodes were mainly caused by serotypes 9V and 19F, suggesting an important role for capsular type. | 1 |
Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD).,We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI + UMEC using two inhalers.,Eligible patients with COPD (aged ≥40 years; ≥1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 μg and placebo or FF/VI 100/25 μg + UMEC 62.5 μg; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning.,Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 24.,The non-inferiority margin for the lower 95% confidence limit was set at − 50 mL.,A total of 1055 patients (844 [80%] of whom were enrolled on combination maintenance therapy) were randomized to receive FF/UMEC/VI (n = 527) or FF/VI + UMEC (n = 528).,Mean change from baseline in trough FEV1 at Week 24 was 113 mL (95% CI 91, 135) for FF/UMEC/VI and 95 mL (95% CI 72, 117) for FF/VI + UMEC; the between-treatment difference of 18 mL (95% CI -13, 50) confirmed FF/UMEC/VI’s was considered non-inferior to FF/VI + UMEC.,At Week 24, the proportion of responders based on St George’s Respiratory Questionnaire Total score was 50% (FF/UMEC/VI) and 51% (FF/VI + UMEC); the proportion of responders based on the Transitional Dyspnea Index focal score was similar (56% both groups).,A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI (24%) and FF/VI + UMEC (27%) groups; the hazard ratio for time to first moderate/severe exacerbation with FF/UMEC/VI versus FF/VI + UMEC was 0.87 (95% CI 0.68, 1.12).,The incidence of adverse events was comparable in both groups (48%); the incidence of serious adverse events was 10% (FF/UMEC/VI) and 11% (FF/VI + UMEC).,Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI + UMEC) on trough FEV1 change from baseline at 24 weeks.,Results were similar on all other measures of efficacy, health-related quality of life, and safety.,GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016). | Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality.,COPD is typified by persistent, progressive airflow limitation and a range of respiratory and systemic symptoms such as breathlessness, coughing, wheezing, depression, anxiety, general fatigue, and sleeping difficulties.,Despite receiving treatment for COPD, many patients suffer from regular symptoms that affect their daily lives and lead to increased morbidity.,These symptoms vary in severity, frequency, and type, and can occur at any time throughout the 24-h day, with over half of patients with COPD experiencing symptoms in the morning, during the day, and at nighttime.,Despite the prevalence of symptoms, patient and physician perception of the impact of COPD symptoms on patients’ lives is not always in concordance.,Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) has the potential to treat the symptoms of COPD in addition to improving lung function.,This review therefore examines the burden of symptoms experienced throughout the day by patients with COPD and the evidence for combined LAMA/LABA treatment in terms of symptom management.,As patients with COPD experience varying symptoms throughout the course of their disease, the role of tailoring treatment to the individual needs of the patient is also examined.,We conclude that the symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day, and have a substantial impact on patients’ health status and quality of life.,In order to provide effective, patient-orientated care, patients with COPD should be evaluated on the basis of lung function, the frequency of symptoms, and patient-perceived impact of symptoms on their lives.,Therapy should be chosen carefully based on individualized assessment, ensuring personalization to the individual needs of the patient. | 1 |
To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009.,A total of 45,837 male residents were observed for a median period of 19.1 years.,Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019.,During follow-up, 268 participants died from COPD.,The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41-0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59-0.68).,These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years.,Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality. | The landmark study of Fletcher and Peto on the natural history of tobacco smoke-related chronic airflow obstruction suggested that decline in the forced expiratory volume in the first second (FEV1) in chronic obstructive pulmonary disease (COPD) is slow at the beginning, becoming faster with more advanced disease.,The present authors reviewed spirometric data of COPD patients included in the placebo arms of recent clinical trials to assess the lung function decline of each stage, defined according to the severity of airflow obstruction as proposed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.,In large COPD populations the mean rate of FEV1 decline in GOLD stages II and III is between 47 and 79 mL/year and 56 and 59 mL/year, respectively, and lower than 35 mL/year in GOLD stage IV.,Few data on FEV1 decline are available for GOLD stage I.,Hence, the loss of lung function, assessed as expiratory airflow reduction, seems more accelerated and therefore more relevant in the initial phases of COPD.,To have an impact on the natural history of COPD, it is logical to look at the effects of treatment in the earlier stages. | 1 |
Mortality and symptom burden from chronic obstructive pulmonary disease (COPD) and lung cancer are similar but there is thought to be an inequality in palliative care support (PCS) between diseases.,This nationally representative study assessed PCS for COPD patients within primary care in the UK.,This was a cohort study using electronic healthcare records (2004-2015).,Factors associated with receiving PCS were assessed using logistic regression for the whole cohort and deceased patients.,There were 92 365 eligible COPD patients, of which 26 135 died.,Only 7.8% of the whole cohort and 21.4% of deceased patients received PCS.,Lung cancer had a strong association with PCS compared with other patient characteristics, including Global Initiative for Chronic Obstructive Lung Disease stage and Medical Research Council Dyspnoea score (whole cohort, lung cancer: OR 14.1, 95% CI 13.1-15; deceased patients, lung cancer: OR 6.5, 95% CI 6-7).,Only 16.7% of deceased COPD patients without lung cancer received PCS compared with 56.5% of deceased patients with lung cancer.,In patients that received PCS, lung cancer co-diagnosis significantly increased the chances of receiving PCS before the last month of life (1-6 versus ≤1 month pre-death: risk ratio 1.4, 95% CI 1.3-1.7).,Provision of PCS for COPD patients in the UK is inadequate.,Lung cancer, not COPD, was the dominant driver for COPD patients to receive PCS.,Palliative care provision for COPD patients without lung cancer is poor in the UKhttp://ow.ly/IIC230gWOOV | Early palliative care is not a common practice for patients with COPD.,Important barriers are the identification of patients for palliative care and the organization of such care in this patient group.,Pulmonologists have a central role in providing good quality palliative care for patients with COPD.,To guide future research and develop services, their view on palliative care for these patients was explored.,A survey study was performed by the members of the Netherlands Association of Physicians for Lung Diseases and Tuberculosis.,The 256 respondents (31.8%) covered 85.9% of the hospital organizations in the Netherlands.,Most pulmonologists (92.2%) indicated to distinguish a palliative phase in the COPD trajectory, but there was no consensus about the different criteria used for its identification.,Aspects of palliative care in COPD considered important were advance care planning conversation (82%), communication between pulmonologist and general practitioner (77%), and identification of the palliative phase (75.8%), while the latter was considered the most important aspect for improvement (67.6%).,Pulmonologists indicated to prefer organizing palliative care for hospitalized patients with COPD themselves (55.5%), while 30.9% indicated to prefer cooperation with a specialized palliative care team (SPCT).,In the ambulatory setting, a multidisciplinary cooperation between pulmonologist, general practitioner, and a respiratory nurse specialist was preferred (71.1%).,To encourage pulmonologists to timely initiate palliative care in COPD, we recommend to conduct further research into more specific identification criteria.,Furthermore, pulmonologists should improve their skills of palliative care, and the members of the SPCT should be better informed about the management of COPD to improve care during hospitalization.,Communication between pulmonologist and general practitioner should be emphasized in training to improve palliative care in the ambulatory setting. | 1 |
Current understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited.,This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use.,This was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395).,The population of interest comprised patients with COPD ≥40 years of age with ≥2 moderate or ≥1 severe exacerbations (prior year) while on inhaled maintenance therapy, with ≥1 blood EOS count.,Data were analyzed during the year prior to index date (last COPD encounter between January 1, 2011 and December 31, 2016).,Four subgroups were analyzed based on a combination of EOS counts (<150 and ≥150 cells/μL) and MITT use (receiving or not receiving).,Among these groups, clinical characteristics, exacerbations, and HCRU were described.,A sensitivity analysis that further stratified EOS into four categories (<150, ≥150-<300, ≥300-<500, and ≥500 cells/μL) was also performed.,The COPD population of interest comprised 34,268 patients.,Subgroups with EOS ≥150 cells/μL vs <150 cells/μL had more comorbidities and experienced significantly higher mean numbers of moderate exacerbations (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 1.93 vs 1.82, P<0.0001; receiving MITT 2.26 vs 2.16, P=0.0062) and COPD-related emergency visits (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 3.0 vs 2.5, P<0.001; receiving MITT 3.4 vs 3.1, P=0.0011).,Increasing EOS category was associated with higher HCRU.,Blood EOS ≥150/μL cells were associated with increased HCRU and higher exacerbation rates compared with EOS <150 cells/μL, irrespective of MITT use.,COPD phenotyping using blood EOS could help identify candidates for additional therapies that target eosinophilic inflammatory pathways. | Readmissions are common following acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and are partially responsible for increased morbidity and mortality in COPD.,Numerous factors have been shown to predict readmission of patients previously admitted to hospital for AECOPD; however, factors related to readmission in patients who are triaged in emergency departments (EDs) and sent directly home are poorly understood.,We postulate that patients seen in the ED for AECOPD and directly sent home have a high readmission rate, and we suspect that inadequate management and follow-up contribute to this high readmission rate.,We conducted a 1-year retrospective study of all patients seen in the ED for AECOPD at an inner-city tertiary care hospital; 30- and 90-day readmission rates for COPD and all-cause admissions to the ED and hospital were determined.,Patients discharged directly home from the ED were compared with those admitted to hospital for management.,Patient, treatment, and system variables that could potentially impact readmission were documented.,Multivariate Poisson regression models were used to determine which factors predicted readmissions.,The readmission rates in the ED group (n=240) were significantly higher than that in the hospitalized group (n=271): 1) the 90-day ED readmissions (1.29 vs 0.51, p<0.0001) and 30-day ED readmissions (0.54 vs 0.20, p<0.0001) (ED vs hospitalized groups) were significantly higher in the ED group; 2) the time to first readmission was significantly shorter in the ED group than in the hospitalized group (24.1±22 vs 31.8±27.8 days; p<0.05).,Cardiovascular comorbidities (p<0.00001), substance abuse disorder (p<0.001), and mental illness (p<0.001) were the strongest predictors of readmission in the ED group.,Age (p<0.01), forced expiratory volume in 1 second (p<0.001), and cardiovascular comorbidities (p<0.05) were the best predictors for both 30- and 90-day COPD readmission rates in the ED group.,Only 50% of the ED group patients received bronchodilators, oral steroids, and antibiotics inclusively, and only 68% were referred for community follow-up.,The need for oral steroids to treat AECOPD predicted future 90-day COPD readmissions in the ED group (p<0.003).,Patients discharged directly home from EDs have a significantly higher risk of readmission to EDs than those who are hospitalized.,One possible reason for this is that COPD management is variable in EDs with <50% receiving appropriate therapy. | 1 |
The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD.,COPD patients have a variety of comorbidities, but little is known about their impact on quality of life.,This study was designed to investigate comorbid factors that may contribute to high CAT scores.,An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects.,Health status was assessed by the CAT, the St.,Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health.,Comorbidities were identified based on patients’ reports, physicians’ records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale.,Dual X-ray absorptiometry measurements of bone mineral density were performed.,The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36.,The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients.,Symptomatic COPD patients have a high prevalence of comorbidities.,A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized.,Clinical trial registered with UMIN (UMIN000003470). | Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies.,To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).,Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years.,We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation.,Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs.,0.9 (1.1) per year, p<0.001) compared to non-inflamed ones.,As a descriptive study our results show associations but do not prove causality.,Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.,Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment. | 1 |
Physical activity (PA) is impaired from the early stages of COPD, is associated with a worsening of disease prognosis, and causes COPD patients to restrict their daily activities in order to avoid breathlessness.,The development of a simple tool to estimate physical activity level (PAL) could be useful for the management of COPD.,We investigated the differences in PA according to the modified Medical Research Council (mMRC) grade in patients with COPD.,A cross-sectional study was performed on stable outpatients with COPD.,PA was measured for 2 weeks using a triaxial accelerometer, and dyspnea grade was evaluated in all patients using the mMRC scale.,Ninety-eight patients were recruited.,Significant differences in PA duration were observed at all intensities according to the mMRC grade.,Despite treatment with controller medications, 59.2% of COPD patients had low PAL, which was <1.5 metabolic equivalents multiplied by hour per day.,COPD patients with an mMRC grade ≥2, which was the most balanced cutoff point in the receiver operating characteristic curve, showed a higher reduction rate of PAL (80.0% at mMRC grade 2, 71.4% at mMRC grade 3, and 100% at mMRC grade 4).,PA differed according to the mMRC grade, and mMRC grade ≥2 could predict a low PAL.,Therefore, assessment of breathlessness by the mMRC questionnaire would be useful to stratify the risks of reduced PA in COPD. | The COPD Assessment Test (CAT™) is a new short health status measure for routine use.,New questionnaires require reference points so that users can understand the scores; descriptive scenarios are one way of doing this.,A novel method of creating scenarios is described.,A Bland and Altman plot showed a consistent relationship between CAT scores and scores obtained with the St George's Respiratory Questionnaire for COPD (SGRQ-C) permitting a direct mapping process between CAT and SGRQ items.,The severity associated with each CAT item was calculated using a probabilistic model and expressed in logits (log odds of a patient of given severity affirming that item 50% of the time).,Severity estimates for SGRQ-C items in logits were also available, allowing direct comparisons with CAT items.,CAT scores were categorised into Low, Medium, High and Very High Impact.,SGRQ items of corresponding severity were used to create scenarios associated with each category.,Each CAT category was associated with a scenario comprising 12 to 16 SGRQ-C items.,A severity 'ladder' associating CAT scores with exemplar health status effects was also created.,Items associated with 'Low' and 'Medium' Impact appeared to be subjectively quite severe in terms of their effect on daily life.,These scenarios provide users of the CAT with a good sense of the health impact associated with different scores.,More generally they provide a surprising insight into the severity of the effects of COPD, even in patients with apparently mild-moderate health status impact. | 1 |
In patients with chronic obstructive pulmonary disease, all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease.,Treatment recommendations are mostly built on results from randomized controlled trials (RCTs) whose methodology ensure internal validity.,However, their relevance may be compromised by the lack of generalizability, due to poor representability of study populations compared to real-life patients.,In order to delimit to whom the results of studies on current and future treatments apply, we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aiming at decreasing exacerbation risk.,We used the Initiatives-BPCO database, a French cohort of 1309 real-life COPD patients monitored in academic centers.,We identified industry-sponsored phase III and IV trials that enrolled more than 500 patients, lasted at least one year and used exacerbations related endpoints.,Eligibility criteria were extracted from each trial and applied to the patients.,The eligibility criteria of 16 RCTs were applied to the 1309 patients.,The most discriminating eligibility criteria were FEV1, minimum exacerbation rate in the previous year and smoking history, responsible for the exclusion of 39.9, 36.7 and 16.8% of patients, respectively.,Altogether, 2.3 to 46.7% of our patients would have satisfied all eligibility criteria.,These analyses confirm that an important gap exists between real-life patients and clinical trials populations in COPD, which limits the relevance of results and therefore should be considered when grading levels of evidence and designing future studies. | This multicenter, cross-sectional, non-interventional trial aimed to investigate adherence barriers to inhaled medicines when compared with oral medicines in Japanese patients with chronic obstructive pulmonary disease (COPD) and asthma.,The self-reporting “Adherence Starts with Knowledge 20” (ASK-20) questionnaire was administered for adherence barriers of inhaled and oral medicines to outpatients with regular clinic attendance.,Patients with COPD and asthma reported different adherence barriers to inhaled medicines.,Independent adherence barriers [odds ratio (95% confidence interval)] to inhaled medicines relative to those for oral medicines among patients with COPD and asthma were those related to item Q8 [“I know if I am reaching my health goals”; 2.49 (1.39-4.47); p=0.0022] and item Q2 [“I run out of my medicine because I do not get refills on time”; 2.69 (1.26-5.75); p=0.0127], respectively.,Among patients with poor adherence to only inhaled medicines, those with COPD and asthma recognized item Q3 [“consuming alcohol and taking medicines”; 6.63 (1.27-34.7); p<0.05] and item Q1 [“forget to take medicines only sometimes”; 4.29 (1.83-10.0); p<0.05], respectively, were recognized as independent adherence barriers to inhaled medicines.,The total ASK-20 scores and total barrier counts in patients with poor adherence to inhaled medicines were significantly higher than in those without poor adherence among patients with asthma (p=0.0057) but not those with COPD (p>0.05).,These results will aid in personalizing education on adherence to inhaled medicines among patients with COPD and asthma. | 1 |
Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria.,The optimum antibiotic choice remains unknown.,We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo.,This was a single-centre, single-blind, randomised placebo-controlled trial.,Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks.,The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance.,99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed.,After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI −0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (−0.33 to 0.55, p=0.62) with doxycycline and 0.08 (−0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively.,There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation.,More treatment-related adverse events occurred with moxifloxacin.,Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms.,Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy.,Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies.,clinicaltrials.gov (NCT01398072). | Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis.,Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD.,Despite current available therapies to control inflammation, neutrophilic bronchitis remains common.,This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load.,We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.,Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications.,Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment.,Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit.,Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment.,A sub-group of participants underwent chest computed tomography scans (n = 15).,Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL.,Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load.,The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062).,For participants who underwent chest CT scans, no alterations were observed.,In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load.,Future studies with a larger sample size are warranted.,Australian New Zealand Clinical Trials Registry ACTRN12609000259246 | 1 |
Patients with COPD using long-term oxygen therapy (LTOT) over 15 h per day have improved outcomes.,As inhalation of dry cold gas is detrimental to mucociliary clearance, humidified nasal high flow (NHF) oxygen may reduce frequency of exacerbations, while improving lung function and quality of life in this cohort.,In this randomised crossover study, we assessed short-term physiological responses to NHF therapy in 30 males chronically treated with LTOT.,LTOT (2-4 L/min) through nasal cannula was compared with NHF at 30 L/min from an AIRVO through an Optiflow nasal interface with entrained supplemental oxygen.,Comparing NHF with LTOT: transcutaneous carbon dioxide (TcCO2) (43.3 vs 46.7 mm Hg, p<0.001), transcutaneous oxygen (TcO2) (97.1 vs 101.2 mm Hg, p=0.01), I:E ratio (0.75 vs 0.86, p=0.02) and respiratory rate (RR) (15.4 vs 19.2 bpm, p<0.001) were lower; and tidal volume (Vt) (0.50 vs 0.40, p=0.003) and end-expiratory lung volume (EELV) (174% vs 113%, p<0.001) were higher.,EELV is expressed as relative change from baseline (%Δ).,Subjective dyspnoea and interface comfort favoured LTOT.,NHF decreased TcCO2, I:E ratio and RR, with a concurrent increase in EELV and Vt compared with LTOT.,This demonstrates a potential mechanistic rationale behind the improved outcomes observed in long-term treatment with NHF in oxygen-dependent patients.,ACTRN12613000028707. | Oxygen therapy improves survival and function in severely hypoxemic chronic obstructive pulmonary disease (COPD) patients based on two landmark studies conducted over 40 years ago.,We hypothesize that oxygen users in the current era may be very different.,We examined trends and subject characteristics associated with oxygen therapy use from 2001-2010 in the United States.,We examined Medicare beneficiaries with COPD who received oxygen from 2001 to 2010.,COPD subjects were identified by: 1) ≥2 outpatient visits >30 days apart within one year with an encounter diagnosis of COPD; or 2) an acute care hospitalization with COPD as the primary or secondary discharge diagnosis.,Oxygen therapy and sustained oxygen therapy were defined as ≥1 and ≥11 claims for oxygen, respectively, in the durable medical equipment file in a calendar year.,Primary outcome measures were factors associated with oxygen therapy and sustained oxygen therapy over the study period.,Oxygen therapy increased from 33.7% in 2001 to 40.5% in 2010 (p-value of trend <0.001).,Sustained oxygen therapy use increased from 19.5% in 2001, peaked in 2008 to 26.9% and declined to 18.5% in 2010.,The majority of subjects receiving oxygen therapy and sustained oxygen therapy were female.,Besides gender, factors associated with any oxygen use or sustained oxygen therapy were non-Hispanic white race, low socioeconomic status and ≥2 comorbidities.,Any oxygen use among fee-for service Medicare beneficiaries with COPD is high.,Current users of oxygen are older females with multiple comorbidities.,Decline in sustained oxygen therapy use after 2008 may be related to reimbursement policy change. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) who are defined as frequent exacerbators suffer with 2 or more exacerbations every year.,The molecular mechanisms responsible for this phenotype are poorly understood.,We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort.,Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR) testing.,Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01) between frequent compared to non-exacerbators.,In sputum cells, only 6 genes were differentially expressed.,The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes.,Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10.,The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively.,There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations. | 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 |
Neutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined.,We sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function.,NET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome.,Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation.,Sputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001).,This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002).,Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01).,Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes.,Consistent results were observed regardless of the method of quantifying sputum NETs.,Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD.,NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity. | Small-airway remodelling is one of the most remarkable pathological features of chronic obstructive pulmonary disease (COPD), in which angiogenesis plays a critical role that contributes to disease progression.,The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF), as well as its receptors, VEGFR1, VEGFR2, are thought to be the major mediators of pathological angiogenesis, and sunitinib exhibits anti-angiogenesis property through VEGF blockage and has been widely used to treat various cancers.,In our study, Sprague-Dawley rats were subjected to lipopolysaccharide (LPS) injection and cigarette smoke (CS) inhalation to induce COPD, following sunitinib administration was conducted.,Haematoxylin-eosin, Masson staining and immunostaining analysis were used to evaluate the pathological changes; quantitative real-time PCR and enzyme-linked immunosorbent assay were performed to provide more compelling data on the function of VEGF, VEGFR1, VEGFR2 in angiogenesis.,Sunitinib treatment was associated with less angiogenesis in small-airway remodelling with a slightly disordered lung architecture, and lower expression level of VEGF, VEGFR1, VEGFR2.,Overall, our results indicate that VEGF is a vital important factor that contributes to the small-airway remodelling in a rat model of COPD through promoting angiogenesis, which mainly depend on the specific binding between VEGF and VEGFR1 and can be effectively attenuated by sunitinib. | 1 |
In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations.,We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥1 exacerbation in the 12 months prior to the study.,Patients received BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice-daily.,Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study.,Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study.,BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups.,The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI.,In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results.,The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count.,In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations. | Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and mortality.,Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties.,Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs.,We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs.,The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year.,Nine RCTs comprising 1666 patients met the inclusion criteria.,Pooled evidence showed macrolides could reduce the frequency of exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56-0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43-0.78, P < 0.01).,Subgroup analysis showed only 6-12 months of erythromycin or azithromycin therapy could be effective.,Moreover, among studies with 6-12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates.,The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups.,A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003-2.39, P = 0.049).,Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD.,However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance.,A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages. | 1 |
Matrix metalloproteinases (MMPs) and C-reactive protein (CRP) are involved in chronic obstructive pulmonary disease (COPD) pathogenesis.,The aim of the present work was to determine plasma concentrations of MMPs and CRP in COPD associated to biomass combustion exposure (BE) and tobacco smoking (TS).,Pulmonary function tests, plasma levels of MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP were measured in COPD associated to BE (n = 40) and TS (n =40) patients, and healthy non-smoking (NS) healthy women (controls, n = 40).,Plasma levels of MMP-1, MMP-7, MMP-9, and MMP-9/TIMP-1 and CRP were higher in BE and TS than in the NS healthy women (p <0.01).,An inverse correlation between MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP plasma concentrations and FEV1 was observed.,Increase of MMPs and CRP plasma concentrations in BE suggests a systemic inflammatory phenomenon similar to that observed in COPD associated to tobacco smoking, which may also play a role in COPD pathogenesis. | A growing body of evidence indicates that matrix metalloproteinases (MMPs) play a role in the pathogenesis of COPD.,Therefore, we conducted a candidate gene association study of 4 promoter polymorphisms that are known to modify expression levels of the MMP-1, MMP-2, and MMP-9 genes and a Gln279Arg polymorphism in exon 6 of MMP-9 that modifies the substrate-binding region.,We examined the association of each variant and haplotypes in 385 male veterans with greater than 20 pack-years of cigarette smoking whose COPD status was characterized using spirometry.,The association of these polymorphisms was also examined with decline of pulmonary function in a subset of participants.,Only the 279Arg variant was more common in participants with COPD and the homozygous variant was associated with a 3-fold increased risk for COPD.,In the haplotype analysis, the haplotype comprising the 249Arg and the CA promoter polymorphism within the MMP-9 gene was associated with risk, suggesting that either 279Arg or a linked variant on this haplotype underlies the association.,No association of this polymorphism was found with decline in pulmonary function.,These studies show that variants of the MMP-9 gene are associated with COPD in this cohort of veterans. | 1 |
Inhaled corticosteroids (ICS) have been associated with decreased lung cancer risk.,However, they have been associated with pulmonary infections (tuberculosis [TB] and pneumonia) in patients with chronic obstructive pulmonary disease (COPD).,TB and pneumonia have increased lung cancer risk.,The association between post-ICS pulmonary infections and lung cancer remains unclear.,We conducted a retrospective cohort study from 2003 to 2010 using the Taiwan National Health Insurance Research Database.,Among the 1,089,955 patients with COPD, we identified 8813 new users of ICS prescribed for a period of 3 months or more and 35,252 non-ICS users who were randomly matched for sex, age and date of ICS use from 2003 to 2005.,Cox proportional hazard regression was used to estimate the hazard ratio (HR) of pulmonary infections in patients with/without ICS use.,The HRs for lung cancer in ICS users with sequential lung infections were as follows; 2.42 (95 % confidence interval [CI], 1.28-4.58) for individuals with TB, 2.37 (95 % CI, 1.01-5.54) for TB and pneumonia, and 1.17(95 % CI, 0.69-1.98) for those with pneumonia.,For non-ICS users with pulmonary infections, the HRs were 1.68 (95 % CI, 0.78-3.65) for individual with TB and pneumonia, 1.42 (95 % CI, 0.89-2.26) for TB, and 0.95 (95 % CI, 0.62-1.46) for individuals with pneumonia.,COPD patients with TB /or pneumonia who used ICS had increased risk of lung cancer.,Because the overall prognosis of lung cancer remains poor, screening tests are recommended for patients with these conditions. | Background: Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations.,The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.,Objective: This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.,Methods: This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico.,After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo.,Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1.,Results: Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001).,The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p ≤ 0.004).,Both budesonide/formoterol doses were more effective than placebo (p ≤ 0.006) for controlling dyspnoea and improving health status (St George’s Respiratory Questionnaire).,All treatments were generally well tolerated.,The incidence of pneumonia was not different for active (3.4-4.0%) and placebo (5.0%) groups.,Conclusions: Budesonide/formoterol pMDI (320/9 μg and 160/9 μg) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD.,Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co-primary variables compared with formoterol DPI 9 μg.,Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo.,Supplementary material is available for this article at 10.2165/00003495-200969050-00004 and is accessible for authorized users. | 1 |
Exercise training improves exercise tolerance in chronic obstructive pulmonary disease (COPD).,Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation, one of the pathophysiological factors contributing to exertional dyspnea in COPD patients.,To determine whether tiotropium enhances the effects of exercise training in patients with COPD.,Multicenter, 25 week randomized, double-blind, placebo-controlled, parallel-group study.,Twelve Italian Pulmonary Units practicing pulmonary rehabilitation.,Two hundred thirty four COPD patients (196 males; mean age: 67.4 ± 7.6; forced expiratory volume at 1 second (FEV1): 41.4 ± 13.0% predicted) were randomised to tiotropium 18 μg or placebo inhalation capsules taken once daily.,Both groups underwent a 8 week pulmonary rehabilitation program (PR) consisting of 3 exercise training session per week.,Baseline, at the end of PR and after 12 weeks, patients completed pulmonary function testing, six minute walking test (6MWT), the Baseline and Transition Dyspnea Index (BDI and TDI), and the St.,George’s Respiratory Questionnaire (SGRQ).,Relative to placebo, tiotropium had larger trough and post-study drug FEV1 responses on all test days.,At the end of and 12 weeks following PR, patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo.,Compared to the period immediately prior to PR, the mean improvement in 6MWT was only 29.7 meters (7.1%) for the combined cohort.,Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo (p < 0.01).,At 12 weeks after PR, TDI focal scores were 2.71 for tiotropium and 2.11 for placebo (p = 0.16).,Reduction in all four SGRQ component scores, indicating an improvement in health-related quality of life, was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant.,During the study period, there were fewer exacerbations and exacerbation days in the tiotropium group.,Although significant improvements were observed with perceived dyspnea, compared to placebo, the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT. | Inspiratory muscle weakness in patients with COPD is of major clinical relevance.,For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD.,Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening.,However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature.,Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness.,The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers.,Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury.,This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD.,Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities.,Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD. | 1 |
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. | Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV1).,Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS) but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered.,We analyzed decline in post-bronchodilator FEV1 and gas transfer (% predicted) over at least 3 years (mean= 6.11, 95% CI 5.80-6.41) in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ) to determine individual rates of decline, implications for prognosis, and potential clinical management.,There was a marked variation in individual rates of FEV1 decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without) to those of rapidly declining COPD.,Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD).,There was no correlation between decline in gas transfer and FEV1 for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025).,These data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management. | 1 |
The characteristics and natural history of GOLD B COPD patients are not well described.,The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed.,We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression.,Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter.,Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed.,Students t tests and Mann Whitney-U tests were used.,One hundred seven (28.9%) of patients were categorised as GOLD B at baseline.,These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted).,More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A.,At 12 months, 25.3% of GOLD B patients progressed to GOLD D.,These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B.,Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline.,A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.,The online version of this article (doi:10.1186/s12890-017-0384-8) contains supplementary material, which is available to authorized users. | Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient’s health-related quality of life (HRQL).,While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health.,This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George’s Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments.,Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions.,Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences.,In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease.,Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions.,The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions.,For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL.,All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities.,Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.,The online version of this article (doi:10.1186/s12890-016-0238-9) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide.,Genetic risk loci provide novel insights into disease pathogenesis.,We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.,We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function.,Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium.,Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types.,We found 14 COPD loci shared with either asthma or pulmonary fibrosis.,COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations.,Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD. | Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis.,The decisive cellular events at early stages of IPF are poorly understood.,While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis.,In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP).,Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion.,These results were corroborated by immunogold labeling for Cldn10.,Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs.,Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities.,Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF. | 1 |
Sputum and blood eosinophil counts predict corticosteroid effects in COPD patients.,Bacterial infection causes increased airway neutrophilic inflammation.,The relationship of eosinophil counts with airway bacterial load in COPD patients is uncertain.,We tested the hypothesis that bacterial load and eosinophil counts are inversely related.,COPD patients were seen at stable state and exacerbation onset.,Sputum was processed for quantitative polymerase chain reaction detection of the potentially pathogenic microorganisms (PPM) H. influenzae, M. catarrhalis and S. pneumoniae.,PPM positive was defined as total load ≥1 × 104copies/ml.,Sputum and whole blood were analysed for differential cell counts.,At baseline, bacterial counts were not related to blood eosinophils, but sputum eosinophil % was significantly lower in patients with PPM positive compared to PPM negative samples (medians: 0.5% vs.,1.25% respectively, p = 0.01).,Patients with PPM positive samples during an exacerbation had significantly lower blood eosinophil counts at exacerbation compared to baseline (medians: 0.17 × 109/L vs.,0.23 × 109/L respectively, p = 0.008), while no blood eosinophil change was observed with PPM negative samples.,These findings indicate an inverse relationship between bacterial infection and eosinophil counts.,Bacterial infection may influence corticosteroid responsiveness by altering the profile of neutrophilic and eosinophilic inflammation.,The online version of this article (doi:10.1186/s12931-017-0570-5) contains supplementary material, which is available to authorized users. | Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology.,We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression.,A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry.,Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression.,Physiological and CT measures indicated disease progression in the whole group.,In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37).,LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38).,The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice. | 1 |
Events of the past decade have stimulated development of new drug formulations and delivery devices that have improved the efficiency, ease of use, and environmental impact of inhaled drug therapy.,Respimat® Soft Mist™ Inhaler is a novel, multidose, propellant-free, hand-held, liquid inhaler that represents a new category of inhaler devices.,The aerosol cloud generated by Respimat contains a higher fraction of fine particles than most pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), and the aerosol spray exits the inhaler more slowly and for a longer duration than with pMDIs.,This translates into higher lung drug deposition and lower oropharyngeal deposition, making it possible to give lower nominal doses of delivered drugs without lowering efficacy.,In clinical trials in patients with COPD, bronchodilator drugs delivered from Respimat were equally effective at half of the dose delivered from a pMDI.,In one study of inhaler preference, Respimat was preferred over the pMDI by patients with COPD and other obstructive lung diseases.,Respimat is a valuable addition to the range of inhaler devices available to the patient with COPD. | Formoterol is a beta2-agonist that has both short and long acting bronchodilator effects.,Beta2-agonists used as bronchodilators have been synthesized as racemates that comprise (R,R) and (S,S)-enantiomers.,Compounds that are beta2-selective derive their bronchodilator effect from an interaction between the (R,R)-enantiomer and the beta2-adrenoceptor.,Arformoterol is the (R,R)-enantiomer and is distinguished from the more commonly used racemic (RR/S,S)-diasteriomer of formoterol.,Overall literature on the use of arformoterol in COPD is very preliminary.,There is some in vitro data that demonstrate significant bronchodilation and inhibition of inflammation with arformoterol, and these effects may be more pronounced than those caused by racemic formoterol.,There are limited clinical trial data that demonstrate that arformoterol produces significant improvement in lung function in COPD; however, many of the subjects involved had marked baseline airway reversibility.,Arformoterol has been very well tolerated in clinical trials and could potentially be used only once every 24 hours (due to its prolonged effect).,It can only be given in nebulized form.,Arformoterol can potentially be given with other inhaled medications. | 1 |
Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure.,Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated.,We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies.,Lymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6 months.,B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses.,Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation.,Lymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy.,These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression.,Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure.,Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3-nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression.,Hydrogen peroxide induced BAFF protein in mouse macrophage cell line.,In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males.,Chronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment. | COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020.,It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation.,This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion.,The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood.,Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease.,Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD.,Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies.,The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD. | 1 |
The global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and it has become a major public health burden worldwide, including in Vietnam.,A large body of preclinical and clinical studies supports the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of lung injury, including COPD.,The aim of this trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) as a supplementary intervention in combination with standard COPD medication treatments in patients with moderate-to-severe COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 and Vietnam Ministry of Health’s guidelines.,This matched case-control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between June 2020 and December 2021.,In this study, 40 patients will be enrolled and assigned into two age-matched, gender-matched and COPD condition-matched groups, including a UC-MSC group and a control group.,Both groups will receive standard COPD medication treatment based on the GOLD 2019 guidelines and the Vietnam Ministry of Health protocol.,The UC-MSC group will receive two doses of thawed UC-MSC product with an intervention interval of 3 months.,The primary outcome measures will include the incidence of prespecified administration-associated adverse events and serious adverse events.,The efficacy will be evaluated based on the absolute changes in the number of admissions, arterial blood gas analysis, lung function and lung fibrosis via CT scan and chest X-ray.,The clinical evaluation will be conducted at baseline and 3, 6 and 12 months postintervention.,Ethical approval was secured from the Ethical Committee of Vinmec International Hospital (number:166/2019/QĐ-VMEC) and Vietnam Ministry of Health (number:2002/QĐ-BYT).,The results will be reported to trial collaborators, publication in peer-reviewed academic journals.,NCT04433104. | We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD.,While safety profile was good, no functional efficacy was observed.,However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.,Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.,In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion.,Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L.,These improvements persisted variably over the 2-year observational period.,No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.,In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements.,These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.,Trial registration: Clinicaltrials.gov NCT00683722. | 1 |
Chronic obstructive pulmonary disease (COPD) and asthma are common diseases with a heterogeneous distribution worldwide.,Here, we present methods and disease and risk estimates for COPD and asthma from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 study.,The GBD study provides annual updates on estimates of deaths, prevalence, and disability-adjusted life years (DALYs), a summary measure of fatal and non-fatal disease outcomes, for over 300 diseases and injuries, for 188 countries from 1990 to the most recent year.,We estimated numbers of deaths due to COPD and asthma using the GBD Cause of Death Ensemble modelling (CODEm) tool.,First, we analysed data from vital registration and verbal autopsy for the aggregate category of all chronic respiratory diseases.,Subsequently, models were run for asthma and COPD relying on covariates to predict rates in countries that have incomplete or no vital registration data.,Disease estimates for COPD and asthma were based on systematic reviews of published papers, unpublished reports, surveys, and health service encounter data from the USA.,We used the Global Initiative of Chronic Obstructive Lung Disease spirometry-based definition as the reference for COPD and a reported diagnosis of asthma with current wheeze as the definition of asthma.,We used a Bayesian meta-regression tool, DisMod-MR 2.1, to derive estimates of prevalence and incidence.,We estimated population-attributable fractions for risk factors for COPD and asthma from exposure data, relative risks, and a theoretical minimum exposure level.,Results were stratified by Socio-demographic Index (SDI), a composite measure of income per capita, mean years of education over the age of 15 years, and total fertility rate.,In 2015, 3·2 million people (95% uncertainty interval [UI] 3·1 million to 3·3 million) died from COPD worldwide, an increase of 11·6% (95% UI 5·3 to 19·8) compared with 1990.,There was a decrease in age-standardised death rate of 41·9% (37·7 to 45·1) but this was counteracted by population growth and ageing of the global population.,From 1990 to 2015, the prevalence of COPD increased by 44·2% (41·7 to 46·6), whereas age-standardised prevalence decreased by 14·7% (13·5 to 15·9).,In 2015, 0·40 million people (0·36 million to 0·44 million) died from asthma, a decrease of 26·7% (−7·2 to 43·7) from 1990, and the age-standardised death rate decreased by 58·8% (39·0 to 69·0).,The prevalence of asthma increased by 12·6% (9·0 to 16·4), whereas the age-standardised prevalence decreased by 17·7% (15·1 to 19·9).,Age-standardised DALY rates due to COPD increased until the middle range of the SDI before reducing sharply.,Age-standardised DALY rates due to asthma in both sexes decreased monotonically with rising SDI.,The relation between with SDI and DALY rates due to asthma was attributed to variation in years of life lost (YLLs), whereas DALY rates due to COPD varied similarly for YLLs and years lived with disability across the SDI continuum.,Smoking and ambient particulate matter were the main risk factors for COPD followed by household air pollution, occupational particulates, ozone, and secondhand smoke.,Together, these risks explained 73·3% (95% UI 65·8 to 80·1) of DALYs due to COPD.,Smoking and occupational asthmagens were the only risks quantified for asthma in GBD, accounting for 16·5% (14·6 to 18·7) of DALYs due to asthma.,Asthma was the most prevalent chronic respiratory disease worldwide in 2015, with twice the number of cases of COPD.,Deaths from COPD were eight times more common than deaths from asthma.,In 2015, COPD caused 2·6% of global DALYs and asthma 1·1% of global DALYs.,Although there are laudable international collaborative efforts to make surveys of asthma and COPD more comparable, no consensus exists on case definitions and how to measure disease severity for population health measurements like GBD.,Comparisons between countries and over time are important, as much of the chronic respiratory burden is either preventable or treatable with affordable interventions.,Bill & Melinda Gates Foundation. | Recently, variations in a component of high-density lipoprotein (HDL), namely apolipoprotein M (apoM), were found to be associated with chronic obstructive pulmonary disease (COPD).,The aim of this study was to evaluate the association between apoM and COPD severity.,Factors associated with apoM, COPD, or coronary artery disease (CAD) were also assessed.,A total of 110 COPD patients and 110 age- and sex-matched non-COPD controls were included.,Among them, thirty COPD patients and seven non-COPD controls had CAD.,ApoM and pentraxin-3 levels were measured by ELISA.,Additionally, the levels of high-sensitivity C-reactive protein (hs-CRP), cholesterol, and triglyceride were assessed using an automatic biochemical analyzer.,Serum apoM levels increased gradually with COPD severity, with the most prominent apoM elevation observed in very severe COPD cases.,In addition, ApoM was correlated with percent-predicted forced expiratory volume in one second (% predicted FEV1) (r = −0.38, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (r = 0.23, P < 0.017), and hs-CRP (r = 0.24, P = 0.01) in COPD patients.,Furthermore, apoM was shown to be a risk factor for COPD onset (OR = 1.095, 95 % CI = 1.034-1.160, P = 0.002), but not associated with CAD in COPD patients.,Serum apoM was elevated in COPD patients and increased gradually with COPD severity.,However, there was no association between apoM and CAD development in COPD patients.,The online version of this article (doi:10.1186/s12944-016-0228-1) contains supplementary material, which is available to authorized users. | 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. | Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways.,Although IL-17A contributes to many chronic inflammatory diseases, it’s role in the inflammatory response of elastase-induced emphysema remains unclear.,In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.,Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice.,Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta.,Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment.,These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema.,Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression. | 1 |
In respiratory disorders, patient- and physician-perceived satisfaction with the maintenance inhaler device is an important factor driving treatment compliance and outcomes.,We examine inhaler preferences in asthma and COPD from patient and physician perspectives, particularly focusing on the relative importance of individual device attributes and patient characteristics guiding inhaler choice.,Real-world data from >7,300 patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS) consulting for routine care were derived from respiratory Disease Specific Programs conducted in Europe, USA, Japan, and China.,Outcome variables included current pattern of inhaled maintenance therapy and device type, physician preference, patient-reported device attribute importance, and satisfaction.,The most commonly prescribed inhalers for maintenance therapy of asthma, COPD, and ACOS were dry powder inhalers (62.8%-88.5% of patients) and pressurized metered dose inhalers (18.9%-35.3% of patients).,One-third of physicians stated no preference for maintenance device when prescribing treatment, and less than one-third of patients reported being “extremely satisfied” with any attribute of their device.,Instructions being “simple and easy to follow” was the inhaler attribute most commonly selected as important.,For approximately one-third of patients across all groups, “ease of use/suitability of inhaler device” was a reason for the prescribing decision, as stated by the physician.,Device characteristics were more likely to impact the prescribing decision in older patients (in asthma and COPD; P<0.01) and those with worse disease severity (in COPD; P<0.001).,A relatively high proportion of physicians had no preference for inhaler type across asthma, COPD, and ACOS.,Simplicity of use was the most important inhaler attribute from a patient’s perspective.,Physicians appeared to place most importance on ease of use and device suitability when selecting inhalers for older patients and those with more severe disease, particularly in COPD. | Arformoterol is the (R,R)-enantiomer of formoterol.,Preclinical studies suggest that it is a stronger bronchodilator than the racemic (R,R/S,S)-formoterol; however, its potential clinical advantages have not been demonstrated.,This study compared the length of stay (LOS), 30-day readmission rates, and doses of rescue medication administered in hospitalized patients with COPD who were treated with nebulized arformoterol or nebulized formoterol.,This retrospective analysis utilized data from Premier, Inc.,(Charlotte, NC, USA), the largest nationwide hospital-based administrative database.,COPD patients ≥40 years of age were included if they were hospitalized between January 2011 and July 2014, had no asthma diagnoses, and were treated with nebulized arformoterol or nebulized formoterol.,LOS was measured from the day the patients initiated the study medication (index day).,Rescue medications were defined as short-acting bronchodilators used from the index day onward.,Multivariate statistical models included a random effect for hospital and controlled for patient demographics, hospital characteristics, admission characteristics, prior hospitalizations, comorbidities, pre-index service use, and pre-index medication use.,A total of 7,876 patients received arformoterol, and 3,612 patients received nebulized formoterol.,There was no significant difference in 30-day all-cause (arformoterol =11.9%, formoterol =12.1%, odds ratio [OR] =0.981, P=0.82) or COPD-related hospital readmission rates (arformoterol =8.0%, formoterol =8.0%, OR =1.002, P=0.98) after adjusting for covariates.,The adjusted mean LOS was significantly shorter for arformoterol-treated vs formoterol-treated patients (4.6 vs 4.9 days, P=0.039), and arformoterol-treated patients used significantly fewer doses of rescue medications vs formoterol-treated patients (5.9 vs 6.6 doses, P=0.006).,During inpatient stays, treating with arformoterol instead of nebulized formoterol may lead to shorter LOS and lower rescue medication use. | 1 |
Chronic infections are associated with exacerbation in patients with chronic obstructive pulmonary disease (COPD).,The major objective of the management of these patients is the prevention and effective treatment of exacerbations.,Patients that have increased sputum production, associated with purulence and worsening shortness of breath, are the ones that will benefit from antibiotic therapy.,It is important to give the appropriate antibiotic therapy to prevent treatment failure, relapse, and the emergence of resistant pathogens.,In some patients, systemic corticosteroids are also indicated to improve symptoms.,In order to identify which patients are more likely to benefit from these therapies, clinical guidelines recommend stratifying patients based on their risk factor associated with poor outcome or recurrence.,It has been identified that patients with more severe disease, recurrent infection and presence of purulent sputum are the ones that will be more likely to benefit from this therapy.,Another approach related to disease prevention could be the use of prophylactic antibiotics during steady state condition.,Some studies have evaluated the continuous or the intermittent use of antibiotics in order to prevent exacerbations.,Due to increased bacterial resistance to antibiotics and the presence of side effects, several antibiotics have been developed to be nebulized for both treatment and prevention of acute exacerbations.,There is a need to design long-term studies to evaluate these interventions in the natural history of the disease.,The purpose of this publication is to review our understanding of the role of bacterial infection in patients with COPD exacerbation, the role of antibiotics, and future interventions. | Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high.,The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care.,We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools.,The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014.,Consecutive admissions were identified by screening admissions and searching coding records.,Admission clinical data, including DECAF indices, and mortality were recorded.,The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve.,In the internal and external validation cohorts, 880 and 845 patients were recruited.,Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted.,Overall mortality was 7.7%.,The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality.,DECAF is a robust predictor of mortality, using indices routinely available on admission.,Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0-1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3-6) for escalation planning or appropriate early palliation.,UKCRN ID 14214. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD) are episodes of worsening of symptoms, leading to substantial morbidity and mortality.,COPD exacerbations are associated with increased airway and systemic inflammation and physiological changes, especially the development of hyperinflation.,They are triggered mainly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation.,Some patients are particularly susceptible to exacerbations, and show worse health status and faster disease progression than those who have infrequent exacerbations.,Several pharmacological interventions are effective for the reduction of exacerbation frequency and severity in COPD such as inhaled steroids, long-acting bronchodilators, and their combinations.,Non-pharmacological therapies such as pulmonary rehabilitation, self-management, and home ventilatory support are becoming increasingly important, but still need to be studied in controlled trials.,The future of exacerbation prevention is in assessment of optimum combinations of pharmacological and non-pharmacological therapies that will result in improvement of health status, and reduction of hospital admission and mortality associated with COPD. | COPD is a significant cause of morbidity and mortality.,In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation.,Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy.,In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention.,In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13.,The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions.,We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. | 1 |
The effects of chronic inhaled and systemic corticosteroids use on COVID-19 susceptibility and severity are unclear.,Since many patients with chronic pulmonary diseases rely on corticosteroids to control disease, it is important to understand the risks of their use during the pandemic.,We aim to study if the use of inhaled or systemic corticosteroids affects the likelihood of developing COVID-19 infection.,We used the National Jewish Health electronic medical record research database to identify a cohort of all subjects who were tested for suspected COVID-19 between March 11 - June 23, 2020.,Testing results, medication use, and comorbidities were obtained from the medical record.,Following a comparison of different propensity score weighting methods, overlap propensity score weighting was used to analyze the association between medication use and COVID-19 diagnosis.,The cohort consisted of 928 patients, of which 12% tested positive.,The majority (66%) of patients had a history of chronic pulmonary diseases.,There was no significant association between inhaled corticosteroid use and testing positive for COVID-19.,Interestingly, systemic corticosteroid use was associated with a lower odds ratio (0.95, 95% CI: 0.91-0.99) of testing positive for COVID-19.,Similar results were noted when the analysis was restricted to those with any chronic pulmonary diseases, with asthma or with chronic obstructive pulmonary disease (COPD).,Our study supports the recommendation that patients with chronic pulmonary diseases, including asthma and COPD who require treatment with either inhaled or systemic corticosteroids, should continue their use during the COVID-19 pandemic. | The aim of this study is to quantify the burden of chronic obstructive pulmonary disease (COPD) - incidence, prevalence, and mortality - and identify trends in Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America.,A structured literature search was performed (January 2000 to September 2010) of PubMed and EMBASE, identifying English-language articles reporting COPD prevalence, incidence, or mortality.,Of 2838 articles identified, 299 full-text articles were reviewed, and data were extracted from 133 publications.,Prevalence data were extracted from 80 articles, incidence data from 15 articles, and mortality data from 58 articles.,Prevalence ranged from 0.2%-37%, but varied widely across countries and populations, and by COPD diagnosis and classification methods.,Prevalence and incidence were greatest in men and those aged 75 years and older.,Mortality ranged from 3-111 deaths per 100,000 population.,Mortality increased in the last 30-40 years; more recently, mortality decreased in men in several countries, while increasing or stabilizing in women.,Although COPD mortality increased over time, rates declined more recently, likely indicating improvements in COPD management.,In many countries, COPD mortality has increased in women but decreased in men.,This may be explained by differences in smoking patterns and a greater vulnerability in women to the adverse effects of smoking.,Point your SmartPhone at the code above.,If you have a QR code reader the video abstract will appear.,Or use: http://dvpr.es/Nl3LKT | 1 |
Loss of skeletal muscle mitochondrial oxidative capacity is well-established in patients with COPD, but the role of mitochondrial breakdown herein is largely unexplored.,Currently, we studied if mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients and associates with the loss of mitochondrial content, and whether it is affected in patients with iron deficiency (ID) or systemic inflammation.,Therefore, mitophagy, autophagy, mitochondrial dynamics and content markers were analysed in vastus lateralis biopsies of COPD patients (N = 95, FEV1% predicted: 39.0 [31.0-53.6]) and healthy controls (N = 15, FEV1% predicted: 112.8 [107.5-125.5]).,Sub-analyses were performed on patients stratified by ID or C-reactive protein (CRP).,Compared with controls, COPD patients had lower muscle mitochondrial content, higher BNIP3L and lower FUNDC1 protein, and higher Parkin protein and gene-expression.,BNIP3L and Parkin protein levels inversely correlated with mtDNA/gDNA ratio and FEV1% predicted.,ID-COPD patients had lower BNIP3L protein and higher BNIP3 gene-expression, while high CRP patients had higher BNIP3 and autophagy-related protein levels.,In conclusion, our data indicates that mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients, and is related to disease severity and loss of mitochondrial content.,Moreover, systemic inflammation is associated with higher BNIP3 and autophagy-related protein levels. | Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology.,Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome.,We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype.,We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study.,PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity.,PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location.,PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques. | 1 |
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. | COPD accounts for the highest rate of hospital admissions among major chronic diseases.,COPD hospitalizations are associated with impaired quality of life, high health care utilization, and poor prognosis and result in an economic and a social burden that is both substantial and increasing.,The aim of this study is to determine the efficacy of a comprehensive case management program (CCMP) in reducing length of stay (LOS) and risk of hospital admissions and readmissions in patients with COPD.,We retrospectively compared outcomes across five large hospitals in Vancouver, BC, Canada, following the implementation of a systems approach to the management of COPD patients who were identified in the hospital and followed up in the community for 90 days.,We compared numbers, rates, and intervals of readmission and LOS during 2 years of active program delivery compared to 1 year prior to program implementation.,A total of 1,564 patients with a clinical diagnosis of COPD were identified from 2,719 hospital admissions during the 3 years of study.,The disease management program reduced COPD-related hospitalizations by 30% and hospitalizations for all causes by 13.6%.,Similarly, the rate of readmission for all causes showed a significant decline, with hazard ratios (HRs) of 0.55 (year 1) and 0.51 (year 2) of intervention (P<0.001).,In addition, patients’ mean LOS (days) for COPD-related admissions declined significantly from 10.8 to 6.8 (P<0.05).,A comprehensive disease management program for COPD patients, including education, case management, and follow-up, was associated with significant reduction in hospital admissions and LOS. | 1 |
This longitudinal, retrospective cohort study of patients with COPD describes baseline characteristics, adherence, and persistence following initiation of inhaled corticosteroids (ICS)/long-acting β2-agonists (LABA)/long-acting muscarinic antagonists (LAMA) from multiple inhaler triple therapy (MITT).,Patients aged ≥40 years receiving MITT between January 2012 and September 2015 were identified from the IQVIA™ Real-world Data Adjudicated Claims-USA database.,MITT was defined as subjects with ≥1 overlapping days’ supply of three COPD medications (ICS, LABA, and LAMA).,Adherence (proportion of days covered, PDC) and discontinuation (defined as a gap of 1, 30, 60, or 90 days of supply in any of the three components of the triple therapy) were calculated for each patient over 12 months of follow-up.,In addition, analyses were stratified by number of inhalers.,In total, 14,635 MITT users were identified (mean age, 62 years).,Mean PDC for MITT at 12 months was 0.37%.,Mean PDC for the ICS/LABA and LAMA component at 12 months was 49% (0.49±0.31; median, 0.47) and 54% (0.54±0.33; 0.56), respectively.,The proportion of adherent patients (PDC ≥0.8) at 12 months was 14% for MITT.,Allowing for a 30-day gap from last day of therapy, 86% of MITT users discontinued therapy during follow-up.,Patients with COPD had low adherence to and persistence with MITT in a real-world setting.,Mean PDC for each single inhaler component was higher than the mean PDC observed with MITT.,Reducing the number of inhalers may improve overall adherence to intended triple therapy. | The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals’ lives may be substantial, yet clinical practice often focuses only on symptoms.,We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals.,Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database.,Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group).,A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment).,Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18).,“Shortness of breath” was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone.,Reported physical impacts included the inability to sleep and socialize, while emotional impacts included “embarrassment, stigma, and/or self-consciousness”, “fear and/or panic”, and “sadness, anxiety, and/or depression”.,Coping mechanisms for normal activities included continuing at reduced pace and avoidance.,Treatment preferences centered on resolving impacts; improved sleep, “speed of action”, and “length of relief” were the most frequently reported ideal treatment factors.,Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se.,Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey.,GSK funded study (H0-15-15502/204821).,The online version of this article (doi:10.1007/s12325-017-0557-0) contains supplementary material, which is available to authorized users. | 1 |
No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD).,Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.,Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors.,Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.,236 COPD patients from five European centres were included.,Results indicated the concept of physical activity in COPD had two domains, labelled “amount” and “difficulty”.,After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14.,Both demonstrated good model fit (person separation index >0.7).,Confirmatory factor analysis supported the bidimensional structure.,Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.,Daily and clinical visit “PROactive physical activity in COPD” instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.,Both PROactive hybrid tools are simple, valid, and reliable measures of physical activity in COPD patientshttp://ow.ly/LJqP8 | 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 |
The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components.,Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown.,The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands.,A cost-utility study was performed, using an individual-level Markov model.,To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial.,In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium.,Cost-utility analysis was performed from the Dutch health care payer’s perspective using a 15-year time horizon in the base-case analysis.,The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%).,Both univariate and probabilistic sensitivity analyses were performed.,Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence.,As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY.,Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY.,Results were robust in univariate and probabilistic sensitivity analyses.,Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence.,Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively.,Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds. | Chronic obstructive pulmonary disease (COPD) is a major burden for the health care system, but the exact costs are difficult to estimate and there are insufficient data available on past and future time trends of COPD-related costs.,The aim of the study was to calculate COPD-related costs in Finland during the years 1996-2006 and estimate future costs for the years 2007-2030.,COPD-related direct and indirect costs in the public health care sector of the whole of Finland during the years 1996-2006 were retrieved from national registers.,In addition, we made a mathematical prediction model on COPD costs for the years 2007-2030 on the basis of population projection and changes in smoking habits.,The total annual COPD-related costs amounted to about 100-110 million Euros in 1996-2006, with no obvious change, but there was a slight decrease in direct costs and an increase in indirect costs during these years.,The estimation model predicted a 60% increase up to 166 million Euros in COPD-related annual costs by the year 2030.,This is caused almost entirely by an increase in direct health care costs that reflect the predicted ageing of the Finnish population, as older age is a significant factor that increases the need for hospitalisation.,The total annual COPD-related costs in Finland have been stable during the years 1996-2006, but if management strategies are not changed a significant increase in direct costs is expected by the year 2030 due to ageing of the population. | 1 |
The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms.,The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.,In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks.,The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26.,Overall, 676 patients completed the study.,The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met.,QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001).,QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001).,QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use.,However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.,Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%).,The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%).,These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year. | The BEACON study evaluated the efficacy and safety of QVA149, a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237), in development for the treatment of patients with chronic obstructive pulmonary disease (COPD), compared with the free-dose concurrent administration of indacaterol plus glycopyrronium (IND+GLY).,In this multicenter, double-blind, parallel group study, patients with stage II or stage III COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] 2010) were randomized (1:1) to once-daily QVA149 (110 μg indacaterol/50 μg glycopyrronium) or concurrent administration of indacaterol (150 μg) and glycopyrronium (50 μg) via the Breezhaler® device (Novartis AG, Basel, Switzerland) for 4 weeks.,The primary endpoint was to evaluate the noninferiority of QVA149 as compared with concurrent administration of IND+GLY, for trough forced expiratory volume in 1 second (FEV1) after 4 weeks of treatment.,The other assessments included FEV1 area under the curve from 0 to 4 hours (AUC0-4 hours) at day 1 and week 4, symptom scores, rescue medication use, safety, and tolerability over the 4-week study period.,Of 193 patients randomized, 187 (96.9%) completed the study.,Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.46 L ± 0.02 and 1.46 L ± 0.18, respectively.,The FEV1 AUC0-4 hours at day 1 and week 4 were similar between the two treatment groups.,Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period.,Overall, 25.6% of patients in QVA149 group and 25.2% in the IND+GLY group experienced an adverse event, with the majority being mild-to-moderate in severity.,No deaths were reported during the study or during the 30 days follow-up period.,The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium. | 1 |
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally.,Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments.,MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis.,Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC.,These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-κB (NF-κB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF).,Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD.,Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease.,Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion. | Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by a progressive and irreversible deterioration of lung function.,Exacerbations of COPD have prolonged negative effects on pulmonary function and a major impact on health status and outcomes.,NLRP3 inflammasome is a cardinal component of the inflammatory response, with marked evidence in stable and exacerbations of COPD.,The aim of our study was to evaluate the NLRP3 inflammasome activity during COPD exacerbation by using an in vitro model.,A549 cells were stimulated with different concentrations (10%, 4%, 2%) of cigarette smoke extract (CSE) with or without LPS (0.1μg/ml) for 24 hours.,Cell viability was assessed by using XTT test.,Levels of inflammatory cytokines (IL-8, MCP-1, and IL-1β) were measured by ELISA and the activity level of NLRP-3 was evaluated by flow cytometry.,Cells exposed to CSE present an increase in inflammatory cytokines (IL-8 and MCP-1) production in a dose-dependent manner.,Incubation with LPS to these cells results in higher levels of IL-8 and MCP-1 compared to stimulation of CSE alone.,NLRP3 inflammasome activity and IL-1β levels were significantly increased in cells exposed to both CSE and LPS compared to CSE alone.,NLRP3 inflammasome is upregulated in an in-vitro model of COPD and COPD exacerbation.,Our findings provide novel biomarkers for COPD exacerbation and may present new targets for future research. | 1 |
Patients with COPD often experience severe exacerbations involving hospitalization, which accelerate lung function decline and reduce quality of life.,This study aimed to develop and validate a predictive model to identify patients at risk of developing severe COPD exacerbations using administrative claims data, to facilitate appropriate disease management programs.,A predictive model was developed using a retrospective cohort of COPD patients aged 55-89 years identified between July 1, 2010 and June 30, 2013 using Humana’s claims data.,The baseline period was 12 months postdiagnosis, and the prediction period covered months 12-24.,Patients with and without severe exacerbations in the prediction period were compared to identify characteristics associated with severe COPD exacerbations.,Models were developed using stepwise logistic regression, and a final model was chosen to optimize sensitivity, specificity, positive predictive value (PPV), and negative PV (NPV).,Of 45,722 patients, 5,317 had severe exacerbations in the prediction period.,Patients with severe exacerbations had significantly higher comorbidity burden, use of respiratory medications, and tobacco-cessation counseling compared to those without severe exacerbations in the baseline period.,The predictive model included 29 variables that were significantly associated with severe exacerbations.,The strongest predictors were prior severe exacerbations and higher Deyo-Charlson comorbidity score (OR 1.50 and 1.47, respectively).,The best-performing predictive model had an area under the curve of 0.77.,A receiver operating characteristic cutoff of 0.4 was chosen to optimize PPV, and the model had sensitivity of 17%, specificity of 98%, PPV of 48%, and NPV of 90%.,This study found that of every two patients identified by the predictive model to be at risk of severe exacerbation, one patient may have a severe exacerbation.,Once at-risk patients are identified, appropriate maintenance medication, implementation of disease-management programs, and education may prevent future exacerbations. | 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 |
COPD is a heterogeneous disease, and the available prognostic indexes are therefore limited.,This study aimed to identify the factors associated with acute exacerbation leading to hospitalization.,This was a retrospective study of consecutive patients with COPD (meeting the Global Initiative for Chronic Obstructive Lung Disease [GOLD] diagnostic criteria) hospitalized at the Ninth Hospital of Xi’an Affiliated Hospital of Xi’an Jiaotong University between October 2014 and September 2016.,During follow-up after first hospitalization, the patients who had been rehospitalized within 1 year for acute exacerbation were grouped into the frequent exacerbation (FE) group, while the others were grouped into the infrequent exacerbation (IE) group.,The baseline demographic, clinical, laboratory, pulmonary function, and imaging data were compared between the two groups.,Compared with the IE group, the FE group had lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (P=0.005), FEV1%pred (P=0.002), maximal mid-expiratory flow (MMEF25-75%pred) (P=0.003), and ratio of carbon monoxide diffusion capacity to alveolar ventilation (DLCO/VA) (P=0.03) and higher resonant frequency (Fres; P=0.04).,According to generations of bronchi, the percentage of the wall area (%WA) of lobes was found to be higher in the FE group.,Emphysema index (EI), mean emphysema density (MED)whole and MEDleft lung in the FE group were significantly worse than in the IE group (P<0.05).,Using logistic regression, exacerbation hospitalizations in the past year (odds ratio [OR] 14.4, 95% CI 6.1-34.0, P<0.001) and EI >10% (OR 2.9, 95% CI 1.2-7.1, P=0.02) were independently associated with frequent acute exacerbation of COPD (AECOPD) hospitalization.,Exacerbation hospitalizations in the past year and imaging features of emphysema (EI) were independently associated with FE hospitalization. | It is unclear whether various bronchodilator reversibility (BDR) criteria affect the prognosis of chronic obstructive pulmonary disease (COPD).,The aim of this study is to evaluate the impact of positive BDR defined according to various BDR criteria on the risk of severe acute exacerbation (AE) in COPD patients.,Patients from four prospective COPD cohorts in South Korea who underwent follow-up for at least 1 year were enrolled in this study.,The assessed BDR criteria included the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society (ATS), American College of Chest Physicians, (ACCP), major criteria of the Spanish definition of asthma-COPD overlap syndrome (ACOS), criteria compatible with ACOS in the Global Initiative for Asthma (GINA), and European Respiratory Society (ERS).,The rate of patients with severe AE who required hospitalization within 1 year due to BDR results according to each set of criteria was analyzed using logistic regression models.,Among a total of 854 patients, the BDR-positive cases varied according to the criteria used.,There was a 3.5% positive BDR rate according to GINA and a 29.9% rate according to the ATS criteria.,Positive BDR according to the GOLD criteria was significantly associated with a decreased risk of severe AE (adjusted odds ratio (aOR) = 0.38; 95% Confidence interval (CI) = 0.15-0.93).,This result remained statistically significant even in a sensitivity analysis that included only participants with a smoking history of at least 10 pack-years and in the analysis for the propensity score-matched participants.,Among different criteria for positive BDR, the use of the GOLD ones was significantly associated with a decreased risk of severe AE in COPD patients.,Increase use of ICS/LABA may have affected this relationship.,The online version of this article (doi:10.1186/s12931-017-0587-9) contains supplementary material, which is available to authorized users. | 1 |
The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes.,FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations.,In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50 μg once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use.,This post-hoc analysis included 2557 men and 805 women.,Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ≥2 exacerbations in the previous year.,Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively).,Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively).,Results were similar for all (mild/moderate/severe) exacerbations.,Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women.,The smaller sample size for women may account for some observed discrepancies in treatment responses.,Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC.,Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis.,Post hoc analysis of the FLAME study.,ClinicalTrials.gov number: NCT01782326.,Registered 1 February 2013. | Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.,Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint.,Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment.,A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.,In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators.,Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses.,Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers.,The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.,The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.,NCT00563381; Study identifier: BI 205.389. | 1 |
The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD).,The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD.,This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD.,It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers.,The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report.,This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations.,The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient.,The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma-COPD overlap syndrome (ACOS).,These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions.,For the low exacerbation risk phenotype, pharmacotherapy with short-acting β2-agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol-ipratropium) is recommended in patients with less symptoms.,If short-acting bronchodilators are not enough to control symptoms, a long-acting β2-agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended.,For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting β2-agonist (budesonide-formoterol, beclomethasone dipropionate-formoterol, fluticasone propionate-salmeterol or fluticasone furoate-vilanterol) is recommended as a first choice.,Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium-indacaterol or umeclidinium-vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting β2-agonist and a long-acting anticholinergic.,If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast.,ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD.,Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD.,Thus, evidence-based recommendation of treatment cannot be given.,The treatment should cover both diseases.,Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (β2-agonist or anticholinergic or both). | There is an ongoing debate on whether patients with chronic obstructive pulmonary disease (COPD) seen in real-life clinical settings are represented in randomized controlled trials (RCTs) of COPD.,It is thought that the stringent inclusion and exclusion criteria of RCTs may prevent the participation of patients with specific characteristics or risk factors.,We surveyed a database of patients recruited into 35 placebo-controlled tiotropium RCTs and also conducted a systematic literature review of large-scale observational studies conducted in patients with a documented diagnosis of COPD between 1990 and 2013.,Patient demographics and comorbidities with a high prevalence in patients with COPD were compared between the two patient populations at baseline.,Using the Medical Dictionary for Regulatory Activities (MedDRA; v 14.0), patient comorbidities in the pooled tiotropium RCTs were classified according to system organ class, pharmacovigilance (PV) endpoints, and Standardised MedDRA Queries to enable comparison with the observational studies.,We identified 24,555 patients in the pooled tiotropium RCTs and 61,361 patients among the 13 observational studies that met our search criteria.,The Global initiative for chronic Obstructive Lung Disease (GOLD) staging of patients in the RCTs differed from that in observational studies: the proportion of patients with GOLD stages I+II disease ranged from 40.0% to 51.5% in the RCTs but 24.5% to 44.1% in the observational studies; for GOLD stage III or IV disease these ranges were 7.2%-45.8% (RCTs) and 13.7-42.1% (observational studies).,The comorbidities with the highest prevalence reported in the RCTs and observational studies were: hypertension (39.4%-40.0% vs 40.1%-60.6%), other ischemic heart disease (12.3%-14.2% vs 12.5%-41.0%), diabetes (10.3%-10.9% vs 4.0%-38.9%), depression (8.5%-9.5% vs 17.0%-20.6%), and cardiac arrhythmia (7.8%-11.4% vs 11.3%-15.8%).,The clinical profile of COPD patients treated in the tiotropium trial program appears to be largely in the range of clinical characteristics, including cardiovascular comorbidities, reported for “real-life patients.”,The tiotropium RCTs tended to include patients with more severe disease than the observational studies. | 1 |
Chronic obstructive pulmonary disease (COPD) is the third-leading cause of death worldwide.,Identifying COPD-associated DNA methylation marks in African-Americans may contribute to our understanding of racial disparities in COPD susceptibility.,We determined differentially methylated genes and co-methylation network modules associated with COPD in African-Americans recruited during exacerbations of COPD and smoking controls from the Pennsylvania Study of Chronic Obstructive Pulmonary Exacerbations (PA-SCOPE) cohort.,We assessed DNA methylation from whole blood samples in 362 African-American smokers in the PA-SCOPE cohort using the Illumina Infinium HumanMethylation27 BeadChip Array.,Final analysis included 19302 CpG probes annotated to the nearest gene transcript after quality control.,We tested methylation associations with COPD case-control status using mixed linear models.,Weighted gene comethylation networks were constructed using weighted gene coexpression network analysis (WGCNA) and network modules were analyzed for association with COPD.,There were five differentially methylated CpG probes significantly associated with COPD among African-Americans at an FDR less than 5 %, and seven additional probes that approached significance at an FDR less than 10 %.,The top ranked gene association was MAML1, which has been shown to affect NOTCH-dependent angiogenesis in murine lung.,Network modeling yielded the “yellow” and “blue” comethylation modules which were significantly associated with COPD (p-value 4 × 10-10 and 4 × 10-9, respectively).,The yellow module was enriched for gene sets related to inflammatory pathways known to be relevant to COPD.,The blue module contained the top ranked genes in the concurrent differential methylation analysis (FXYD1/LGI4, gene significance p-value 1.2 × 10-26; MAML1, p-value 2.0 × 10-26; CD72, p-value 2.1 × 10-25; and LPO, p-value 7.2 × 10-25), and was significantly associated with lung development processes in Gene Ontology gene-set enrichment analysis.,We identified 12 differentially methylated CpG sites associated with COPD that mapped to biologically plausible genes.,Network module comethylation patterns have identified candidate genes that may be contributing to racial differences in COPD susceptibility and severity.,COPD-associated comethylation modules contained genes previously associated with lung disease and inflammation and recapitulated known COPD-associated genes.,The genes implicated by differential methylation and WGCNA analysis may provide mechanistic targets contributing to COPD susceptibility, exacerbations, and outcomes among African-Americans.,Trial Registration: NCT00774176, Registry: ClinicalTrials.gov, URL: www.clinicaltrials.gov, Date of Enrollment of First Participant: June 2004, Date Registered: 04 January 2008 (retrospectively registered).,The online version of this article (doi:10.1186/s12931-016-0459-8) contains supplementary material, which is available to authorized users. | 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 |
Olodaterol is a long-acting β2-agonist with a 24-hour bronchodilator profile.,Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy.,Patients received olodaterol 5 μg or 10 μg or placebo once daily for 48 weeks.,Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0-3) response (change from baseline), and trough FEV1 response at 12 weeks.,Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks.,Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively.,In both studies, olodaterol 5 μg and 10 μg significantly improved the FEV1 AUC0-3 response (P<0.0001) and trough FEV1 (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo.,Secondary end points supported the efficacy of olodaterol.,These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy. | Objective To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.,Data sources Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.,Study selection Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality.,Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I2 statistic.,Results Five randomised controlled trials were eligible for inclusion.,Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P=0.02; I2=0%).,Both 10 µg (2.15, 1.03 to 4.51; P=0.04; I2=9%) and 5 µg (1.46, 1.01 to 2.10; P=0.04; I2=0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality.,The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P=0.04), limiting the analysis to three trials of one year’s duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00).,The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.,Conclusions This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease. | 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. | The causal association between depression, anxiety, and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD) is unclear.,We therefore conducted a systematic review of prospective cohort studies that measured depression, anxiety, and HRQoL in COPD.,Electronic databases (Medline, Embase, Cumulative Index to Nursing and Allied Health Literature [CINAHL], British Nursing Index and Archive, PsycINFO and Cochrane database) were searched from inception to June 18, 2013.,Studies were eligible for inclusion if they: used a nonexperimental prospective cohort design; included patients with a diagnosis of COPD confirmed by spirometry; and used validated measures of depression, anxiety, and HRQoL.,Data were extracted and pooled using random effects models.,Six studies were included in the systematic review; of these, three were included in the meta-analysis for depression and two were included for the meta-analysis for anxiety.,Depression was significantly correlated with HRQoL at 1-year follow-up (pooled r=0.48, 95% confidence interval 0.37-0.57, P<0.001).,Anxiety was also significantly correlated with HRQoL at 1-year follow-up (pooled r=0.36, 95% confidence interval 0.23-0.48, P<0.001).,Anxiety and depression predict HRQoL in COPD.,However, this longitudinal analysis does not show cause and effect relationships between depression and anxiety and future HRQoL.,Future studies should identify psychological predictors of poor HRQoL in well designed prospective cohorts with a view to isolating the mediating role played by anxiety disorder and depression. | 1 |
Based on blood and sputum samples, up to 40% of patients with COPD have eosinophilic inflammation; however, there is little epidemiology data characterizing the health care burden within this sub-population.,Given that COPD-attributable medical costs in the USA are predicted to approach $50 billion by 2020, we analyzed the effect of blood eosinophil counts and exacerbations on health care resource utilization and costs.,This cross-sectional study used electronic medical records and insurance claims data from the Reliant Medical Group (January 2011-December 2015).,Eligible patients were ≥40 years of age, continuously enrolled during the year of interest (2012, 2013, 2014, or 2015), had ≥1 COPD-related code in the preceding year, and documented maintenance therapy use.,Patients with ≥1 blood eosinophil count recorded were stratified into 2 cohorts: <150 cells/µL and ≥150 cells/µL.,Endpoints included demographics, clinical characteristics, health care resource utilization, and costs.,The impact of blood eosinophil count and exacerbation patterns on health care resource utilization and costs was assessed with multivariate analyses.,On average, 2,832 eligible patients were enrolled annually, of whom ~28% had ≥1 eosinophil count recorded during the year.,The ≥150 cells/µL cohort had numerically higher all-cause and COPD-related health care resource utilization and cost each year compared with the <150 cells/µL cohort, but varied by service and year.,Among patients with exacerbations, the ≥150 cells/µL cohort exhibited significantly higher COPD-related costs compared with the <150 cells/µL cohort.,Blood eosinophil counts may be a useful biomarker for burden of disease in a subgroup of patients with COPD. | Eosinophilic COPD appears to be a distinct patient subgroup with an increased corticosteroid response.,Eosinophilic COPD has been labelled as part of the asthma COPD overlap syndrome (ACOS).,We compared the clinical characteristics of eosinophilic COPD patients (without any clinical history of asthma) and COPD patients with a childhood history of asthma.,COPD patients with asthma were characterised by more allergies and more exacerbations, but less eosinophilic inflammation.,While terms such as “ACOS” are used to “lump” patients together, we report distinct differences between eosinophilic COPD and COPD patients with asthma, and propose that these groups should be split rather than lumped. | 1 |
Dysbiosis of the gut microbiome is involved in the pathogenesis of various diseases, but the contribution of gut microbes to the progression of chronic obstructive pulmonary disease (COPD) is still poorly understood.,We carried out 16S rRNA gene sequencing and short-chain fatty acid analyses in stool samples from a cohort of 73 healthy controls, 67 patients with COPD of GOLD stages I and II severity, and 32 patients with COPD of GOLD stages III and IV severity.,Fecal microbiota from the three groups were then inoculated into recipient mice for a total of 14 times in 28 days to induce pulmonary changes.,Furthermore, fecal microbiota from the three groups were inoculated into mice exposed to smoke from biomass fuel to induce COPD-like changes.,We observed that the gut microbiome of COPD patients varied from that of healthy controls and was characterized by a distinct overall microbial diversity and composition, a Prevotella-dominated gut enterotype and lower levels of short-chain fatty acids.,After 28 days of fecal transplantation from COPD patients, recipient mice exhibited elevated lung inflammation.,Moreover, when mice were under both fecal transplantation and biomass fuel smoke exposure for a total of 20 weeks, accelerated declines in lung function, severe emphysematous changes, airway remodeling and mucus hypersecretion were observed.,These data demonstrate that altered gut microbiota in COPD patients is associated with disease progression in mice model.,The online version contains supplementary material available at 10.1186/s12931-021-01872-z. | 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. | 1 |
Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD).,To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes.,A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015.,Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint.,Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group).,Each association was assessed at 6 months and study end.,Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation.,Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George’s Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end.,Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028).,CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001).,The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively.,A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations.,This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.,The online version of this article (doi:10.1186/s12931-017-0566-1) contains supplementary material, which is available to authorized users. | 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. | 1 |
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments.,In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression.,The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology.,The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription.,Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression).,However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling.,Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD.,Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression.,This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD. | Familial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees.,The aim was to determine whether the familial transmission of COPD is related to disease in biological and/or adoptive parents.,Historic cohort study.,80 214 (50% females).,The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born in 1932-2004 (n=80 214) between 1 January 1964 and 31 December 2010 for COPD (n=1978).,The risk of COPD was estimated in adoptees with at least one biological parent with COPD but no adoptive parent with COPD (n=162) compared with adoptees without a biological or adoptive parent with COPD.,The risk of COPD was also determined in adoptees with at least one adoptive parent but no biological parent with COPD (n=110), and in adoptees with both affected biological and adoptive parents (n=162).,COPD in adoptees.,Adoptees with COPD in at least one biological parent but no adoptive parent were more likely to have COPD than adoptees without a biological or adoptive parent with COPD (standardised incidence ratio, SIR=1.98 (95% CI 1.69 to 2.31)).,The familial SIR for adoptees with both a biological parent and an adoptive parent with COPD was 1.68 (95% CI 1.39 to 2.00).,Adoptees with at least one adoptive parent with COPD but no biological parent with COPD were not at an increased risk of COPD (SIR=1.12 (95% CI 0.92 to 1.35)).,The findings of the study show that the familial transmission of COPD is associated with COPD in biological but not adoptive parents, suggesting that genetic or early life factors are important in the familial transmission of COPD. | 1 |
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. | Resistance training (RT) is thought to be effective in preventing muscle depletion, whereas endurance training (ET) is known to improve exercise capacity and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD).,Our objectives were to assess the efficiency of combining RT with ET compared with ET alone.,We identified eligible studies through a systematic multi-database search.,One author checked titles and abstracts for relevance using broad inclusion criteria, whilst two independent authors checked the full-text copies for eligibility.,Two authors independently extracted data, and we assessed the risk of bias and quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation guidelines.,We included 11 randomized controlled trials (331 participants) and 2 previous systematic reviews.,The meta-analyses showed equal improvements in HRQoL, walking distance and exercise capacity.,However, we found moderate quality evidence of a significant increase in leg muscle strength favouring a combination of RT and ET (standardized mean difference of 0.69 (95% confidence interval: 0.39-0.98).,In conclusion, we found significantly increased leg muscle strength favouring a combination of RT with ET compared with ET alone.,Therefore, we recommend that RT should be incorporated in rehabilitation of COPD together with ET. | 1 |
Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD).,Both the twice-daily long-acting β2-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD.,This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.,We searched PubMed for placebo-controlled studies evaluating long-term (≥24 weeks) use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012.,We summarized data relating to exacerbations and adverse events, particularly events related to COPD.,From 20 studies examined (8774 LABA-treated patients), there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths.,Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo.,Incidences of COPD-related adverse events were similar for active and placebo treatments.,The incidence of adverse events typically associated with the β2-agonist drug class such as skeletal muscle tremors and palpitations was low (often <1% of patients), and there were no reports of increased incidence of cardiac arrhythmias.,The systemic effects of β2-adrenoceptor stimulation, such as high glucose and potassium levels, were considered minor.,Current evidence from clinical studies of the safety and tolerability profile of LABAs supports their long-term use in COPD. | 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 |
There is a wide variability in measurement methodology of physical activity.,This study investigated the effect of different analysis techniques on the statistical power of physical activity outcomes after pulmonary rehabilitation.,Physical activity was measured with an activity monitor armband in 57 patients with COPD (mean ± SD age, 66 ± 7 years; FEV1, 46 ± 17% predicted) before and after 3 months of pulmonary rehabilitation.,The choice of the outcome (daily number of steps [STEPS], time spent in at least moderate physical activity [TMA], mean metabolic equivalents of task level [METS], and activity time [ACT]), impact of weekends, number of days of assessment, postprocessing techniques, and influence of duration of daylight time (DT) on the sample size to achieve a power of 0.8 were investigated.,The STEPS and ACT (1.6-2.3 metabolic equivalents of task) were the most sensitive outcomes.,Excluding weekends decreased the sample size for STEPS (83 vs 56), TMA (160 vs 148), and METS (251 vs 207).,Using 4 weekdays (STEPS and TMA) or 5 weekdays (METS) rendered the lowest sample size.,Excluding days with < 8 h wearing time reduced the sample size for STEPS (56 vs 51).,Differences in DT were an important confounder.,Changes in physical activity following pulmonary rehabilitation are best measured for 4 weekdays, including only days with at least 8 h of wearing time (during waking hours) and considering the difference in DT as a covariate in the analysis.,ClinicalTrials.gov; No.: NCT00948623; URL: www.clinicaltrials.gov | The performance of daily activities is a major challenge for people with chronic obstructive pulmonary disease (COPD).,The Functional Performance Inventory (FPI) was developed based on an analytical framework of functional status and qualitative interviews with COPD patients describing these difficulties.,The 65-item FPI was reduced to a 32-item short form (SF) through a systematic process of qualitative and quantitative item reduction and formatted for greater clarity and ease of use.,This study examined the content validity of the reduced, reformatted form of the instrument, the FPI-SF.,Qualitative cognitive interviews were conducted with COPD patients recruited from three geographically diverse pulmonary clinics in the United States.,Interviews were designed to assess respondent interpretation of the instrument, evaluate clarity and ease of completion, and identify any new activities participants found important and difficult to perform that were not represented by the existing items.,Twenty subjects comprised the sample; 12 (60%) were male, 14 (70%) were Caucasian, the mean age was 63.0 ± 11.3 years, 12 (60%) were retired, the mean forced expiratory volume in 1 second (FEV1) was 1.5 ± 0.5 L, and the mean percent predicted FEV1 was 48.4% ± 13.1%.,Participants understood the FPI-SF as intended, including instructions, items, and response options.,Two minor formatting changes were suggested to improve clarity of presentation.,Participants found the content of the FPI-SF to be comprehensive, with items covering activities they felt were important and often difficult to perform.,These results, together with its development history and previously tested quantitative properties, suggest that the FPI-SF is content valid for use in clinical studies of COPD. | 1 |
Thiazolidinediones (TZDs) are oral antihyperglycemic medications that are selective agonists to peroxisome proliferator-activated receptor gamma and have been shown to have potent anti-inflammatory effects in the lung.,The purpose of this study was to assess whether exposure to TZDs is associated with a decreased risk of chronic obstructive pulmonary disease (COPD) exacerbation.,A cohort study was performed by collecting data on all US veterans with diabetes and COPD who were prescribed oral antihyperglycemic medications during from period of October 1, 2005 to September 30, 2007.,Patients who had two or more prescriptions for TZDs were compared with patients who had two or more prescriptions for an alternative oral anti-hyperglycemic medication.,Multivariable negative binomial regression was performed with adjustment for potential confounding factors.,The primary outcome was COPD exacerbations, including both inpatient and outpatient exacerbations.,We identified 7,887 veterans who were exposed to TZD and 42,347 veterans who were exposed to non-TZD oral diabetes medications.,COPD exacerbations occurred in 1,258 (16%) of the TZD group and 7,789 (18%) of the non-TZD group.,In multivariable negative binomial regression, there was a significant reduction in the expected number of COPD exacerbations among patients who were exposed to TZDs with an incidence rate ratio of 0.86 (95% CI 0.81-0.92).,Exposure to TZDs was associated with a small but significant reduction in risk for COPD exacerbation among diabetic patients with COPD. | Inflammation and remodeling of the small airways are major determinants of the progression and severity of COPD.,The present study explored the correlation between sputum p38 mitogen-activated protein kinase (MAPK) activity and airway inflammation and reduction of lung function in the patients with chronic obstructive pulmonary disease (COPD).,Sputum samples were collected from 48 COPD patients and 12 healthy persons.,Sputum p38 MAPK activity was measured by Western blotting and sputum levels of CXCL8 and neutrophil, and lung function was measured.,The correlation between p38MAPK activity and airway inflammation and reduction of lung function was analyzed.,Our results showed the significantly increased expression of phospho-p38 MAPK and CXCL8 in the sputum samples of the COPD patients.,The p38 MAPK activity was remarkably correlated with the CXCL8 level and neutrophils infiltration in the airway, and the decline of lung function in the COPD patients.,These findings suggest the pivotal role of p38 MAPK in the airway inflammation of COPD patients.,We propose p38 MAPK as a potential target for the treatment of COPD. | 1 |
The Continuing to Confront COPD International Patient Survey estimated the prevalence and burden of COPD across 12 countries.,Using data from this survey we evaluated the economic impact of COPD.,This cross-sectional, population-based survey questioned 4,343 subjects aged 40 years and older, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology.,Direct cost measures were based on exacerbations of COPD (treated and those requiring emergency department visits and/or hospitalisation), contacts with healthcare professionals, and COPD medications.,Indirect costs were calculated from work loss values using the Work Productivity and Activity Impairment scale.,Combined direct and indirect costs estimated the total societal costs per patient.,The annual direct costs of COPD ranged from $504 (South Korea) to $9,981 (USA), with inpatient hospitalisations (5 countries) and home oxygen therapy (3 countries) being the key drivers of direct costs.,The proportion of patients completely prevented from working due to their COPD ranged from 6% (Italy) to 52% (USA and UK) with 8 countries reporting this to be ≥20%.,Total societal costs per patient varied widely from $1,721 (Russia) to $30,826 (USA) but a consistent pattern across countries showed greater costs among those with increased burden of COPD (symptoms, health status and more severe disease) and a greater number of comorbidities.,The economic burden of COPD is considerable across countries, and requires targeted resources to optimise COPD management encompassing the control of symptoms, prevention of exacerbations and effective treatment of comorbidities.,Strategies to allow COPD patients to remain in work are important for addressing the substantial wider societal costs. | Patients with COPD on long term oxygen therapy frequently do not adhere to their prescription, and they frequently do not use their ambulatory oxygen systems as intended.,Reasons for this lack of adherence are not known.,The aim of this study was to obtain in-depth information about perceptions and use of prescribed ambulatory oxygen systems from patients with COPD to inform ambulatory oxygen design, prescription and management.,A qualitative design was used, involving semi-structured face-to-face interviews informed by a grounded theory approach.,Twenty-seven UK community-dwelling COPD patients using NHS prescribed ambulatory systems were recruited.,Ambulatory oxygen systems comprised cylinders weighing 3.4 kg, a shoulder bag and nasal cannulae.,Participants reported that they: received no instruction on how to use ambulatory oxygen; were uncertain of the benefits; were afraid the system would run out while they were using it (due to lack of confidence in the cylinder gauge); were embarrassed at being seen with the system in public; and were unable to carry the system because of the cylinder weight.,The essential role of carers was also highlighted, as participants with no immediate carers did not use ambulatory oxygen outside the house.,These participants highlighted previously unreported problems that prevented them from using ambulatory oxygen as prescribed.,Our novel findings point to: concerns with the lack of specific information provision; the perceived unreliability of the oxygen system; important carer issues surrounding managing and using ambulatory oxygen equipment.,All of these issues, as well as previously reported problems with system weight and patient embarrassment, should be addressed to improve adherence to ambulatory oxygen prescription and enhance the physical and social benefits of maintaining mobility in this patient group.,Increased user involvement in both system development and service provision planning, could have avoided many of the difficulties highlighted by this study. | 1 |
The constructs and interdependency of physical behaviors are not well described and the complexity of physical activity (PA) data analysis remains unexplored in COPD.,This study examined the interrelationships of 24-hour physical behaviors and investigated their associations with participant characteristics for individuals with mild-moderate airflow obstruction and healthy control subjects.,Vigorous PA (VPA), moderate-to-vigorous PA (MVPA), light PA (LPA), stationary time (ST), average movement intensity (vector magnitude counts per minute), and sleep duration for 109 individuals with COPD and 135 healthy controls were obtained by wrist-worn accelerometry.,Principal components analysis (PCA) examined interrelationships of physical behaviors to identify distinct behavioral constructs.,Using the PCA component loadings, linear regressions examined associations with participant (+, positive correlation; -, negative correlation), and were compared between COPD and healthy control groups.,For both groups PCA revealed ST, LPA, and average movement intensity as distinct behavioral constructs to MVPA and VPA, labeled “low-intensity movement” and “high-intensity movement,” respectively.,Sleep was also found to be its own distinct behavioral construct.,Results from linear regressions supported the identification of distinct behavioral constructs from PCA.,In COPD, low-intensity movement was associated with limitations with mobility (−), daily activities (−), health status (+), and body mass index (BMI) (−) independent of high-intensity movement and sleep.,High-intensity movement was associated with age (−) and self-care limitations (−) independent of low-intensity movement and sleep.,Sleep was associated with gender (0= female, 1= male; [−]), lung function (−), and percentage body fat (+) independent of low-intensity and high-intensity movement.,Distinct behavioral constructs comprising the 24-hour day were identified as “low-intensity movement,” “high-intensity movement,” and “sleep” with each construct independently associated with different participant characteristics.,Future research should determine whether modifying these behaviors improves health outcomes in COPD. | For patients with COPD, physical activity (PA) is recommended as the core component of pulmonary rehabilitation, but there is lack of a validated questionnaire for assessing the PA effectively.,To evaluate the reliability and validity of the Chinese version of Physical Activity Scale for the Elderly (PASE-C) in patients with COPD.,A cross-sectional study was conducted with 167 outpatients aged 60 years or older with COPD.,Test−retest reliability and internal consistency were calculated by intraclass correlation coefficient (ICC) and Cronbach’s coefficient α, respectively.,Validity was evaluated by correlation with the International Physical Activity Questionnaire-Short (IPAQ-S), data of pedometer, Self-Efficacy for Managing Chronic Disease 6-Item Scale (SES6), Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), grip strength, and disease characteristics.,The PASE-C had an excellent seven-day test−retest reliability (ICC=0.98) and an acceptable internal consistency (Cronbach’s α=0.71).,The content validity was supported by an item-content validity index, a scale-content validity index/universal agreement, and a scale-content validity index/average value of 0.70-1, 0.70, and 0.93, respectively.,Concurrent validity was tested by correlation with IPAQ-S (r=0.651).,Criterion validity was confirmed by correlation with the walking steps (r=0.611) and energy expenditure (r=0.493).,For construct validity, PASE-C had correlations with SES6 (r=0.396), HADS for depression (r=−0.234), seven subscales of SF-36 (r=0.182-0.525), grip strength (r=0.341), and disease characteristics including the duration of COPD (r=−0.215), modified British Medical Research Council scale (r=−0.354), forced expiratory volume in one second as percentage of predicted (r=0.307), and Global Initiative for Chronic Obstructive Lung Disease grade (r=−0.264), with a good construct validity (all P<0.05).,The PASE-C has acceptable reliability and validity for patients aged 60 years or older with COPD, and it can be used as a valid tool to measure the PA of patients with COPD in the People’s Republic of China. | 1 |
Effective self-management in chronic obstructive pulmonary disease (COPD) is crucial to reduce hospital admissions and improve outcomes for patients.,This includes early detection and treatment of exacerbations by patients themselves.,To explore patients’ current understanding and experience of managing and identifying COPD exacerbations at home.,A qualitative, interview-based study was carried out in patients’ homes.,Interviews were audio-recorded, transcribed and analysed using a grounded theory approach.,Forty-four patients (17 women, 27 men; age range 55-85 years), with moderate-to-very-severe COPD, were recruited to the interview study from primary and secondary care settings in Oxford, UK, during 2012-2013.,Patients identified exacerbations on the basis of measurable, ‘visible’ symptoms, such as cough and sputum and ‘invisible’ symptoms, such as chest sensations and bodily knowledge.,Most patients seemed to use a combination of these approaches when identifying exacerbations, according to the symptoms that had the most impact on their well-being.,Patients used additional self-management strategies during an exacerbation, such as self-medication (antibiotics and steroids) and monitored their recovery.,Contact with health-care professionals usually occurred when patients felt no longer able to manage themselves.,Patients use both assessment of objective biomarkers, which are aligned with medical knowledge, and subjective symptoms based on their experience, to identify and manage exacerbations of COPD.,Health-care professionals and clinicians should acknowledge this ‘expert patient’ knowledge and integrate this into patients’ care plans to facilitate early recognition and treatment of exacerbations. | Patients with chronic obstructive pulmonary disease (COPD) can experience 'exacerbations' of their conditions.,An exacerbation is an event defined in terms of subjective descriptors or symptoms, namely dyspnoea, cough and sputum that worsen sufficiently to warrant a change in medical management.,There is a need for reliable markers that reflect the pathological mechanisms that underlie exacerbation severity and that can be used as a surrogate to assess treatment effects in clinical studies.,Little is known as to how existing study variables and suggested markers change in both the stable and exacerbation phases of COPD.,In an attempt to find the best surrogates for exacerbations, we have reviewed the literature to identify which of these markers change in a consistent manner with the severity of the exacerbation event.,We have searched standard databases between 1966 to July 2004 using major keywords and terms.,Studies that provided demographics, spirometry, potential markers, and clear eligibility criteria were included in this study.,Central tendencies and dispersions for all the variables and markers reported and collected by us were first tabulated according to sample size and ATS/ERS 2004 Exacerbation Severity Levels I to III criteria.,Due to the possible similarity of patients in Levels II and III, the data was also redefined into categories of exacerbations, namely out-patient (Level I) and in-patient (Levels II & III combined).,For both approaches, we performed a fixed effect meta-analysis on each of the reported variables.,We included a total of 268 studies reported between 1979 to July 2004.,These studies investigated 142,407 patients with COPD.,Arterial carbon dioxide tension and breathing rate were statistically different between all levels of exacerbation severity and between in out- and in-patient settings.,Most other measures showed weak relationships with either level or setting, or they had insufficient data to permit meta-analysis.,Arterial carbon dioxide and breathing rate varied in a consistent manner with exacerbation severity and patient setting.,Many other measures showed weak correlations that should be further explored in future longitudinal studies or assessed using suggested mathematical modelling techniques.,The online version of this article (doi:10.1186/1465-9921-7-74) contains supplementary material, which is available to authorized users. | 1 |
Background: The comorbidities and clinical signs of coronavirus disease 2019 (COVID-19) patients have been reported mainly as descriptive statistics, rather than quantitative analysis even in very large investigations.,The aim of this study was to identify specific patients’ characteristics that may modulate COVID-19 hospitalization risk.,Research design and methods: A pooled analysis was performed on high-quality epidemiological studies to quantify the prevalence (%) of comorbidities and clinical signs in hospitalized COVID-19 patients.,Pooled data were used to calculate the relative risk (RR) of specific comorbidities by matching the frequency of comorbidities in hospitalized COVID-19 patients with those of general population.,Results: The most frequent comorbidities were hypertension, diabetes mellitus, and cardiovascular and/or cerebrovascular diseases.,The RR of COVID-19 hospitalization was significantly (P < 0.05) reduced in patients with asthma (0.86, 0.77-0.97) or chronic obstructive pulmonary disease (COPD) (0.46, 0.40-0.52).,The most frequent clinical signs were fever and cough.,Conclusion: The clinical signs of hospitalized COVID-19 patients are similar to those of other infective diseases.,Patients with asthma or COPD were at lower hospitalization risk.,This paradoxical evidence could be related with the protective effect of inhaled corticosteroids that are administered worldwide to most asthmatic and COPD patients. | Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae.,We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK.,In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform.,The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020.,For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting β agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date.,For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting β agonist (SABA) only within the 4 months before the index date.,We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort.,We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates.,We calculated e-values to quantify the effect of unmeasured confounding on our results.,We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date.,People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]).,Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]).,Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43).,Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD.,Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity.,UK Medical Research Council. | 1 |
Peak flow meter with questionnaire and mini-spirometer are considered as alternative tools to spirometry for screening of asthma and chronic obstructive pulmonary disease.,However, the accuracy of these tools together, in clinical settings for disease diagnosis, has not been studied.,Two hundred consecutive patients with respiratory complaints answered a short symptom questionnaire and performed peak expiratory flow measurements, standard spirometry with Koko spirometer and mini-spirometry (COPD-6).,Spirometry was repeated after bronchodilation.,Physician made a final diagnosis of asthma, chronic obstructive pulmonary disease and others.,One eighty nine patients (78 females) with age 51 ± 17 years with asthma (115), chronic obstructive pulmonary disease (33) and others (41) completed the study.,“Breathlessness > 6months” and “cough > 6months” were important symptoms to detect obstructive airways disease.,“Asymptomatic period > 2 weeks” had the best sensitivity (Sn) and specificity (Sp) to differentiate asthma and chronic obstructive pulmonary disease.,A peak expiratory flow of < 80% predicted was the best cut-off to detect airflow limitation (Sn 90%, Sp 50%).,Respiratory symptoms with PEF < 80% predicted, had Sn 84 and Sp 93% to detect OAD.,COPD-6 device under-estimated FEV1 by 13 mL (95% CI: −212, 185).,At a cut-off of 0.75, the FEV1/FEV6 had the best accuracy (Sn 80%, Sp 86%) to detect airflow limitation.,Peak flow meter with few symptom questions can be effectively used in clinical practice for objective detection of asthma and chronic obstructive pulmonary disease, in the absence of good quality spirometry.,Mini-spirometers are useful in detection of obstructive airways diseases but FEV1 measured is inaccurate.,A simple questionnaire and peak flow meter measurements can help doctors differentiate between asthma and chronic lung disease.,In clinical settings where access to specialist equipment and knowledge is limited, it can be challenging for doctors to tell the difference between asthma and chronic obstructive pulmonary disease (COPD).,To determine a viable alternative method for differentiating between these diseases, Rahul Kodgule and colleagues at the Chest Research Foundation in Pune, India, trialed a simplified version of two existing symptom questionnaires, combined with peak flow meter measurements.,They assessed 189 patients using this method, and found it aided diagnosis with high sensitivity and specificity.,Breathlessness, cough and wheeze were the minimal symptoms required for COPD diagnosis, while the length of asymptomatic periods was most helpful in distinguishing asthma from COPD. | Introduction.,Awareness of the healthcare providers on chronic obstructive pulmonary disease (COPD), which is an important cause of mortality and morbidity in our country and all over the world, and on pulmonary rehabilitation (PR) which plays an important role in its nonpharmacological treatment will provide effectiveness in diagnosis and treatment of COPD.,The present study aimed at determining knowledge level of the healthcare providers about COPD and PR.,Materials and Methods.,In this cross-sectional study, family practitioners and staff of home-care in central county of Manisa City were applied a questionnaire in order to determine their knowledge level on COPD and pulmonary rehabilitation during the in-service training on “pulmonary rehabilitation, home-care services for the pulmonary diseases, and respiratory exercises.”,Results.,65.5% of the healthcare providers responded to the survey.,Rate of those correctly knowing at least one of four items was 97.2%.,No responder knew all items correctly.,Average value for correct answers was 5.30 ± 2.1 (range: 1-10).,The physicians, men, and those working in family health centers had higher level of knowledge on COPD compared to nonphysician healthcare providers (p = 0.006), women (p = 0.002), and those working in other practices (p = 0.019), respectively.,Conclusion.,Knowledge level of the primary healthcare providers on COPD and PR remains inadequate.,Dynamic postgraduate training on this topic will be useful in referring the patients to centers giving service for this condition. | 1 |
The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287).,As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies.,These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD.,In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min).,Adverse events (AEs) were pooled from both studies.,Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups.,Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes.,AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively.,There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents.,There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.,Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity.,The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment. | Lung hyperinflation and exercise intolerance are hallmarks of chronic obstructive pulmonary disease (COPD).,However, their relationship remains uncertain.,A combined analysis of two placebo-controlled, randomized studies examined the effects of the long-acting muscarinic antagonist umeclidinium (UMEC) and long-acting β2-agonist vilanterol (VI) separately and in combination on static hyperinflation, exercise endurance time (EET), and their relationship in patients with COPD.,Patients with moderate-to-severe stable COPD and resting functional residual capacity >120% predicted were randomized to UMEC/VI 62.5/25 μg, UMEC 62.5 μg, VI 25 μg, or placebo for 12 weeks.,Inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), and EET in an endurance shuttle-walk test were measured.,In this post hoc analysis, IC/TLC, RV/TLC, and IC were used as hyperinflation markers.,After 12 weeks, UMEC/VI and UMEC and VI showed significant improvements in hyperinflation versus placebo when measured by absolute change from baseline in IC/TLC (trough and 3 hours postdose [P≤0.011]).,UMEC/VI showed significant improvements versus UMEC and VI in absolute changes in IC/TLC (trough and 3 hours postdose [P≤0.001]).,Statistical significance for comparisons with placebo and between treatments for absolute changes in IC and percentage changes in RV/TLC followed similar patterns to those for absolute changes in IC/TLC.,UMEC/VI showed significant improvements in EET versus placebo at day 2 and week 12, measured as change from baseline in seconds (P≤0.002) and as a percentage from baseline (P≤0.005).,There was a lack of evidence to suggest a correlation between improvements in static hyperinflation and EET at any time point.,Although the dual bronchodilator UMEC/VI demonstrated greater improvements in static hyperinflation markers than UMEC or VI and significant improvements in exercise endurance, no direct relationship was observed between static hyperinflation and exercise endurance. | 1 |
Chronic obstructive pulmonary disease (COPD) is commonly associated with heart failure (HF) in clinical practice since they share the same pathogenic mechanism.,Both conditions incur significant morbidity and mortality.,Therefore, the prognosis of COPD and HF combined is poorer than for either disease alone.,Nevertheless, usually only one of them is diagnosed.,An active search for each condition using clinical examination and additional tests including plasma natriuretic peptides, lung function testing, and echocardiography should be obtained.,The combination of COPD and HF presents many therapeutic challenges.,The beneficial effects of selective β1-blockers should not be denied in stable patients who have HF and coexisting COPD.,Additionally, statins, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers may reduce the morbidity and mortality of COPD patients.,Moreover, caution is advised with use of inhaled β2-agonists for the treatment of COPD in patients with HF.,Finally, noninvasive ventilation, added to conventional therapy, improves the outcome of patients with acute respiratory failure due to hypercapnic exacerbation of COPD or HF in situations of acute pulmonary edema.,The establishment of a combined and integrated approach to managing these comorbidities would seem an appropriate strategy.,Additional studies providing new data on the pathogenesis and management of patients with COPD and HF are needed, with the purpose of trying to improve quality of life as well as survival of these patients. | 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 |
Exacerbations of chronic obstructive pulmonary disease (COPD) carry significant consequences for patients and are responsible for considerable health-care costs-particularly if hospitalization is required.,Despite the importance of hospitalized exacerbations, relatively little is known about their determinants.,This study aimed to analyze predictors of hospitalized exacerbations and mortality in COPD patients.,This was a retrospective population-based cohort study.,We selected 900 patients with confirmed COPD aged ≥35 years by simple random sampling among all COPD patients in Cantabria (northern Spain) on December 31, 2011.,We defined moderate exacerbations as events that led a care provider to prescribe antibiotics or corticosteroids and severe exacerbations as exacerbations requiring hospital admission.,We observed exacerbation frequency over the previous year (2011) and following year (2012).,We categorized patients according to COPD severity based on forced expiratory volume in 1 second (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 1-4).,We estimated the odds ratios (ORs) by logistic regression, adjusting for age, sex, smoking status, COPD severity, and frequent exacerbator phenotype the previous year.,Of the patients, 16.4% had ≥1 severe exacerbations, varying from 9.3% in mild GOLD grade 1 to 44% in very severe COPD patients.,A history of at least two prior severe exacerbations was positively associated with new severe exacerbations (adjusted OR, 6.73; 95% confidence interval [CI], 3.53-12.83) and mortality (adjusted OR, 7.63; 95%CI, 3.41-17.05).,Older age and several comorbidities, such as heart failure and diabetes, were similarly associated.,Hospitalized exacerbations occurred with all grades of airflow limitation.,A history of severe exacerbations was associated with new hospitalized exacerbations and mortality. | The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.,The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990-2005, using the healthcare databases from the province of Quebec, Canada.,Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified.,The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.,The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively.,The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th.,The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first.,Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.,The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation.,Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) are progressively limited in their ability to undertake normal everyday activities by a combination of exertional dyspnoea and peripheral muscle weakness.,COPD is characterised by expiratory flow limitation, resulting in air trapping and lung hyperinflation.,Hyperinflation increases acutely under conditions such as exercise or exacerbations, with an accompanying sharp increase in the intensity of dyspnoea to distressing and intolerable levels.,Air trapping, causing increased lung hyperinflation, can be present even in milder COPD during everyday activities.,The resulting activity-related dyspnoea leads to a vicious spiral of activity avoidance, physical deconditioning, and reduced quality of life, and has implications for the early development of comorbidities such as cardiovascular disease.,Various strategies exist to reduce hyperinflation, notably long-acting bronchodilator treatment (via reduction in flow limitation and improved lung emptying) and an exercise programme (via decreased respiratory rate, reducing ventilatory demand), or their combination.,Optimal bronchodilation can reduce exertional dyspnoea and increase a patient's ability to exercise, and improves the chance of successful outcome of a pulmonary rehabilitation programme.,There should be a lower threshold for initiating treatments appropriate to the stage of the disease, such as long-acting bronchodilators and an exercise programme for patients with mild-to-moderate disease who experience persistent dyspnoea. | 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) includes chronic bronchitis and emphysema.,Environmental exposure, primarily cigarette smoking, can cause high oxidative stress and is the main factor of COPD development.,Cigarette smoke also contributes to the imbalance of oxidant/antioxidant due to exogenous reactive oxygen species (ROS).,Moreover, endogenously released ROS during the inflammatory process and mitochondrial dysfunction may contribute to this disease progression.,ROS and reactive nitrogen species (RNS) can oxidize different biomolecules such as DNA, proteins, and lipids leading to epithelial cell injury and death.,Various detoxifying enzymes and antioxidant defense systems can be involved in ROS removal.,In this review, we summarize the main findings regarding the biological role of ROS, which may contribute to COPD development, and cytoprotective mechanisms against this disease progression. | Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung disease.,Sialic acid-binding immunoglobulin-type lectins 9 (Siglec-9) is predominantly expressed on innate immune cells and has been shown to exert regulatory effect on immune cells through glycan recognition.,Soluble Siglec-9 (sSiglec-9), the extracellular region of Siglec-9, might fulfill its function partly by competitive inhibiting siglec-9 binding to its ligands; however, the role of Siglec-9 and sSiglec-9 in the pathogenesis COPD remain largely unknown.,In this study, we showed that Siglec-9 expression in alveolar and peripheral blood neutrophil were increased in COPD patients by immunofluorescence and flow cytometry, respectively.,Plasma levels of sSiglelc-9 were elevated in COPD patients by ELISA.,In vitro, Siglec-9 expression and/or sSiglelc-9 levels were up-regulated by cigarette smoke extract (CSE), lipopolysaccharide (LPS), some cytokines, and dexamethasone (DEX).,Recombinant sSiglce-9 increased oxidative burst in neutrophil and enhanced neutrophil chemotaxis toward IL-8 independent on CXCR1 and CXCR2 expression, but it did not affect neutrophil apoptosis or secretions of inflammatory cytokines.,In conclusion, Siglec-9 was complementarily increased to induce a negative feedback loop to limit neutrophil activation in COPD, sSiglce-9 enhanced neutrophil ROS and chemotaxis toward IL-8 likely via competitively inhibiting ligands binding to Siglec-9. | 1 |
In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD).,However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory.,The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients.,A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition.,Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St George’s Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire).,Severity of exacerbation was graded as moderate or severe according to health care utilization.,Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year.,Random effects modeling, within hierarchical linear modeling, was used for analysis.,During follow-up, 419 (96% moderate) acute exacerbations were registered.,At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life.,However, no significant difference in FEV1 decline over time was found between the two groups (54.7±13 mL/year versus 85.4±15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively).,This was also the case for all other measurements.,Our results suggest that frequent moderate exacerbations do not contribute to accelerated clinical and functional decline in COPD patients who are ex-smokers. | Fibrinogen is a marker of systemic inflammation and may be important in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD).,We used baseline data from Atherosclerosis Risk in Communities and Cardiovascular Health Studies to determine the relation between fibrinogen levels and COPD and to examine how fibrinogen levels at baseline affected outcomes of death, development of COPD, lung function decline, and COPD-hospitalizations.,Our study sample included 20,192 subjects, of whom 2995 died during the follow-up period.,The mean fibrinogen level was 307.6 mg/dL and 10% of the sample had levels >393.0 mg/dL.,Subjects with Stage 3 or 4 COPD were more likely to have a fibrinogen level >393.0 mg/dL (odds ratio 2.28, 95% confidence interval [CI]: 1.79-2.95).,In the longitudinal adjusted models, fibrinogen levels >393 mg/dL predicted mortality (hazards ratio 1.54, 95% CI: 1.39-1.70), COPD-related hospitalization (hazards ratio 1.45, 95% CI: 1.27-1.67), and incident Stage 2 COPD (odds ratio 1.36, 95% CI: 1.07-1.74).,Similar findings were seen with continuous fibrinogen levels.,In the Atherosclerosis Risk in Communities/Cardiovascular Health Studies cohort data, higher fibrinogen levels are predictors of mortality, COPD-related hospitalizations, and incident Stage 2 COPD. | 1 |
Both chronic Obstruction Pulmonary Disease (COPD) and lung cancer are leading causes of death globally.,Although COPD and lung cancer coexist frequently, it is unknown whether lung cancer patients with COPD harbor distinct genomic characteristics compared to those without COPD.,In this study, we retrospectively analyzed genomic sequencing data from 272 patients with lung adenocarcinoma (LUAD) and compared the genetic alterations in LUAD patients with and without COPD.,Integrative analysis of whole-genome and exome sequencing data revealed that COPD and non-COPD groups showed high concordance in mutational burden and spectra.,Notably, we also found that EGFR mutations were more prevalent in LUAD patients without COPD, whereas mutated LRP1B was more frequently observed in LUAD patients with COPD.,In addition, multi-variable analysis with logistic regression demonstrated that mutation of LRP1B was a predictive marker for the presence of COPD in the patients with LUAD.,Our analysis demonstrated for the first time the high concordance in genomic alterations between the tumors from LUAD patients with and without COPD.,We also identified higher prevalence of LRP1B among the LUAD patients with COPD, which might help understand the underlying mechanisms which link COPD and lung cancer. | •COPD is a risk factor for lung cancer beyond their shared aetiology.,•Both are driven by oxidative stress.,•Both are linked to cellular aging, senescence and telomere shortening.,•Both have been linked to genetic predisposition.,•Both show altered epigenetic regulation of gene expression.,COPD is a risk factor for lung cancer beyond their shared aetiology.,Both are driven by oxidative stress.,Both are linked to cellular aging, senescence and telomere shortening.,Both have been linked to genetic predisposition.,Both show altered epigenetic regulation of gene expression.,Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden.,Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking.,Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying genetic predisposition, telomere shortening, mitochondrial dysfunction or premature aging.,In the majority of smokers, the burden of smoking may be dealt with by the body’s defense mechanisms: anti-oxidants such as superoxide dismutases, anti-proteases and DNA repair mechanisms.,However, in the case of both diseases these fail, leading to cancer if mutations occur or COPD if damage to the cell and proteins becomes too great.,Alternatively COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage, chronic exposure to pro-inflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation.,Understanding the mechanisms that drive these processes in primary cells from patients with these diseases along with better disease models is essential for the development of new treatments. | 1 |
Exacerbations of COPD represent an important medical and health care problem.,Certain susceptible patients suffer recurrent exacerbations and as a consequence have a poorer prognosis.,The effects of bronchial infection, either acute or chronic, and of the inflammation characteristic of the disease itself raise the question of the possible role of antibiotics and anti-inflammatory agents in modulating the course of the disease.,However, clinical guidelines base their recommendations on clinical trials that usually exclude more severe patients and patients with more comorbidities, and thus often fail to reflect the reality of clinicians attending more severe patients.,In order to discuss aspects of clinical practice of relevance to pulmonologists in the treatment and prevention of recurrent exacerbations in patients with severe COPD, a panel discussion was organized involving expert pulmonologists who devote most of their professional activity to day hospital care.,This article summarizes the scientific evidence currently available and the debate generated in relation to the following aspects: bacterial and viral infections, chronic bronchial infection and its treatment with cyclic oral or inhaled antibiotics, inflammatory mechanisms and their treatment, and the role of computerized tomography as a diagnostic tool in patients with severe COPD and frequent exacerbations. | Moraxella catarrhalis causes approximately 10% of exacerbations in chronic obstructive pulmonary disease (COPD) and also colonizes the lower airway in stable patients.,Little is known about the effects of colonization by M. catarrhalis on airway inflammation and protease-antiprotease balance, and how these changes compare to those seen during exacerbations.,Since COPD is a progressive inflammatory disease, elucidating the effects of bacterial colonization and exacerbation on airway inflammation is relevant to understanding disease progression in COPD.,Our aims were (1) Analyze changes in airway inflammation in colonization and exacerbation of COPD due to M. catarrhalis; (2) Explore protease-antiprotease balance in colonization and exacerbation due to M. catarrhalis.,Our hypothesis were (1) Acquisition of a new strain of M. catarrhalis in COPD increases airway inflammation from baseline and alters the protease-antiprotease balance towards a more proteolytic environment; (2) These changes are greater during exacerbations associated with M. catarrhalis as compared to colonization.,Thirty-nine consecutive COPD patients with 76 acquisitions of a new strain of M. catarrhalis over a 6-year period were identified in a prospective study.,Seventy-six pre-acquisition sputum supernatant samples, obtained just before acquisition of M catarrhalis, and 76 acquisition samples (34 were associated with exacerbation, 42 with colonization) were analyzed for IL-8, TNF-α, Neutrophil Elastase (NE) and Secretory leukocyte protease inhibitor (SLPI).,Changes were compared in paired samples from each patient.,IL-8, TNF-α and NE were significantly elevated after acquisition of M. catarrhalis, compared to pre-acquisition samples (p =< 0.001 for all three).,These changes were present in colonization (p = 0.015 for IL-8; p =< 0.001 for TNF-α and NE) as well as in exacerbation (p =< 0.001 for all three), compared to pre-acquisition levels.,SLPI was significantly lower after acquisition (p =< 0.001), in colonization (p =< 0.001) as well as in exacerbation (p = 0.004), compared to pre-acquisition levels.,SLPI levels correlated negatively with NE levels (R2 = 0.07; p = 0.001).,Acquisition of M. catarrhalis in COPD causes increased airway inflammation and worsening protease-antiprotease imbalance during exacerbations and also in colonization, even in the absence of increased symptoms.,These effects could contribute to progression of airway disease in COPD. | 1 |
Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD.,Secondary analyses were performed to examine the effect of background long-acting beta2-agonist (LABA) use on the efficacy and safety of nebulized GLY.,In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily.,Lung function, patient-reported outcomes, exacerbations, and safety were assessed.,Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P<0.001) and St George’s Respiratory Questionnaire total score (SGRQ; LABA-yes: −2.957 and −3.888; LABA-no: −3.301 and −2.073, respectively; P<0.05).,Incidence of treatment-emergent adverse events (TEAEs) was similar in LABA subgroups, and lower in GLY 25 µg vs placebo.,In the 48-week active-controlled study, GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 (LABA-yes: 0.106 and 0.092 L; LABA-no: 0.096 and 0.096 L, respectively) and in SGRQ total score (LABA-yes: −5.190 and −3.094; LABA-no: −4.368 and −4.821, respectively).,Incidence of TEAEs was similar between GLY and TIO, and across LABA subgroups.,Exacerbation rates were similar across treatments and LABA subgroups, and cardiovascular events of special interest were more frequent in the LABA-no subgroup.,Nebulized GLY, combined with LABA, did not generate any additional safety signals.,Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA. | Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD).,In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days’ administration of doses up to 700 μg.,In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days.,A total of 355 COPD patients (mean age 62 years, mean forced expiratory volume in 1 s [FEV1] 44% of predicted) were randomized in a double-blind, placebo-controlled parallel group study.,Inhaled corticosteroids as well as short-acting bronchodilators were permitted.,Once-daily treatments (44, 88, 175 or 350 μg revefenacin or matching placebo) were administered by a standard jet nebulizer, for 28 days.,The primary endpoint was change from baseline in D28 trough FEV1, and secondary endpoints included weighted mean FEV1 over 0 to 24 h and rescue medication (albuterol) use.,Safety evaluations included adverse events, laboratory assessments, electrocardiograms and 24-h Holter profiles.,Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); 44 μg produced a sub-therapeutic response.,At doses ≥88 μg, more than 80% of patients achieved at least a 100-mL increase from baseline FEV1 in the first 4 h post dose compared with 33% of placebo patients.,For doses ≥88 μg, D28 24 h weighted mean differences from placebo for FEV1 were numerically similar to respective trough FEV1 values, indicating bronchodilation was sustained for 24 h post dose.,Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day.,The 350 μg dose did not demonstrate additional efficacy over that observed with 175 μg revefenacin.,Revefenacin was generally well tolerated, with minimal reports of systemic anti-cholinergic effects.,These data suggest that 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials.,Revefenacin offers the potential for the first once-daily LAMA for nebulization in patients with COPD who require or prefer a nebulized drug delivery option.,ClinicalTrials.gov NCT02040792.,Registered January 16, 2014. | 1 |
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. | The mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood.,Inhaled corticosteroids (ICSs) are widely used in COPD, but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown.,The aim of this study was to evaluate the effect of ICSs following pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme-2 (ACE2).,We evaluated the effect of ICS administration on pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration.,Mice deficient in the type I IFN-α/β receptor (Ifnar1−/−) and administration of exogenous IFN-β were used to study the functional role of type-I interferon signaling in ACE2 expression.,We compared sputum ACE2 expression in patients with COPD stratified according to use or nonuse of ICS.,ICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous IFN-β administration, and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect.,ICS administration attenuated expression of ACE2 in airway epithelial cell cultures from patients with COPD and in mice with elastase-induced COPD-like changes.,Compared with ICS nonusers, patients with COPD who were taking ICSs also had reduced sputum expression of ACE2.,ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2.,This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD. | 1 |
Viruses are a common cause of exacerbations in chronic obstructive pulmonary disease (COPD).,They activate toll-like receptors (TLRs) 3, 7, and 8, leading to a pro-inflammatory response.,We have characterized the responses of TLR3 and TLR7/8 in lung tissue explants from COPD patients and control smokers.,We prepared lung whole tissue explants (WTEs) from patients undergoing surgery for confirmed or suspected lung cancer.,In order to mimic the conditions of viral infection, we used poly(I:C) for TLR3 stimulation and R848 for TLR7/8 stimulation.,These TLR ligands were used alone and in combination.,The effects of tumor necrosis factor α (TNFα) neutralization and dexamethasone on TLR responses were examined.,Inflammatory cytokine release was measured by enzyme-linked immunosorbent assay and gene expression by quantitative real-time polymerase chain reaction.,WTEs from COPD patients released higher levels of pro-inflammatory cytokines compared with WTEs from smokers.,Activation of multiple TLRs led to a greater than additive release of TNFα and CCL5.,TNFα neutralization and dexamethasone treatment decreased cytokine release.,This WTE model shows an enhanced response of COPD compared with controls, suggesting an increased response to viral infection.,There was amplification of innate immune responses with multiple TLR stimulation. | Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD).,We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD.,Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients.,Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models.,Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells.,None of the TLR4 SNPs was associated with FEV1 level.,Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time.,This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD. | 1 |
Early integration of palliative home care (PHC) might positively affect people with chronic obstructive pulmonary disease (COPD).,However, PHC as a holistic approach is not well integrated in clinical practice at the end-stage COPD.,General practitioners (GPs) and community nurses (CNs) are highly involved in primary and home care and could provide valuable perspectives about barriers to and facilitators for early integrated PHC in end-stage COPD.,Three focus groups were organised with GPs (n = 28) and four with CNs (n = 28), transcribed verbatim and comparatively analysed.,Barriers were related to the unpredictability of COPD, a lack of disease insight and resistance towards care of the patient, lack of cooperation and experience with PHC for professional caregivers, lack of education about early integrated PHC, insufficient continuity of care from hospital to home, and lack of communication about PHC between professional caregivers and with end-stage COPD patients.,Facilitators were the use of trigger moments for early integrating PHC, such as after a hospital admission or when an end-stage COPD patient becomes oxygen-dependent or housebound, positive attitudes towards PHC in informal caregivers, more focus on early integration of PHC in professional caregivers’ education, implementing advance care planning in healthcare and PHC systems, and enhancing communication about care and PHC.,The results provide insights for clinical practice and the development of key components for successful practice in a phase 0-2 Early Integration of PHC for end-stage COPD (EPIC) trial, such as improving care integration, patients’ disease insight and training PHC nurses in care for end-stage COPD.,Research in Belgium provides insights into the possible implementation of early palliative care (PC) for patients with chronic obstructive pulmonary disease (COPD).,While many sufferers of end-stage COPD would benefit emotionally and physically from palliative home care in their final months, many only receive PC in their last few days.,Charlotte Scheerens at End-of-life Care Research Group, Ghent University and Vrije Universiteit Brussel (VUB) and co-workers at Ghent University and Vrije Universiteit Brussel (VUB) conducted focus group discussions with 28 general practitioners and 28 community nurses to establish the main barriers to and facilitators for palliative home care implementation for end-stage COPD.,Barriers included the unpredictability of the disease, lack of patient understanding of COPD, and complex communication issues between staff across primary care, hospitals and community settings.,Identifying ‘triggers’ to implement PC-oxygen dependence, for example-and improving communication and understanding of COPD at all levels could facilitate early integration of palliative home care (PHC). | To evaluate the nonclinical outcomes of a proactive palliative care program funded and operated by a health system for Medicare Advantage plan beneficiaries.,Observational, retrospective study using propensity‐based matching.,A health system in southern California.,Individuals who received the intervention between 2007 and 2014 (n = 368) were matched with 1,075 comparison individuals within each of four disease groups: cancer, chronic obstructive pulmonary disease, heart failure, and dementia.,All were known to be dead at the time of the retrospective study, were Medicare Advantage beneficiaries, and had 2 years of usage data before death.,Median age at death for each disease group was older than 80.,Home‐ and clinic‐based palliative care (PC) services provided by a multidisciplinary team.,Outcomes included hospital costs, other healthcare costs, readmission rates, hospital admissions and bed days, intensive care unit use in final 30 days of life, and death within 30 days of an admission.,Intervention participants in all four disease groups had less hospital use and lower hospital costs nonintervention participants, which drove lower overall healthcare costs.,In the final 6 months of life, healthcare costs for the intervention groups stayed largely the same from month to month, whereas costs for comparison participants increased dramatically.,In the context of an alternative payment model in which the provider was “at risk” of bearing the costs of care, a proactive PC program helped to avoid the escalation in hospital use and costs commonly seen in the final months of life. | 1 |
The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research.,The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls.,Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups.,Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO.,Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values.,To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile.,While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters.,Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r = −0.52, p = 0.005 and r = −0.61, p = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r = −0.25, p = 0.47 and r = −0.15, p = 0.96, respectively), and may be driving overall associations in the general cohort.,In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO.,These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD. | Fibrinogen is a marker of systemic inflammation and may be important in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD).,We used baseline data from Atherosclerosis Risk in Communities and Cardiovascular Health Studies to determine the relation between fibrinogen levels and COPD and to examine how fibrinogen levels at baseline affected outcomes of death, development of COPD, lung function decline, and COPD-hospitalizations.,Our study sample included 20,192 subjects, of whom 2995 died during the follow-up period.,The mean fibrinogen level was 307.6 mg/dL and 10% of the sample had levels >393.0 mg/dL.,Subjects with Stage 3 or 4 COPD were more likely to have a fibrinogen level >393.0 mg/dL (odds ratio 2.28, 95% confidence interval [CI]: 1.79-2.95).,In the longitudinal adjusted models, fibrinogen levels >393 mg/dL predicted mortality (hazards ratio 1.54, 95% CI: 1.39-1.70), COPD-related hospitalization (hazards ratio 1.45, 95% CI: 1.27-1.67), and incident Stage 2 COPD (odds ratio 1.36, 95% CI: 1.07-1.74).,Similar findings were seen with continuous fibrinogen levels.,In the Atherosclerosis Risk in Communities/Cardiovascular Health Studies cohort data, higher fibrinogen levels are predictors of mortality, COPD-related hospitalizations, and incident Stage 2 COPD. | 1 |
The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components.,Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown.,The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands.,A cost-utility study was performed, using an individual-level Markov model.,To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial.,In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium.,Cost-utility analysis was performed from the Dutch health care payer’s perspective using a 15-year time horizon in the base-case analysis.,The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%).,Both univariate and probabilistic sensitivity analyses were performed.,Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence.,As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY.,Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY.,Results were robust in univariate and probabilistic sensitivity analyses.,Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence.,Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively.,Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds. | Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible disease responsible for the deaths of 3 million people worldwide in 2005, and predicted to be the third leading cause of death worldwide by 2030.,Many COPD models developed to date have followed a Markov structure, in which patients or populations can move between defined health states over successive time periods or cycles.,In COPD, health states are typically based on disease severity defined solely by lung function, as described by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.,These current modelling methods may restrict the ability to reflect the disease progression/clinical pathway or clinical practice.,Given these limitations in previous COPD models, the authors aimed to develop a more flexible model that could improve on the description of the clinical disease pathway.,The overall objective of this model was to inform the development of policies, guidelines or cost-effectiveness analyses.,A second objective was to validate the model in relation to existing epidemiology studies of COPD.,A patient simulation model was developed in Microsoft Excel™.,The predictability of the model was tested by populating it with data from natural history of disease studies as well as with clinical trial data.,Each patient moves through the model with demographic characteristics randomly generated from a set distribution.,These characteristics determine the risk of clinical events occurring in the model.,The validation with these studies found the model to have generally good predictive ability, yielding in this way a good degree of external validity.,The micro-simulation model is a flexible approach for modelling COPD that allows consideration of complex COPD treatment pathways.,The model was found to be generally robust in terms of predicting clinical outcomes of published studies when tested against other studies.,It has significant potential as a tool for supporting future COPD treatment positioning decisions as well as to inform the development of policies, guidelines or cost-effectiveness analyses. | 1 |
The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by an interaction of environmental influences, particularly cigarette smoking, and genetic determinants.,Given the global increase in COPD, research on the genomic variants that affect susceptibility to this complex disorder is reviving.,In the present study, we investigated whether single nucleotide polymorphisms in 'a disinter-grin and metalloprotease' 33 (ADAM33) are associated with the development and course of COPD.,We genotyped 150 German COPD patients and 152 healthy controls for the presence of the F+1 and S_2 SNPs in ADAM 33 that lead to the base pair exchange G to A and C to G, respectively.,To assess whether these genetic variants are influential in the course of COPD, we subdivided the cohort into two subgroups comprising 60 patients with a stable and 90 patients with an unstable course of disease.,In ADAM33, the frequency of the F+1 A allele was 35.0% among stable and 43.9% among unstable COPD subjects, which was not significantly different from the 35.5% found in the controls (P = 0.92 and P = 0.07, respectively).,The frequency of the S_2 mutant allele in subjects with a stable COPD was 23.3% (P = 0.32), in subjects with an unstable course 30.6% (P = 0.47).,The study shows that there is no significant difference in the distribution of the tested SNPs between subjects with and without COPD.,Furthermore, these polymorphisms appear to have no consequences for the stability of the disease course. | Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD).,We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals.,We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2.,Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. | 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 aim of this study was to measure HrQoL during acute exacerbations of COPD using generic and disease-specific instruments, and to assess completeness, proportion with best or worst health state, sensitivity to change and discriminative ability for each instrument.,EQ-5D, SF-12 and SGRQ were obtained from COPD patients with GOLD stage III and IV hospitalized for an acute exacerbation both at admission and discharge.,To assess the instruments' properties, utility values were calculated for EQ-5D and SF-12, and a total score was derived from the SGRQ.,Mean utilities ranged from 0.54 (SF-12, stage IV) to 0.62 (EQ-5D, stage III) at admission, and from 0.58 (SF-12, stage IV) to 0.84 (EQ-5D, stage III) at discharge.,Completeness was best for EQ-5D and SGRQ, while no utility value for the SF-12 could be calculated for more than 30%.,For SGRQ subscales, the minimal score occurred in up to 11% at admission, while full health was observed for the EQ-5D at discharge in 13%.,Sensitivity to change was generally good, whereas discrimination between COPD stages was low for the EQ-5D.,Acute exacerbations seriously impair health status and quality of life.,The EQ-5D is generally suitable to measure HrQoL in exacerbations of severe COPD, although the high proportion of patients reporting full health at discharge poses a problem.,The main issue with the SF-12 is the high proportion of missing values in a self-assessed setting.,Properties of the SGRQ were satisfactory.,However, since no utility values can be derived from this disease-specific instrument, it is not suitable for cost-utility analyses in health-economic evaluations. | 1 |
COPD is a significant cause of morbidity and mortality.,In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation.,Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy.,In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention.,In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13.,The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions.,We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. | Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality.,COPD is typified by persistent, progressive airflow limitation and a range of respiratory and systemic symptoms such as breathlessness, coughing, wheezing, depression, anxiety, general fatigue, and sleeping difficulties.,Despite receiving treatment for COPD, many patients suffer from regular symptoms that affect their daily lives and lead to increased morbidity.,These symptoms vary in severity, frequency, and type, and can occur at any time throughout the 24-h day, with over half of patients with COPD experiencing symptoms in the morning, during the day, and at nighttime.,Despite the prevalence of symptoms, patient and physician perception of the impact of COPD symptoms on patients’ lives is not always in concordance.,Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) has the potential to treat the symptoms of COPD in addition to improving lung function.,This review therefore examines the burden of symptoms experienced throughout the day by patients with COPD and the evidence for combined LAMA/LABA treatment in terms of symptom management.,As patients with COPD experience varying symptoms throughout the course of their disease, the role of tailoring treatment to the individual needs of the patient is also examined.,We conclude that the symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day, and have a substantial impact on patients’ health status and quality of life.,In order to provide effective, patient-orientated care, patients with COPD should be evaluated on the basis of lung function, the frequency of symptoms, and patient-perceived impact of symptoms on their lives.,Therapy should be chosen carefully based on individualized assessment, ensuring personalization to the individual needs of the patient. | 1 |
Chronic obstructive pulmonary disease (COPD) and asthma are common diseases with a heterogeneous distribution worldwide.,Here, we present methods and disease and risk estimates for COPD and asthma from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 study.,The GBD study provides annual updates on estimates of deaths, prevalence, and disability-adjusted life years (DALYs), a summary measure of fatal and non-fatal disease outcomes, for over 300 diseases and injuries, for 188 countries from 1990 to the most recent year.,We estimated numbers of deaths due to COPD and asthma using the GBD Cause of Death Ensemble modelling (CODEm) tool.,First, we analysed data from vital registration and verbal autopsy for the aggregate category of all chronic respiratory diseases.,Subsequently, models were run for asthma and COPD relying on covariates to predict rates in countries that have incomplete or no vital registration data.,Disease estimates for COPD and asthma were based on systematic reviews of published papers, unpublished reports, surveys, and health service encounter data from the USA.,We used the Global Initiative of Chronic Obstructive Lung Disease spirometry-based definition as the reference for COPD and a reported diagnosis of asthma with current wheeze as the definition of asthma.,We used a Bayesian meta-regression tool, DisMod-MR 2.1, to derive estimates of prevalence and incidence.,We estimated population-attributable fractions for risk factors for COPD and asthma from exposure data, relative risks, and a theoretical minimum exposure level.,Results were stratified by Socio-demographic Index (SDI), a composite measure of income per capita, mean years of education over the age of 15 years, and total fertility rate.,In 2015, 3·2 million people (95% uncertainty interval [UI] 3·1 million to 3·3 million) died from COPD worldwide, an increase of 11·6% (95% UI 5·3 to 19·8) compared with 1990.,There was a decrease in age-standardised death rate of 41·9% (37·7 to 45·1) but this was counteracted by population growth and ageing of the global population.,From 1990 to 2015, the prevalence of COPD increased by 44·2% (41·7 to 46·6), whereas age-standardised prevalence decreased by 14·7% (13·5 to 15·9).,In 2015, 0·40 million people (0·36 million to 0·44 million) died from asthma, a decrease of 26·7% (−7·2 to 43·7) from 1990, and the age-standardised death rate decreased by 58·8% (39·0 to 69·0).,The prevalence of asthma increased by 12·6% (9·0 to 16·4), whereas the age-standardised prevalence decreased by 17·7% (15·1 to 19·9).,Age-standardised DALY rates due to COPD increased until the middle range of the SDI before reducing sharply.,Age-standardised DALY rates due to asthma in both sexes decreased monotonically with rising SDI.,The relation between with SDI and DALY rates due to asthma was attributed to variation in years of life lost (YLLs), whereas DALY rates due to COPD varied similarly for YLLs and years lived with disability across the SDI continuum.,Smoking and ambient particulate matter were the main risk factors for COPD followed by household air pollution, occupational particulates, ozone, and secondhand smoke.,Together, these risks explained 73·3% (95% UI 65·8 to 80·1) of DALYs due to COPD.,Smoking and occupational asthmagens were the only risks quantified for asthma in GBD, accounting for 16·5% (14·6 to 18·7) of DALYs due to asthma.,Asthma was the most prevalent chronic respiratory disease worldwide in 2015, with twice the number of cases of COPD.,Deaths from COPD were eight times more common than deaths from asthma.,In 2015, COPD caused 2·6% of global DALYs and asthma 1·1% of global DALYs.,Although there are laudable international collaborative efforts to make surveys of asthma and COPD more comparable, no consensus exists on case definitions and how to measure disease severity for population health measurements like GBD.,Comparisons between countries and over time are important, as much of the chronic respiratory burden is either preventable or treatable with affordable interventions.,Bill & Melinda Gates Foundation. | Moraxella catarrhalis causes approximately 10% of exacerbations in chronic obstructive pulmonary disease (COPD) and also colonizes the lower airway in stable patients.,Little is known about the effects of colonization by M. catarrhalis on airway inflammation and protease-antiprotease balance, and how these changes compare to those seen during exacerbations.,Since COPD is a progressive inflammatory disease, elucidating the effects of bacterial colonization and exacerbation on airway inflammation is relevant to understanding disease progression in COPD.,Our aims were (1) Analyze changes in airway inflammation in colonization and exacerbation of COPD due to M. catarrhalis; (2) Explore protease-antiprotease balance in colonization and exacerbation due to M. catarrhalis.,Our hypothesis were (1) Acquisition of a new strain of M. catarrhalis in COPD increases airway inflammation from baseline and alters the protease-antiprotease balance towards a more proteolytic environment; (2) These changes are greater during exacerbations associated with M. catarrhalis as compared to colonization.,Thirty-nine consecutive COPD patients with 76 acquisitions of a new strain of M. catarrhalis over a 6-year period were identified in a prospective study.,Seventy-six pre-acquisition sputum supernatant samples, obtained just before acquisition of M catarrhalis, and 76 acquisition samples (34 were associated with exacerbation, 42 with colonization) were analyzed for IL-8, TNF-α, Neutrophil Elastase (NE) and Secretory leukocyte protease inhibitor (SLPI).,Changes were compared in paired samples from each patient.,IL-8, TNF-α and NE were significantly elevated after acquisition of M. catarrhalis, compared to pre-acquisition samples (p =< 0.001 for all three).,These changes were present in colonization (p = 0.015 for IL-8; p =< 0.001 for TNF-α and NE) as well as in exacerbation (p =< 0.001 for all three), compared to pre-acquisition levels.,SLPI was significantly lower after acquisition (p =< 0.001), in colonization (p =< 0.001) as well as in exacerbation (p = 0.004), compared to pre-acquisition levels.,SLPI levels correlated negatively with NE levels (R2 = 0.07; p = 0.001).,Acquisition of M. catarrhalis in COPD causes increased airway inflammation and worsening protease-antiprotease imbalance during exacerbations and also in colonization, even in the absence of increased symptoms.,These effects could contribute to progression of airway disease in COPD. | 1 |
The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.,The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990-2005, using the healthcare databases from the province of Quebec, Canada.,Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified.,The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.,The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively.,The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th.,The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first.,Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.,The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation.,Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality. | Exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant increases in resource utilization and cost to the health care system.,COPD patients with chronic bronchitis and a history of exacerbations pose an additional burden to the system.,This study examined health care utilization and cost among these patients.,For this retrospective analysis, data were extracted from a large national health plan with a predominantly Medicare population.,This study involved patients who were aged 40-89 years, had been enrolled continuously for 24 months or more, had at least two separate insurance claims for COPD with chronic bronchitis (International Classification of Diseases, Ninth Revision, Clinical Modification code 491.xx), and had pharmacy claims for COPD maintenance medications between January 1, 2007, and March 31, 2009.,Two years of data were examined for each patient; the index date was defined as the first occurrence of COPD.,Baseline characteristics were obtained from the first year of data, with health outcomes tracked in the second year.,Severe exacerbation was defined by COPD-related hospitalization or death; moderate exacerbation was defined by oral or parenteral corticosteroid use.,Adjusted numbers of exacerbations and COPD-related costs per patient were estimated controlling for demographic and clinical characteristics.,The final study sample involved 8554 patients; mean age was 70.1 ± 8.6 years and 49.8% of the overall population had exacerbation, 13.9% had a severe exacerbation only, 29.1% had a moderate exacerbation only, and 6.8% had both a severe and moderate exacerbation.,COPD-related mean annual costs were $4069 (all figures given in US dollars) for the overall population and $6381 for patients with two or more exacerbations.,All-cause health care costs were $18,976 for the overall population and $23,901 for patients with history of two or more exacerbations.,Severity of exacerbations, presence of cardiovascular disease, diabetes, and long-term oxygen use were associated with higher adjusted costs.,The results indicate that despite treatment with maintenance medications, COPD patients continue to have exacerbations resulting in higher costs.,New medications and disease management interventions are warranted to reduce the severity and frequency of exacerbations and the related cost impact of the disease. | 1 |
Oral taxa are often found in the chronic obstructive pulmonary disease (COPD) lung microbiota, but it is not clear if this is due to a physiologic process such as aspiration or experimental contamination at the time of specimen collection.,Microbiota samples were obtained from nine subjects with mild or moderate COPD by swabbing lung tissue and upper airway sites during lung lobectomy.,Lung specimens were not contaminated with upper airway taxa since they were obtained surgically.,The microbiota were analyzed with 16S rRNA gene qPCR and 16S rRNA gene hypervariable region 3 (V3) sequencing.,Data analyses were performed using QIIME, SourceTracker, and R.,Streptococcus was the most common genus in the oral, bronchial, and lung tissue samples, and multiple other taxa were present in both the upper and lower airways.,Each subject’s own bronchial and lung tissue microbiota were more similar to each other than were the bronchial and lung tissue microbiota of two different subjects (permutation test, p = 0.0139), indicating more within-subject similarity than between-subject similarity at these two lung sites.,Principal coordinate analysis of all subject samples revealed clustering by anatomic sampling site (PERMANOVA, p = 0.001), but not by subject.,SourceTracker analysis found that the sources of the lung tissue microbiota were 21.1% (mean) oral microbiota, 8.7% nasal microbiota, and 70.1% unknown.,An analysis using the neutral theory of community ecology revealed that the lung tissue microbiota closely reflects the bronchial, oral, and nasal microbiota (immigration parameter estimates 0.69, 0.62, and 0.74, respectively), with some evidence of ecologic drift occurring in the lung tissue.,This is the first study to evaluate the mild-moderate COPD lung tissue microbiota without potential for upper airway contamination of the lung samples.,In our small study of subjects with COPD, we found oral and nasal bacteria in the lung tissue microbiota, confirming that aspiration is a source of the COPD lung microbiota. | Genome Wide Association Studies (GWAS) and expression quantitative trait locus (eQTL) analyses have identified genetic associations with a wide range of human phenotypes.,However, many of these variants have weak effects and understanding their combined effect remains a challenge.,One hypothesis is that multiple SNPs interact in complex networks to influence functional processes that ultimately lead to complex phenotypes, including disease states.,Here we present CONDOR, a method that represents both cis- and trans-acting SNPs and the genes with which they are associated as a bipartite graph and then uses the modular structure of that graph to place SNPs into a functional context.,In applying CONDOR to eQTLs in chronic obstructive pulmonary disease (COPD), we found the global network “hub” SNPs were devoid of disease associations through GWAS.,However, the network was organized into 52 communities of SNPs and genes, many of which were enriched for genes in specific functional classes.,We identified local hubs within each community (“core SNPs”) and these were enriched for GWAS SNPs for COPD and many other diseases.,These results speak to our intuition: rather than single SNPs influencing single genes, we see groups of SNPs associated with the expression of families of functionally related genes and that disease SNPs are associated with the perturbation of those functions.,These methods are not limited in their application to COPD and can be used in the analysis of a wide variety of disease processes and other phenotypic traits. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient’s condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization.,Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function.,A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated.,COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy.,Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations.,For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate.,Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis.,Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids.,A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations. | To evaluate risk factors associated with exacerbation frequency in primary care.,Information on exacerbations of chronic obstructive pulmonary disease (COPD) has mainly been generated by secondary care-based clinical cohorts.,Retrospective observational cohort study.,Electronic medical records database (England and Wales).,58 589 patients with COPD aged ≥40 years with COPD diagnosis recorded between 1 April 2009 and 30 September 2012, and with at least 365 days of follow-up before and after the COPD diagnosis, were identified in the Clinical Practice Research Datalink.,Mean age: 69 years; 47% female; mean forced expiratory volume in 1s 60% predicted.,Data on moderate or severe exacerbation episodes defined by diagnosis and/or medication codes 12 months following cohort entry were retrieved, together with demographic and clinical characteristics.,Associations between patient characteristics and odds of having none versus one, none versus frequent (≥2) and one versus frequent exacerbations over 12 months follow-up were evaluated using multivariate logistic regression models.,During follow-up, 23% of patients had evidence of frequent moderate-to-severe COPD exacerbations (24% one; 53% none).,Independent predictors of increased odds of having exacerbations during the follow-up, either frequent episodes or one episode, included prior exacerbations, increasing dyspnoea score, increasing grade of airflow limitation, females and prior or current history of several comorbidities (eg, asthma, depression, anxiety, heart failure and cancer).,Primary care-managed patients with COPD at the highest risk of exacerbations can be identified by exploring medical history for the presence of prior exacerbations, greater COPD disease severity and co-occurrence of other medical conditions. | 1 |
Heterogeneity of COPD results in different therapeutic effects for different patients receiving the same treatment.,COPD patients need to be individually treated according to their own characteristics.,The purpose of this study was to explore the differences in different CT phenotypic COPD by molecular metabolites through the use of metabolomics.,According to the characteristics of CT imaging, 42 COPD patients were grouped into phenotype E (n=20) or phenotype M (n=24).,Each COPD patient received tiotropium bromide powder for inhalation for a therapeutic period of 3 months.,All subjects were assigned into phenotype E in pre-therapy (EB, n=20), phenotype E in post-therapy (EA, n=20), phenotype M in pre-therapy (MB, n=22), phenotype M in post-therapy (MA, n=22), or normal control (N, n=24).,The method of metabolomics based on 1H nuclear magnetic resonance (1H-NMR) was used to compare the changes in serum metabolites between COPD patients and normal controls and between different phenotypes of COPD patients in pre- and post-therapy.,Patients with COPD phenotype E responded better to tiotropium bromide than patients with COPD phenotype M in terms of pulmonary function and COPD assessment test scores.,There were differences in metabolites in COPD patients vs normal control people.,Differences were also observed between different COPD phenotypic patients receiving the treatment in comparison with those who did not receive treatment.,The changes of metabolites involved lactate, phenylalanine, fructose, glycine, asparagine, citric acid, pyruvic acid, proline, acetone, ornithine, lipid, pyridoxine, maltose, betaine, lipoprotein, and so on.,These identified metabolites covered the metabolic pathways of amino acids, carbohydrates, lipids, genetic materials, and vitamin.,The efficacy of tiotropium bromide on COPD phenotype E is better than that of phenotype M.,Metabolites detected by 1H-NMR metabolomics have potentialities of differentiation of COPD and healthy people, discrimination of different COPD phenotypes, and giving insight into the individualized treatment of COPD. | Chronic obstructive pulmonary disease (COPD) has seriously impacted the health of individuals and populations.,In this study, proton nuclear magnetic resonance (1H NMR)-based metabonomics combined with multivariate pattern recognition analysis was applied to investigate the metabolic signatures of patients with COPD.,Serum and urine samples were collected from COPD patients (n = 32) and healthy controls (n = 21), respectively.,Samples were analyzed by high resolution 1H NMR (600 MHz), and the obtained spectral profiles were then subjected to multivariate data analysis.,Consistent metabolic differences have been found in serum as well as in urine samples from COPD patients and healthy controls.,Compared to healthy controls, COPD patients displayed decreased lipoprotein and amino acids, including branched-chain amino acids (BCAAs), and increased glycerolphosphocholine in serum.,Moreover, metabolic differences in urine were more significant than in serum.,Decreased urinary 1-methylnicotinamide, creatinine and lactate have been discovered in COPD patients in comparison with healthy controls.,Conversely, acetate, ketone bodies, carnosine, m-hydroxyphenylacetate, phenylacetyglycine, pyruvate and α-ketoglutarate exhibited enhanced expression levels in COPD patients relative to healthy subjects.,Our results illustrate the potential application of NMR-based metabonomics in early diagnosis and understanding the mechanisms of COPD. | 1 |
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