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Background: Chronic obstructive pulmonary disease (COPD) is associated with several extra-pulmonary effects of which skeletal muscle wasting is one of the most common and contributes to reduced quality of life, increased morbidity and mortality. The molecular mechanisms leading to muscle wasting are not fully understood. Proteomic analysis of human skeletal muscle is a useful approach for gaining insight into the molecular basis for normal and pathophysiological conditions.Methods: To identify proteins involved in the process of muscle wasting in COPD, we searched differentially expressed proteins in the vastus lateralis of COPD patients with low fat free mass index (FFMI), as a surrogate of muscle mass (COPDL, n = 10) (FEV1 33 ± 4.3% predicted, FFMI 15 ± 0.2 Kg.m-2), in comparison to patients with COPD and normal FFMI (COPDN, n = 8) and a group of age, smoking history, and sex matched healthy controls (C, n = 9) using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) technology, combined with mass spectrometry (MS). The effect of silencing DOT1L protein expression on markers of cell arrest was analyzed in skeletal muscle satellite cells (HSkMSCs) in vitro and assessed by qPCR and Western blotting.Results: A subset of 7 proteins was differentially expressed in COPDL compared to both COPDN and C. We found an increased expression of proteins associated with muscle homeostasis and protection against oxidative stress, and a decreased expression of structural muscle proteins and proteins involved in myofibrillogenesis, cell proliferation, cell cycle arrest and energy production. Among these was a decreased expression of the histone methyltransferase DOT1L. In addition, silencing of the DOT1L gene in human skeletal muscle satellite cells in vitro was significantly related to up regulation of p21 WAF1/Cip1/CDKN1A, a marker of cell arrest and ageing.Conclusions: 2D-DIGE coupled with MS identified differences in the expression of several proteins in the wasted vastus lateralis that are relevant to the disease process. Down regulation of DOT1L in the vastus lateralis of COPDL patients may mediate the muscle wasting process through up regulation of markers of cell arrest and senescence. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD. Methods: We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPDL) (FEV1 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m-2) with patients with COPD and normal FFMI (COPDN) (FEV1 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m-2) and a group of age and sex matched healthy controls (C) (FEV1 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m-2) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting. Results: A subset of 42 genes was differentially expressed in COPDL in comparison to both COPDN and C (PFP < 0.05; -1.5 ⩾ FC ⩾ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPDL. Conclusions: This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD. [ABSTRACT FROM AUTHOR]

Rationale and Objectives Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender. Materials and Methods We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models. Results Women had a lesser PMA and a greater SAT area than men (difference range for PMA, 13.3–22.8 cm 2 ; for SAT, 11.8–12.4 cm 2 ; P < .05 for all comparisons) at both anatomic levels. These differences in PMA and SAT remained significant after adjustment for age and body mass index. Within-gender regression models adjusted for age showed that SAT was directly associated with C-reactive protein (for aortic arch level, P = .04) and fibrinogen (for both anatomic locations, P = .003) only in women, whereas PMA was not associated with any biomarkers in either gender. Conclusions It appears that in subjects with COPD, there are gender-based differences in the relationships between subcutaneous adipose tissue and inflammatory biomarkers. [ABSTRACT FROM AUTHOR]

The pathogenesis of chronic obstructive pulmonary disease is not fully understood. The objective of this study was to compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, sex, and cigarette smoking matched healthy controls. Patients with chronic obstructive pulmonary disease (n 37) and healthy controls (n = 19) were matched by age, sex, and smoking status. Circulating hematopoietic progenitor cells (CD34= or CD133+ mononuclear cells) and endothelial progenitor cells (CD34+KDR+ or CD34+CD133+KDR+ mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared with controls (8.4 ± 0.6 vs. 5.9 ± 0.4 × 109 cells/l; P = 0.02). CD34+ hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared with controls (0.99 0.12 vs. 1.9 0.12%; P 0.02); however, there were no differences in the absolute number of CD34, CD34KDR, or CD34CD133KDR cells (P 0.05 for all). Endothelial cellcolony forming units were increased in patients with chronic obstructive pulmonary disease compared with controls (13.7 5.2 vs. 2.7 0.9 colonies; P 0.048). In contrast to previous studies, the number of circulating progenitor cells was not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis plays a central role in the development of emphysema. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort. Methods: We assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register. Results: We studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV1% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ⩽ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively). Conclusions: Increased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality. Trial registration: Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28. [ABSTRACT FROM AUTHOR]

Background: Admission to hospital with chronic obstructive pulmonary disease (COPD) is associated with deprivation and season. However, it is not known whether deprivation and seasonality act synergistically to influence the risk of hospital admission with COPD. Aims: To investigate whether the relationship between season/temperature and admission to hospital with COPD differs with deprivation. Methods: All COPD admissions (ICD10 codes J40-J44 and J47) were obtained for the decade 2001-2010 for all Scottish residents by month of admission and 2009 Scottish Index of Multiple Deprivation (SIMD) quintile. Confidence intervals for rates and absolute differences in rates were calculated and the proportion of risk during winter attributable to main effects and interactions were estimated. Monthly rates of admission by average daily minimum temperatures were plotted for each quintile of SIMD. Results: Absolute differences in admission rates between winter and summer increased with greater deprivation. In the most deprived quintile, in winter 19.4% (95% Cl 17.3% to 21.4%) of admissions were attributable to season/deprivation interaction, 61 .2% (95% Cl 59.5% to 63.0%) to deprivation alone, and 5.2% (95% Cl 4.3% to 6.0%) to winter alone. Lower average daily minimum temperatures over a month were associated with higher admission rates, with stronger associations evident in the more deprived quintiles. Conclusions: Winter and socioeconomic deprivation-related factors appear to act synergistically, increasing the rate of COPD admissions to hospital more among deprived people than among affluent people in winter than in the summer months. Similar associations were observed for admission rates and temperatures. Interventions effective at reducing winter admissions for COPD may have potential for greater benefit if delivered to more deprived groups. [ABSTRACT FROM AUTHOR]

ABSTRACT Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 ± 49.5 Hounsfield units [HU] versus 183.8 ± 46.1 HU versus 212.1 ± 54.4 HU, p < 0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation correlated positively with forced expiratory volume in 1 second (FEV1, r = 0.062, p = 0.014), FEV1/forced vital capacity (FVC) ratio ( r = 0.102, p < 0.001), body mass index ( r = 0.243, p < 0.001), fat-free mass index (FFMI, r = 0.265, p < 0.001), and C-reactive protein ( r = 0.104, p < 0.001), and correlated negatively with extent of emphysema ( r = −0.090, p < 0.001), Agatston score ( r = −0.177, p < 0.001), and interleukin-8 ( r = −0.054, p = 0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation ( r = −0.057, p = 0.022) and hospitalization ( r = −0.078, p = 0.002) rates but was not associated with all-cause mortality. In conclusion, CT-measured bone attenuation was lower in COPD subjects compared with nonsmoker controls but not compared with smoker controls, after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition, and coronary artery calcification but was not associated with all-cause mortality. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease. [ABSTRACT FROM AUTHOR]

Summary: Purpose: COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration. Methods: We have conducted a pilot study in eleven COPD patients (FEV1 41.3 ± 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (ΔQMVC) as the main outcome. Results: Mean quadriceps muscle strength decreased in control legs (ΔQMVC −2.9 ± 5.3 N, p = ns) but increased in the stimulated legs (ΔQMVC 19.2 ± 6.1 N, p < 0.01). The difference in ΔQMVC between groups was statistically significant (p < 0.05). The effect of NMES was directly related to the stimulation intensity (∑mA) applied throughout the 14 sessions (r = 0.76, p < 0.01). All patients tolerated NMES without any side effects. Conclusions: NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early post-exacerbation pulmonary rehabilitation. [ABSTRACT FROM AUTHOR]

Background: In 2008 NHS Lothian implemented a COPD tele-monitoring service incorporating a touch-screen computer for daily recording of symptoms and weekly oximetry and spirometry measurement. Data were transmitted by secure broadband link to a call centre where trained workers monitored data and contacted clinicians according to an agreed algorithm. Aims: To explore the perceptions of patients and professionals about the pilot implementation of the COPD tele-monitoring service. Methods: In-depth interviews were undertaken with patients and professionals before and after installation of the tele-monitoring equipment. Interviews were recorded, transcribed and thematically analysed. Data on use of healthcare resources were obtained from primary care records. Results: Twenty of the 27 patients in the pilot and 25 professionals participated. (n=55 interviews and one focus group). Patients were generally positive about the technology, which they perceived enabled earlier recognition of exacerbations and facilitated access to clinical advice. In contrast, clinicians had concerns about false positive symptom scores, difficulties in interpreting physiological data, overtreatment (reflected in a large increase in antibiotics and steroid prescribing), and an increased workload. Conclusions: Tele-monitoring was perceived by patients as improving access to professional care, but raised concerns for clinicians about possible over-treatment and how best to organise services to support the technology. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) thoracic imaging provides accurate assessment of both the extent and distribution of emphysema. These measurements have been used to describe chronic obstructive pulmonary disease (COPD) phenotypes and have been related to clinical outcomes in COPD. [ABSTRACT FROM AUTHOR]

Summary: Introduction: We assessed the utility of EBC pH as a biomarker in COPD in a large cohort of well-characterised individuals with COPD and control subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. We also determined short term reproducibility and the response of EBC to oral prednisolone. Methods: EBC was collected with R-TubesTM, using techniques for sampling and measurement that have been shown to be reproducible. Results: EBC pH was lower in COPD (n = 676, 7.29 ± SD 0.60) and in smoking controls (n = 31, 7.18 ± 0.85), compared with non-smoking controls (n = 50, 7.59 ± 0.44, p = 0.0008 and 0.0033 respectively), but was not different between COPD and smoking controls. There was no relationship between EBC pH and disease severity, as assessed by the percent predicted FEV1, nor with airway inflammation as assessed by sputum leukocyte counts. Treatment with 20 mg.day-1 prednisolone for 4 weeks did not change EBC pH. Conclusion: EBC pH is lower in COPD than in healthy control non-smokers, but does not differentiate COPD from smokers without COPD, relate to disease severity or to airway inflammation, and does not respond to corticosteroids. EBC pH therefore does not appear to be a useful biomarker in COPD. [ABSTRACT FROM AUTHOR]

Summary: Background: COPD patients have varying degrees of airways disease and emphysema. CT scanning can differentiate these pathological subtypes. We evaluated airway dimensions and emphysema severity with low dose CT scanning in COPD patients to determine relationships with clinical features of the disease. Methods: Fifty six patients with COPD had a low dose thoracic CT scan. Airways were analysed using novel software as either proximal (1st and 2nd generation) or distal (3rd to 6th generation); the extent of emphysema was assessed as the percentage of pixels less than −950 Hounsfield units. CT measures were related to clinical features of COPD. Results: Thicker walls in the proximal airways were associated with clinical features that may represent a bronchitic phenotype (MRC Bronchitis Score; β = 0.20, p = 0.003, Frequent Exacerbations; β = 0.14, p = 0.017, Total St George’s Score; β = 0.50, p = 0.001 and body mass index [BMI]; β = 0.26, p = 0.049); these associations were independent of emphysema. BMI was negatively correlated with the degree of emphysema (β = −0.41, p = 0.001). Airway wall thickness was negatively correlated with CT measured emphysema for both proximal and more distal airways (r = −0.30, p = 0.025 and r = −0.32, p = 0.015). Conclusions: CT measured airway dimensions are associated with several clinical measures of COPD; these are related to a bronchitic phenotype and the effect is independent of emphysema. [ABSTRACT FROM AUTHOR]

The article presents the study on the implications of telemetric chronic obstructive pulmonary disease (COPD) monitoring device. It has the capacity to engage the patient in their care and enables timely response to deterioration. The approach resonates key health service policies which include the shift of care into the community, the drive for technological solutions and the significance of expert patients and self-management of long-term conditions.

Cardiovascular disease (CVD) contributes significantly to morbidity and mortality in COPD. There is a high prevalence of traditional risk factors in this patient group including smoking, sedentary behaviour and low socio-economic class. However, large studies have shown that airflow limitation is an independent risk factor for CVD. Therefore there may be a 'COPD effect' that contributes to CVD in this condition, adding to the body of evidence that COPD has important systemic consequences, as well as being a lung disease. In this article, we review the evidence for CVD in COPD. Next, we examine systemic factors present in COPD, and link these to the pathogenesis of atherosclerosis, including inflammation, oxidative stress and hypoxia. Finally, we review those studies that have investigated therapeutic interventions in COPD that may modify cardiovascular risk. [ABSTRACT FROM AUTHOR]

• An investigational NTHi vaccine was tested for the first time in adults with COPD. • The vaccine had acceptable safety and reactogenicity. • Vaccine-elicited antibody concentrations were higher than baseline 1 year post-dose 2. Loss of airway microbial diversity is associated with non-typeable Haemophilus influenzae (NTHi) infection and increased risk of exacerbation in chronic obstructive pulmonary disease (COPD). We assessed the safety and immunogenicity of an investigational vaccine containing NTHi antigens, recombinant protein D (PD) and combined protein E and Pilin A (PE-PilA), and AS01 adjuvant in adults with moderate/severe COPD and prior exacerbations. In this phase 2, observer-blind, controlled trial (NCT02075541), 145 COPD patients aged 40–80 years randomly (1:1) received two doses of NTHi vaccine or placebo 60 days apart, on top of standard care. Reactogenicity in the 7-day post-vaccination period was higher following NTHi vaccine than placebo. Most solicited adverse events (AEs) were mild/moderate. At least one unsolicited AE was reported during the 30-day post-vaccination period by 54.8% of NTHi vaccine and 51.4% of placebo recipients. One serious AE (placebo group) was assessed by the investigator as vaccine-related. Anti-PD, anti-PE and anti-PilA geometric mean antibody concentrations increased up to 30 days after each NTHi vaccine dose, waned thereafter, but remained higher than baseline (non-overlapping confidence intervals) up to 13 months post-dose 2. The frequency of specific CD4+ T cells increased following two doses of NTHi vaccine and remained higher than baseline. Exploratory analysis showed a statistically non-significant lower yearly rate of moderate/severe exacerbations in the NTHi vaccine group than following placebo (1.49 versus 1.73) in the one-year period post-dose 2, with estimated vaccine efficacy of 13.3% (95% confidence interval −24.2 to 39.5; p = 0.44). The NTHi vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in adults with COPD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Exercise tolerance is an important clinical aspect of chronic obstructive pulmonary disease that can be easily and reliably measured with the 6-minute walking test (6MWT). To improve the utility of the 6MWT for patient and health care system management, the interpretation of the functional status measure in relation to death and hospitalization should be elucidated. Methods: Three-year, prospective, multicenter observational study to evaluate the predictive power of 6MWD for death or exacerbation-related hospitalization and to evaluate the factors that help determine 6MWD. Results: We measured 6MWD at baseline and annually in 2110 patients with clinically stable Global Initiative for Obstructive Lung Disease (GOLD) stage II–IV COPD and recorded exacerbation-related hospitalizations and all-cause mortality. During the study, 200 patients died and 650 were hospitalized. Using receiver operating characteristics, the best predictive thresholds of the 6MWD were 334 m for increased risk of death and 357 m for exacerbation-related hospitalization (area under the curve 0.67 and 0.60 respectively); however, the discriminatory thresholds, especially for mortality, were influenced by age. The mean (SE) 6MWD declined by 1.6 (1.2) m per year in GOLD II, 9.8 (1.3) m per year in GOLD III, and 8.5 (2.4) m per year in GOLD IV. Conclusion: The 6MWD provides prognostic information that may be useful for identifying high-risk patients with COPD. [Copyright &y& Elsevier]