Systemic inflammation and mortality in chronic obstructive pulmonary disease

Cardiovascular diseases and cancer (especially lung cancer) are leading causes of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Some have implicated systemic inflammation, which is commonly observed in COPD, as the potential mechanistic bridge between COPD and these disorders. This concept has been supported by animal studies especially in rabbits, which have clearly demonstrated the effect of local lung inflammation on systemic inflammation and on the progression of atherosclerosis and by cross-sectional population-based studies, which have shown a significant relationship between systemic inflammation, as measured by circulating C-reactive protein (CRP) and the risk of cardiovascular diseases in COPD patients. These data have been further extended by a recent study that has elucidated the temporal nature of the relationship between systemic inflammation and the risk of cardiovascular events and cancer in COPD patients. This study showed that baseline CRP levels predicted the incidence of cardiovascular events and cancer-specific mortality over 7 to 8 years of follow-up. CRP levels also predicted all-cause mortality. Collectively, these data indicate that systemic inflammation may play an important role in mediating the extra-pulmonary complications of COPD. Systemic inflammation may contribute substantially to the overall morbidity and mortality of COPD patients.     

Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease

Background

There has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients. We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort.

Methods

We prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012. Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test.

Results

Airway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p < 0.001, p = 0.049 and p = 0.261, respectively). Increasing total bacterial load was associated with increasing airway (p < 0.01) but not systemic inflammation (p > 0.05). Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads. Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p < 0.05), and was significantly greater than with other PPMs. No association was observed between inflammation and health status (p > 0.05).

Conclusions

Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique. The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae. However, discordance between inflammation and health status was observed.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0114-1) contains supplementary material, which is available to authorized users.     

The effects of depression,anxiety and sleep disturbances on cognitive impairment in patients with chronic obstructive pulmonary disease

The purpose of this study was to investigate the effects of depression, anxiety and sleep disturbances on cognitive functions in chronic obstructive pulmonary disease (COPD) patients. In this prospective case-control study, demographic data, smoking history, depression, anxiety, sleep quality and cognitive status of 48 COPD patients and 36 healthy volunteers aged 40–90 years were recorded. The Beck depression inventory (BDI), the Beck anxiety inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) were used to assess depression, anxiety and sleep quality, respectively in COPD patients. Cognitive performance was studied by the mini-mental state examination. The mean age of patients with COPD was 65.3 ± 9.4 years, and disease duration was 9.6 ± 7.8 years. Male sex ratio, smoking, BDI score, BAI score, total PSQI score, sleep latency, sleep duration, average use of sleep aids and sleep disturbances in patients with COPD were significantly higher than the control group (p < 0.05). When cognitive impairment was compared by age, FVC, FEV, FEV/FVC, PEF values and smoking, no statistically significant relationship was found (p > 0.05). A statistically significant relationship was established between cognitive impairment and severity of disease, presence of anxiety, presence of depression and sleep quality. In our study, we found that sleep disorders, depression and anxiety comorbid with COPD increased cognitive impairment as well as the severity of disease. We believe that this finding is important in terms of reducing the risk of cognitive impairment, preventing misdiagnosis and treatment of the aforementioned comorbid diseases.     

DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.

Methods

We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) <0.7 and FEV₁ < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLC_CT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLC_CT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.

Results

Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10⁻⁸).

Conclusions

In COPD, TLC_CT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0097-y) contains supplementary material, which is available to authorized users.     

Comorbidity and sex-related differences in mortality in oxygen-dependent chronic obstructive pulmonary disease

Background

It is not known why survival differs between men and women in oxygen-dependent chronic obstructive pulmonary disease (COPD). The present study evaluates differences in comorbidity between men and women, and tests the hypothesis that comorbidity contributes to sex-related differences in mortality in oxygen-dependent COPD.

Methods

National prospective study of patients aged 50 years or older, starting long-term oxygen therapy (LTOT) for COPD in Sweden between 1992 and 2008. Comorbidities were obtained from the Swedish Hospital Discharge Register. Sex-related differences in comorbidity were estimated using logistic regression, adjusting for age, smoking status and year of inclusion. The effect of comorbidity on overall mortality and the interaction between comorbidity and sex were evaluated using Cox regression, adjusting for age, sex, Pa_O2 breathing air, FEV₁, smoking history and year of inclusion.

Results

In total, 8,712 patients (55% women) were included and 6,729 patients died during the study period. No patient was lost to follow-up. Compared with women, men had significantly more arrhythmia, cancer, ischemic heart disease and renal failure, and less hypertension, mental disorders, osteoporosis and rheumatoid arthritis (P<0.05 for all odds ratios). Comorbidity was an independent predictor of mortality, and the effect was similar for the sexes. Women had lower mortality, which remained unchanged even after adjusting for comorbidity; hazard ratio 0.73 (95% confidence interval, 0.68–0.77; P<0.001).

Conclusions

Comorbidity is different in men and women, but does not explain the sex-related difference in mortality in oxygen-dependent COPD.     

综合护理模式对慢性阻塞性肺疾病急性加重合并Ⅱ型呼吸衰竭患者的影响

目的探讨综合护理模式对无创呼吸机治疗慢性阻塞性肺疾病急性加重(AECOPD)合并Ⅱ型呼吸衰竭患者的临床疗效。方法选取2013年1月~2016年1月我院收治行无创呼吸机治疗的AECOPD合并Ⅱ型呼吸衰竭患者120例,随机分为对照组和实验组各60例,对照组采用常规护理模式,实验组在常规护理模式的基础上给予综合护理干预,分别采用焦虑自评量表(SAS)、抑郁自评量表(SDS)对AECOPD合并Ⅱ型呼吸衰竭患者护理前后进行评分,分析护理前后两组患者血气分析指标、SAS评分、SDS评分及护理满意度情况。结果护理前,两组患者的动脉血气分析指标(PO2、PCO2、pH)、SAS评分、SDS评分比较,差异无统计学意义(P0.05)。护理后,两组患者动脉血气分析指标(PO2、PCO2、pH)均有改善,实验组的各项指标改善程度显著优于对照组,SAS评分和SDS评分均低于对照组,患者满意度(96.7%)显著高于对照组(78.3%),差异均有统计学意义(均P0.01)。结论综合护理可显著提高无创呼吸机治疗AECOPD合并Ⅱ型呼吸衰竭患者的临床疗效,有效缓解其焦虑及抑郁情绪,提高患者护理满意度。     

慢性阻塞性肺疾病患者继发肺部真菌感染的临床分析

目的探讨慢性阻塞性肺疾病(COPD)患者继发肺部真菌感染的临床特点。方法回顾性分析2008年1月到2010年12月安徽医科大学第一附属医院收治的COPD继发肺部真菌感染患者病例,并对其耐药情况进行比较。结果本组199例COPD患者检出白色念珠菌137例(68.84%),光滑念珠菌32例(16.08%),热带念珠菌17例(8.54%),克柔念珠菌9例(4.52%),毛霉菌3例(1.51%),清酒假丝酵母菌1例(0.50%);白色念珠菌检出率有下降趋势,热带念珠菌有上升趋势;196例真菌对伏立康唑、氟康唑、两性霉素B、伊曲康唑、氟胞嘧啶的耐药率分别为3.6%、5.1%、1.0%、8.7%和0;2008年至2010年白色念珠菌和光滑念珠菌耐药率变化差异无统计学意义。结论 COPD患者继发肺部真菌感染病原菌仍以白色念珠菌为主,其次为光滑念珠菌和热带念珠菌;白色念珠菌和光滑念珠菌耐药率无明显改变。     

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.     

MAPK signaling in the quadriceps of patients with chronic obstructive pulmonary disease

Muscle atrophy in chronic obstructive pulmonary disease (COPD) is associated with reduced exercise tolerance, muscle strength, and survival. The molecular mechanisms leading to muscle atrophy in COPD remain elusive. The mitogen-activated protein kinases (MAPKs) such as p38 MAPK and ERK 1/2 can increase levels of MAFbx/Atrogin and MuRF1, which are specifically involved in muscle protein degradation and atrophy. Our aim was to investigate the level of activation of p38 MAPK, ERK 1/2, and JNK in the quadriceps of patients with COPD. A biopsy of the quadriceps was obtained in 18 patients with COPD as well as in 9 healthy controls. We evaluated the phosphorylated as well as total protein levels of p38 MAPK, ERK 1/2, and JNK as well as MAFbx/Atrogin and MuRF1 in these muscle samples. The corresponding mRNA expression was also assessed by RT-PCR. Ratios of phosphorylated to total level of p38 MAPK (P = 0.02) and ERK 1/2 (P = 0.01) were significantly elevated in patients with COPD compared with controls. Moreover, protein levels of MAFbx/Atrogin showed a tendency to be greater in patients with COPD (P = 0.08). mRNA expression of p38 MAPK (P = 0.03), ERK 1/2 (P = 0.02), and MAFbx/Atrogin (P = 0.04) were significantly elevated in patients with COPD. In addition, phosphorylated-to-total p38 MAPK ratio (Pearson's r = -0.45; P < 0.05) and phosphorylated-to-total ERK 1/2 ratio (Pearson's r = -0.47; P < 0.05) were negatively associated with the mid-thigh muscle cross-sectional area. These data support the hypothesis that the MAPKs might play a role in the development of muscle atrophy in COPD.     

Relation of pressure and flow of pulmonary circulation in patients with chronic obstructive pulmonary disease

A series of 31 patients with various degrees of chronic obstructive pulmonary disease underwent right heart catheterization using flow-directed thermodilution catheters. Both rest and supine exercise values were obtained. The patients were divided into two groups on the basis of their reduction in forced expiratory volume in 1 s (FEV1). In patients with FEV1 values of greater than or equal to 1,300 ml (group 1), the arterial oxygen partial pressure (PaO2) did not significantly change with exercise, while in patients with FEV1 of less than or equal to 1,200 ml (group 2) PaO2 significantly (p less than 0.05) fell in response to exercise. In group 2, a significant increase of total pulmonary resistance (TPR) with exercise was found (p less than 0.01). Pulmonary vascular resistance (PVR) remained unchanged in both subgroups. It is suggested that the value of PVR for subgroup 2 is artificially low because an important variable, namely pulmonary artery wedge pressure, is influenced by alveolar pressure in patients with an uneven distribution of perfusion and ventilation at pulmonary venous pressures lower than alveolar pressure. The steeper slope of the pressure-flow relationship in these patients is probably due to an increased vascular tone caused by chronic hypoxia at rest and further fall of PaO2 and rise of arterial CO2 partial pressure in response to exercise.     

Proteinases in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, and we have little specific therapy to offer these patients. One potential strategy to limit loss of lung function in COPD would be to inhibit matrix-degrading proteinases. Several serine proteinases and matrix metalloproteinases are expressed in association with COPD in humans. Application of gene-targeted macrophage elastase and neutrophil elastase to a mouse model of cigarette-smoke-induced emphysema has uncovered roles for these proteinases in airspace enlargement, and has identified many interactions between these proteolytic systems.     

The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD)

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV₁ and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4^th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.     

Regenerative defect in vastus lateralis muscle of patients with chronic obstructive pulmonary disease

Background

Impaired skeletal muscle regeneration could contribute to the progression of muscle atrophy in patients with chronic obstructive pulmonary disease (COPD).

Methods

Satellite cells and myogenesis-related proteins were compared between healthy subjects and patients with COPD, with or without muscle atrophy. Satellite cells were isolated and cultured to assess their proliferative and differentiation aptitudes.

Results

Although satellite cell numbers in muscle samples were similar between groups, the proportion of muscle fibers with central nuclei was increased in COPD. In muscle homogenates, increased expression of MyoD and decreased expression of myogenin and MRF4 were observed in COPD. In cultured satellite cells of patients with COPD, increased protein content was observed for Pax7, Myf5 (proliferation phase) and myogenin (differentiation phase) while myosin heavy chain protein content was significantly lower during differentiation.

Conclusion

In COPD, the number of central nuclei was increased in muscle fibers suggesting a greater number of attempts to regenerate muscle tissue than in healthy subjects. Myogenesis signaling was also altered in muscle homogenates in patients with COPD and there was a profound reduction in the differentiation potential in this population as indicated by a reduced ability to incorporate myosin heavy chain into newly formed myotubes. Collectively, these results indicate that skeletal muscle regenerative capacity termination is impaired in COPD and could contribute to the progression of muscle atrophy progression in this population.     

Body mass index and mortality in chronic obstructive pulmonary disease: a meta-analysis

Background

The association between body mass index (BMI) and mortality in patients suffering from chronic obstructive pulmonary disease (COPD) has been a subject of interest for decades. However, the evidence is inadequate to draw robust conclusions because some studies were generally small or with a short follow-up.

Methods

We carried out a search in MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE database for relevant studies. Relative risks (RRs) with 95% confidence interval (CI) were calculated to assess the association between BMI and mortality in patients with COPD. In addition, a baseline risk-adjusted analysis was performed to investigate the strength of this association.

Results

22 studies comprising 21,150 participants were included in this analysis. Compared with patients having a normal BMI, underweight individuals were associated with higher mortality (RR  = 1.34, 95% CI  = 1.01–1.78), whereas overweight (RR  = 0.47, 95% CI  = 0.33–0.68) and obese (RR  = 0.59, 95% CI  = 0.38–0.91) patients were associated with lower mortality. We further performed a baseline risk-adjusted analysis and obtained statistically similar results.

Conclusion

Our study showed that for patients with COPD being overweight or obese had a protective effect against mortality. However, the relationship between BMI and mortality in different classes of obesity needed further clarification in well-designed clinical studies.     

Dietary modulation of oxidative stress in chronic obstructive pulmonary disease patients

Abstract

A total of 267 clinically stable chronic obstructive pulmonary disease (COPD) patients provided complete data about diet and oxidative stress markers in order to assess the relationship between antioxidant rich food groups and nutrients, and serum markers of oxidative stress in COPD. Dietary data of the last 2 years was assessed using a validated food frequency questionnaire (122 items). Levels of carbonyls, nitrotyrosine, malondialdehyde and reduced glutathione (GSH) were measured in serum. Vitamin E intake was inversely associated with levels of carbonyls (p = 0.05) and olive oil was positively associated with GSH levels (p = 0.01), in active smokers. Intake of vegetables was related to a decrease of malondialdehyde levels (p = 0.04) in former smokers. No statistically significant associations were found between remaining dietary antioxidants and serum oxidative stress markers. These results provide new data for a potential dietary modulation of systemic oxidative stress in COPD patients, particularly in those that continue smoking.     

Circadian-rhythm differences among emergency department patients with chronic obstructive pulmonary disease exacerbation

The purpose of the study was determine whether patients with chronic obstructive pulmonary disease (COPD) exacerbation who present to the emergency department (ED) during the night (00:00 to 07:59 h) vs. other times of the day have more severe COPD exacerbation, require more intensive treatment, and have worse clinical outcomes. A multicenter cohort study was completed involving 29 EDs in the United States and Canada. Using a standard protocol, consecutive ED patients with COPD exacerbation were interviewed, and their charts were reviewed. Of 582 patients enrolled, 52% were women, and the median age was 71 yrs (interquartile range, 64-77 yrs). Nighttime patients (15% of cohort) did not differ from patients presenting at other times except that they were less likely to have private insurance, more likely to have a history of corticosteroid use, and have a shorter duration of symptoms exacerbation. Except for a few features indicative of more severe COPD exacerbation (such as higher respiratory rate at ED presentation, greater likelihood of receiving noninvasive positive pressure ventilation, and increased risk of endotracheal intubation), nighttime patients did not differ from other patients with respect to ED management. Nighttime patients were approximately three-fold more likely to be intubated in the ED (odds ratio, 3.46; 95% confidence interval, 1.10-10.9). There were no day-night differences regarding ED disposition and post-ED relapse. Except for some features indicating more severe exacerbation, nighttime ED patients had similar chronic COPD characteristics, received similar treatments in the ED, and had similar clinical outcomes compared with patients presenting to the ED at other times of the day.     

Organization of metabolic pathways in vastus lateralis of patients with chronic obstructive pulmonary disease

The objective of this study was to determine whether patients with chronic obstructive lung disease (COPD) display differences in organization of the metabolic pathways and segments involved in energy supply compared with healthy control subjects. Metabolic pathway potential, based on the measurement of the maximal activity (V(max)) of representative enzymes, was assessed in tissue extracted from the vastus lateralis in seven patients with COPD (age 67 +/- 4 yr; FEV(1)/FVC = 44 +/- 3%, where FEV(1) is forced expiratory volume in 1 s and FVC is forced vital capacity; means +/- SE) and nine healthy age-matched controls (age 68 +/- 2 yr; FEV(1)/FVC = 75 +/- 2%). Compared with control, the COPD patients displayed lower (P < 0.05) V(max) (mol.kg protein(-1).h(-1)) for cytochrome c oxidase (COX; 21.2 +/- 2.0 vs. 28.7 +/- 2.2) and 3-hydroxyacyl-CoA dehydrogenase (HADH; 2.54 +/- 0.14 vs. 3.74 +/- 0.12) but not citrate synthase (CS; 2.20 +/- 0.16 vs. 3.19 +/- 0.5). While no differences between groups were observed in V(max) for creatine phosphokinase, phosphorylase (PHOSPH), phosphofructokinase (PFK), pyruvate kinase, and lactate dehydrogenase, hexokinase (HEX) was elevated in COPD (P < 0.05). Enzyme activity ratios were higher (P < 0.05) for HEX/CS, HEX/COX, PHOSPH/HADH and PFK/HADH in COPD compared with control. It is concluded that COPD patients exhibit a reduced potential for both the electron transport system and fat oxidation and an increased potential for glucose phosphorylation while the potential for glycogenolysis and glycolysis remains normal. A comparison of enzyme ratios indicated greater potentials for glucose phosphorylation relative to the citric acid cycle and the electron transport chain and glycogenolysis and glycolysis relative to beta-oxidation.