Analysis of Systemic Biomarkers in COPD Patients

The finding that α1‐antitrypsin (AAT) deficiency, PiZZ, a well‐established genetic risk factor for COPD, is related to high levels of circulating AAT polymers, prompted us to measure serum levels of such polymers and selected markers of inflammation in age‐ and gender‐matched patients with stable COPD and control subjects with and without severe AAT deficiency, and to assess their relationship with each other and with the genetic AAT‐variant. We found that COPD individuals (n = 20), independent of AAT‐variant, had significantly higher serum levels of AAT and its polymers, MMP‐9, sICAM‐1, VEGF and sE‐selectin than controls (n = 30). Subjects with PiZZ COPD (n = 10) showed significantly elevated serum levels of AAT‐polymers, sE‐selectin and sICAM‐1, while patients with PiMM COPD (n = 10) showed higher levels of MMP‐9, VEGF, IL‐8 and MCP‐1 than controls. By using factor analysis we were able to split the analysed biomarkers into two independent components: the first containing MMP‐9, MCP‐1, IL‐8 and VEGF and the second—AAT and its polymers and sE‐selectin. The result from the binomial logistic regression showed that 95.2 percent of the control individuals and 94.7 percent of the COPD patients can be correctly classified on the basis of the measured serum biomarkers. These observations highlight the importance of the finding sets of biomolecules, which could offer new strategies for the diagnosis of COPD and may have value for monitoring progression of COPD.     

COPD heterogeneity: Gender differences in the multidimensional BODE index

Background:

The BODE index was recently validated as a multidimensional tool for the evaluation of patients with COPD. The influence of gender on the BODE index has not been studied.

Hypothesis:

The contribution of each component of the disease to the BODE index may differ according to gender.

Methods:

We evaluated age, forced expiratory volume in one second (FEV₁), Modified Medical Research Council (MMRC) score, 6-min walk distance (6MWD), and body mass index (BMI) in 52 men and 52 women with COPD and the same BODE index. We compared the studied parameters between men and women and then performed a multiple regression analysis by gender.

Results:

We found statistically significant differences between men and women in all parameters: FEV₁ % (55 ± 17 vs 63 ± 18, p < 0.001), MMRC [1 (0–2) vs 1 (1–2) p = 0.03], BMI [28 (26–30) vs 25 (22–30), p = 0.05], and 6MWD [546 (451–592) vs 462 (419–520), p = 0.001]. Multiple regression analysis revealed that each component of the BODE index had different weight (β standardized coefficient) in men and women respectively: FEV₁% (0.74 vs 0.62), MMRC (0.31 vs 0.48), BMI (−0.09 vs −0.17), and 6MWD (0.13 vs 0.10).

Conclusions:

The contribution of each component to the BODE index differs by gender in subjects with similar BODE scores. Long term longitudinal studies will help determine the significance of our findings.     

The Association of Metabolic Syndrome with Adipose Tissue Hormones and Insulin Resistance in Patients with COPD without Co-morbidities

Chronic obstructive pulmonary disease (COPD) and metabolic syndrome represent common causes of morbidity and mortality in ageing populations. The effect of the co-existence of COPD and metabolic syndrome on adipose tissue hormones and insulin resistance as well as the differences between COPD patients with and without metabolic syndrome have not been adequately studied. The prevalence of metabolic syndrome, based on Adult Treatment Panel III (ATP III) criteria, was evaluated in 114 male patients with COPD without significant co-morbidities. Pulmonary functions tests (PFTs), arterial blood gases, quality of life and BODE index were assessed. Blood samples were obtained for the assessment of adipose tissue hormones and insulin resistance. The overall prevalence of metabolic syndrome was 21%, being more prevalent in earlier stages of COPD. Patients with COPD and metabolic syndrome were younger with higher body-mass index (BMI), had better pulmonary function, less static hyperinflation and air-trapping, better diffusing capacity for carbon monoxide and BODE index. These patients had higher levels of leptin, lower levels of adiponectin and increased insulin resistance, as expressed by HOMA index, compared with patients without metabolic syndrome. Metabolic syndrome was more prevalent in younger patients with less severe COPD. These patients may constitute a specific COPD phenotype with greater leptin to adiponectin imbalance and insulin resistance, despite smaller impairment in PFTs. The prognosis and differences of these patients compared with other COPD phenotypes needs to be determined in prospective studies.     

COPD合并T2DM患者血清visfatin与CRP的关系

目的探讨COPD合并2型糖尿病（T2DM）患者血清内脂素（visfatin）与C反应蛋白（CRP）的关系;研究visfatin与CRP对机体糖脂代谢与炎症免疫的影响。方法用酶联免疫吸附法（ELISA）测定血清visfatin水平;速率散射免疫比浊法检测CRP;全自动生化仪测定生化指标。结果 COPD合并2型糖尿病组血清visfatin与CRP水平较正常对照组明显升高[（36.20±3.62）μg/L/（69.75±8.92）mg/Lvs（15.04±0.71）μg/L/（4.75±2.43）mg/L],有统计学差异（P〈0.05）。结论 COPD合并2型糖尿病患者血清visfatin与CRP水平明显升高。     

Diagnostic and Prognostic Value of Inflammatory Parameters Including Neopterin in the Setting of Pneumonia,COPD, and Acute Exacerbations

Acute exacerbations and community-acquired pneumonia (CAP) are severe complications in patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed inflammatory parameters in serum including C-reactive protein (CRP), procalcitonin (PCT), and serum neopterin (NPT) to determine their potential to differentiate between patients with CAP+COPD and with acute exacerbations of COPD (AECOPD) without pneumonia. 102 (39 women and 63 men) patients were included in this retrospective study, of whom 48 presented with CAP without underlying COPD, 20 with CAP+COPD and 34 with AECOPD. CRP, PCT, and blood counts were determined by routine automated tests, and NPT concentrations were determined by ELISA. The ratios of CRP to NPT levels were calculated. Upon patient admission, CRP, PCT, and NPT levels were significantly higher in patients with CAP compared to those in AECOPD patients. CRP/NPT ratio was lower in AECOPD compared to CAP (+/?COPD) patients. Positive correlations were found between duration of hospitalization and CRP levels and the CRP/NPT ratio at study entry. Patients who were readmitted within 30 days tended to have higher NPT levels at initial presentation. Patients under ongoing corticosteroid treatment presented with lower inflammatory parameters. The CRP/NPT-ratio was suited well to discriminate between AECOPD and CAP on the basis of COPD, a CRP/NPT cutoff of 0.346 provided a sensitivity of 65% and a specificity of 79%. The combinatory use of inflammatory patterns might help to differentiate patients with AECOPD from those with CAP on the basis of COPD.     

Evaluation of Left Ventricular Function and its Relationship With Multidimensional Grading System (BODE Index) in Patients With COPD

Cardiovascular disease (CVD) is one of the main causes of morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients however data regarding left ventricle (LV) function in COPD is limited. We, in this study, aimed to evaluate the LV systolic function and its relation to BODE index in COPD patients with the utility of two-dimensional speckle tracking echocardiography (2D-STE). The study involved 125 COPD patients and 30 control subjects. All patients underwent 2D-echocardiography, pulmonary function tests and -minute walk tests. The patients were divided into four quartiles according to BODE index score. COPD patients had lower mitral annulus systolic velocity (Sm), average global longitudinal strain (GLS), average global longitudinal strain rate systolic (GLSRs), average GLSR early diastolic (GLSRe), average GLSR late diastolic (GLSRa), tricuspid annular plane systolic excursion (TAPSE) and peak systolic myocardial velocity (Sm-RV) (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p = 0.002 respectively) than control subjects. There were significant differences between BODE index quartiles in terms of Sm, average GLS and average GLSRs. Patients were divided into two groups according to median value of GLS (> –18.6 and ≤ –18.6). BODE index quartiles were found to be independent predictors of decreased GLS in multivariate logistic regression analysis (p = 0.030). Increased BODE index was associated with impaired LV mechanics in patients with COPD.     

COPD患者CRP、IL-6、IL-10水平与心血管事件的相关性

目的探讨COPD患者CRP、IL-6、IL-10水平与其心血管事件的相关性。方法选择2013年5月至2014年2月我院收治的60例伴有心血管疾病的COPD老年患者作为观察组,并选择同期60例无合并心血管疾病的COPD老年患者作为对照组。通过放免法检测两组患者体内CRP、IL-6、IL-10水平观察其与患者心血管事件的相关性。结果观察组CRP、IL-6分别为(16.4±2.6)ng/L和(12.8±0.6)mg/L,显著高于对照组,差异具有统计学意义(P0.05);观察组IL-10水平为(8.4±1.2)ng/L,显著低于对照组,差异具有统计学意义(P0.05);随着病情程度加重,CRP、IL-6水平逐渐增加,重度患者含量明显高于轻度患者(P0.05);IL-10水平随着程度加重而降低,重度患者明显低于轻度(P0.05)。结论合并心血管疾病的COPD患者体内炎症反应明显,炎症因子CRP、IL-6升高,抗炎因子IL-10降低,因此检测细胞因子水平在一定程度上可反映病情程度。     

Effects of interval-load versus constant-load training on the BODE index in COPD patients

The BODE index is frequently used to assess functional capacity in patients with COPD. The aim of this study was to investigate the effectiveness of interval-load training (ILT) to improve the BODE index in comparison to the commonly implemented constant-load training (CLT).Forty-two patients with COPD [FEV₁: (mean ± SEM) 42 ± 3% predicted] were randomly allocated to either ILT (n = 21) or CLT (n = 21). The training program consisted of cycling exercise 3 days/week for 10 weeks. Patients assigned to ILT exercised at a mean intensity of 126 ± 4% of baseline peak work rate (Wpeak) with 30-s work periods alternated with 30-s rest periods for 45 min per day, whereas patients allocated to CLT exercised at a mean intensity of 76 ± 5% of baseline Wpeak for 30 min per day. The BODE index and its components: body mass index, FEV₁, MMRC dyspnea score and the 6-min walk test (6-MWT) as well as cycling Wpeak were assessed before and after both exercise training regimes.Both ILT and CLT significantly (p < 0.001) decreased the BODE index (from 4.8 ± 0.5 to 4.0 ± 0.5 units and from 4.4 ± 0.5 to 3.8 ± 0.5 units, respectively). In addition, both ILT and CLT significantly decreased the MMRC dyspnea score by 0.4 ± 0.1 units and increased the 6-MWT (by 52 ± 16 and 44 ± 12 m, respectively) as well as cycling Wpeak (by 14 ± 2 and 10 ± 2 W, respectively). The magnitude of these changes was not significantly different between ILT and CLT. Consequently, ILT is equally effective to CLT in terms of improving the BODE index in patients with COPD and as such it may constitute an alternative rehabilitative modality in COPD.     

Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD

Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-α and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-α and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.     

Plasma homocysteine is elevated in COPD patients and is related to COPD severity

Background:

Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls.

Methods:

We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP).

Results:

There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV₁ was 2.25 (0.77) vs 1.43 (0.60) L; FEV₁% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV₁% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023.

Conclusions:

Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity.     

Obesity and immune function relationships

The immunological processes involved in the collaborative defence of organisms are affected by nutritional status. Thus, a positive chronic imbalance between energy intake and expenditure leads to situations of obesity, which may influence unspecific and specific immune responses mediated by humoral and cell mediated mechanisms. Furthermore, several lines of evidence have supported a link between adipose tissue and immunocompetent cells. This interaction is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. However, limited and often controversial information exist comparing immunity in obese and non‐obese subjects as well as about the cellular and molecular mechanisms implicated. In general terms, clinical and epidemiological data support the evidence that the incidence and severity of specific types of infectious illnesses are higher in obese persons as compared to lean individuals together with the occurrence of poor antibody responses to antigens in overweight subjects. Leptin might play a key role in linking nutritional status with T‐cell function. The complexities and heterogeneity of the host defences concerning the immune response in different nutritional circumstances affecting the energy balance require an integral study of the immunocompetent cells, their subsets and products as well as specific and unspecific inducer/regulator systems. In this context, more research is needed to clarify the clinical implications of the alterations induced by obesity on the immune function.     

Plasma Inflammatory Mediators Associated with Bone Metabolism in COPD

ABSTRACT

The association of osteoporosis with COPD is well established, but the relationship between systemic inflammatory mediators and bone metabolism has not been explored. Plasma samples from 40 COPD patients awaiting lung transplantation were analyzed for 27 inflammatory mediators using a multiplex protein array. C-telopeptide type I collagen (CTx), a marker of bone resorption, was measured with ELISA, and N-terminal procollagen propeptide (P1NP), a marker of bone formation, was ascertained with a radioimmunoassay. Associations between inflammatory mediators versus CTx and P1NP with adjustments for steroid and bisphosphonate use were determined. Mean age was 59 years (± 6) and FEV₁ was 23.5% (± 8.3%) predicted. Ninety-five percent of the subjects had low bone mineral density measured by dual x-ray absorptiometry (DXA). Tumor necrosis factor alpha and interleukin 4 were positively associated with CTx and P1NP. RANTES and eotaxin were inversely associated with CTx and P1NP. Interleukin 2 and interferon gamma were also directly associated with P1NP. Biologically plausible systemic mediators are associated with bone metabolism in patients with severe COPD, offering potential insight into risk factors and underlying mechanisms of bone disease. Furthermore, they may be useful in monitoring disease activity, and serve as targets for biological therapy.     

Correlation between serum biomarkers and BODE index in patients with stable COPD

Background and objective: The BODE index, based on BMI, obstructive ventilatory impairment, dyspnoea scale and exercise capacity, has been used to evaluate the severity of patients with COPD. However, the correlations between serum biomarkers and the BODE index in patients with stable COPD are not widely studied. This study evaluated potential serum biomarkers for their ability to identify smokers with COPD and reflect disease severity. Methods: A comparative study was conducted of 100 clinically stable COPD patients and 50 matched healthy smokers and the difference in levels of biomarkers between the COPD patients and healthy smokers was measured. Serum inflammatory mediators measured were growth‐related oncogene‐α (GRO‐α), IL‐8, tumour necrosis factor‐α (TNF‐α), matrix metalloproteinase‐9 (MMP‐9) and monocyte chemoattractant protein‐1 (MCP‐1). Variables included age, pack‐years, current or ex‐smoker status, inhaler or oral steroid use and BODE index components, including airflow obstruction, the distance walked in 6MWD, modified Medical Research Council (MMRC) dyspnoea scale and BMI. The association between serum biomarkers and the components of the BODE index was assessed in the COPD patients. Results: The level of serum MCP‐1 was significantly different between the COPD group and the healthy smoker group (P = 0.003). Significant results in univariate and multivariate analysis of the association between biomarkers and BODE components were: serum MCP‐1 correlated with FEV₁% and 6MWD; serum IL‐8 and GRO‐α correlated with steroid use; serum TNF‐α correlated with steroid use and FEV₁%; and serum MMP‐9 correlated with MMRC dyspnoea scale. Conclusions: No single specific serum inflammatory mediator was completely correlated with BODE variable parameters in patients with stable COPD. Serum MCP‐1 may be an important biomarker for identifying COPD subjects from healthy smokers and classifying COPD severity.     

IL-8 Gene Variants are Associated with Lung Function Decline and Multidimensional BODE Index in COPD Patients But Not with Disease Susceptibility: A Validation Study

Background and objective: COPD is a leading cause of dead worldwide and tobacco smoking is its major risk factor. IL8 is a proinflammatory chemokine mainly involved in the acute inflammatory reaction. The aim of this study was to test the association of IL-8, CXCR1 and CXCR2 gene variants and COPD susceptibility as part of a replication study and explore the effect of these variations in disease progression. Methods: 9 tagSNPs were genotyped in 728 Caucasian individuals (196 COPD patients, 80 smokers and 452 non-smoking controls). Pulmonary compromise was evaluated using spirometry and clinical parameters at baseline and annually over a 2 years period. We also determined plasma levels of TNF-α, IL-6, IL-8 and IL-16 in COPD patients. Results: There was a lack of association between gene variants or haplotypes with predisposition to COPD. No correlation was observed between the polymorphisms and cytokines levels. Interestingly, significant associations were found between carriers of the rs4073A (OR = 3.53, CI 1.34-9.35, p = 0.01), rs2227306C (OR = 5.65, CI 1.75–18.88, p = 0.004) and rs2227307T (OR = 4.52, CI = 1.49–12.82, p = 0.007) alleles in the IL-8 gene and patients who scored higher in the BODE index and showed an important decrease in their FEV₁ and FVC during the 2 years follow-up period (p < 0.05). Conclusions: Despite no association was found between the studied genes and COPD susceptibility, three polymorphisms in the IL-8 gene appear to be involved in a worse progression of the disease, with an affectation beyond the pulmonary function and importantly, a reduction in lung function along the follow-up years.