Plasma metabolomics and clinical predictors of survival differences in COPD patients.

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

Longitudinal assessment in COPD patients: multidimensional variability and outcomes.

The value and timing of multidimensional assessments in chronic obstructive pulmonary disease (COPD) remains unclear because there is little information about their variability and relationship to outcome. The aim of this study was to determine the progression of COPD using clinical and spirometric variability over time with mortality as the outcome. We determined the annual intra-individual variability of forced expiratory volume in 1 s (FEV1) and BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index in 403 patients with at least five measurements. The pattern was defined as "stable" if the annual change remained constant in ≥66% of the observations and "unstable" if it did not meet that threshold. We explored the minimum number of yearly observations that related to mortality in the 704 patients of the cohort. The "unstable" pattern of FEV1 was seen in 53% and 40% of patients using a threshold of 40 mL·year(-1) and 100 mL·year(-1), respectively. There was a slightly more "stable" pattern in the BODE index (62% for 1 point). A profile associated with mortality was defined by a baseline measurement followed by annual measurements for 2 years of the BODE index, but not its individual components, including FEV1 (p<0.001). Progression of COPD measured using FEV1 is inconsistent and relates poorly to outcome. Monitoring the more stable BODE index better assesses disease progression.

Inflammatory and repair serum biomarker pattern: association to clinical outcomes in COPD.

BACKGROUND: The relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair. METHODS: We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot]. RESULTS: Levels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05). CONCLUSIONS: In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival.

The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is thought to result in rapid and progressive loss of lung function usually expressed as mean values for whole cohorts. OBJECTIVES: Longitudinal studies evaluating individual lung function loss and other domains of COPD progression are needed. METHODS: We evaluated 1,198 stable, well-characterized patients with COPD (1,100 males) recruited in two centers (Florida and Tenerife, Spain) and annually monitored their multidomain progression from 1997 to 2009. Patients were followed for a median of 64 months and up to 10 years. Their individual FEV(1) (L) and BODE index slopes, expressed as annual change, were evaluated using regression models for repeated measures. A total of 751 patients with at least three measurements were used for the analyses. MEASUREMENTS AND MAIN RESULTS: Eighteen percent of patients had a statistically significant FEV(1) slope decline (-86 ml/yr; 95% confidence interval [CI], -32 to -278 ml/yr). Higher baseline FEV(1) (relative risk, 1.857; 95% CI, 1.322-2.610; P < 0.001) and low body mass index (relative risk, 1.071; 95% CI, 1.035-1.106; P < 0.001) were independently associated with FEV(1) decline. The BODE index had a statistically significant increase (0.55, 0.20-1.37 point/yr) in only 14% of patients and these had more severe baseline obstruction. Concordance between FEV1 and BODE change was low (κ Cohen, 16%). Interestingly, 73% of patients had no significant slope change in FEV1 or BODE. Only the BODE change was associated with mortality in patients without FEV(1) progression. CONCLUSIONS: The progression of COPD is very heterogeneous. Most patients show no statistically significant decline of FEV(1) or increase in BODE. The multidimensional evaluation of COPD should offer insight into response to COPD management.

Microalbuminuria and hypoxemia in patients with chronic obstructive pulmonary disease.

RATIONALE: Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. There is evidence of vascular dysfunction in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the prevalence and relationship of MAB with clinical and physiological parameters in stable patients with COPD. METHODS: We measured urinary albumin rate (urinary albumin to creatinine ratio: UACR), smoking history, arterial blood pressure, gas exchange, body mass index, lung function, BODE index (body mass index, airflow obstruction, dyspnea, exercise performance), and comorbidity index in 129 patients with stable COPD and 51 smokers with normal spirometry without known cardiovascular disease. MAB levels were compared between groups. A multivariate analysis was performed to determine the best determinants of MAB levels. MEASUREMENTS AND MAIN RESULTS: MAB was higher in patients with COPD than in control smokers (8 [5th-95th percentile (P5₋95), 2.9-113] vs. 4.2 [P5₋95, 1.8-22.7] mg/g, P < 0.001]). The difference remained significant even after using the standard pathologic threshold (MAB, 30-299 mg/g in women and 20-299 mg/g in men; 24% in patients with COPD vs. 6% in control smokers; P = 0.005). In patients with COPD, there was a negative correlation between Pa(O2) and MAB (r = -0.40, P < 0.001). Using multivariate analysis, MAB was only associated with the Pa(O2) (relative risk, 0.934; 95% confidence interval, 0.880-0.992; P < 0.001) and with the systolic arterial blood pressure (relative risk, 1.034; 95% confidence interval, 1.011-1.057; P = 0.003). CONCLUSIONS: MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. Further studies are necessary to investigate whether MAB could be an early simple biomarker of cardiovascular compromise in patients with COPD.