COPD association and repeatability of blood biomarkers in the ECLIPSE cohort

Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
Respiratory research (Impact Factor: 3.09). 11/2011; 12(1):146. DOI: 10.1186/1465-9921-12-146
Source: PubMed


There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) cohort.
Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients.
Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201) reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved.
Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD). Further analysis of more promising biomarkers may reveal utility in subsets of patients. Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation.
SCO104960, identifier NCT00292552.

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Available from: Bruce E Miller, Jul 28, 2015
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    • "While it is typically associated with COPD and ageing,3 systemic inflammation has recently been linked to some forms of asthma.4 In COPD, systemic inflammation with chronic low-grade elevation of circulating pro-inflammatory mediators such as C-reactive protein (CRP) and interleukin 6 (IL-6) is associated with accelerated disease progression, characterized by acute exacerbations,5 COPD-related hospitalization,6 and rapid decline of force expiratory volume in 1 second (FEV1).6 These same markers of systemic inflammation are also associated with ageing and comorbid diseases, such as cardiovascular disease (CVD),7 obesity,8 diabetes,8 and are believed to actively participate in the pathogenesis of these conditions. "
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    ABSTRACT: Purpose The role of systemic inflammation on asthma-COPD overlap syndrome is unknown. This study aimed to examine systemic inflammation in asthma-COPD overlap syndrome, and to identify associations between clinical characteristics and inflammatory mediators in asthma-COPD overlap syndrome. Methods In 108 adults older than 55 years comprising healthy controls (n=29), asthma (n=16), COPD (n=21) and asthma-COPD overlap syndrome (n=42), serum high sensitivity C-reactive protein and Interleukin 6 (IL-6) were assayed. Spirometry, induced sputum, quality of life, comorbidities and medications were assessed, and their associations with asthma-COPD overlap syndrome were analyzed using logistic regression. Associations between systemic inflammatory mediators and clinical characteristics were tested in multivariate linear regression models. Results Patients with asthma-COPD overlap syndrome had significantly elevated IL-6 levels compared with healthy controls and asthmatics. Age, comorbidity index and IL-6 level were independently associated with asthma-COPD overlap syndrome. FEV1% predicted was inversely associated with IL-6 level, and cardiovascular disease was associated with an increased IL-6 level. Systemic markers were not associated with airway inflammation. Conclusions Systemic inflammation is commonly present in asthma-COPD overlap syndrome, and asthma-COPD overlap syndrome resembled COPD in terms of systemic inflammation. IL-6 is a pivotal inflammatory mediator that may be involved in airflow obstruction and cardiovascular disease and may be an independent treatment target.
    Full-text · Article · Jul 2014 · Allergy, asthma & immunology research
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    • "Apart from previous exacerbation history, we currently have no good tools to identify frequent exacerbators. Use of biomarkers for detection of early COPD could be a possible new way [15,16] of predicting prognosis to aid both the GP and his/her patients, but until now no biomarkers of disease activity have been shown to predict a COPD trajectory. However, through an ongoing collaboration [17] we have established a working relationship with specialists in molecular medicine. "
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    ABSTRACT: Background Chronic Obstructive Pulmonary Disease (COPD) is the most common severe chronic disease in primary care. It is typically diagnosed at a late stage, and it is also difficult to predict its trajectory and hence to tailor treatment and rehabilitation. The overall aim is to study determinants of exacerbations of COPD treated in primary care and to study, if the prognosis is related to patient-related, healthcare system markers or levels of the potential biomarkers such as microfibrillar-associated protein 4 (MFAP4) and surfactant protein D (SP-D). Furthermore, we aim to establish a cohort of COPD patients treated in Danish primary care comprising register data, data captured from the GPs’ electronic patient record system (EPR) and a biobank in order to make analyses on factors associated with different tractories of COPD treated in primary care. Methods/design A cohort study of incident and prevalent COPD patients treated and followed by their GPs using data capture, which is a computer system collecting data from the GPs’ own EPR and transferring them to the Danish General Practice Research Database. The participating COPD patients were investigated at a baseline consultation by their own GP, and the results were registered using a pop-up menu by the GP. During the consultation blood samples were taken and the patients were given a questionnaire. The patients will then be followed prospectively at yearly consultations and in between these consultations by means of the data capture system. The collected data will also be combined with register data from other sources. The data collection started in December 2012, and so far 30 practices with 77 GPs have included about 350 patients. The study aims to include 2000 patients till the end of 2016, and after that to continue to collect data on these patients using the data capture system. Discussion The GP currently lacks tools to predict trajectory of their COPD patients. The measurement of lung function only reflects loss of lung capacity and not disease activity. Use of biomarkers for detection of early COPD could be a possible way of predicting trajectory to aid both the GP and his/her patients. This study aims to provide evidence of determinants of a COPD trajectory, including novel specific biomarkers and other patient- and healthcare system-related markers. Trial registration Protocol Registration System, Identifier: NCT01698151
    Full-text · Article · May 2014 · BMC Pulmonary Medicine
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    • "Recent advances using inflammatory biomarkers suggest that quantification of serum proteins are effective in the diagnosis, classification, prognosis, and treatment response of COPD [5,21]. Both CRP and fibrinogen are acute-phase inflammatory biomarkers that are normally used in clinic, their concentrations will generally rise in response to infections but decline with the clinical recovery [22,23]. In this study, we found most patients had much higher concentrations of CRP and fibrinogen at exacerbation, probably triggered by bacterial and/or viral infections [24,25]. "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) exacerbations are accompanied with increased systemic inflammation, which accelerate the pulmonary function injury and impair the quality of life. Prompt and effective treatments for COPD exacerbations slow down the disease progression, but an objective instrument to assess the efficacy of the treatments following COPD exacerbations is lacking nowadays. The COPD Assessment Test (CAT) is an 8-item questionnaire designed to assess and quantify health status and symptom burden in COPD patients. We hypothesize that the change in CAT score is related to the treatment response following COPD exacerbations. 78 inpatients with clinician-diagnosed acute exacerbation of COPD (AECOPD) completed the CAT, St George's Respiratory Questionnaire (SGRQ) and modified Medical Research Council (mMRC) Dyspnea Scale both at exacerbation and the 7th day of therapy, and a subgroup of 39 patients performed the pulmonary function test. Concentrations of serum C-reactive protein (CRP) and plasma fibrinogen were assayed at the same time. Correlations between the CAT and other measurements were examined. After 7 days' therapy, the CAT and SGRQ scores, mMRC grades, as well as the concentrations of CRP and fibrinogen all decreased significantly (P < 0.001). Meanwhile, the FEV1% predicted had a significant improvement (P < 0.001). The CAT scores were significantly correlated with concurrent concentrations of CRP and fibrinogen, SGRQ scores, FEV1% predicted and mMRC grades (P<0.05). The change in CAT score was positively correlated with the change of CRP (r = 0.286, P < 0.05), SGRQ score (r = 0.725, P < 0.001) and mMRC grades (r = 0.593, P < 0.001), but not with fibrinogen (r = 0.137, P > 0.05) or FEV1% predicted (r = -0.101, P > 0.05). No relationship was found between the changes of SGRQ score and CRP and fibrinogen (P>0.05). The CAT is associate with the changes of systemic inflammation following COPD exacerbations. Moreover, the CAT is responsive to the treatments, similar to other measures such as SGRQ, mMRC dyspnea scale and pulmonary function. Therefore, the CAT is a potentially useful instrument to assess the efficacy of treatments following COPD exacerbations.
    Full-text · Article · Mar 2014 · BMC Pulmonary Medicine
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