Biomarker Commons

Elevated N-terminal pro-brain natriuretic peptide is associated with mortality in tobacco smokers independent of airflow obstruction.

PLoS One. 2011;6(11):e27416

Authors: Stamm JA, Belloli EA, Zhang Y, Bon J, Sciurba FC, Gladwin MT

Abstract
BACKGROUND: Tobacco use is associated with an increased prevalence of cardiovascular disease. N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers. We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease.
METHODS: Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality.
RESULTS: Subjects were followed for a median of 562 (IQR 252-826) days. Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index. By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02). By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07-4.46, p = 0.031).
CONCLUSIONS: Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death. Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival.

PMID: 22087311 [PubMed - indexed for MEDLINE]

Biomarkers in chronic obstructive pulmonary disease.

Transl Res. 2012 Apr;159(4):228-37

Authors: Rosenberg SR, Kalhan R

Abstract
Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple phenotypes that cannot be identified through measurement of lung function alone. The importance of COPD risk assessment, phenotype identification, and diagnosis of exacerbation magnify the need for validated biomarkers in COPD. A large number of potential biomarkers have already been assessed and some appear promising, in particular fibrinogen, which is likely to be the first COPD biomarker presented to the Food and Drug Administration for qualification in the drug approval process. Blood fibrinogen and c-reactive protein (CRP) have been associated with the presence of COPD and, in some instances, future risk of developing COPD in targeted populations. Sputum neutrophil counts have been used preliminarily as biomarkers of favorable response to therapy in COPD, but use in clinical settings may be limited. Other potential blood biomarkers include pulmonary and activation-regulated chemokine (PARC/CCL-18) and the clara cell secretory protein 16 (CC-16). Integrative indices, such as the BODE index, provide a framework to determine prognosis, predict outcome, and may be responsive to therapeutic interventions. Computed tomography provides a means to assess phenotypes and identify the relative extents of small airways disease and emphysema, which themselves may inform prognosis and therapeutic decision making. Fibrinogen and other markers of systemic inflammation are elevated in the context of acute COPD exacerbations and may also identify those at risk of accelerated lung function decline and hospitalization. So far, no single biomarker in COPD warrants wide acceptance emphasizing the need for future investigation of biomarkers in large-scale longitudinal studies.

PMID: 22424427 [PubMed - indexed for MEDLINE]

Self-assembled micellar formulation of chafuroside A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.

Eur J Pharm Sci. 2012 Jan 23;45(1-2):184-9

Authors: Onoue S, Matsui T, Aoki Y, Ishida H, Nukaya H, Kou K, Yamada S

Abstract
Chafuroside A (CFA), a poorly water-soluble flavone C-glycoside, was firstly isolated from oolong tea, and it acts as a potent anti-inflammatory agent. The present study was undertaken to develop a water-soluble formulation of CFA using a self-assembled micellar (SAM) system, with the aim of improved dissolution behavior and potent anti-inflammatory effects. The SAM formulation of CFA (CFA/SAM) was characterized in terms of its morphology, particle size distribution, crystallinity, and dissolution behavior. In dissolution testing, the CFA/SAM exhibited marked improvement in dissolution behavior when compared with crystalline CFA, and then, nano-micellar particles were constituted with a mean diameter of 84 nm. The therapeutic potential of the crystalline CFA and CFA/SAM was assessed using an experimental asthma/chronic obstructive pulmonary disease (COPD)-like model. Orally-administered CFA at 0.5mg/kg or higher could attenuate inflammatory symptoms in a dose-dependent manner, as evidenced by decreases of infiltrated granulocytes, including macrophages and neutrophils, and myeloperoxidase, a specific biomarker for neutrophilia. Biomarker profiling demonstrated that the CFA/SAM at 0.1mg CFA/kg was equipotent to CFA at 1.0mg/kg in ameliorating antigen-induced airway inflammation, suggesting the better pharmacological effect of CFA/SAM due to improved dissolution behavior. From these observations, the SAM formulation might be an efficacious approach for enhancing the therapeutic potential of CFA for treatment of inflammatory diseases.

PMID: 22108345 [PubMed - indexed for MEDLINE]

Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function.

Am J Respir Crit Care Med. 2012 Feb 15;185(4):373-81

Authors: Qiu W, Baccarelli A, Carey VJ, Boutaoui N, Bacherman H, Klanderman B, Rennard S, Agusti A, Anderson W, Lomas DA, DeMeo DL

Abstract
RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure.
OBJECTIVES: To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease.
METHODS: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n = 1,085 and 369 subjects).
MEASUREMENTS AND MAIN RESULTS: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 × 10(-23); FEV(1)/FVC, 1.5 × 10(-35); FEV(1), 2.2 × 10(-40)).
CONCLUSIONS: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This large-scale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.

PMID: 22161163 [PubMed - indexed for MEDLINE]

COPD association and repeatability of blood biomarkers in the ECLIPSE cohort.

Respir Res. 2011;12:146

Authors: Dickens JA, Miller BE, Edwards LD, Silverman EK, Lomas DA, Tal-Singer R,

Abstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
TRIAL REGISTRATION: SCO104960, clinicaltrials.gov identifier NCT00292552.

PMID: 22054035 [PubMed - indexed for MEDLINE]

Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease.

Clin Physiol Funct Imaging. 2012 Jan;32(1):71-9

Authors: Korsgren M, Linden M, Entwistle N, Cook J, Wollmer P, Andersson M, Larsson B, Greiff L

Abstract
AIM: Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD).
MATERIALS: Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 μg). Blood was analysed for C-reactive protein (CRP), α(1)-antitrypsin and neutrophils/leucocytes, and sputum was analysed for biomarkers of neutrophil inflammation and remodelling activities, i.e. neutrophil elastase (NE) protein/activity and α(1)-antitrypsin. Levels of tumour necrosis factor-α (TNFα) were measured in both blood and sputum. Urine was collected 0-24 and 24-48 h postchallenge, and desmosine, a biomarker of elastin degradation, was measured.
RESULTS: Lipopolysaccharide inhalation induced dose-dependent flu-like symptoms and increases in plasma CRP and α(1)-antitrypsin as well as increases in blood neutrophil/leucocyte numbers. Furthermore, LPS produced increases in sputum TNFα and sputum NE activity. Urine levels of desmosine were unaffected by the LPS challenge. All subjects recovered 48 h postchallenge, and indices of inflammatory activity were significantly lower at this observation point cf 24 h postchallenge.
CONCLUSION: Inhalation of LPS in healthy volunteers can be used as a safe and stable model of neutrophil inflammation. Blood/plasma and sputum indices can be employed to monitor the response to LPS. We suggest that this model may be used for initial human studies of novel COPD-active drugs.

PMID: 22152082 [PubMed - indexed for MEDLINE]

Systemic biomarkers in exacerbations of COPD: the evolving clinical challenge.

Chest. 2012 Feb;141(2):396-405

Authors: Koutsokera A, Stolz D, Loukides S, Kostikas K

Abstract
BACKGROUND: Exacerbations of COPD (ECOPD) remain a major cause of mortality and morbidity. Despite advances in the understanding of their pathophysiology, their assessment relies primarily on clinical presentation, which can be variable and difficult to predict. A large number of biomarkers already have been assessed in this context, and some appear to be promising.
METHODS: An online search for articles published until December 2010 was conducted using three terms for ECOPD, five terms for biomarkers, and five terms for the sampling method. Biomarkers were evaluated for their potential role in the establishment and confirmation of the diagnosis of ECOPD, the evaluation of etiology and severity, the prediction of prognosis, and the guidance of treatment decisions.
RESULTS: Several systemic biomarkers have been measured in the context of ECOPD, and most have been found to increase at ECOPD onset and to subside during the course of exacerbations. Correlations have been reported among these biomarkers, but direct associations with clinical variables have been more difficult to establish. Although there are several limitations yet to be addressed, some of the biomarkers, most notably C-reactive protein for the identification of an ECOPD and procalcitonin for antibiotic guidance, may provide clinically relevant information.
CONCLUSIONS: So far, no single biomarker has been able to gain wide acceptance, but some provide clinically useful information. The evaluation of such biomarkers in large decision-making studies is expected to become an area of intense investigation in the near future.

PMID: 21835899 [PubMed - indexed for MEDLINE]

Proteomics in asthma and COPD phenotypes and endotypes for biomarker discovery and improved understanding of disease entities.

J Proteomics. 2011 Dec 10;75(1):192-201

Authors: O'Neil SE, Lundbäck B, Lötvall J

Abstract
The application of proteomics to respiratory diseases, such as asthma and COPD, has been limited compared to other fields, like cancer. Both asthma and COPD are recognised to be multi-factorial and complex diseases, both consisting of clusters of multiple disease phenotypes. The complexity of these diseases combined with the inaccessibility and invasiveness of disease relevant samples have provided a hurdle to the progress of respiratory proteomics. Advances in proteomic instrumentation and methodology have led to the possibility to identify proteomes in much smaller quantities of biological material. This review focuses on the efforts in respiratory proteomics in relation to asthma and COPD, and the importance of identifying subgroups of disease entities to establish appropriate biomarkers, and to enhance the understanding of underlying mechanisms in each subgroup. Careful phenotype characterisation of patient subpopulations is required to make improvement in the field of heterogeneous diseases such as asthma and COPD, and the clusters of phenotypes are likely to encompass subgroups of disease with distinct molecular mechanisms; endotypes. The utilisation of modern advanced proteomics in endotypes of asthma and COPD will likely contribute to the increased understanding of disease mechanisms, establishment of biomarkers for these endotypes and improved patient care.

PMID: 22037230 [PubMed - indexed for MEDLINE]

Alpha-1 antitrypsin is elevated in exhaled breath condensate and serum in exacerbated COPD patients.

Respir Med. 2012 Jan;106(1):120-6

Authors: Koczulla AR, Noeske S, Herr C, Koepke J, Jörres RA, Nell C, Schmid S, Vogelmeier C, Bals R

Abstract
BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) significantly contribute to COPD-related morbidity. Diagnosis of COPD exacerbations may be improved by analyzing biomarkers such as alpha-1 antitrypsin (AAT). AAT is an acute-phase protein and inhibitor of neutrophil elastase. Deficiency of AAT may result in early-onset respiratory symptoms. Measurement of exhaled breath condensate (EBC) is a noninvasive method to investigate biomarkers present in the epithelial lining fluid, such as AAT.
OBJECTIVE: To investigate whether AAT can be detected and quantified in EBC and to compare AAT levels in the EBC of healthy controls, patients with COPD, and during exacerbations of COPD.
METHODS: EBC from 10 healthy controls, 17 subjects with COPD, and 18 subjects with exacerbations of COPD was collected with the RTube™ device. AAT from EBC and serum were quantified by ELISA.
RESULTS: AAT in EBC was detectable in every individual. Patients with exacerbations of COPD had significantly increased AAT values (mean, 514.33 pg/mL, [SD 279.41 ]) compared with healthy controls (mean, 251.32 pg/mL, [SD 44.71]) and stable COPD patients (mean, 242.01 pg/mL [SD 65.74]) (P=0.0003; P=0.00003). EBC AAT showed only a correlation trend with serum AAT (r=0.3, P=0.054).
CONCLUSIONS: AAT in EBC was detectable and quantifiable. AAT measured in EBC was significantly increased during exacerbations of COPD and can potentially be used as a biomarker in exacerbations.

PMID: 21872457 [PubMed - indexed for MEDLINE]

Elevated placenta growth factor predicts pneumonia in patients with chronic obstructive pulmonary disease under inhaled corticosteroids therapy.

BMC Pulm Med. 2011;11:46

Authors: Cheng SL, Wang HC, Cheng SJ, Yu CJ

Abstract
BACKGROUND: An increased incidence of pneumonia in patients with chronic obstructive pulmonary disease (COPD) under inhaled corticosteroid (ICS) therapy was noticed in previous studies. We performed a prospective study to elucidate the risk factors for the development of pneumonia in this group of patients.
METHODS: A prospective, non-randomized study with patients diagnosed as having COPD from 2007 to 2008 identified in the Far Eastern Memorial Hospital were recruited. We recorded data for all patients, including clinical features and signs, demographic data, lung function status, and medications. Bio-markers such as C-reactive protein (CRP) and placenta growth factor (PlGF) were checked at first diagnosis. Every acute exacerbation was also recorded, especially pneumonia events, which were confirmed by chest radiography. Multivariate analysis was performed with stepwise logistic regression for pneumonia risk factors.
RESULTS: 274 patients were diagnosed as having COPD during the study period and 29 patients suffered from pneumonia with a prevalence of 10.6%. The rate was significantly higher in patients with ICS therapy (20/125, 16%) compared with those without ICS (9/149, 6%) (p = 0.02). We stratified ICS therapy into medium dose (500-999 ug/day fluticasone equivalent, 71 patients) and high dose (1000 ug/day and higher fluticasone equivalent, 54 patients) group. There was no statistical difference in the incidence of pneumonia between these two group (medium dose: 13/71, 18.3% vs. high dose: 7/54, 12.9%, p = 0.47). Multivariate analysis was performed to identify the risk factors for developing pneumonia and included forced expiratory volume in one second (FEV1) less than 40% of predicted (odds ratio (OR) 2.2, 95% confidence interval (CI): 1.1-6.9), ICS prescription ((OR) 2.4, 95% (CI): 1.3-8.7), the presence of diabetes mellitus (DM) (OR 2.6, 95% CI: 1.2-9.4) and PlGF level over 40 pg/L (OR 4.1, 95% CI: 1.5-9.9).
CONCLUSION: ICS therapy in patients with COPD increased the risk of pneumonia. However, there was no relationship between the incidence of pneumonia and dosage of ICS. Additionally, advanced COPD status, DM and elevated PlGF level were independent risk factors for the development of pneumonia. PlGF would be a good novel biomarker for predicting pneumonia.

PMID: 21962211 [PubMed - indexed for MEDLINE]

Measurement of soluble perforin, a marker of CD8+ T lymphocyte activation in epithelial lining fluid.

Respir Med. 2011 Dec;105(12):1885-90

Authors: Shiratsuchi N, Asai K, Kanazawa H, Kyoh S, Tochino Y, Kodama T, Hirata K

Abstract
BACKGROUND: CD8(+) T lymphocytes in the peripheral airways have been suggested to be involved in the pathogenesis of COPD. However, the significance of CD8(+) T lymphocyte activation in COPD is not well understood. A biomarker of CD8(+) T lymphocyte activation in patients with COPD is required.
METHODS: Thirty COPD patients and twenty-one healthy controls (eleven ex-smokers and ten who had never smoked or were light ex-smokers) were included in this study. We separately obtained epithelial lining fluid (ELF) from central and peripheral airways using a bronchoscopic microsampling technique. Levels of perforin in ELF were measured and we examined correlations between its values and patients characteristics including pulmonary function.
RESULTS: Perforin levels in both the central and peripheral airways in COPD patients were significantly higher than those in the healthy control groups. In the healthy control groups, there was no significant difference in perforin levels between central and peripheral airways. However, in COPD patients, perforin levels in peripheral airways were significantly higher than those in central airways. Perforin levels in peripheral airways were significantly correlated with FEV(1) (percent predicted), FEV(1)/FVC, and DLco (percent predicted) in COPD patients.
CONCLUSION: The microsampling technique is safe and useful for separately obtaining ELF from central and peripheral airways. Levels of perforin in ELF from peripheral airways were significantly increased and correlated with the degree of pulmonary dysfunction. Perforin might reflect inflammation involving CD8(+) T-lymphocytes. This novel biomarker might enable better understanding of the pathogenesis of COPD.

PMID: 21827966 [PubMed - indexed for MEDLINE]