Biomarkers in Chronic Obstructive Pulmonary Disease

Alexandros G. Mathioudakis MD1, Efstathia I. Evangelopoulou MD2.
1Medical Department, Southport and Ormskirk NHS Trust, UK. 2 Respiratory Department, General Hospital of Nikaia St. Panteleimon, Greece.

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Cite as: Mathioudakis AG, Evangelopoulou EI. Biomarkers in Chronic Obstructive Pulmonary Disease. Alveolus 2013; 1(1):3-5.

Being an heterogeneous, progressive chronic disease, characterised by exacerbations and remissions, COPD requires accurate but also simple and cheap means to assess it's phenotype, inflammatory profile, activity and progression.These are also compulsory for the evaluation of prognosis, of new therapeutic strategies and the impact of aggravating and alleviating factors. Clearly, spiromerty is currently the most accurate means of evaluating the disease stage and progression, while DLCO enables us to differentiate predominantly bronchitic and predominantly emphysematic patients. However, recent studies demonstrate the value of the assessment of the inflammatory profile and activity and their contingent contribution to the management of both stable COPD and exacerbations.


During the last years, several novel biomarkers, either circulatory or exhaled or identified at the sputum, have emerged as a new tool for the evaluation, classification and management of COPD. These biomarkers can be categorised as either markers of the disease severity, lung function, prognosis and inflammatory phenotype (during clinical stability) or markers of the exacerbation aetiology and prognosis or both[1]. A last category that has been identified recently includes biomarkers that predict the COPD risk in healthy people (without asthma or COPD diagnosis)[2].


Several biomarkers are already used in the clinical practice, like the general markers of inflammation[3]. C-reactive protein is used to assess the inflammatory levels, prognosis and mortality of COPD (both in exacerbation and clinical stability) and to differentiate the etiological origin of the exacerbation (higher CRP in infectious exacerbations). Procalcitonin is also used to assess predict the cause of the exacerbation and to assess the treatment effect. A recent study by Marcun R et al. showed that the classic cardiac biomarkers (Troponin T and NT-proBNP) could also predict the outcome after hospitalisation for an acute exacerbation of COPD[4], while an older study showed that BNP can be used as a marker of severity and can predict the need for intensive care[5].
Apart from the circulatory biomarkers, exhaled NO and sputum markers are used. Exhaled NO reflects the up-regulation of NO by inflammatory cytokines and mediators in central or peripheral airway cites. According to a recent review by Gelb AF et al, the predominant airway site of increased NO production can also be estimated, clarifying the exact level of inflammation in the bronchial tree[6]. Regarding induced sputum, which is currently used chiefly in research, last week Zanini A et al reported a series of cases of COPD exacerbations treated according to their sputum neutrophilia (neutrophilia: infectious exacerbation/ eosinophilia: non-infectious)[7].
The fact that over 10 articles studying different COPD biomarkers have already been published during the last month, including a study by Cockayne DA et al. who analysed over 140 possible proteinic biomarkers[8] indicates that this is a very "hot" research topic. Cockayne DA et al. found that a set of 5 analyses (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. Proteins of the EGFR pathway, EN-RAGE, NGAL and MPO also highlighted as possible biomarkers. Other studies suggested exhaled eicosanoids and biomarkers of oxidative stress[9], circulatory PAI-1, desmosines and TIMP-1[10], serum surfactant protein D[11] and serum micro-RNAs[12]as promising biomarkers. An interesting review on the non-invasive biomarkers of lung inflammation in smokers highlights the fact that the pathological and pathophysiological characteristics of COPD could exist for a large period prior to clinical disease[13].

Finally, a month ago Agusti A et al. (ECLIPSE study) suggested a novel COPD phenotype characterised by persistent systemic inflammation, based on six classic circulating inflammatory biomarkers, namely CRP, IL-6, IL-8, fibrinogen and TNF-a. They identified an increased risk of all-cause mortality associated with this phenotype albeit it is characterised by the same pulmonary abnormalities[14], highlighting the role of COPD biomarkers in clinical practice. 


[1] Angela Koutsokera, Daiana Stolz, Stelios Loukides, Konstantinos Kostikas. Systemic Biomarkers in Exacerbations of COPD: The Evolving Clinical Challenge. Chest 2012;141;396-405. Epub 2011 Aug 11. Very interesting review/ Comprehensive tables 3,4
[2] Rosenberg SR, Kalhan R. Biomarkers in Chronic Obstructive Pulmonary Disease. Transl Res. 2012 Apr;159(4):228-37. Epub 2012 Feb 7. Interesting recent review
[3] Lacoma A, Prat C, Andreo F, Dominquez J. Biomarkers in the management of COPD. Eur Respir Rev 2009; 18:(112)96-104.
[4] Marcun R, Sustic A, Brguljan PM, et al. Cardiac biomarkers predict outcome after hospitalisation for an acute exacerbation of chronic obstructive pulmonary disease. Int J Cardiol. 2012 Jun 3. [Epub ahead of print]
[5] Stolz D, Breidthardt T, Christ-Crain M et al. Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD. Chest 2008; 133:1088-94.
[6] Gelb AF, Barnes PJ, George SCk et al. Review of exhaled nitric oxide in chronic obstructive pulmonary disease. J Breath Res. 2012 Jun 7;6(4):047101. [Epub ahead of print]
[7] Zanini A, Patrona SD, Facchini AL, Spanevello A. Induced sputum in the management of COPD: clinical implications. Monaldi Arch Chest Dis. 2012 Mar;77(1):23-5. Biomarkers in clinical practice
[8] Cockayne DA, Cheng DT, Waschki Bk et al. Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD patients with Differing Levels of Disease Severity. PLoS One. 2012;7(6):e38629. Epub 2012 Jun 12. Analyzed 140 proteins.
[9] Antczak A, Ciebiada M, Pietras T, et al. Exhaled eicosanoids and biomarkers of oxidative stress in exacerbation of chronic obstructive pulmonary disease. Arch Med Sci. 2012 May 9;8(2):277-85.
[10] Engstrom G, Lindberg C, Gerhardsson de Verdier M, et al. Blood biomarkers and measures of pulmonary function-A study from the Swedish twin registry. Respir Med. 2012 Jun 9. [Epub ahead of print]
[11] Ju CR, Liu W, Chen RC. Serum surfactant protein D: Biomarker of chronic obstructive pulmonary disease. Dis Markers. 2012 Jan 1; 32(5):281-7.
[12] Akbas F, Coskunpinar E, Aynacı E, et al. Analysis of serum micro-RNAs as potential biomarker in chronic obstructive pulmonary disease. Exp Lung Res. 2012 Jun 11. [Epub ahead of print]
[13] Malerba M, Montuschi P. Non-invasive biomarkers of lung inflammation in smoking subjects. Curr Med Chem. 2012;19(2):187-96. Biomarkers - Smokers
[14] Agusti A, Edwards LD, Rennard SI, et al. Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype. PLoS One. 2012; 7(5): e37483. Biomarkers in clinical practice


Conflicts of Interest: None