Biomarkers in COPD – Challenging, Real or Illusive

Open access

Abstract

Biomarker research in COPD is becoming the most rapidly progressing sphere in respiratory medicine. Although “omics” generate a huge amount of biomarkers, fibrinogen is the only one validated by the European Medicines Agency. Thousands of studies analyzing different biological samples from the respiratory tract, collected in different ways, using various kits and techniques are generating more and more data, rendering biomarkers very confusing rather than having practical value. It seems that in order to be applicable and validated, biomarkers should be analysed in an accurately described cohort of patients, homogeneous in disease severity and activity. As COPD has multiple mechanisms of pathobiology it raises the issue of which is the most appropriate biological sample reflecting each of them. Unified criteria for tissue sampling, validated kits for respiratory tract probes and standardized technologies should be announced. The review presents the biomarkers that are currently validated and raises the problem of standardization.

1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95.

2. Clark KD, Wardrobe-Wong N, Elliott JJ, et al. Patterns of lung disease in a “normal” smoking population: are emphysema and airflow obstruction found together? Chest 2001;120(3):743-7.

3. Cote CG. Surrogates of mortality in chronic obstructive pulmonary disease. Am J Med 2006;119(10 Suppl 1):S54-S62.

4. Abu Hussein N, Ter Riet G, Schoenenberger L, et al. The ADO index as a predictor of two-year mortality in general practice-based chronic obstructive pulmonary disease cohorts. Respiration 2014;88(3):208-14.

5. Camiciottoli G, Bigazzi F, Bartolucci M, et al. BODE-index, modified BODE-index and ADO-score in chronic obstructive pulmonary disease: relationship with COPD phenotypes and CT lung density changes. COPD 2012;9(3):297-304.

6. Jones R, Price D, Chavannes N, et al. Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets. NPJ Prim Care Respir Med 2016;21:283-94.

7. Domingo-Salvany A, Lamarca R, Ferrer M, et al. Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166(5):680-5.

8. Jones PW, Brusselle G, Dal Negro RW, et al. Properties of the COPD assessment test in a cross-sectional European study. Eur Respir J 2011;38(1):29-35.

9. Dijkstra AE, Postma DS, ten Hacken N, et al. Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross-sectional study. Respir Res 2013;14:11.

10. Han MK, Kazerooni EA, Lynch DA, et al. Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011;261:274-82.

11. Smith BM, Austin JH, Newell JD Jr, et al. Pulmonary emphysema subtypes on computed tomography: the MESA COPD study. Am J Med 2014;127(1):94. e7-23.

12. Zulueta JJ, Wisnivesky JP, Henschke CI, et al. Emphysema scores predict death from COPD and lung cancer. Chest 2012;141:1216-23.

13. Agusti A, Calverley P, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122.

14. O’Brien C, Guest PJ, Hill SL, et al. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000;55:635-42.

15. Kitch BT, Levy BD, Fanta CH. Late onset asthma: epidemiology, diagnosis and treatment. Drugs Aging 2000;17:385-97.

16. Goeminne PC, Nawrot TS, Ruttens D, et al. Mortality analysis. Respir Med 2014;108:287-96.

17. Martínez-García MA, de la Rosa Carrillo D, Soler-Cataluña JJ, et al. Prognostic value of bronchiectasis inpatients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:823-31.

18. O’Hare PE, Ayres JF, O’Rourke RL, et al. Coronary artery calcification on computed tomography correlates with mortality in chronic obstructive pulmonary disease. J Comput Assist Tomogr 2014;38:753-9.

19. Williams MC, Murchison JT, Edwards LD, et al. Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax 2014;69:718-23.

20. Francis SM, Larsen JE, Pavey SJ, et al. Expression profiling identifies genes involved in emphysema severity. Respir Res 2009;10:81.

21. Savarimuthu Francis SM, Larsen JE, Pavey SJ, et al. Genes and gene ontologies common to airflow obstruction and emphysema in the lungs of patients with COPD. PLoS ONE 2011;6:e17442.

22. Hanaoka M, Ito M, Droma Y, et al. Comparison of gene expression profiling between lung fibrotic and emphysematous tissues sampled from patients with combined pulmonary fibrosis and emphysema. Fibrogenesis Tissue Repair 2012;5:17.

23. Steiling K, van den Berge M, Hijazi K, et al. A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med 2013;187:933-42

24. Morrison HM, Welgus HG, Stockley RA, et al. Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity. Am J Respir Cell Mol Biol 1990;2(3):263-9

25. Bathoorn E, Liesker J, Postma D, et al. Safety of sputum induction during exacerbations of COPD. Chest 2007;131:432-8.

26. Carter RI, Ungurs MJ, Mumford RA, et al. Aα-Val360: a marker of neutrophil elastase and COPD disease activity. Eur Respir J 2013;41(1):31-38.

27. Leeming DJ, Byrjalsen I, Sand JM, et al. Biomarkers of collagen turnover are related to annual change in FEV>1 in patients with chronic obstructive pulmonary disease within the ECLIPSE study. BMC Pulm Med 2017;17(1):164-78.

28. Berg I, Hanson C, Sayles H, et al. Vitamin D, vitamin D binding protein, lung function and structure in COPD. Respir Med 2013;107:1578-88.

29. Cheng DT, Kim DK, Cockayne DA, et al. Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:948-57.

30. Park HY, Churg A, Wright JL, et al. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1413-9.

31. Vestbo J, Edwards LD, Scanlon PD, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011;365:1184-92.

32. Cockayne DA, Cheng DT, Waschki B, et al. Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity. PLoS One 2012;7:e38629.

33. Dicker AJ, Crichton ML, Pumphrey EG, et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2017;6749(17):30746-7.

34. Zemans RL, Jacobson S, Keene J, et al. Multiple biomarkers predict disease severity, progression and mortality in COPD. Respir Res 2017;18(1):117-31.

35. Bradford E, Jacobson S, Varasteh J, et al. The value of blood cytokines and chemokines in assessing COPD. Respir Res 2017;18(1):180-9.

36. Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA 2013;309:2353-61.

37. Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:1065-72.

38. Agustí 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:e37483.

39. Holmgaard DB, Mygind LH, Titlestad IL, et al. Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease. BMC Pulm Med 2013;13:77.

40. Duvoix A, Dickens J, Haq I, et al. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax 2013;68:670-6.

41. Kawamatawong T, Apiwattanaporn A, Siricharoonwong W. Serum inflammatory biomarkers and clinical outcomes of COPD exacerbation caused by different pathogens. Int J Chron Obstruct Pulmon Dis 2017;12:1625-30.

42. Rahimirad S, Ghaffary MR, Rahimirad MH, et al. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease. Tuberk Toraks 2017;65(1):25-31.

43. Yao C, Liu X, Tang Z. Prognostic role of neutrophillymphocyte ratio and platelet-lymphocyte ratio for hospital mortality in patients with AECOPD. Int J Chron Obstruct Pulmon Diseases 2017;12:2285-90.

44. Mendy A, Forno E, Niyonsenga T, et al. Blood biomarkers as predictors of long-term mortality in COPD. Clin Respir J 2017. doi: 10.1111/crj.12752. [Epub ahead of print].

45. Paone G, Conti V, Vestri A, et al. Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients. Dis Markers 2011;31:91-100.

46. Singh D, Fox SM, Tal-Singer R, et al. Induced sputum genes associated with spirometric and radiological disease severity in COPD ex-smokers. Thorax 2011;66:489-95.

47. Koutsokera A, Kostikas K, Nicod LP, et al. Pulmonary biomarkers in COPD exacerbations: a systematic review. Respir Res 2013;14:111-120.

48. Tufvesson E, Ekberg M, Bjermer L. Inflammatory biomarkers in sputum predict COPD exacerbations. Lung 2013;191:413-6.

49. Tworek D, Antczak A. Eosinophilic COPD - a distinct phenotype of the disease Adv Respir Med 2017;85:271-6.

50. Pérez-de-Llano L, Cosio BG. Asthma-COPD overlap is not a homogeneous disorder: further supporting data. Respir Res 2017;18(1):183-96.

51. Gao J, Zhou W, Chen B, et al. Sputum cell count: biomarkers in the differentiation of asthma, COPD and asthma-COPD overlap. Int J Chron Obstruct Pulmon Dis 2017;12:2703-10.

52. Lee H, Hong Y, Lim MN, et al. Inflammatory biomarkers and radiologic measurements in never-smokers with COPD: A cross-sectional study from the CODA cohort. Chron Respir Dis. 2017. doi: 10.1177/1479972317736293. [Epub ahead of print]

53. Papaioannou AI, Kostikas K, Papaporfyriou A, et al. Emphysematous phenotype is characterized by low blood eosinophils: a cross-sectional study. COPD 2017;14(6):635-40.

54. Basanta M, Ibrahim B, Dockry R, et al. Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study. Respir Res 2012;13:72-86.

55. Hattesohl AD, Jörres RA, Dressel H, et al. Discrimination between COPD patients with and without alpha 1-antitrypsin deficiency using an electronic nose. Respirology 2011;16:1258-64.

56. Fens N, de Nijs SB, Peters S, et al. Exhaled air molecular profiling in relation to inflammatory subtype and activity in COPD. Eur Respir J 2011;38:1301-9.

57. Warwick G, Thomas PS, Yates DH. Non-invasive biomarkers in exacerbations of obstructive lung disease. Respirology 2013;18:874-84.

58. Gao J, Zhang M, Zhou L, et al. Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2017;12:1287-93.

59. Ling SH, van Eeden SF. Particulate matter air pollution exposure: role in the development and exacerbation of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2009;4:233-43.

60. Gan WQ, FitzGerald JM, Carlsten C, et al. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013;187:721-7.

61. Dadvand P, Nieuwenhuijsen MJ, Agustí À, et al. Air pollution and biomarkers of systemic inflammation and tissue repair in COPD patients. Eur Respir J 2014;44:603-13.

62. Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS ONE 2011;6:e163842009;374:733-43.

63. Wang L, Hao K, Yang T, et al. Role of the lung microbiome in the pathogenesis of chronic obstructive pulmonary disease. Chin Med J (Engl) 2017;130(17):2107-11.

64. Lee J, Sandford AJ, Connett JE, et al. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD). PLoS ONE2012;7:e35567.

65. Rode L, Bojesen SE, Weischer M, et al. Short telo-mere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals. Thorax 2013;68:429-35.

66. Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest 2009;135:173-80.

67. Mac Nee W. Accelerated lung aging: a novel pathogenic mechanism of chronic obstructive pulmonary disease (COPD). Biochem Soc Trans 2009;37:819-23.

68. Yanagisawa S, Papaioannou AI, Papaporfyriou A, et al. Decreased serum sirtuin-1 in COPD. Chest 2017;152(2):343-52.

69. Caramori G, Casolari P, Barczyk A, et al. COPD immuno-pathology. Semin Immunopathol 2016;38(4): 497-515.

70. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360(23):2445-54.

71. John-Schuster G, Hager K, Conlon TM, et al. Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD. Am J Physiol Lung Cell Mol Physiol 2014;307(9):L692-L706.

72. Di Stefano A, Caramori G, Capelli A, et al. STAT-4 activation in smokers and patients with COPD. Eur Respir J 2004;24(1):78-85.

73. Cosio MG. Autoimmunity, T-cells and STAT-4 in the pathogenesis of chronic obstructive pulmonary disease. Eur Respir J 2004;24(1):3-5.

74. Korn S, Wiewrodt R, Walz YC, et al. Characterization of the interstitial lung and peripheral blood T cell receptor repertoire in cigarette smokers. Am J Respir Cell Mol Biol 2005;32(2):142-8.

75. Renaud-Picard B, Toussaint J, Leclercq A, et al. Membranous microparticles and respiratory disease. Rev Mal Respir 2017;34(10):1058-71.

76. Kubo H. Extracellular vesicles in lung disease. Chest 2017;3692(17):31195-99.

77. Tan DBA, Armitage J, Teo TH, et al. Elevated levels of circulating exosome in COPD patients are associated with systemic inflammation. Respir Med 2017;132:261-4.

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The Journal of Medical University-Plovdiv

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