Indian Journal of Clinical Biochemistry

, Volume 33, Issue 3, pp 334–340 | Cite as

Diagnostic Potential of Circulating Biomarkers in Adenosine Deaminase Diagnosed Pleural Tuberculosis Cases

  • Bineeta KashyapEmail author
  • Nisha Goyal
  • N. P. Singh
  • Iqbal R. Kaur
Original Article


Pleural tuberculosis accounts for nearly 20% of Extra pulmonary tuberculosis. Adenosine deaminase, commonly used biomarker for the diagnosis, is non specific and there is paucity of literature on its correlation with conventional or newer methods for the diagnosis of extra pulmonary forms of TB. The aim of the study was to assess diagnostic potential of T cell function markers [interferon (IFN-γ), interleukin (IL-2) and IFN-γ/IL-2 ratio]; macrophage activation marker [neopterin]; and oxidative stress markers [protein carbonyl and malondialdehyde (MDA)] in pleural tuberculosis. 26 pleural TB cases diagnosed on the basis of suggestive chest X-ray and raised serum ADA levels and healthy controls were included in the study. Pleural fluid specimens were subjected to Zeihl Neelsen staining and culture on Lowenstein Jensen medium. Serum IFN-γ, IL-2, neopterin and protein carbonyl levels detection were done by ELISA and MDA levels were determined by measuring the thiobarbituric acid reactive substances. Median serum levels of IFN-γ, IL-2, IFN-γ/IL-2 ratio, neopterin, protein carbonyl and MDA were significantly different between cases and controls. Levels of all biomarkers except IL-2 were significantly higher in cases with contact history. Mean levels of ADA and ESR were 46.27 U/L and 46.62 mm/hr in PTB cases. AUC for IFN-γ, IL-2, IFN-γ/IL-2 ratio, neopterin, protein carbonyl and MDA were significantly discriminative for cases and controls. IFN-γ/IL-2 ratio was best discriminatory biomarker with highest area under ROC curve. Though no correlation was seen between ADA and any of the six biomarkers, ESR levels correlated significantly with all biomarkers except IL-2 by spearman’s correlation coefficient. Though all the circulating biomarkers under study provide useful supportive evidence for the diagnosis of PTB, further studies involving diverse control groups particularly non-PTB effusion are needed to validate these results.


Pleural Tuberculosis ADA Biomarkers 



Dr. Rahul Sharma for statistical analysis and Dr. Rajat Jhamb for clinical specimens.

Compliance with Ethical Standards

Conflict of interest

Author Nisha Goyal declares that she has no conflict of interest. Author Bineeta Kashyap declares that she has no conflict of interest. Author NP Singh declares that he has no conflict of interest. Author Iqbal R Kaur declares that she has no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    World Health Organization. Global tuberculosis report 2016. Geneva: World Health Organization, 2016.
  2. 2.
    Govt. of India. Revised National TB Control Programme: Annual Status Report. Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, New Delhi India. 2014.
  3. 3.
    Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res. 2004;120(4):316–53.PubMedGoogle Scholar
  4. 4.
    Solovic I, Jonsson J, Korzeniewska-Kosela M. Challenges in diagnosing extrapulmonary tuberculosis in the European Union, 2011. Euro Surveill. 2013;18:12.Google Scholar
  5. 5.
    Biomarkers working group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.CrossRefGoogle Scholar
  6. 6.
    Helmy NA, Eissa SA, Masoud HH, Elessawy AF, Ahmed RI. Diagnostic value of adenosine deaminase in tuberculous and malignant pleural effusion. Egypt J Chest Dis Tuberc. 2012;61(4):413–7.CrossRefGoogle Scholar
  7. 7.
    Gopi A, Madhavan SM, Sharma SK, Shan SA. Diagnosis and treatment of tuberculous pleural effusion. Chest. 2006;131:880–9.CrossRefGoogle Scholar
  8. 8.
    Porcel JM. Tuberculous pleural effusion. Lung. 2009;187:263–70.CrossRefPubMedGoogle Scholar
  9. 9.
    Doosoo J. Tuberculous pleurisy: an update. Tuberc Respir Dis. 2014;76:153–9.CrossRefGoogle Scholar
  10. 10.
    Light WR. Pleural diseases. 5th ed. Baltimore: Lippincot, Williams and Wilkins; 2007.Google Scholar
  11. 11.
    Stead WW, Eichenholz A, Straus HK. Operative and pathologic findings in twenty four patients with syndrome of idiopathic pleurisy with effusion presumably tuberculous. Am Rev Tuberc. 1955;71:473–502.PubMedGoogle Scholar
  12. 12.
    Vorster MJ, Allwood BW, Diacon AH, Koegelenberg CFN. Tuberculous pleural effusions: advances and controversies. J Thorac Dis. 2015;7(6):981–91.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Davies PD. Tuberculous pleuritis. In: Bouros D, editor. Pleural disease. New York: Marcel Dekker; 2004. p. 677–97.CrossRefGoogle Scholar
  14. 14.
    Ruan SY, Chuang YC, Wang JY, Lin JW, Chien JY, Huang CT, et al. Revisiting tuberculous pleurisy: pleural fluid characteristics and diagnostic yield of mycobacterial culture in an endemic area. Thorax. 2012;67:822–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Porcel JM, Vives M. Differentiating tuberculous from malignant pleural effusions: a scoring model. Med Sci Monit. 2003;9:175–80.Google Scholar
  16. 16.
    Light RW. Clinical practice. Pleural effusion. N Engl J Med. 2002;346:1971–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Barua R, Hossain M. Adenosine deaminase in diagnosis of tuberculosis: a review. Anwer Khan Mod Med Coll J. 2014;5:43–8.CrossRefGoogle Scholar
  18. 18.
    Garcia-Zamalloa A, Taboada-Gomez J. Diagnostic accuracy of adenosine deaminase and lymphocyte proportion in pleural fluid for tuberculous pleurisy in different prevalence scenarios. PLoS ONE. 2012;7(6):e38729. doi: 10.1371/journal.pone.0038729.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Valdés L, Alvarez D, San José E, Penela P, Valle JM, García-Pazos JM, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med. 1998;158:2017–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Burgess LJ, Maritz FJ, Le Roux I, Taljaard JJ. Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis. Chest. 1996;109:414–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Yurt S, Küçükergin C, Yigitbas BA, Seckin S, Tigin HC, Kosar AF. Diagnostic utility of serum and pleural levels of adenosine deaminase 1-2, and interferon- in the diagnosis of pleural tuberculosis. Multidiscip Respir Med. 2014;9:12.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Aoe K, Hiraki A, Murakami T, Eda R, Maeda T, Sugi K, et al. Diagnostic significance of interferon-gamma in tuberculous pleural effusions. Chest. 2003;123:740–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Wongtim S, Silachamroon U, Ruxrungtham K, Udompanicha V, Limthongkula S, Charoenlapa P, et al. Interferon gamma for diagnosing tuberculous pleural effusions. Thorax. 1999;54:921–4.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jiang J, Shi HZ, Liang QL, Qin SM, Qin XJ. Diagnostic value of interferon-gamma in tuberculous pleurisy: a metaanalysis. Chest. 2007;131:1133–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Meldau R, Peter J, Theron G, Calligaro G, Allwood B, Symons G, et al. Comparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-γ for the evaluation of pleural tuberculosis: a prospective cohort study. BMC Pulm Med. 2014;14:58.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li YH, Xie CM. A study on the Th1/Th2 cytokines in the pathogenesis of human tuberculous pleuritis. Zhonghua Jie He He Hu Xi Za Zhi. 2004;27:324–7 (in Chinese, English abstract).PubMedGoogle Scholar
  27. 27.
    Cok G, Parildar Z, Basol G, Kabaroglu C, Bayindir U, Habif S, et al. Pleural fluid neopterin levels in tuberculous pleurisy. Clin Biochem. 2007;40(12):876–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Tozkoparan E, Deniz O, Cakir E, Yaman H, Ciftci F, Gumus S, et al. The diagnostic values of serum, pleural fluid and urine neopterin measurements in tuberculous pleurisy. Int J Tuberc Lung Dis. 2005;9:1040–5.PubMedGoogle Scholar
  29. 29.
    Baganha MF, Mota Pinto A, Pego MA, Marques MA, Rosa MA, Cordeiro AJ. Neopterin in tuberculous and neoplastic pleural fluids. Lung. 1992;170:155–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Immanuel C, Rajeswari R, Rahman F, Kumaran PP, Chandrasekaran V, Swamy R. Serial evaluation of serum neopterin in HIV seronegative patients treated for tuberculosis. Int J Tuberc Lung Dis. 2001;5(2):185–90.PubMedGoogle Scholar
  31. 31.
    Gunes O, Erbaycu AE, Çakan A, Örmen M, Özsoz A, Önvural B. The diagnostic value of malondialdehyde level in pleural effusions. Eurasian J Pulmonol. 2003;5(4):213–9.Google Scholar

Copyright information

© Association of Clinical Biochemists of India 2017

Authors and Affiliations

  • Bineeta Kashyap
    • 1
    • 2
    Email author
  • Nisha Goyal
    • 1
  • N. P. Singh
    • 1
  • Iqbal R. Kaur
    • 1
  1. 1.Department of MicrobiologyUniversity College of Medical Sciences & Guru Teg Bahadur HospitalNew DelhiIndia
  2. 2.New DelhiIndia

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