Skip to main content

Diagnostic accuracy of interferon (IFN)-γ inducible protein 10 (IP-10) as a biomarker for the discrimination of active and latent tuberculosis

Abstract

To assess the potency of Interferon (IFN)-γ inducible protein 10 (IP-10) stimulated by recombinant PE35 and PPE68 as a biomarker in differentiating between active and latent tuberculosis. Patients with active pulmonary TB (PTB) (n = 30), latent TB infection (LTBI) (n = 29), and BCG-vaccinated healthy controls (HCs) (n = 30) were enrolled and blood samples were taken from them. The diagnostic performance of IP-10 was evaluated by the Receiver operator characteristic (ROC) curve and the area under the curve (AUC) and their 95% confidence intervals (CI) were calculated. The median IP-10 concentrations following stimulation with recombinant PE35 and PPE68 were significantly higher in TB-infected group (both PTB and LTBI) compared with HCs (P < 0.05). It was also significantly higher in PTB patients compared with individuals with LTBI (P < 0.05). The discriminatory performance of IP-10 following stimulation with recombinant PE35 and PPE68 (assessed by AUC) between TB patients and HCs were similar (AUC: 0.79 [95% CI 0.68–0.89] and 0.79 [95% CI 0.69–0.89], respectively). AUCs of IP-10 following stimulation with recombinant PE35 and PPE68 for distinguishing between PTB and LTBI groups were 0.63 (95% CI 0.47–0.79) and 0.61 (0.45–0.77), respectively. Under the selected cut-off values, the sensitivity and specificity of IP-10 for distinguishing of TB-infected and HCs after stimulation with recombinant PE35 was 74.5% and 73%, respectively and after stimulation with recombinant PPE68 were 76.5% and 63%, respectively. Moreover, the sensitivity and specificity of IP-10 for differentiating of PTB and LTBI following stimulation with recombinant PE35 and PPE68 were 770 pg/ml (sensitivity: 63%; specificity: 62%) and 502 pg/ml (sensitivity: 80%; specificity: 52%), respectively. IP-10 stimulated by recombinant PE35 and PPE68 is a promising biomarker for TB diagnosis. However, it doesn’t have desirable sensitivity and specificity in distinguishing between PTB and LTBI.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Wallis RS, Pai M, Menzies D, Doherty TM, Walzl G, Perkins MD et al (2010) Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice. Lancet 375(9729):1920–1937

    CAS  Article  Google Scholar 

  2. Chegou NN, Heyckendorf J, Walzl G, Lange C, Ruhwald M (2014) Beyond the IFN-γ horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis. Eur Respir J 43(5):1472–1486

    CAS  Article  Google Scholar 

  3. Mamishr S, Pourakbari B, Marjani M, Mahmoudi S (2014) Diagnosis of latent tuberculosis infection among immunodeficient individuals: review of concordance between interferon-γ release assays and the tuberculin skin test. Br J Biomed Sci 71(3):115–124

    Article  Google Scholar 

  4. Won E-J, Choi J-H, Cho Y-N, Jin H-M, Kee HJ, Park Y-W et al (2017) Biomarkers for discrimination between latent tuberculosis infection and active tuberculosis disease. J Infect 74(3):281–293

    Article  Google Scholar 

  5. Hur Y-G, Kang YA, Jang S-H, Hong JY, Kim A, Lee SA et al (2015) Adjunctive biomarkers for improving diagnosis of tuberculosis and monitoring therapeutic effects. J Infect 70(4):346–355

    Article  Google Scholar 

  6. Frahm M, Goswami ND, Owzar K, Hecker E, Mosher A, Cadogan E et al (2011) Discriminating between latent and active tuberculosis with multiple biomarker responses. Tuberculosis 91(3):250–256

    CAS  Article  Google Scholar 

  7. Mahmoudi S, Pourakbari B, Mamishi S (2017) Interferon gamma release assay in response to PE35/PPE68 proteins: a promising diagnostic method for diagnosis of latent tuberculosis. Eur Cytokine Netw 28(1):36–40

    CAS  PubMed  Google Scholar 

  8. Wergeland I, Pullar N, Assmus J, Ueland T, Tonby K, Feruglio S et al (2015) IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy. J Infect 70(4):381–391

    CAS  Article  Google Scholar 

  9. Mamishi S, Pourakbari B, Teymuri M, Rubbo P-A, Tuaillon E, Keshtkar A et al (2014) Diagnostic accuracy of IL-2 for the diagnosis of latent tuberculosis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis 33(12):2111–2119

    CAS  Article  Google Scholar 

  10. Chen T, Li Z, Yu L, Li H, Lin J, Guo H et al (2016) Profiling the human immune response to Mycobacterium tuberculosis by human cytokine array. Tuberculosis 97:108–117

    CAS  Article  Google Scholar 

  11. Ruhwald M, Dominguez J, Latorre I, Losi M, Richeldi L, Pasticci MB et al (2011) A multicentre evaluation of the accuracy and performance of IP-10 for the diagnosis of infection with M. tuberculosis. Tuberculosis 91(3):260–267

    Article  Google Scholar 

  12. Mihret A, Bekele Y, Bobosha K, Kidd M, Aseffa A, Howe R et al (2013) Plasma cytokines and chemokines differentiate between active disease and non-active tuberculosis infection. J Infect 66(4):357–365

    Article  Google Scholar 

  13. Lighter J, Rigaud M, Huie M, Peng C, Pollack H (2009) Chemokine IP-10: an adjunct marker for latent tuberculosis infection in children. Int J Tuberc Lung Dis 13(6):731–736

    PubMed  Google Scholar 

  14. Whittaker E, Gordon A, Kampmann B (2008) Is IP-10 a better biomarker for active and latent tuberculosis in children than IFNγ? PLoS ONE 3(12):e3901

    Article  Google Scholar 

  15. Mamishi S, Pourakbari B, Shams H, Marjani M, Mahmoudi S (2016) Improving T-cell assays for diagnosis of latent TB infection: confirmation of the potential role of testing Interleukin-2 release in Iranian patients. Allergol Immunopathol 44(4):314–321

    CAS  Article  Google Scholar 

  16. Hong JY, Lee HJ, Kim SY, Chung KS, Kim EY, Jung JY et al (2014) Efficacy of IP-10 as a biomarker for monitoring tuberculosis treatment. J Infect 68(3):252–258

    Article  Google Scholar 

  17. Rhoades ER, Cooper AM, Orme IM (1995) Chemokine response in mice infected with Mycobacterium tuberculosis. Infect Immun 63(10):3871–3877

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Goletti D, Raja A, Kabeer BSA, Rodrigues C, Sodha A, Butera O et al (2010) IFN-γ, but not IP-10, MCP-2 or IL-2 response to RD1 selected peptides associates to active tuberculosis. J Infect 61(2):133–143

    Article  Google Scholar 

  19. Ruhwald M, Bjerregaard-Andersen M, Rabna P, Kofoed K, Eugen-Olsen J, Ravn P (2007) CXCL10/IP-10 release is induced by incubation of whole blood from tuberculosis patients with ESAT-6, CFP10 and TB7. 7. Microbes Infect 9(7):806–812

    CAS  Article  Google Scholar 

  20. Ruhwald M, Bodmer T, Maier C, Jepsen M, Haaland M, Eugen-Olsen J et al (2008) Evaluating the potential of IP-10 and MCP-2 as biomarkers for the diagnosis of tuberculosis. Eur Respir J 32(6):1607–1615

    CAS  Article  Google Scholar 

  21. Mamishi S, Pourakbari B, Marjani M, Bahador A, Mahmoudi S (2015) Discriminating between latent and active tuberculosis: the role of interleukin-2 as biomarker. J Infect 70(4):429–431

    Article  Google Scholar 

  22. Pourakbari B, Mamishi S, Marjani M, Rasulinejad M, Mariotti S, Mahmoudi S (2015) Novel T-cell assays for the discrimination of active and latent tuberculosis infection: the diagnostic value of PPE family. Mol Diagn Ther 19(5):309–316

    CAS  Article  Google Scholar 

  23. Mahmoudi S, Mamishi S, Ghazi M, Sadeghi RH, Pourakbari B (2013) Cloning, expression and purification of Mycobacterium tuberculosis ESAT-6 and CFP-10 antigens. Iran J Microbiol 5(4):374

    PubMed  PubMed Central  Google Scholar 

  24. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3(1):32–35

    CAS  Article  Google Scholar 

  25. Wang X, Jiang J, Cao Z, Yang B, Zhang J, Cheng X (2012) Diagnostic performance of multiplex cytokine and chemokine assay for tuberculosis. Tuberculosis 92(6):513–520

    CAS  Article  Google Scholar 

  26. Borgström E, Andersen P, Atterfelt F, Julander I, Källenius G, Maeurer M et al (2012) Immune responses to ESAT-6 and CFP-10 by FASCIA and multiplex technology for diagnosis of M. tuberculosis infection; IP-10 is a promising marker. PLoS ONE 7(11):e43438

    Article  Google Scholar 

  27. Jeong YH, Hur Y-G, Lee H, Kim S, Cho J-E, Chang J et al (2015) Discrimination between active and latent tuberculosis based on ratio of antigen-specific to mitogen-induced IP-10 production. J Clin Microbiol 53(2):504–510

    CAS  Article  Google Scholar 

  28. Biraro IA, Kimuda S, Egesa M, Cose S, Webb EL, Joloba M et al (2016) The use of interferon gamma inducible protein 10 as a potential biomarker in the diagnosis of latent tuberculosis infection in Uganda. PLoS ONE 11(1):e0146098

    Article  Google Scholar 

  29. Chegou NN, Black GF, Kidd M, Van Helden PD, Walzl G (2009) Host markers in QuantiFERON supernatants differentiate active TB from latent TB infection: preliminary report. BMC Pulm Med 9(1):21

    Article  Google Scholar 

Download references

Funding

This work was supported by a grant from the Tehran University of Medical Sciences, Tehran, Iran with project Grant Number (94-04-159-31392).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Babak Pourakbari.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mamishi, S., Mahmoudi, S., Banar, M. et al. Diagnostic accuracy of interferon (IFN)-γ inducible protein 10 (IP-10) as a biomarker for the discrimination of active and latent tuberculosis. Mol Biol Rep 46, 6263–6269 (2019). https://doi.org/10.1007/s11033-019-05067-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-019-05067-0

Keywords

  • M. tuberculosis
  • IP-10
  • PE35
  • PPE68
  • Active tuberculosis
  • Latent tuberculosis