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Clinical Evaluation of New Biomarkers including IFN-γ for the Diagnosis of Active Tuberculosis Disease

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DOI: 10.4236/jtr.2015.34020    2,642 Downloads   3,027 Views   Citations

ABSTRACT

Background: The aim of this study was to evaluate the clinical potential of new biomarkers such as IL-2, TNF-α, MCP-1, MIP-1β including IFN-γ for the diagnosis of active tuberculosis (TB) disease. Materials and Methods: The subjects consisted of 31 patients with active TB disease and 62 patients with non-TB disease. We measured IFN-γ using QuantiFERON-TB Gold In Tube, and IL-2, TNF-α, MCP-1, and MIP-1β using the supernatant from whole blood stimulated with MTB (Mycobacterium tuberculosis)-specific antigens. Results: In the patient group with active TB disease, while the positive response rate of IFN-γ was 74%, that of IL-2 using the supernatant was 61%, TNF-α was 71%, MCP-1 was 81% and MIP-1β was 81%. In the patient group with non-TB disease, while the positive response rate of IFN-γ was 11%, that of IL-2using the supernatant was 32%, TNF-α was 26%, MCP-1 was 23% and MIP-1β was 19%. All biomarker levels of the patients with active TB disease using the supernatant were significantly higher than those of the patients with non-TB disease. While MIP-1β was the most sensitive of all the biomarkers (sensitivity: 80.6%), IFN-γ was the best in terms of specificity (specificity: 87.0%). Conclusions: Several biomarkers, apart from IL-2, showed similar results compared to IFN-γ. The combination of IFN-γ and other new biomarkers may increase the diagnostic accuracy of active TB.

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Kobashi, Y. , Mouri, K. , Kato, S. and Oka, M. (2015) Clinical Evaluation of New Biomarkers including IFN-γ for the Diagnosis of Active Tuberculosis Disease. Journal of Tuberculosis Research, 3, 136-148. doi: 10.4236/jtr.2015.34020.

References

[1] Mandalakas, A.M., Hesseling, A.C., Chegou, N.N., Kirchner, H.L., Zhu, X., Marais, B.J., et al. (2008) High Level of Discordant IGRA Results in HIV-Infected Adults and Children. International Journal Tuberculosis and Lung Disease, 12, 417-423.
[2] Lange, C., Pai, M., Drobniewski, F. and Migliori, B. (2009) Interferon-Gamma Release Assays for the Diagnosis of Active Tuberculosis: Sensible or Silly? European Respiratory Journal, 3, 1250-1253.
http://dx.doi.org/10.1183/09031936.00019709
[3] Walzl, G., Roacher, K., Hanekom, W., Scriba, T.J. and Zumla, A. (2011) Immunological Biomarkers of Tuberculosis. Nature Review Immunology, 11, 3443-3454. http://dx.doi.org/10.1038/nri2960
[4] Lindestam, A.C.S., Gerasimova, A., Mele, F., Henderson, R., Swann, J., Greenbaum, J.A., et al. (2013) Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed Against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset. PLoS Pathology, 9, e1003130.
http://dx.doi.org/10.1371/journal.ppat.1003130
[5] Dorhri, A., Reece, S.T. and Kaufmann, S.H.E. (2011) For Better or for Worse: The Immune Response against Mycobacterium tuberculosis Balances Pathology and Protection. Immunology Review, 240, 235-251. http://dx.doi.org/10.1111/j.1600-065X.2010.00994.x
[6] Ruhwald, M. and Ravn, P. (2009) Biomarkers for Latent TB Infection. Expert Review Respiratory Medicine, 3, 387- 401. http://dx.doi.org/10.1586/ers.09.31
[7] Harari, A., Rozot, V., Enders, F.B., Perreau, M., Stalder, J.M., Nicod, L.P., Cavassini, M., et al. (2011) Dominant TNF-α+ Mycobacterium tuberculosis-Specific CD4+ T Cell Responses Discriminate between Latent Infection and Active Disease. Nature Medicine, 17, 372-376. http://dx.doi.org/10.1038/nm.2299
[8] Krummel, B., Strassburg, A., Ernst, M., Reiling, N., Eker, B., Rath, H., et al. (2010) Potential Role for IL-2 ELISpot in Differentiating Recent and Remote Infection in Tuberculosis Contact Tracing. PLoS ONE, 5, e22670. http://dx.doi.org/10.1371/journal.pone.0011670
[9] Ruhwald, M., Dominguez, J., Latorre, I., Lasi, M., Richeldi, L., Pasticci, M.B., et al. (2011) A Multicenter Evaluation of the Accuracy and Performance of IP-10 for the Diagnosis of Infection with M. tuberculosis. Tuberculosis (Edinb), 91, 260-267. http://dx.doi.org/10.1016/j.tube.2011.01.001
[10] Kellar, K.L., Gehrke, J., Weis, S.E., Mahmutoric-Mayhew, A., Darila, B., Zajdowicz, M.J., et al. (2011) Multiple Cytokines Are Released When Blood from Patients with Tuberculosis Is Stimulated with Mycobacterium tuberculosis Antigens. PLoS ONE, 6, e26545.
http://dx.doi.org/10.1371/journal.pone.0026545
[11] Frahm, M., Goswami, N.D., Owzar, K., Hecker, E., Mosher, A., Cadogan, E., et al. (2011) Discriminating between Latent and Active Tuberculosis with Multiple Biomarker Responses. Tuberculosis, 91, 250-256.
http://dx.doi.org/10.1016/j.tube.2011.02.006
[12] Borgstrom, E., Andersen, P., Andersson, L., Julander, I., Kallenius, G., Maeurer, M., et al. (2011) Detection of Proliferative Responses to ESAT-6 and CFP-10 by FASCIA Assay for Diagnosis of Mycobacterium tuberculosis Infection. Journal of Immunological Methods, 370, 55-64.
http://dx.doi.org/10.1016/j.jim.2011.05.008
[13] Chegou, N., Black, G., Kidd, M., van Helden, P.D., Walze, G., et al. (2009) Host Markers in Quantiferon Supernatants Differentiate Active TB from Latent TB Infection; Preliminary Report. BMC Pulmonary Medicine, 9, 21. http://dx.doi.org/10.1186/1471-2466-9-21
[14] Griffith, D.E., Alsamit, T., Brown-Elliot, B.A., Catanzero, A., Daley, C., Gordin, F., et al. (2007) An Official ATS/ IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacteria Diseases. American Journal of Respiratory Critical Care Medicine, 157, 367-416.
http://dx.doi.org/10.1164/rccm.200604-571ST
[15] Mazurek, G.H., Jereb, J., Vernon, A., LoBue, P., Goldberg, S., Castro, K., et al. (2010) Updated Guidelines for Suing Interferon Gamma Release Assays to Detect Mycobacterium Tuberculosis Infection—United States. MMWR Recommend Report, 59, 1-25.
[16] Hanley, J.A. and McNeil, B.J. (1982) The Meaning and Use of the Area under a Receiver Operating Characteristics (ROC) Curve. Radiology, 143, 29-36. http://dx.doi.org/10.1148/radiology.143.1.7063747
[17] Zweig, M.H. and Campbell, G. (1993) Receiver Operating Characteristics (ROC) Plots: A Fundamental Evaluation Tool in Clinical Medicine. Clinical Chemistry, 39, 561-577.
[18] Chegou, N.N., Heyckendorf, J., Waltl, G., Lange, C. and Ruhwald, M. (2014) Beyond the IFN-γ Horizon: Biomarkers for Immunodiagnosis of Infection with Mycobacterium tuberculosis. European Respiratory Journal, 43, 1472-1486. http://dx.doi.org/10.1183/09031936.00151413
[19] Millington, K.A., Innes, J.A., Hackforth, S., Hinks, T.S., Deeks, J.J., Dosanjh, D.P., et al. (2007) Dynamic Relationship between IFN-γ and IL-2 Profile of Mycobacterium tuberculosis-Specific T Cells and Antigen Load. Journal of Immunology, 178, 5217-5226. http://dx.doi.org/10.4049/jimmunol.178.8.5217
[20] Wang, S., Diao, N., Lu, C., Wu, J., Gao, T., Chen, J., et al. (2012) Evaluation of the Diagnostic Potential of IP-10 and IL-2 as Biomarkers for the Diagnosis of Active and Latent Tuberculosis in a BCG-Vaccinated Population. PLoS ONE, 7, e51338. http://dx.doi.org/10.1371/journal.pone.0051338
[21] Borgstrom, E., Andersen, P., Atterfelt, F., Julander, I., Kallenius, 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, e43438.
http://dx.doi.org/10.1371/journal.pone.0043438
[22] Biselli, R., Mariotti, S., Sargentini, V., Sauzallo, I., Lastilla, M., Mengoni, F., et al. (2012) Detection of Interleukin-2 in Addition to Interferon-γ Discriminate Active Tuberculosis Patients, Latently Infected Individuals, and Controls. Clinical Microbiological Infection, 16, 1282-1284.
http://dx.doi.org/10.1111/j.1469-0691.2009.03104.x
[23] Day, C.L., Abrahams, D.A., Lerumo, L., Janse van Rensburg, E., Stone, L., Orie, T., et al. (2011) Functional Capacity of Mycobacterium tuberculosis-Specific T Cell Responses in Human Is Associated with Mycobacterial Load. Journal of Immunology, 187, 2222-2232.
http://dx.doi.org/10.4049/jimmunol.1101122
[24] Sester, U., Fousse, M., Dirks, J., Mack, U., Prasse, A., Singh, M., et al. (2011) Whole-Blood Flow-Cytometric Analysis of Antigen-Specific CD4 T-Cell Cytokine Profiles Distinguishes Active Tuberculosis from Non-Active States. PLoS ONE, 6, e17813. http://dx.doi.org/10.1371/journal.pone.0017813
[25] Casey, R., Blumenkrantz, D., Millington, K., Montamat-Sicotte, D., Kon, O.M., Wickremasinghe, M., et al. (2010) Enumeration of Functional T-Cell Subsets by Fluorescence-Immunospot Defines Signatures of Pathogen Burden in Tuberculosis. PLoS ONE, 5, e15619. http://dx.doi.org/10.1371/journal.pone.0015619
[26] Sargentini, V., Mariotti, S., Carrara, S., Gramiccioni, C., Manara, M., Tagliapietra, G., et al. (2009) Cytometric Detection of Antigen-Specific IFN-Gamma/IL-2 Secreting Cells in the Diagnosis of Tuberculosis. BMC Infectious Disease, 9, 99. http://dx.doi.org/10.1186/1471-2334-9-99
[27] Petruccioli, E., Petrone, L., Vanini, V., Sampaolesi, A., Gualono, G., Girardi, E., et al. (2013) IFN-γ/TNF-α Specific Cells and Effector Memory Phenotype Associate with Active Tuberculosis. Journal of Infection, 66, 475-486. http://dx.doi.org/10.1016/j.jinf.2013.02.004
[28] 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. European Journal of Clinical Microbiology and Infectious Disease, 33, 2111-2118.
http://dx.doi.org/10.1007/s10096-014-2190-z
[29] Mamishi, S., Pourakbari, B., Marjani, M., Bahador, A. and Mahmoudi, S. (2015) Discriminating between Latent and Active Tuberculosis: The Role of Interleukin-2 as Biomarker. Journal of Infection, 70, 429-431.
http://dx.doi.org/10.1016/j.jinf.2014.12.011
[30] Hasan, Z., Cliff, J.M., Dockrell, H.M., Jamil, B., Irfan, M., Ashraf, M., et al. (2009) CCL2 Responses to Mycobacterium Tuberculosis Are Associated with Disease Severity in Tuberculosis. PLoS ONE, 4, e8459.
http://dx.doi.org/10.1371/journal.pone.0008459
[31] Bibova, I., Linhartova, I., Stanek, O., Rusnakova, V., Kubista, M., Suchanek, M., et al. (2012) Detection of Immune Cell Response to M. tuberculosis-Specific Antigens by Quantitative Polymerase Chain Reaction. Diagnostic Microbiology and Infectious Disease, 72, 68-78.
http://dx.doi.org/10.1016/j.diagmicrobio.2011.09.024
[32] Ruhwald, M., Bjerregaard-Andersen, M., Rabna, P., Eugen-Olsen, J. and Ravn, P. (2009) IP-10, MCP-1, MCP-2, MCP-3, and IL-1RA Hold Promise as Biomarkers Fir Infection with M. tuberculosis in a Whole Blood Based T-Cell Assay. BMC Research Notes, 2, 19. http://dx.doi.org/10.1186/1756-0500-2-19
[33] Rubbo, P.A., Nagot, Moing, V.L., Brabet, M., Bourdin, A., Nogue, E., et al. (2012) Multi-Cytokine Detection Improves Latent Tuberculosis Diagnosis in Healthcare Workers. Journal of Clinical Microbiology, 50, 1711-1717. http://dx.doi.org/10.1128/JCM.00117-12
[34] Maurer, M. and von Stebut, E. (2004) Macrophage Inflammatory Protein-1. International Journal of Biochemical Cell Biology, 36, 1882-1886. http://dx.doi.org/10.1016/j.biocel.2003.10.019

  
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