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Submitted
Sep 25, 2025
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Nov 27, 2025
Published
Dec 30, 2025
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Abstract

Tuberculosis (TB) remains a major global health concern, with more than 10 million new cases reported annually. Conventional sputum-based diagnostics such as microscopy, culture, and GeneXpert MTB/RIF show limited sensitivity in children, individuals with HIV, and extrapulmonary TB, highlighting the need for accurate non-sputum alternatives. This systematic review evaluates the diagnostic performance of serological and other non-sputum biomarkers for active TB, focusing on both host and pathogen derived targets. Eleven eligible studies (2016–2024) involving 2,548 participants were analyzed. The reviewed studies employed multiplex immunoassays and protein microarrays to assess immune markers and M. tuberculosis antigens. Key findings indicate that several cytokines (e.g., IFN-γ, IP-10, IL-27) and antibodies to ESAT-6, CFP-10, and Ag85B differentiated active from latent infection. Multi-antigen panels achieved sensitivity and specificity above 85%, while saliva, serum, and skin-based assays showed potential for non-invasive and field-applicable diagnosis. The novelty of this review lies in its integrative approach analyzing both host and pathogen biomarkers, which are often studied separately. Such multi-marker, non-sputum serological strategies could complement current TB diagnostics and provide reliable, accessible tools for use in resource-limited and high HIV prevalence settings

Keywords

Tuberculosis Serological biomarkers Antibody response Non-sputum diagnostic methods Mycobacterium tuberculosis

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1.
Diah Erwati WO, Rukmana A. Serological and Non-Sputum Biomarkers for Tuberculosis Diagnosis: A Systematic Review of Host- and Pathogen-Derived Signatures. EKSAKTA [Internet]. 2025 Dec. 30 [cited 2026 Mar. 15];26(04):516-29. Available from: https://eksakta.ppj.unp.ac.id/index.php/eksakta/article/view/626

References

  1. [1] World Health Organization. (2024). WHO consolidated guidelines on tuberculosis. Module 6: tuberculosis and comorbidities. World Health Organization.
  2. [2] Ministry of Health of the Republic of Indonesia. (2023).Tuberculosis Control Annual Report. Ministry of Health.
  3. [3] Walzl, G., McNerney, R., du Plessis, N., Bates, M., McHugh, T. D., Chegou, N. N., & Zumla, A. (2018). Tuberculosis: advances and challenges in development of new diagnostics and biomarkers. The Lancet Infectious Diseases, 18(7), e199-e210.
  4. [4] Li Y, et al. (2022). Evaluation of the GeneXpert MTB/RIF Ultra assay for the diagnosis of pulmonary and extrapulmonary tuberculosis in China. Front Microbiol.13:1012212.
  5. [5] Graham, S. M., Marais, B. J., & Amanullah, F. (2022). Tuberculosis in children and adolescents: progress and perseverance. Pathogens, 11(4), 392.
  6. [6] MacLean, E., Broger, T., Yerlikaya, S., Fernandez-Carballo, B. L., Pai, M., & Denkinger, C. M. (2019). A systematic review of biomarkers to detect active tuberculosis. Nature microbiology, 4(5), 748-758.
  7. [7] Du Preez K, et al. (2024). Advances in TB diagnostics: Integration of host and pathogen biomarkers. Eur J Med Res.29(1):92.
  8. [8] Nogueira, B. M., Krishnan, S., Barreto‐Duarte, B., Araújo‐Pereira, M., Queiroz, A. T., Ellner, J. J., ... & Andrade, B. B. (2022). Diagnostic biomarkers for active tuberculosis: progress and challenges. EMBO Molecular Medicine, 14(12), e14088.
  9. [9] World Health Organization. (2011). Commercial serodiagnostic tests for diagnosis of tuberculosis: policy statement (No. WHO/HTM/TB/2011.5). World Health Organization.
  10. [10] Jaganath, D., Rajan, J., Yoon, C., Ravindran, R., Andama, A., Asege, L., ... & Cattamanchi, A. (2020). Evaluation of multi-antigen serological screening for active tuberculosis among people living with HIV. PloS one, 15(6), e0234130.
  11. [11] Demissie, A., Leyten, E. M., Abebe, M., Wassie, L., Aseffa, A., Abate, G., ... & VACSEL Study Group. (2006). Recognition of stage-specific mycobacterial antigens differentiates between acute and latent infections with Mycobacterium tuberculosis. Clinical and vaccine immunology, 13(2), 179-186.
  12. [12] Huang W, et al. (2023). Proteomic profiling of TB patient serum reveals immune biomarkers with diagnostic potential. Front Immunol. 14:1172456.
  13. [13] Li, J., Wang, Y., Yan, L., Zhang, C., He, Y., Zou, J., ... & Zhang, X. (2022). Novel serological biomarker panel using protein microarray can distinguish active TB from latent TB infection. Microbes and Infection, 24(8), 105002.
  14. [14] Tanriver, G., Khan, S. A., Góra, A., Chegou, N. N., & Mahmoudi, S. (2025). Exploring the multifaceted roles of resuscitation-promoting factors in tuberculosis: Implications for diagnosis, vaccine development, and drug targeting. Biotechnology Reports, e00886.
  15. [15] Shaukat S, et al. (2023). Cytokine biomarkers for differentiating active from latent tuberculosis infection. BMC Infect Dis.23:456.
  16. [16] Lu, Y., Chillarige, Y., Izurieta, H. S., Wei, Y., Xu, W., Lu, M., ... & Forshee, R. A. (2019). Effect of age on relative effectiveness of high-dose versus standard-dose influenza vaccines among US Medicare beneficiaries aged≥ 65 years. The Journal of infectious diseases, 220(9), 1511-1520.
  17. [17] Chen Y, et al. (2024). Combined host and pathogen-derived biomarkers for tuberculosis diagnosis. Sci Rep.14:5218.
  18. [18] Chatterjee A, et al. (2024). Serological and molecular biomarkers for TB detection: Current progress and perspectives. Lancet Microbe. 5(4):e251–e260.
  19. [19] Kumar V, et al. (2022). Integration of multi-omics data for tuberculosis biomarker discovery. Nat Commun. 13:7341.
  20. [20] Broger T, et al. (2024). Host biomarker combinations for tuberculosis diagnosis and treatment monitoring. Front Immunol. 15:1382081.
  21. [21] Wang H, et al. (2025). Advances in non-sputum-based tuberculosis diagnostics: Current developments and challenges. Biomedicines. 13(9):2076.
  22. [22] Jacobs, R., Maasdorp, E., Malherbe, S., Loxton, A. G., Stanley, K., Van Der Spuy, G., ... & Chegou, N. N. (2016). Diagnostic potential of novel salivary host biomarkers as candidates for the immunological diagnosis of tuberculosis disease and monitoring of tuberculosis treatment response. PloS one, 11(8), e0160546.
  23. [23] Cao, S. H., Chen, Y. Q., ZHENG, S. H., ZHANG, Z. G., & LI, C. Y. (2018). Screening of serum biomarkers for distinguishing between latent and active tuberculosis using proteome microarray. Biomedical and Environmental Sciences, 31(7), 515-526.
  24. [24] Peng, Z., Chen, L., & Zhang, H. (2020). Serum proteomic analysis of Mycobacterium tuberculosis antigens for discriminating active tuberculosis from latent infection. Journal of International Medical Research, 48(3), 0300060520910042.
  25. [25] Li, Z., Hu, J., Liu, P., Cui, D., Di, H., & Wu, S. (2021). Microarray-based selection of a serum biomarker panel that can discriminate between latent and active pulmonary TB. Scientific Reports, 11(1), 14516.
  26. [26] Tran, A. C., Boariu, E., García-Bengoa, M., Kim, M. Y., Vergara, E. J., Mussá, T., & Reljic, R. (2023). Serological analysis reveals differential antibody responses between TB patients and latently infected individuals from the TB endemic country of Mozambique. Frontiers in medicine, 10, 1286785.
  27. [27] Nziza, N., Cizmeci, D., Davies, L., Irvine, E. B., Jung, W., Fenderson, B. A., ... & Alter, G. (2022). Defining discriminatory antibody fingerprints in active and latent tuberculosis. Frontiers in immunology, 13, 856906.
  28. [28] Ayalew, S., Wegayehu, T., Wondale, B., Tarekegn, A., Tessema, B., Admasu, F., ... & Mihret, A. (2024). Candidate serum protein biomarkers for active pulmonary tuberculosis diagnosis in tuberculosis endemic settings. BMC infectious diseases, 24(1), 1329.
  29. [29] Morris, T. C., Hoggart, C. J., Chegou, N. N., Kidd, M., Oni, T., Goliath, R., ... & Hamilton, M. S. (2021). Evaluation of host serum protein biomarkers of tuberculosis in sub-Saharan Africa. Frontiers in immunology, 12, 639174.
  30. [30] Liu, C., Zhao, Z., Fan, J., Lyon, C. J., Wu, H. J., Nedelkov, D., ... & Hu, Y. (2017). Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring. Proceedings of the National Academy of Sciences, 114(15), 3969-3974.
  31. [31] Yuan, Y., Xia, L., Wu, Q., Liu, X., & Lu, S. (2023). Utility of recombinant fusion protein ESAT6-CFP10 skin test for differential diagnosis of active tuberculosis: A prospective study. Frontiers in Immunology, 14, 1162177.
  32. [32] World Health Organization. (2024). WHO consolidated guidelines on tuberculosis. Module 3: diagnosis–rapid diagnostics for tuberculosis detection. World Health Organization.
  33. [33] World Health Organization. (2025). Target product profile for tuberculosis screening tests. World Health Organization.
  34. [34] Gaeddert, M., Glaser, K., Chendi, B. H., Sultanli, A., Koeppel, L., MacLean, E. L., ... & Denkinger, C. M. (2024). Host blood protein biomarkers to screen for tuberculosis disease: a systematic review and meta-analysis. Journal of Clinical Microbiology, 62(11), e00786-24.
  35. [35] Li, Z., Hu, Y., Wang, W., Zou, F., Yang, J., Gao, W., ... & Chen, X. (2024). Integrating pathogen-and host-derived blood biomarkers for enhanced tuberculosis diagnosis: a comprehensive review. Frontiers in Immunology, 15, 1438989.
  36. [36] Dewi, D. N. S. S., Mertaniasih, N. M., Soedarsono, Hagino, K., Yamazaki, T., Ozeki, Y., ... & Matsumoto, S. (2023). Antibodies against native proteins of Mycobacterium tuberculosis can detect pulmonary tuberculosis patients. Scientific Reports, 13(1), 12685.