The diagnosis of latent tuberculosis infection (LTBI): currently available tests, future developments, and perspectives to eliminate tuberculosis (TB) The diagnosis of latent tuberculosis infection (LTBI)

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Jean Pierre Zellweger
Giovanni Sotgiu
Massimo Corradi
Paolo Durando


Tuberculosis - TB, Latent Tuberculosis Infection - LTBI, Diagnostic Tests, Elimination, Occupational Health, Public Health


Introduction: Despite great efforts, tuberculosis (TB) is still a major public health threat worldwide. For decades, TB control programs have focused almost exclusively on infectious TB active cases.  However, it is evident that this strategy alone cannot achieve TB elimination. To achieve this objective a comprehensive strategy directed toward integrated latent tuberculosis infection (LTBI) management is needed. Recently it has been recognized that LTBI is not a stable condition but rather a spectrum of infections (e.g., intermittent, transient or progressive) which may lead to incipient, then subclinical, and finally active TB disease. Aim: Provide an overview of current available LTBI diagnostic test including updates, future developments and perspectives. Results: There is currently no test for the direct identification of live MT infection in humans. The diagnosis of LTBI is indirect and relies on the detection of an immune response against MT antigens, assuming that the immune response has developed after a contact with the biological agent. Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are the main diagnostic tools for LTBI, however, both present strengths and limitations. The most ancient diagnostic test (TST) can be associated with several technical errors, has limited positive predictive value, is being influenced by BCG vaccination and several conditions can reduce the skin reactivity. Notwithstanding these limitations, prompt identification of TST conversion, should orientate indications for preventive therapy of LTBI. IGRAs have superior specificity, are not affected by M. bovis, BCG vaccination and other environmental mycobacteria. However, they present some logistical and organisational constraints and are more expensive. Currently, the WHO guidelines recommend that either a TST or an IGRA can be used to detect LTBI in high-income and upper middle-income countries with estimated TB incidences less than 100 per 100,000 population. Two skin tests (C-TB and Diaskintest), using only two specific M. tuberculosis antigens (ESAT-6 and CFP-10) instead of the tuberculin solution, have recently been developed but, to date, none of these tests is available on the European market. Conclusion: Early identification and treatment of individuals with LTBI is an important priority for TB control in specific groups at risk within the population: this is of crucial meaning in recently infected cases both at the community level and in some occupational settings. Currently there is no gold standard test for LTBI: an improved understanding of the available tests is needed to develop better tools for diagnosing LTBI and predicting progression to clinical active disease.

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1. Abubakar, I., et al., Prognostic value of interferon-gamma release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study. Lancet Infect Dis, 2018;
2. Aggerbeck, H., et al., C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: A phase 3 trial. PLoS One, 2018. 13(9): p. e0204554;
3. Ahmed, A., et al., Interferon-gamma Release Assays in Children <15 Years of Age. Pediatrics, 2020. 145(1);
4. Altet, N., et al., Predicting the Development of Tuberculosis with the Tuberculin Skin Test and QuantiFERON Testing. Ann Am Thorac Soc, 2015. 12(5): p. 680-8;
5. Bamrah, S., et al., Tuberculosis among the homeless, United States, 1994-2010. Int J Tuberc Lung Dis. 2013 Nov;
6. Banaei, N., R.L. Gaur, and M. Pai, Interferon Gamma Release Assays for Latent Tuberculosis: What Are the Sources of Variability? J Clin Microbiol, 2016. 54(4): p. 845-50;
7. Binswanger, I.A., et al., Tuberculosis testing in correctional officers: a national random survey of jails in the United States. Int J Tuberc Lung Dis. 2010 Apr;
8. Bozorgmehr. K, et al., Yield of active screening for tuberculosis among asylum seekers in Germany: a systematic review and meta-analysis. Euro Surveill. 2017;
9. CDC - Epidemiology of Tuberculosis in Correctional Facilities, United States, 1993–2017;
10. Chiappini, E., et al., QuantiFERON-TB Gold In-Tube test performance in a large pediatric population investigated for suspected tuberculosis infection. Paediatr Respir Rev, 2019. 32: p. 36-47;
11. Cohen, A., et al., The global prevalence of latent tuberculosis: a systematic review and meta-analysis. Eur Respir J, 2019. 54(3);
12. Dara. M, et al., Tuberculosis care among refugees arriving in Europe: a ERS/WHO Europe Region survey of current practices. Eur Respir J. 2016 Sep;
13. Drain, P.K., et al., Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Clin Microbiol Rev, 2018. 31(4);
14. Esmail, H., et al., Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography. Nat Med, 2016. 22(10): p. 1090-1093;
15. European Centre for Disease Prevention and Control. Guidance on tuberculosis control in vulnerable and hard-to-reach populations. Stockholm: ECDC; 2016;
16. European Centre for Disease Prevention and Control. Systematic review on the diagnosis, treatment, care and prevention of tuberculosis in prison settings. Stockholm: ECDC; 2017;
17. European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2020 – 2018 data. Stockholm: ECDC;
18. Gualano, G., et al., Tuberculin skin test - Outdated or still useful for Latent TB infection screening? Int J Infect Dis, 2019. 80S: p. S20-S22;
19. Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med. 2016;
20. Huebner, R.E., M.F. Schein, and J.B. Bass, Jr., The tuberculin skin test. Clin Infect Dis, 1993. 17(6): p. 968-75;
21. Isler MA, Rivest P, Mason J and Brassard P. Screening employees of services for homeless individuals in Montréal for tuberculosis infection. J Infect Public Health. 2013 Jun;
22. Kamakia, R., et al., Potential biomarkers associated with discrimination between latent and active pulmonary tuberculosis. Int J Tuberc Lung Dis, 2017. 21(3): p. 278-285;
23. Kik, S.V., et al., An evaluation framework for new tests that predict progression from tuberculosis infection to clinical disease. Eur Respir J, 2018. 52(4);
24. Kim SH, Jo KW, Shim TS. QuantiFERON-TB Gold PLUS versus QuantiFERON- TB Gold In-Tube test for diagnosing tuberculosis infection. Korean J Intern Med. 2020;
25. Kunst. H., et al., Tuberculosis and latent tuberculous infection screening of migrants in Europe: comparative analysis of policies, surveillance systems and results. Int J Tuberc Lung Dis. 2017 Aug 1;
26. Lambert. L.A., et al., Tuberculosis in Jails and Prisons: United States, 2002-2013. Am J Public Health. 2016 Dec;
27. Lo Bue P.A., Mermin J.H. Latent tuberculosis infection: the final frontier of tuberculosis elimination in the USA. Lancet Infect Dis. 2017;
28. Lönnroth. K., et al., Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;
29. Lönnroth. K., et al., Tuberculosis in migrants in low-incidence countries: epidemiology and intervention entry points. Int J Tuberc Lung Dis. 2017 Jun 1;
30. Mack, U., et al., LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J, 2009. 33(5): p. 956-973.
31. Mancuso, J.D., et al., Discordance among commercially available diagnostics for latent tuberculosis infection. Am J Respir Crit Care Med, 2012. 185(4): p. 427-34;
32. Matteelli, A., et al., Tuberculosis elimination: where are we now? Eur Respir Rev. 2018;
33. Menzies D, Use of interferon-gamma release assays for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults. Uptodate 2020. Available on line at: (last accessed 27-05-2000)
34. Menzies, D., Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir.Crit Care Med., 1999. 159(1): p. 15-21;
35. Miramontes R, Hill AN, Yelk Woodruff RS, et al. Tuberculosis infection in the United States: prevalence estimates from the National Health and Nutrition Examination Survey, 2011–2012. PLoS One 2015;
36. Mitchell. C.S, et al., Risk of tuberculosis in correctional healthcare workers. J Occup Environ Med. 2005 Jun;
37. Moffa. M, et al., A systematic scoping review of environmental health conditions and hygiene behaviors in homeless shelters. Int J Hyg Environ Health. 2019 Apr;
38. Moran-Mendoza, O., et al., Tuberculin skin test size and risk of tuberculosis development: a large population-based study in contacts. Int J Tuberc Lung Dis, 2007. 11(9): p. 1014-1020.
39. Mulder, C., et al., Tuberculin skin test reaction depends on type of purified protein derivative: implications for cut-off values. Int J Tuberc Lung Dis, 2019. 23(12): p. 1327-1334;
40. Pai, M., et al., Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev, 2014. 27(1): p. 3-20;
41. Pai M, Sotgiu G. Diagnostics for latent TB infection: incremental, not transformative progress. Eur Respir J. 2016;
42. Placidi. D., et al., Tuberculin skin test (TST) survey among healthcare workers (HCWs) in hospital: a systematic review of the literature. G Ital Med Lav Ergon. 2007 Jul-Sep;
43. Rakotosamimanana, N., et al., Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study. Eur Respir J, 2015;
44. Ruhwald, M., et al., Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med, 2017;
45. Scotto G, Fazio V, Lo Muzio L. Tuberculosis in the immigrant population in Italy: state-of-the-art review. Infez Med. 2017 Sep 1;
46. Sotgiu. G., et al., QuantiFERON TB Gold Plus for the diagnosis of tuberculosis: a systematic review and meta-analysis. J Infect 2019;
47. Starshinova, A., et al., A comparison of intradermal test with recombinant tuberculosis allergen (diaskintest) with other immunologic tests in the diagnosis of tuberculosis infection. Int J Mycobacteriol, 2018. 7(1): p. 32-39;
48. Sweeney, T.E., H.R. Wong, and P. Khatri, Robust classification of bacterial and viral infections via integrated host gene expression diagnostics. Sci Transl Med, 2016. 8(346): p. 346ra91;
49. Tissot, F., et al., Influence of bacille Calmette-Guerin vaccination on size of tuberculin skin test reaction: to what size? Clin Infect Dis., 2005. 40(2): p. 211-217;
50. Turner, C.T., et al., Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study. Lancet Respir Med, 2020. 8(4): p. 407-419;
51. Uden. L., et al., Risk of Tuberculosis Infection and Disease for Health Care Workers: An Updated Meta-Analysis. Open Forum Infect Dis. 2017 Aug 29;
52. Warsinske, H., R. Vashisht, and P. Khatri, Host-response-based gene signatures for tuberculosis diagnosis: A systematic comparison of 16 signatures. PLoS Med, 2019. 16(4): p. e1002786;
53. Warsinske, H.C., et al., Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response. JAMA Netw Open, 2018. 1(6): p. e183779;
54. Winje, B.A., et al., Stratification by interferon-gamma release assay level predicts risk of incident TB. Thorax, 2018;
55. World Health Organization, Towards tuberculosis elimination: an action framework for low-incidence countries. 2014, WHO;
56. World Health Organization. Global tuberculosis report 2019 [Internet]. Geneva (CH): World Health Organization, 2018. Available on line at: (last accessed 27-05-2000)
57. Zak, D.E., et al., A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet, 2016. 387(10035): p. 2312-22.