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Table of Contents
Year : 2011  |  Volume : 5  |  Issue : 2  |  Page : 35-37

Diagnosis of latent tuberculosis infection: The tuberculin skin test and interferon gamma release assays

Department of Medicine, Ahmadu Bello University Teaching Hospital, PMB 06, Shika-Zaria, Kaduna State, Nigeria

Date of Web Publication17-Feb-2012

Correspondence Address:
Mukhtar A Adeiza
Department of Medicine, Ahmadu Bello University Teaching Hospital, PMB 06, Shika-Zaria, Kaduna State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0331-3131.92946

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How to cite this article:
Adeiza MA. Diagnosis of latent tuberculosis infection: The tuberculin skin test and interferon gamma release assays. Ann Nigerian Med 2011;5:35-7

How to cite this URL:
Adeiza MA. Diagnosis of latent tuberculosis infection: The tuberculin skin test and interferon gamma release assays. Ann Nigerian Med [serial online] 2011 [cited 2021 Apr 19];5:35-7. Available from: https://www.anmjournal.com/text.asp?2011/5/2/35/92946

   Introduction Top

The clinical manifestations of tuberculosis (TB) represent a complex interaction between the causative organism, Mycobacterium tuberculosis, and the human host immune response. [1] TB is the most common cause of infectious disease-related mortality worldwide after the human immunodeficiency virus (HIV). The World Health Organization (WHO) estimates that 2 billion people are infected worldwide, and according to the 2010 global TB report, there were an estimated 9.4 million incident cases of TB with 12% of these occurring in HIV-positive patients. [2] The bulk of this disease burden resides in sub-Saharan Africa and the majorities of these infections are asymptomatic and may reactivate later in life. This huge global reservoir is termed latent tuberculosis infection (LTBI) and constitutes an important source of infection and a continuous source of transmission. The goal of testing for LTBI is to identify individuals who are at increased risk for the development of TB and therefore would benefit from treatment. Currently, there is no available gold standard or confirmatory test for the diagnosis of LTBI and available surrogates are not without limitations with respect to technical issues with test performance, cost, specificity, sensitivity, effect of Bacille Calmette-Guérin (BCG) vaccine, and environmental mycobacteria.

   Latent Tuberculosis Infection Top

LTBI is a subclinical or asymptomatic infection with M. tuberculosis without clinical, bacteriological, or radiological evidence of active disease. Primary infection with M. tuberculosis leads to clinical disease in only~10% of individuals. In the remaining cases, the ensuing immune response arrests further growth of M. tuberculosis. The pathogen is completely eradicated in only~10% of people, while the immune response in the remaining~90% of individuals only succeeds in containment of infection [3] as some bacilli escape killing by blunting the microbicidal mechanisms of immune cells (such as phagosome-lysosome fusion, antigen presentation by MHC class I, class II, and CD1 molecules, production of nitric oxide, and other reactive nitrogen intermediates) and remain in nonreplicating (dormant or latent) state in old lesions. [3],[4] Of these latently infected individuals, 5%-10% will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by HIV coinfection. [4] Other factors that increase the risk of reactivation of latent TB include old TB with lung scarring, immunosuppression, organ transplantation, malignant disease, end-stage renal failure, and diabetes mellitus. [5]

Even though there is no gold standard for the diagnosis of LTBI, [6] attempt at measuring LTBI using surrogates is important for the overall control of the disease. Offering antituberculous treatment to individuals with LTBI by currently available tests significantly decreases their risk of developing active TB. For years, the diagnosis of LTBI infection relied on the tuberculin skin test (TST) which is known to have several limitations compromising its sensitivity and specificity. Recently, immune-based blood tests were developed with the hope of improving the diagnosis of LTBI. [7]

   Tuberculin Skin Test Top

For more than 100 years, the usual method used to diagnose LTBI was the TST, which clearly shows, after injecting a purified protein derivative (PPD), a state of prior hypersensitivity in the body when confronted with this substance. [8] The TST measures an immunological response: cell-mediated immunity (CMI) to a previously acquired infection with a mycobacterium that shares antigens with those contained in the tuberculin. [9] It is a form of a delayed type hypersensitivity (DTH) response to a complex cocktail of >200 M. tuberculosis antigens and the test result is usually read as induration (in mm) recorded 48-72 hours after intradermal injection of PPD. [4],[6] A positive TST indicates that the reacting person has, at some preceding point in time, became infected with a Mycobacterium that has left an immunological imprint. [9]

The criteria for a positive TST vary considerably and depend on the innoculum and type of PPD preparation used in the test. In the United States, 5 tuberculin units (TUs) are generally used and the induration of ≥5 mm in very high-risk groups like HIV-seropositive or organ transplant recipient or in a person in contact with a known case of active TB is considered as positive. [5] However, in foreign-born persons originating from high TB incidence countries or persons at higher risk of exposure to M. tuberculosis (such as health care professionals, residents of long-term care facilities or patients with chronic diseases), induration of ≥10 mm is regarded as positive TST. For those with no risks, an induration of ≥15 mm is considered positive. These guidelines ignored the effect of BCG vaccination when interpreting the TST. [4]

Skin testing is most suitable for detecting M. tuberculosis infection in developing countries where >80% of the global TB cases occur, [4] as it does not require extensive laboratory facilities and health care workers are already familiar with administering and reading skin tests. However, TST has several inherent problems as the antigens present in PPD are also present in the vaccine strain Mycobacterium bovis BCG and several environmental mycobacteria. Hence, TST has lower specificity as the test cannot differentiate between infection with M. tuberculosis, prior vaccination with M. bovis BCG, or sensitization with environmental mycobacteria. Furthermore, sensitivity of TST is limited in immunocompromised individuals due to anergy. [4],[10] These factors have compromised the sensitivity and specificity of TST for the diagnosis of LTBI. It is important to keep in mind that a negative TST does not exclude infection or active disease. Testing with tuberculin PPD is dependent on the presence of an intact cell-mediated immune response. In the setting of HIV infection, reduced CMI and decreasing CD4+ T-lymphocyte counts can lead to decreased DTH responsiveness, resulting in false-negative skin tests.

   Interferon Gamma Release Assays Top

In recent years, several immunodiagnostic assays have been developed for diagnosing M. tuberculosis infection. These assays, referred to as interferon (IFN)-γ release assays (IGRAs), have been specifically designed to overcome the problem of low specificity of the TST. In fact, they detect cellular immune response to antigens which are absent in BCG and most environmental mycobacteria, and specifically present in M. tuberculosis. [11] Two such antigens, early-secreted antigenic target (ESAT)-6 and culture filtrate protein (CFP)-10, encoded in the mycobacterial genomic region of difference (RD)-1 [12],[13] were first evaluated in a 6-day lymphocyte stimulation test and found to be sensitive and specific for diagnosing TB. Subsequently, other IGRAs were developed that differed from the classical LST with respect to the in vitro incubation period, the type of cells cultured; whole blood, frozen or fresh peripheral blood mononuclear cells (PBMCs), and the way that the IFN-γ response is detected by enzyme-linked immunosorbent assay (ELISA; Cellestis Ltd, Australia) or enzyme-linked immunospot assay (ELISPOT/T-SPOT.TB; Oxford Immunotec, UK). At present, the third generation of this test, called QuantiFERON-TB Gold In Tube (QFT-GIT), is already on the market and includes a third mycobacterial antigen: the TB 7.7 and tubes specifically designed to collect blood samples for this test. [13]

The new IGRAs are unaffected by prior BCG vaccination, show considerable promise, and have excellent specificity. [6] They are ex vivo tests, thus reducing the potential risk of adverse events and boosting. [14] They also have the important operational advantage of requiring only a single patient visit. In the last few years, there has been an explosion of studies evaluating IGRAs in different settings and study populations. [15] Adetifa et al., comparing the T-SPOT.TB (ELISPOT) and QFT-GIT in the Gambia, showed that the ELISPOT test was more sensitive than the QFT-GIT (78.7% vs 64.0%) for diagnosing TB disease. The two tests performed similarly in the diagnosis of LTBI in TB contacts, but there was significant discordance between the IGRAs and the TST. [16] Current evidence suggests that the IGRAs perform similarly to the TST in identifying HIV-infected individuals with LTBI and the decision to use either test should be based on country guidelines, resource, and logistical considerations. [17]

In resource-rich countries, IGRAs are increasingly being utilized and some guidelines have suggested replacing TST by IGRAs or using them as confirmatory tests in those with positive TST results. In some evaluation, this two-step approach is the most cost-effective. These guidelines also recommended using IGRAs in situations where TST may not be reliable (e.g., in immunocompromised patients). [18],[19],[20],[21] The question is whether IGRA tests should complement or replace TST. The latter test is cheap and sensitive for diagnosis of LTBI. However, in BCG-vaccinated individuals, its specificity is clearly inferior to that of the IGRAs. These expensive tests may not be affordable to many developing countries and therefore, it is likely that TST will remain in use in many parts of the world. [7]

   Conclusion Top

In comparison, the TST lacks specificity, requires multiple visits, and is affected by BCG, environmental mycobacteria, and boosting but is cheap and can be easily performed by well-trained personnel. In contrast, the IGRAs require single visit, can be performed ex vivo, have higher specificity, but are expensive and sometimes discordant with the TST. The IGRAs are an important step in the search for better diagnostic tests for LTBI, but the bulk of the literature are from cross-sectional studies carried out in high resource, low TB prevalence settings, and there is a need to test their performance in longitudinal studies conducted in low resource, high TB prevalence settings like sub-Saharan Africa where the burden of immunosuppresion due the HIV pandemic is high.

   References Top

1.Schluger NW. The pathogenesis of tuberculosis: the first one hundred (and twenty-three) years. Am J Respir Cell Mol Biol 2005;32:251-6.  Back to cited text no. 1
2.World Health Organization. Global tuberculosis control: Geneva: Surveillance, planning, financing, WHO report 2010. Available from: http://whqlibdoc.who.int/publications/2010/97892415640 69_eng.pdf. [Last accessed 2011 Feb 24].  Back to cited text no. 2
3.Ahmad S. Pathogenesis, immunology and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol 2011;2011:814943.  Back to cited text no. 3
4.Ahmad S. New approaches in the diagnosis and treatment of latent tuberculosis infection. Respir Res 2010;11:169.  Back to cited text no. 4
5.American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47.  Back to cited text no. 5
6.Menzies D, Pai M, Comstock G. Meta-analysis: New tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54.  Back to cited text no. 6
7.Al-Orainy IO. Diagnosis of latent tuberculosis infection: Can we do better? Ann Thorac Med 2009;4:5-9.  Back to cited text no. 7
8.Asuquo AE, Dairo AN, Abia-Bassey L, Meremiku MM, Thumamo BP. Tuberculin Skin Test (TST) indurations in smear positive TB patients and healthy individuals in Calabar, Nigeria. Ethnomed 2009;3:75-9.  Back to cited text no. 8
9.Reider HL, Chadha VK, Nagelkerke NJD, van Leth F, van der Werf MJ. Guidelines for conducting tuberculin skin test surveys in high-prevalence countries. Int J Tuberc Lung Dis 2011;15:S1-26.  Back to cited text no. 9
10.Dheda K, Schwander SK, Zhu B, van Zyl-Smit RN, Zhang Y. The immunology of tuberculosis: From bench to bedside. Respirology 2010;15:433-50.  Back to cited text no. 10
11.Ariga H, Harada N. Evolution of IGRA research. Kekkaku 2008;83:641-52.  Back to cited text no. 11
12.Butera O, Chiacchio T, Carrara S, Casetti R, Vanini V, Meraviglia S, et al. New tools for detecting latent tuberculosis infection: Evaluation of RD1-specific long-term response. BMC Infect Dis 2009;9:182.  Back to cited text no. 12
13.Arias Guillen M, Palomar R, Arias M. Advances in the diagnosis of latent tuberculosis infection in patients receiving renal replacement therapy. Nefrologia 2011;31:137-41.  Back to cited text no. 13
14.Pai M, Menzies D. The New IGRA and the Old TST: Making good use of disagreement. Am J Respir Crit Care Med 2007;175:529-31.  Back to cited text no. 14
15.Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An update. Ann Intern Med 2008;149:177-84.  Back to cited text no. 15
16.Adetifa IM, Lugos MD, Hammond A, Jeffries D, Donkor S, Adegbola RA, et al. Comparison of two interferon gamma release assays in the diagnosis of Mycobacterium tuberculosis infection and disease in The Gambia. BMC Infect Dis 2007;7:122.  Back to cited text no. 16
17.Cattamanchi A, Smith R, Steingart KR, MetCalfe JZ, Date A, Coleman C, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: A systematic review and meta-analysis. J Acquir Immune Defic Syndr 2011;56:230-8.  Back to cited text no. 17
18.The National Institute for Clinical Excellence. Tuberculosis: National clinical guideline for diagnosis, management, prevention and control. Clinical Guideline (no. 33). March 2006. Available from: http://www.nice.org.uk. [Last accessed on 2011 Dec 20].  Back to cited text no. 18
19.Canadian Tuberculosis Committee. Interferon gamma release assays for latent tuberculosis infection. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2007;33:1-18.  Back to cited text no. 19
20.Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K; CDC. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep 2010;59:1-25.  Back to cited text no. 20
21.European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC; 2011.  Back to cited text no. 21

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