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Latent Infection and Interferon-Gamma Release Assays

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  • Authors: Madhukar Pai1, Marcel Behr2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
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    Affiliations: 1: McGill International TB Center and Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada; 2: McGill International TB Center and Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0023-2016
  • Received 01 July 2016 Accepted 01 August 2016 Published 21 October 2016
  • Madhukar Pai, madhukar.pai@mcgill.ca
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  • Abstract:

    The identification of individuals with latent tuberculosis infection (LTBI) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). Basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. Unfortunately, there is no diagnostic test that resolves the various stages within the spectrum of infection. Two main immune-based approaches are currently used for identification of LTBI: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST can use either the conventional purified protein derivative or more specific antigens. Extensive research suggests that both TST and IGRA represent indirect markers of exposure and indicates a cellular immune response to . The imperfect concordance between these two tests suggests that neither test is perfect, presumably due to both technical and biological reasons. Neither test can accurately differentiate between LTBI and active TB. Both IGRA and TST have low sensitivity in a variety of immunocompromised populations. Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. For fundamental applications, basic research is necessary to identify those at highest risk of disease with a positive TST and/or IGRA. For clinical applications, the identification of such biomarkers can help prioritize efforts to interrupt progression to disease through preventive therapy.

  • Citation: Pai M, Behr M. 2016. Latent Infection and Interferon-Gamma Release Assays. Microbiol Spectrum 4(5):TBTB2-0023-2016. doi:10.1128/microbiolspec.TBTB2-0023-2016.

Key Concept Ranking

Clinical and Public Health
1.110798
Enzyme-Linked Immunospot Assay
0.5889466
Enzyme-Linked Immunosorbent Assay
0.56920314
Interferon-gamma Release Assays
0.5497325
T Helper Cells
0.49942437
1.110798

References

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27. Geluk A, van Meijgaarden KE, Franken KL, Wieles B, Arend SM, Faber WR, Naafs B, Ottenhoff TH. 2004. Immunological crossreactivity of the Mycobacterium leprae CFP-10 with its homologue in Mycobacterium tuberculosis. Scand J Immunol 59:66–70 http://dx.doi.org/10.1111/j.0300-9475.2004.01358.x. [CrossRef]
28. Pollock L, Basu Roy R, Kampmann B. 2013. How to use: interferon γ release assays for tuberculosis. Arch Dis Child Educ Pract Ed 98:99–105 http://dx.doi.org/10.1136/archdischild-2013-303641. [PubMed][CrossRef]
29. Hoffmann H, Avsar K, Göres R, Mavi SC, Hofmann-Thiel S. 2016. Equal sensitivity of the new generation QuantiFERON-TB Gold plus in direct comparison with the previous test version QuantiFERON-TB Gold IT. Clin Microbiol Infect 22:701–703. [PubMed][CrossRef]
30. Pai M, Riley LW, Colford JM Jr. 2004. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 4:761–776 http://dx.doi.org/10.1016/S1473-3099(04)01206-X. [PubMed][CrossRef]
31. Pai M, Sotgiu G. 2016. Diagnostics for latent TB infection: incremental, not transformative progress. Eur Respir J 47:704–706 http://dx.doi.org/10.1183/13993003.01910-2015. [PubMed][CrossRef]
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33. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, Bossink A, Magdorf K, Hölscher C, Kampmann B, Arend SM, Detjen A, Bothamley G, Zellweger JP, Milburn H, Diel R, Ravn P, Cobelens F, Cardona PJ, Kan B, Solovic I, Duarte R, Cirillo DM, C Lange for the TBNET. 2009. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 33:956–973 http://dx.doi.org/10.1183/09031936.00120908. [CrossRef]
34. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K, Wilkinson RJ, Pai M. 2012. Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 12:45–55 http://dx.doi.org/10.1016/S1473-3099(11)70210-9. [CrossRef]
35. Slater ML, Welland G, Pai M, Parsonnet J, Banaei N. 2013. Challenges with QuantiFERON-TB Gold assay for large-scale, routine screening of U.S. healthcare workers. Am J Respir Crit Care Med 188:1005–1010 http://dx.doi.org/10.1164/rccm.201305-0831OC. [PubMed][CrossRef]
36. Dorman SE, Belknap R, Graviss EA, Reves R, Schluger N, Weinfurter P, Wang Y, Cronin W, Hirsch-Moverman Y, Teeter LD, Parker M, Garrett DO, Daley CL, Tuberculosis Epidemiologic Studies Consortium. 2014. Interferon-γ release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States. Am J Respir Crit Care Med 189:77–87. [PubMed]
37. Zwerling A, Benedetti A, Cojocariu M, McIntosh F, Pietrangelo F, Behr MA, Schwartzman K, Menzies D, Pai M. 2013. Repeat IGRA testing in Canadian health workers: conversions or unexplained variability? PLoS One 8:e54748. doi:10.1371/journal.pone.0054748 http://dx.doi.org/10.1371/journal.pone.0054748. [PubMed][CrossRef]
38. Joshi M, Monson TP, Joshi A, Woods GL. 2014. IFN-γ release assay conversions and reversions: challenges with serial testing in U.S. health care workers. Ann Am Thorac Soc 11:296–302 http://dx.doi.org/10.1513/AnnalsATS.201310-378OC. [PubMed][CrossRef]
39. Tagmouti S, Slater M, Benedetti A, Kik SV, Banaei N, Cattamanchi A, Metcalfe J, Dowdy D, van Zyl Smit R, Dendukuri N, Pai M, Denkinger C. 2014. Reproducibility of interferon gamma (IFN-γ) release assays: a systematic review. Ann Am Thorac Soc 11:1267–1276 http://dx.doi.org/10.1513/AnnalsATS.201405-188OC. [PubMed][CrossRef]
40. Banaei N, Gaur RL, Pai M. 2016. Interferon-gamma release assays for latent tuberculosis: what are the sources of variability? J Clin Microbiol 54:845–850 http://dx.doi.org/10.1128/JCM.02803-15. [PubMed][CrossRef]
41. Pai M, Banaei N. 2013. Occupational screening of health care workers for tuberculosis infection: tuberculin skin testing or interferon-γ release assays? Occup Med (Lond) 63:458–460 http://dx.doi.org/10.1093/occmed/kqt105.
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43. Aggerbeck H, Giemza R, Joshi P, Tingskov PN, Hoff ST, Boyle J, Andersen P, Lewis DJ. 2013. Randomised clinical trial investigating the specificity of a novel skin test (C-Tb) for diagnosis of M. tuberculosis infection. PLoS One 8:e64215. doi:10.1371/journal.pone.0064215 http://dx.doi.org/10.1371/journal.pone.0064215. [CrossRef]
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50. Pai M, Elwood K. 2012. Interferon-gamma release assays for screening of health care workers in low tuberculosis incidence settings: dynamic patterns and interpretational challenges. Can Respir J 19:81–83 http://dx.doi.org/10.1155/2012/420392. [CrossRef]
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53. Stop TB Partnership’s New Diagnostics Working Group. 2016. Draft target product profile: test for progression of tuberculosis infection.http://www.finddx.org/wp-content/uploads/2016/05/TPP-LTBIprogression.pdf.
54. FIND, McGill International TB Centre, UNITAID. 2015. TB Diagnostics Market in Select High-Burden Countries: Current Market and Future Opportunities for Novel Diagnostics. UNITAID, Geneva, Switzerland. http://unitaid.org/images/marketdynamics/publications/TB_Diagnostics_Market_in_Select_High-Burden_Countries_Current_Market_and_Future_Opportunities_for__Novel_Diagnostics.pdf.
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2016-10-21
2017-05-29

Abstract:

The identification of individuals with latent tuberculosis infection (LTBI) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). Basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. Unfortunately, there is no diagnostic test that resolves the various stages within the spectrum of infection. Two main immune-based approaches are currently used for identification of LTBI: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST can use either the conventional purified protein derivative or more specific antigens. Extensive research suggests that both TST and IGRA represent indirect markers of exposure and indicates a cellular immune response to . The imperfect concordance between these two tests suggests that neither test is perfect, presumably due to both technical and biological reasons. Neither test can accurately differentiate between LTBI and active TB. Both IGRA and TST have low sensitivity in a variety of immunocompromised populations. Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. For fundamental applications, basic research is necessary to identify those at highest risk of disease with a positive TST and/or IGRA. For clinical applications, the identification of such biomarkers can help prioritize efforts to interrupt progression to disease through preventive therapy.

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Figures

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FIGURE 1

A proposed framework for considering tuberculosis (TB) infection as a spectrum. In this model, from Esmail, Barry, and Wilkinson, after initial exposure, TB bacteria can be eliminated by innate immune mechanisms. Once infection is established and an acquired, adaptive immune response has been generated, interferon-gamma release assay (IGRA) or tuberculin skin test (TST) might become positive. Infection can be eliminated by the acquired immune response, but if antigen-specific effector T-cell memory persists, TST or IGRA might remain positive, even though infection is cleared. Over time, T-cell memory responses can wane, resulting in TST or IGRA reversions. If is controlled but not eliminated by the acquired immune response, the individual might enter a state of quiescent infection, in which both symptoms and culturable bacilli are absent and with a greater proportion of bacilli in a dormant rather than replicative state. Immunosuppression (e.g., HIV or drugs such as tumor necrosis factor blockers) during this state might lead to rapid progression to active disease. If bacilli are grown on culture and symptoms and signs are absent, this might be a subclinical state. If bacilli are grown on culture and symptoms appear, then this reflects active TB disease (which can range from smear-negative TB to advanced cavitary/miliary TB). (Reproduced from reference 9 with permission.)

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0023-2016
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FIGURE 2

How to administer and read the tuberculin skin test (TST). TST involves an intradermal injection of 5 tuberculin units (5-TU) of PPD-S (purified protein derivative) or 2 TU of PPD RT23. A delayed-type hypersensitivity reaction might occur within 48 to 72 hours. This reaction will cause erythema (redness) and induration of the skin at the injection site. Only the transverse induration is measured as shown above and interpreted using risk-stratified cut-offs. (Adapted from reference 18 .)

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0023-2016
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FIGURE 3

Immunological principles that underlie the existing, commercial interferon-gamma release assays. IFN-γ, interferon-gamma; PBMC, peripheral blood mononuclear cells; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunospot assay. (Reproduced from reference 28 with permission.)

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FIGURE 4

Sources of variability in the QuantiFERON-TB (QFT) Gold In-Tube assay. This graphic illustrates the sources of variability that affect the reproducibility of the QFT-Gold In-Tube assay. Variability can be due to preanalytical, analytical, postanalytical, manufacturing, and immunological factors. (Reproduced from reference 15 with permission.)

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Tables

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TABLE 1

A comparison of available diagnostics for latent TB infection

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0023-2016
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TABLE 2

Some suggested approaches to reduce test variability with IGRAs

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0023-2016

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