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Chapter 17 : Latent Infection and Interferon-Gamma Release Assays

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Abstract:

Diagnosis and treatment of latent tuberculosis infection (LTBI) is one of the interventions recommended by the World Health Organization (WHO) to end the TB epidemic worldwide and is one of the elements of the post-2015 End TB Strategy ( ). While several high-income countries, notably the United States and Canada, have implemented and scaled up programs to detect and treat LTBI, developing countries have mostly focused on active TB disease control, a much bigger priority in these settings.

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0023-2016
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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 with permission.)

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. 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 .)

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. 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 with permission.)

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0023-2016
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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 with permission.)

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0023-2016
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Tables

Generic image for table
Table 1

A comparison of available diagnostics for latent TB infection

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0023-2016
Generic image for table
Table 2

Some suggested approaches to reduce test variability with IGRAs

Citation: Pai M, Behr M. 2017. Latent Infection and Interferon-Gamma Release Assays, p 379-388. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0023-2016

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