Gamma interferon release assays for detection of Mycobacterium tuberculosis infection

Abstract

Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

FIG 1

Proposed framework for considering tuberculosis infection as a spectrum. (Reproduced from reference by permission from Macmillan Publishers Ltd.)

FIG 2

Countries where BCG vaccine is given after infancy or multiple times (at present or in the past). In these settings, IGRAs may be more specific than TST for latent TB infection. (Adapted from reference , which was published under a Creative Commons license.)

FIG 3

Sources of variability in the QuantiFERON-TB Gold In-Tube assay.

FIG 4

Serial testing with IGRAs reveals underlying phenotypes. The persistently positive pattern is seen in individuals who are repeatedly IGRA positive for a long time. Unstable conversion refers to individuals who convert their IGRA result from negative to positive and then revert again to negativity. Stable conversion refers to individuals who convert their IGRA result and stay converted, at least in the short term. Persistently negative refers to individuals who stay repeatedly IGRA negative for a long time. (Reproduced from reference by permission from Macmillan Publishers Ltd.)

FIG 5

Unadjusted incidence rates for development of active tuberculosis in the short term (median follow-up of 3 years), stratified by IGRA result. Incidence rate estimates are per 1,000 person-years of follow-up, stratified by IGRA result at baseline. Table 3 provides details for each of the studies. (Reproduced from reference with permission from Elsevier.)