Diagnosing latent tuberculosis in high-risk individuals: rising to the challenge in high-burden areas

Abstract

A key challenge to greater progress in tuberculosis (TB) control is the reservoir of latent TB infection (LTBI), which represents a huge long-lived reservoir of potential TB disease. In parts of Africa, as many as 50% of 15-year-olds and 77%-89% of adults have evidence of LTBI. A second key challenge to TB control is the human immunodeficiency virus (HIV)-associated TB epidemic, and Africa alone accounts for one-quarter of the global burden of HIV-associated TB. HIV co-infection promotes both reactivation TB from LTBI and rapidly progressive primary TB following recent exposure to Mycobacterium tuberculosis. Preventing active TB and tackling latent infection in addition to the Directly Observed Treatment, Short-Course (DOTS) strategy could improve TB control in high-burden settings, especially where there is a high prevalence of HIV co-infection. Current strategies include intensified case finding (ICF), TB infection control, antiretroviral therapy (ART), and isoniazid preventive therapy (IPT). Although ART has been widely rolled out, ICF and IPT have not. A key factor limiting the rollout and effectiveness of IPT and ICF is the limitations of existing tools to both diagnose LTBI and identify those persons most at risk of progressing to active TB. In this review, we examine the obstacles and consider current progress toward the development of new tools to address this pressing global problem.

Figure 1.

What does the future hold? New approaches and next-generation interferon γ (IFN- γ) release assays (IGRAs). Two main strategies are available to improve on current IGRAs: the first involves the measurement of additional cytokine levels, and the second involves the incorporation of additional antigens [93]. The latter has already been shown to increase test sensitivity (without compromising specificity) when Rv2645 (TB7.7) was added to the enzyme-linked immunosorbent assay platform to create QuantiFERON-TB Gold In-Tube [97, 101] and when RV3879c was added to the enzyme-linked immunospot (ELISPOT) platform to create ELISPOT^PLUS [102]. Further research into the diagnostic utility of additional antigens is required, including that of heparin-binding hemagglutinin (HBHA) [–110]. The other strategy to improve IGRAs has also been investigated, and Ruhwald et al [111] have reported that measuring IFN-γ inducible protein 10 (IP-10) levels in addition to IFN-γ levels significantly improved diagnostic sensitivity for active tuberculosis (ATB) by 4% over QuantiFERON-TB Gold In-Tube test alone (while only slightly decreasing specificity from 100% to 98%; P < .009). The simultaneous measurement of interleukin 2 (IL-2) levels has also raised hopes for improving on IGRAs, because IFN- γ and IL-2 T-cell cytokine secretion profiles have been shown to correlate with pathogen load and the successful response to tuberculosis treatment [–114]. Ultimately, all of these novel approaches urgently need to be validated in large prospective studies to quantify their clinical utility and evaluate their prognostic power in both low- and high-burden settings. IL-8, interleukin 8; IL-12p40, interleukin 12p40; LTBI, latent tuberculosis infection.