The ongoing challenge of latent tuberculosis

Abstract

The global health community has set itself the task of eliminating tuberculosis (TB) as a public health problem by 2050. Although progress has been made in global TB control, the current decline in incidence of 2% yr−1 is far from the rate needed to achieve this. If we are to succeed in this endeavour, new strategies to reduce the reservoir of latently infected persons (from which new cases arise) would be advantageous. However, ascertainment of the extent and risk posed by this group is poor. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we outline a basis for our current understanding of latent TB and highlight areas where innovation leading to development of novel diagnostic tests, drug regimens and vaccines may assist progress. We argue that the pool of individuals at high risk of progression may be significantly smaller than the 2.33 billion thought to be immune sensitized by Mycobacterium tuberculosis and that identifying and targeting this group will be an important strategy in the road to elimination.

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

“…Two recent studies performed in high-TB transmission settings showed a limited utility of IGRAs as biomarkers of shortterm response to LTBI treatment (38,39). Moreover, an IGRA(1) test has a low (,7%) diagnostic power to predict TB reactivation over time, again suggesting that only a subset of IGRA(1) individuals bear viable MTB with reactivation potential (3,40).…”

“…Approximately 90% of immunocompetent individuals with LTBI will never develop active TB (1). In fact, 80% of human lung calcified granulomas do not contain viable Mycobacterium tuberculosis (MTB) (2), suggesting that most immunocompetent individuals can either clear or effectively contain infection (3)(4)(5). Therefore, new biomarkers to reliably identify the 10% of immunocompetent patients with LTBI with reactivation potential are highly desirable.…”

“…Immunoassays for LTBI include tuberculin skin test (TST); IFN-g release assays (IGRA); and investigationally, flow cytometry (FC)-based assays of T-cell markers (8)(9)(10). Because these tests assess cell-mediated immune responses against MTB antigens, positivity can potentially result from the following: (1) active but incompletely effective anti-MTB immune responses; (2) active, effective immune containment (e.g., calcified granuloma); (3) immune memory after completely effective bacterial clearance; or (4) false-positive reactions (3)(4)(5). The first scenario, and potentially in the second scenario (if a patient develops immunosuppression), represent situations where patients truly require treatment, but no single immunoassay distinguishes these patient subsets from the other immunereactive subsets (3,5).…”

Evaluation of Treatment Indications, Tuberculin Skin Test, and Bacillus Calmette-Guerin Vaccination Scars in the Cases of Latent Tuberculosis Infection Treatment

“…Both tests are based on the cell-mediated immune response to MTB antigens. The IGRA is an immune response to merely 2 or 3 tuberculosis antigens but the TST is immune response to 200 tuberculosis antigens [2,3,5]. From positive TST to negative TST is known reversion.…”

Resuscitation-promoting factors are important determinants of the pathophysiology inMycobacterium tuberculosisinfection

“…The prevailing view, however, is that LTBI is best viewed as a range of infection states extending from infection eradicated by the host immune response to subclinical active infection, at particularly high risk of reactivation (Esmail et al, 2014). It is thought that bacillary replication is curtailed by the host immune response, however, if this balance is perturbed by factors such as immunosuppression due to human immunodeficiency virus (HIV) infection or anti-tumor necrosis factor therapy, bacillary replication resumes leading to reactivation and clinical disease (Paige & Bishai, 2010).…”