Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis

Abstract

New approaches to control the spread of tuberculosis (TB) are needed, including tools to predict development of active TB from latent TB infection (LTBI). Recent studies have described potential correlates of risk, in order to inform the development of prognostic tests for TB disease progression. These efforts have included unbiased approaches employing “omics” technologies, as well as more directed, hypothesis-driven approaches assessing a small set or even individual selected markers as candidate correlates of TB risk. Unbiased high-throughput screening of blood RNAseq profiles identified signatures of active TB risk in individuals with LTBI, ≥1 year before diagnosis. A recent infant vaccination study identified enhanced expression of T-cell activation markers as a correlate of risk prior to developing TB; conversely, high levels of Ag85A antibodies and high frequencies of interferon (IFN)-γ specific T-cells were associated with reduced risk of disease. Others have described CD27−IFN-γ+CD4+ T-cells as possibly predictive markers of TB disease. T-cell responses to TB latency antigens, including heparin-binding haemagglutinin and DosR-regulon-encoded antigens have also been correlated with protection.Further studies are needed to determine whether correlates of risk can be used to prevent active TB through targeted prophylactic treatment, or to allow targeted enrolment into efficacy trials of new TB vaccines and therapeutic drugs.

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

“…However, IGRA1 and TST1 prevalence can reach up to 50% in the Gambia and 80% in South Africa (3), and although IGRAs and the TST have a high (approximately 80%) sensitivity for Mtb infection, they have poor positive predictive values of 2.7% and 1.5%, respectively, for TB progression. Therefore, dozens of individuals would require prophylactic treatment to prevent progression to TB in a single individual (35,36). The World Health Organization recently published guidelines for an incipient TB target product profile to predict TB progression (8) in order to ensure that individuals at high risk of TB progression are not falsely excluded (7,18) but instead are referred for additional investigation for TB or offered prophylactic treatment (37).…”

“…Such a test can potentially be developed into a screening test for risk of progression during TB contact investigation implemented by national public health structures (13,35,36). The next steps include assessment of the performance of RISK4 and the two-transcript C1QC/TRAV27 signature in other settings, including nonAfrican populations, and determination of the feasibility of developing a near-patient test for targeted intervention.…”

A novel blood test for tuberculosis prevention and treatment

“…However, if the RNA signature performs as predicted, the NNT would be more than halved, which might make large-scale, targeted TB preventive therapy feasible, even in high-TB-incidence countries. [10,11] The RNA signature is being assessed in a clinical trial to identify healthy adults at high risk of TB disease, and to test whether targeted short-course preventive therapy (3 months of once weekly, high-dose isoniazid plus rifapentine (3HP)) can prevent TB disease in individuals who test positive for the RNA signature. The Correlate of Risk (COR) Targeted Intervention Study (CORTIS), [12] currently underway at 5 sites across SA, intends to screen >10 000 healthy adults for the RNA signature and follow 3 200 participants over 15 months for incident TB disease.…”

The new “Hesitation Blues”: initiating Mycobacterium avium complex lung disease therapy

“…Animal models have been pivotal in understanding tuberculosis (TB) pathophysiology. An important recent example is work in a primate TB model demonstrating that latent TB and active TB comprise not a simple two-state process, but rather, are part of a spectrum of states [9]. While there are candidate murine and primate models of MAC and M. abscessus lung disease, there is not yet an animal model that is unambiguously analogous to human NB MAC or M. abscessus lung disease [10][11][12].…”

“…Understanding the fundamentals of NB MAC lung disease pathophysiology would be enormously helpful in the search for identifiable disease progression markers. Even though the understanding of TB pathophysiology is well ahead of NB MAC lung disease, the search for markers of TB disease progression continues [9]. …”