Predictive biomarkers for progression to active tuberculosis

Individuals with latent tuberculosis infection (LTBI) carry an increased risk of progression to active TB. However, a substantial but unknown proportion of people with LTBI will not develop TB. This may be because their immune systems are able to persistently control mycobacterial replication or because they are no longer infected with live bacteria. The risk of reactivation, disease, and mortality increases significantly in Mycobacterium tuberculosis-infected individuals who experience immune suppression. This immune suppression may result from HIV co-infection, treatment with tumor necrosis factor (TNF)-α inhibitors, the use of other immune regulators prescribed for inflammatory diseases and transplantation, or compromised immunity associated with noncommunicable diseases such as type 2 diabetes.

The outcome of M. tuberculosis infection is therefore not a simple two-state process of either LTBI or active TB. Instead, it represents a continuous spectrum of disease states that differ by pathogen and host “activity.” These differences require diverse diagnostic and treatment strategies.

When evaluating the positive predictive value (PPV) of diagnostic tests to identify which LTBI cases will progress to active TB, estimates remain low. Assuming a 2-year cumulative TB incidence of 2% and a 50% effectiveness of isoniazid preventive treatment, the optimal achievable PPV is approximately 16%. The minimal target PPV under the same scenario is about 6%. In contrast, current generations of interferon-γ release assays (IGRAs), as outlined in World Health Organization latent TB infection guidelines, have a PPV of only 2–3%. In parallel with the development of target product profiles (TPP), a framework for validating such tests is being formulated.

To improve prediction, a 16-gene transcriptomic correlate of risk (COR) was developed. Measurement of the 16-gene COR was transitioned from RNA sequencing (HiSeq2000; Illumina) to a high-throughput, microfluidic, real-time PCR platform to enable cheaper and simpler gene expression analysis. The PCR-based 16-gene transcriptomic COR signature was validated through blind prediction in two independent cohorts of South African and Gambian individuals—progressors and controls—from a prospective household TB contact study (GC6–74, the Biomarkers for TB Consortium). In these validation cohorts, the signature demonstrated a sensitivity of 54% and a specificity of 83%.

Ongoing analyses aim to further explore the biological processes that underlie TB progression in adolescents. Notably, all 16 genes comprising the COR signature are regulated by type I and type II interferons (IFNs). This suggests that chronic peripheral activation of the IFN response—previously associated with active TB disease at the time of diagnosis—also precedes the onset of active TB disease.

Sources:

1. Petruccioli, E., Scriba, T.J., Petrone, L., Hatherill, M., Cirillo, D.M., Joosten, S.A., Ottenhoff, T.H., Denkinger, C.M. and Goletti, D., 2016. Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis. European Respiratory Journal, 48(6), pp.1751-1763.