Host blood RNA signatures predict the outcome of tuberculosis treatment

Abstract

Biomarkers for tuberculosis treatment outcome will assist in guiding individualized treatment and evaluation of new therapies. To identify candidate biomarkers, RNA sequencing of whole blood from a well-characterized TB treatment cohort was performed. Application of a validated transcriptional correlate of risk for TB revealed symmetry in host gene expression during progression from latent TB infection to active TB disease and resolution of disease during treatment, including return to control levels after drug therapy. The symmetry was also seen in a TB disease signature, constructed from the TB treatment cohort, that also functioned as a strong correlate of risk. Both signatures identified patients at risk of treatment failure 1–4 weeks after start of therapy. Further mining of the transcriptomes revealed an association between treatment failure and suppressed expression of mitochondrial genes before treatment initiation, leading to development of a novel baseline (pre-treatment) signature of treatment failure. These novel host responses to TB treatment were integrated into a five-gene real-time PCR-based signature that captures the clinically relevant responses to TB treatment and provides a convenient platform for stratifying patients according to their risk of treatment failure. Furthermore, this 5-gene signature is shown to correlate with the pulmonary inflammatory state (as measured by PET-CT) and can complement sputum-based Gene Xpert for patient stratification, providing a rapid and accurate alternative to current methods.

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

“…Candidate site-specific signatures of risk for TB disease progression and final, simplified qRT-PCR-based candidate signatures were developed using the pair ratios algorithm (see the online supplement), which was previously described (29) and is a variation of the pairwise approach used to discover the ACS COR signature (25). To summarize, the step-by-step procedure for computing the four-gene COR signature (RISK4) scores using sample qRT-PCR measurements was as follows: (31) were adapted to the qRT-PCR platform, where we refer to them as DIAG4 and DIAG3, respectively.…”

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response

“…Participants considered for this report were 99 newly diagnosed, culture-confirmed, pulmonary TB patients who successfully completed follow-up as part of the previously published Catalysis treatment response cohort [44][45][46]. They were HIV-uninfected adults, recruited at primary health care clinics in the northern regions of Cape Town, South Africa.…”

“…We previously conducted and reported qualitative scan assessments by comparing each lesion's intensity at M6 to the intensity at Dx. 46 Three different response patterns were described: (1) A 'resolved' scan response pattern showed no lesion with more than minimally increased FDG intensity when compared to surrounding lung tissue M6. (2) An 'improved' pattern indicates that all lesions improved during treatment, but one or more lesion showed residual FDG avidity at M6.…”

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

“…Biomarkers that define the optimal duration of drug therapy would be of great interest to increase the number of cured patients. As examples for potential candidates, different approaches including transcriptomics and cytokine analyses have revealed markers that correlate with treatment response and predict cure at very early time points during therapy . Genetic markers for drug toxicity, such as certain n‐acetyltransferase 2 (NAT2) polymorphisms causing higher susceptibility for isoniazid induced liver toxicity, may also be identified for second‐line antituberculosis drugs (e.g.…”