Biomarker Panel Differentiates Active and Latent Tuberculosis Infections

A set of biomarkers detectable in the blood accurately identifies individuals with active tuberculosis (ATB) and differentiates them from patients with latent Mycobacterium tuberculosis infection (LTBI) and from recovered TB patients.

The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of ATB remains challenging and relies on extensive medical evaluation and detection of M. tuberculosis (Mtb) in the patient’s sputum. Furthermore, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results.

In an effort to modernize detection of patients with ATB, investigators at Emory University (Atlanta, Georgia, USA) used polychromatic flow cytometry to evaluate the expression of immune activation markers on Mtb-specific CD4+ T-cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment.

For this study the investigators enrolled individuals from the Atlanta, GA, USA area with asymptomatic LTBI, with untreated ATB, and patients undergoing treatment for ATB. In addition, the biomarkers identified were applied for evaluation of individuals with ATB and LTBI recruited from the Western Cape in South Africa.

Results revealed that frequencies of Mtb-specific IFN (interferon)-gamma+CD4+ T-cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-gamma+, HLA-DR+IFN-gamma+, and Ki-67+IFN-gamma+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.

"In this study, we have identified T-cell biomarkers that accurately identify ATB patients. These biomarkers have the potential to lead to new blood-based diagnostics for TB as well as provide a set of tools for monitoring treatment response and cure," said senior author Dr. Jyothi Rengarajan, assistant professor of medicine at Emory University. "Blood-based biomarkers will be particularly useful in situations where sputum-based diagnosis of TB is more difficult. Because these biomarkers provide a gauge of Mtb load within individuals, they could also have utility as surrogate markers of treatment response and as predictors of treatment efficacy, cure, and relapse in patients undergoing treatment for drug-susceptible as well as drug-resistant TB.

The study was published in the March 30, 2015, online edition of the Journal of Clinical Investigation.

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