Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response
Toidi Adekambi, … , Susan M. Ray, Jyothi Rengarajan
Toidi Adekambi, … , Susan M. Ray, Jyothi Rengarajan
Published March 30, 2015
Citation Information: J Clin Invest. 2015;125(5):1827-1838. https://doi.org/10.1172/JCI77990.
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Clinical Research and Public Health Immunology Infectious disease Microbiology

Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Abstract

BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection.

METHODS. Using polychromatic flow cytometry, we evaluated 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.

RESULTS. Frequencies of Mtb-specific IFN-γ+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-γ+, HLA-DR+IFN-γ+, and Ki-67+IFN-γ+, 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.

CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure.

TRIAL REGISTRATION. Registration is not required for observational studies.

FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.

Authors

Toidi Adekambi, Chris C. Ibegbu, Stephanie Cagle, Ameeta S. Kalokhe, Yun F. Wang, Yijuan Hu, Cheryl L. Day, Susan M. Ray, Jyothi Rengarajan

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Figure 7

Longitudinal monitoring of the frequencies of activated Mtb-specific CD4+ T cells during anti-TB treatment in ATB patients.

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Longitudinal monitoring of the frequencies of activated Mtb-specific CD4...
(A) Frequencies of CD38+IFN-γ+, HLA-DR+IFN-γ+, Ki-67+IFN-γ+, and CD45RA– IFN-γ+CD4+ T cells in 10 different ATB patients (P1 to P10) over the course of anti-TB treatment after stimulation with Mtb-CW. Treatment response and culture conversion were monitored in sputum by smear microscopy and culture. These results are shown for the time of diagnosis (day 0) and at time points following treatment initiation. Detection of AFB in sputum specimens by smear and culture is indicated by a positive (+) result. The smear grade recorded for each positive result is indicated numerically (4+, 3+, 2+, or +). A negative (–) result by either smear or culture indicates that Mtb was not detected in sputum specimens at those time points and indicates that that sample was not tested. Cumulative data for patients P1 to P10 are presented for (B) CD38+IFN-γ+, (C) HLA-DR+IFN-γ+, and (D) Ki-67+IFN-γ+ T cells over the course of anti-TB treatment. Values are expressed as median on the y axis and as follow-up days on the x axis. The 2-month intensive phase (HRZE), 4-month continuation phase (HR), and follow-up (fu) posttreatment completion are indicated.