POSSIBILITIES OF ANTIGEN-SPECIFIC CYTOKINE RELEASEESSAYS FOR DIFFERENTIAL DIAGNOSIS OF ACTIVEAND LATENT TUBERCULOSIS INFECTION

Abstract

Introduction: The review examines pathogenetically significant cytokine biomarkers for differentiating latent tuberculosis
infection and active tuberculosis.
Purpose: The purpose of this review is to analyze the capabilities of cytokines antigen-specific release assays, in
addition to the interferon-gamma (IFN-γ) release assay, for the differential diagnosis of active tuberculosis (ATB) and latent
tuberculosis infection (LTBI). The need for such an analysis is determined by the limited capabilities of the IFN-γ antigenspecific release test (IGRA) for the differentiation of LTBI and ATB.

Methods: The review was conducted using electronic databases (Google Scholar, PubMed, Scopus, Cochrane Library)
to identify publications exploring the potential of cytokines antigen-specific release assays as a diagnostic tool for the
differential diagnosis of LTBI and ATB. The inclusion criteria were: full-text publications assessing the antigen-specific
production of one or more cytokines both upon stimulation with "traditional" immunodominant antigens (ESAT-6 and CFP-10)
and other MBT antigens, including phase-dependent ones. The exclusion criteria were: publications evaluating the
production of only one antigen-specific IFN-γ; articles in which controls were not reliably tested for LTBI; articles analyzing
unstimulated cytokine production; articles in which the differentiating potential of the studied cytokines was not revealed.
Results: The most studied cytokines, both individually and in combination, were IFN-γ, tumor necrosis factor-alpha
(TNF-α), Interleukin-2 (IL-2), Interferon gamma-induced protein-10 (IP-10), Interleukin-13 (IL-13), Interleukin-10 (IL-10). The
differences in the results obtained are apparently related to the use of various laboratory methods for assessing the level of
antigen-specific cytokine production (incubation time, reading format, concentration calculation formulas, etc.), genetic
characteristics of the studied population, as well as the use of Mycobacterium tuberculosis antigens (MBT) with different
immunodominance.
Conclusion: Several cytokines have shown promise as phase-dependent biomarkers for the differential diagnosis of
LTBI and ATB. At the same time, the use of a combination of cytokines improves the diagnosis. To identify a reliable phasedependent cytokine, it is necessary to unify approaches to methods for assessing cytokine production and the complex of
stimulating MBT antigens.