Abstract
Background Immune parameters (IP) have been extensively studied to distinguish between latent tuberculosis (LTBI) and active tuberculosis (TB). Objective To determine the IP associated with LTBI, compared to active TB and individuals not infected by M. tuberculosis published in literature. Methods We conducted a systematic search using Google Scholar and PubMed databases, combining the MeSH terms latent tuberculosis, Mycobacterium tuberculosis, cytokines, and biological markers, with the free terms, biomarkers and cytokines. Spanish, English, and Portuguese articles comparing the concentration of IP associated with LTBI, either in plasma/serum or in vitro, in adults and nonimmunocompromised versus individuals with TB or without M. tuberculosis infection between 2006 July and 2018 July were included. Two blinded reviewers carried out the searches, read the abstracts, and selected the articles for analysis. Participants' information, diagnostic criteria, IP, detection methods, and biases were collected. Results We analyzed 36 articles (of 637 abstracts) with 93 different biomarkers in different samples. We found 24 parameters that were increased only in active TB (TGF-α, CSF3, CSF2, CCL1 [I-309], IL-7, TGF-β1, CCL3 [MIP-1α], sIL-2R, TNF-β, CCL7 [MCP-3], IFN-α, fractalkine, I-TAG, CCL8 [MCP-2], CCL21 [6Ckine], PDGF, IL-22, VEGF-A, LXA4, PGE2, PGF2α, sCD163, sCD14, and 15-Epi-LXA4), five were elevated in LTBI (IL-5, IL-17F, IL-1, CCL20 [MIP-3α], and ICAM-1), and two substances were increased among uninfected individuals (IL-23 and basic FGF). We found high heterogeneity between studies including failure to account for the time/illness of the individuals studied; varied samples and protocols; different clinical classification of TB; different laboratory methods for IP detection, which in turn leads to variable units of measurement and assay sensitivities; and selection bias regarding TST and booster effect. None of the studies adjusted the analysis for the effect of ethnicity. Conclusions It is mandatory to harmonize the study of immune parameters for LTBI diagnosis. This systematic review is registered with PROSPERO CRD42017073289.
Highlights
Immune parameters (IP) have been extensively studied to distinguish between latent tuberculosis (LTBI) and active tuberculosis (TB)
Among the main ones described are IFN-γ, produced by T CD4+, CD8+, and NK cells, and IL-1 and TNF-α, secreted by macrophages and lymphocytes, known to prevent the growth and multiplication of mycobacteria in host cells [6, 7]. Additional biomarkers such as IL-2, IL-5, IL-10, IL-1RA, and MCP have been studied for their ability to differentiate between the LTBI and active TB [8], and it is believed that the cellular and immune profile expressed during tuberculous infection depends to a great extent on the stage of disease, i.e., LTBI or active, where immune biomarkers present in blood could have the ability to differentiate with greater precision between both stages [9]
The host response is measured in order to determine M. tuberculosis infection in the form of skin tests or IGRAs, but this approach is limited by the inability to differentiate LTBI from active TB infection
Summary
Immune parameters (IP) have been extensively studied to distinguish between latent tuberculosis (LTBI) and active tuberculosis (TB). Latent tuberculosis (LTBI) is defined as the presence of a positive tuberculin skin test (TST) or interferon-γ (IFNγ) release assays (IGRAs) in the absence of clinical or radiographic signs of disease These accepted tests are imperfect for LTBI diagnosis for several reasons: (1) the sensitivity and specificity are between 71 and 82% for TST and 81 and 86% for IGRAs [1], (2) the sensitivity is reduced in immunocompromised patients, (3) there is inability to differentiate between LTBI and active tuberculosis (TB), (4) a positive TST or IGRA result does not automatically imply LTBI, as individuals who eliminate the infection successfully might still be TST- or IGRA-positive because of memory T cell responses, which partly explains the low predictive value of TST and IGRAs [1], and (5) genetic factors may impact test sensitivity. Additional biomarkers such as IL-2, IL-5, IL-10, IL-1RA, and MCP have been studied for their ability to differentiate between the LTBI and active TB [8], and it is believed that the cellular and immune profile expressed during tuberculous infection depends to a great extent on the stage of disease, i.e., LTBI or active, where immune biomarkers present in blood could have the ability to differentiate with greater precision between both stages [9]
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