Abstract
As an ancient infectious disease, tuberculosis (TB) is still the leading cause of death from a single infectious agent worldwide. Latent TB infection (LTBI) has been recognized as the largest source of new TB cases and is one of the biggest obstacles to achieving the aim of the End TB Strategy. The latest data indicate that a considerable percentage of the population with LTBI and the lack of differential diagnosis between LTBI and active TB (aTB) may be potential reasons for the high TB morbidity and mortality in countries with high TB burdens. The tuberculin skin test (TST) has been used to diagnose TB for > 100 years, but it fails to distinguish patients with LTBI from those with aTB and people who have received Bacillus Calmette–Guérin vaccination. To overcome the limitations of TST, several new skin tests and interferon-gamma release assays have been developed, such as the Diaskintest, C-Tb skin test, EC-Test, and T-cell spot of the TB assay, QuantiFERON-TB Gold In-Tube, QuantiFERON-TB Gold-Plus, LIAISON QuantiFERON-TB Gold Plus test, and LIOFeron TB/LTBI. However, these methods cannot distinguish LTBI from aTB. To investigate the reasons why all these methods cannot distinguish LTBI from aTB, we have explained the concept and definition of LTBI and expounded on the immunological mechanism of LTBI in this review. In addition, we have outlined the research status, future directions, and challenges of LTBI differential diagnosis, including novel biomarkers derived from Mycobacterium tuberculosis and hosts, new models and algorithms, omics technologies, and microbiota.
Highlights
Tuberculosis (TB) is one of the top 10 causes of death and is the leading cause of death from a single infectious agent worldwide (Gong et al, 2018; World Health Organization (WHO), 2020)
It has been reported that approximately one-fourth of the global population is latently infected with M. tuberculosis and that 5–15% of them may progress to active TB (aTB) within 2 years, while the remaining individuals with latent TB infection (LTBI) are at a constant risk of reactivation (Houben and Dodd, 2016; Pai and Behr, 2016)
A previous study analyzed the expression of CD27 and CCR4 biomarkers in IFN-γ+CD4+ T cells collected from patients with aTB and patients with LTBI and found that the proportion of CD27−IFN-γ+CD4+ T cells or CCR4+ IFN-γ+CD4+ T cells was significantly higher in patients with aTB than in those with LTBI in response to purified protein derivative (PPD) or early secreted antigenic target 6 (ESAT-6)/culture filtrate protein 10 (CFP-10) recombinant proteins and that the proportion of CD27−CCR4+IFN-γ+CD4+ T cells was significantly associated with aTB
Summary
Tuberculosis (TB) is one of the top 10 causes of death and is the leading cause of death from a single infectious agent worldwide (Gong et al, 2018; WHO, 2020). The novel C-Tb skin test is based on a mixture of antigens ESAT-6 and CFP10 It combines the advantages of the field friendliness of TST and the high specificity of IGRAs. Two phase III clinical trials have investigated the safety and efficacy of the C-Tb skin test, QuantiFERON-TB Gold In-Tube (QFT-GIT), and TST, suggesting that C-Tb and QFT-GIT results were concordant in 94% of participants and that the safety profile of the C-Tb skin test was similar to that of the TST and QFT-GIT in HIV-negative adults and children as well as HIV-positive individuals with active or latent M. tuberculosis infection (Ruhwald et al, 2017; Aggerbeck et al, 2018). A phase III clinical trial conducted in 1,559 participants found that the EC-Test and IGRAs have fairly high specificity and consistency (88.77%) (Chinese Antituberculosis Association et al, 2020) Taken together, these three new tests are designed to detect immune responses stimulated with recombinant ESAT-6 and CFP-10 antigens to help address the problem of false-positive TST results that occur in patients who have received BCG vaccination (Ruhwald et al, 2016). But can be influenced by infections of M. kansasii, M. szulgai, and M. marinum (Andersen et al, 2000)
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