What is the future of latent tuberculosis diagnostics? A PRISMA-compliant systematic review

Latent tuberculosis infection (LTBI) affects approximately one quarter of the global population and represents a major reservoir for future active tuberculosis (ATB). Current immunological diagnostics, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), are unable to reliably distinguish LTBI from ATB, limiting their clinical utility for targeted prevention strategies. To systematically evaluate emerging diagnostic approaches for distinguishing LTBI from ATB in immunocompetent adults. A two-phase systematic review was conducted in accordance with PRISMA 2020 guidelines. In the initial phase, PubMed and Scopus were searched from January 2005 to May 2022 for primary studies evaluating diagnostic tests intended to differentiate LTBI from ATB. Eligible studies included immunocompetent adults and reported diagnostic performance metrics. Studies involving immunocompromised populations, children, pregnancy, animal models, or secondary literature were excluded. Risk of bias was assessed using QUADAS-2, and certainty of evidence narratively using GRADE. Sensitivity and specificity were extracted where available. The second phase conducted a similar search from May 2022 to 2026 to capture more up-to-date results. Fifteen studies comprising 3,967 participants met inclusion criteria. Diagnostic approaches included immunological assays ( n = 11) and transcriptional profiling ( n = 4). Four approaches demonstrated promising diagnostic performance: (i) T-SPOT machine-based learning algorithm cforest model - sensitivity 92.80% and specificity 89.86%; (ii) microRNA-based diagnostic biomarkers: let-7d-5p and miR-140-5p, which, in combination, established a sensitivity of 100% and specificity of 100% (internal test set; no independent validation cohort). (iii) Multi-antigen ELISA-based IgG logistic regression model sensitivity of 93.33% and specificity of 93.10% (iv) Composite T-SPOT.TB diagnostic model sensitivity of 93.21% and specificity of 90.00%. Considerable heterogeneity was observed in reference standards and biomarker thresholds. Several emerging diagnostics demonstrate promising accuracy for distinguishing LTBI from ATB in immunocompetent adults. However, heterogeneity in study design and reference standards limits immediate clinical translation. Future research should prioritize standardization, validation in high-burden settings, and evaluation in immunologically diverse populations.