Despite huge efforts, tuberculosis (TB) is still a major public health threat worldwide, it is estimated that a quarter of the global population is infected by Mycobacterium tuberculosis (Mtb). For controlling TB and reducing Mtb transmission it is fundamental to diagnose TB infection (TBI) as well as the progressors from TBI to disease to identify those requiring preventive therapy. At present, there is no gold standard test for TBI diagnosis although several new methodologies have been attempted. This review provides an update on the most recent approaches to develop reliable tests to diagnose TBI and progressors from infection to disease. Experimental tests are based on either the direct identification of Mtb (i.e., Mtb DNA upon host cells isolation; Mtb proteins or peptides) or host response (i.e., levels and quality of specific anti-Mtb antibodies; host blood transcriptome signatures). The experimental tests described are very interesting. However, further investigation and randomized clinical trials are needed to improve the sensitivity and specificity of these new research-based tests. More reliable proofs-of-concept and simplification of technical procedures are necessary to develop new diagnostic tools for identifying TBI patients and those that will progress from infection to TB disease.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat. Approximately one-quarter of the world’s population has an Mtb-specific immune response and are classified as having tuberculosis infection (TBI), with a lifelong 5–10% risk of developing TB disease. This risk is elevated in individuals with immune-mediated inflammatory diseases (IMID) undergoing immunosuppressive therapies. To evaluate the diagnostic accuracy of the 3-gene TB-SCORE for TB disease in individuals within the TB spectrum, including those with TBI-IMID in a low TB endemic country, we prospectively enrolled 104 individuals with TB, TBI, TBI-IMID, and healthy donors. The 3-gene TB-SCORE and Mtb-specific response were evaluated and correlated with the participant’s clinical status. Patients with TB disease showed a significantly lower TB-SCORE compared to other cohorts. ROC analysis showed moderate diagnostic accuracy for TB disease (AUC 0.70–0.71). TB-SCORE was unaffected by IMID status or timing of Mtb exposure. Mtb-specific CD4⁺ T cells had no correlation to TB-SCORE. This is the first evaluation of TB-SCORE as a diagnostic tool for TB disease in a low-endemic setting. While further validation is needed, our findings support its potential as a biomarker for TB disease, even in complex clinical settings involving IMID.