Host biosignatures as diagnostic tools for Tuberculosis in low and high endemic regions

Host blood biomarkers with diagnostic potential for Tuberculosis (TB) identified so far are yet to be translated for clinical use due to limited validation and confirmatory studies across different settings. With the increasing movement of people across countries and continents, the disease is not limited to high-burden settings. Discriminating TB from other diseases with similar clinical manifestations is also crucial for developing an accurate diagnostic tool. This thesis aimed to evaluate the diagnostic and prognostic potential of previously identified soluble inflammatory and gene expression blood biomarkers and signatures in a total of 210 patients with TB disease, 150 Latently TB infected, and 78 individuals with other respiratory infections from low and high TB endemic regions at diagnosis and during therapy. Various combinations of inflammatory biomarkers in plasma showed improved performance compared to individual biomarkers. A 5-marker signature identified TB from other respiratory diseases irrespective of endemic settings in a joint cohort of South African and Norwegian patients. The plasma levels of several biomarkers also changed significantly in response to anti-TB treatment. Furthermore, two single plasma biomarkers (CCL1/I-309 and IL-2Ra) were the most accurate in discriminating between TB disease and Latent TB irrespective of HIV infection. When gene expression profiles were evaluated, the most accurate diagnostic performance was achieved with a combination of 5 genes showing potential in discriminating TB from lower respiratory tract infections among hospitalised patients in Norway. Overall, newly identified biomarkers met the WHO target product profile criteria for a non-sputum biomarker-based triage test requiring further investigation in larger, prospective, diverse patient cohorts across geographical regions.