Characterisation of Tuberculosis Infection using PET-CT Imaging and Clinical Tools

<p dir="ltr">Tuberculosis (TB) infection is increasingly recognised as a spectrum of infection, with a variable risk of progressing to active TB disease. Heterogeneity of TB infection is not informed by current clinical diagnostic tools of TB infection, including interferon-gamma release assay (IGRA) and tuberculin skin test (TST). This thesis aims to characterise TB infection using existing clinical tools and 18F-FDG-PET-CT imaging.</p><p dir="ltr">The thesis presents findings from several sub-studies across four cohorts. The Leicester TB service database (TBIT) and the prospective longitudinal cohort study (ISIT-TB) investigated the relationships between index disease phenotypes and quantitative and serial IGRA responses with infection transmission and prospective TB risks in pulmonary TB contacts. A sub-study (CITI) of the ISIT-TB study and a prospective longitudinal study (EVENT-TB) explored PET-CT to characterise TB infection states in recent TB contacts.</p><p dir="ltr">Findings from the TBIT and ISIT-TB cohorts identified that bacterial burden, especially Xpert MTB/RIF Ultra grades in respiratory samples, and rapidly progressive disease in index cases are key factors influencing infection transmission and disease progression in contacts. IGRA conversion in contacts was associated with shorter symptom duration in index cases and higher prospective TB risk. However, among persistently IGRA-positive contacts, serial IGRA responses were not predictive of incident TB. In the CITI study, four distinct PET-CT-based TB infection phenotypes were proposed, with features confirmed to be attributable to Mycobacterium tuberculosis (Mtb) infection through sampling and culture of FDG-avid sites. PET-CT features were further refined using semi-automated quantification and the use of a reference organ to correct for physiological variation in FDG uptake. Notably, PET-CT abnormalities were observed prior to IGRA conversion, and PET positivity in contacts correlated with high bacillary burden in index cases. Contacts who progressed to active TB exhibited greater increases in volumetric PET parameters between baseline and three months.</p><p dir="ltr">In summary, this thesis highlights how index disease phenotypes and PET-CT imaging provide novel insights into the characterisation of TB infection in contacts. The findings also underscore the potential of PET-CT as a powerful research tool in TB infection studies.</p>