Browsing by Author "Awoniyi, Dolapo Olaitan"
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- ItemImmunological markers for active TB and early treatment response indicators(Stellenbosch : Stellenbosch University, 2017-03) Awoniyi, Dolapo Olaitan; Walzl, Gerhard; Diacon, Andreas; Chegou, Novel N.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human GeneticsBackground The difficulty in diagnosing tuberculosis (TB) and evaluating TB treatment response are two major problems that are hampering the defeat of this infectious disease. The current TB diagnostic tools have several limitations and these call for the development of a simple, rapid and accurate diagnostic test that is suitable for use in poor-resource settings. Aim and Objectives This thesis aims to identify host markers for the development of a rapid and simple test for TB diagnosis and for monitoring early TB treatment response. The objectives are: 1. To investigate the diagnostic accuracy of host markers detected in Mycobacterium tuberculosis (Mtb) antigen-stimulated overnight whole blood culture supernatant. 2. To investigate the profiles of inflammatory markers of active TB patients undergoing treatment in a 14-day EBA trial for treatment monitoring potential. 3. To investigate the combined performance of the responses of IgG, IgM and IgA to selected mycobacterial antigens for their diagnostic potential. Methodology Participants were recruited as part of the recently concluded EDCTP-funded AE-TBC study and a 14-day phase II randomised clinical trial (early bactericidal activity (EBA) study of seven treatment arms). Sputum and blood samples were collected at different time points and multiplex cytokine array analysis performed on plasma or serum samples by Luminex and anti-mycobacterial antibodies detected by ELISA. Results After overnight stimulation of whole blood with ESAT-6/CFP-10, RV0081, Rv1284 and Rv2034, the most promising diagnostic markers were CRP, Ferritin, SAA and IP-10. Unstimulated host markers yielded the best discriminatory power. A six-marker biosignature comprised mostly of unstimulated cytokine levels shows promise for active TB diagnosis. Stellenbosch University https://scholar.sun.ac.za iii There were significant changes for CRP, IL-6, VEGF, sIL-2Rα, Ferritin, and sTNFRII from baseline to end of 14 day EBA evaluation in several treatment arms. However, none of these markers mirrored the decrease in the measured bacterial load in sputum. A four-marker combination only accounted for 20% of the variation in observed in both TTP and CFU. The highest sensitivity and specificity was obtained with anti-16 kDa IgA (95%/95%) and anti-MPT64 IgA (95%/90%). A higher accuracy was obtained with a 3 or 4 antibody combination. Anti-16 kDa IgA and anti-16 kDa IgM, decreased significantly while anti-LAM IgG and anti-TB-LTBI IgG increased significantly at the end of month six anti-TB treatment. Conclusion Host biomarkers hold promise as a diagnostic tool in TB disease. In spite of the moderate accuracy of Mtb antigen-stimulated host markers, these could still have value in difficult to diagnose TB, like paediatric TB or extrapulmonary TB, and should be evaluated in future studies. Although host markers only explained a small degree of the variation in bacterial measures in early bactericidal activity studies, their potential role in overall treatment effect remains to be investigated. Serodiagnostic markers against novel Mtb antigens showed potential for future development into a simpler format for use at the point-of-care. These results should be validated in large scale studies in appropriate participant groups.