Doctoral Degrees (Molecular Biology and Human Genetics)

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Browsing Doctoral Degrees (Molecular Biology and Human Genetics) by Subject "Antibiotics"

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    Evaluating TB treatment responses by [18F]FDG-PET/CT imaging
    (Stellenbosch : Stellenbosch University, 2016-12) Malherbe, Stephanus Theron; Walzl, Gerhard; Warwick, James; Ronacher, Katharina; Biomedical Sciences: Molecular Biology and Human Genetics
    BACKGROUND Tuberculosis (TB) presents a massive health care problem around the world and the rate of unfavourable outcomes after TB treatment remains unacceptably high. The absence of a gold standard to determine when antibiotics have induced sterilising cure confounds the development of new approaches to treat pulmonary tuberculosis (PTB). Positron Emission Tomography/Computerised Tomography (PET/CT) is well established in the staging, treatment planning and response assessment of cancer. In animal models, 18F-FDG PET/CT has been used to accurately describe disease progression after infection and response to treatment in Pulmonary Tuberculosis (PTB) and human studies with small sample sizes have shown PET/CT to be promising in monitoring the effect of treatment using simple descriptive techniques. PET uptake intensity is influenced by numerous patient and equipment factors. Reproducible segmentation and quantification of lesions become particularly important in diseases with heterogenic morphology, vague lesion borders and multi-focal distribution throughout an organ or system, such as PTB. OBJECTIVE To discover if the functional and anatomical information gained by FDG PET/CT scans on patients with PTB before, during and after treatment can be applied to provide insight into the dynamics of Mycobacterium tuberculosis (MTB) versus host interaction, aid treatment response assessment and facilitate the discovery of biomarkers to monitor treatment response. METHODS We recruited 99 newly diagnosed adult, HIV-negative, PTB patients and performed PET/CT scans at diagnosis, month 1 and month 6 of treatment, as well as 1 year later. We collected clinical specimens for microbiological testing and biomarker discovery. Scans were evaluated qualitatively and we developed and implemented an automated technique to standardise uptake, segment lung lesions and quantify the scan information. We compared the qualitative and quantitative data to clinical and microbiological outcomes. RESULTS We detected PET/CT imaging response patterns consistent with active disease plus the presence of MTB mRNA in sputum and bronchoalveolar lavage fluid in a substantial proportion of PTB patients after standard treatment and one year later, including patients with a durable cure and others who later developed recurrent disease. However, quantification of PET/CT parameters provided results that correlated very well with microbiological outcomes. A large cavity volume was the best prognostic indicator of failure, while a suboptimal reduction in total glycolytic activity was the best prognostic indicator of recurrent disease. Quantified results also showed promise to serve as reference in discovering novel biomarkers of treatment response. CONCLUSION The presence of MTB mRNA in the context of non-resolving and intensifying lesions on PET/CT might indicate ongoing transcription. Thus, that even apparently curative PTB treatment may not eradicate all organisms in most patients, and points to an important complementary role for the immune response in maintaining a disease-free state. The correlation of quantified scan characteristics with microbiological outcomes, provided insight into factors that influence successful treatment. The promising implementation of these parameters in biomarker discovery suggests that PET/CT might be a useful tool that leads to new, improved ways to monitor treatment response.