Evaluating TB treatment responses by [18F]FDG-PET/CT imaging

Malherbe, Stephanus Theron (2016-12)

Thesis (PhD)--Stellenbosch University, 2016.

Thesis

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.

Agtergrond Tuberkulose veroorsaak ‘n massiewe gesondheidsprobleem regoor die wêreld en die insidensie van slegte uitkomste na die afloop van behandeling is onaanvaarbaar hoog. Die gebrek aan ‘n goue standaard om vas te stel of antibiotika steriliserende genesing bereik het, belemmer die ontwikkeling van nuwe metodes om tuberkulose te behandel. Positron Emmissie Topografie/Rekenaar Topografie (PET/RT) is ‘n gevestigde modaliteit in die diagnose, stadiëring en assesering van repons tot behandeling van kanker. In diere studies is 18F-FDG-PET/RT reeds gebruik om die progressie ná infeksie en die reaksie tot behandeling van pulmonale tuberkulose (PTB) akkuraat aan te toon. In voorlopige menslike studies het PET/RT ook belofte getoon in monitering van die effek van behandeling deur middel van eenvoudige beskrywende tegnieke. Die intensiteit van PET opname word beïnvloed deur verskeie eienskappe van die pasiënt en die toerusting. Die konsekwente segmentasie en kwantifisering van letsels is van uiterste belang in siektes met heterogene morfologie, onduidelike grense en ‘n wye verspreiding deur ‘n orgaansisteem - soos in geval van PTB. Doelwitte Om te ontdek of die funksionele en anatomiese inligting wat verkry word deur PET/RT beeldings ondersoeke op pasiënte voor, gedurende en na behandeling toegepas kan word om insig te gee in die dinamiese interaksies tussen Mycobacterium tuberculosis (MTB) en die gasheer. Metodes Ons het 99 nuut gediagnoseerde volwasse, HIV-negatiewe pasiënte met pulmonale TB gewerf en PET/CT skanderings uitgevoer by diagnose, asook maand 1 en maand 6 van behandeling; en 1 jaar na die afloop van behandeling. Ons het kliniese monsters versamel vir mikrobiologiese toetse en biomerker ontdekking. Ons het die beelde kwalitatief asseseer, asook ‘n ge-outomatiseerde metode om letsels te segmenteer en kwantifiseer ontwikkel en geïmplementeer. Die kwalitatiewe en kwantitatiewe uitslae is met kliniese en mikrobiologiese uitkomstes vergelyk. Resultate Ons het PET/RT respons patrone waargeneem wat inpas met aktiewe letsels, asook die teenwoordigheid van MTB mRNA in sputum en bronchoalveolêre spoeling vloeistof, in ‘n wat genees is. Die gekwantifiseerde resultate het wel baie goed met die mikrobiologiese uitkomstes gekorreleer. ‘n Groot kaviteit volume was die beste prognostiese aanwyser van gefaalde behandeling en onvoldoende vermindering van die totale glikolitiese aktiwiteit was die beste aanwyser van herhalende PTB na behandeling. Gekwantifiseerde resultate het ook belofte getoon as ‘n hulpmiddel in die ontdekking van nuwe biomerkers in perifere bloed van behandelings respons. Gevolgtrekking Die teenwoordigheid van MTB mRNA in die konteks van letsels wat nie opklaar nie en selfs intensifiseer op PET/RT, kan voortdurende transkripsie aandui. Dit kan voorstel dat selfs ooglopend genesende PTB behandeling nie al die organismes in die gasheer eradikeer nie; en ‘n belangrike komplimentêre rol vir die van die immuunrespons om ‘n siekte-vrye toestand te handhaaf. Die korrelasie van gekwanifiseerde beelding karakteristieke met mikrobiologiese uitkomstes en die belowende aanwending in biomerker ontdekking, stel voor dat dit tot potensiële hulp kan wees om behandelingsresponse beter te moniteer.

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