Whole Genome Sequencing to streamline TB diagnosis, improve TB surveillance and optimize individualized TB treatment a pragmatic trial

Tuberculosis (TB) continues to be an important public health problem with more than 10 million new cases and over 1 million deaths annually. In low burden regions such as Flanders, immigration and drug resistance pose important hurdles to TB control efforts. Due to the challenges in the current diagnostic pathway, patients suffering from drug resistant TB often receive suboptimal treatment in the first months following their diagnosis, which can amplify drug resistance and lead to transmission of drug resistant strains in the community. Whole genome sequencing (WGS) of Mycobacterium tuberculosis as part of routine TB diagnosis is an attractive prospect as WGS rapidly interrogates the entire 4.4 Mbp M. tuberculosis genome. This information would generate the most comprehensive resistance profile for each patient and allow rapid initiation of the most effective and patient-friendly individualized treatment for each person diagnosed with active TB. Furthermore, WGS would not only contribute to diagnostics but also to public health surveillance, as the results of the WGS assay performed for diagnostic purposes will generate phylogenetic data for routine surveillance of
transmission events and outbreak detection. Coupling genomic diagnostics and epidemiology would transform the approach to TB control in Flanders towards a 21st century innovative digital disease detection platform and surveillance system. WGS thus has great potential to become the future cornerstone of routine TB diagnosis, care and surveillance in Flanders. We propose to perform a pragmatic multicenter theragnostic trial of WGS of M. tuberculosis to streamline TB diagnosis, improve TB surveillance and optimize individualized treatment of drug resistant TB to improve treatment outcomes. A pragmatic trial undertaken in real-life conditions will generate the data required for policy development, facilitate the translation of results into routine practice and thus contribute to TB control in Flanders.