Understanding ischemia in children with tuberculous meningitis (iThemba): a protocol paper

One million children develop tuberculosis (TB) each year and a quarter of these die. TB meningitis (TBM) is the most severe form of TB disease and even if diagnosed and treated, 20% die and over 50% of survivors are left with permanent neurological disability. Much of the morbidity and mortality associated with TBM is due to infarction yet, despite this, our understanding of the pathogenesis of infarction in TBM remains limited, especially in children. The iThemba study (Understanding ischemia in children with tuberculous meningitis), aims to recruit 100 children with probable or confirmed TBM and obtain samples of blood and cerebrospinal fluid (CSF). All children will undergo MRI and FDG PET/CT at baseline and will have repeat MRI with further blood and CSF samples collected at 2 weeks’ follow-up. MRI will then be carried out at 24 weeks with neurodevelopmental assessment at 48 weeks. Neuroimaging will focus on methods to identify and characterize ischemic penumbra and evaluate how this correlates with clinical outcomes. RNA sequencing of blood and CSF will be used to identify differentially expressed genes and identify implicated biological pathways between children with and without infarction. Targeted proteomic profiling will be performed on plasma and CSF to determine differences in protein abundance, with a focus on proteins involved in coagulation and endothelial function. Finally, we will integrate transcriptomic, proteomic and radiomic data to generate a comprehensive understanding of the pathogenesis of infarction in children with TBM. We aim to group children into relevant biological/anatomical phenotypes, each of which may benefit from a different therapeutic approach. Using computer simulation, we will then explore the impact of potential therapeutic interventions on biological pathways for each distinct phenotype. This work may pave the way for the development of point-of-care tests at diagnosis that could allow for stratified novel therapeutic approaches in future. A more comprehensive understanding of the pathophysiology of infarction in children with TBM would permit targeted host-directed therapies, with the potential to moderate or eliminate the consequences of this devastating condition.