Background

Tuberculous meningitis (TBM) is the leading cause of bacterial meningitis in children in many global settings and the most lethal and disabling form of tuberculosis, disproportionately affecting infants and young children. TBM can affect patients of all ages, however the peak incidence of disease is seen in early childhood (2-4 years of age) when the brain is still developing.

Death and long-term disability from TBM remain unacceptably high with 20% of children with TBM dying and over 50% of those who survive suffering some form of long-term disability. Although children have lower mortality than adults with TBM, they can suffer serious long-term physical and neurocognitive sequelae which have substantial socioeconomic impact.

Diagnosing TBM in children can be challenging owing to non-specific symptoms often mistaken for other common childhood infections, the paucibacillary nature of disease, and inadequately sensitive tools to diagnose the disease.  Delays in diagnosis and initiation of appropriate therapy invariably result in poor outcomes and much of the damage has already occurred even before the child is started on therapy.  There is an urgent need to diagnose early and better understand the mechanisms of disease in children with TBM. In doing so, new knowledge will help direct future research into novel host-directed therapy and reduce the burden of disability.

Aims

This study seeks to examine mortality and detailed neurodevelopmental outcomes in Vietnamese and Indonesian children with TBM, analyzing their clinical and neuroradiological features and disease severity. We use new “omic” technology to combine clinical data and samples, identifying specific metabolic and inflammatory pathways, such as tryptophan metabolism, which could affect the health outcomes of children with TBM.

Study Design

It is planned 100 children from Indonesia (Jakarta and Bandung) and 50 children from Ho Chi Minh City, with TBM, will be enrolled.  Disease phenotype, severity, clinical outcomes, and complications will be collected at time of enrolment through to 18 month follow-up.  Serial blood and CSF sampling, and neuroimaging will be taken during the course of the study.

In-depth neurodevelopmental and neurocognitive testing post TB meningitis will be conducted in Vietnamese and Indonesian children. This information will inform future surveillance and interventions to improve long-term function.

In-depth clinical data from PediPOT will be integrated with INTERCEPT.

Community advisory boards (CAB) consisting of parents/carers of children affected by TBM will be formed in both countries.  The CAB will be advised on the development of hospital discharge material for children recovering from TB meningitis and for the families who care for them.