Host Directed Therapies for Tuberculous Meningitis

Abstract

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

Keywords: Dexamethasone; Host Directed Therapies; Tuberculous Meningitis.

Figure 1.. CT axial, MRI T2 axial, CT sagittal and MRI T1 post-gadolinium sagittal images at 3–4 month intervals of a 16-month-old HIV-infected female with stage III TBM.

The initial CT axial and sagittal scans ( A, F) showed a large right sided middle cerebral artery infarction, hydrocephalus as well as multiple small rim-enhancing foci in the prepontine cisterns. After 3 months of anti-TB and 2 months of anti-retroviral therapy, they presented with a depressed level of consciousness. MRI T2 axial ( B) and MRI T1 post-gadolinium sagittal ( G) demonstrated multiple TB abscesses in the interpeduncular, prepontine and chiasmic cisterns (paradoxical HIV related TB IRIS) as well as right cerebral hemisphere spongiotic changes (old infaction). Thalidomide was initiated following a poor response to 1 week of high dose corticosteroids. This resulted in rapid improvement in the level of consciousness, gradual decrease in the size of the TB abscesses and loss of T2 signal (i.e. inflammation), which is a marker of cure as it represents gradual calcification. ( C– E & H– J).

Figure 2.. Schematic of relevant biochemical pathways which, if targeted with future host directed therapies, may improve outcomes in TBM.

A: Drugs which reduce glutamate ‘glutamate grabbers’ by increasing breakdown of glutamate (either recombinant glutamic-oxaloacetic transaminase (GOT1), or others that mimic its action) may decrease neuro-excitotoxicity associated with brain injury in TBM. B: Phosphodiesterase inhibitors reduce breakdown of cAMP to 5’AMP leading to increased neuronal survival, immune modulation, and increase in axon plasticity and myelination. C: Interruption of the tryptophan pathway via modulation of Indoleamine 2,3-dioxygenase (IDO) activity may have neuroprotective effect, although more data to understand the role of downstream metabolites particularly the contribution of kyruneic acid in antagonism of glutamate receptors is needed.