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.
Highlights
A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM)
Aspirin resulted in absolute risk reduction of stroke in 19.1% and significant reduction in mortality compared to placebo (21.7% vs 43.4%, p=0.02)
In a study of tryptophan genome wide single nucleotide polymorphism (SNP) data we identified 11 quantitative trait loci associated with cerebrospinal fluid (CSF) tryptophan concentrations, and found that these quantitative trait loci were predictive of patient survival[19]
Summary
This article is included in the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) gateway. Existing Host Directed Therapies for Tuberculous Meningitis Dexamethasone Adjunctive corticosteroids reduce mortality from TBM, at least in the short term[1,3,4]. In a large study of clinical and intracerebral inflammatory phenotype and 9-month survival in adults with TBM from Vietnam, multiple pro-inflammatory and anti-inflammatory CSF cytokines were significantly reduced in HIV uninfected individuals who died vs in HIV uninfected who survived[14]. In a HIV-positive subgroup (n=98) from a randomized trial of adjunctive corticosteroids for TBM in Vietnamese adults, dexamethasone was associated with a non-significant trend towards improved survival[1]. A study of adults with HIV-associated TBM showed global increase in pro-inflammatory cytokine concentrations, running counter to theory that immunosuppressed HIV co-infected individuals have lower intracerebral inflammation[14]. While thrombosis might be common in the context of vasculitis, autopsies on TBM patients failed to demonstrate
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