Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone

Abstract

Adjunctive treatment with anti-inflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the pro-inflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased LTB4, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world’s population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pre-treatment levels of cerebrospinal fluid (CSF) pro-inflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including TNF. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pre-treatment CSF cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

“…For example, TT homozygotes, with increased expression of LTA4H, had the highest survival benefit when treated with dexamethasone in a Vietnamese cohort, although this was not observed in an Indonesian cohort (37). Indeed, steroids may only confer a modest survival benefit in studies, likely secondary to the absence of the T allele in the vast majority of people worldwide (37). Conversely, dexamethasone is associated with a number of adverse events (38,39) and has drug-drug interaction with rifampin (40).…”

“…leukotriene A4 hydrolase expression (LTA4H), tryptophan metabolism (36)] may affect mortality in patients with TB meningitis. For example, TT homozygotes, with increased expression of LTA4H, had the highest survival benefit when treated with dexamethasone in a Vietnamese cohort, although this was not observed in an Indonesian cohort (37). Indeed, steroids may only confer a modest survival benefit in studies, likely secondary to the absence of the T allele in the vast majority of people worldwide (37).…”

“…Dexamethasone is included in the standard of care for the treatment of patients with TB meningitis (36,37). However, the benefit of steroids in HIV-positive patients with TB meningitis remains unclear.…”

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

“…The use of unbiased genetic screens and candidate gene approaches in zebrafish larvae has shed light on granuloma biology (Ramakrishnan, 2013). Hypersusceptible zebrafish mutants displaying accelerated granuloma necrosis have identified innate immune host determinants that protect against necrosis and that are relevant to human TB Clay et al, 2008;Pagan et al, 2015;Roca and Ramakrishnan, 2013;Roca et al, 2022;Roca et al, 2019;Tobin et al, 2012;Tobin et al, 2010;Whitworth et al, 2021a;Whitworth et al, 2021b).…”

MUC5AC genetic variation is associated with tuberculosis meningitis CSF cytokine responses and mortality

“…Variants that influence functional responses in tissues of interest represent attractive secondary traits that can be correlated with TB susceptibility, and these correlations may provide insight into genetic mechanisms of disease susceptibility (25)(28). Because CSF TNF concentrations have been linked with TBM outcomes and pathogenesis (23, 29), we evaluated variants in the mucin gene region for association with TNF and other CSF cytokines, followed by evaluation of candidate susceptibility SNPs with tuberculosis outcomes, including pulmonary TB and TBM susceptibility, morbidity, and mortality.…”