Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis

Abstract

Background.Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM.Methods.We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations.Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)–uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79–5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype.Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

The pathogenesis of tuberculous meningitis

“…It was also demonstrated that (i) genotype correlated with pretreatment CSF leukocytosis and survival and (ii) those benefiting from adjunctive dexamethasone were carriers of the “hyperinflammatory” TT genotype . Several follow‐up studies to further investigate the relevance of this finding have tended to reproduce an association with susceptibility to disease, but not necessarily outcome . The two largest of these both published in 2017 investigated the association in Vietnamese and Indonesian populations.…”

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe

“…2). Follow-up studies of tuberculous meningitis patients in Vietnam [74] and Indonesia [75], with all patients receiving adjunctive dexamethasone, have yielded conflicting results regarding the impact of LTA4H promoter mutations on tuberculous meningitis outcomes, and more work remains to untangle these relationships. Yet it is becoming clear that both the susceptibility to tuberculosis and the outcomes of treatment are dependent on an appropriate immune response that is neither ineffectually weak nor inappropriately robust.…”

Human Genomics of Mycobacterium tuberculosis Infection and Disease

“…In such an event, treatment of TBM patients would need to be personalized based on their LTA4H genotype. This question was addressed in two recent large studies in Vietnam and Indonesia with inconsistent results (58, 59). A possible reconciliation of the divergent observation regarding the role of the LTA4H genotype on survival may be that the impact of the LTA4H gene is most noticeable in a subset of TBM patients (60).…”