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.

Keywords: Leukotriene A4 hydrolase genotype; cytokines; inflammatory response; survival.; tuberculous meningitis.

Figure 1.

Kaplan–Meier survival curves stratified by LTA4H genotype. Survival in all patients with tuberculous meningitis (A), those without human immunodeficiency virus (HIV) infection (B), and those with HIV infection (C). In HIV-uninfected patients, case-fatality rates were 7.1% (3 of 42) in those with genotype TT, 21.4% (40 of 187) in those with genotype CT, and 18.7% (39 of 209) in those with genotype CC. In HIV-infected patients, case-fatality rates were 34.8% (16 of 46) in those with genotype TT, 42.1% (61 of 145) in those with genotype CT, and 38.8% (52 of 134) in those with genotype CC. Overall likelihood ratio test for an effect of LTA4H genotype on survival revealed P values of .24 for all patients, .05 for HIV-uninfected patients (P = .08 for the effect of TT vs CT, and P = .04 for the effect of TT vs CC), and .87 for HIV-infected patients.

Figure 2.

Cerebrospinal fluid (CSF) levels of cytokine expression, by LTA4H genotype, in human immunodeficiency virus (HIV)–uninfected (A) and HIV-infected (B) patients with tuberculous meningitis. Concentrations are in picograms/milliliter for all cytokines except interleukin 6 (IL-6), for which concentrations are in nanograms/milliliter. A, Data are for 147 patients with LTA4H genotype CC, 141 with genotype CT, and 16 with genotype TT. B, Data are for 104 patients with LTA4H genotype CC, 87 with genotype CT, and 28 with genotype TT. Statistical comparisons were made using a linear trend test corrected for multiple testing across the 10 cytokines. Only P values of ≤ .05 are shown. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.

Figure 3.

Cerebrospinal fluid (CSF) levels of cytokine expression, by patients outcome, in human immunodeficiency virus (HIV)–uninfected (A) and HIV-infected (B) patients with tuberculous meningitis. Concentrations are in picograms/milliliter for all cytokines except interleukin 6 (IL-6), for which concentrations are in nanograms/milliliter. A, Data are for 248 patients with an outcome of survival (S) and 56 with an outcome of death (D). B, Data are for 133 patients with an outcome of S and 86 with an outcome of D. Statistical comparisons were based on Cox regression models of the univariable effect of (log-transformed) CSF cytokines expression levels on 9-month survival corrected for multiple testing across the 10 cytokines. Only P values of ≤ .05 are shown. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.

Figure 4.

Cerebrospinal fluid (CSF) levels of cytokine expression, by modified British Medical Research Council (BMRC) grade 1, grade 2, and grade 3 disease severity, in human immunodeficiency virus (HIV)–uninfected (A) and HIV-infected (B) patients with tuberculous meningitis. Concentrations are in picograms/milliliter for all cytokines except interleukin 6 (IL-6), for which concentrations are in nanograms/milliliter. A, Data are for 108 patients with BMRC grade 1 disease severity, 141 with grade 2, and 55 with grade 3. B, Data are for 98 patients with BMRC grade 1 disease severity, 79 with grade 2, and 42 with grade 3. Statistical comparisons were made using a linear trend test corrected for multiple testing across the 10 cytokines. Only P values of ≤ .05 are shown. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.

Figure 5.

Cerebrospinal fluid (CSF) levels of cytokine expression in human immunodeficiency virus (HIV)–infected (I) and HIV-uninfected (UI) patients with tuberculous meningitis. Concentrations are in picograms/milliliter for all cytokines except interleukin 6 (IL-6), for which concentrations are in nanograms/milliliter. Statistical comparisons between HIV-infected and HIV-uninfected were made by the Mann–Whitney test corrected for multiple testing across the 10 cytokines. Only P values of ≤ .05 are shown. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.