Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis.
Nguyen Thuy Thuong Thuong,Dorothee Heemskerk,Trinh T. B. Tram,Le Thi Phuong Thao,Lalita Ramakrishnan,Vu T. N. Ha,Nguyen Duc Bang,Tran Thi Hong Chau,Nguyen Phu Huong Lan,Maxine Caws,Maxine Caws,Sarah J. Dunstan,Nguyen Van Vinh Chau,Marcel Wolbers,Nguyen Thi Hoang Mai,Guy E. Thwaites +15 more
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TLDR
The genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from tuberculosis, is hypothesized to influence pretreatment inflammatory phenotype and survival from TBM.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.read more
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Angharad G Davis,Angharad G Davis,Angharad G Davis,Ursula K. Rohlwink,Alize Proust,Anthony Figaji,Robert J. Wilkinson +6 more
TL;DR: The steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host are reviewed and the immune response and the clinical manifestations arising are discussed.
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