Thuong Nguyen T T, Heemskerk Dorothee, Tram Trinh T B, Thao Le T P, Ramakrishnan Lalita, Ha Vu T N, Bang Nguyen D, Chau Tran T H, Lan Nguyen H, Caws Maxine, Dunstan Sarah J, Chau Nguyen V V, Wolbers Marcel, Mai Nguyen T H, Thwaites Guy E
Oxford University Clinical Research Unit.
Nuffield Department of Medicine, University of Oxford.
J Infect Dis. 2017 Apr 1;215(7):1020-1028. doi: 10.1093/infdis/jix050.
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.
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.
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.
LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.
结核性脑膜炎（TBM）是最具破坏性的结核病形式，但对其病理生理学知之甚少。我们推测，决定炎症类花生酸表达的白三烯A4水解酶（由LTA4H编码）的基因型会影响脑内炎症，并预测TBM患者的生存情况。
我们对764例成年TBM患者的治疗前临床和脑内炎症表型以及9个月生存率进行了特征分析。所有患者均进行了单核苷酸多态性rs17525495基因分型，炎症表型由脑脊液（CSF）白细胞和细胞因子浓度定义。
根据Cox回归分析，LTA4H基因型可预测未感染人类免疫缺陷病毒（HIV）患者的生存情况，TT基因型患者比CC基因型患者更有可能从TBM中存活下来（单变量P = 0.040，多变量P = 0.037）。未感染HIV的TT基因型患者脑脊液促炎细胞因子浓度较高，CT和CC基因型患者的浓度则处于中等和较低水平。脑脊液细胞因子浓度升高与病情加重相关，但脑脊液白细胞和细胞因子浓度低的患者死于TBM的可能性更大。HIV感染独立预测TBM导致的死亡（风险比，3.94；95%置信区间，2.79 - 5.56），且与脑脊液细胞因子浓度整体升高相关，与LTA4H基因型无关。
LTA4H基因型和HIV感染会影响TBM患者治疗前的炎症表型和生存情况。LTA4H基因型可能预测未感染HIV个体对辅助性皮质类固醇的反应性。
