A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.
Whitworth L., Coxon J., van Laarhoven A., Thuong NTT., Dian S., Alisjahbana B., Ganiem AR., van Crevel R., Thwaites GE., Troll M., Edelstein PH., Sewell R., Ramakrishnan L.
Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A<sub>4</sub> hydrolase (<i>LTA4H</i>) gene encoding an enzyme that regulates inflammatory eicosanoids. <i>LTA4H</i> TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an <i>LTA4H</i> TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that <i>LTA4H</i> TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. <i>LTA4H</i> genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.