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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.

Original publication

DOI

10.7554/elife.61722

Type

Journal article

Journal

eLife

Publication Date

08/01/2021

Volume

10

Addresses

Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.