Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone

Abstract

Significance Despite appropriate antibiotic treatment, tuberculous meningitis carries a high mortality ascribed to overexuberant inflammation. Genetic variations in the enzyme, LTA4H, alter inflammation, with individuals carrying the inflammation-associated LTA4H variant benefitting from antiinflammatory steroids administered alongside antibiotics. A prior study found poor correlation between LTA4H genotype and cerebrospinal fluid levels of cytokines, key mediators of inflammation. The study used “frequentist” statistical methods that can fail to detect true differences. Using Bayesian statistics, which can detect significant differences not found by frequentist methods, we found good correlation between LTA4H genotype and cytokine levels, and cytokine levels and outcome even independent of LTA4H genotype. These findings suggest that LTA4H and additional inflammation factors affect outcome and suggest tailoring steroid therapy to cytokine levels. Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world’s population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.