Laarhoven AV, et al. - Researchers compared the cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis vs those without, and evaluated the connection between metabolite concentrations and mortality. For the outcome of tuberculous meningitis, cerebral tryptophan metabolism, which is known to impact the growth of Mycobacterium tuberculosis and CNS inflammation, was important. In tuberculous meningitis, CSF tryptophan concentrations were under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. The outcomes of tuberculous meningitis could be improved by interventions targeting tryptophan metabolism.

Methods

• Experts measured 425 metabolites using liquid chromatography-mass spectrometry in CSF and serum from 33 HIV-negative Indonesian patients with confirmed or probable tuberculous meningitis and 22 control participants with complete clinical data between March 12, 2009, and Oct 27, 2013 in this observational cohort study at the Hasan Sadikin Hospital.
• Metabolite concentrations association with survival were validated in a second cohort of 101 patients from the same center.
• To identify tryptophan quantitative trait loci, genome-wide single nucleotide polymorphism typing was used, which were used for survival analysis in a third cohort of 285 patients.

Results

• Compared to controls, concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis, particularly in those who died during follow-up.
• Between patients with tuberculous meningitis and controls, only 5 (1%) of the 390 metobolites detected in serum differed.
• CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; compared with patients who died (9 times) and to controls (31 times), concentrations were lower in patients who survived.
• The relationship of low CSF tryptophan with patient survival was confirmed in the validation cohort (hazard ratio 0·73; 95% CI 0·64–0·83; p < 0·0001; per each halving).
• They identified 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis (p < 0·00001).
• Survival was predicted by these quantitative trait loci in the third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083).