Characterization of CSF tryptophan metabolites in South African children with tuberculous meningitis

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OBJECTIVES: Tuberculous meningitis (TBM), a severe form of tuberculosis, remains difficult to diagnose and is fatal if left untreated. Children are particularly vulnerable to the disease due to their immature immune systems. Often, diagnosis is delayed by nonspecific symptoms, leading to a more advanced stage of disease at presentation. Tryptophan metabolism has been linked to disease severity in adult TBM; however, its role in children remains largely unexplored. This study investigates cerebrospinal fluid (CSF) tryptophan metabolism, both the serotonin and kynurenine pathways, in paediatric TBM. METHODS: We used liquid chromatography-tandem mass spectrometry to measure tryptophan and the metabolites of the tryptophan-kynurenine/serotonin pathways in a total of 130 CSF samples - TBM (n = 51), non-meningitis controls (NMC; n = 49) and viral meningitis (VM; n = 30). We further correlated the metabolites with CSF and magnetic resonance imaging (MRI) parameters. RESULTS: CSF tryptophan levels were reduced in both TBM and VM compared to NMC, and the differences were statistically significant (NMC vs TBM, P < 0.001; NMC vs VM, P < 0.001). However, TBM and VM showed no significant differences (TBM vs VM, P > 0.05). Furthermore, tryptophan showed a moderate negative correlation with CSF lymphocyte count (r = -0.5). Quinolinic acid was the most elevated metabolite in TBM, distinguishing it from VM and NMC, with areas under the curve (AUCs) of 0.736 (95% confidence interval [CI]: 0.617-0.844) and 0.804 (95% CI: 0.716-0.887), respectively. Quinolinic acid also correlated positively with both basal enhancement (r = 0.51) and hydrocephalus (r = 0.58). CONCLUSION: CSF tryptophan depletion occurs in both TBM and VM, reflecting the activation of indoleamine-2,3-dioxygenase as a common immune response, and is therefore not disease-specific. However, elevated downstream kynurenine metabolites indicate greater pathway activation in TBM. Quinolinic acid could serve as a potential marker for TBM; its correlation with basal enhancement and hydrocephalus, key features of TBM, further suggests its specificity to TBM.

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