Arjan van Laarhoven1, Sofiati Dian2, Raúl Aguirre-Gamboa3, Julian Avila-Pacheco4, Isis Ricaño-Ponce3, Carolien Ruesen5, Jessi Annisa6, Valerie A C M Koeken5, Lidya Chaidir1, Yang Li3, Tri Hanggono Achmad7, Leo A B Joosten5, Richard A Notebaart8, Rovina Ruslami9, Mihai G Netea10, Marcel M Verbeek11, Bachti Alisjahbana6, Vinod Kumar3, Clary B Clish4, A Rizal Ganiem12, Reinout van Crevel13. 1. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands; TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. 2. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands; TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; Department of Neurology, Faculty of Medicine, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, Indonesia. 3. Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands. 4. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. 5. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. 6. TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. 7. TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; Department of Biochemistry, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. 8. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands; Laboratory of Food Microbiology, Wageningen University and Research, Wageningen, Netherlands. 9. TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. 10. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands; Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania. 11. Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, Netherlands. 12. TB-HIV Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; Department of Neurology, Faculty of Medicine, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, Indonesia. 13. Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. Electronic address: reinout.vancrevel@radboudumc.nl.
Abstract
BACKGROUND: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality. METHODS: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we 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. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients. FINDINGS: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association 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). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0·00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083). INTERPRETATION: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis. FUNDING: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health.
BACKGROUND: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality. METHODS: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we 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. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients. FINDINGS: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association 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). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0·00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083). INTERPRETATION: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis. FUNDING: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health.
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