Tryptophan is metabolized mainly through the kynurenine pathway through indoleamine 2,3-dioxygenase 1 (IDO1), generating kynurenine and its downstream metabolites (blue box). IDO1 is partly …
Patients were stratified by cerebrospinal fluid (CSF) tryptophan concentrations tertiles.
Distributions of leukocytes, polymorphonuclear cells, mononuclear cells, protein, and the ratio of CSF/blood glucose in Indonesian (purple) and Vietnamese (yellow) patients are depicted by violin …
The concentrations of tryptophan metabolites (in log2 scale) were measured in cerebrospinal fluid (CSF) samples from Indonesian (purple) and Vietnamese (yellow) tuberculous meningitis (TBM) patients …
Patients were stratified by tertiles based on cerebrospinal fluid (CSF) tryptophan concentrations (red = high tryptophan, gray = intermediate tryptophan, blue = low tryptophan).
Holm-adjusted Wilcoxon rank-sum test p-values are presented :*p<0.05, **p<0.01.
(A) Comparing CSF culture-negative versus -positive patients and (B) among patients with a positive CSF Xpert, in culture-positive and -negative tuberculous meningitis (TBM) patients, CSF tryptophan …
(A) Relative concentrations based on peak ion intensity and (B) absolute concentrations in μM. Boxplots are shown with Holm-adjusted Wilcoxon rank-sum test p-values are presented: (*p<0.05, **p<0.01,…
Relative concentrations based on peak ion intensities are shown. CSF and plasma concentrations are not directly comparable. Boxplots are shown with Holm-adjusted Wilcoxon rank-sum test p-values are …
Significant Spearman’s correlation coefficients are presented in the correlation matrix, while the ones with not significant correlations were blank. Red indicates positive correlations, and blue …
Of note, 71 patients had undetectable plasma levels of 3-indolacetic acid and were removed from this graph.
The boxplots on the left of each plot show the association of metabolites with cytokines below the detection limit. Abbreviations: IFN-γ: interferon gamma, TNF-α: tumor necrosis factor alpha, LOD: …
Inflammatory markers were clustered based on their correlation coefficients using hierarchical clustering. Red indicates positive correlation, and blue indicated negative correlation.
Tuberculous meningitis | Non-infectious control | Bacterial meningitis* | Cryptococcal meningitis* | |
---|---|---|---|---|
(n = 1069) | (n = 54) | (n = 50) | (n = 60) | |
Clinical features | ||||
Age, years | 34 (27–44) | 35 (25–44) | 46 (34–57) | 33 (27–37) |
Sex, % male | 700 (65.5%) | 30 (55.6%) | 12 (60.0%) | 26 (78.8%) |
Glasgow Coma Scale | 14 (12–15) | 15 (12–15) | 13 (9–14) | 15 (13–15) |
HIV, % positive | 284 (26.6%) | 11 (20.4%) | 0 (0%) | 60 (100%) |
Tuberculous meningitis grade (%) | ||||
Grade I | 287 (27.3%) | - | - | - |
Grade II | 584 (55.6%) | - | - | - |
Grade III | 179 (17.0%) | - | - | - |
Cerebrospinal fluid features | ||||
Leukocytes, cells/μl | 150 (49–336) | 2 (1–3) | 1900 (739–5460) | 86 (24–192) |
Neutrophils, cells/μl | 22 (3–99) | 1 (0–1) | 1527 (538–4986) | 17 (6–109) |
Mononuclear cells, cells/μl | 98 (38–207) | 2 (1–3) | 307 (134–646) | 31 (6–89) |
Protein, g/l | 1.46 (0.90–2.40) | 0.40 (0.26–0.59) | 1.90 (1.10–3.80) | 0.76 (0.58–1.60) |
CSF to blood glucose ratio | 0.28 (0.17–0.40) | 0.60 (0.56–0.70) | 0.46 (0.17–1.00) | 0.50 (0.30–1.00) |
M. tuberculosis culture or ZN staining or GeneXpert positive | 686 (64.17%) | - | - | - |
Outcomes | ||||
Outcome at day 60 | ||||
Alive | 825 (77.2%) | - | - | - |
Deceased | 231 (21.6%) | - | - | - |
Lost to follow-up | 13 (1.2%) | - | - | - |
Outcome at day 180 | ||||
Alive | 731 (68.4%) | - | - | - |
Deceased | 304 (28.4%) | - | - | - |
Lost to follow-up | 34 (3.2%) | - | - | - |
Categorical variables are presented in N (%); continuous variables are presented in median (IQR). Abbreviation: CSF = cerebrospinal fluid.
Clinical metadata available for 40% of bacterial meningitis and 56% of cryptococcal meningitis patients.
Metabolites | HR* | 95% CI* | p-value | FDR† |
---|---|---|---|---|
Tryptophan | 1.16 | 1.10, 1.24 | <0.001 | <0.001 |
Kynurenine | 1.00 | 0.93, 1.07 | >0.9 | >0.9 |
Kynurenic acid | 1.00 | 0.93, 1.07 | 0.9 | >0.9 |
3-Hydroxyanthranilic acid | 1.01 | 0.97, 1.05 | 0.6 | 0.9 |
Xanthurenic acid | 0.95 | 0.90, 1.00 | 0.05 | 0.2 |
Quinolinic acid | 0.92 | 0.85, 1.00 | 0.038 | 0.2 |
Niacinamide | 1.03 | 0.95, 1.11 | 0.5 | 0.8 |
3-Indoleacetic acid | 1.11 | 0.96, 1.29 | 0.2 | 0.4 |
N-Acetylserotonin | 1.01 | 0.94, 1.09 | 0.7 | 0.9 |
5-Methoxytryptophol | 1.11 | 0.93, 1.32 | 0.3 | 0.5 |
Baseline cerebrospinal fluid (CSF) metabolites were measured in 1069 TBM patients. Cox regression models were stratified by cohort and adjusted by sex, age, and HIV status. Hazard ratio (HR) was calculated per twofold increase in metabolite concentration. Bold: False Discovery Rate (FDR) < 0.05.
HR = hazard ratio, CI = confidence interval.
FDR = false discovery rate; Benjamini and Hochberg correction for multiple testing.
Metabolite | Early mortality (days 0–14) | Late mortality (days 14–180) | ||||||
---|---|---|---|---|---|---|---|---|
HR* | 95% CI* | p-value | FDR† | HR* | 95% CI* | p-value | FDR† | |
Tryptophan | 1.14 | 1.06, 1.23 | <0.001 | 0.005 | 1.17 | 1.08, 1.26 | <0.001 | <0.001 |
Kynurenine | 1.03 | 0.95, 1.13 | 0.4 | 0.6 | 1 | 0.91, 1.10 | >0.9 | >0.9 |
Kynurenic acid | 1.05 | 0.96, 1.14 | 0.3 | 0.5 | 0.95 | 0.86, 1.04 | 0.3 | 0.5 |
3-Hydroxyanthranilic acid | 1.02 | 0.97, 1.06 | 0.5 | 0.6 | 1.01 | 0.96, 1.06 | 0.6 | 0.7 |
Xanthurenic acid | 0.96 | 0.90, 1.03 | 0.2 | 0.5 | 0.96 | 0.89, 1.04 | 0.3 | 0.5 |
Quinolinic acid | 0.89 | 0.81, 0.98 | 0.02 | 0.1 | 0.9 | 0.81, 1.00 | 0.052 | 0.2 |
Niacinamide | 1.02 | 0.92, 1.12 | 0.7 | 0.7 | 1.05 | 0.95, 1.16 | 0.3 | 0.5 |
3-Indoleacetic acid | 1.1 | 0.92, 1.32 | 0.3 | 0.5 | 1.18 | 0.97, 1.43 | 0.093 | 0.2 |
N-Acetylserotonin | 1.05 | 0.96, 1.14 | 0.3 | 0.5 | 0.96 | 0.88, 1.06 | 0.4 | 0.5 |
5-Methoxytryptophol | 1.09 | 0.87, 1.35 | 0.5 | 0.6 | 1.29 | 1.04, 1.59 | 0.02 | 0.1 |
Baseline cerebrospinal fluid (CSF) metabolites were measured in 1069 TBM patients. Cox regression models were stratified by sites and adjusted by age, sex, and GCS. Bold: False Discovery Rate (FDR) < 0.05.
HR = hazard ratio, CI = confidence interval.
Benjamini and Hochberg correction for multiple testing.
Metabolite | HR* | 95% CI* | p-value | FDR† |
---|---|---|---|---|
Tryptophan | 0.8 | 0.56, 1.16 | 0.2 | 0.4 |
Kynurenine | 1.54 | 1.22, 1.93 | <0.001 | 0.002 |
Kynurenic acid | 1.2 | 1.01, 1.43 | 0.036 | 0.2 |
3-Hydroxyanthranilic acid | 1.13 | 1.00, 1.28 | 0.045 | 0.2 |
Xanthurenic acid | 1.11 | 0.98, 1.25 | 0.1 | 0.3 |
Quinolinic acid | 0.99 | 0.88, 1.12 | 0.9 | 0.9 |
Niacinamide | 0.92 | 0.79, 1.07 | 0.3 | 0.4 |
3-Indoleacetic acid | 1.04 | 0.97, 1.12 | 0.3 | 0.4 |
N-Acetylserotonin | 1.05 | 0.91, 1.22 | 0.5 | 0.6 |
5-Methoxytryptophol | 1.04 | 0.85, 1.28 | 0.7 | 0.8 |
Baseline plasma tryptophan metabolites were measured in a subset 300 patients. Cox regression models were stratified by sites and adjusted by age, sex, and GCS. Bold: False Discovery Rate (FDR) < 0.05.
HR = hazard ratio, CI = confidence interval.
Benjamini and Hochberg correction for multiple testing.
The source data includes clinical metadata and LC-MS data before pre-processing.