Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections

Novoselova, Natalia; Kuhn, Maike; Seegers, Lena Marie; Kaever, Volkhard; Müller‐Vahl, Kirsten; Trebst, Corinna; Skripuletz, Thomas; Stangel, Martin; Peßler, Frank

doi:10.1093/infdis/jiz048

Cited by 44 publications

(47 citation statements)

References 20 publications

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“…This analysis revealed two analytes, PC ae C44:6 and kynurenine (P < 0.005, Fisher's exact test). Subsequent detailed analysis of kynurenine identified it as a biomarker for both bacterial and viral CNS infections [4]. As shown in Fig.…”

Section: Elevated Pc Ae C44:6 Concentrations In Csf From Patients Witmentioning

confidence: 98%

“…2413-2014). Recruitment of patients, processing of CSF and sociodemographic and standard laboratory diagnostic data of the diagnostic groups are also described in [4,7,8]. Briefly, CSF was obtained during clinically indicated lumbar puncture and processed within 2 h. The following standard diagnostic CSF parameters were analyzed directly after lumbar puncture: leukocyte count (counted manually with a Fuchs-Rosenthal counting chamber), protein concentration (Bradford dye-binding assay), lactate concentration (photometric assay), Q-albumin ratio (albumin concentration in CSF/albumin concentration in serum), IgG-index (IgG concentration in CSF/ IgG concentration in serum divided by Q-albumin ratio; age-adjusted reference limit = 4 + (age/15).…”

Section: Study Population and Biosamplesmentioning

confidence: 99%

“…Details of the measurement procedure are described in [7]. Other aspects of the resulting data set, which do not include PC ae C44:6, have been published separately [4,7,8]. References [7,8] feature comprehensive analyses of the data set, but PC ae C44:6 was excluded from those analyses due to the high frequency of concentrations below limit of detection (LOD) in the samples other than bacterial meningitis.…”

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

“…In addition, the inability to tease out the isomers making up PC ae C44:6 limits the biological interpretation of our results. On the other hand, clear strengths of the study are the availability of detailed clinical data, case definitions according to standard criteria, processing of CSF samples by the treating clinicians within a narrow time window and according to unified protocols [4], and the use of a broadly validated robust mass-spectrometric measuring system [18].…”

Section: Limitations and Strengths Of This Studymentioning

confidence: 99%

“…Emerging evidence suggests that measuring concentrations of small molecules in CSF can help to identify CSF biomarkers for various aspects of central nervous system (CNS) infections such as differentiating between infectious and autoimmune etiologies [4], assessing CNS complications of chronic infections [5,6], or detecting CNS extension of infections with a presumed primary site outside of the CNS [7]. We have recently shown that major changes in CSF metabolite populations occur in viral CNS infections [4,7,8] and that certain membrane phospholipids, when measured in cell-free CSF, constitute highly accurate CSF biomarkers for meningoencephalitis during varicella zoster virus (VZV) reactivation [7] and for a diagnosis of enterovirus meningitis even in patients with normal CSF cell counts [8]. However, these analyses also showed that in virally infected, autoimmune, or non-inflamed samples many metabolites including phospholipids were present in only low concentrations, raising the hypothesis that some of them may be selectively more abundant in CSF from bacterial meningitis and may therefore constitute biomarkers for this challenging/ life-threatening infectious disease.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

et al. 2020

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Background: The timely diagnosis of bacterial meningitis is of utmost importance due to the need to institute antibiotic treatment as early as possible. Moreover, the differentiation from other causes of meningitis/encephalitis is critical because of differences in management such as the need for antiviral or immunosuppressive treatments. Considering our previously reported association between free membrane phospholipids in cerebrospinal fluid (CSF) and CNS involvement in neuroinfections we evaluated phosphatidylcholine PC ae C44:6, an integral constituent of cell membranes, as diagnostic biomarker for bacterial meningitis. Methods:We used tandem mass spectrometry to measure concentrations of PC ae C44:6 in cell-free CSF samples (n = 221) from patients with acute bacterial meningitis, neuroborreliosis, viral meningitis/encephalitis (herpes simplex virus, varicella zoster virus, enteroviruses), autoimmune neuroinflammation (anti-NMDA-receptor autoimmune encephalitis, multiple sclerosis), facial nerve and segmental herpes zoster (shingles), and noninflammatory CNS disorders (Bell's palsy, Tourette syndrome, normal pressure hydrocephalus).Results: PC ae C44:6 concentrations were significantly higher in bacterial meningitis than in all other diagnostic groups, and were higher in patients with a classic bacterial meningitis pathogen (e.g. Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus) than in those with less virulent or opportunistic pathogens as causative agents (P = 0.026). PC ae C44:6 concentrations were only moderately associated with CSF cell count (Spearman's ρ = 0.45; P = 0.009), indicating that they do not merely reflect neuroinflammation. In receiver operating characteristic curve analysis, PC ae C44:6 equaled CSF cell count in the ability to distinguish bacterial meningitis from viral meningitis/encephalitis and autoimmune CNS disorders (AUC 0.93 both), but had higher sensitivity (91% vs. 41%) and negative predictive value (98% vs. 89%). A diagnostic algorithm comprising cell count, lactate and PC ae C44:6 had a sensitivity of 97% (specificity 87%) and negative predictive value of 99% (positive predictive value 61%) and correctly diagnosed three of four bacterial meningitis samples that were misclassified by cell count and lactate due to low values not suggestive of bacterial meningitis. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

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Section: Elevated Pc Ae C44:6 Concentrations In Csf From Patients Witmentioning

confidence: 98%

Section: Study Population and Biosamplesmentioning

confidence: 99%

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

Section: Limitations and Strengths Of This Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

et al. 2020

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Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway

Luo

Möhn

Skripuletz

et al. 2021

Ann Clin Transl Neurol

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Objective: To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE). Methods: This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA. Results: Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups. Interpretation: The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

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Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease

et al. 2021

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The high morbidity and mortality of neuroinflammatory diseases drives significant interest in understanding the underlying mechanisms involved in the innate and adaptive immune response of the central nervous system (CNS). Diagnostic biomarkers are important to define treatable neuroinflammation. Metabolomics is a rapidly evolving research area offering novel insights into metabolic pathways, and elucidation of reliable metabolites as biomarkers for diseases. This review focuses on the emerging literature regarding the detection of neuroinflammation using cerebrospinal fluid (CSF) metabolomics in human cohort studies. Studies of classic neuroinflammatory disorders such as encephalitis, CNS infection and multiple sclerosis confirm the utility of CSF metabolomics. Additionally, studies in neurodegeneration and neuropsychiatry support the emerging potential of CSF metabolomics to detect neuroinflammation in common CNS diseases such as Alzheimer's disease and depression. We demonstrate metabolites in the tryptophan–kynurenine pathway, nitric oxide pathway, neopterin and major lipid species show moderately consistent ability to differentiate patients with neuroinflammation from controls. Integration of CSF metabolomics into clinical practice is warranted to improve recognition and treatment of neuroinflammation.

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Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections

Cited by 44 publications

References 20 publications

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway

Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease

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