Abstract
BackgroundThe 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.MethodsWe 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).ResultsPC 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.ConclusionsIncreased CSF PC ae C44:6 concentrations in bacterial meningitis likely reflect ongoing CNS cell membrane stress or damage and have potential as additional, sensitive biomarker to diagnose bacterial meningitis in patients with less pronounced neuroinflammation.
Highlights
Initiating antibiotic treatment as early as possible is important to optimize clinical outcome of bacterial meningitis [1, 2]
We have recently shown that major changes in cerebrospinal fluid (CSF) metabolite populations occur in viral central nervous system (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]
Elevated PC ae C44:6 concentrations in CSF from patients with bacterial meningitis Within the entire data set comprising 188 analytes, we searched for analytes whose measured concentrations were > limit of detection (LOD) preferentially in bacterial meningitis compared to the noninfected/noninflamed samples
Summary
Initiating antibiotic treatment as early as possible is important to optimize clinical outcome of bacterial meningitis [1, 2]. 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] These analyses 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 constitute biomarkers for this challenging/ life-threatening infectious disease. 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
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