Ability of Procalcitonin and C-Reactive Protein for Discriminating between Bacterial and Enteroviral Meningitis in Children Using Decision Tree.

Bacterial meningitis (BM) is a public health burden in developing countries, including Central Asia. This disease is characterized by a high mortality rate and serious neurological complications. Delay with the start of adequate therapy is associated with an increase in mortality for patients with acute bacterial meningitis. Cerebrospinal fluid culture, as a gold standard in bacterial meningitis diagnosis, is time-consuming with modest sensitivity, and this is unsuitable for timely decision-making. It has been shown that bacterial meningitis differentiation from viral meningitis could be done through different parameters such as clinical signs and symptoms, laboratory values, such as PCR, including blood and cerebrospinal fluid (CSF) analysis. In this study, we proposed the method for distinguishing the bacterial form of meningitis from enteroviral one. The method is based on the machine learning process deriving making decision rules. The proposed fast-and-frugal trees (FFTree) decision tree approach showed an ability to determine procalcitonin and C-reactive protein (CRP) with cut-off values for distinguishing between bacterial and enteroviral meningitis (EVM) in children. Such a method demonstrated 100% sensitivity, 96% specificity, and 98% accuracy in the differentiation of all cases of bacterial meningitis in this study. These findings and proposed method may be useful for clinicians to facilitate the decision-making process and optimize the diagnostics of meningitis.

A study on correlations of procalcitonin and interleukin-6 with viral meningitis.

OBJECTIVE: To study the change rules of inflammatory factors in cerebrospinal fluid (CSF) and serum of patients with viral meningitis. PATIENTS AND METHODS: 742 patients with suspected viral meningitis admitted to Department of Neurosurgery in our hospital from August 2012 to May 2016 were selected as research objects and retrospectively analyzed. 536 patients were diagnosed with viral meningitis by CSF with the lumbar puncture and brain computed tomography (CT), while the other 206 patients were diagnosed with non-infectious nervous system disease, as the control group. The levels of inflammatory factors interleukin-6 (IL-6) in peripheral blood and procalcitonin (PCT) in cerebrospinal fluid were detected and compared between two groups of patients. RESULTS: Compared with those in control group, the white blood cell (WBC) count, and levels of serum IL-6 and PCT in cerebrospinal fluid of patients with viral meningitis were all increased (p<0.01). PCT and IL-6 were positively correlated with viral meningitis (r=0.8267, 0.9234). The sensitivity of the two items was 77.81% and 81.32%, respectively, and the specificity was 90.53% and 88.64%, respectively. CONCLUSIONS: The levels of inflammatory factors IL-6 and PCT in serum and CSF of patients with viral meningitis are slightly increased. The detection of the expression levels of IL-6 and PCT in patients with viral meningitis is of great significance for the preliminary diagnosis and rehabilitation of viral meningitis.

CSF lactate for accurate diagnosis of community-acquired bacterial meningitis.

CSF lactate measurement is recommended when nosocomial meningitis is suspected, but its value in community-acquired bacterial meningitis is controversial. We evaluated the diagnostic performance of lactate and other CSF parameters in a prospective cohort of adult patients with acute meningitis. Diagnostic accuracy of lactate and other CSF parameters in patients with microbiologically documented episodes was assessed by receiver operating characteristic (ROC) curves. The cut-offs with the best diagnostic performance were determined. Forty-five of 61 patients (74%) had a documented bacterial (n = 18; S. pneumoniae, 11; N. meningitidis, 5; other, 2) or viral (n = 27 enterovirus, 21; VZV, 3; other, 3) etiology. CSF parameters were significantly different in bacterial vs. viral meningitis, respectively (p < 0.001 for all comparisons): white cell count (median 1333 vs. 143/mm(3)), proteins (median 4115 vs. 829 mg/l), CSF/blood glucose ratio (median 0.1 vs. 0.52), lactate (median 13 vs. 2.3 mmol/l). ROC curve analysis showed that CSF lactate had the highest accuracy for discriminating bacterial from viral meningitis, with a cutoff set at 3.5 mmol/l providing 100% sensitivity, specificity, PPV, NPV, and efficiency. CSF lactate had the best accuracy for discriminating bacterial from viral meningitis and should be included in the initial diagnostic workup of this condition.

Detection of Delta-like 1 ligand for the diagnosis of tuberculous meningitis: An effective and rapid diagnostic method.

OBJECTIVE: To investigate the diagnostic value of Delta-like 1 ligand (DLL1) in cerebrospinal fluid (CSF) and serum, in tuberculous meningitis (TBM). METHODS: Patients with a definite diagnosis of central nervous system infection (TBM, viral meningitis/encephalitis or bacterial meningitis) were prospectively enrolled alongside patients with intracranial metastatic tumour and patients with no diagnosis (who served as controls). DLL1 content in CSF and serum was measured quantitatively by enzyme-linked immunosorbent assay; analyses were blinded. RESULTS: A total of 173 patients were enrolled: 62 with TBM; 38 with viral meningitis/encephalitis; 26 with bacterial meningitis; 17 with intracranial metastatic tumour; 30 with no diagnosis. CSF DLL1 content was highest for TBM; there were no differences in CSF DLL1 between the other groups. Serum DLL1 content was highest for the TBM and intracranial metastatic tumour groups, with significant differences between the TBM group and the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups. There were no differences in serum DLL1 between the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups, or between the TBM group and the tumour group. CONCLUSION: As a new biomarker, DLL1 may be of great clinical importance in the diagnosis of TBM.

Pearls & Oy-sters: chronic mumps meningoencephalitis with low CSF glucose and acute hydrocephalus in an adult.

Chronic lymphocytic meningoencephalitis with low glucose and increased adenosine deaminase (ADA) levels in the CSF together with hydrocephalus represents a diagnostic challenge of varied etiology and only seldom is due to a viral (mumps) infection.

Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) presents as a severe autosomal recessively inherited neurological brain disease. Clinical and neurological manifestations closely resemble those of congenital viral infection and are generally attributed to a perturbation of innate immunity including a long lasting lymphocytosis and production of interferon-alpha (IFNalpha) in the central nervous system. To clarify the innate immune response evoked in these diseases, we used a 30-mer multiplexed luminex system to measure multiple cytokines and growth factors in the cerebrospinal fluid and serum of patients with AGS and viral meningitis or encephalitis, and febrile controls in whom infection could not be substantiated. In addition to the previously described IFNalpha, both AGS and viral diseases were characterized by expression of CXCL10 and CCL2. In contrast to AGS, viral infection resulted in high levels of IL-6 and CXCL8 in the CNS. Postmortem immunohistochemical staining of brain sections showed that in both AGS and viral CNS infection, astrocytes were responsible for the production of cytokines and not the infiltrating leukocytes. In summary, our data indicate that astrocytes are the predominant cell type responsible for the production of IFNalpha and CXCL10 in AGS. Whereas IFNalpha is assumed to be involved in the neurodegeneration, calcifications and seizures in AGS, CXCL10 may act as the chemoattractant responsible for the influx of activated lymphocytes into the brain. The lack of the inflammatory cytokines IL-6 and CXCL8 in AGS suggest that the neuroinflammatory reaction in this disease is distinct from viral disease.

[Expression of inflammatory mediators in meningitis].

BACKGROUND: Infectious diseases cause a systemic inflammatory reaction. In some cases of meningitis it is difficult to determine whether the disease is of bacterial, viral or non-infectious origin. In order to distinguish between bacterial and viral diseases the levels of various inflammatory markers are used to determine the severity of the disease and the clinical prognosis. OBJECTIVE: The purpose of this study was to determine whether the levels of different markers can be used to distinguish between bacterial or viral meningitis or non-infectious neurological disease. METHODS: Patients with bacterial meningitis (n= 8), viral meningitis (n= 17), non-infectious neurological diseases (n = 17) and healthy subjects (n = 15) were studied. The levels of soluble CD14 (sCD 14), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and soluble adhesion molecule-1 (sICAM-1) were determined in the blood of all participants and in spinal fluid only in patients who had clinical indication to perform lumbar puncture. RESULTS: All the patients showed significant differences in the levels of blood and CSF markers measured compared to healthy subjects. In the blood, although some differences were significant, there was overlapping between all values of the measured markers in patient blood samples excluding IL-6, for which levels were significantly different between the bacterial and viral meningitis. Interestingly, the levels of all markers showed significant differences among all groups of patients. CONCLUSIONS: Among the blood markers examined, IL-6 can be used to distinguish between bacterial and viral diseases. However, the levels of cytokines examined in CSF, can serve to distinguish between bacterial and viral meningitis and non-infectious diseases.

[Concentration of interleukin 6 and 10 in tick-borne and purulend encephalomeningitis]. / Stezenie interleukiny 6 i 10 w kleszczowym oraz ropnym zapaleniu mózgu i opon mózgowo-rdzeniowych.

UNLABELLED: The aim of the study was to evaluate concentrations of interleukin 6 (IL-6) and interleukin (IL-10) in serum and cerebrospinal fluid (csf) of patients with tick-borne encephalitis (tbe) and purulent meningitis before and after 4 weeks of treatment. MATERIAL AND METHODS: Group I consisted of 23 patients with tbe and group II - 16 patients with bacterial meningitis. Group III (control) consisted of 10 healthy men. RESULTS AND CONCLUSIONS: In patients with tbe and purulent meningitis concentrations of IL-6 and IL-10 in serum and csf were initially increased and tended to remain increased after 4 weeks of treatment. It suggests significant role of IL-6 and IL-10 in inflammatory process within cns. Higher concentrations of IL-6 than IL-10 in csf than in serum suggests their local synthesis within cns and tendency to the limitation of the inflammatory response to the intratecal compartment. Concentrations of both IL-6 and IL-10 in csf and serum remained sgnificantly higher in patints with purulent meningits than in tbe, both before and after treatment. This observation may be helpful in diagnosing the ethiology of meningitis and meningoencephalitis and monitoring the course of the disease.

Serum procalcitonin and cerebrospinal fluid cytokines level in children with meningitis.

AIMS: To determine the level of serum procalcitonin and cerebrospinal fluid cytokines in children with bacterial or viral meningitis and to document the use of these parameters in differential diagnosis. RESULTS: Before the start of antibiotic treatment, serum procalcitonin and tumor necrosis factor alpha levels were found to be higher in acute bacterial meningitis compared with viral meningitis and with the control group. Similarly, cerebrospinal fluid interleukin-6 levels were found to be significantly higher in children with acute bacterial meningitis compared with viral meningitis. However, no significant difference was determined between groups in respect to the cerebrospinal fluid interleukin-8 level. CONCLUSION: Serum procalcitonin and cerebrospinal fluid tumor necrosis factor alpha levels can be used in the early diagnosis of bacterial meningitis. Similarly, they may be useful adjuncts in differential diagnosis of bacterial and viral meningitis.

Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.

The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6-10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (-43%, P<0.001). Patients with advanced Alzheimer's disease and cerebral inflammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not significantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no significant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the flux of 24S-hydroxycholesterol from the brain.

[Rapid diagnosis of the type of meningitis (bacterial or viral) by the assay of serum procalcitonin]. / Diagnostic rapide du type de méningite (bactérienne ou virale) par le dosage de la procalcitonine sérique.

OBJECTIVE: It has been shown that serum procalcitonin (PCT) can be used to differentiate bacterial from viral meningitis in children in all cases. The aim of this study was to demonstrate the interest of PCT in the management of suspected meningitis in adults. PATIENTS AND METHODS: We conducted a prospective study including 179 consecutive patients admitted to the emergency department for suspected meningitis. All samples were taken at patient admission. The discriminant potential between bacterial and viral meningitis was studied for cerebrospinal fluid parameters (cytology, protein, glucose, lactate) and serum parameters (C reactive protein, PCT). RESULTS: Thirty-two patients had bacterial meningitis, 90 had viral meningitis and meningitis was ruled out in 57. Among all studied parameters, the most discriminant for distinguishing between bacterial and viral meningitis in 100% of the cases proved to be serum procalcitonin with a threshold value of 0.93 ng/ml. CONCLUSION: Serum procalcitonin is an interesting parameter in the emergency department for management of meningitis suspicion in adults.

[Procalcitonin, C-reactive protein and interleukin 6 in bacterial and viral meningitis in children]. / Procalcitonine, protéine C-réactive et interleukine 6 dans les méningites bactériennes et virales de l'enfant.

OBJECTIVES: In young children with meningitis, blood or cerebrospinal fluid (CSF) analysis cannot differentiate all cases of viral meningitis (VM) from bacterial meningitis (BM). Empirical antibiotic therapy is often given. As new markers are needed, we compared serum proCalcitonin (PCT) with CSF analysis for C-reactive protein (CRP) and interleukin-6 (IL6). PATIENTS AND METHODS: PCT was measured with a chemoluminescent assay in the sera of 23 children (aged 3 months to 14 years) hospitalized for BM and in 51 patients with VM. RESULTS: Initial CRP (mean 143.3 mg/l, range 28-351 and mean 13.9, range 1-48), CSF proteins (mean 2.2, range 0.4-4.74 and mean 0.57, range 0.12-2.72) and white blood cell count in CSF (range 240-17500 and 20-3200) in BM and VM respectively, were not sufficiently discriminative to distinguish between BM and VM. Twenty-four of the 51 patients with VM were given antibiotics. IL6 values at admission showed an overlap zone (> 100 pg/ml in 7/19 patients with VM and < 100 pg/ml in 1/8 patients with BM. PCT was discriminative in all cases: mean PCT in BM was 61 micrograms/l (range 4.8-335) and 0.33 in VM (range 0-1.7; p < 0.001). No production of PCT was detected in CSF. After antibiotic therapy, PCT decreased and reached undetectable levels after recovery. CONCLUSION: PCT is a sensitive and specific marker for early diagnosis of viral meningitis versus bacterial meningitis in children.

[Procalcitonin, a marker of bacterial meningitis in children]. / La procalcitonine, indicateur d'infection bactérienne dans les méningites de l'enfant.

Procalcitonin (PCT) is a new marker connected to systemic bacterial infection. Blood values are parallel to the severity of the disease. In the present Knowledge on PCT, the usefulness is focused on acute pediatric pathology, ICU, and the follow up of grafts and surgery. This paper dwells on the interest in the differential diagnosis for meningitis (viral versus bacterial). At the opposite of CRP and IL6, a very clear cut off for all the cases has been found. The cut off in this study is about 2-3 micrograms/l. PCT, at the difference of cytokines is a very stable molecule in the blood sample. Also a very small quantity of serum (or plasma) 20 microliters is sufficient for one assay. In the future, a point of care assay will be available and should be very interesting in the emergency wards (pediatric or adult ICU). The origin of PCT seems to be--but perhaps not exclusively--mononuclear cells. The absence of an animal model (except monkeys) is actually a difficulty to progress.

Levels of interleukin-6, CRP and alpha 2 macroglobulin in cerebrospinal fluid (CSF) and serum as indicator of blood-CSF barrier damage.

We measured the levels of interleukin-6 (IL-6), albumin, C-reactive protein (CRP) and alpha 2 macroglobulin (alpha 2M), all of which have different spectrums of molecular weight, in the cerebrospinal fluid (CSF) and serum in 121 patients to evaluate damage to the blood-cerebrospinal fluid barrier (BCB) in meningitis. There was an extraordinary high level of IL-6 in the CSF when patients had bacterial or viral meningitis, but the level returned to a normal range within a week in almost all of these cases. There were no significant differences in CSF albumin levels among the different disease groups. The CRP level in CSF is considered to correlate with the serum level, and CSF CRP was higher in bacterial meningitis than in viral meningitis, however, CRP in CSF was increased in some of the infectious diseases without meningitis. The alpha 2M in CSF, which tends to be at extraordinarily high levels when there is damage to the BCB, correlated highly with CSF cell counts. CSF IL-6 seemed to be a useful indicator to identify the acute active phase of meningitis. CRP and alpha 2M in CSF are considered to be useful to differentiate bacterial meningitis, bacterial infection without meningitis and viral meningitis. Extraordinarily high levels of alpha 2M, which has a high molecular weight, in CSF is indicative of BCB damage.

[Erythrocyte metabolism in meningococcal infection and purulent meningitis]. / Metaboliszm éritrotsitov pri meningokokkovoi infektsii i gnoinykh meningitakh.

The red blood cell metabolic parameters ATP, ADP, sigma AN, ATP/ADP, ATP/ATP, energy charge, PAD, 2,3-DPH, Pn were studied in 106 patients with generalized meningococcus infection (GMI) and meningitis of other etiology over their natural history. There was a typical adaptative red blood cell response that featured glycolytic stimulation on hypoxia that ran with impaired red blood cell energy metabolism (RBCEM), negative energy balance. It was the most pronounced at the peak of disease. RBCEM changes occurred in the presence of antioxidative disorders of red blood cells as lowered PAD levels. When early complications, such as shock, brain edema, death developed, there was a high incidence of signs of erythrocytic biochemical disadaptation. The RBCEM changes were associated with the magnitude of cytolysis, i.e. serum AST and AST/ALT levels. The significance of the metabolic changes found in the red blood cells in the pathogenesis and clinical picture of GMI and purulent meningitis is discussed in the paper.

Detection of herpes simplex virus DNA by polymerase chain reaction in the cerebrospinal fluid of patients with viral meningoencephalitis using primers for the glycoprotein D gene.

A novel set of primers for polymerase chain reaction (PCR) which amplified the portion of US6 sequence coding for the main type-common neutralizing epitope of glycoprotein D (gD) was used for detection of herpes simplex virus (HSV) DNA in 44 cerebrospinal fluid (CSF) samples from 29 patients with clinical symptoms of viral meningitis or meningoencephalitis. The primers in question amplified the DNA of 9 out of 10 low-passage HSV-1 isolates and of 5 out of 10 HSV-2 low-passage isolates as well as the DNA of all laboratory strains examined when tested in the supernatant fluid of infected cells cultures. The PCR was positive in 5 CSF samples (taken on days 2, 4, 8, 10 and 56 after the onset of symptoms, but not later than day 8 after starting acyclovir (ACV) therapy) obtained from 4 patients with intrathecal antibody response. The PCR was repeatedly negative in CSF of 15 patients who had antibodies to HSV in serum and CSF, but did not show intrathecal antibody production. It was also negative in 10 patients who had no HSV antibodies in CSF. Our results confirmed that positive PCR for HSV DNA in the CSF is an indication for starting and/or continuing ACV therapy even in the absence of classical symptoms of HSV encephalitis.

Interferon-gamma secretion by in vivo activated cytotoxic T lymphocytes from the blood and cerebrospinal fluid during mumps meningitis.

Functional studies of cerebrospinal fluid T lymphocytes during acute viral infections of the nervous system are rare. Recently, we had the opportunity to investigate the requirements for interferon-gamma (IFN-gamma) production of human in vivo activated (primary) cytotoxic T lymphocytes (CTL) generated during acute viral meningitis. Two HLA-B7-restricted, CD4-, CD8+ CTL clones from cerebrospinal fluid of one patient with mumps meningitis were studied. Although lytic activity was restricted by HLA-B7, the clones produced similar amounts of IFN-gamma when stimulated with HLA-matched and mismatched mumps virus-infected target cells. In addition, peripheral blood mononuclear cells of infected patients secreted significant amounts of IFN-gamma when incubated with autologous or allogeneic (HLA-A/B-mismatched) mumps virus-infected target cells. T cells capable of lytic activity and IFN-gamma secretion could only be isolated from venous blood during the initial phase of the infection. We suggest that the ability of human in vivo activated CTL to secrete INF-gamma early during the course of inflammation and in a HLA-unrestricted fashion is important for the elimination of viruses invading the central nervous system.