Cerebrospinal fluid concentrations of interleukin-1 beta, tumour necrosis factor-alpha, and interferon gamma in bacterial meningitis

To investigate the role of the inflammatory cytokines, the cerebrospinal fluid concentrations of interleukin (IL)-1 beta, tumour necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were measured in 11 children with bacterial meningitis and two with mycoplasmic meningoencephalitis and compared with those in 50 children with aseptic meningitis and 15 with non-pleocytotic cerebrospinal fluid. Concentrations of IL-1 beta and TNF-alpha were each significantly higher in the cerebrospinal fluid of patients with bacterial meningitis than in those with aseptic meningitis or those with non-pleocytotic cerebrospinal fluid. IFN-gamma was detected at low concentrations in the cerebrospinal fluid of only 2/11 of those with bacterial meningitis. On the other hand, the IFN-gamma concentration was the highest in the cerebrospinal fluid of patients with aseptic meningitis. These results suggest that the inflammatory cytokines are differently released in the intrathecal space infected with viruses or bacteria.     

Cerebrospinal fluid concentrations of interleukin-1 beta, tumour necrosis factor-alpha, and interferon gamma in bacterial meningitis.

To investigate the role of the inflammatory cytokines, the cerebrospinal fluid concentrations of interleukin (IL)-1 beta, tumour necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were measured in 11 children with bacterial meningitis and two with mycoplasmic meningoencephalitis and compared with those in 50 children with aseptic meningitis and 15 with non-pleocytotic cerebrospinal fluid. Concentrations of IL-1 beta and TNF-alpha were each significantly higher in the cerebrospinal fluid of patients with bacterial meningitis than in those with aseptic meningitis or those with non-pleocytotic cerebrospinal fluid. IFN-gamma was detected at low concentrations in the cerebrospinal fluid of only 2/11 of those with bacterial meningitis. On the other hand, the IFN-gamma concentration was the highest in the cerebrospinal fluid of patients with aseptic meningitis. These results suggest that the inflammatory cytokines are differently released in the intrathecal space infected with viruses or bacteria.     

Cefoperazone pharmacokinetics in acute childhood meningitis

We studied the serum pharmacokinetics and cerebrospinal fluid concentrations of cefoperazone in 15 children with acute meningitis. Mean cefoperazone concentrations of 117 micrograms/ml in the serum and 3.8 micrograms/ml in the cerebrospinal fluid were noted 2 hours after a single 100 mg/kg dose. Following multiple 50 or 100 mg/kg doses, the mean peak serum cefoperazone concentrations were 232 and 498 micrograms/ml, respectively, with an overall mean elimination phase half-life of 2.12 hours. The data best fit a linear, two-compartment model. Cerebrospinal fluid concentrations 1.5 to 2.5 hours after the end of cefoperazone infusions ranged from 1.4 to 19.2 micrograms/ml for all doses and states of illness. This represented 1.2% to 6.4% of simultaneous serum values. The cerebrospinal fluid inhibitory titer was greater than or equal to 1:16 in 17 of 18 specimens tested against a strain of Haemophilus influenzae type b resistant to both chloramphenicol and ampicillin. In the doses given, cefoperazone produces adequate cerebrospinal fluid concentrations and bioactivity to treat the common bacterial forms of acute meningitis in infants and children.     

Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.

Hyponatraemia has been described in association with a number of acute infectious diseases, mainly bacterial and tuberculous meningitis and pneumonia, and has been attributed to inappropriate secretion of arginine vasopressin (AVP). The mechanism of inappropriate AVP production is uncertain, but there is experimental evidence to suggest that fever may stimulate secretion of AVP into plasma and cerebrospinal fluid. In this study, AVP concentrations in plasma and cerebrospinal fluid from 37 febrile children with infections have been compared with those from 27 afebrile control subjects. Ten of the febrile children had meningitis (eight bacterial, two viral) and the remainder a variety of other infectious diseases. Seventy four per cent of febrile infected children were hyponatraemic (serum sodium less than 135 mmol/l) compared with only 8% of the afebrile controls. Plasma AVP concentrations were significantly higher in the febrile patients (median 2.92 pmol/l, range 1.0-23.25, n = 28) than in controls (median 1.67 pmol/l, range 0.57-6.0, n = 14) but there was no significant difference in cerebrospinal fluid AVP concentrations. There was no difference in plasma AVP concentrations between patients with meningitis and those with infections not involving the central nervous system. Careful attention should be paid to fluid and electrolyte balance in all children with acute infections.     

Significance of polymorphonuclear leukocytes in CSF of bacteremic children

A retrospective study was performed of 32 bacteremic children not receiving preadmission antibiotic therapy who had a diagnostic lumbar puncture for analysis of cerebrospinal fluid at the time of initial evaluation for an acute illness. In each instance, the CSF contained polymorphonuclear leukocytes without pleocytosis. Of these 32 bacteremic patients, 88% had a CSF differential cell count with 20% or fewer polymorphonuclear cells, and greater than 90% had glucose and protein concentration within the range of normal limits. All patients had a Gram-stained smear of CSF which revealed no organisms. In no instance was a CSF culture positive for a bacterial pathogen. In the bacteremic child not pretreated with antibiotics, cerebrospinal fluid which contains total white blood cell, glucose, and protein concentrations within limits of normal, a differential cell count with 20% or fewer polymorphonuclear leukocytes, and Gram-stained smear which reveals no organisms is not indicative of risk for bacterial meningitis.     

Cerebrospinal fluid C-reactive protein in meningitis: diagnostic value and pathophysiology

We examined the diagnostic value of C-reactive protein (CRP) in cerebrospinal fluid (CSF) on initial lumbar puncture in a prospective study including 126 patients (30 neonates, 96 infants and children) suspected of having meningitis. Twenty patients were considered to have bacterial and 25 were considered to have viral meningitis. In infants and children, a retrospectively chosen cut-off CRP titre of 4 (i.e. 0.4 mg/l CRP) had a sensitivity of 100% and a specificity of 94% for differentiating bacterial meningitis from both viral meningitis and normal. It was a more sensitive and selective test for differentiating bacterial from viral meningitis on initial CSF examination than was the CSF leucocyte count, glucose concentration or protein concentration. In neonates, no such cut-off CRP titre could be found, presumably due to the immaturity of the blood-CSF-barrier (Bl-CSF-B) during the first weeks of life. In a parallel study including a non-selected group of 13 infants and children (4 without, 9 with bacterial meningitis), the serum/CSF CRP concentration ratios were determined and inserted in the individual Bl-CSF-B diagrams according to Felgenhauer. The results were fully consistent with the hypothesis that the CRP concentration in CSF reflects the normal permeability characteristics of the Bl-CSF-B, or the degree of its impairment. Based on our results, we recommend the CSF CRP estimation in the routine evaluation of infants and children suspected of having meningitis.Abbreviations CRP C-reactive protein - CSF cerebrospinal fluid - Bl-CSF-B blood-cerebrospinal fluid-barrier - Qp Concentration ratio in serum/CSF of a given protein P - IgG immunoglobulin G - R (Å) hydrodynamic radius in ångström     

Lactoferrin, C-reactive Protein, α-1-Antitrypsin and Immunoglobulin GA in Cerebrospinal Fluid in Meningitis

ABSTRACT. Cerebrospinal fluid measurements of lactoferrin and α-1-antitrypsin showed significant elevation in bacterial meningitis in children. 8 of 10 lactoferrin values and 6 of 11 α-1-antitrypsin values were above the upper range of controls. Both proteins correlated well with the total number of leukocytes in the cerebrospinal fluid. C-reactive protein, measured by either agglutination or radial immunodiffusion in the cerebrospinal fluid, failed to demonstrate any asefulness in diagnosing bacterial meningitis. Neither elevated serum C-reactive protein in cases of bacterial meningitis, nor sepsis, gave detectable concentrations of C-reactive protein in the cerebrospinal fluid.     

Lactoferrin, C-reactive protein, alpha-1-antitrypsin and immunoglobulin GA in cerebrospinal fluid in meningitis

Cerebrospinal fluid measurements of lactoferrin and alpha-1-antitrypsin showed significant elevation in bacterial meningitis in children. 8 of 10 lactoferrin values and 6 of 11 alpha-1-antitrypsin values were above the upper range of controls. Both proteins correlated well with the total number of leukocytes in the cerebrospinal fluid. C-reactive protein, measured by either agglutination or radial immunodiffusion in the cerebrospinal fluid, failed to demonstrate any usefulness in diagnosing bacterial meningitis. Neither elevated serum C-reactive protein in cases of bacterial meningitis, nor sepsis, gave detectable concentrations of C-reactive protein in the cerebrospinal fluid.     

Cerebrospinal fluid C-reactive protein in the diagnosis of meningitis in children

The mortality rate of bacterial meningitis in infants and children is still high (40-50%). Such a mortality rate can be reduced by establishing a prompt and accurate diagnosis. Until now the diagnosis of meningitis is still an important clinical problem. The examination of cerebrospinal fluid C-reactive protein had been done in 44 clinical meningitis patients in the Paediatrics Department, Dr. Sardjito General Hospital qualitatively by means of latex agglutination slide test. Cerebrospinal fluid C-reactive protein was positive in 90% (18/20) of bacterial meningitis patients compared to 8.3% (2/24) of non bacterial meningitis patients. The sensitivity and specificity of cerebrospinal fluid C-reactive protein were 90% and 91.7% respectively and these values were more sensitive and specific than those of white cell count, absolute polymorphonuclear, glucose and protein levels and the cerebrospinal fluid smear (50-80% and 80-91% respectively) which had been performed in the diagnosis of meningitis. It can be concluded that the examination of cerebrospinal fluid C-reactive protein can be used as a diagnostic tool of bacterial meningitis.     

Cerebrospinal fluid lactic acidosis in bacterial meningitis.

A rapid, microenzymatic method was used to measure cerebrospinal fluid lactate levels in 205 children with suspected bacterial meningitis. Fifty children with normal CSF containing fewer than 0.005 X 10(9)/l WBC, no segmented neutrophils, glucose 3.4 +/- 0.8 mmol/l (61.2 +/- 14.4 mg/100 ml), and a protein of less than 0.30 g/l had CSF lactate levels below 2.0 mmol/l (18 mg/100 ml) (mean and standard deviation 1.3 +/- 0.3 mmol/l (11.8 +/- 2.7 mg/100 ml)). In 31 cases of proved viral meningitis as with 58 cases of clinically diagnosed viral meningitis, levels were below 3.8 mmol/l (34.5 mg/100 ml), being 2.3 +/- 0.6 mmol/l (20.9 +/- 5.4 mg/100 ml), and 2.1 +/- 0.7 mmol/l (19.1 +/- 6.4 mg/100 ml) respectively. Sixty-six cases of bacterial meningitis had CSF lactate levels ranging from 3.9 mmol/l (35.4 mg/100 ml) to greater than 10.0 mmol/l (90.0 mg/100 ml). Longitudinal studies in 7 children with bacterial meningitis showed that cerebrospinal fluid lactate levels differentiated bacterial from viral meningitis up to 4 days after starting treatment with antibiotics. Use of CSF lactate measurement for monitoring the efficacy of treatment is illustrated in a case of bacterial meningitis due to Pseudomonas aeruginosa. The origin of the cerebrospinal fluid lactate acidosis and the role of lactate in the pathophysiological cycle leading to intensification of brain tissue hypoxia and cellular damage is discussed with respect to the short-term prognosis and the long-term neurological sequelae.     

Lipopolysaccharide binding protein is a potential marker for invasive bacterial infections in children

BACKGROUND: The aim of this study was to test the hypothesis that elevated lipopolysaccharide binding protein (LBP) serum concentration is a useful marker in the early diagnosis of invasive bacterial infection in children. We measured LBP in serum and cerebrospinal fluid (CSF) of children with proven invasive infection caused by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. PATIENTS AND METHODS: Samples were collected from 39 children (aged 2 months to 17 years) with bacterial sepsis (n = 19) or meningitis (n = 20). Bacterial infection was diagnosed when a blood or CSF culture was positive and clinical signs of invasive infection were present. The control group consisted of serum (n = 60) and CSF (n = 19) samples from children with neurologic disease, juvenile idiopathic arthritis or viral infection. In 10 patients with bacterial infection, follow-up samples (24 and 48 hours) were available. LBP values were measured by an immunochemiluminescence analyzer (IMMULITE; DPC Biermann, Bad Nauheim, Germany) and compared with tumor necrosis factor-alpha and interleukin-8 concentrations. RESULTS: The median LBP serum concentrations in patients with bacterial infection were markedly elevated compared with the control groups (45.0 [33.1-55.2] versus 8.3 [6.8-10.1] microg/mL [median and 5-95% confidence interval]; P < 0.0001). Follow-up serum values of LBP were persistently elevated despite adequate antibiotic treatment, whereas tumor necrosis factor-alpha and interleukin-8 concentrations decreased. In contrast, LBP concentrations in the CSF were below the detection limit of 0.5 microg/mL in 67% of patients with bacterial meningitis (median <0.5 microg/mL), whereas tumor necrosis factor-alpha and interleukin-8 levels were highly elevated. CONCLUSION: LBP serum concentration is elevated in serum of children with invasive bacterial infection and could be a promising diagnostic marker.     

C-reactive protein is useful in distinguishing Gram stain-negative bacterial meningitis from viral meningitis in children.

OBJECTIVE: To clarify to what extent Gram stain-negative bacterial meningitis can be distinguished from viral meningitis by assessment of cerebrospinal fluid (CSF) and blood indices and serum C-reactive protein (CRP) in children over 3 months of age. DESIGN: Common CSF indices, blood leukocyte counts, and serum CRP values were compared between patients with bacterial meningitis who had a positive CSF bacterial culture but a negative Gram stain and patients with viral meningitis. POPULATION: Three hundred twenty-five consecutive patients with CSF culture-proven bacterial meningitis, for whom Gram stain was negative in 55 cases, and 182 children with proven or presumed viral meningitis. RESULTS: Significant differences between patients with bacterial and viral meningitis were found in all indices with large overlap in all except serum CRP. In patients with bacterial meningitis, the mean CSF glucose concentration, protein concentration, leukocyte count, blood leukocyte count, and serum CRP were 2.9 mmol/L (52 mg/dL), 1.88 g/L, 4540 x 10(6)/L, 18.0 x 10(9)/L, and 115 mg/L; and in those with viral meningitis, mean values were 3.3 mmol/L (59 mg/dL), 0.52 g/L, 240 x 10(6)/L, 10.6 x 10(9)/L, and <20 mg/L, respectively. Of the tests investigated in this study, only serum CRP was capable of distinguishing Gram stain-negative bacterial meningitis from viral meningitis on admission with high sensitivity (96%), high specificity (93%), and high negative predictive value (99%). CONCLUSION: Exclusion of bacterial meningitis with only the conventional tests is difficult. Combined with careful physical examination and CSF analyses, serum CRP measurement affords substantial aid.     

Correlation of interleukin-1 beta and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis

Because interleukin-1 beta (IL-1 beta) and cachectin (tumor necrosis factor) are thought to mediate the body's response to microbial invasion, we measured IL-1 beta and tumor necrosis factor concentrations in paired cerebrospinal fluid (CSF) samples (on admission to the hospital, CSF1; 18 to 30 hours later, CSF2) from 106 infants and children with bacterial meningitis. In CSF1, IL-1 beta was detected in 95% of samples; the mean (+/- 1 SD) concentration was 944 +/- 1293 pg/ml. Patients with CSF1 IL-1 beta concentrations greater than or equal to 500 pg/ml were more likely to have neurologic sequelae (p = 0.001). Tumor necrosis factor was present in 75% of CSF1 samples; the mean concentration was 787 +/- 3358 pg/ml. In CSF2 the mean IL-1 beta concentration was 135 +/- 343 pg/ml, and IL-1 beta concentrations correlated significantly with CSF2 leukocyte count, with glucose, lactate, protein, and tumor necrosis factor concentrations, and with neurologic sequelae. Tumor necrosis factor was detected in CSF2 specimens of 53 of 106 patients, with a mean concentration of 21 +/- 65 pg/ml. Of the 106 patients, 47 received dexamethasone therapy at the time of diagnosis. These patients had significantly lower concentrations of IL-1 beta and higher glucose and lower lactate concentrations in CSF2, and they had a significantly shorter duration of fever compared with the values in patients not treated with steroids (p less than or equal to 0.002). Our data suggest a possible role of IL-1 beta and tumor necrosis factor as mediators of meningeal inflammation in patients with bacterial meningitis, and might explain, in part, the beneficial effect of dexamethasone as adjunctive treatment in this disease.     

Endotoxin concentrations in cerebrospinal fluid correlate with clinical severity and neurologic outcome of Haemophilus influenzae type B meningitis

Endotoxin concentrations were measured in paired samples of cerebrospinal fluid from 38 patients with Haemophilus influenzae type b meningitis. On admission, the median concentration of endotoxin in cerebrospinal fluid was 104 ng/mL and decreased rapidly in follow-up samples. From 17 to 48 hours after admission, 50% of the patients had concentrations of less than 1 ng/mL. Endotoxin concentrations correlated significantly with concentrations of interleukin 1 beta, protein, and glucose in cerebrospinal fluid, duration of secondary fever, and neurologic abnormalities during hospitalization and on follow-up examinations. Twenty-eight percent of patients with endotoxin concentrations of 100 ng/mL or more on admission had long-term complications, compared with none of those with lower endotoxin concentrations (relative risk, 2.31; 95% confidence interval, 1.53 to 3.48). These results indicate that quantitation of endotoxin in cerebrospinal fluid could be a valuable aid in identifying those children at increased risk of complications during Haemophilus influenzae type b meningitis and provide additional evidence that the Haemophilus influenzae type b meningitis lipo-oligosaccharide is important in the pathogenesis of meningitis.     

Computed tomography in bacterial meningitis of childhood

The hospital records of 85 children with bacterial meningitis were reviewed and a subset of 25 children who underwent computed tomography of the head were identified. The major stated indications for computed tomography were fever (8 patients), seizures (4 patients), signs of increased intracranial pressure (4 patients), focal neurologic dysfunction (3 patients) and recurrent meningitis (2 patients). Abnormal findings were demonstrated by computed tomography in 20 of 25 patients but in 8 patients consisted solely of nonspecific dilatation of spaces containing cerebrospinal fluid or of basilar enhancement. The yield of information that was useful either diagnostically or therapeutically was low; positive findings of obvious clinical relevance were present in only 2 cases. Computed tomography provides an accurate means of diagnosing intracranial complications of bacterial meningitis. It must be used conservatively, however, to limit expense and radiation exposure and enhance the yield of potentially relevant information. Computed tomography is indicated for children with persistent neurologic dysfunction, persistently positive cerebrospinal fluid cultures or recurrent meningitis, whereas it is of little value for children with prolonged fever alone.     

Neurobrucellosis in children

Reports on nervous system involvement in brucellosis are rare in children. We report nine children with neurobrucellosis. The clinical presentation included meningitis in six patients, one with encephalitis, one with meningoencephalitis and one with meningomyeloencephalitis. The blood from all patients showed elevation in Brucella microagglutination test titers (greater than or equal to 1:640) and in Brucella-specific enzyme-linked immunosorbent assay for IgM (greater than or equal to 1:800), IgG (greater than or equal to 1:800) and IgA (greater than or equal to 1:800) antibodies. Brucella melitensis was recovered from the blood in five patients and from the cerebrospinal fluid in three patients. The cerebrospinal fluid showed lymphocytic pleocytosis in eight patients with elevated protein in three, decreased glucose in four and a Brucella microagglutination test titer of greater than or equal to 1:80 in all. Treatment with a combination of oral tetracyclines with intramuscular streptomycin was successful in five patients, rifampin with streptomycin in two, tetracycline with rifampin in one and tetracycline, rifampin and streptomycin in one. No relapses, mortality or sequelae occurred in our patients.     

C-reactive protein and bacterial meningitis

We have studied prospectively the C-reactive protein values in the cerebrospinal fluid of 54 patients with bacterial meningitis, tuberculous meningitis, and severe malarial infection and convulsions without infections of the central nervous system. CSF CRP above 1 mg/l was observed in 23 out of 28 patients with bacterial meningitis (sensitivity of 82%). The specificity was 73% at the 1 mg/l level. Five out of 19 patients with severe malarial infection had CSF CRP levels above 1 mg/l. Two patients with TB meningitis were also studied. Both of them had CSF CRP above 1 mg/l. Five patients with febrile convulsions or sepsis without meningitis had CSF CRP below 1 mg/l. It is concluded that CSF CRP would not be used as a useful discriminatory test in areas where malaria and TB meningitis are common.     

Prediction of bacterial meningitis in children with meningeal signs: reduction of lumbar punctures

Physicians often have to perform a lumbar puncture to ascertain the diagnosis in patients with meningeal signs, because of the serious consequences of missing bacterial meningitis The aim of this study was to derive and validate a clinical rule to predict bacterial meningitis in children with meningeal signs, to guide decisions on the performance of lumbar punctures. Information was collected from records of patients (aged 1 mo to 15 y) consulting the emergency department of the Sophia Children's Hospital between 1988 and 1998 with meningeal signs. Bacterial meningitis was defined as cerebrospinal fluid (CSF) leucocyte count >5 cells μl^?1 with a positive bacterial culture of CSF or blood. The diagnostic value of predictors was judged using multivariate logistic modelling and area under the receiver operating characteristic curves (ROC area). In the derivation set (286 patients, years 1988–1995) the duration of the main complaint, vomiting, meningeal irritation, cyanosis, petechiae and disturbed consciousness were independent clinical predictors of bacterial meningitis. The ROC area of this model was 0.92. The only independent predictor from subsequent laboratory tests was the serum C‐reactive protein concentration, increasing the ROC area to 0.95. Without missing a single case, this final model identified 99 patients (35%) without bacterial meningitis. Validation on 74 consecutive patients in 3 subsequent years (1996–1998) yielded similar results. Conclusion: This prediction rule identifies about 35% of the patients with meningeal signs in whom a lumbar puncture can be withheld without missing a single case of bacterial meningitis. For the individual patient this prediction rule is valuable in deciding whether or not to perform a lumbar puncture.     

Borrelia infection in children

All children (less than or equal to 15 years) admitted during 1986 to Sachs Children's Hospital and presenting signs of facial palsy and/or meningitis, or with a history of known tick bite followed by headache, fatigue and muscle pain, were investigated for antibodies to Borrelia in serum and cerebrospinal fluid. (The hospital's catchment area has a high incidence of tick-borne Borrelia infections.) Significantly elevated antibody titre was found in 15 of the 33 patients, in three cases only in cerebrospinal fluid. Eight of the 15 children had facial palsy, which was concomitant with meningitis in six cases. Intravenous penicillin was given to all 15 patients with positive antibody titre, and additionally to three severely ill small children with facial palsy and meningitis. Furthermore, two cases of erythema chronicum migrans, which is considered pathognomonic for Borrelia infection, were treated with penicillin perorally. Cases of Borrelia infection occurred throughout the year, but with a peak in August. To emphasize the variety of symptoms, three cases are presented in some detail.     

Bacterial meningitis in children whose cerebrospinal fluid contains polymorphonuclear leukocytes without pleocytosis

A retrospective study was performed of 424 children who received diagnostic lumbar puncture for analysis of cerebrospinal fluid during evaluation of an acute illness. In 106 children, the CSF contained polymorphonuclear leukocytes without pleocytosis. Of these 106 patients, 90 percent had a CSF differential cell count with 20 percent or less PMN's and 88 percent had glucose and protein concentrations within the range of normal limits. All patients had a Gram-stained smear of CSF that revealed no organisms. In no instance was a CSF culture positive for a bacterial pathogen. In most instances, cerebrospinal fluid that contains total white cell count and glucose/protein concentrations within limits of normal, Gram-stained smear which reveals no organisms, and a differential cell count with less than 20 percent PMN's is not indicative of risk for bacterial meningitis. If the clinical situation warrants, the majority of children with this profile do not require hospitalization and initiation of empiric antibiotic therapy pending CSF culture results.