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.     

Lactoferrin in relation to acute phase proteins in sera from newborn infants with severe infections

Serum lactoferrin concentrations were elevated in 22 out of 49 newborn infants with suspected and verified severe bacterial as well as viral infections, suggesting that this protein resembled an acute phase reactant. In the infants suspected of having septicemia, high concentrations of C-reactive protein appeared to indicate a severe bacterial infection. Like lactoferrin, however, haptoglobin, orosomucoid, 1-antitrypsin and 1-antichymotrypsin discriminated only poorly or not at all between infants with severe bacterial infections and those in which such infections were unlikely. Thus, serum CRP concentrations remained the most valuable of the acute phase reactants tested as an aid in ruling out septicemia in the neonatal period.     

Tumour necrosis factor-alpha in infectious meningitis.

During a one year period tumour necrosis factor-alpha (TNF-alpha) was prospectively determined in the cerebrospinal fluid of 49 patients with infectious meningitis. TNF-alpha was found in the cerebrospinal fluid of 15 of 18 patients with bacterial meningitis. In 11 patients who had cerebrospinal fluid positive for TNF-alpha it was detected in only one serum (in low concentration). There was no significant correlation between the concentration of TNF-alpha in cerebrospinal fluid and the patient''s age, duration of illness and fever, body temperature, and serum C reactive protein. However, cerebrospinal fluid protein concentrations of greater than or equal to 2 g/l and leucocyte values of greater than or equal to 2.5 X 10(9)/l were more often associated with high TNF-alpha concentrations (greater than or equal to 500 pg/ml). In contrast with bacterial meningitis, none of the 31 samples of cerebrospinal fluid from patients with viral meningitis was positive for TNF-alpha. Thus this investigation supports the conclusion, drawn from animal studies on TNF-alpha in the cerebrospinal fluid, that the presence of TNF-alpha is indicative of bacterial meningitis. Absence of TNF-alpha cerebrospinal fluid, however, was found here not to exclude a bacterial aetiology of the infection.     

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.     

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     

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.     

Diagnostic Value of Serum Procalcitonin Level in Differentiating Bacterial from Nonbacterial Meningitis in Children

Objective:

Acute bacterial meningitis in pediatrics remains a serious and potentially lethal disease. Its prognosis is critically dependent on rapid diagnosis and treatment. The use of biological markers, like procalcitonin, has been proposed to facilitate the accuracy of the initial diagnosis of bacterial meningitis. The aim of this study was assessment the diagnostic values of serum procalcitonin (PCT) assay in the diagnosis and differentiation of acute bacterial from non bacterial meningitis.

Methods:

45 patients with suspicion of meningitis were enrolled in the study and were clinically evaluated and investigated by lumbar punctures for cerebrospinal fluid analysis, C-reactive protein and differential leukocyte count. Patients with clinical and laboratory suggestion of bacterial causes were regarded as bacterial meningitis group (29 patients), and those who were suggestive of nonbacterial causes were regarded as nonbacterial group (16 patients).

Findings:

Serum procalcitonin levels were significantly higher in bacterial meningitis group (637±325 pg/ml) compared with non-bacterial meningitis (380±170 pg/ml); P<0.001. Procalcitonin levels were more sensitive and specific (79%, 81%) than C-reactive protein (76%, 75%) and white blood cell count (72%, 75%) in the diagnosis of bacterial meningitis.

Conclusion:

Elevated serum procalcitonin level could be a predictor of bacterial causes of meningitis and is more sensitive and specific than other diagnostic predictors.     

Serum procalcitonin and other biologic markers to distinguish between bacterial and aseptic meningitis

OBJECTIVE: To identify the biologic tests that best distinguish between bacterial and aseptic meningitis in an emergency department (ED). STUDY DESIGN: All children hospitalized for bacterial meningitis between 1995 and 2004 or for aseptic meningitis between 2000 and 2004 were included in a retrospective cohort study. Predictive values of blood (C-reactive protein, procalcitonin [PCT], white blood cell [WBC] count, neutrophil count) and cerebrospinal fluid (CSF) findings (protein, glucose, WBC count, neutrophil count) available in the ED were determined. Tests with the best predictive value were identified by using univariate and multivariate analyses and ROC curves comparison. RESULTS: Among the 167 patients included, 21 had bacterial meningitis. The CSF gram-stain and bacterial antigen test had 86% and 60% sensitivity rates, respectively. PCT (>/=0.5 ng/mL) and CSF protein (>/=0.5 g/L) were the best biologic tests, with 89% and 86% sensitivity rates, 89% and 78% specificity rates, adjusted odds ratios of 108 (95% CI, 15-772) and 34 (95% CI, 5-217), and areas under the ROC curves of 0.95 and 0.93, respectively. CONCLUSION: PCT and CSF protein had the best predictive value to distinguish between bacterial and aseptic meningitis in children.     

Bacterial meningitis presenting with normal cerebrospinal fluid

At a large children's hospital cases of bacterial meningitis with normal initial cerebrospinal fluid determinations other than culture or antigen detection assays were reviewed in an attempt to determine clinical or other laboratory findings accompanying this presentation. During a 5-year period from January, 1980, through December, 1985, 7 of 261 pediatric meningitis patients (2.7%) fulfilled these criteria. Ages ranged from 3 weeks to 18 months. All 7 patients were hospitalized for observation with all but 1 begun on empiric antibiotic therapy. Laboratory parameters such as a complete blood count, sedimentation rate or C-reactive protein did not influence decisions for management. Cerebrospinal fluid antigen detection assays were negative in all but one patient with pneumococcal meningitis. Review of these cases did not reveal unique indicators for bacterial meningitis. The results emphasize that the physician must rely on clinical judgment in initiating empiric antimicrobial therapy once apparently normal cerebrospinal fluid parameters are observed.     

Evaluation of cerebrospinal fluid (CSF) C-reactive protein in the diagnosis of suspected meningitis

Cerebrospinal fluid C-reactive protein (CSF-CRP) was studied in 183 consecutive infants and children with suspected meningitis, using a nephelometric technique. Cerebrospinal fluid C-reactive protein was above an empirically chosen level of 1 mg/1 in seven of 19 children with culture-proven bacterial meningitis, in only one of 15 children with viral meningitis, and three of 139 children with no meningitis. All 10 children with partially treated meningitis had CSF-CRP levels below 1 mg/1. There was good correlation between CSF-CRP and total protein levels in children with bacterial meningitis (R value 0.4999 P less than 0.05). The test was not sensitive enough for early differentiation between bacterial and viral meningitis. The test also did not add extra information regarding aetiology in partially treated meningitis.     

Diagnosis of meningitis with reagent strips

OBJECTIVE: To determine the usefulness of reagent strips in the evaluation of pleocytosis, cerebrospinal fluid glucose and protein levels for early and rapid diagnosis of meningitis in children. METHODS: We included cerebrospinal fluid samples of 164 children admitted to the outpatient clinic of Communicable Diseases of the General Pediatric Center (Funda??o Hospitalar do Estado de Minas Gerais, CGP-FHEMIG) during the daytime hours from May of 1997 to May 1999, and who presented with clinical suspicion of meningitis. Patients ranged in age from one month to 12 years (median 12 months). Results from the cytological and biochemical assay (cellularity, cerebrospinal fluid glucose and protein levels) were obtained from 154 patients. These results were subsequently compared with the reaction of cerebrospinal fluid in reagent strips. RESULTS: The cytological and biochemical assay identified 43 cases of probable bacterial meningitis, 19 of probable viral meningitis, and 83 with no alterations. According to the reagent strips, there were 41 cases of probable bacterial meningitis, 2 of probable viral meningitis, and 71 with no alterations. By comparing the results of reagent strips and those of the cytological and biochemical assay, we obtained values for sensitivity, specificity, positive and negative predictive values, and accuracy (respectively 90.7; 98.1; 95.1; 96.4; and 96.1). Statistical analysis using McNemer test did not indicate significant differences between the two methods in the diagnosis of bacterial meningitis (P=0.68). Kappa statistics indicated a high level of agreement between the tests (P<0.0001). CONCLUSIONS: Our results suggest that reagent strips may be a useful additional resource in the diagnosis of bacterial meningitis, especially when it is difficult to collect a sufficient amount of cerebrospinal fluid or to indicate the initial treatment.     

A season of aseptic meningitis in Germany: epidemiologic,clinical and diagnostic aspects

OBJECTIVE: We assessed epidemiologic, clinical and laboratory features of aseptic meningitis during one season of multiserotype enteroviral meningitis in East Germany in 70 consecutive patients with aseptic meningitis admitted to the Children's University Hospital Leipzig. RESULTS: Patients, age 1 to 16 years, typically presented with headache, emesis and fever, whereas signs of meningeal irritation were only moderately expressed in one-half of the patients. The median number of leukocytes in the CSF was 151 cells/mm(3) (range, 2 to 1,820) with a high percentage of polymorphonuclear cells (PMNs). Initial blood counts showed mild leukocytosis and pronounced PMN predominance (78.9 +/- 1.3%). The percentage of PMNs in the peripheral blood decreased in favor of mononuclear cells after 3 days to a pattern more compatible with viral infection as opposed to that suggestive for bacteria in the beginning. Mean cerebrospinal fluid values of protein, glucose and lactate and the C-reactive protein were mildly elevated or normal. Nonpolio enteroviruses were detected in 30 of 70 patients. Subsequent serotyping revealed echovirus type 13 (13 patients), type 6 (2), type 30 (1) and coxsackie B virus type 5 (2). There were no differences in demographic or clinical data between enterovirus positive and negative patients. CONCLUSIONS: Even though individual laboratory values do not solely allow discrimination between viral and bacterial meningitis, the combined epidemiologic, clinical and laboratory data facilitate the diagnosis of aseptic meningitis in most cases. Viral diagnostics, identifying echovirus type 13 that thus far has not been associated with epidemics of meningitis, adds important epidemiologic information.     

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.     

Serum C-reactive protein in the differential diagnosis of childhood meningitis

BACKGROUND: Although determination of serum C-reactive protein (CRP) is considered one of the most useful tests for differentiating between bacterial and aseptic meningitis, its diagnostic accuracy in comparison with other laboratory parameters is yet to be further evaluated. METHODS: A total of 192 pediatric cases, aged between 2 months and 14 years, comprising patients with bacterial meningitis (n = 66) and aseptic meningitis (n = 126), were retrospectively analyzed on the basis of data from the initial examination. The area under the best fit binormal curve of the receiver operating characteristics (Az) for CRP was determined and compared with that for several other analytic parameters, including white blood cell count and erythrocyte sedimentation rate of peripheral blood, standard cerebrospinal fluid analysis variables and the combination test (probability of acute bacterial meningitis (pABM)) derived from Hoen's model. RESULTS: Compared with each of the other variables, the Az for serum CRP (0.97 +/- 0.02) was found to be significantly greater (P < 0.01) for all except pABM (0.99 +/- 0.01; P > 0.05). False-negative cases among the CRP test results were found to have been examined too early. CONCLUSIONS: The diagnostic accuracy of a single CRP determination was found to be equivalent to that of the most effective combination test. Patients with meningitis in whom serum CRP values are determined at least 12 h after the onset of fever and are < 2 mg/dL are far less likely to have bacterial meningitis.     

THE CLINICAL USEFULNESS OF C-REACTIVE PROTEIN (CRP) DETERMINATIONS IN BACTERIAL MENINGITIS AND SEPTICEMIA IN INFANCY

Abstract. Sabel, K.-G. and Hanson, L. Å. (Department of Paediatrics, Children's Hospital, and Department of Immunology, Institute of Medical Microbiology, University of Göteborg, Sweden). The clinical usefulness of C-reactive protein (CRP) determinations in bacterial meningitis and septicemia in infancy. Acta Paediatr Scand, 63: 381, 1974.–The possibility of using CRP for diagnosis and follow-up of infants with bacterial meningitksepticemia was investigated. CRP was quantitated with the single radial immunodiffusion technique. In 37 infants 0–12 months old with purulent meningitis and/or septicemia, CRP was increased in 32. The same proportion of increased CRP was found in the neonatal cases as in the older infants. Peak values to <50 µg/ml were found in 2/3 of all cases, E. coli infections showing the most uniform pattern of high CRP values. The period of increased CRP was closely related to risk of recurrence of the infection. After CRP had returned to normal levels no recurrence occurred. In cases of neonatal E. coli infections CRP was found to be the best single parameter indicating persistence of infection, and in a group of H. influenzae idfection CRP was as good as cultures of cerebrospinal fluid, white blood cell count and protein in cerebrospinal fluid. The findings show that CRP is a useful parameter to show the presence of meningitis and/or septicemia in infancy including the neonatal period. CRP is an easy test which can be used to direct antibiotic treatment since it rapidly detects persistence of infection or recurrences.     

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.     

Cerebrospinal fluid C-reactive protein measurement--a bedside test in the rapid diagnosis of bacterial meningitis

C-reactive protein (C-RP) determinations were performed by the Latex agglutination method on the cerebrospinal fluid (CSF) samples of 212 patients with clinical features suggestive of meningitis. Patients were grouped as follows Group I: bacterial meningitis and partially treated bacterial meningitis (n = 22). Group II: viral encephalitis (n = 11). Group III: tuberculous meningitis (n = 18). Group IV: (i) febrile convulsions (n = 87); (ii) epileptic seizures (n = 70); (iii) intracranial haemorrhage (n = 4). C-RP was a better indicator of bacterial meningitis (sensitivity 91 per cent) than the Gram's stain (sensitivity 46 per cent). C-RP was positive in 91 per cent of patients in Group I, none in Groups II and III and 0.6 per cent in Group IV. C-RP determination in CSF proved to be a useful indicator of bacterial meningitis and served to distinguish it from viral encephalitis, tuberculous meningitis, febrile convulsions and other central nervous system disorders.     

Concentrations of nucleotides, nucleosides, purine bases and urate in cerebrospinal fluid of children with meningitis

The release of agents mediating inflammation in meningitis may bring about neuronal hypoxia, under which circumstances ATP concentrations decrease and its degradation products increase and are released into the cerebrospinal fluid. In this study of alterations in neuronal energy metabolism in meningitis, AMP, IMP, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high performance liquid chromatography in the cerebrospinal fluid of 54 children aged between 1 month and 13 years suffering from meningitis (25 viral, 24 bacterial and 5 tuberculous cases) and 63 controls. Compared to the controls, patients with viral meningitis exhibited high concentrations of IMP, adenosine, guanosine, adenine, guanine and xanthine; patients with bacterial meningitis exhibited high concentrations of IMP, inosine, guanosine, adenosine, hypoxanthine, xanthine and urate; and patients with tuberculous meningitis exhibited high concentrations of AMP, guanosine, xanthine and uratc. Viral and bacterial cases did not differ significantly for any of the metabolites studied. AMP and urate concentrations were significantly higher in patients with tuberculous cases compared with viral or bacterial meningitis cases.