Helmy A. Qurtom, MRCP; Qusay A. Al-Salah, MRCP; Mahmoud M. Lubani, MD; Kamel I. Doudin, MD; Dinesh C. Sharda, FRCP; Areckal I. John, MD From the Department of Pediatrics, Farwania (Drs. Qurtom, Al-Saleh, Lubani, Doudin, and Sharda) and Adan Hospital (Dr. John), Kuwait. Address reprint requests and correspondence to Dr. Qurtom: P.O. Box 43182, 32046 Hawalli, Kuwait. Accepted for publication 25 May 1988. A 6-year prospective study was carried out on 339 infants and children with clinical suspicion of meningitis or febrjle convulsion where C-reactive protein (CRP) determination was done for all patients. The patients were divided into four groups. The serum CRP was positive in 16 of 111 children with viral meningitis, in 50 of 65 with culture-proved bacterial meningitis, in 10 of 17 with partially treated meningitis, and in two of 146 with a first attack of febrile convulsion. The test was nonspecific for routine application, and it was not sensitive for the early differentiation of bacterial, viral, and partially treated meningitis although CRP assay may be a useful additional parameter in the differentiation of various types of meningitis. HA Qurtom, QA Al-Salah, MM Lubani, KI Doudin, DC Sharda, AI John, The Value of C-Reactive Protein in Children with Meningitis. 1989; 9(2): 171-174 Readily available quantitative methods to measure C-reactive protein (CRP) have increased interest in this acute phase reactant. 1-3 Levels of CRP, which is a normal constituent of plasma produced by hepatocytes, rise in bacterial but not in viral meningitis. 4,5 In this report we present our findings of CRP in 339 consecutive infants and children. The aim of this study was to determine whether the serum CRP determination could be helpful to differentiate bacterial from viral meningitis. 6,7 Patients and Methods Three hundred thirty-nine consecutive infants and children suspected of having meningitis were admitted to the Department of Pediatrics, Farwania and Adan Hospitals, Kuwait, between May 1981 and October 1987. Initially all patients were subjected to a lumbar puncture, and CSF was studied for cells, biochemical analysis, and culture. A blood specimen for CRP estimation, complete blood cell count, an erythrocyte sedimentation rate (Westergren method), and blood culture was collected at the time of diagnosis. The CRP was measured by latex agglutination slide test. An aliquot of the test serum was used, and 1:20, 1:40, and 1:80 dilutions of the sample were made with glycine-buffered saline. Thirty microliters of each solution were placed on a glass slide in separate wells, and 30 μl of anti-crp antibody-coated latex particles were added to each well. The slide was manually agitated at room temperature for 3 minutes, then examined with the naked eye under indirect incandescent illumination. A positive slide consisted of any visible agglutination of 3 or greater when evaluated in the manner of Newman et al. 8 A negative slide was smooth or slightly agranular with no visible agglutination. A CRP level of 6 mg/l or less was considered normal. Red blood cells and leukocytes in CSF were counted in counting chambers; CSF glucose was analyzed using
the hexokinase method and protein by the Folin method. Red blood cells and leukocytes in CSF were counted in counting chambers; CSF glucose was analyzed using the hexokinase method and protein by the Folin method. Results The results of CRP in blood, CSF cells, and biochemistry tests are shown in Table 1. The patients were divided into four groups. Group 1 Group 1 comprised 111 infants and children with viral meningitis with a mean age of 4.9 years (range, 23 days to 12 years). There were 78 boys and 33 girls, a male-to-female ratio of 2.36:1; cases occurred throughout the year with a peak in October through February. A preceding history of viral upper respiratory infection was recorded in 60% of cases. Fourteen patients (12.6%) had clinical evidence of mumps. Viral meningitis was diagnosed only if compatible CSF cellular response and biochemical analysis were accompanied by spontaneous recovery without antimicrobial treatment and if the CSF and blood cultures were negative. In all patients with viral meningitis the CSF leukocyte count was more than 10 10 6 /L but less than 1200 10 6 /L in all except six cases where the count ranged from 1270 to 1780 l0 6 /L. A differential count of CSF white cells showed a predominance of lymphocytes (a differential fraction of more than 0.60 of the total) except in five cases where polymorphonuclear lymphocytes predominated. The CSF glucose was more than 2.5 mmol/ L in 110 patients (99.1%), and protein was less than 0.80 g/l in 107 patients (96.4%). The CRP in blood was not detected in 95 patients (85.6%). None of our patients received antibiotics prior to diagnosis, and spontaneous recovery occurred in all patients without antibiotics, although they received symptomatic treatment. All patients were followed up in the pediatric outpatient department for a mean period of 20.2 months where a full neurologic assessment was done, and none had neurologic, ocular, otologic, or other sequelae. Group 2 In group 2, 65 infants and children between the ages of 1 month and 12 years had Gram stain and/ or cultureproved bacterial meningitis 38 with Hemophilus influenzae, 11 with Streptococcus pneumoniae, eight with Neisseria meningitidis, three with Listeria monocytogenes, two with staphylococcus coagulase-positive organisms, one with group B streptococcus, one with group D streptococcus, and one with Escherichia coli (Table 2). Fifty patients (76.9%) with culture-proved bacterial meningitis had CRP present in blood (Table 3). The CSF cells and biochemistry were also compatible with the diagnosis of bacterial meningitis.
Table 1. CSF characteristics in patients with bacterial, viral and partially treated meningitis. present CSFWBC (10 6 /L) CSFPMN (10 6 /L) CSF protein (g/l) CSF glucose (mmol/l) Group 1: Viral meningitis 16/111 Range 10 1200 0 790 0.18 0.89 2.2 3.6 Mean 219 137 0.76 3.2 Group 2: Bacterial meningitis 50/65 Range 82 16,800 76 16,123 0.68 4.73 0.4 3.2 Mean 4147 3983 1.95 1.6 Group 3: Partially treated meningitis 10/17 Range 65 1850 10 1380 0.19 2.16 1.2 3.4 Mean 582 414 0.73 2.0 Group 4: Febrile illness 2/146 Range 0 5 0 5 0.16 0.90 3.2 4.2 Mean 3 2 0.32 3.6 Table 2. CRP in serum of patients with culture-proved bacterial meningitis. Organism isolated from CSF culture (no.) present No. (%) absent No. (%) H. influenzae type B (38) 30 (79.0) 8 (21.0) S. pneumoniae (11) 8 (72.7) 3 (27.3) N. meningitidis (8) 6 (75.0) 2 (25.0) type B(6) 5 type C(2) 1 L. monocytogenes (3) 2 (66.6) 1(33.3) Staphylococcus 1 (50.0) 1(50.0) coagulase-positive (2) Group B streptococcus (1) 1(100.0) 0 Group D streptococcus (1) 1(100.0) 0 E.coli(1) 1(100.0) 0 Group 3 Group 3 comprised 17 children, aged 12 months to 3 years, with suspected meningitis who were given antibiotics prior to diagnosis. Ten had received procaine penicillin injections, four oral penicillin, one oral trimethoprim-sulfamethoxazole, and two had been given several antibiotics. In all of these patients the CSF cells and biochemistry were compatible with the diagnosis of bacterial meningitis, but the CSF cultures were negative. Blood CRP was present in 10 cases (58.8%) (Table. 1). All children were subsequently treated with antibiotics. Group 4 Group 4 comprised 146 nonmeningitic infants and children, aged 6 months to 5 years, admitted with the first attack of febrile convulsion or acute febrile illness in whom meningitis was suspected. The CSF showed no pleocytosis and biochemistry was normal, except in two children who had elevated CSF protein (Table 1) and serum CRP was present in two children.
Sensitivity and Specificity In calculating sensitivity, specificity, and predictive value of a positive and negative test, 9 we considered the following points: positive values in bacterial meningitis were considered true positives, negative values in bacterial meningitis false negatives, positive values in viral meningitis and nonmeningitis cases false positives, negative values in viral meningitis and nonmeningitis group true negatives. The partially treated meningitis group was excluded from the calculations of sensitivity, specificity, and predictive value, for their etiology was unknown. Accordingly, the sensitivity was 76.9%, and specificity 93.0%; the predictive value of a positive test was 73.5%, and the predictive value of a negative test was 94.1%. In comparing the results of CRP to routine tests performed on spinal fluid (Table 3), the predictive value of CRP was not more sensitive in differentiating bacterial from nonbacterial meningitis than CSF glucose, protein, and cells. Table 3. Sensitivity, specificity, and predictive values of various CSF findings for differentiating bacterial from viral meningitis. Screening parameter Presence of serum CRP CSF WBC (500 10 6 /L) CSF PMN (200 10 6 /L) CSF glucose (2.2mmol/L) CSF protein (0.10 g/l) CSF Gram stain positivity Sensitivity 50/65 57/65 62/65 64/65 61/65 49/65 (76.9%) (87.7%) (95.4%) (98.5%) (93.8%) (75.4%) Specificity 239/257 250/257 253/257 256/257 253/257 257/257 (93.0%) (97.3%) (98.4%) (99.6%) (98.4%) (100.0%) Predictive value 50/68 57/64 62/66 64/65 61/65 49/49 of positive test (73.5%) (89.1%) (93.9%) (98.5%) (93.8%) (100.0%) Predictive value 239/254 250/258 253/256 256/257 253/257 257/273 of negative test (94.1%) (96.9%) (98.8%) (99.6%) (98.4%) (94.1%) Discussion Since the identification of CRP, 10 a great deal of knowledge has accumulated regarding the unique structural and functional relationship it has with acute bacterial infections. 11,12 The presence of CRP in the serum of children with infection suggests that measurement of CRP should be valuable as a predictor of bacterial sepsis and meningitis. 3 Using radioimmunoassay, Beer et al 13 reported that CRP determination in serum reliably differentiates between bacterial and viral meningitis, which supported earlier similar findings. 2,6 Our data demonstrate that CRP in serum does not differentiate reliably between bacterial and viral meningitis in 15 of 65 patients with bacterial meningitis CRP was not detected in the serum, and 16 of 111 patients with viral meningitis and two of 146 of the normal nonmeningitic children had CRP present in serum. The sensitivity of the serum CRP was only 76.9%, and the specificity was 93.0%. Moreover, the predictive value of a positive test was 73.5%, and the predictive value of negative test was 94.1%. This casts doubts on the utility of the test and its diagnostic applicability. Only 50 of 65 patients with culture-proved bacterial meningitis had positive CRP in blood. Thus, 15 children and infants with bacterial meningitis would have been missed if the diagnosis had been based solely on the presence of CRP in blood. In the viral meningitis group 16 of 111 patients had CRP in the blood. Thus, the blood CRP correlated better in the viral than in the bacterial group. The sensitivity of the serum CRP in different series varied from 36.8% to 100%, and the specificity varied from 94.0% to 97.6%. 7,11,13,14 Thus, CRP in the serum is nonspecific for routine application, and it is not sensitive enough for early differentiation of bacterial and viral meningitis. 14,15 To conclude, this study, as well as other studies, 13-15 has demonstrated that CRP in serum is nonspecific for routine application. The test is also not sensitive for early differentiation of bacterial and viral meningitis, although the measurement of CRP in serum may be a useful additional parameter in the differentiation of various types of meningitis. References 1. Pepys MB. C-reactive protein: fifty years on. Lancet 1981;1(8221):653-7. 2. Corrall CJ, Pepple JM, Moxon ER, Hughes WT. C-reactive protein in spinal fluid of children with meningitis. J Pediatr 1981;99(3):365-9.
3. Sabel KG, Henson LA. The clinical usefulness of C-reactive protein (CRP) determination in bacterial meningitis and septicemia in infancy. Acta Pediatr Scand 1974;63:381-8. 4. Wager O, Jansson E. C-reactive protein in serous meningitis and paralytic poliomyelitis. Ann Med Exp Fenn 1957;35:352-6. 5. Jansson E, Jalava L, Wager O. C-reactive protein in bacterial meningitis. Ann Med Exper Fenn 1959;37:371-6. 6. Peltola HO. C-reactive protein for rapid monitoring of infections of the central nervous system. Lancet 1982; 1(8279) :980-2. 7. Clarke D, Cost K. Use of serum C-reactive protein in differentiating septic from aseptic meningitis in children. J Pediatr 1983; 102(5) :718-20. 8. Newman RB, Stevens RW, Gaffar HA. Latex agglutination test for the diagnosis of Haemophilus influenzae meningitis. J Lab Clin Med 1970;76:107-13. 9. Statland BE, Winkel P, Burke MD, Galen RS. Quantitative approaches used in evaluating laboratory measurement and other clinical data. In: Henry JB, ed. Clinical diagnosis and management by laboratory methods. 16th ed. Philadelphia: WB Saunders, 1979:528. 10. Tillett WS, Francis T Jr. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1932;52:561-71. 11. Oliveira EB, Gotschlich C, Liu TY. Primary structure of human C-reactive protein. J Biol Chem 1979;254(2):489-502. 12. Kindmark CO. Stimulating effect of C-reactive protein on phagocytosis of various species of pathogenic bacteria. Clin Exp Immunol 1971 ;8:941-8. 13. debeer FC, Kirsten GF, Gie RP, et al. Value of C-reactive protein measurement in tuberculous, bacterial and viral meningitis. Arch Dis Child 1984;59(7):653-6. 14. Benjamin DR, Opheim KE, Brewer L. Is C-reactive protein useful in the management of children with suspected bacterial meningitis? Am J Clin Pathol 1984;81(6):779-82. 15. Shaltout A, El-Shirbiny A, Killander J, et al. Evaluation of cerebrospinal fluid (CSF) C-reactive protein in the diagnosis of suspected meningitis. Ann Trop Paediatr 1986;6(1):31-5.