ORIGINAL CONTRIBUTION bacterial meningitis, pediatric
Acute Phase Reactants and Risk of Bacterial Meningitis Among Febrile Infants and Children Study objective: To test the hypothesis that quantitation of either C-reactive protein (CRP) or the total peripheral WBC count can improve clinical detection of underlying bacterial meningitis among young febrile chiIdren. Design: Cross-sectional survey of selected symptoms of central nervous
system infection, signs of meningeal irritation and~or elevated intracranial pressure, levels of CRP in serum, and total peripheral WBC counts among unselected pediatric patients undergoing lumbar punctures for evaluation of acute febrile illnesses. Setting: Emergency department and acute care "'walk-in" clinic of an urban, university-affiliated general hospital. Participants: 160 previously well, acutely febrile infants and children (median age, 6 months). Results: The prevalence of bacterial meningitis was 6%. Sensitivity of symptoms was 1.00 and specificity was 0.17. Sensitivity of signs was 0.70 and specificity was 0.81. Of the acute phase reactants, sensitivity of a CRP level of more than 1.0 mg/dL was 0.80, while that of a total peripheral WBC count of more than 15,000/mm 3 was 0.40. The presence of signs and/ or a CRP level of more than 1.0 mg/dL correctly identified all children with bacterial meningitis (sensitivity, 1.00). The absence of signs and a CRP level of 1.0 mg/dL or less correctly identified 71 of 150 children without bacterial meningitis (specificity, 0.47). Of 125 children without menirlgeaI signs, the combination of symptoms and a C R P level of more than 1.0 mg/dL correctly identified all three children with bacterial meningitis (sensitivity, 1.00). The absence of these symptoms and~or a CRP level of 1.0 mg/dL or less correctly identified 80 of 122 children without bacterial meningitis (specificity, 0.66). Conclusion: Quantitation of CRP but not the total peripheral WBC count can increase the sensitivity of physical examination findings and the specificity of symptoms for the diagnosis of bacterial meningitis. Measurement of CRP in serum is useful as an adjunct to history and physical examination ,for the detection of acute bacterial meningitis in the acutely febrile child. [Lembo RM, Marchant CD: Acute phase reactants and risk of bacterial meningitis among febrile infants and childrerl. Ann Emerg Med January 1991;20:36-44.]
Robert M Lembo, MD* New Haven, Connecticut Colin D Marchant, MD1Boston, Massachusetts From the Departments of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;* and Tufts University School of Medicine, Boston, Massachusetts.t Received for publication July 14, 1989. Revision received May 1, 1990. Accepted for publication July 12, 1990. Presented in part at the 96th meeting of the Society for Pediatric Research in Washington, DC, May 1986. Address for reprints: Robert M Lembo, MD, Department of Pediatrics, New York University -- Bellevue Medical Center, 550 First Avenue, New York, New York 10016.
INTRODUCTION Bacterial meningitis remains a significant cause of morbidity and mortality in the United States. Its incidence is highest in children less than 1 year old. 1 Early and accurate clinical identification of the child with bacterial meningitis is important because prompt therapy with appropriate antimicrobial agents ~ and possibly dexamethasone g correlates with a favorable outcome. Identification of the child with bacterial meningitis is most difficult in the age group at greatest risk. Several reports indicate that children less than 16 months old with culture-documented bacterial meningitis may lack suggestive physical findings such as a bulging fontanelle, nuchal rigidity, and Kernig's or Brudzinski% signs.4, 5 These patients may manifest only fever or a suggestive history at the time of initial presentation. Although no combination of laboratory tests can replace clinical acumen
20:1 January 1991
Annals of Emergency Medicine
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MENINGITIS Lembo & Marchant
when assessing the child with fever, m e a s u r e m e n t of total peripheral WBC count and the total band count have been reported to be useful in the decision-making process.6, z Recent reports also indicate that quantification of another acute phase reactant, C-reactive protein (CRP), is useful in the early identification of febrile children with occult bacteremia 8 or septicemiag, 10 and is helpful in the differentiation between bacterial and viral illnesses such as epiglottitis and croup, g1 Previous studies of CRP and central nervous system infection have focused on its role in differentiating a bacterial etiology from a nonbacterial etiology.12,13 No study has addressed the role of CRP for the identification of bacterial meningitis in the febrile child. The purpose of this prospective study was to determine whether quantification of serum CRP is of value in assessing the risk of bacterial meningitis in febrile infants and children presenting to the ED.
TABLE 1. Characteristics of study
TABLE 2. Diagnostic efficacy of
patients Characteristic No. of patients Median age (mo) Median temperature(C) Sex (male:female) Indication for lumbar puncture Meningeal signs alone Meningeal signs and suggestive history Suggestive history alone Sepsis workup* Diagnosis Bacterial meningitis Aseptic meningitis Other bacterial infection Other illnesses Prior antibiotics Seizure Bacteremia Hospitalized
individual variables No. (%) 160 6 39 84:76 2 (1) 33 (21) 102 (64) 23 (14) 10 14 10 126 24 16 8 107
(6) (9) (6) (79) (15) (10) (5) (67)
*Age and fever risk faclors (18); seizure wilh fever (five).
PATIENTS A N D M E T H O D S
The study protocol was approved by the Committee on Investigations in Humans of the Cuyahoga County H o s p i t a l . F r o m F e b r u a r y 1984 through August 1985, children presenting to the ED or Acute Care Clinic of the Cleveland Metropolitan General Hospital for evaluation of an acute febrile episode were eligible for inclusion in the study. Patients were enrolled if after a complete history and physical examination, the managing physician decided that bacterial meningitis could be the source of fever or if the child was less than 2 months old and was to have cerebrospinal fluid (CSF) obtained as part of a standard "sepsis workup." Patients were excluded if they had a history of malignancy, immunodeficiency, or intracranial surgery or were receiving immunosuppressive therapy. All patients underwent a lumbar puncture. Before the procedure, blood was drawn and sent for automated complete blood count and culture. Excess blood received by the laboratory was centrifuged and stored at - 7 0 C for quantification of CRP. Patients were assigned one of four diagnoses: bacterial meningitis, aseptic m e n i n g i t i s , e x t r a m e n i n g e a l source of bacterial infection, or other febrile illness. Bacterial meningitis 60/37
was defined on the basis of the recovery of a bacterial pathogen from CSF by standard culture techniques or by the identification of specific bacterial antigen in combination with a positive Gram stain of CSF in the absence of a positive culture. Aseptic meningitis was defined on the basis of a CSF pleocytosis (more than 10 total nucleated cells/mm 3 with less than 1,000 red blood cells/mm3), sterile cultures of blood and CSF, and a negative CSF Gram stain and bacterial antigen tests in the absence of p r i o r t r e a t m e n t w i t h oral antimicrobial agents. Extrameningeal sources of bacterial infection were defined based on a positive c u l t u r e of blood, urine, stool, or pleural fluid in the absence of bacterial meningitis. Patients with a sterile CSF pleocytosis who had received antibiotics orally for more than 24 hours before lumbar puncture were considered to have had meningitis of uninterpretable etiology and were subsequently excluded from analysis. CRP was quantified in serum by rate i m m u n o n e p h e l o m e t r y on a Beckman Auto ICS Analyzer (Beckman Instruments, Inc, Brea, California) according to methods reported previously. 14,1s The lower limit of Annals of Emergency Medicine
Variable Meningeal signst Symptoms* CRP > 1.0 mg/dL TPWBC > 15,000/ mm3
Index of Efficacy (%) No. of Sensi- SpeciPatienls Uvity ficity PPA* NPA 35 135
70 100
81 17
20 7
98 100
75
80
55
11
98
56
40
64
7
94
*PPA, positive predictive acuracy; NPA, negative predictive accuracy; CRP, C-reactive protein; TPWBC, total peripheral white blood cell count. tAny sign of meningeal irritation (eg, nuchal rigidity, Kernig's sign, or Brudzinski's sign) or increased intracranial pressure (full/bulging anterior fontanelle). ~,Any symptom of central nervous syslem infection (irritabigty, lethargy, headache, or sliff neck).
TABLE 3. Results of stepwise logistic
regression analysis modeling relationship among signs, symptoms, acute phase reactants, and bacterial meningitis Variable Meningeal signs CRP > 1.0 mg/dL Symptoms ]-PWBC > 15,000/mm3
x2 8.83 2.71 1.15 0.43
P 003]. f .099J .283 .512
*Two-variable model (X2 - 14.71; P - .0006)
CRP detected by the assay was 0.6 mg/dL. Individual samples were processed in lots by a technician blinded to clinical data. The level of CRP considered to represent the upper limit of normal in serum was 1.0 mg/ dL. 16 T h e t o t a l p e r i p h e r a l WBC count was quantified in samples o f blood obtained by venipuncture by automated counting devices (Coulter Model S or S plus II, Coulter Electronics, Hialeah, Florida). A level of more than 15,000/mm 3 was considered elevated. Children were stratified by their history or physical examination findings at presentation. A history of irritability and poorly consoled crying, lethargy, or headache or stiff neck c o n s t i t u t e d the positive s y m p t o m group, whereas the absence of all of these variables by report constituted the absent s y m p t o m group. Those with meningeal signs (nuchal rigidity and Kernig's or Brudzinski's signs) or signs of increased intracranial 20:1 January 1991
MENINGITIS Lembo & Marchant
TABLE4. Relationships among meningeal signs alone, the combination of meningeal signs and CRP, and bacterial meningitis in all children Bacterial Meningitis
Other Illnesses
Total
7 (20)1, 3 i2) J 10 (11)] 0 (0) I t
28 122 79 71
35 125 89 71
Meningealsigns present Meningearsigns absent Signspresentand/or CRP > 1.0 mg/dL Signs absent and CRP % 1.0 mg/dL Total number of children was 160. *P = .001 by Fisher's exact test (sensitivity, 0.70; specificity, 0.81). rp = .02 by Fisher's exact test (sensitivity, 1.00; specificity, 0.47).
TABLE 5. Relationships among symptoms alone; the comMnation of symptoms and CRP, and bacterial meningitis among children v~thout meningeal signs Bacterial Meningitis
Other illnesses
Total
3 (33)], r 0 (0) J 3 (7) ] 0 (0) It
99 23 42 80
102 23 45 80
Symptomspresent Symptomsabsent Symptomspresentand CRP > 1.0 mg/dL Symptomsabsent and/or CRP -
Acute Phase Reactants and Risk of Bacterial Meningitis Among Febrile Infants and Children Study objective: To test the hypothesis that quantitation of either C-reactive protein (CRP) or the total peripheral WBC count can improve clinical detection of underlying bacterial meningitis among young febrile chiIdren. Design: Cross-sectional survey of selected symptoms of central nervous
system infection, signs of meningeal irritation and~or elevated intracranial pressure, levels of CRP in serum, and total peripheral WBC counts among unselected pediatric patients undergoing lumbar punctures for evaluation of acute febrile illnesses. Setting: Emergency department and acute care "'walk-in" clinic of an urban, university-affiliated general hospital. Participants: 160 previously well, acutely febrile infants and children (median age, 6 months). Results: The prevalence of bacterial meningitis was 6%. Sensitivity of symptoms was 1.00 and specificity was 0.17. Sensitivity of signs was 0.70 and specificity was 0.81. Of the acute phase reactants, sensitivity of a CRP level of more than 1.0 mg/dL was 0.80, while that of a total peripheral WBC count of more than 15,000/mm 3 was 0.40. The presence of signs and/ or a CRP level of more than 1.0 mg/dL correctly identified all children with bacterial meningitis (sensitivity, 1.00). The absence of signs and a CRP level of 1.0 mg/dL or less correctly identified 71 of 150 children without bacterial meningitis (specificity, 0.47). Of 125 children without menirlgeaI signs, the combination of symptoms and a C R P level of more than 1.0 mg/dL correctly identified all three children with bacterial meningitis (sensitivity, 1.00). The absence of these symptoms and~or a CRP level of 1.0 mg/dL or less correctly identified 80 of 122 children without bacterial meningitis (specificity, 0.66). Conclusion: Quantitation of CRP but not the total peripheral WBC count can increase the sensitivity of physical examination findings and the specificity of symptoms for the diagnosis of bacterial meningitis. Measurement of CRP in serum is useful as an adjunct to history and physical examination ,for the detection of acute bacterial meningitis in the acutely febrile child. [Lembo RM, Marchant CD: Acute phase reactants and risk of bacterial meningitis among febrile infants and childrerl. Ann Emerg Med January 1991;20:36-44.]
Robert M Lembo, MD* New Haven, Connecticut Colin D Marchant, MD1Boston, Massachusetts From the Departments of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;* and Tufts University School of Medicine, Boston, Massachusetts.t Received for publication July 14, 1989. Revision received May 1, 1990. Accepted for publication July 12, 1990. Presented in part at the 96th meeting of the Society for Pediatric Research in Washington, DC, May 1986. Address for reprints: Robert M Lembo, MD, Department of Pediatrics, New York University -- Bellevue Medical Center, 550 First Avenue, New York, New York 10016.
INTRODUCTION Bacterial meningitis remains a significant cause of morbidity and mortality in the United States. Its incidence is highest in children less than 1 year old. 1 Early and accurate clinical identification of the child with bacterial meningitis is important because prompt therapy with appropriate antimicrobial agents ~ and possibly dexamethasone g correlates with a favorable outcome. Identification of the child with bacterial meningitis is most difficult in the age group at greatest risk. Several reports indicate that children less than 16 months old with culture-documented bacterial meningitis may lack suggestive physical findings such as a bulging fontanelle, nuchal rigidity, and Kernig's or Brudzinski% signs.4, 5 These patients may manifest only fever or a suggestive history at the time of initial presentation. Although no combination of laboratory tests can replace clinical acumen
20:1 January 1991
Annals of Emergency Medicine
36/59
MENINGITIS Lembo & Marchant
when assessing the child with fever, m e a s u r e m e n t of total peripheral WBC count and the total band count have been reported to be useful in the decision-making process.6, z Recent reports also indicate that quantification of another acute phase reactant, C-reactive protein (CRP), is useful in the early identification of febrile children with occult bacteremia 8 or septicemiag, 10 and is helpful in the differentiation between bacterial and viral illnesses such as epiglottitis and croup, g1 Previous studies of CRP and central nervous system infection have focused on its role in differentiating a bacterial etiology from a nonbacterial etiology.12,13 No study has addressed the role of CRP for the identification of bacterial meningitis in the febrile child. The purpose of this prospective study was to determine whether quantification of serum CRP is of value in assessing the risk of bacterial meningitis in febrile infants and children presenting to the ED.
TABLE 1. Characteristics of study
TABLE 2. Diagnostic efficacy of
patients Characteristic No. of patients Median age (mo) Median temperature(C) Sex (male:female) Indication for lumbar puncture Meningeal signs alone Meningeal signs and suggestive history Suggestive history alone Sepsis workup* Diagnosis Bacterial meningitis Aseptic meningitis Other bacterial infection Other illnesses Prior antibiotics Seizure Bacteremia Hospitalized
individual variables No. (%) 160 6 39 84:76 2 (1) 33 (21) 102 (64) 23 (14) 10 14 10 126 24 16 8 107
(6) (9) (6) (79) (15) (10) (5) (67)
*Age and fever risk faclors (18); seizure wilh fever (five).
PATIENTS A N D M E T H O D S
The study protocol was approved by the Committee on Investigations in Humans of the Cuyahoga County H o s p i t a l . F r o m F e b r u a r y 1984 through August 1985, children presenting to the ED or Acute Care Clinic of the Cleveland Metropolitan General Hospital for evaluation of an acute febrile episode were eligible for inclusion in the study. Patients were enrolled if after a complete history and physical examination, the managing physician decided that bacterial meningitis could be the source of fever or if the child was less than 2 months old and was to have cerebrospinal fluid (CSF) obtained as part of a standard "sepsis workup." Patients were excluded if they had a history of malignancy, immunodeficiency, or intracranial surgery or were receiving immunosuppressive therapy. All patients underwent a lumbar puncture. Before the procedure, blood was drawn and sent for automated complete blood count and culture. Excess blood received by the laboratory was centrifuged and stored at - 7 0 C for quantification of CRP. Patients were assigned one of four diagnoses: bacterial meningitis, aseptic m e n i n g i t i s , e x t r a m e n i n g e a l source of bacterial infection, or other febrile illness. Bacterial meningitis 60/37
was defined on the basis of the recovery of a bacterial pathogen from CSF by standard culture techniques or by the identification of specific bacterial antigen in combination with a positive Gram stain of CSF in the absence of a positive culture. Aseptic meningitis was defined on the basis of a CSF pleocytosis (more than 10 total nucleated cells/mm 3 with less than 1,000 red blood cells/mm3), sterile cultures of blood and CSF, and a negative CSF Gram stain and bacterial antigen tests in the absence of p r i o r t r e a t m e n t w i t h oral antimicrobial agents. Extrameningeal sources of bacterial infection were defined based on a positive c u l t u r e of blood, urine, stool, or pleural fluid in the absence of bacterial meningitis. Patients with a sterile CSF pleocytosis who had received antibiotics orally for more than 24 hours before lumbar puncture were considered to have had meningitis of uninterpretable etiology and were subsequently excluded from analysis. CRP was quantified in serum by rate i m m u n o n e p h e l o m e t r y on a Beckman Auto ICS Analyzer (Beckman Instruments, Inc, Brea, California) according to methods reported previously. 14,1s The lower limit of Annals of Emergency Medicine
Variable Meningeal signst Symptoms* CRP > 1.0 mg/dL TPWBC > 15,000/ mm3
Index of Efficacy (%) No. of Sensi- SpeciPatienls Uvity ficity PPA* NPA 35 135
70 100
81 17
20 7
98 100
75
80
55
11
98
56
40
64
7
94
*PPA, positive predictive acuracy; NPA, negative predictive accuracy; CRP, C-reactive protein; TPWBC, total peripheral white blood cell count. tAny sign of meningeal irritation (eg, nuchal rigidity, Kernig's sign, or Brudzinski's sign) or increased intracranial pressure (full/bulging anterior fontanelle). ~,Any symptom of central nervous syslem infection (irritabigty, lethargy, headache, or sliff neck).
TABLE 3. Results of stepwise logistic
regression analysis modeling relationship among signs, symptoms, acute phase reactants, and bacterial meningitis Variable Meningeal signs CRP > 1.0 mg/dL Symptoms ]-PWBC > 15,000/mm3
x2 8.83 2.71 1.15 0.43
P 003]. f .099J .283 .512
*Two-variable model (X2 - 14.71; P - .0006)
CRP detected by the assay was 0.6 mg/dL. Individual samples were processed in lots by a technician blinded to clinical data. The level of CRP considered to represent the upper limit of normal in serum was 1.0 mg/ dL. 16 T h e t o t a l p e r i p h e r a l WBC count was quantified in samples o f blood obtained by venipuncture by automated counting devices (Coulter Model S or S plus II, Coulter Electronics, Hialeah, Florida). A level of more than 15,000/mm 3 was considered elevated. Children were stratified by their history or physical examination findings at presentation. A history of irritability and poorly consoled crying, lethargy, or headache or stiff neck c o n s t i t u t e d the positive s y m p t o m group, whereas the absence of all of these variables by report constituted the absent s y m p t o m group. Those with meningeal signs (nuchal rigidity and Kernig's or Brudzinski's signs) or signs of increased intracranial 20:1 January 1991
MENINGITIS Lembo & Marchant
TABLE4. Relationships among meningeal signs alone, the combination of meningeal signs and CRP, and bacterial meningitis in all children Bacterial Meningitis
Other Illnesses
Total
7 (20)1, 3 i2) J 10 (11)] 0 (0) I t
28 122 79 71
35 125 89 71
Meningealsigns present Meningearsigns absent Signspresentand/or CRP > 1.0 mg/dL Signs absent and CRP % 1.0 mg/dL Total number of children was 160. *P = .001 by Fisher's exact test (sensitivity, 0.70; specificity, 0.81). rp = .02 by Fisher's exact test (sensitivity, 1.00; specificity, 0.47).
TABLE 5. Relationships among symptoms alone; the comMnation of symptoms and CRP, and bacterial meningitis among children v~thout meningeal signs Bacterial Meningitis
Other illnesses
Total
3 (33)], r 0 (0) J 3 (7) ] 0 (0) It
99 23 42 80
102 23 45 80
Symptomspresent Symptomsabsent Symptomspresentand CRP > 1.0 mg/dL Symptomsabsent and/or CRP -
