Development and Validation of a Multivariable Predictive Model to

Distinguish Bacterial From Aseptic Meningitis in Children in the

Post-Haemophilus influenzae Era
Lise E. Nigrovic, MD*; Nathan Kuppermann, MD, MPH; and Richard Malley, MD*
ABSTRACT. Context. Children with meningitis are
routinely admitted to the hospital and administered
broad-spectrum antibiotics pending culture results because distinguishing bacterial meningitis from aseptic
meningitis is often difficult.
Objective. To develop and validate a simple multivariable model to distinguish bacterial meningitis from
aseptic meningitis in children using objective parameters
available at the time of patient presentation.
Design. Retrospective cohort study of all children
with meningitis admitted to 1 urban childrens hospital
from July 1992 through June 2000, randomly divided into
derivation (66%) and validation sets (34%).
Patients. Six hundred ninety-six previously healthy
children aged 29 days to 19 years, of whom 125 (18%) had
bacterial meningitis and 571 (82%) had aseptic meningitis.
Intervention. Multivariable logistic regression and
recursive partitioning analyses identified the following
predictors of bacterial meningitis from the derivation set:
Gram stain of cerebrospinal fluid (CSF) showing bacteria, CSF protein >80 mg/dL, peripheral absolute neutrophil count >10 000 cells/mm3, seizure before or at time of
presentation, and CSF absolute neutrophil count >1000
cells/mm3. A Bacterial Meningitis Score (BMS) was developed on the derivation set by attributing 2 points for
a positive Gram stain and 1 point for each of the other
variables.
Main Outcome Measure. The accuracy of the BMS
when applied to the validation set.
Results. A BMS of 0 accurately identified patients
with aseptic meningitis without misclassifying any child
with bacterial meningitis in the validation set. The negative predictive value of a score of 0 for bacterial meningitis was 100% (95% confidence interval: 97%100%). A
BMS >2 predicted bacterial meningitis with a sensitivity
of 87% (95% confidence interval: 72%96%).
Conclusions. The BMS accurately identifies children
at low (BMS 0) or high (BMS >2) risk of bacterial
meningitis. Outpatient management may be considered
for children in the low-risk group. Pediatrics 2002;110:
712719; prediction model, bacterial meningitis, aseptic
meningitis.

From the *Department of Medicine and Divisions of Infectious Diseases

and Emergency Medicine, Childrens Hospital and Harvard Medical
School, Boston, Massachusetts, and the Department of Internal Medicine,
Division of Emergency Medicine and the Department of Pediatrics, University of California, Davis, School of Medicine, Davis, California.
Received for publication Feb 19, 2002; accepted May 20, 2002.
Reprint requests to (R.M.) Divisions of Infectious Diseases and Emergency
Medicine, Childrens Hospital, 300 Longwood Ave, Boston MA 02115.
E-mail: richard.malley@tch.harvard.edu
PEDIATRICS (ISSN 0031 4005). Copyright 2002 by the American Academy of Pediatrics.

712

ABBREVIATIONS. CSF, cerebrospinal fluid; WBC, white blood

cell count; Hib, Haemophilus influenzae type b; ANC, absolute
neutrophil count; RBC, red blood cells; ROC, receiver operating
characteristic; BMS, Bacterial Meningitis Score; NPV, negative predictive value; CI, confidence interval; PPV, positive predictive
value.

acterial meningitis remains an important cause

of morbidity and mortality in children despite
the advent of highly effective bacterial conjugate vaccines. In the United States each year, there
are close to 6000 new cases of bacterial meningitis, of
which approximately half occur in children younger
than 18 years of age.1 Streptococcus pneumoniae and
Neisseria meningitidis are the major bacterial pathogens in children beyond the immediate neonatal period1 and have associated overall mortality rates of
6% to 12%2 4 and 3% to 5%,1,5 respectively. Despite
antimicrobial therapy, up to 25% of survivors of
bacterial meningitis have significant sequelae, such
as neurologic deficits or hearing loss.6
Because discrimination between bacterial meningitis and aseptic meningitis at the time of presentation is often difficult, children with cerebrospinal
fluid (CSF) pleocytosis are routinely admitted to the
hospital to receive broad-spectrum antibiotics pending bacterial culture results. Previously, investigators
have evaluated means to distinguish bacterial from
aseptic meningitis before the results of blood and/or
CSF cultures are available. When evaluated on patients not previously treated with antibiotics, the CSF
Gram stain has been reported to have a sensitivity
between 60% and 92%.7,8 Other rapidly available
parameters, such as the peripheral white blood cell
count (WBC) and the CSF WBC with differential,
have wide zones of overlap in patients with bacterial
and aseptic meningitis.9 14 Measurements of CSF
leukocyte aggregation, CSF lactate, and serum procalcitonin lack either sensitivity or specificity and are
not routinely available.1522 The serum concentration
of C-reactive protein has been evaluated as well, but
has limited value as it may be low early in bacterial
disease or elevated in patients with viral infections.23,24 Endogenous inflammatory mediators such
as CSF tumor necrosis factor-, interleukin-1, or
interleukin-6 have good predictive power but are not
routinely available in the clinical setting.25,26
Two multivariable models have previously been
developed to distinguish bacterial versus aseptic
meningitis. The first studywhich was derived from

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an all-ages population and before the widespread

introduction of Haemophilus influenzae type b (Hib)
conjugate vaccine, and which used CSF absolute
neutrophil count (ANC), CSF-blood glucose ratio,
age, and time of year demonstrated excellent sensitivity and specificity for the prediction of bacterial
versus aseptic meningitis.27 A second, more recent
study was based on a pediatric population in the era
of universal Hib vaccination and used the following
dichotomous predictors: CSF WBC 30 cells/mm3,
CSF-blood glucose ratio 40%, CSF glucose 40
mg/dL, CSF protein 45 mg/dL, positive Gram
stain, peripheral band count 500 cells/mm3, and
age 6 months.13 This model also had excellent predictive ability; however, the authors did not attempt
to validate their findings, which makes it difficult to
assess the robustness and generalizability of their
model.
Because most children admitted to the hospital for
meningitis have viral rather than bacterial infections,
we wished to develop and validate a simple model to
predict bacterial versus aseptic meningitis in a pediatric population in the era of Hib vaccination. We
also sought to identify a low-risk group of patients
who may be candidates for outpatient management.
METHODS
Patient Population
We reviewed the charts of all patients aged 29 days to 19 years
who were admitted to Childrens Hospital, Boston, between July
1, 1992, and June 30, 2000, with a final diagnosis of meningitis. A
computerized search tool was used to identify patients with the
following International Classification of Diseases diagnosis codes:
bacterial meningitis (320.0 320.9), viral meningitis (046.0 048.9),
tuberculous meningitis (013.0), and unspecified meningitis (321.0
322.9).

Definitions
Patients were defined as having bacterial meningitis if either of
the following 2 criteria were met: 1) the CSF culture was positive
for a bacterial pathogen; or 2) the presence of CSF pleocytosis (7
WBC per mm3)28 and either a positive blood culture or CSF latex
agglutination test positive for S pneumoniae, N meningitidis, H
influenzae, or Streptococcus agalactiae (group B Streptococcus). Patients in whom CSF culture revealed an organism usually associated with contamination (such as Staphylococcus epidermidis or
Propionobacterium acnes in previously healthy patients) were excluded.
Patients were categorized as having aseptic meningitis if they
had CSF pleocytosis with negative bacterial cultures as well as
negative CSF latex agglutination tests, if performed. Patients meeting this definition but who had been given systemic antibiotics
within 72 hours before lumbar puncture and blood culture (n
108) were not included in the analysis because the accuracy of
these pretreated cultures could not be assured and thus, we
could not be certain that these patients truly had aseptic meningitis.

Exclusion Criteria
To eliminate patients who would have required hospitalization
regardless of the risk of bacterial meningitis, the following criteria
were developed. We excluded patients who recently underwent
neurosurgical procedures (n 34), presented with clinical sepsis
or purpura fulminans (n 22), or were immunosuppressed (because of chemotherapy for oncologic diagnoses [n 5], who
underwent organ transplantation [n 3], had human immunodeficiency infection [n 4], or had primary immunodeficiencies [n
2]). We also excluded patients (n 10) who had other focal
bacterial infections requiring inpatient treatment that were recognized at the time of admission, including children younger than 3

months with urinary tract infections (n 7), as well as children

with brain abscesses (n 2) or periorbital cellulitis (n 1).

Data Collection
We collected the following variables by a review of the computerized and/or written medical records and entered the information onto structured data sheets: date of birth, date of admission and discharge, gender, previous and present medical history
conditions, duration and peak of fever at admission, antibiotic
pretreatment, occurrence and timing of seizures, peripheral WBC
and differential, CSF WBC and differential, CSF red blood cell
count (RBC), CSF glucose, CSF protein, Gram stain, blood and CSF
cultures, and latex agglutination studies if performed. The presence of seizures was based on classification of the treating physician. The enteroviral season was defined as the time period between June 1 and October 31.29 The laboratory values obtained
closest in time to the lumbar puncture were used. When 2 CSF cell
counts were performed, the tube with fewest RBCs was used
regardless of the recorded tube number.

Statistical Methods
Univariate and multivariate analyses were conducted using the
Statistical Program for the Social Sciences.30 Confidence intervals
for proportions were calculated using Stata statistical software.31
Answer Tree statistical software was used to perform recursive
partitioning of the data.32
The database was randomly divided into a derivation set comprising two thirds of the patients and a validation set comprising
the remaining patients. The Student t test was used to compare
means between the derivation and validation sets and to identify
variables in the derivation set that were significantly associated
(P .05) with bacterial meningitis. To limit the number of variables considered, only those that were objective, biologically plausible, readily available at the time of hospital presentation, and
correlated with bacterial meningitis in previous studies were chosen. Because of the colinearity of some of these variables, we
selected peripheral ANC over WBC and CSF ANC over CSF WBC
based on inspection of the receiver operating characteristic (ROC)
curves of these variables against bacterial meningitis. To obtain a
simple and practical model, continuous predictors were dichotomized using rounded whole number values that allowed effective
discrimination between bacterial meningitis and aseptic meningitis. We selected these cutoffs by identifying predictor variable
values associated with a point of the ROC curve with the best
sensitivity-specificity trade off. These optimal cutoff points typically occur where the ROC curve turns the corner, at which
point each incremental gain in sensitivity results in a substantial
loss of specificity. We then rounded off these values for numerical
and clinical simplicity.
We then performed 2 multivariable statistical analyses on the
derivation set to identify significant predictors of bacterial meningitis. Only those patients with complete information on all candidate variables were considered in the multivariable analyses.
First, we entered the candidate variables as described above into a
forward stepwise multivariable logistic regression analysis. Variables independently associated (P .05) with bacterial meningitis
in this analysis were then ranked according to the magnitude of
the -coefficient.
Second, we performed binary recursive partitioning using the
candidate variables described above (ie, the same dichotomous
predictors used in the logistic regression analysis) using a classification tree algorithm32 to identify the most important predictors
of bacterial meningitis. As another form of multivariate analysis,
recursive partitioning may be superior to logistic regression when
the goal is to correctly classify patients with the outcome of
interest with the highest sensitivity rather than obtain overall
model accuracy. Recursive partitioning also explores interactions
between predictor variables natively in the algorithm. Finally, the
trees developed by the recursive partitioning software are easily
interpreted by investigators and clinicians alike and are well
suited for use in clinical decision-making.33,34 In the decision tree
development of the derivation set, we considered the same candidate variables as were considered in the logistic regression
analysis, and we then hand pruned the resultant tree for simplicity
and plausibility.
For ease of use in the clinical setting, we then created a Bacterial
Meningitis Score (BMS), using the predictor variables identified by

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713

both of these multivariable statistical methods. The relative

weighting of each component variable of the BMS score was based
on its value in the logistic regression analysis. The performance
of the BMS was then evaluated on patients in the validation set.
We also conducted 2 subset analyses of the data. To estimate
the performance of the model in the era of routine pneumococcal
conjugate vaccination, we performed a subgroup analysis excluding cases of S pneumoniae meningitis. Patients with missing values
were excluded in the multivariable analyses. We also analyzed the
subset of patients between 29 and 60 days of age to determine how
well the prediction model identified children with bacterial meningitis among this younger, high-risk group.
Approval for review of the medical records was granted by the
institutional review board of Childrens Hospital, Boston.

RESULTS
Patient Characteristics

We identified 696 children, including 125 (18%)

with bacterial meningitis and 571 (82%) with aseptic
meningitis. Cases of bacterial meningitis were
caused by the following pathogens: S pneumoniae (79,
63%), N meningitidis (21, 17%), group B Streptococcus
(13, 10%), H influenzae (6, 5%, all nontypeable), Listeria monocytogenes (3, 2%), enteric Gram-negative
rods (2, 2%), and other streptococci (1, 1%). No cases
of tuberculous meningitis were identified.
The bacterial pathogen was identified in both CSF
and blood culture in 60 patients (48%), CSF culture
alone in 35 (28%), blood culture alone in 28 (22%),
and by latex agglutination alone in 2 (2%). Of the
pretreated patients with bacterial meningitis, the
pathogen was identified in both CSF and blood culture in 18 patients (35%), CSF culture alone in 12
(23%), blood culture alone in 22 (42%) and by CSF
latex agglutination alone in 0. Of patients with bacterial meningitis, 42% had antibiotics administered
within 72 hours before lumbar puncture (42% oral
and 58% parenteral antibiotics). Latex agglutination
tests were performed in 61 patients. Four patients
died, all with bacterial meningitis (3% of total patients with bacterial meningitis).
Comparison of the Derivation and Validations Sets

Patients were randomly divided into 2 sets: the

derivation set (n 456, 66% of patients) and the
validation set (n 240, 34% of patients). Patients in
TABLE 1.

the derivation set were, on average, older at presentation and more likely to be male (Table 1). There
were no other statistically significant differences between the derivation and validation sets.
Univariate Analysis of the Derivation Set

Patients with bacterial meningitis were significantly more likely to be admitted in the nonenteroviral season and to have had seizures at or before
presentation than patients with aseptic meningitis.
Other variables commonly associated with bacterial
infection were also significantly different in patients
with bacterial compared with aseptic meningitis, including the peripheral ANC, CSF ANC, CSF glucose,
CSF protein, and positive Gram stain (Table 2).
Optimum cut offs for continuous variables were
then selected by analyzing the ROC curve for each
variable, as previously described (Fig 1). The following dichotomous variables were thus selected for
consideration in the multivariate analyses: admission
during nonenteroviral season, seizure at or before
presentation, peripheral ANC 10 000 cells/mm3,
CSF ANC 1000 cells/mm3, CSF glucose 35 mg/
dL, CSF protein 80 mg/dL, and positive Gram
stain.
Multivariate Analyses
Logistic Regression

The variables listed above were entered into a

forward stepwise logistic regression analysis, to
identify independent predictors of bacterial meningitis (Table 3). The presence of a positive Gram stain
was the most significant predictor of bacterial meningitis ( 5.6). The other variables independently
associated with bacterial meningitis in this analysis
were CSF protein 80 mg/dL, peripheral ANC
10 000 cells/mm3, seizure at or before presentation,
and CSF ANC 1000 cell/mm3. Only 4% of patients
were excluded from this analysis because of missing
values.
Recursive Partitioning

Recursive partitioning was used to identify important predictors in the derivation set (Fig 2). The same

Characteristics of Patients in the Derivation Set and Validation Set*

Variable

Derivation Set
( Standard Derivation)
N 456

Validation Set
( Standard Deviation)
N 240

Median age in mo (interquartile range)

Male gender, n (%)
Peak fever (C)
Duration of fever (d)
Antibiotic pretreatment, n (%)
Enteroviral season, n (%)
Seizure at or before presentation, n (%)
Mortality, n (%)
Peripheral WBC (103 cells/mm3)
CSF WBC (cells/mm3)
CSF glucose (mg/dL)
CSF protein (mg/dL)
Positive Gram stain, n (%)
Bacterial meningitis, n (%)

5.0 (2.072.0)
281 (62%)
39.0 1.0
2.1 1.7
36 (8%)
291 (64%)
33 (7%)
4 (1%)
13.5 6.8
844 2759
53 19
89 137
64 (14%)
86 (19%)

3.0 (1.739.6)
126 (53%)
39.0 0.8
2.0 1.8
16 (7%)
154 (64%)
11 (5%)
0 (0%)
13.6 9.6
611 1501
55 19
75 74
31 (13%)
39 (16%)

* Means and their standard deviations are given for all continuous variables (with the exception of
age, which is presented as a median because of substantial skewness).
P .05.

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TABLE 2.
Univariate Comparisons of Candidate Predictor Variables in the Derivation Set Between Patients With Bacterial and
Aseptic Meningitis*
Variable

Enteroviral season, n (%)

Seizure at or before
presentation, n (%)
Peripheral ANC ( 103
cells/mm3)
CSF ANC (cells/mm3)
CSF glucose (mg/dL)
CSF protein (mg/dL)
Positive Gram stain, n (%)

Bacterial
Meningitis
N 86
22 (26%)
19 (22%)
14.2
2928
37
230
62 (72%)

Aseptic
Meningitis
N 370

Difference Between
Means or Proportions
(95% CI)

P Value

269 (73%)
14 (4%)

47% (3757)
18% (927)

.001
.001

6.0

8.2 (6.110.4)

.001

2820 (17203920)
19 (1226)
173 (20226)
72% (6281)

.001
.001
.001
.001

108
56
57
2 (0.5%)

* Means are given for continuous variables and proportions for categorical variables.

Fig 1. ROC curves for each of the continuous univariate candidate predictors: peripheral ANC, CSF ANC, CSF glucose, and CSF protein.
Arrow heads indicate the identified cut offs for dichotomization of the variables (see text). The 45 line through the origin represents the
ROC curve of a test whose decision ability is no better than chance.
TABLE 3.

Multivariate Logistic Regression Analysis*

Predictor

Gram stain
CSF protein 80 mg/dL
Peripheral ANC 10 000 cells/mm3
Seizure at or before presentation
CSF ANC 1000 cells/mm3

P
Coefficient Value
5.6
2.2
2.0
1.8
1.7

95%
CI

.001 3.87.4
.001 1.03.4
.002 0.73.2
.03
0.23.4
.04 0.033.5

* Table gives the coefficient, P value, and odds ratio for each
independent predictor (P .05).

variables identified as independent predictors in the

logistic regression analysis were identified as important predictors in the recursive partitioning analysis.
The most important variable, identified at the top of
the resultant decision tree, was the Gram stain result.
For the patients with negative CSF Gram stains, the

other predictors in the decision tree accurately discriminated bacterial from aseptic meningitis. At each
step of the decision tree, the risk of bacterial meningitis can be estimated for any particular combination
of predictor variables.
Prediction Model

Based on the results of both the logistic regression

and the recursive partitioning analyses, we developed the BMS. Because the presence of a positive
Gram stain was the strongest independent predictor
of bacterial meningitis using both analytical methods, with the relative magnitude of the -coefficient
roughly twice that of the other variables, 2 points
were attributed to a positive Gram stain and 1 point
for each of the remaining variables. The range of the
resulting BMS was thus 0 to 6 points (Table 4).

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Fig 2. Results of the recursive partitioning analysis on the derivation set. Each box gives the number (and percentage) of patients with
bacterial and aseptic meningitis given the particular combination of predictor variables. Patients missing predictor variables have been
excluded (n 19).

The performance of the BMS was then tested on

the validation set (Fig 3). A BMS of 0 accurately
identified patients with aseptic meningitis without
misclassifying any child with bacterial meningitis as
having aseptic meningitis. The negative predictive
value (NPV) of a score of 0 for bacterial meningitis
was 100% (144/144, 95% confidence interval [CI]:
97%100%), and the specificity was 73% (144/196,
95% CI: 91%100%). A BMS 2 predicted bacterial
meningitis with a sensitivity of 87% (33/38, 95% CI:
72%96%), and a positive predictive value of 87%
(33/38, 95% CI: 72%96%).
When applied to the entire data set, the BMS misclassified only 3.3% of the patients. Of all patients
with a BMS 0 in the derivation and validation data
sets (predicted to have a low likelihood of bacterial
meningitis), 2 of 404 patients (0.5%; 95% CI: 0.06%
1.8%) actually had bacterial meningitis. The 2 patients thus misclassified were both in the derivation
set. One was a 7-month-old child with pneumococcal
meningitis who had a CSF WBC of 11 cells/mm3 and
peripheral ANC of 4.5 103 cells/mm3. This patient
had been pretreated with parenteral antibiotics before the lumbar puncture. The second patient was a
6-month-old child with meningococcal meningitis
TABLE 4.

Predictor

* Possible scores range from 0 to 6.

716

with CSF WBC of 10 cells/mm3 and peripheral ANC

of 8.0 103 cells/mm3.
Subset Analyses

Bacterial Meningitis Score*

Positive Gram stain

CSF protein 80 mg/dL
Peripheral ANC 10 000 cells/mm3
Seizure at or before presentation
CSF ANC 1000 cells/mm3

Fig 3. Performance of the BMS for patients with aseptic and

bacterial meningitis in the validation set. Error bars represent the
upper end of the 95% CI. Above each bar is the number and
percentage of patients with aseptic or bacterial meningitis with a
given score. Patients missing predictor variables have been excluded (n 6).

Points
Present

Absent

2
1
1
1
1

0
0
0
0
0

We performed 2 subset analyses. In the first subset

analysis, we evaluated the performance of the model
after exclusion of patients infected with S pneumoniae. In our study, 63% of the children with bacterial meningitis cases were infected with S pneumoniae. Because the conjugate pneumococcal vaccine
reduces the incidence of invasive pneumococcal infections attributable to vaccine-type strains,35 the
prediction rule was reexamined after exclusion of

PREDICTIVE MODEL TO DISTINGUISH BACTERIAL FROM ASEPTIC MENINGITIS

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children with pneumococcal meningitis. When applied to the validation set, a BMS of 0 predicted
aseptic meningitis with 73% sensitivity (144/196,
95% CI: 67% 80%), 100% specificity (11/11, 95% CI:
72%100%), and positive predictive value of 100%
(144/144, 95% CI: 97%100%). A BMS 2 predicted
bacterial meningitis with 100% sensitivity (11/11,
95% CI: 72%100%), 97% specificity (191/196, 95%
CI: 94%99%), and 69% positive predictive value
(11/16, 95% CI: 41% 89%).
We performed a second subanalysis to evaluate
the performance of the prediction rule on patients
younger than 2 months old, because these children
are typically difficult to evaluate clinically and likely
have different risk of bacterial meningitis than older
patients. Of the 77 patients between 29 to 60 days of
age in the validation set, the prediction model accurately identified the 3 patients with bacterial meningitis.
DISCUSSION

Because accurately distinguishing bacterial meningitis from aseptic meningitis at the time of presentation is difficult, children with CSF pleocytosis are
routinely admitted to the hospital for treatment with
broad-spectrum antibiotics while awaiting results of
bacterial cultures. We have developed a scoring system based on multivariate logistic regression and
recursive partitioning analyses of data obtained from
hospitalized children with bacterial and aseptic meningitis. This prediction rule is based solely on data
that are objective and readily available at the time of
presentation. As shown by the performance of the
BMS on the validation set, this score accurately identifies patients both at high and very low risk of
bacterial meningitis.
Several findings of the current study are consistent
with prior investigations. We found Gram stain, seizure at or before presentation, peripheral ANC, CSF
ANC, and CSF protein to be significant univariate
predictors of bacterial meningitis, as shown in previous analyses.711,13,14 The considerable overlap of
these variables between the patients with aseptic and
bacterial meningitis, however, limits their discriminative ability when applied as univariate predictors.
Our study differs from previous studies in being
the first validated multivariate model derived from a
pediatric population in the postconjugate Hib vaccine era. As compared with the multivariate model
developed by Spanos and colleagues,27 our study
population comprises only children from an era in
which meningitis attributable to Hib has become
exceedingly rare because of widespread vaccination
(and indeed, no cases of Hib meningitis were found
in our population). In the model by Spanos, age was
a highly predictive variable, whereas the age of the
patient was not a significant predictor in our study.
This difference may reflect the fact that their study
included patients of all ages (1 month), whereas
our study included only pediatric patients (29
days18 years of age). Finally, although aseptic meningitis is more likely to occur in the enteroviral season, we did not find that time of the year provided
significant independent discriminative power with

respect to the prediction of bacterial versus aseptic

meningitis. The predictive model by Freedman and
colleagues13 was developed on a pediatric population in the era of widespread Hib vaccination, but the
absence of validation makes it difficult to ascertain
the generalizability of their findings.
The use of the BMS score could have important
implications for clinicians caring for children with
meningitis. First, it is simple to use, as it is based on
variables that are readily available at the time of
initial patient evaluation. Second, it allows for rapid
and accurate discrimination of patients at either high
or very low risk of bacterial meningitis. The determination that a patient has a high risk of bacterial
meningitis would allow for prompt recognition of
the severity of illness and immediate antibiotic administration and hospitalization, with transfer to a
tertiary pediatric facility, if necessary. Conversely,
patients with a BMS score of 0 can be considered to
be at very low risk of bacterial meningitis. Hospitalization may not necessarily be warranted for some of
these patients. Four hundred four (60%) admitted
patients in our study had a BMS of 0 and thus could
have been considered to be at very low risk of bacterial meningitis (with a misclassification rate of
0.5%). A subset of these patientsincluding those
who were very well appearing, well hydrated, and
without any signs of neurologic or hemodynamic
compromise could conceivably have been followed
as outpatients, perhaps after the administration of a
long-acting parenteral antibiotic.36,37
Potential limitations of our study should be considered. Ideally, a prediction rule should be derived,
and then be validated prospectively on a separate
population.38 However, because the incidence of bacterial meningitis is relatively low, our study was
based on a retrospective analysis of data from hospitalized children over an 8-year period. We confirmed the validity and robustness of this model by
evaluating the performance of the BMS on a separate,
randomly selected, subset of patients. Although evaluation of the general appearance of the patients and
prospective validation of the model would be ideal,
the fact that all the variables used in the BMS are
objective historical and laboratory parameters gathered at the time of initial presentation makes it unlikely that the results would greatly change had the
study been conducted prospectively using the same
predictor variables. We also had high rate of complete data collection; 96% of the patients in the database had no missing data for the analyzed variables.
Because patients with aseptic meningitis who were
pretreated were excluded from the analysis, this
model should not be applied to patients who have
received systemic antibiotics within 72 hours of lumbar puncture.
The incidence of bacterial meningitis in our study
was 18%, considerably higher than reported population estimates. This likely reflects referral bias, as
patients with bacterial meningitis were transferred
from other hospitals for admission more often than
those with aseptic meningitis (52% vs 6%). Because
this bias affects the prevalence of bacterial meningitis
in our patient population, the PPVs and NPVs of the

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BMS must be interpreted with this in mind. In contrast, however, the sensitivity and specificity of our
scoring system are not affected by this potential bias.
Finally, several of the lumbar puncture results may
have been confounded by the presence of a high CSF
RBC (10 000 cells/mm3). From the outset of the
study, we chose not to attempt to apply any correction factor in these cases, as there is no routinely
accepted method to adjust for CSF WBC or protein in
the presence of elevated CSF RBC.39,40 We believe
that this decision did not adversely affect our results,
however, because the number of children in which
the CSF RBC was elevated was relatively low (n
23, 3% of all patients), but similar to other centers,13
and all of these patients had aseptic meningitis. This
would tend to bias against our model because of the
corresponding increase in CSF WBC and protein in
these children with aseptic meningitis who had elevated CSF RBC.
The epidemiology of bacterial meningitis in the
United States has been substantially transformed
over the past decade with the advent of universal
Hib immunization. The incidence of bacterial meningitis in children is likely to be reduced further over
the next few years as a consequence of pneumococcal
conjugate immunization. Nevertheless, because of
the multiple pathogens responsible for pediatric
meningitis,1 the possibility of pneumococcal serotype replacement41 43 and the realities of underimmunization44 and vaccine failures,45,46 a prediction
rule such as the BMS that identifies patients at very
low risk of bacterial meningitis and who may be
considered for outpatient therapy may be beneficial
to patients and result in important cost savings.
ACKNOWLEDGMENTS
We wish to acknowledge the support provided by a resident
research grant from the American Academy of Pediatrics (to Dr
Nigrovic) and a grant by the Meningitis Research Foundation (to
Dr Malley).

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DOGS HELP PROTECT PEOPLE PRONE TO EPILEPTIC SEIZURES

Florida Is Poised to Recognize Their Role

. . . In Florida . . . the State Legislature unanimously passed a bill last week that
extends to people who have seizure disorders the right to be accompanied in public
places by a trained service dog. . . Florida may be the first state to pass such a
measure. . . A study of patients and their seizure-alert dogs by the University of
Floridas Epilepsy Clinic in 1998 determined that some dogs do detect seizures, but
the scientists did not have the money to investigate whether early detection was a
spontaneous reaction or trainable behavior. . . One nonprofit agency that trains the
dogs, Canine Assistants, Inc. of Alpharetta, Georgia, says it has placed 17 Golden
and Labrador Retrievers with epileptic owners in 7 years, expects to place 10 this
year alone and has a waiting list for 60 dogs.

Canedy D. New York Times. March 29, 2002

Noted by JFL, MD

ARTICLES
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719

Development and Validation of a Multivariable Predictive Model to Distinguish

Bacterial From Aseptic Meningitis in Children in the Post- Haemophilus
influenzae Era
Lise E. Nigrovic, Nathan Kuppermann and Richard Malley
Pediatrics 2002;110;712
DOI: 10.1542/peds.110.4.712
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright 2002 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on May 12, 2015

Development and Validation of a Multivariable Predictive Model to Distinguish

Bacterial From Aseptic Meningitis in Children in the Post- Haemophilus
influenzae Era
Lise E. Nigrovic, Nathan Kuppermann and Richard Malley
Pediatrics 2002;110;712
DOI: 10.1542/peds.110.4.712

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/110/4/712.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2002 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on May 12, 2015