Clinical Prediction Rule for

Distinguishing Bacterial From

Aseptic Meningitis
Santiago Mintegi, PhD,a Silvia García, PhD,a María José Martín, MD,c Isabel Durán, MD,d
Eunate Arana-Arri, PhD, Scientific Coordination Unit, Biocruces Bizkaia Health Research Institute, Cruces University Hospital,
Osakidetza, Bilbao, Basque Country, Spain,e Catarina Livana Fernandez, MD,a Javier Benito, PhD,a Susanna Hernández-Bou, MD,b
Meningitis Group of the Spanish Society of Pediatric Emergencies

BACKGROUND:New biomarkers like procalcitonin and C-reactive protein may help design an abstract
accurate decision support tool used to identify children with pleocytosis at low or high risk of
bacterial meningitis. Our objective was to develop and validate a score (that we call the
meningitis score for emergencies [MSE]) to distinguish bacterial meningitis from aseptic
meningitis in children with pleocytosis when initially evaluated at the emergency department.
METHODS: We included children between 29 days and 14 years old with meningitis admitted to
25 Spanish emergency departments. A retrospective cohort from between 2011 and 2016 was
used as the derivation set and a prospective cohort recruited during 2017 and 2018 was used
as the validation set.
RESULTS: Among the 1009 patients included, there were 917 cases of aseptic meningitis and
92 of bacterial meningitis. Using multivariable logistic regression analysis, we identified the
following predictors of bacterial meningitis from the derivation set: procalcitonin .1.2
ng/mL, cerebrospinal fluid (CSF) protein .80 mg/dL, CSF absolute neutrophil count .1000
cells per mm3, and C-reactive protein .40 mg/L. Using the derivation set, we developed the
MSE, assigning 3 points for procalcitonin, 2 points for CSF protein, and 1 point for each of the
other variables. An MSE $1 predicted bacterial meningitis with a sensitivity of 100%
(95% confidence interval [CI]: 95.0%–100%), a specificity of 83.2 (95% CI: 80.6–85.5), and
a negative predictive value of 100% (95% CI 99.4–100.)
The MSE accurately distinguishes bacterial from aseptic meningitis in children
CONCLUSIONS:
with CSF pleocytosis.

e
Scientific Coordination Unit, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Osakidetza, WHAT’S KNOWN ON THIS SUBJECT: No single variable
Bilbao, Basque Country, Spain; aBiocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, distinguishes bacterial from aseptic meningitis in
Osakidetza and University of the Basque Country, Universidad del País Vasco/Euskal Herriko Unibertsitatea, children with cerebrospinal fluid pleocytosis.
Bilbao, Basque Country, Spain; bPediatric Emergency Department, Hospital Sant Joan de Déu, Barcelona, Combinations of several variables have been used to
Catalonia, Spain; cPediatric Emergency Department, Niño Jesus University Children’s Hospital, Madrid, Spain; and distinguish these two types of meningitis.
d
Pediatric Emergency Department, Regional University Hospital of Malaga, Malaga, Spain
WHAT THIS STUDY ADDS: The meningitis score for
Dr Mintegi conceptualized and designed the study, supervised data collection, analyzed the data,
emergencies can be used to guide initial clinical decision-
and wrote the initial draft of the manuscript; Dr García collaborated in the design of the data
making in children with cerebrospinal fluid pleocytosis,
collection system and critically revised the manuscript; Drs Martín and Benito reviewed the design
of the data collection system and critically revised the manuscript; Dr Arana-Arri collaborated in the without misclassifying children with bacterial meningitis.
design of the study, analyzed the data, and critically revised the manuscript; Dr Fernandez reviewed Including procalcitonin and C-reactive protein achieves
the design of the data collection system, supervised data collection, and critically revised the a more accurate decision support tool.
manuscript; Dr Hernández-Bou reviewed the design of the data collection system, coordinated the
inclusion of emergency departments from the Meningitis Group of the Spanish Society of Pediatric To cite: Mintegi S, García S, Martín MJ, et al. Clinical
Emergencies, and critically revised the manuscript; and all authors approved the final manuscript Prediction Rule for Distinguishing Bacterial From Aseptic
as submitted. Meningitis. Pediatrics. 2020;146(3):e20201126

Downloaded from www.aappublications.org/news at OCLU - Database Specialist on August 25, 2020

PEDIATRICS Volume 146, number 3, September 2020:e20201126 ARTICLE
Since the widespread introduction of
conjugate vaccines, most cases of
pediatric meningitis are aseptic, and
viruses remain the most common
cause.1–3 Children with viral
meningitis, a self-limiting condition,
require only supportive care. In
contrast, although uncommon,4
bacterial meningitis carries high
mortality and morbidity rates,
underlining the importance of
prompt and appropriate treatment.
Classically, because it is often difficult
to distinguish between bacterial and
aseptic meningitis, when children are
evaluated in the emergency
department (ED), those with
cerebrospinal fluid (CSF) pleocytosis
are admitted to the hospital to receive
antibiotics pending bacterial culture
results.5
No single variable distinguishes
bacterial from aseptic meningitis, and
overlaps found in values of variables
between patients with aseptic and
bacterial meningitis limit their
discriminative ability when applied as
univariate predictors. Thus,
combinations of several variables
have been used to distinguish these
two types of meningitis. Among the
clinical prediction rules, only the
bacterial meningitis score (BMS)5 was
found to accurately identify children
with CSF pleocytosis at low or high
risk of bacterial meningitis. This score
may be helpful to guide clinical
decision-making for the management
of children presenting to EDs with
CSF pleocytosis,6 and it is easy to
apply.7 It was developed after the
widespread introduction of a highly
effective bacterial vaccine against
Haemophilus influenzae type b and
validated in a postpneumococcal
conjugated vaccine cohort.6
Nevertheless, a few cases of bacterial
meningitis may be missed with use of
the BMS.8,9
In recent decades, C-reactive protein
(CRP) and procalcitonin have been
added to screening tests in febrile
children. Globally, CRP and
procalcitonin levels are the
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2 MINTEGI et al
parameters providing the most
diagnostic value in feverish children
used to detect those with serious
bacterial infection.10 Procalcitonin
offers some advantages to identify
patients with invasive bacterial
infections,11–14 specifically
meningococcal diseases,15 including
meningitis.11,16 In a previous series,
the replacement of the peripheral
absolute neutrophil count (ANC) with
procalcitonin significantly increased
the specificity of the BMS.17
Our main objective of this study was
to develop and validate a score, which
we have called the meningitis score
for emergencies (MSE), to distinguish
bacterial meningitis from aseptic
meningitis in children with
pleocytosis when initially evaluated
at the ED. Our secondary objective
was to compare the performance of
the new decision support tool to
the BMS.
Our hypothesis was that including
procalcitonin and CRP would achieve
a more accurate decision support tool
for distinguishing bacterial from
aseptic meningitis in children with
CSF pleocytosis.
METHODS
Study Design
This was a cohort study of children
between 29 days and 14 years old
diagnosed with meningitis in 25
pediatric EDs that are members of the
Infectious Diseases Working Group of
the Spanish Society of Pediatric
Emergencies.18,19
Inclusion Criteria
To be included, the children were
required to have CSF pleocytosis and
data on all the following: blood and
CSF bacterial cultures, white blood
cell (WBC) count, serum CRP, and
procalcitonin.
Exclusion Criteria
We excluded the following children:
those who were ,29 days old,
critically ill, with purpura, and not
previously healthy and/or treated
with antibiotics within 72 hours
before the lumbar puncture.
Patient Identification and Data
Collection
To create the derivation set, the
patients were retrospectively
included from December 31, 2016,
backward to a maximum of 6 years
(until January 2011), depending on
when procalcitonin testing was
introduced in each hospital.
Regardless of the date when the
procalcitonin levels started to be
measured, the study period for each
hospital was required to be a multiple
of 12 months to avoid possible bias
due to seasonal variations. In the
retrospective phase of the study,
patients were identified by using the
electronic records of the hospitals
included in the study. Data on
patients and episodes were obtained
from the electronic health records of
the pediatric EDs and health system.
Researchers were asked to review all
episodes corresponding to children
diagnosed with meningitis following
the coding system of the Spanish
Society of Pediatric Emergencies
(based on International Classification
of Diseases, Ninth Revision). Cases of
children diagnosed with meningitis
and found to have CSF pleocytosis
were reviewed.
The validation set was created by
prospectively including patients in
2017 and 2018. In the prospective
phase, patients were identified by the
physician responsible who completed
the questionnaires after ED discharge
for patients who were discharged
from the ED and after hospital
discharge for patients who were
admitted to the hospital to obtain
complete patient information and
both ED and hospital outcomes.
For all the patients included, data for
following variables were collected
and entered onto structured data
sheets: date of birth, sex, date of
admission and discharge, previous
and current medical history of
conditions including seizures,
duration and peak of fever at
admission, antibiotic pretreatment,
peripheral WBC count and ANC, CSF
WBC count and ANC, CSF red blood
cell count, CSF glucose, CSF protein,
Gram-stain if obtained, blood and CSF
culture results, results of polymerase
chain reaction (PCR) tests (both
bacterial and viral) if performed, and
disposition on discharge. The
laboratory values included were
those obtained when the child arrived
at the ED.
Specific electronic questionnaires
were completed via Google Drive for
all children included. Questionnaires,
in addition to a study manual, were
distributed to site investigators (ED
physicians) before the initiation
of the study to check the text
understandability and
appropriateness for data collection to
ensure clarity of the final data
collected. The completed
questionnaires were then sent
electronically to the principal
investigator (S.M.).
Definitions
Bacterial Meningitis
Bacterial meningitis was defined as
patients with either one of the
following two criteria: (1)
identification of bacterial pathogen in
CSF by growth in bacterial culture
and/or, for Neisseria meningitidis or
Streptococcus pneumoniae, genomic
detection in CSF using the PCR
technique (RealCycler MENE and
RealCycler MENELI; Progenie
Molecular, Valencia, Spain); or (2) the
presence of CSF pleocytosis ($10
WBCs per mm3) and either a positive
blood culture result and/or, for N
meningitidis or S pneumoniae,
genomic detection in blood using the
PCR technique. Certain bacterial
species (including Staphylococcus
epidermidis, Propionibacterium
acnes, Streptococcus viridans,
Corynebacterium spp., and other
diphtheroids) isolated in otherwise
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PEDIATRICS Volume 146, number 3, September 2020
healthy patients were considered to
be contaminants.
Aseptic Meningitis
Aseptic meningitis included patients
with CSF pleocytosis and negative
CSF and blood bacterial cultures as
well as negative genomic detection of
N meningitidis and S pneumoniae
using the PCR technique, if
performed.
Pleocytosis
Pleocytosis was defined as having CSF
WBCs $10 cells per mL, corrected for
the presence of CSF red blood cells by
using a 1:500 ratio of leukocytes to
erythrocytes usually found in
peripheral blood.20 We also corrected
the CSF protein (for every 1000-cell
increase in CSF red blood cells per
mm3, we considered that CSF protein
increased by 1.1 mg/dL).21
Well-Appearing
We defined well-appearing children
as those who had a normal pediatric
assessment triangle in the case of EDs
in which these data are systematically
recorded and, otherwise, if the
findings of the physical examination
documented in the patient medical
record indicated no clinical suspicion
of sepsis. Descriptors that led to
exclusion included but were not
limited to “poor/bad general
appearance,” “irritable,” “cyanosis,”
“hypotonic,” and “cutis marmorata.”
Critically Ill Children
Critically ill children were those with
severe mental disturbance, evidence
of cerebral herniation, or need for
respiratory or hemodynamic support.
Previously Healthy Children
Previously healthy children were
defined as those without any of the
following risk factors: (1)
immunosuppression (associated with
cancer, chronic renal failure, sickle
cell disease, or being a transplant
recipient); (2) the presence of
a mechanical device (indwelling
catheter, ventriculoperitoneal shunt,
auditory prostheses); (3) history of
an invasive diagnostic or therapeutic
procedure in the previous 10 days; or
(4) CSF fistula. In the derivation set,
this was determined after reviewing
the entire chart of the patient, not
only ED documentation. In the
validation set, after reviewing the
entire chart and asking to the parents.
Statistical Methods
We included the patients identified
retrospectively in a derivation set.
Subsequently, the validation set
comprised the patients recruited
prospectively.
Derivation Set
We conducted a receiver operating
characteristic (ROC) curve analysis
including the following variables: CSF
ANC, CSF WBC count, CSF protein,
CSF glucose, serum CRP, serum
procalcitonin, serum WBC count, and
serum ANC. Those revealing an area
under the receiver operating
characteristic curve (AUC) higher
than 0.90 were selected for the score.
We used the Youden index to identify
the optimal cutoff points for these
variables. Lastly, variables
independently associated with
bacterial meningitis were ranked
according to the magnitude of the
b-coefficient.
The performance of the score was
then tested in the validation set.
Specifically, the clinical decision rule
derived from the derivation set was
applied to the validation cohort. We
used the AUC as a measure of the
discriminatory performance. To
establish the diagnostic accuracy of
the score, sensitivity, negative
predictive value (NPV), and negative
likelihood ratio were determined.
Comparison With the BMS
We compared sensitivity, specificity,
positive predictive value, and NPV of
the two scores and the number of
cases of bacterial meningitis missed
including all the patients in the
validation set in which the Gram-stain
3
TABLE 1 Characteristics of the Patients Included in the Derivation and Validation Sets
Variable Derivation Set (n = 819) Validation Set (n = 190)
Female, n (%) 311 (38.0) 69 (36.3)
Age, mo 48 (36–72) 48 (27–84)
Highest temperature at home, °C 38.2 (37.7–38.9) 38.4 (37.8–39.0)
Temperature at the ED, °C 37.4 (36.9–38) 37.2 (36.5–37.9)
Duration of fever, h 24 (12–24) 24 (12 – 48)
Blood test results
Procalcitonin, ng/mL 0.13 (0.09–0.30) 0.10 (0.05–0.33)
CRP, mg/L 8.0 (2.1–23.0) 8.1 (3.0–34.7)
WBC count, 3103 cells per mm3 12 100 (9260–15 400) 12 690 (9300–17 000)
ANC, cells per mm3 9540 (7100–12 600) 9755 (6391–13 242)
CSF test results
WBC count, cells per mm3 126 (50–310) 163.0 (57–464)
ANC, cells per mm3 43 (10–148) 72 (10–246)
Bacterial meningitis, n (%) 61 (7.4) 31 (16.3)
Except for sex and bacterial meningitis, data are expressed as median (interquartile range).

was performed. We also compared
the AUC of the new score and BMS.
All the analyses were conducted by
using SPSS version 23 (IBM SPSS
Statistics, IBM Corporation).
Estimation of the Sample Size
Derivation Set
In a multicenter study including
children with meningitis conducted
by the Research Network of the
Spanish Society of Pediatric
Emergencies,17 the prevalence of
bacterial meningitis was 6.2%. To
achieve an accuracy of 5.0% in the
estimation of percentages with
a normal 95% bilateral asymptotic
confidence interval (CI), we needed to
include 90 patients in the study;
hence, assuming a 10% drop-out rate,
we needed to recruit 100 patients
diagnosed with bacterial meningitis.
In the aforementioned study,17 we
diagnosed 1 child .2 years of age
with bacterial meningitis per 20 000
ED episodes, and 1 patient per 51 000
ED episodes would have met the
inclusion criteria for the study. On the
basis of these data, we would have
required ∼5 100 000 ED episodes.
Considering that in the current study,
we also included infants between
2 months and 2 years old, the number
of ED episodes was expected be
somewhat lower.
Validation Set
We estimated that it would be
sufficient to include 30 children
diagnosed with bacterial meningitis
in a 2-year period.
Role of the Funding Source
We received no funding.
Ethics and Human Subjects
We obtained overall approval from
the Clinical Research Ethics
Committee of Basque Country.
Informed consent was required for
participants in the prospective phase
of the study.
RESULTS
Patient Characteristics
Globally, we registered 5 167 945 ED
presentations corresponding to
children ,14 years old in 25
pediatric EDs. Among these, 1509
patients aged between 29 days
and 14 years old had pleocytosis
and were diagnosed with
meningitis (1341 cases of
aseptic meningitis and 168 of
bacterial meningitis), but 488 were
excluded (412 with aseptic
meningitis and 76 bacterial
meningitis). Hence, finally, we
included 1009 patients between
29 days and 14 years old (917
with aseptic meningitis and 92
bacterial meningitis). Bacterial
meningitis was caused by the
following pathogens: N meningitidis
in 38 cases (41.3%), S pneumoniae
in 35 (38.5%), group B Streptococcus
in 5 (5.5%), Streptococcus pyogenes
in 4 (4.3%), Enterococcus faecalis in 2
(2.2%), H influenzae in 2 (2.2%),
Escherichia coli in 1 (1.1%), Listeria
monocytogenes in 1 (1.1%),
Salmonella typhimurium in 1 (1.1%),
Streptococcus bovis in 1 (1.1%),
Kingella kingae in 1 (1.1%), and
Fusobacterium necrophorum in 1
(1.1%). Of these patients included,
819 (758 aseptic meningitis and 61
bacterial meningitis) were in the
derivation set and 190 (159 aseptic
meningitis and 31 bacterial
meningitis) were in the validation set
(Supplemental Fig 2).
The main characteristics of the
patients included are shown in
Table 1.
Selection of the Variables for the
Score by Using the AUC Curve in the
Derivation Set
In the ROC curve analysis, CSF ANC,
CSF protein, serum CRP, and serum
procalcitonin revealed an AUC .90%
(Supplemental Fig 3).
Selection of the Optimal Cutoff Point
by Using the Youden Index in the
Derivation Set
Using the Youden index, we
established the following cutoff
points: serum procalcitonin of 1.2 ng/

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4 MINTEGI et al
TABLE 2 Bivariate Comparison of Predictors in the Derivation Set Between Those With Aseptic
Meningitis and Bacterial Meningitis
b-Coefficient
CSF ANC .1.000/µL 11.136
Serum CRP .40 mg/L 16.271
CSF protein .80 mg/dL 31.491
Serum procalcitonin .1.20 ng/mL 65.606
CSF WBC count .500/µL 1.591
Serum ANC .10.000/mL 0.297
Serum WBC count .16.000/mL 1.09
CSF glucose .50 mg/L 0.943
mL, serum CRP of 40 mg/L, CSF
protein of 80 mg/dL, and CSF ANC
1000 per µL (Supplemental Fig 4).
The bivariate comparison of
predictors is shown in Table 2.
Development of the Prediction Model
According to the Magnitude of the
b-Coefficient
We developed the MSE on the basis of
the results of the logistic regression
(Table 3).
We assigned points to the 4 variables
on the basis of the relative magnitude
of the b-coefficient. Specifically, 3
points were assigned to the serum
procalcitonin level higher than
1.2 ng/mL, 2 points to CSF protein
.80 mg/dL, and 1 point for each of
the other variables (CSF ANC .1000
per µL and serum CRP .40 mg/L)
(Table 4). The range of the resulting
MSE was thus 0 to 7 points.
Validation Set
We tested the performance of the
MSE in the validation set. An MSE $1
predicted bacterial meningitis with
a sensitivity of 100% (95% CI:
89.0%–100%) and a specificity of
77.4 (95% CI: 70.3–83.2). Similar
values were found when applying the
MSE to both derivation and validation
sets (Table 4). Distributions of all the
TABLE 3 Multivariate Logistic Regression Analysis
b-Coefficient
Serum procalcitonin .1.20 ng/mL 484.50
Serum CRP .40 mg/L 66.02
CSF ANC .1000/µL 73.18
CSF protein .80 mg/dL 117.80
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PEDIATRICS Volume 146, number 3, September 2020
and aseptic meningitis in children
between 2 months and 14 years old
95% CI Significance with CSF pleocytosis, without
1.86–66.61 .008 misclassifying those with bacterial
3.50–75.62 .000 meningitis. As shown in the validation
6.81–145.67 .000 set, the inclusion of procalcitonin and
14.80–290.93 .000 CRP levels improves the accuracy of
0.06–41.61 .780
a previous validated decision support
0.33–2.65 .277
0.00–2.97 .994 tool for this context, the BMS.
0.12–7.51 .956
We recommend that physicians admit
and give antibiotics to all febrile
children with pleocytosis and MSE
patients included in the study with
$1. On the other hand, a less
bacterial and aseptic meningitis
conservative management can be
related to the value of the MSE are
considered for those well-appearing,
shown in Fig 1. No children diagnosed
previously healthy febrile children
with bacterial meningitis in the
without purpura with pleocytosis and
derivation or validation sets had an
MSE ,2 who have no received
MSE ,2.
antibiotics within 72 hours before the
Comparison to BMS lumbar puncture. In this set of
patients, discharge without
Finally, we compared the
antibiotics may be recommended if
performance of the MSE to the BMS
adequate outpatient follow-up can be
(Table 5) and the AUC of the new
ensured.
score and BMS (Supplemental Fig 5).
Procalcitonin and CRP have
In the validation set, 2 patients with
BMS = 0 were diagnosed with commonly been used in the
management of children at risk for
bacterial meningitis: a 1-month-old
boy with meningitis with serious bacterial infection.10 In fact,
procalcitonin and CRP have shown
Streptococcus agalactiae (no seizure,
negative Gram-stain result, CSF a better performance than WBC count
and ANC to distinguish serious
protein = 74.5 mg/dL, CSF ANC = 127
per µL, peripheral ANC = 2590 per µL, bacterial infections from viral
illnesses. In addition, procalcitonin
serum procalcitonin = 92.4 ng/mL,
and serum CRP = 122.7 mg/L) and offers some advantages in the
identification of patients with
a 3-year-old girl with meningococcal
meningitis (no seizure, negative invasive bacterial infections,11–14
specifically patients with
Gram-stain result, CSF protein =
60 mg/dL, CSF ANC = 900 per µL, meningococcal diseases,15 including
peripheral ANC = 9600 per µL, serum meningitis.11,16 In line with this, in
procalcitonin = 20.50 ng/mL, and a previous series, the replacement of
serum CRP = 123.7 mg/L). the peripheral ANC with procalcitonin
significantly increased the specificity
of the BMS.17 The BMS includes 5
DISCUSSION dichotomous predictors (seizures
In this large multicenter study, the during or before presentation, the
MSE accurately identified bacterial ANC in peripheral blood and in CSF,
CSF protein, and CSF Gram-stain).5 In
our study, 2 patients with bacterial
meningitis had a BMS of 0. One of
95% CI P them was a 3-year-old girl with
161.46–1453.87 ,.0001 meningococcal meningitis. This
31.05–140.38 ,.0001 supports that some children with
36.10–148.33 ,.0001 meningococcal meningitis may not be
52.55–264.06 ,.0001 correctly classified with the BMS.8
5
TABLE 4 MSE
Predictor
Serum procalcitonin .1.20 ng/mL
Serum CRP .40 mg/L
CSF ANC .1000/µL
CSF protein.80 mg/dL
This is worrisome because
a significant percentage of patients
with meningococcal meningitis may
not develop a rash22; it also supports
the inclusion of procalcitonin, which
has a good performance in identifying
patients with meningococcal
infection. The second missed patient
was a 1-month-old boy with S
agalactiae meningitis. In young
febrile infants, procalcitonin has
shown a better performance than
traditional tests in identifying infants
at high risk of invasive bacterial
infections, including meningitis.12
Nevertheless, considering that few
infants ,2 months with bacterial
meningitis might be misclassified, it
was later suggested that the BMS be
used in children .2 months of
age.6,23
Like Nigrovic et al,5 we excluded
certain patients for our study: infants
,29 days old, those critically ill, those
with purpura, and those not
previously healthy. This seems
FIGURE 1
Distribution of children with bacterial and aseptic meningitis by MSE.
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6 MINTEGI et al
Points
Present Absent
3 0
1 0
1 0
2 0
reasonable. In fact, when a physician
strongly suspects bacterial
meningitis, the administration of
intravenous antibiotics should not be
delayed. On the other hand, we also
excluded, as did Nigrovic et al,5
children treated with antibiotics
within 72 hours before the lumbar
puncture because it would be difficult
to know whether they truly had
aseptic meningitis.
Gram-stain is an excellent tool for
distinguishing bacterial form aseptic
meningitis. The CSF Gram-stain result
is positive in ∼75% of cases of
bacterial meningitis.24 When the
Gram-stain result is positive, the
specificity is higher than 97%.25 In
addition, CSF Gram staining is rapid,
inexpensive, and well validated for
detecting bacteria. We decided not to
include the Gram-stain in the MSE
score for two reasons. First, it is not
available 24 hours a day and 7 days
a week in all EDs. In addition, it
seems difficult not to put a child with
CSF pleocytosis and a positive Gram-
stain result on antibiotics. In fact,
broad-spectrum antimicrobial
therapy should be continued until
CSF culture results are available.26
We recommend prescribing
antibiotics to a child with pleocytosis
and a positive Gram-stain result
regardless of the value of the MSE.
Nevertheless, we did not find any
cases of children diagnosed with
bacterial meningitis and a positive
Gram-stain result and an MSE ,2.
This study has certain limitations. We
only included children with
pleocytosis considered by Nigrovic et
al5 suitable to be assessed by using
a score in the ED. Hence, this score
should not be applied to certain
patients: those who are ,29 days old,
critically ill, with purpura, not
previously healthy, and/or treated
with antibiotics within 72 hours
before the lumbar puncture. On the
other hand, we conducted the study
in 25 Spanish EDs. It is possible that
the distribution of the causes of
bacterial meningitis varies in other
countries and would alter the
performance of the MSE and BMS.
Nevertheless, we consider that the
distribution of the main pathogens
involved in bacterial meningitis is
likely to be similar in other countries
with similar vaccination policies and
coverage and that the MSE is able to
help identify a population suitable for
outpatient management without
antibiotics. In addition, we first
developed this clinical prediction rule
and, afterward, we performed
a prospective validation, which is
typically the preferred approach for
such tools despite this being difficult
in the case of bacterial meningitis
because of its rarity in high-income
countries. Nevertheless, external
validation would be appropriate to
confirm our results. On the other
hand, in the derivation set, it is
possible to have missed some
patients with fever and CSF
pleocytosis not coded as “meningitis.”
It was not possible for all the
TABLE 5 Comparison of the Accuracy of the BMS and the MSE for Distinguishing Bacterial and
Aseptic Meningitis
Score
Validation set (n = 190)
BMS
$1
$2
MSE
$1
All the patients
(derivation 1 validation
set) (n = 1009)
BMS
$1
$2
MSE
$1
PPV, positive predictive value.
hospitals to check all the lumbar
punctures performed in the
derivation set, but all blood and CSF
cultures were checked and no child
with identification of a bacterial
pathogen in the CSF or blood was
missed. In addition, we think that not
coding meningitis for children with
pleocytosis is not expected in Spanish
EDs included in the Infectious Diseases
Working Group of the Spanish Society
of Pediatric Emergencies. We do not
think that this may bias the results of
the study. Finally, the distribution of
aseptic and bacterial meningitis varied
in the derivation and validation sets.
Nonetheless, we do not believe that this
is likely to have influenced the results
and main conclusion of the study.
CONCLUSIONS
MSE accurately distinguishes
bacterial from aseptic meningitis in
children with CSF pleocytosis. The
inclusion of procalcitonin and CRP
improves the performance of the
BMS. The MSE can be used to guide
initial clinical decision-making in
children with CSF pleocytosis without
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PEDIATRICS Volume 146, number 3, September 2020
Universitari Arnau de Vilanova de
Lleida), Silvia García (Hospital
Sensitivity, Specificity, PPV, % NPV, % Bacterial Universitario Cruces), Ana Isabel
% (95% CI) % (95% CI) (95% CI) (95% CI) Meningitis Mohedas Tamayo (Hospital
Missed, % Universitario de Fuenlabrada),
(95% CI)
Alberto Barasoain (Hospital
Universitario Fundación Alcorcón),
Helvia Benito (Hospital Universitario
93.5 50.3 26.9 97.6 6.5
(77.1–98.8) (42.3–58.3) (19.0–36.3) (90.6–99.6) (1.8–20.7) Río Hortega), Nuria Gilabert
87.1 93.7 73.0 97.4 12.9 Iriondo (L’Hospital Universitari
(69.2–95.8) (88.4–96.8) (55.6–85.6) (93.0–99.2) (5.1–28.9) Son Espases), Esther Crespo
Rupérez (Hospital Virgen de la
100 77.4 46.3 100 0 (0–11.0)
Salud Toledo), Santos García
(89.0–100) (70.3–83.2) (34.9–58.1) (97.0–100)
(La Paz Regional Hospital),
Virginia Gómez Barrena (Hospital
Universitario Miguel Servet),
Nuria Cortés Alvarez (Hospital
96.7 51.3 16.6 99.4 3.3%
Universitario Mútua Terrassa), Laia
(90.1–99.2) (48.0–54.5) (13.6–20.1) (98.0–99.8) (1.1–9.1)
90.2 95.3 65.9 99.0 9.8 Sánchez Torrent (Hospital General,
(81.8–95.2) (93.7–96.5) (56.8–73.9) (98.0–99.5) (5.2–17.6) Parc Sanitari Sant Joan de Déu),
Sandra Moya Villanueva (Hospital
100 83.2 37.4 100 0 (0–5) Universitari Parc Taulí), Susanna
(95.0–100) (80.6–85.5) (31.4–43.8) (99.4–100)
Hernández-Bou (Hospital General,
Parc Sanitari Sant Joan de Déu), Mª
Ángeles Martín (Instituto Valenciano
misclassifying children with bacterial de Pediatrïa, Unidad de Pediatrïa
meningitis. Integral Quiron, Quirón Valencia
Hospital), Esther Lera Carballo
(Vall d’Hebron University Hospital),
ACKNOWLEDGMENTS Maria Teresa Alonso (Hospital
We acknowledge Mariano Plana Universitario Virgen del Rocío),
(Barbastro), Ana Fernández Lorente Amalia Pérez (Hospital de
(Hospital Universitario Basurto), Zumárraga), Marta Velazquez
Laura Míguez-Martín (Hospital (Hospital de Terrassa, Consorci
Universitario de Cabueñes), Jose Sanitari de Terrassa).
Angel Muñoz Bernal (Hospital
Universitario Donostia), Diana
Martínez Cirauqui (Complejo ABBREVIATIONS
Hospitalario de Navarra), Javier ANC: absolute neutrophil count
Melgar Pérez (Hospital de Dénia), AUC: area under the receiver
Sara Pons (Hospital Universitaro operating characteristic
Dr Peset), María José Martín Díaz curve
(Hospital Infantil Universitario BMS: bacterial meningitis score
Niño Jesús de Madrid), Aristides CI: confidence interval
Rivas Garcia (Hospital General CRP: C-reactive protein
Universitario Gregorio Marañón), Mª CSF: cerebrospinal fluid
Ángeles García Herrero (Hospital ED: emergency department
Universitario Príncipe de Asturias de MSE: meningitis score for
Alcalá de Henares), Irene García de emergencies
Diego (Hospital Universitario del NPV: negative predictive value
Tajo), Carlos Miguel Angelats PCR: polymerase chain reaction
(Hospital Francesc de Borja de ROC: receiver operating
Gandía), Isabel Durán Hidalgo characteristic
(Hospital Regional Universitario de WBC: white blood cell
Málaga), Laura Minguell (L’Hospital
7
DOI: https://doi.org/10.1542/peds.2020-1126
Accepted for publication Jun 16, 2020
Address correspondence to Santiago Mintegi, PhD, Pediatric Emergency Department, Cruces University Hospital, Plaza de Cruces s/n, 48903 Barakaldo, Bizkaia,
Spain. E-mail: santiago.mintegi@osakidetza.eus
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2020 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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 Clinical Prediction Rule for Distinguishing Bacterial From Aseptic Meningitis
Santiago Mintegi, Silvia García, María José Martín, Isabel Durán, Eunate Arana-Arri,
Catarina Livana Fernandez, Javier Benito, Susanna Hernández-Bou and Meningitis
Group of the Spanish Society of Pediatric Emergencies
Pediatrics originally published online August 25, 2020;

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 Clinical Prediction Rule for Distinguishing Bacterial From Aseptic Meningitis
Santiago Mintegi, Silvia García, María José Martín, Isabel Durán, Eunate Arana-Arri,
Catarina Livana Fernandez, Javier Benito, Susanna Hernández-Bou and Meningitis
Group of the Spanish Society of Pediatric Emergencies
Pediatrics originally published online August 25, 2020;

The online version of this article, along with updated information and services, is
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http://pediatrics.aappublications.org/content/early/2020/08/21/peds.2020-1126

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