BRIEF REPORT
Influence of Admission Findings on
Death and Neurological Outcome
from Childhood Bacterial Meningitis
Irmeli Roine,1 Heikki Peltola,2 Josefina Fernández,4 Inés Zavala,5
Antonio González Mata,7 Silvia González Ayala,9 Antonio Arbo,12
Rosa Bologna,10 Greta Miño,6 José Goyo,8 Eduardo López,11
Solange Dourado de Andrade,13 and Seppo Sarna3
1
Universidad Diego Portales, Facultad de Ciencias de la Salud, Santiago, Chile;
Helsinki University Central Hospital, Hospital for Children and Adolescents, and
3
Department of Public Health, University of Helsinki, Finland; 4Clinica Infantil Dr.
Robert Reid Cabral, Santo Domingo, Dominican Republic; 5Hospital de Niños Dr.
Roberto Gilbert and 6Hospital del Niño Dr. Francisco de Icaza Bustamante,
Guayaquil, Ecuador; 7Hospital Pediatrico Dr. Agustin Zubillaga, Barquisimeto,
and 8Hospital Universitario de los Andes, Mérida, Venezuela; 9Hospital de
Niños Sor Maria Ludovica, La Plata, and 10Hospital de Pediatrı́a Dr. Juan P.
Garrahan and 11Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires,
Argentina; 12Instituto de Medicina Tropical, Universidad Nacional de Asunción,
Paraguay; and 13Fundacão de Medicina Tropical do Amazonas, Institute for
Tropical Diseases, Manaus, Brazil
2
A post hoc analysis of 654 children with bacterial meningitis
showed that the level of consciousness is the most important
predictor of death and/or neurological sequelae, more than
is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies
examining treatment efficacy.
In childhood bacterial meningitis, the causative agent is considered to play such a pivotal role for outcome that most clinical
studies are analyzed according to the disease etiology [1–3].
This would be justified if etiology had a clearly greater impact
on outcome than do other, well-known prognostic indices, such
as age [4], CSF glucose concentration [4], level of consciousness
[4, 5], and the risk of mortality score [6].
The ranking of the importance of admission findings requires
a large number of data; otherwise, significance may be missed
even it exists (beta error [7]). We used our exceptionally large
series of 654 children with bacterial meningitis [8] to determine,
post hoc, through multiple logistic regression analyses, the in-
Received 5 November 2007; accepted 12 December 2007; electronically published 17 March
2008.
Reprints or correspondence: Dr. Irmeli Roine, Los Misioneros 2237, Providencia, Santiago,
Chile ([email protected]).
Clinical Infectious Diseases 2008; 46:1248–52
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4608-0018$15.00
DOI: 10.1086/533448
1248 • CID 2008:46 (15 April) • BRIEF REPORT
dependent predictors of outcome. Only simple criteria, which
could be expected to be available in developing countries, where
most patients with meningitis live, were included.
Patients and methods. This is a post hoc analysis of prospectively collected hospital admission and outcome data from
654 children with bacterial meningitis from the 10 hospitals
listed in the affiliations [8]. The study, the patients, and the
treatments were described in detail elsewhere [8].
Eighty-six (13%) of the 654 children died. At hospital discharge, 556 (98%) of the 568 survivors were evaluated for the
presence of predefined severe neurological sequelae (table 1);
44 (8%) were detected. Predefined milder neurological sequelae
were sought for in 555 (98%) children; 102 (18%) were found
(table 1). Detailed analysis of hearing impairment among study
subjects will be published elsewhere.
The admission data were projected against 3 outcome measures: death, death or severe neurological sequelae, and death
or any neurological sequelae—first by use of univariate analysis
and then by multivariate analysis.
Student’s t test and the x2 test were used in the univariate
analyses. Continuous variables without normal distribution
were log transformed before analysis.
Variables with a P value !.1 in univariate analysis were submitted to a binary logistic regression model with use of each
of the outcomes, 1 at a time, as the dependent variable. In this
analysis, the continuous variables, which do not have a clinically
relevant unit of change (such as 1 month), were dichotomized
using cutoff limits employed elsewhere (e.g., 20 mg/dL of CSF
glucose [4]). Glasgow Coma Score was stratified into 4 categories (15–13, 12–10, 9–7. and ⭐6), and each lower category
was compared with the highest category (i.e., 15–13). Meningitidis caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b (Hib) were compared with those caused by other or unknown agents. Because
this analysis included only patients for whom all data were
available—this was not always the case—the number of patients
is dissimilar in tables 1 and 2.
The variables, which show a P value !.05 in the multivariate
analysis, are considered to be independent predictors of the
dependent variable. The results are expressed as ORs with 95%
CIs. Statistical calculations were performed using StatView software, version 5.1 (SAS).
Results. Young age, convulsions, delay in presentation, low
Glasgow Coma Score, slow capillary-filling time, low CSF glucose and high protein concentrations, low blood leukocyte
count, low blood hemoglobin level, and pneumococcal etiology
1916 (5529)
1575 (6270)
189/221 (86)
32/221 (14)
30/132 (23)
1/110 (1)
23/191 (12)
Streptococcus pneumoniae
Neisseria meningitidis
Other or unknown agent
!.001
!.001
.35
!.001
.07
.27
!.001
.59
40/188 (21)
2/108 (2)
!.001
45/215 (21)
43/131 (33)
.47f
!.001
106 (49)
.52
8.4 (2.2)
12.5 (10.6)
9 (17)
249 (194)
1515 (3830)
3.0 1.2
93 18
127 26
10 (15–3)
5
148/188 (79)
106/108 (98)
88/131 (67)
170/215 (79)
104 (53)
9.5 (2.9)
35/204 (17)
96 (41)
7 (9)
232 (36)
Yes
!.001
!.001
.06
!.001
.32
.005
!.001
.68
!.001
!.001
.76
.53
!.001
59/189 (31)
8/107 (7)
62/129 (48)
102/214 (48)
106 (53)
8.5 (2.5)
11.8 (11.1)
10 (21)
200 (157)
1450 (4812)
2.7 1.1
93 19
127 29
11 (15–3)
5
.72
85/211 (40)
!.001 121/221 (55)
.001
.97
!.001
P
15.7 (11.1) !.001
19 (39)
139 (153)
1990 (5500)
2.2 0.8
95 17
120 25
14 (15–4)
3
166/463 (36)
128/476 (27)
49/457 (11)
213 (42)
512 (80)
14 (42)
No
!.001
!.001
.009
!.001
!.001
.08
!.001
.13
!.001
.03
.93
!.001
P
130/189 (69)
99/107 (93)
67/129 (52)
112/214 (52)
103 (52)
9.7 (3.0)
.08
!.001
.002
!.001
.68
!.001
16.3 (11.0) !.001
21 (41)
138 (158)
2180 (5733)
2.0 1.0
95 19
120 30
14 (15–5)
3
125/368 (34)
86/378 (23)
39/365 (11)
171 (42)
18 (50)
409 (64)
No
Death or any
neurological sequelaeb
(n p 641)
b
Severe sequelae were sought for in 556 of 568 of the children who survived; 44 were found: blindness (7), quadriplegia (8), hydrocephalus requiring a shunt (4), and severe psychomotor retardation (25).
Milder neurological sequelae were sought for in 555 of 568 of the children who survived; 102 were found: hemiparesis (21), monoparesis (14), paraparesis (1), moderate psychomotor retardation (13), and
ataxia (53).
c
Irritability, vomiting, absent look, neck rigidity, or convulsions observed by mother.
d
No. of results if not available from all.
e
During present illness, before bacterial meningitis was diagnosed.
f
Compared with all other patients without this etiology.
a
NOTE. Data are no. (%) of patients, proportion (%) of patients, or mean SD, unless otherwise indicated. IQR, interquartile value.
168/191 (88)
102/132 (77)
109/110 (99)
105 (52)
25/113 (22)
54 (42)
130 (20)
7 (9)
Yes
Death or severe
neurological sequelaea
(n p 642)
.54
44/117 (38)
!.001 79/124 (64)
.04
.25
.03
P
15.3 (11.0)
.003
9.3 (3.0)
!.001
106 (52)
11.7 (13.7)
8.5 (2.6)
Glucose, mg/dL (n p 577)
Etiology
Haemophilus influenzae
Leukocytes, ⫻103/mm3 (n p 601)
Hemoglobin, g/dL (n p 603)
18 (38)
143 (154)
2.2 0.9
3.0 1.2
Capillary-filling time, s (n p 612)
CSF, median values (IQR values)
Leukocytes per mm3 (n p 555)
8 (15)
254 (310)
95 17
121 25
91 19
125 27
Systolic blood pressure, mm Hg (n p 493)
Pulse, rate per min (n p 595)
Glucose mg/dL (n p 571)
Protein g/dL (n p 651)
Blood, median values (IQR values)
13 (15–3)
3
184/513 (36)
163/529 (31)
9 (15–3)
5
Median (range) (n p 612)
IQR value
Prior use of antimicrobial agents
Convulsions before hospital admissione
Glasgow Coma Score
30/76 (39)
49/81 (60)
61/506 (12)
15/73 (21)
e
244 (43)
31 (36)
Female sex
First symptomsc,d 148 h before presentation
568 (87)
12 (41)
No
86 (13)
8 (11)
Yes
No. of patients
Age, median months (IQR value) (n p 647)
Variable
Death
(n p 654)
Table 1. Univariate analysis of the associations between admission findings and death, death or severe neurological sequelae, and death or any neurological sequelae in
childhood bacterial meningitis by Student’s t test and the x2 test.
Table 2. Multivariate analysis of the associations between hospital admission findings and death, death or severe neurological
sequelae, and death or any neurological sequelae in childhood bacterial meningitis.
Death or severe
neurological sequelae
(n p 356)
Death
a
(n p 332 )
Variable
Death or any
neurological sequelae
(n p 296)
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
3.09 (1.06–9.02)
3.27 (0.93–11.56)
.04
.07
3.51 (1.49–8.25)
10.64 (3.66–30.99)
!.001
5.70 (1.96–16.57)
3.67 (1.79–7.53)
!.001
⭐6
c
Age
First symptoms 148 h before presentation
Convulsions before hospital admission
8.98 (2.26–35.69)
1.00 (0.99–1.01)
.002
.96
28.83 (6.77–122.77)
1.00 (0.99–1.01)
!.001
!.001
.46
12.94 (2.84–58.92)
0.99 (0.98–1.002)
1.88 (0.61–5.78)
1.44 (0.58–3.54)
.27
.43
3.43 (1.19–9.88)
1.76 (0.82–3.79)
.02
.15
1.51 (0.61–3.75)
2.20 (1.11–4.37)
.38
.02
Systolic blood pressure !90 mm Hg
Pulse rate ⭓120 per min
Capillary-filling time 13 s
CSF
1.49 (0.62–3.58)
…
5.11 (1.80–14.54)
.37
…
.002
…
1.32 (0.61–2.89)
2.17 (0.75–6.29)
…
.48
.16
0.74 (0.36–1.49)
1.62 (0.84–3.14)
4.56 (1.43–14.55)
.40
.15
.01
…
1.53 (0.58–4.04)
2.72 (1.12–6.63)
…
.39
.03
1.15 (0.53–2.48)
1.25 (0.56- 2.79)
5.52 (2.42–12.59)
.72
.59
1.04 (0.53–2.02)
2.56 (1.27–5.15)
.92
.009
!.001
1.76 (0.81–3.82)
.15
1.28 (0.55–2.98)
.56
2.65 (1.21–5.77)
.01
2.16 (1.13–4.12)
.02
2.65 (0.85–8.30)
.09
2.49 (0.83–7.46)
.10
1.45 (0.43–4.23)
.61
Haemophilus influenzae
Streptococcus pneumoniae
1.03 (0.33–3.20)
1.72 (0.58–5.14)
.96
.33
0.66 (0.24–1.77)
1.14 (0.43–3.05)
.40
.79
1.89 (0.82–4.35)
1.04 (0.40–2.69)
.13
.94
Neisseria meningitidis
0.48 (0.05–4.43)
.51
0.48 (0.09–2.68)
.40
0.30 (0.06–1.56)
.15
Glasgow Coma Scoreb
12–10
9–7
Leukocytes !1000/mm3
Glucose ⭐20 mg/dL
Protein ⭓250 g/dL
.004
.001
.13
Blood
Leukocytes !15,000/mm3
Hemoglobin !7 g/dL
Etiologyd
NOTE. All values are the result of binomial logistic regression analysis.
a
b
c
d
No. of patients with all of the tested data available.
Compared with the Glasgow Coma Score of 15–13.
Each additional month after age 2 months.
Compared with patients with other or unknown etiology.
were associated with an increased risk of all 3 outcome measures
in univariate analysis (table 1). Meningococcal etiology showed
an association with better prognosis. Several other variables had
some prognostic importance, but not throughout all outcomes.
In multiple logistic regression, the only factor that emerged
as an independent predictor for the 3 outcomes was the Glasgow Coma Score (table 2).
Death. The lowering level of consciousness began to increase the risk of death when the Glasgow Coma Score was
12–10 (OR, 3.09; 95% CI, 1.06–9.02; P p .04). When it was
⭐6, the risk was 9-fold higher, compared with patients with a
Glasgow Coma Score of 15–13 (OR, 8.98; 95% CI, 2.26–35.69;
P p .002). Also, a capillary-filling time 13 s (OR, 5.11; 95%
CI, 1.80–14.54; P p .002) and a CSF protein concentration
⭓250 g/dL (OR, 2.72; 95% CI, 1.12–6.63; P p .03) added to
the likelihood of death. Etiology and other findings played a
lesser role (P 1 .05).
Death or severe neurological sequelae. The impact of the
level of consciousness on this outcome measurement was even
1250 • CID 2008:46 (15 April) • BRIEF REPORT
more pronounced than on the other outcome measurements
(table 2). Each lowering category of Glasgow Coma Score increased the risk, first 3.51 times (95% CI, 1.49–8.25; P p
.004), then 10.64 times (95% CI, 3.66–30.99; P ! .001), and,
finally, 28.83 times (95% CI, 6.77–122.77; P ! .001). Next in
importance came a high CSF protein concentration (OR, 5.52;
95% CI, 2.42–12.59; P ! .001). Also, a WBC response !15,000/
mm3 (OR, 2.65; 95% CI, 1.21–5.77; P p .01) and the presence
of symptoms for 148 h before hospital admission (OR, 3.43;
95% CI, 1.19–9.88; P p .02) worsened this prognosis. Again,
etiology and other findings played a lesser role (P 1 .05).
Death or any neurological sequelae. Five variables had a
significant impact on this outcome. The level of consciousness
was again pivotal, with the Glasgow Coma Score of 12–10
increasing the risk 3.67 times (95% CI, 1.79–7.53; P ! .001),
the 9–7 score increasing the risk 5.70 times (OR, 4.56; 95% CI,
1.96–16.57; P p .001), and the ⭐6 score increasing the risk
12.94 times (OR, 4.56; 95% CI, 2.84–58.92; P ! .001; table 2).
Next in importance was a capillary-filling time 13 s (OR, 4.56;
Table 3.
Mortality according to causative agent and the child’s level of consciousness on hospital admission.
Glasgow Coma Score
15–13
Variable
All patients
Haemophilus influenzae
Streptococcus pneumoniae
a
b
c
d
e
12–10
⭐6
9–7
No. of
a
patients
No. (%)
who died
No. of
a
patients
No. (%)
who died
No. of
a
patients
No. (%)
who died
360
131
17 (5)
b
4 (3 )
7 (13b)
155
23 (15)
66
c
20
18
55
51
41
9 (18 )
7 (17c)
No. of
a
patients
No. (%)
who died
22 (33)
31
20 (65)
d
10
16
8 (80 )
10 (63e)
9 (45 )
6 (33d)
e
No. of patients with the specified Glasgow Coma Score at hospital admission.
P p .02, by Fisher’s exact test, for the value of the difference between the results.
P p .94, by x2 test, for the value of the difference between the results.
P p .46, by x2 test, for the value of the difference between the results.
P p .41, by Fisher’s exact test, for the value of the difference between the results.
95% CI, 1.43–14.55; P p .01). Also, a low CSF glucose concentration (OR, 2.56; 95% CI, 1.27–5.15; P p .009), lack of
blood leukocytosis (OR, 2.02; 95% CI, 1.05–3.88; P p .04), and
convulsions before hospital admission (OR, 2.10; 95% CI, 1.03–
4.25; P p .04) raised the chances of this adverse outcome. Etiology and other findings played a lesser role (P 1 .05).
Hib vs. S. pneumoniae meningitis. The Glasgow Coma
Score ranged from normal (15) to low (3) in both groups, but
the median score of patients with S. pneumoniae meningitis
(12; interquartile range value, 5) was lower than that of patients
with Hib meningitis (13; interquartile range value, 3; P p
.001). If the child was not very ill on presentation, with a score
of 15–13 on the Glasgow Coma Score, the risk of death was
almost 5 times greater with S. pneumoniae than with Hib meningitis (13% vs. 3%; P p .02) (table 3). Once the child had a
score of ⭐12, it was the Glasgow Coma Score that predicted
the outcome, not the agent.
Discussion. The pivotal observation of this study is that
the child’s level of consciousness at hospital admission is the
most important predictor of outcome from bacterial meningitis, even more so than the disease etiology. Pneumococcal
meningitis was more deleterious than other meningitides only
if the child was clinically not very ill. After the Glasgow Coma
Score decreased to !13, the window of opportunity to save the
child or to prevent neurological sequelae closed fast, and the
level of consciousness at hospital admission, not the agent, was
the main predictor of the chances of recovery.
Surprisingly, all the other tested variables had a lesser impact
on the prognosis. Although CSF protein concentration was
important, its influence was limited to the severest outcomes
of death and/or severe neurological sequelae. The often-quoted
CSF glucose concentration was significant, but only when the
milder neurological sequelae were included in the analysis, not
for the more severe prognosis. Several individual variables were
of value for single outcomes, but they lost their significance
when examined in the context of the other predictors.
The Glasgow Coma Score was initially developed to grade
disease for patients with acute brain damage [9, 10], but it is
also widely used in other conditions in which functions of the
CNS are impaired. Previous studies [5] have shown that the
level of consciousness is 1 of the important prognostic variables
in bacterial meningitis, but, to our knowledge for the first time,
our large series permitted a comparative, quantitative analysis
and put it face to face against other factors. Our findings are
in a good agreement with studies of head injury, in which
patients were stratified into 3 prognostic categories: mild injury
(score, 15–13 [11]), moderate injury (score, 12–9), and severe
injury (score, !9 [12]).
There were limitations to our study. Collecting data from 10
different institutions and laboratories and the subjectivity in
use of the Glasgow Coma Score might have caused some inconsistency in the results. On the other hand, for this reason,
if we did not see an association between a variable and an
outcome, the practical significance of such an observation is
questionable.
On the whole, our results underline how the potential benefits from any given treatment of childhood bacterial meningitis
are concretely and fundamentally restricted by the severity of
the compromise of consciousness on hospital admission. They
caution against meta-analysis of treatment efficacy that joins
together different populations from profoundly dissimilar conditions and assumes both that the individual studies would be
comparable and that the causative agent would predict the
disease outcomes. In view of our findings, external validity can
be reached only if the patient’s condition on hospital admission,
as well as etiology, is included as a covariate.
Acknowledgments
Financial support. Dr. Ralf Clemens, then with GlaxoSmithKline, provided initial study funding. The Alfred Kordelin, Päivikki and Sakari Sohlberg, and Sigfrid Jusélius foundations helped to finance the study.
BRIEF REPORT • CID 2008:46 (15 April) • 1251
Potential conflicts of interest. H.P. is currently a scientific consultant
of the Serum Institute of India. All other authors: no conflicts.
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