Jurnal meningitis

Acta Pædiatrica ISSN 0803-5253
REGULAR ARTICLE
A 15-year retrospective analysis of prognostic factors in childhood
bacterial meningitis
Liang Yi Justin Wee ([email protected])1, Raymond Reinaldo Tanugroho1, Koh Cheng Thoon2,3,4, Chia Yin Chong2,3,4, Chew Thye Choong3,4,5,
Subramania Krishnamoorthy1, Matthias Maiwald4,6,7, Nancy Wen Sim Tee4,6, Natalie Woon Hui Tan2,3,4
1.Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore City, Singapore
2.Infectious Disease Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore City, Singapore
3.Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
4.Duke-National University of Singapore Graduate Medical School, Singapore City, Singapore
5.Neurology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore City, Singapore
6.Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore City, Singapore
7.Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
Keywords
Bacterial meningitis, Disease severity, Paediatric,
Prognostic factors, Sequelae
ABSTRACT
Aim: This retrospective chart review aimed to identify factors in childhood bacterial
Correspondence
Dr Liang Yi Justin Wee, Department of Paediatrics,
KK Women’s and Children’s Hospital, 100 Bukit
Timah Road, Singapore 229899, Singapore.
Tel: (+65) 6225 5554 |
Fax: (+65) 6394 2488|
Email: [email protected]
Methods: The study included 112 episodes of microbiologically confirmed bacterial
Received
7 May 2015; revised 6 August 2015;
accepted 23 September 2015.
DOI:10.1111/apa.13228
meningitis that predicted disease severity and long-term outcome.
meningitis in children aged three days to 15 years who were admitted to a Singapore
hospital from 1998 to 2013.
Results: The mortality rate was 6%, and 44% required intensive care unit (ICU) admission.
Predictive factors associated with ICU admission included pneumococcal meningitis, with
an odds ratio (OR) of 5.2 and 95% confidence interval (CI) of 1.5–18.2, leukopenia (OR
5.6, 95% CI 1.7–17.9) and a cerebrospinal fluid (CSF):serum glucose ratio <0.25 (OR 4.5,
95% CI 1.4–14.4). An initial CSF white blood cell count >1000/mm3 (OR 0.26, 95% CI
0.086–0.76) was negatively associated with ICU admission. Five years after meningitis,
32% had residual sequelae, and the associated prognostic factors were Haemophilus
influenzae type b (Hib) meningitis (OR 29.5, 95% CI 2–429), seizures during their
inpatient stay (OR 10.6, 95% CI 1.9–60.2) and septic shock (OR 8.4, 95% CI 1.1–62.1).
Conclusion: As mortality was low in this bacterial meningitis study, ICU admission was
used as a marker of disease severity. These findings underscore the importance of the
pneumococcal and Hib meningitis vaccines.
INTRODUCTION
Bacterial meningitis can have potentially devastating consequences, especially in infancy and childhood. Compared
to viral or aseptic meningitis, it carries a higher risk of
mortality and morbidity if left untreated (1). Globally, the
risk of long-term disabling sequelae from bacterial meningitis has been estimated at around 20% (2,3). The negative
health impact from childhood bacterial meningitis persists
even into adulthood, as it is associated with lower educational achievement and less economic self-sufficiency in
adult life (4).
During the last two decades, vaccines against Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis have been introduced.
Abbreviations
CSF, Cerebrospinal fluid; CI, Confidence interval; GBS, Group B
Streptococcus; GCS, Glasgow Coma Scale; Hib, Haemophilus
influenzae type b; ICU, Intensive care unit; IQR, Interquartile
range; OR, Odds ratio; PCR, Polymerase chain reaction.
e22
They have been shown to reduce the incidence of
invasive disease, including meningitis, due to these
organisms (5–7). In Singapore, the pneumococcal vaccine
was added to the national childhood immunisation
schedule in 2009, followed by the Hib vaccine in 2013.
However, prior to the official addition of the Hib vaccine
Key Notes
This study aimed to identify factors that predicted
disease severity and long-term outcome in cases of
microbiologically confirmed childhood bacterial meningitis from 1998 to 2013.
These factors include pneumococcal and Haemophilus
influenzae type b meningitis, which are vaccinepreventable diseases.
ICU admission can be used as a marker of disease
severity in place of the mortality rate in settings
where there is relatively low mortality from bacterial
meningitis.
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
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Wee et al.
into the national childhood immunisation schedule, there
was already wide uptake of this vaccine from 2005
onwards, with national Hib vaccine coverage reaching
>80% during the period 2004–2012 (8). Conversely,
pneumococcal vaccine coverage in Singapore was only
an estimated 60% in 2012 (9).
Current mortality rates from childhood acute bacterial
meningitis range between 5 and 10%, even in developed
regions (10–12). This is a reduction compared to the period
before such vaccines were introduced, when mortality rates
were upwards of 15% (13). As such, the number of children
who succumb to meningitis has been reduced. However, it
has been reported that more than 40% of children with
bacterial meningitis are still admitted to the intensive care
unit (ICU) (14), resulting in higher medical costs and
increased length of hospital stay.
Therefore, the aims of this study were to identify
predictive factors at initial presentation associated with
subsequent ICU admission, as well as prognostic factors
for the development of long-term sequelae in children
afflicted with bacterial meningitis in Singapore over a
15-year period. Conventionally, most studies relating to
disease severity in childhood bacterial meningitis have
focused on factors affecting the mortality rate. However,
in light of the decreasing mortality due to meningitis, we
decided to use the requirement for ICU admission as a
marker of disease severity in place of the mortality rate.
MATERIALS AND METHODS
We conducted a retrospective study of children under
18 years of age who were admitted with acute bacterial
meningitis to the Department of Paediatrics of KK Women’s
and Children’s Hospital, Singapore, between January 1998
and May 2013. It is the largest paediatric tertiary hospital in
Singapore with more than 350 paediatric beds and 175 000
attendances at its children’s emergency department per
year. Cases were selected on the basis of positive identification of the causative organism from cerebrospinal fluid
(CSF), via either bacterial culture, latex-based antigen
detection or polymerase chain reaction (PCR). A list of all
patients meeting the above criteria was obtained from the
hospital’s infection control unit, based on data from the
microbiology laboratory. Subsequently, the medical records
of these cases were reviewed to confirm that they had
clinical and laboratory parameters consistent with a diagnosis of acute bacterial meningitis and were eligible for
inclusion into the study. Children who had previous
neurosurgical instrumentation or skull fracture were
excluded from the analysis.
Altered mental state on initial physical examination was
defined as irritability, a Glasgow Coma Scale (GCS) score
of less than eight, a decrease in the GCS score by two or
more points from the baseline or an inability to sense or
respond to outside stimuli. Tachycardia and hypotension
were defined according to age-appropriate normal values.
Respiratory distress was defined as increased respiratory
rate beyond age-appropriate normal values, chest wall
retractions, grunting or nasal flaring. Cut-off points for
anaemia and leukopenia were taken from the age-specific
haematological reference ranges used in the hospital
laboratory.
All patients who had survived meningitis were followed
up by a paediatric neurologist or infectious disease physician. Their records were reviewed for the presence or
absence of any long-term complications at six months, one
year, two years and five years after the acute episode of
meningitis. The long-term complications were as follows:
sensorineural hearing loss diagnosed by a comprehensive
audiologic assessment by an otolaryngologist, cortical
blindness, developmental delay or learning difficulties
assessed by the attending paediatrician at follow-up, cerebral palsy or other persistent neuromotor deficits, hydrocephalus, epilepsy and feeding difficulty requiring assisted
feeding via a nasogastric tube or gastrostomy. If a case had
one or more of these on follow-up, that case was assessed to
have residual sequelae at that time point. Cases who were
lost to follow-up, who died or who had not reached that
particular time point by May 2013, when the study was
concluded, were excluded from the analysis of these longterm complications.
Data were analysed using the SPSS v17.0 software (IBM,
Armonk, New York, USA). Differences between categorical
variables were analysed for statistical significance using the
chi-square test. Variables with p values of <0.25 on
univariate analysis were selected for multivariate analysis
via binary logistic regression using the forward conditional
method to identify factors that predicted disease severity
and development of sequelae. p values of <0.05 were
considered to be statistically significant.
The study was approved by the SingHealth Centralised
Institutional Review Board.
RESULTS
Initially, 121 cases of childhood bacterial meningitis were
identified from data provided by the microbiology laboratory. After review, two cases were excluded as they had
prior neurosurgical intervention and seven cases were
excluded as their medical records were incomplete or
unavailable. A final total of 112 meningitis cases were
included in the study, as shown in Figure 1.
Demographics
A total of 109 patients whose ages ranged from three days
to 15 years were included. However, a total of 112
episodes of meningitis were analysed as three patients
had recurrent meningitis. The median age was 0.33 years,
with an interquartile range (IQR) of 0.08–1.92 years. We
noted that 59 cases (53%) were male, 63 (56%) were of
Chinese ethnicity, 29 (26%) were of Malay ethnicity, 13
(12%) were of Indian ethnicity, and the remaining seven
cases (6%) were from other ethnic groups. This matched
the proportion of each ethnic group under the age of 15
in Singapore’s population in 2014 (15). With regard to
age, 32 cases (29%) were neonates up to one month of
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
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Prognostic factors in bacterial meningitis
Wee et al.
Progress during hospitalisation
Of the 112 cases, seven (6%) were given intravenous
dexamethasone. The most common acute complications
were 44 (39%) cases of seizures requiring antiepileptic
drugs, 28 (25%) cases of subdural empyema and 21 (19%)
cases of septic shock. Other complications included 16
(14%) cases of syndrome of inappropriate antidiuretic
hormone secretion, 14 (15%) cases of cerebral oedema
and three (3%) cases of disseminated intravascular coagulation. Haemodialysis for acute renal failure was required in
three of the cases (3%). ICU admission was required in 49
(44%) cases, and the median length of ICU stay was 6 days
(IQR 3–9 days).
Figure 1 Number of cases remaining in study population at each time point.
age, 47 (42%) were infants between one month and one
year of age, and the remaining 33 cases (29%) were
children aged one year and above. Four cases had preexisting comorbidities of hypogammaglobulinaemia, biliary atresia complicated by hypersplenism and pancytopenia, acute lymphocytic leukaemia and a congenital defect
of the oval window. Prior to admission, 21 cases (19%)
were given treatment with oral antibiotics. The median
length of hospital stay was 21 days (IQR 13–28).
Causative organisms
The causative organisms involved are shown in Table 1.
Group B streptococci (GBS; Streptococcus agalactiae) and
Escherichia coli were more common in neonates, whereas
in children aged one year and above, encapsulated bacteria
such as Hib, Streptococcus pneumoniae and Neisseria
meningitidis made up the vast majority of cases. In the first
half of the study period (1998–2004), 12 (24%) of the 51
cases were due to Hib, compared with four (6%) of the 61
cases from 2005 to 2013. This was a significantly higher
proportion with an odds ratio (OR) of 4.3 and a 95%
confidence interval (CI) of 1.3–14.5. The proportion of
cases due to Streptococcus pneumoniae between 2009 and
2013, after the pneumococcal vaccine was introduced into
Singapore’s national childhood immunisation schedule,
remained nearly the same at seven (19%) of the 36 cases
during that period compared with 15 (20%) of the 76 cases
previously.
Three patients had recurrent meningitis. One child with
no known comorbidities had two episodes of group B
Salmonella meningitis. Another child with no known
comorbidities had two episodes of group D Salmonella
meningitis. The patient with congenital defect of the oval
window had pneumococcal meningitis first and then this
was followed by Hib meningitis. The defect was subsequently repaired.
e24
Outcomes
We found that seven (6%) of the 112 cases succumbed to
meningitis and one other case died of an unrelated cause,
which was an idiosyncratic drug reaction. Of these seven,
the causative organisms were two cases of Streptococcus
pneumoniae, two cases of GBS and one case each of
Escherichia coli, Streptococcus pyogenes and Klebsiella
pneumoniae.
Table 2 shows the number of cases who were still being
followed up, as well as the number of cases suffering from
specific complications at each time point. Five years after
meningitis, 23 (32%) of the 73 cases still had residual
sequelae. All three patients with recurrent meningitis were
readmitted after completing the full course of antibiotic
therapy for the first episode of meningitis and had not been
discharged against medical advice. Two of these patients did
not complete five years of follow-up after meningitis, while
the third had no residual sequelae five years after meningitis.
Prognostic factors
As previously mentioned, due to the small number of cases
who succumbed to meningitis, the requirement for ICU
admission was used instead of mortality as an indicator of
disease severity. In the first half of the study period (1998–
Table 1 Causative organisms in the study population (n = 112)
Organism
Group B Streptococcus
Streptococcus pneumoniae
Haemophilus influenzae type b
Escherichia coli
Neisseria meningitidis
Salmonella species
Other Gram-positive bacteria1
Other Gram-negative bacteria2
Number (%)
23
22
16
15
12
9
9
6
(21)
(20)
(14)
(13)
(11)
(8)
(8)
(5)
1
Other Gram-positive bacteria included Streptococcus bovis (three
cases), Streptococcus milleri (two cases), Listeria monocytogenes
(two cases), Enterococcus faecalis (one case) and Streptococcus pyogenes
(one case).
2
Other Gram-negative bacteria included Klebsiella pneumoniae (two cases),
Pseudomonas aeruginosa (one case), Morganella morganii (one case),
Proteus mirabilis (one case) and Edwardsiella tarda (one case).
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
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Wee et al.
Table 2 Progress at outpatient follow-up
Percentage (number of patients)
Time point
Total number still on follow up
Residual sequelae present
Complications
Developmental delay or learning difficulties
Epilepsy on antiepileptic drugs
Cerebral palsy or other neuromotor deficits
Sensorineural hearing loss
Hydrocephalus/shunt placement
Requirement for assisted feeding
Cortical blindness
Six months
One year
Two years
Five years
93
44% (41)
86
36% (31)
81
36% (29)
73
32% (23)
30%
22%
17%
11%
10%
8%
4%
27%
15%
17%
8%
8%
5%
5%
27%
15%
17%
8%
9%
5%
5%
26%
16%
19%
5%
10%
4%
6%
(28)
(20)
(16)
(12)
(9)
(7)
(4)
2004), 26 (47%) of the 55 cases required ICU admission,
which was not significantly different from the second half of
the study period (2005–2013) when 23 (40%) of the 57
cases required ICU admission (OR 1.3, 95% CI 0.63–2.8).
All clinically relevant predictive factors with regard to ICU
admission are listed in Table 3. Multivariate analysis
showed that risk factors associated with ICU admission
included pneumococcus as the causative organism (OR 5.2,
95% CI 1.5–18.2), leukopenia on initial blood count (OR
5.6, 95% CI 1.7–17.9) and a CSF:serum glucose ratio <0.25
(OR 4.5, 95% CI 1.4–14.4). A CSF white blood cell count >
1000/mm3 (OR 0.26, 95% CI 0.086–0.76) was found
to be negatively associated with a requirement for ICU
admission.
Five years after meningitis, 19 (59%) of the 32 cases
who required ICU admission had residual sequelae,
compared to only four (10%) of the 41 cases who did
not (OR 13.5, 95% CI 3.9–47.2). During the first half of
the study period (1998–2004), 17 (47%) of the 36 cases
had residual sequelae five years after meningitis, compared to the second half of the study period (2005–2013)
when six (16%) of 37 cases had residual sequelae (OR
4.6, 95% CI 1.6–13.8). All clinically relevant prognostic
factors with regard to residual sequelae five years after
meningitis are listed in Table 4. Multivariate analysis
showed that risk factors associated with residual sequelae
five years after meningitis include Hib as the causative
organism (OR 29.5, 95% CI 2–429), seizures during
inpatient stay requiring antiepileptic drugs (OR 10.6,
95% CI 1.9–60.2) and septic shock (OR 8.4, 95% CI
1.1–62.1).
We looked at the feasibility of examining the prognostic factors for patients in the neonatal period as a
subgroup. This showed that 14 (44%) of the 32 neonatal
cases were admitted to ICU and five (20%) of the 25
neonatal cases for which data were available had residual
sequelae after five years of follow-up. However, due to
the small number of neonatal patients (n = 32), we did
not analyse the prognostic factors for neonates and nonneonates separately.
(23)
(13)
(15)
(9)
(7)
(4)
(4)
(22)
(12)
(14)
(9)
(7)
(4)
(4)
(19)
(12)
(14)
(6)
(7)
(3)
(4)
DISCUSSION
The rates of mortality and development of long-term
sequelae in our study population, which were 6% and
32% respectively, were comparable to similar statistics
from other developed countries (2,3,10–12). The microbiological profile of the study cases was similar to that
observed in other developed countries. In South Korea,
an analysis of 402 cases of childhood bacterial meningitis,
of which 29.9% were neonates, showed GBS to be the
most common causative organism (24.6%), followed by
Streptococcus pneumoniae (22.6%) and Haemophilus
influenzae (16.7%) (10). Organisms associated with the
genitourinary tract such as GBS and Escherichia coli
were implicated by other studies in the majority of
neonatal meningitis cases (16).
In our study, pneumococcus as the causative organism,
leukopenia on initial blood count and a CSF:serum glucose
ratio <0.25 were found to be factors predictive of increased
disease severity, as indicated by the need for ICU admission,
whereas a high CSF white blood cell count (>1000/mm3)
was found to be associated with a lower likelihood of
requiring ICU admission. A similar study from Taiwan
concluded that pneumococcal meningitis had the highest
mortality rate, whereas Hib meningitis was associated with
the highest rate of sequelae (17). Leukopenia is reflective of
severe sepsis, and lower peripheral blood and CSF white
blood cell counts may indicate inadequacy of the immune
response. Chao et al. (18) found an association between
low CSF white blood cell counts and higher mortality in
pneumococcal meningitis. Nigrovic et al. (19) found that
pretreatment with parenteral antibiotics prior to lumbar
puncture did not change CSF white blood cell counts, but
was associated with higher CSF glucose and lower CSF
protein levels. Hence, a lower CSF white blood cell count
may be a useful predictor of disease severity in established
bacterial meningitis regardless of whether parenteral antibiotics were administered before the lumbar puncture. Lower
glucose levels in the CSF have been associated with
increased inflammation and cytokine levels (20) and have
been shown to return to normal sooner in patients receiving
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
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Wee et al.
Table 3 Predictive factors for ICU admission
Factor
Male gender
Age
Up to one month
Between one month and one year
One year and above
Causative organism
Streptococcus pneumoniae
Hib
GBS
History
Fever ≥48 hours prior to presentation
Initial laboratory tests
Anaemia
Leukopenia
Thrombocytopenia
CRP > 100 mg/mL
Bacteraemia
CSF white blood cell count > 1000/mm3
CSF:serum glucose ratio <0.25
CSF protein > 1 g/L
CSF Gram stain positive
Prevalence in study
population (%)
Univariate OR (95% CI)
p-value
Multivariate OR1 (95% CI)
p-value
53
0.44 (0.21–0.95)
0.038
–
0.41
29
42
29
1.0 (0.45–2.3)
0.70 (0.33–1.5)
1.5 (0.65–3.3)
1
0.44
0.41
Not done
Not done
Not done
20
14
21
2.8 (1.0–7.2)
1.3 (0.47–3.9)
0.64 (0.25–1.7)
0.054
0.6
0.48
5.2 (1.5–18.2)
Not done
Not done
54
1.45 (0.68–3.2)
0.34
Not done
28
24
16
44
74
38
66
78
53
1.3
3.7
1.1
1.7
4.3
0.40
3.6
4.9
1.6
0.67
0.007
1
0.18
0.003
0.044
0.009
0.005
0.25
Not done
5.6 (1.7–17.9)
Not done
–
–
0.26 (0.086–0.76)
4.5 (1.4–14.4)
–
Not done
(0.55–2.9)
(1.5–9.2)
(0.38–2.9)
(0.82–3.7)
(1.6–11.6)
(0.18–0.92)
(1.4–9.5)
(1.5–15.5)
(0.78–3.5)
0.009
0.004
0.79
0.20
0.014
0.01
0.08
1
The odds ratio (OR) for significant risk factors after multivariate analysis was indicated as the multivariate OR.
anti-inflammatory medications such as dexamethasone
(21). The inflammatory response in bacterial meningitis
has been implicated in the pathogenesis of meningitisassociated brain injury and neuronal death, via the release
of potentially cytotoxic agents such as reactive oxygen
species and proteolytic enzymes by leucocytes recruited
during the inflammatory response (22). Increased central
nervous system inflammation, which can be indicated by a
low CSF glucose level, would therefore be expected to result
in a higher risk of neurological complications and a higher
likelihood of being admitted to the ICU.
Prognostic factors for the development of long-term
sequelae of bacterial meningitis were found to be the
development of seizures or septic shock while in hospital
and Hib as the causative organism. Hib is known to cause a
high rate of sequelae in children with acute bacterial
meningitis (17). In a meta-analysis of prognostic studies,
the median risk of at least one major long-term complication was 9.5% in Hib meningitis (2). The decrease in the
likelihood of residual sequelae in the second half of the
study was likely to have been due to the significant
reduction in the incidence of Hib meningitis during the
same period. Repeated seizures are known to cause
neuronal cell death via excessive neuronal activation (23),
and there is evidence that markers of neuronal injury are
present after even a single seizure (24). Therefore, it is not
surprising that seizures during the course of meningitis are
associated with the subsequent development of sequelae.
Septic shock is the result of an excessive immune response
to the offending organism in meningitis (25) and, as
e26
previously mentioned, the meningitis-associated brain
injury associated with the inflammatory response can result
in long-term neurological sequelae. Another mechanism by
which septic shock causes neuronal damage is cerebral
hypoperfusion, which will result in ischaemic injury.
Merkelbach et al. (26) found that meningitis patients with
decreased cerebral arterial blood flow velocity and cerebral
arterial narrowing, which denotes a low perfusion state, had
worse neurological outcomes. In light of this, we suggest
that treatment of children with bacterial meningitis should
focus on reducing the frequency and duration of seizures
and maintaining cerebral perfusion as these are most
strongly associated with the future development of neurological sequelae.
Previous large epidemiological studies or meta-analyses
found significant prognostic factors for neurological sequelae to be prolonged fever for more than seven days prior to
admission, the absence of petechiae, a low CSF white blood
cell count, a CSF glucose <40 mg/dL (2.22 mmol/L) and
positive blood cultures for bacteria (27–29). Predictors of
mortality were found to be shock, severe respiratory distress
and a low peripheral white blood cell count (28,30). Coma,
seizures and a high CSF protein level have been reported to
predict both mortality and neurological sequelae (27–30).
In our study, very few cases presented with prolonged fever
or petechial rash, and this was probably due to the easy
access to tertiary-level care in Singapore. Factors which are
themselves criteria for ICU admission, such as coma or
seizures, were excluded from the analysis of predictive
factors relating to disease severity. Other than these, many
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
Prognostic factors in bacterial meningitis
Wee et al.
Table 4 Prognostic factors for residual sequelae five years after meningitis
Factor
Male gender
Age
Up to one month
Between one month and one year
One year and above
Causative organism
Streptococcus pneumoniae
Hib
GBS
History
Fever ≥48 hours prior to presentation
Drowsiness, lethargy or irritability
Initial physical examination
Altered mental state
Tachycardia or hypotension
Respiratory distress
Initial laboratory tests
Anaemia
Leukopenia
Thrombocytopenia
CRP > 100 mg/mL
Bacteraemia
CSF white blood cell count > 1000/mm3
CSF:serum glucose ratio <0.25
CSF protein > 1 g/L
CSF Gram stain positive
Complications during inpatient stay
Subdural empyema
Seizures requiring antiepileptic drugs
Septic shock
SIADH1
Prevalence in study
population (%)
Univariate OR (95% CI)
p-value
Multivariate OR (95% CI)
p-value
53
0.37 (0.13–1.1)
0.079
–
0.41
29
42
29
0.42 (0.13–1.3)
1.5 (0.56–4.1)
1.6 (0.50–5.2)
0.185
0.456
0.535
–
Not done
Not done
0.051
20
14
21
2.1 (0.64–7.4)
6.9 (1.5–29.7)
0.41 (0.12–1.39)
0.323
0.009
0.174
Not done
29.5 (2.0–429)
–
54
57
1.9 (0.67–5.4)
0.87 (0.32–2.4)
0.304
0.803
Not done
Not done
51
45
26
1.5 (0.56–4.13)
0.84 (0.31–2.3)
3.8 (1.3–11.0)
0.457
0.804
0.016
Not done
Not done
–
28
24
16
44
74
38
66
78
53
2.0
2.0
1.7
2.1
4.5
0.64
4.2
0.38
0.90
(0.68–6.1)
(0.68–5.7)
(0.48–6.1)
(0.78–5.8)
(0.93–21.7)
(0.21–2.0)
(1.1–16.9)
(0.10–1.5)
(0.33–2.4)
0.25
0.27
0.5
0.20
0.072
0.59
0.042
0.23
1
Not
Not
Not
–
–
Not
–
–
Not
25
39
19
14
1.5
9.3
7.4
3.2
(0.52–4.4)
(2.9–29.7)
(2.0–27.7)
(0.77–13.3)
0.58
<0.001
0.002
0.13
0.013
0.25
0.074
done
done
done
0.28
0.45
done
0.33
0.55
done
Not done
10.6 (1.9–60.2)
8.4 (1.1–62.1)
–
0.008
0.036
0.70
1
Syndrome of inappropriate antidiuretic hormone secretion.
of the predictive and prognostic factors that we identified
have also been found in previous studies of childhood
bacterial meningitis, and this further supports their validity.
Our study had some limitations. Relatively strict inclusion criteria were applied, requiring positive identification
of bacteria from the CSF. While the purpose of this was to
exclude aseptic or viral meningitis cases from the analysis,
as PCR or other confirmatory tests for viral meningitis were
not available during the early part of the study period, this
would have excluded cases of probable bacterial meningitis
for which no pathogen was found in the CSF. In addition, it
is likely that patients with true bacterial meningitis who had
been pretreated with antibiotics before hospital admission
were missed. However, the advantage of these strict criteria
is that the conclusions drawn from this study are likely to be
more representative of childhood bacterial meningitis, as
meningitis in all study cases was confirmed to be bacterial
in origin.
Other limitations relate to the follow-up period. Five
years after meningitis, 23 (22%) of the 104 cases who
survived had defaulted on their follow-up and hence were
not included in the analysis. However, the incidence of
most prognostic factors was similar between those patients
who were still being followed up and those who were lost to
follow-up five years after meningitis. Of all the prognostic
factors analysed, the only factors with a significant difference in frequency between these two groups were tachycardia or hypotension on initial examination, which was
more common in the group that was still being followed up
(OR 2.6, 95% CI 1.1–6.4), age over one year, which was
more common in the group lost to follow-up (OR 0.29, 95%
CI 0.12–0.72), and GBS as the causative organism, for
which all affected patients were still on follow-up five years
after meningitis.
Additionally, the presence of developmental delay or
learning difficulties was based on the attending physician’s
assessment at follow-up, with formal developmental assessment not being routinely carried out. Therefore, minor
neurological sequelae might have gone unnoticed, especially in infants and preschoolers where learning difficulties
are less easily detectable. This was likely to have been the
reason why the percentage of cases in the neonatal age
group with residual sequelae five years after meningitis
(20%) was lower than for the study population as a whole.
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2016 105, pp. e22–e29
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Prognostic factors in bacterial meningitis
Wee et al.
Further research could focus on the longer-term follow-up
of childhood meningitis survivors into adulthood, to be able
to detect more subtle degrees of neurological sequelae and
their impact, if any, on occupational and social function.
5.
6.
CONCLUSIONS
This study represents the experience of a single large medical
centre in a developed, multi-ethnic Asian country over a long
time period of 15 years, with a study population of patients
who all had microbiologically confirmed bacterial meningitis.
Furthermore, 70% of the initial cases had completed an
extended follow-up period of five years. In view of the small
number of cases who succumbed to meningitis, we used the
requirement for ICU admission as a marker of disease
severity, which becomes more relevant than raw mortality
in settings with a low overall incidence of bacterial meningitis.
We found that predictive factors for increased severity of
childhood acute bacterial meningitis, necessitating ICU
admission, included pneumococcus as the causative organism, leukopenia on initial blood count and a CSF:serum
glucose ratio <0.25. Patients with a CSF white blood cell
count >1000/mm3 were less likely to require ICU admission.
Recognition of these common clinical and laboratory parameters, possibly as part of a severity score, can allow for better
allocation of resources by identifying patients who may need
closer monitoring or warrant more aggressive treatment.
Prognostic factors for residual sequelae five years after
meningitis include Hib as the causative organism, seizures
during the child’s inpatient stay and septic shock. Knowledge
of these factors would help to identify those patients who may
need more intensive outpatient rehabilitation. It is also
important to note that both pneumococcal and Hib meningitis are vaccine-preventable diseases, further underscoring
the importance of vaccination against these organisms.
7.
8.
9.
10.
11.
12.
13.
14.
CONFLICTS OF INTEREST
The authors have no competing interests to declare.
15.
FUNDING
No funding was received for this study from any organisation.
16.
17.
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