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Lancet Neurology
Published as: Lancet Neurol. 2010 March ; 9(3): 254263.

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Adjunctive dexamethasone in bacterial meningitis: a metaanalysis of individual patient data


Diederik van de Beeka, Jeremy J Farrard,e,h,*, Jan de Gansa, Nguyen Thi Hoang Maid,
Elizabeth M Molyneuxf, Heikki Peltolag, Tim E Petoj, Irmeli Roinek, Mathew Scarboroughf,i,
Constance Schultszb,e, Guy E Thwaitesl, Phung Quoc Tuand,e, and AH Zwindermanc

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aDepartment of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center,
Amsterdam, Netherlands bCentre for Poverty-related and Communicable Diseases, Academic
Medical Center, Amsterdam, Netherlands cDepartment of Clinical Epidemiology and Biostatistics,
Academic Medical Center, Amsterdam, Netherlands dHospital for Tropical Diseases, Ho Chi Minh
City, Vietnam eOxford University Clinical Research Unit, Ho Chi Minh City, Vietnam fCollege of
Medicine, University of Malawi, Blantyre, Malawi gHelsinki University Central Hospital, Hospital for
Children and Adolescents, Helsinki, Finland hCentre for Tropical Medicine, Oxford University,
Oxford, UK iNuffield Department of Clinical Laboratory Science, Oxford University, Oxford,
UK jNuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK kFaculty of Health
Sciences, University Diego Portales, Santiago, Chile lCentre for Molecular Microbiology and

Infection, Imperial College, London, UK

Summary
BackgroundDexamethasone improves outcome for some patients with bacterial meningitis, but
not others. We aimed to identify which patients are most likely to benefit from dexamethasone
treatment.

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MethodsWe did a meta-analysis of individual patient data from the randomised, double-blind,
placebo-controlled trials of dexamethasone for bacterial meningitis in patients of all ages for which
raw data were available. The pre-determined outcome measures were death at the time of first followup, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelae
at first follow-up, and death or severe bilateral hearing loss at first follow-up. Combined odds ratios
(ORs) and tests for heterogeneity were calculated using conventional Mantel-Haenszel statistics. We
also did exploratory analysis of hearing loss among survivors and other exploratory subgroup
analyses by use of logistic regression.
FindingsData from 2029 patients from five trials were included in the analysis (833 [410%]
aged <15 years). HIV infection was confirmed or likely in 580 (286%) patients and bacterial
meningitis was confirmed in 1639 (808%). Dexamethasone was not associated with a significant
reduction in death (270 of 1019 [265%] on dexamethasone vs 275 of 1010 [272%] on placebo; OR
097, 95% CI 079119), death or severe neurological sequelae or bilateral severe deafness (423%

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*Correspondence to: Jeremy Farrar, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, Quan
5, Ho Chi Minh City, Vietnam jfarrar@oucru.org.
This document was posted here by permission of the publisher. At the time of deposit, it included all changes made during peer review,
copyediting, and publishing. The U.S. National Library of Medicine is responsible for all links within the document and for incorporating
any publisher-supplied amendments or retractions issued subsequently. The published journal article, guaranteed to be such by Elsevier,
is available for free, on ScienceDirect.

van de Beek et al.

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vs 443%; 092, 076111), death or any neurological sequelae or any hearing loss (542% vs 574%;
089, 074107), or death or severe bilateral hearing loss (364% vs 389%; 089, 073169).
However, dexamethasone seemed to reduce hearing loss among survivors (241% vs 295%; 077,
060099, p=004). Dexamethasone had no effect in any of the prespecified subgroups, including
specific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Pooling
of the mortality data with those of all other published trials did not significantly change the results.
InterpretationAdjunctive dexamethasone in the treatment of acute bacterial meningitis does not
seem to significantly reduce death or neurological disability. There were no significant treatment
effects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or any
subgroup of patients with bacterial meningitis thus remains unproven.
FundingWellcome Trust UK.

Introduction

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The yearly incidence of bacterial meningitis is estimated to be 2660 cases per 100000 in
Europe and might be ten times higher in less developed countries. Experimental models have
shown that outcome is related to the severity of the inflammatory process in the subarachnoid
space, and treatment with corticosteroids results in a reduction of the inflammatory response
and improved outcome. These findings have prompted several randomised controlled trials of
corticosteroids for bacterial meningitis. Initial results suggested that the main beneficial effect
of the corticosteroid dexamethasone was to reduce the risk of hearing loss in children with
Haemophilus influenzae type b meningitis. Additional data extended the likely benefit to those
with Streptococcus pneumoniae meningitis. In 2004, a meta-analysis of five randomised
controlled trials showed that treatment with corticosteroids reduced both mortality and
neurological sequelae in adults with bacterial meningitis, without detectable adverse effects.
Subsequently, a Cochrane meta-analysis of data from 20 randomised controlled trials and
involving 2750 people showed an overall mortality benefit and a reduction in neurological
sequelae in patients treated with adjuvant corticosteroids. However, three large randomised
controlled trials published after this analysis showed conflicting results. Adjunctive
corticosteroids seem to benefit some patients with bacterial meningitis but not others, and how
to select patients who are likely to benefit is unclear. Our aim was to address this question with
a meta-analysis of data from five major trials for which individual patient data were available.

Methods
Study selection

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Relevant trials were identified previously as part of a Cochrane review (figure 1). Individual
patient data from five randomised, double-blind, placebo-controlled trials of dexamethasone
for bacterial meningitis published since 2001 were included in the analysis; individual patient
data could not be acquired from the older trials. The characteristics of the included studies are
shown in table 1.
The study from South America used a 22 design to randomly assign children with bacterial
meningitis to dexamethasone plus glycerol, dexamethasone plus placebo, glycerol plus
placebo, or placebo plus placebo. Data were available from children who were assigned
dexamethasone plus placebo or placebo only but not from those who were given glycerol.
During the study, the randomisation schedule was altered from a ratio of two dexamethasone
per three placebo (randomisation schedule 1) to one dexamethasone per one placebo
(randomisation schedule 2). Therefore, analyses from this study were stratified according to
randomisation schedule. The study in Malawian adults used a 22 design to randomly assign
patients to dexamethasone or placebo and to intravenous or intramuscular ceftriaxone. In all
studies, patients were enrolled on the basis of clinically suspected bacterial meningitis and CSF

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criteria. All the studies used computer-generated randomisation to allocate patients to


dexamethasone or placebo. Treatment concealment was adequate in all studies.
Definitions and outcome measures

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The members of the study group met in October, 2006, and September, 2007, to discuss data
sharing and the analysis plan, including the definitions of subgroups, which were specified
before the data were collated, the final database created, and the analysis started. The principal
investigators provided the raw data, which were checked by a statistician (PQT).
Inconsistencies and outlying data were clarified with the principal investigators and resolved
from their raw data before the analysis.

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15 data fields for each patient were selected for the analyses. The dataset included prognostic
factors for unfavourable outcome and potential modifiers of the treatment effect of
dexamethasone, such as antibiotic treatment before admission, HIV infection, and
malnutrition. Definitions were agreed during the two study-group meetings. Values for
continuous variables were reassigned into categories. Exposure to antibiotics before
randomisation was defined by administration of effective oral or intravenous antibiotics within
48 h before the first dose of study drug was received. Malnutrition was defined by individual
investigators: patients who were not assessed were categorised according to the local
prevalence of malnutrition. HIV tests were not done on every patient and an assessment was
made of the likelihood of HIV infection based on local epidemiology. All untested Malawian
adults were defined as likely to be HIV positive. No assumption was made for untested
Malawian children. All other untested adults or children were defined as likely to be HIV
negative. Impairment of consciousness was categorised by use of the Glasgow coma scale or
the Blantyre coma score (table 2). The causative pathogen was defined by CSF microscopy,
CSF or blood culture, PCR, or latex agglutination.

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The predetermined outcome measures were death at the time of first follow-up; death or severe
neurological sequelae (including severe bilateral hearing loss) at 1 month follow-up; death or
any neurological sequelae (including any degree of hearing loss) at first follow-up; and death
or severe bilateral hearing loss at first follow-up. The number of studies that contributed to
each outcome is shown by degrees of freedom (df=number of studies minus 1). Additionally,
as part of a post-hoc exploratory analysis and to analyse every possible endpoint of interest,
we analysed hearing loss of any degree among survivors. The severity of neurological sequelae
in the adult studies was defined using the Glasgow outcome score or the modified Rankin
scale. In the paediatric studies, severe neurological disability was defined as blindness,
quadraparesis, hydrocephalus requiring a shunt, or severe psychomotor retardation. Hearing
loss was categorised as moderate or severe according to definitions used in the individual
studies.
Statistical analysis
All analyses were stratified according to study site (including two strata from the South
American study) to account for any possible centre effect, including differences in mortality
between centres. If appropriate, analyses were also stratified according to the baseline variable
of interest. Combined odds ratios (ORs) and tests for heterogeneity were calculated using
conventional Mantel-Haenszel statistics. We also used exploratory analyses with logistic
regression. The main purpose of the analysis was to establish whether dexamethasone had a
differential effect in different subgroups of patients; hence, heterogeneity between the
subgroups (I2 values) with significance levels were calculated for each subgroup analysis. Tests
for heterogeneity were calculated without allowing for multiple comparisons, to increase the
sensitivity of detecting any evidence of between-subgroup heterogeneity. To maximise the
power of finding significant heterogeneity, missing values were removed, except where

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indicated, from the subgroup analyses. A continuity correction was made for zero events.
Significance tests, with the appropriate degrees of freedom, were calculated to test for possible
heterogeneity between studies for each subgroup analysis.

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To calculate the combined ORs for death from studies included in the Cochrane reviews but
not otherwise included in the present study, results available from the published literature were
combined by use of conventional Mantel-Haenszel statistics. Calculation of combined ORs
and 95% CIs, tests of heterogeneity between studies, and logistic regression analyses were
done by use of STATA version 10.
Role of the funding source
The study sponsors had no role in the study design, collection, analysis, and interpretation of
the data, or the decision to submit the manuscript for publication. T E Peto had full access to
all data in the study. All authors approved and were responsible for submission of the
manuscript.

Results

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The baseline characteristics were similar in placebo and dexamethasone groups within the five
studies (table 2). 1019 (502%) patients received dexamethasone and 1010 (498%) patients
received placebo. 833 (411%) patients were less than 15 years old, of whom 415 received
dexamethasone and 418 received placebo. 1196 adults (aged 15 years) were included, of
whom 604 (505%) received dexamethasone and 592 (495%) received placebo. The ages of
five patients were unknown.
HIV co-infection was confirmed in 549 (415%) of 1322 patients tested, of whom 391 (714%)
were adults and 158 (288%) were children. An HIV test was not done in 707 (348%) patients
but, on the basis of epidemiological risk, was judged likely to be positive in 31 untested adults
from Malawi and negative in adults from Europe and children from South America. No
assumption was made about 139 untested children from Malawi. In total, 286 confirmed or
likely HIV-infected patients received dexamethasone and 294 received placebo.

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The diagnosis of bacterial meningitis was microbiologically confirmed in 1639 (808%)


patients and was most frequently caused by S pneumoniae (759 cases), H influenzae (297
cases), and Neisseria meningitidis (239 cases). The most common causative bacteria per study
were as follows: Europe, N meningitis (38%); Malawi (children), S pneumoniae (40%);
Vietnam, Streptococcus suis (32%); Malawi (adults), S pneumoniae (59%); and South
America, H influenzae (47%). Mortality in the placebo groups differed substantially between
studies: 15% in Europe, 31% in Malawian children, 12% in Vietnam, 53% in Malawian adults,
and 16% in South America.
Dexamethasone was not associated with a significant reduction in death, death or severe
neurological sequelae (including severe bilateral hearing loss), death or any neurological
sequelae (including any hearing loss), or death or severe bilateral hearing loss, if all patients
were included in the analysis (table 3). However, hearing loss (of any severity) in survivors
was less common in the dexamethasone group (162 [241%] of 672 vs 195 [295%] of 660;
OR 077 [95% CI 060099], p=004).
The subgroup analyses for all outcome measures are shown in figures 2 and 3, and the
webappendix. Duration of symptoms before treatment, severity of coma at start of treatment,
whether dexamethasone was given before or after antibiotics, and HIV infection status did not
significantly influence treatment response. Dexamethasone was more effective in patients aged
older than 55 years in analyses of death (OR 041 [95% CI 020084], p=001), death or severe

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neurological sequelae (OR 053 [030084], p=003), and death or any neurological sequelae
(OR 056 [031100], p=005). However, there was no clear evidence of heterogeneity between
the different age groups (death, 2=69, 3 df, p=007, I2 545%; death or severe neurological
sequelae, 2=66, 3 df, p=009, I2=534%; death or any neurological sequelae, 2=44, 3 df,
p=023, I2=303%). Further exploratory analyses, using age as a continuous variable, did not
show any consistent interaction between age and a treatment effect (data not shown). There
was also no effect in a post-hoc analysis that restricted the study to patients treated with
ceftriaxone (webappendix).

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The data were explored to identify evidence of heterogeneity between the studies. 23 subgroups
were explored, each with five different endpoints. In patients with moderate CNS impairment
on admission, there was some evidence of heterogeneity between three of the five endpoints.
In the subgroup of patients with moderate CNS impairment on admission, there was evidence
of benefit in death or severe neurological sequelae or bilateral hearing loss in the European
study (OR 019 [95% CI 004082], p=001), but also evidence of harm in the study of children
in Malawi (OR 370 [1361008], p=0006). However, no evidence of heterogeneity was
observed in patients with either no or little CNS impairment or with severe CNS impairment.
Overall, there was no evidence of any difference in outcome for any of the CNS subgroups in
any of the five endpoints. The effect of HIV was explored by adjustment with logistic regression
analysis and also by studying only patients with proven HIV status. However, HIV status did
not have an effect on dexamethasone treatment outcome (webappendix). We further explored
the relation between age, HIV status, and dexamethasone treatment effect (table 4). In HIVnegative adults, dexamethasone was associated with a reduction in death or severe neurological
sequelae, including severe bilateral hearing loss (OR 068 [95% CI 048095], p=002), death
or any neurological sequelae, including any hearing loss (OR 067 [050091], p=001), and
death or severe bilateral hearing loss (OR 061 [042089], p=001). However, this effect of
dexamethasone was not present in HIV-negative children, or in HIV-positive children and
adults.
Gastrointestinal bleeding was reported in all studies: 13 (13%) of 1021 patients on
dexamethasone and 19 (19%) of 1014 patients on placebo (p=014). Hyperglycaemia and
infection by herpes simplex virus and varicella zoster virus were reported in some but not all
studies. Hyperglycaemia was recorded by the trials in Malawian and European adults and was
significantly associated with dexamethasone treatment (79 of 390 [203%] on dexamethasone
vs 60 of 376 [160%] on placebo; p=002). Neither infection with herpes simplex virus (labial
infection in all) nor infection with varicella zoster virus were significantly associated with
dexamethasone treatment.

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Dexamethasone did not significantly affect mortality in a combined analysis with the data from
other studies included in the Cochrane analysis (OR 088 [95% CI 073104], p=014; figure
4). 349 (180%) of 1944 patients who received dexamethasone died, compared with 384
(198%) of 1939 patients who received placebo. There was no evidence of significant
heterogeneity between the trials.

Discussion
The aim of this analysis was to establish whether any subgroups of patients with acute bacterial
meningitis might benefit from adjunctive dexamethasone and thereby explain any differences
between individual trial results. Extensive exploration of 15 prespecified subgroups did not
show robust evidence that a particular subgroup would benefit. The apparent benefit in adults
aged over 55 years might have occurred by chance. However, it is unclear whether it is more
likely to have occurred by chance than the findings of no benefit in other subgroups.

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This analysis of 2029 patients from five trials showed that treatment with adjunctive
dexamethasone did not significantly reduce mortality, neurological disability, or severe hearing
loss in bacterial meningitis. Combination of these results with those from older published trials,
for which the raw data were not obtainable, did not show any evidence that dexamethasone
was significantly effective in reducing these outcomes overall. However, a post-hoc analysis
on the incidence of deafness among survivors suggested that adjunctive dexamethasone
treatment reduced the rate of hearing loss (OR 077 [95% CI 060099; p=004), irrespective
of whether patients had received antibiotics before dexamethasone treatment. The use of
adjunctive dexamethasone treatment was not associated with an increased risk of adverse
events.

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Factors previously considered relevant to the decision to start dexamethasone treatment in


patients with suspected or proven bacterial meningitis could not explain differences in results
between the five trials. These factors include duration of symptoms before treatment, severity
of impaired consciousness at start of treatment, whether dexamethasone was given before or
after antibiotics, and HIV infection status. Because the results of the prespecified analysis failed
to show any significant heterogeneity, extensive post-hoc analyses were done with the
inclusion of an additional deafness endpoint. Such analyses are usually considered unreliable,
particularly if no statistical allowance is made for multiple comparisons, because of the high
chance of a false-positive result. However, the extra analyses were undertaken to allow the
identification of subgroups of interest for further possible study. These exploratory post-hoc
analyses suggested a possible overall effect on deafness among survivors and on death and
severe neurological sequelae in the subgroup of HIV-negative adults (OR 068 [95% CI 054
099], p=002). This apparent treatment effect ceased to be significant after adjustment for
multiple comparisons.
This meta-analysis is, as are all meta-analyses, limited by the possibility that more
heterogeneity exists between the studies than has been identified. If such heterogeneity were
to exist, combining the studies would be inappropriate. Formal tests for heterogeneity between
studies and between subgroups failed to show any convincing evidence of heterogeneity.
However, such tests are insensitive and could miss important effects. We have therefore
explored the data exhaustively for relevant subgroups of patients that could reveal possible
causes of heterogeneity, although little such evidence was found.
On the basis of previous meta-analyses, the administration of dexamethasone to children with
H influenzae type b meningitis before the start of antibiotic therapy is thought to reduce the
incidence of deafness. However, we found no evidence of a benefit of adjunctive
dexamethasone in all children or in any subgroup of children with this infection.

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In summary, these data indicate that patients with bacterial meningitis neither benefit from nor
are harmed by treatment with adjunctive dexamethasone. Despite an individual patient data
meta-analysis of more than 2000 patients, we have been unable to determine conclusively
whether a subgroup of patients might benefit. To establish with certainty whether
dexamethasone has a place in the treatment of adult patients with bacterial meningitis, a large
multinational randomised controlled trial would be necessary. This represents a formidable
challenge and one that is not likely to be met for many years. In the meantime, we suggest the
benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial
meningitis remains unproven and there is little support for its routine use in the treatment of
this disease.
Contributors

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The study was conceived by JJF. All the authors contributed to the study design and the
selection of data for analysis. The analysis was done by PQT, TEP, and AHZ. The paper was
written by DvdB, JJF, TEP, MS, and GET, with review and comment from all the authors.
Conflicts of interest

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We have no conflicts of interest.

Web Extra Material


Supplementary Material1. Supplementary webappendix.

Acknowledgments
Acknowledgments
This work was supported by the Wellcome Trust UK. DvdB is supported by grants from the Netherlands Organization
for Health Research and Development (NWO-Veni grant 2006 [916.76.023]) and the Academic Medical Center (AMC
Fellowship 2008). TEP is supported by the UK National Institute for Health Research, Biomedical Research Centre,
Oxford, UK. We thank Sarah Walker (Medical Research Council, Clinical Trials Unit, London, UK) for independent
statistical advice.

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Figure 1.

Literature search

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Figure 2.

Subgroup analyses for death


BM=bacterial meningitis. OR=odds ratio.

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Figure 3.

Subgroup analyses for death


BM=bacterial meningitis. OR=odds ratio.

Published as: Lancet Neurol. 2010 March ; 9(3): 254263.

van de Beek et al.

Page 13

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Figure 4.

Effect of adjunctive dexamethasone therapy on death


Trials included in the rest of this study and other studies included in the Cochrane systematic
review are shown. OR=odds ratio. *Study 1 in Lebel. Study 2 in Lebel.

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van de Beek et al.

Page 14

Table 1

Characteristics of the five studies included in the analysis

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Study period

Patients (n)

Age

Inclusion criteria

Dexamethasone dose

Empirical antibiotic*

Primary outcome

Europe

19922001

301

>16 years

Clinically
suspected BM
plus CSF criteria

10 mg four times daily


for 4 days

Intravenous
amoxicillin 2 g every 4
h (77% of patients)

Unfavourable
outcome (defined
by a Glasgow
outcome score of
14) at 8 weeks

Malawi (child)

19972001

598

2 months
to 13
years

Clinically
suspected BM
plus CSF criteria

04 mg/kg twice daily


for 2 days

Intravenous
benzylpenicillin 200
000 IU/kg every 24 h
plus chloramphenicol
100 mg/kg every 24 h

Death at 1 month

Vietnam

19962005

429

>14 years

Clinically
suspected BM
plus CSF criteria

04 mg/kg twice daily


for 4 days

Intravenous
ceftriaxone 2 g every
12 h

Death at 1 month

Malawi (adult)

20022005

465

>15 years

Clinically
suspected BM
plus CSF criteria

16 mg twice daily for


4 days

Intravenous or
intramuscular
ceftriaxone 2 g every
12 h

Death at 1 month

South America

19962003

236

2 months
to 16
years

Clinically
suspected BM
plus CSF or blood
criteria

015 mg/kg four times


daily for 2 days

Intravenous
ceftriaxone 80100
mg/kg every 24 h

Death, severe
neurological
sequelae, or
audiological
sequelae at
hospital discharge

BM=bacterial meningitis.
*

Dexamethasone was given before or with the first dose of per-protocol parenteral antibiotic in all five studies.

23% of patients received other antibiotic treatment.

22 design with patients randomly assigned to dexamethasone or placebo and to intravenous or intramuscular ceftriaxone.

22 design with patients randomly assigned to dexamethasone plus glycerol, dexamethasone plus placebo, placebo plus glycerol, or placebo plus
placebo; patients assigned to receive glycerol with either dexamethasone or placebo were excluded from the individual patient data meta-analysis;
data from this trial were analysed as two strata according to randomisation schedule.

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Unknown

2 (1%)

Unknown

Unknown

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..

301

Not assessed (likely yes)

Not assessed (likely no)

Normal

103 (34%)

2 (1%)

Unknown

Level of consciousness

42 (14%)

120 beats per min

Heart rate

Positive/tested

0/0

..

No

HIV infection*

..

Yes

Malnutrition

5 (2%)

Yes

Prior antibiotic exposure

233 (77%)

Yes

Symptoms <48 h

Men

169 (56%)

102

Sex

198

>55

515

1655

<5

Age (years)

219 (37%)

8 (1%)

513 (86%)

157/459 (34%)

3 (05%)

..

288 (48%)

307 (52%)

127 (21%)

2 (03%)

266 (44%)

337 (56%)

168

429

Malawi (child)(n=598)

147 (34%)

12 (3%)

58 (14%)

3/429 (1%)

..

8 (2%)

375 (87%)

46 (11%)

238 (55%)

2 (05%)

121 (28%)

315 (73%)

106

322

Vietnam(n=429)

84 (18%)

8 (2%)

118 (25%)

389/434 (90%)

..

..

..

..

123 (26%)

5 (1%)

121 (26%)

230 (50%)

16

447

Malawi (adult)(n=465)

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Europe(n=301)

23 (18%)

5 (4%)

75 (60%)

0/0

..

61 (48%)

59 (47%)

6 (5%)

14 (11%)

46 (36%)

15 (12%)

91 (72%)

73 (58%)

117

Randomisation schedule 1
(n=126)

South America

17 (16%)

7 (6%)

56 (51%)

0/0

..

62 (56%)

41 (37%)

7 (6%)

11 (10%)

35 (32%)

9 (8%)

93 (84%)

63 (57%)

17

90

Randomisation schedule 2
(n=110)

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Baseline characteristics of patients included in the analysis

593 (29%)

42 (2%)

862 (42%)

549/1322 (42%)

424 (21%)

476 (23%)

763 (38%)

366 (18%)

25 (1%)

574 (28%)

35 (2%)

925 (46%)

1187 (58%)

224

967

197

636

Total (n=2029)

288 (28%)

19 (2%)

430 (42%)

269/663 (41%)

215 (21%)

237 (23%)

380 (37%)

187 (18%)

9 (1%)

281 (28%)

17 (2%)

471 (46%)

601 (59%)

112

490

99

316

Dexamethasone (n=1019)

305 (30%)

23 (2%)

432 (43%)

280/659 (42%)

209 (21%)

239 (24%)

383 (38%)

179 (18%)

16 (2%)

293 (29%)

18 (2%)

454 (45%)

586 (58%)

112

477

98

320

Placebo (n=1010)

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Table 2
van de Beek et al.
Page 15

68 (23%)

28 (9%)

Moderate impairment

Severe impairment

Unknown

Unknown

144 (24%)

166 (55%)

78 (26%)

5 (2%)

10009999

>10000

Unknown

122 (40%)

10 (3%)

>20

Unknown

Published as: Lancet Neurol. 2010 March ; 9(3): 254263.

97 (32%)

9 (3%)

<250

Unknown

Unknown

112 (37%)

115 (38%)

4 (1%)

..

Streptococcus pneumoniae

Neisseria meningitidis

Haemophilus influenzae

Streptococcus suis

Causative pathogen

215 (71%)

Yes

Bacteria on CSF microscopy

195 (65%)

250

CSF protein (mg/dL)

169 (56%)

20

CSF glucose (mg/dL)

258 (43%)

44 (15%)

..

170 (28%)

67 (11%)

238 (40%)

427 (71%)

160 (27%)

26 (4%)

412 (69%)

92 (15%)

31 (5%)

475 (79%)

2 (03%)

172 (29%)

8 (3%)

100999

22 (4%)

70 (12%)

373 (62%)

2 (03%)

84 (14%)

125 (21%)

168 (28%)

099

CSF white cell count (cells per L)

7 (2%)

<10 g/dL

Haemoglobin

102 (34%)

Mild impairment

137 (32%)

8 (2%)

29 (7%)

77 (18%)

249 (57%)

11 (2%)

227 (53%)

191 (45%)

2 (05%)

248 (58%)

179 (42%)

2 (05%)

72 (17%)

253 (59%)

95 (22%)

7 (2%)

36 (8%)

14 (3%)

3 (1%)

46 (11%)

88 (20%)

145 (34%)

..

3 (06%)

20 (4%)

275 (59%)

15 (3%)

263 (57%)

91 (20%)

33 (7%)

341 (73%)

61 (13%)

72 (16%)

332 (71%)

8 (2%)

20 (4%)

158 (34%)

186 (40%)

93 (20%)

31 (7%)

181 (39%)

90 (19%)

129 (28%)

162 (35%)

Malawi (adult)(n=465)

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Vietnam(n=429)

..

66 (52%)

4 (3%)

22 (18%)

34 (27%)

74 (59%)

26 (20%)

77 (61%)

23 (18%)

9 (7%)

53 (42%)

64 (51%)

8 (6%)

16 (13%)

55 (44%)

40 (32%)

7 (6%)

6 (5%)

90 (71%)

5 (4%)

16 (13%)

25 (20%)

57 (45%)

Randomisation schedule 1
(n=126)

South America

..

46 (42%)

4 (4%)

35 (32%)

24 (22%)

69 (63%)

4 (4%)

73 (66%)

33 (30%)

3 (3%)

46 (42%)

61 (56%)

14 (13%)

19 (17%)

47 (43%)

27 (24%)

3 (3%)

3 (3%)

73 (66%)

11 (10%)

17 (16%)

65 (59%)

Randomisation schedule 2
(n=110)

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Malawi (child)(n=598)

137 (7%)

297 (15%)

239 (12%)

759 (37%)

73 (4%)

1297 (64%)

301 (15%)

533 (26%)

1195 (59%)

177 (9%)

572 (28%)

1280 (63%)

39 (2%)

349 (17%)

937 (46%)

564 (28%)

140 (7%)

148 (7%)

738 (36%)

10 (05%)

275 (14%)

452 (22%)

699 (34%)

Total (n=2029)

72 (7%)

135 (13%)

122 (12%)

383 (38%)

38 (4%)

641 (63%)

148 (14%)

283 (28%)

588 (58%)

87 (8%)

284 (28%)

648 (64%)

22 (2%)

187 (18%)

450 (44%)

286 (28%)

76 (7%)

67 (7%)

367 (36%)

6 (06%)

137 (13%)

239 (23%)

349 (34%)

Dexamethasone (n=1019)

65 (6%)

162 (16%)

117 (12%)

376 (37%)

35 (4%)

656 (65%)

153 (15%)

250 (25%)

607 (60%)

90 (9%)

288 (29%)

632 (62%)

17 (2%)

162 (16%)

487 (48%)

280 (28%)

64 (6%)

79 (8%)

371 (37%)

4 (04%)

138 (14%)

213 (21%)

350 (35%)

Placebo (n=1010)

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Europe(n=301)

van de Beek et al.


Page 16

40 (13%)

261 (87%)

Definitely not bacterial meningitis

Unknown (probable bacterial


meningitis)

Bacterial diagnosis confirmed


microbiologically

305 (51%)

524 (88%)

74 (12%)

11 (2%)

38 (6%)

215 (50%)

340 (78%)

78 (18%)

11 (3%)

68 (16%)

21 (5%)

233 (50%)

325 (70%)

102 (22%)

38 (8%)

5 (1%)

22 (5%)

50 (40%)

98 (78%)

27 (21%)

1 (1%)

3 (2%)

3 (2%)

Randomisation schedule 1
(n=126)

South America

59 (54%)

91 (83%)

19 (17%)

5 (4%)

1 (1%)

Randomisation schedule 2
(n=110)

1019 (50%)

1639 (81%)

340 (17%)

50 (25%)

119 (6%)

88 (4%)

Total (n=2029)

..

815 (80%)

176 (17%)

28 (3%)

52 (5%)

51 (5%)

Dexamethasone (n=1019)

..

824 (81%)

164 (16%)

22 (2%)

67 (7%)

37 (4%)

Placebo (n=1010)

Glasgow coma scale is categorised in adults as 15=normal, 1114=mild impairment, 810=moderate impairment, 37=severe impairment. Blantyre coma score is categorised as 5=normal, 34=mild impairment, 2=moderate impairment, 01=severe impairment.

The use of urine reagent strips in the trials from Malawi provided semi-quantitative estimates of CSF glucose and protein. Protein and glucose concentrations were measured with a urine dipstick (Multistix 8SG Bayer), which provided colour-coded results of (protein/glucose)
negative (0/0 mg/dL); trace (<30/100 mg/dL); 1+ (31100/101250 mg/dL); 2+ (101300/251500 mg/dL); 3+ (3012000/5011000 mg/dL); 4+ (>2000/>1000 mg/dL).

HIV serostatus was not available in patients in the European or South American trials; patients in these trials were assumed to be HIV negative. In the Vietnam trial, four untested patients were assumed to be HIV negative and in the Malawi adult trial, 31 untested patients were
assumed to be HIV positive. In the Malawi paediatric trial, 139 (23%) patients were not tested and no assumption was made about their serostatus. Positive values only include patients tested and not those assumed to be positive.

Data are number (%).

Allocated to dexamethasone treatment

157 (52%)

27 (9%)

Other

Treatment allocation

3 (1%)

Other aerobic gram negative bacilli

Malawi (adult)(n=465)

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Vietnam(n=429)

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Malawi (child)(n=598)

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Europe(n=301)

van de Beek et al.


Page 17

Published as: Lancet Neurol. 2010 March ; 9(3): 254263.

055 (031099, 004)

075 (034167, 048)

Death or
severe
bilateral
hearing loss

Any hearing
loss in
survivors

080 (051128, 035)

103 (073145, 086)

102 (074142, 089)

120 (087166, 028)

096 (070140, 096)

077 (049121, 026)

064 (038108, 009)

081 (055118, 027)

075 (048117, 020)

082 (045151, 053)

Vietnam

080 (044145, 045)

108 (073158, 070)

103 (067156, 091)

102 (069150, 093)

116 (080167, 043)

Malawi (adult)

Data are OR (95% CI, p value) unless otherwise stated. OR values below 1 suggest a beneficial effect of steroids.

049 (028084, 001)

060 (034111, 007)

Death or
severe
neurological
sequelae or
bilateral
severe
deafness

Death or any
neurological
sequelae or
any hearing
loss

044 (020096, 003)

Death

Malawi (child)

059 (021165, 031)

107 (049232, 087)

129 (060277, 051)

074 (035155, 042)

146 (063337, 037)

Randomisation schedule 1

South America

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Europe

081 (030214, 066)

070 (029169, 043)

084 (039179, 065)

074 (033167, 052)

074 (027200, 055)

Randomisation schedule 2

077 (060099, 004)

089 (073169, 023)

089 (074107, 023)

092 (076111, 039)

097 (079119, 075)

Overall

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Primary endpoints for each study and for all patients assigned to steroid therapy

162/672 (241%)

343/942 (364%)

541/999 (542%)

424/1003 (423%)

270/1019 (265%)

Dexamethasone

Events/total (%)

195/660 (295%)

363/934 (389%)

567/988 (574%)

439/992 (443%)

275/1010 (272%)

Placebo

03

62

71

65

65

2 (5 df)

100

028

022

026

026

00%

198%

293%

232%

227%

I2

Test for heterogeneity

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Table 3
van de Beek et al.
Page 18

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van de Beek et al.

Page 19

Table 4

Exploratory analyses of the influence of age and HIV infection on the treatment effect of dexamethasone

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HIV negative

HIV positive

Overall

Test for heterogeneity

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2 (3 df)

I2

099 (080123, 099)

107

001

720%

090 (073110, 029)

48

019

374%

077 (035171, 053)

088 (072107, 018)

60

011

501%

113 (075170, 055)

062 (030129, 020)

089 (072109, 026)

81

004

285%

087 (046163, 066)

109 (037319, 087)

077 (059099, 006)

09

083

00%

Adult

Child

Adult

Child

Death

066 (042102, 006)

143 (096212, 007)

119 (081175, 036)

054 (028103, 006)

Death or
severe
neurological
sequelae or
bilateral
severe
deafness

068 (048095, 002)

109 (077155, 062)

110 (073166, 067)

077 (036166, 044)

Death or any
neurological
sequelae or
any hearing
loss

067 (050091, 001)

109 (077156, 062)

115 (073182, 054)

Death or
severe
bilateral
hearing loss

061 (042089, 001)

116 (080167, 043)

Any hearing
loss in
survivors

076 (052113, 017)

067 (042107, 009)

Data are OR (95% CI, p value) unless otherwise stated. Adults were defined as 15 years. HIV negative includes patients who tested negative or were
likely to be negative. HIV positive includes those who tested positive or were likely to be positive.

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