The Lancet Meningitis

Adjunctive dexamethasone in bacterial meningitis: a meta-analysis 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

aDepartment of Neurology, Centre of Infection and Immunity Amsterdam, Academic Medical Center,Amsterdam, Netherlands bCentre for Poverty-related and Communicable Diseases, AcademicMedical Center, Amsterdam, Netherlands cDepartment of Clinical Epidemiology and Biostatistics,Academic Medical Center, Amsterdam, Netherlands dHospital for Tropical Diseases, Ho Chi MinhCity, Vietnam eOxford University Clinical Research Unit, Ho Chi Minh City, Vietnam fCollege ofMedicine, University of Malawi, Blantyre, Malawi gHelsinki University Central Hospital, Hospital forChildren 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 HealthSciences, University Diego Portales, Santiago, Chile lCentre for Molecular Microbiology andInfection, Imperial College, London, UK

SummaryBackgroundDexamethasone improves outcome for some patients with bacterial meningitis, butnot others. We aimed to identify which patients are most likely to benefit from dexamethasonetreatment.

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 whichraw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelaeat 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. Wealso did exploratory analysis of hearing loss among survivors and other exploratory subgroupanalyses by use of logistic regression.

FindingsData from 2029 patients from five trials were included in the analysis (833 [410%]aged

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, includingspecific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Poolingof 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 notseem to significantly reduce death or neurological disability. There were no significant treatmenteffects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or anysubgroup of patients with bacterial meningitis thus remains unproven.

FundingWellcome Trust UK.

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

MethodsStudy selection

Relevant trials were identified previously as part of a Cochrane review (figure 1). Individualpatient data from five randomised, double-blind, placebo-controlled trials of dexamethasonefor bacterial meningitis published since 2001 were included in the analysis; individual patientdata could not be acquired from the older trials. The characteristics of the included studies areshown in table 1.

The study from South America used a 22 design to randomly assign children with bacterialmeningitis to dexamethasone plus glycerol, dexamethasone plus placebo, glycerol plusplacebo, or placebo plus placebo. Data were available from children who were assigneddexamethasone 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 dexamethasoneper three placebo (randomisation schedule 1) to one dexamethasone per one placebo(randomisation schedule 2). Therefore, analyses from this study were stratified according torandomisation schedule. The study in Malawian adults used a 22 design to randomly assignpatients to dexamethasone or placebo and to intravenous or intramuscular ceftriaxone. In allstudies, patients were enrolled on the basis of clinically suspected bacterial meningitis and CSF

van de Beek et al. Page 2

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

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criteria. All the studies used computer-generated randomisation to allocate patients todexamethasone or placebo. Treatment concealment was adequate in all studies.

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

15 data fields for each patient were selected for the analyses. The dataset included prognosticfactors for unfavourable outcome and potential modifiers of the treatment effect ofdexamethasone, such as antibiotic treatment before admission, HIV infection, andmalnutrition. Definitions were agreed during the two study-group meetings. Values forcontinuous variables were reassigned into categories. Exposure to antibiotics beforerandomisation was defined by administration of effective oral or intravenous antibiotics within48 h before the first dose of study drug was received. Malnutrition was defined by individualinvestigators: patients who were not assessed were categorised according to the localprevalence of malnutrition. HIV tests were not done on every patient and an assessment wasmade of the likelihood of HIV infection based on local epidemiology. All untested Malawianadults were defined as likely to be HIV positive. No assumption was made for untestedMalawian children. All other untested adults or children were defined as likely to be HIVnegative. Impairment of consciousness was categorised by use of the Glasgow coma scale orthe Blantyre coma score (table 2). The causative pathogen was defined by CSF microscopy,CSF or blood culture, PCR, or latex agglutination.

The predetermined outcome measures were death at the time of first follow-up; death or severeneurological sequelae (including severe bilateral hearing loss) at 1 month follow-up; death orany neurological sequelae (including any degree of hearing loss) at first follow-up; and deathor severe bilateral hearing loss at first follow-up. The number of studies that contributed toeach 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 sequelaein the adult studies was defined using the Glasgow outcome score or the modified Rankinscale. In the paediatric studies, severe neurological disability was defined as blindness,quadraparesis, hydrocephalus requiring a shunt, or severe psychomotor retardation. Hearingloss was categorised as moderate or severe according to definitions used in the individualstudies.

Statistical analysisAll analyses were stratified according to study site (including two strata from the SouthAmerican study) to account for any possible centre effect, including differences in mortalitybetween centres. If appropriate, analyses were also stratified according to the baseline variableof interest. Combined odds ratios (ORs) and tests for heterogeneity were calculated usingconventional Mantel-Haenszel statistics. We also used exploratory analyses with logisticregression. The main purpose of the analysis was to establish whether dexamethasone had adifferential effect in different subgroups of patients; hence, heterogeneity between thesubgroups (I2 values) with significance levels were calculated for each subgroup analysis. Testsfor heterogeneity were calculated without allowing for multiple comparisons, to increase thesensitivity of detecting any evidence of between-subgroup heterogeneity. To maximise thepower 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 possibleheterogeneity between studies for each subgroup analysis.

To calculate the combined ORs for death from studies included in the Cochrane reviews butnot otherwise included in the present study, results available from the published literature werecombined by use of conventional Mantel-Haenszel statistics. Calculation of combined ORsand 95% CIs, tests of heterogeneity between studies, and logistic regression analyses weredone by use of STATA version 10.

Role of the funding sourceThe study sponsors had no role in the study design, collection, analysis, and interpretation ofthe data, or the decision to submit the manuscript for publication. T E Peto had full access toall data in the study. All authors approved and were responsible for submission of themanuscript.

ResultsThe baseline characteristics were similar in placebo and dexamethasone groups within the fivestudies (table 2). 1019 (502%) patients received dexamethasone and 1010 (498%) patientsreceived placebo. 833 (411%) patients were less than 15 years old, of whom 415 receiveddexamethasone and 418 received placebo. 1196 adults (aged 15 years) were included, ofwhom 604 (505%) received dexamethasone and 592 (495%) received placebo. The ages offive 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%) patientsbut, on the basis of epidemiological risk, was judged likely to be positive in 31 untested adultsfrom Malawi and negative in adults from Europe and children from South America. Noassumption was made about 139 untested children from Malawi. In total, 286 confirmed orlikely HIV-infected patients received dexamethasone and 294 received placebo.

The diagnosis of bacterial meningitis was microbiologically confirmed in 1639 (808%)patients and was most frequently caused by S pneumoniae (759 cases), H influenzae (297cases), and Neisseria meningitidis (239 cases). The most common causative bacteria per studywere as follows: Europe, N meningitis (38%); Malawi (children), S pneumoniae (40%);Vietnam, Streptococcus suis (32%); Malawi (adults), S pneumoniae (59%); and SouthAmerica, H influenzae (47%). Mortality in the placebo groups differed substantially betweenstudies: 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 severeneurological sequelae (including severe bilateral hearing loss), death or any neurologicalsequelae (including any hearing loss), or death or severe bilateral hearing loss, if all patientswere included in the analysis (table 3). However, hearing loss (of any severity) in survivorswas 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 thewebappendix. 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 notsignificantly influence treatment response. Dexamethasone was more effective in patients agedolder 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 betweenthe different age groups (death, 2=69, 3 df, p=007, I2 545%; death or severe neurologicalsequelae, 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 notshow any consistent interaction between age and a treatment effect (data not shown). Therewas also no effect in a post-hoc analysis that restricted the study to patients treated withceftriaxone (webappendix).

The data were explored to identify evidence of heterogeneity between the studies. 23 subgroupswere explored, each with five different endpoints. In patients with moderate CNS impairmenton 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 evidenceof benefit in death or severe neurological sequelae or bilateral hearing loss in the Europeanstudy (OR 019 [95% CI 004082], p=001), but also evidence of harm in the study of childrenin Malawi (OR 370 [1361008], p=0006). However, no evidence of heterogeneity wasobserved 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 inany of the five endpoints. The effect of HIV was explored by adjustment with logistic regressionanalysis and also by studying only patients with proven HIV status. However, HIV status didnot have an effect on dexamethasone treatment outcome (webappendix). We further exploredthe relation between age, HIV status, and dexamethasone treatment effect (table 4). In HIV-negative adults, dexamethasone was associated with a reduction in death or severe neurologicalsequelae, including severe bilateral hearing loss (OR 068 [95% CI 048095], p=002), deathor any neurological sequelae, including any hearing loss (OR 067 [050091], p=001), anddeath or severe bilateral hearing loss (OR 061 [042089], p=001). However, this effect ofdexamethasone was not present in HIV-negative children, or in HIV-positive children andadults.

Gastrointestinal bleeding was reported in all studies: 13 (13%) of 1021 patients ondexamethasone and 19 (19%) of 1014 patients on placebo (p=014). Hyperglycaemia andinfection by herpes simplex virus and varicella zoster virus were reported in some but not allstudies. Hyperglycaemia was recorded by the trials in Malawian and European adults and wassignificantly associated with dexamethasone treatment (79 of 390 [203%] on dexamethasonevs 60 of 376 [160%] on placebo; p=002). Neither infection with herpes simplex virus (labialinfection in all) nor infection with varicella zoster virus were significantly associated withdexamethasone treatment.

Dexamethasone did not significantly affect mortality in a combined analysis with the data fromother studies included in the Cochrane analysis (OR 088 [95% CI 073104], p=014; figure4). 349 (180%) of 1944 patients who received dexamethasone died, compared with 384(198%) of 1939 patients who received placebo. There was no evidence of significantheterogeneity between the trials.

DiscussionThe aim of this analysis was to establish whether any subgroups of patients with acute bacterialmeningitis might benefit from adjunctive dexamethasone and thereby explain any differencesbetween individual trial results. Extensive exploration of 15 prespecified subgroups did notshow robust evidence that a particular subgroup would benefit. The apparent benefit in adultsaged over 55 years might have occurred by chance. However, it is unclear whether it is morelikely 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 adjunctivedexamethasone did not significantly reduce mortality, neurological disability, or severe hearingloss 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 dexamethasonewas significantly effective in reducing these outcomes overall. However, a post-hoc analysison the incidence of deafness among survivors suggested that adjunctive dexamethasonetreatment reduced the rate of hearing loss (OR 077 [95% CI 060099; p=004), irrespectiveof whether patients had received antibiotics before dexamethasone treatment. The use ofadjunctive dexamethasone treatment was not associated with an increased risk of adverseevents.

Factors previously considered relevant to the decision to start dexamethasone treatment inpatients with suspected or proven bacterial meningitis could not explain differences in resultsbetween the five trials. These factors include duration of symptoms before treatment, severityof impaired consciousness at start of treatment, whether dexamethasone was given before orafter antibiotics, and HIV infection status. Because the results of the prespecified analysis failedto show any significant heterogeneity, extensive post-hoc analyses were done with theinclusion of an additional deafness endpoint. Such analyses are usually considered unreliable,particularly if no statistical allowance is made for multiple comparisons, because of the highchance of a false-positive result. However, the extra analyses were undertaken to allow theidentification of subgroups of interest for further possible study. These exploratory post-hocanalyses suggested a possible overall effect on deafness among survivors and on death andsevere neurological sequelae in the subgroup of HIV-negative adults (OR 068 [95% CI 054099], p=002). This apparent treatment effect ceased to be significant after adjustment formultiple comparisons.

This meta-analysis is, as are all meta-analyses, limited by the possibility that moreheterogeneity exists between the studies than has been identified. If such heterogeneity wereto exist, combining the studies would be inappropriate. Formal tests for heterogeneity betweenstudies and between subgroups failed to show any convincing evidence of heterogeneity.However, such tests are insensitive and could miss important effects. We have thereforeexplored the data exhaustively for relevant subgroups of patients that could reveal possiblecauses of heterogeneity, although little such evidence was found.

On the basis of previous meta-analyses, the administration of dexamethasone to children withH influenzae type b meningitis before the start of antibiotic therapy is thought to reduce theincidence of deafness. However, we found no evidence of a benefit of adjunctivedexamethasone in all children or in any subgroup of children with this infection.

In summary, these data indicate that patients with bacterial meningitis neither benefit from norare harmed by treatment with adjunctive dexamethasone. Despite an individual patient datameta-analysis of more than 2000 patients, we have been unable to determine conclusivelywhether a subgroup of patients might benefit. To establish with certainty whetherdexamethasone has a place in the treatment of adult patients with bacterial meningitis, a largemultinational randomised controlled trial would be necessary. This represents a formidablechallenge and one that is not likely to be met for many years. In the meantime, we suggest thebenefit of adjunctive dexamethasone for all or any subgroup of patients with bacterialmeningitis remains unproven and there is little support for its routine use in the treatment ofthis disease.

Contributors



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

Conflicts of interest

We have no conflicts of interest.

Web Extra MaterialSupplementary Material1. Supplementary webappendix.

AcknowledgmentsAcknowledgments

This work was supported by the Wellcome Trust UK. DvdB is supported by grants from the Netherlands Organizationfor Health Research and Development (NWO-Veni grant 2006 [916.76.023]) and the Academic Medical Center (AMCFellowship 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 independentstatistical advice.

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Figure 1.Literature search



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Figure 2.Subgroup analyses for deathBM=bacterial meningitis. OR=odds ratio.



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Figure 3.Subgroup analyses for deathBM=bacterial meningitis. OR=odds ratio.



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Figure 4.Effect of adjunctive dexamethasone therapy on deathTrials included in the rest of this study and other studies included in the Cochrane systematicreview are shown. OR=odds ratio. *Study 1 in Lebel. Study 2 in Lebel.



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Table 1

Characteristics of the five studies included in the analysis

Study period Patients (n) Age Inclusion criteria Dexamethasone dose Empirical antibiotic* Primary outcome

Europe 19922001 301 >16 years Clinicallysuspected BMplus CSF criteria

10 mg four times dailyfor 4 days

Intravenousamoxicillin 2 g every 4h (77% of patients)

Unfavourableoutcome (definedby a Glasgowoutcome score of14) at 8 weeks

Malawi (child) 19972001 598 2 monthsto 13years

Clinicallysuspected BMplus CSF criteria

04 mg/kg twice dailyfor 2 days

Intravenousbenzylpenicillin 200000 IU/kg every 24 hplus chloramphenicol100 mg/kg every 24 h

Death at 1 month

Vietnam 19962005 429 >14 years Clinicallysuspected BMplus CSF criteria

04 mg/kg twice dailyfor 4 days

Intravenousceftriaxone 2 g every12 h

Death at 1 month

Malawi (adult) 20022005 465 >15 years Clinicallysuspected BMplus CSF criteria

16 mg twice daily for4 days

Intravenous orintramuscularceftriaxone 2 g every12 h

Death at 1 month

South America 19962003 236 2 monthsto 16years

Clinicallysuspected BMplus CSF or bloodcriteria

015 mg/kg four timesdaily for 2 days

Intravenousceftriaxone 80100mg/kg every 24 h

Death, severeneurologicalsequelae, oraudiologicalsequelae athospital 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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elin

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arac

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f pat

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the

anal

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Eur

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n=30

1)M

alaw

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)V

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am(n

=429

)M

alaw

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ult)(

n=46

5)So

uth

Am

eric

aT

otal

(n=2

029)

Dex

amet

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ne (n

=101

9)Pl

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0)

Ran

dom

isat

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sche

dule

1(n

=126

)R

ando

mis

atio

n sc

hedu

le 2

(n=1

10)

Age

(yea

rs)

55

102

010

616

00

224

112

112

Unk

now

n0

11

00

35

23

Sex

Men

169

(56%

)33

7 (5

6%)

315

(73%

)23

0 (5

0%)

73 (5

8%)

63 (5

7%)

1187

(58%

)60

1 (5

9%)

586

(58%

)

Sym

ptom

s 20

122

(40%

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(5%

)24

8 (5

8%)

72 (1

6%)

53 (4

2%)

46 (4

2%)

572

(28%

)28

4 (2

8%)

288

(29%

)

Unk

now

n10

(3%

)92

(15%

)2

(05

%)

61 (1

3%)

9 (7

%)

3 (3

%)

177

(9%

)87

(8%

)90

(9%

)

CSF

pro

tein

(mg/

dL)

250

195

(65%

)41

2 (6

9%)

191

(45%

)34

1 (7

3%)

23 (1

8%)

33 (3

0%)

1195

(59%

)58

8 (5

8%)

607

(60%

)

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ocument

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Eur

ope(

n=30

1)M

alaw

i (ch

ild)(n

=598

)V

ietn

am(n

=429

)M

alaw

i (ad

ult)(

n=46

5)So

uth

Am

eric

aT

otal

(n=2

029)

Dex

amet

haso

ne (n

=101

9)Pl

aceb

o (n

=101

0)

Ran

dom

isat

ion

sche

dule

1(n

=126

)R

ando

mis

atio

n sc

hedu

le 2

(n=1

10)

Oth

er a

erob

ic g

ram

neg

ativ

e ba

cilli

3 (1

%)

38 (6

%)

21 (5

%)

22 (5

%)

3 (2

%)

1 (1

%)

88 (4

%)

51 (5

%)

37 (4

%)

Oth

er27

(9%

)11

(2%

)68

(16%

)5

(1%

)3

(2%

)5

(4%

)11

9 (6

%)

52 (5

%)

67 (7

%)

Def

inite

ly n

ot b

acte

rial m

enin

gitis

00

11 (3

%)

38 (8

%)

1 (1

%)

050

(25

%)

28 (3

%)

22 (2

%)

Unk

now

n (p

roba

ble

bact

eria

lm

enin

gitis

)40

(13%

)74

(12%

)78

(18%

)10

2 (2

2%)

27 (2

1%)

19 (1

7%)

340

(17%

)17

6 (1

7%)

164

(16%

)

Bac

teria

l dia

gnos

is c

onfir

med

mic

robi

olog

ical

ly26

1 (8

7%)

524

(88%

)34

0 (7

8%)

325

(70%

)98

(78%

)91

(83%

)16

39 (8

1%)

815

(80%

)82

4 (8

1%)

Tre

atm

ent a

lloca

tion

Allo

cate

d to

dex

amet

haso

ne tr

eatm

ent

157

(52%

)30

5 (5

1%)

215

(50%

)23

3 (5

0%)

50 (4

0%)

59 (5

4%)

1019

(50%

)..

..

Dat

a ar

e nu

mbe

r (%

).

* HIV

sero

stat

us w

as n

ot a

vaila

ble

in p

atie

nts i

n th

e Eu

rope

an o

r Sou

th A

mer

ican

tria

ls; p

atie

nts i

n th

ese

trial

s wer

e as

sum

ed to

be

HIV

neg

ativ

e. In

the

Vie

tnam

tria

l, fo

ur u

ntes

ted

patie

nts w

ere

assu

med

to b

e H

IV n

egat

ive

and

in th

e M

alaw

i adu

lt tri

al, 3

1 un

test

ed p

atie

nts w

ere

assu

med

to b

e H

IV p

ositi

ve. I

n th

e M

alaw

i pae

diat

ric tr

ial,

139

(23%

) pat

ient

s wer

e no

t tes

ted

and

no a

ssum

ptio

n w

as m

ade

abou

t the

ir se

rost

atus

. Pos

itive

val

ues o

nly

incl

ude

patie

nts t

este

d an

d no

t tho

se a

ssum

ed to

be

posi

tive.

Gla

sgow

com

a sc

ale

is c

ateg

oris

ed in

adu

lts a

s 15=

norm

al, 1

114

=mild

impa

irmen

t, 8

10=m

oder

ate

impa

irmen

t, 3

7=se

vere

impa

irmen

t. B

lant

yre

com

a sc

ore

is c

ateg

oris

ed a

s 5=n

orm

al, 3

4=m

ild im

pairm

ent,

2=m

oder

ate

impa

irmen

t, 0

1=se

vere

impa

irmen

t.

The

use

of u

rine

reag

ent s

trips

in th

e tri

als f

rom

Mal

awi p

rovi

ded

sem

i-qua

ntita

tive

estim

ates

of C

SF g

luco

se a

nd p

rote

in. P

rote

in a

nd g

luco

se c

once

ntra

tions

wer

e m

easu

red

with

a u

rine

dips

tick

(Mul

tistix

8SG

Bay

er),

whi

ch p

rovi

ded

colo

ur-c

oded

resu

lts o

f (pr

otei

n/gl

ucos

e)ne

gativ

e (0

/0 m

g/dL

); tra

ce (20

00/>

1000

mg/

dL).


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Tabl

e 3

Prim

ary

endp

oint

s for

eac

h st

udy

and

for a

ll pa

tient

s ass

igne

d to

ster

oid

ther

apy

Eur

ope

Mal

awi (

child

)V

ietn

amM

alaw

i (ad

ult)

Sout

h A

mer

ica

Ove

rall

Eve

nts/

tota

l (%

)T

est f

or h

eter

ogen

eity

Ran

dom

isat

ion

sche

dule

1R

ando

mis

atio

n sc

hedu

le 2

Dex

amet

haso

nePl

aceb

o2

(5 d

f)p

I2

Dea

th0

44 (0

20

096

, 00

3)0

96 (0

70

140

, 09

6)0

82 (0

45

151

, 05

3)1

16 (0

80

167

, 04

3)1

46 (0

63

337

, 03

7)0

74 (0

27

200

, 05

5)0

97 (0

79

119

, 07

5)27

0/10

19 (2

65%

)27

5/10

10 (2

72%

)6

50

2622

7%

Dea

th o

rse

vere

neur

olog

ical

sequ

elae

or

bila

tera

lse

vere

deaf

ness

060

(03

41

11, 0

07)

120

(08

71

66, 0

28)

075

(04

81

17, 0

20)

102

(06

91

50, 0

93)

074

(03

51

55, 0

42)

074

(03

31

67, 0

52)

092

(07

61

11, 0

39)

424/

1003

(42

3%)

439/

992

(44

3%)

65

026

232

%

Dea

th o

r any

neur

olog

ical

sequ

elae

or

any

hear

ing

loss

049

(02

80

84, 0

01)

102

(07

41

42, 0

89)

081

(05

51

18, 0

27)

103

(06

71

56, 0

91)

129

(06

02

77, 0

51)

084

(03

91

79, 0

65)

089

(07

41

07, 0

23)

541/

999

(54

2%)

567/

988

(57

4%)

71

022

293

%

Dea

th o

rse

vere

bila

tera

lhe

arin

g lo

ss

055

(03

10

99, 0

04)

103

(07

31

45, 0

86)

064

(03

81

08, 0

09)

108

(07

31

58, 0

70)

107

(04

92

32, 0

87)

070

(02

91

69, 0

43)

089

(07

31

69, 0

23)

343/

942

(36

4%)

363/

934

(38

9%)

62

028

198

%

Any

hea

ring

loss

insu

rviv

ors

075

(03

41

67, 0

48)

080

(05

11

28, 0

35)

077

(04

91

21, 0

26)

080

(04

41

45, 0

45)

059

(02

11

65, 0

31)

081

(03

02

14, 0

66)

077

(06

00

99, 0

04)

162/

672

(24

1%)

195/

660

(29

5%)

03

100

00%

Dat

a ar

e O

R (9

5% C

I, p

valu

e) u

nles

s oth

erw

ise

stat

ed. O

R v

alue

s bel

ow 1

sugg

est a

ben

efic

ial e

ffec

t of s

tero

ids.


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ocument

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Table 4

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

HIV negative HIV positive Overall Test for heterogeneity

Adult Child Adult Child 2 (3 df) p I2

Death 066 (042102, 006) 143 (096212, 007) 119 (081175, 036) 054 (028103, 006) 099 (080123, 099) 107 001 720%

Death orsevereneurologicalsequelae orbilateralseveredeafness

068 (048095, 002) 109 (077155, 062) 110 (073166, 067) 077 (036166, 044) 090 (073110, 029) 48 019 374%

Death or anyneurologicalsequelae orany hearingloss

067 (050091, 001) 109 (077156, 062) 115 (073182, 054) 077 (035171, 053) 088 (072107, 018) 60 011 501%

Death orseverebilateralhearing loss

061 (042089, 001) 116 (080167, 043) 113 (075170, 055) 062 (030129, 020) 089 (072109, 026) 81 004 285%

Any hearingloss insurvivors

076 (052113, 017) 067 (042107, 009) 087 (046163, 066) 109 (037319, 087) 077 (059099, 006) 09 083 00%

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


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