Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data

Abstract

SummaryBackgroundDexamethasone 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.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 follow-up, 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 [41·0%] aged <15 years). HIV infection was confirmed or likely in 580 (28·6%) patients and bacterial meningitis was confirmed in 1639 (80·8%). Dexamethasone was not associated with a significant reduction in death (270 of 1019 [26·5%] on dexamethasone vs 275 of 1010 [27·2%] on placebo; OR 0·97, 95% CI 0·79–1·19), death or severe neurological sequelae or bilateral severe deafness (42·3% vs 44·3%; 0·92, 0·76–1·11), death or any neurological sequelae or any hearing loss (54·2% vs 57·4%; 0·89, 0·74–1·07), or death or severe bilateral hearing loss (36·4% vs 38·9%; 0·89, 0·73–1·69). However, dexamethasone seemed to reduce hearing loss among survivors (24·1% vs 29·5%; 0·77, 0·60–0·99, p=0·04). 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.

Bacterial meningitis in solid organ transplant recipients: a population‐based prospective study

“…The use of dexamethasone in bacterial meningitis has been proven effective in patients in high‐income countries with S. pneumoniae meningitis 14; however, no effect has been established in patients with L. monocytogenes meningitis or in immunocompromised patients with human immunodeficiency virus infection 15. As RTR were found to have a different spectrum of causative microorganisms, it is unclear whether adjunctive dexamethasone has a role in the treatment of SOT patients.…”

Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice

“…Hence, one cannot rule-out this disagreement as a potential source of discrepancy between the current and published results, although it does not seem likely that it could completely account for it (6,7). First, two recent meta-analyses of placebo-controlled trials demonstrated that commencing dexamethasone before (or with) the first antibiotic dose or after antibiotic treatment had already started had no impact on its effects (8,9). In the present analysis, dexamethasone had no effect on mortality or full recovery in the entire cohort, but also in the subgroup of patients who received antibiotics before dexamethasone, as well as in the subgroup in which dexamethasone was started immediately before or with the first antibiotic dose.…”

“…This particular schedule was recently reported to apparently improve the outcomes of pneumococcal diseases in daily practice in a developed European country (7). On the other hand, recent meta-analyses of placebo-controlled trails indicate that the effect of early dexamethasone in adults is seemingly less robust than theoretically expected, and might be affected by trial quality, socio-economic level of the country (reflecting on access to medical care, HIV infection prevalence and treatment possibilities, but probably also on other factors), causative agent and level of evidence of bacterial infection (5,(8)(9)(10). Overall, the survival benefit is uncertain, although some benefit might be confined to the patients with pneumococcal meningitis in high-income countries (5,(8)(9)(10).…”

“…On the other hand, recent meta-analyses of placebo-controlled trails indicate that the effect of early dexamethasone in adults is seemingly less robust than theoretically expected, and might be affected by trial quality, socio-economic level of the country (reflecting on access to medical care, HIV infection prevalence and treatment possibilities, but probably also on other factors), causative agent and level of evidence of bacterial infection (5,(8)(9)(10). Overall, the survival benefit is uncertain, although some benefit might be confined to the patients with pneumococcal meningitis in high-income countries (5,(8)(9)(10). The most consistent benefit seems to be the reduced risk of hearing loss, but this again does not seem to hold in the low-income countries and only a trend was observed in high quality trials (8,9).…”

“…Overall, the survival benefit is uncertain, although some benefit might be confined to the patients with pneumococcal meningitis in high-income countries (5,(8)(9)(10). The most consistent benefit seems to be the reduced risk of hearing loss, but this again does not seem to hold in the low-income countries and only a trend was observed in high quality trials (8,9). Interestingly, as indicated by both a recent meta-analysis of individual patient data from 5 trials and a recent Cochrane group meta-analysis (by the same authors) -the (lack of) dexamethasone effect was not affected by its commencement prior to (or with) the first antibiotic dose (as advocated in agreement with the "anti-inflammation" concept) vs. its commencement after antibiotic treatment had already begun (8,9).…”