Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study

Abstract

Background: CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults.

Methods: In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality.

Findings: We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80-1·09).

Interpretation: Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms.

Funding: National Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research.

Figure 1

Sampling method for selection of patients with culture-positive and culture-negative CSF IPMS=Integrated Patient Management System. WCC=white cell count.

Figure 2

Kaplan-Meier survival analysis of patients with pneumococcal meningitis, tuberculous meningitis, culture-negative meningitis, and cryptococcal meningitis Dashed vertical lines represent 2 weeks, 10 weeks, and 1 year. Cryptococcal meningitis data are previously published 2012–2014 referral hospital outcomes for comparison.

Figure 3

Kaplan-Meier analysis of survival for patients with culture-negative meningitis (A) Probability of survival of patients with CSF WCC 0–2 cells per μL, CSF WCC 3–20 cells per μL, and CSF WCC above 20 cells per μL. (B) Probability of survival of patients with CSF WCC above 20 cells per μL by neutrophil versus lymphocyte (≥50% lymphocytes) predominance. Dashed vertical lines represent 2 weeks, 10 weeks, and 1 year. Note that a proportion of patients with WCC above 20 cells per μL did not have a WCC differential. CSF=cerebrospinal fluid. WCC=white cell count.