Meningitis: a frequently fatal diagnosis in Africa
Authors: Anne von Gottberg, Graeme Meintjes
Journal: The Lancet Infectious Diseases (2019)

In The Lancet Infectious Diseases, Mark W Tenforde and colleagues1Tenforde MW Mokomane M Leeme TB et al.Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.Lancet Infect Dis. 2019; 19: 740-749Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar report the mortality findings of the 2004–15 Botswana national meningitis survey. This was a nationwide laboratory-based audit with linkage to the national HIV and death registries. 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 their analyses, in addition to a random selection of patients with CSF WCC of up to 20 cells per μL. 10-week and 1-year mortality was 47% (112/238) and 49% (117/238) for pneumococcal meningitis, 46% (22/48) and 56% (27/48) for tuberculous meningitis, and 41% (1181/2900) and 49% (1408/2900) for culture-negative meningitis. Most deaths occurred within the first 10 weeks after lumbar puncture. Across the different diagnostic groups 64–76% of patients had documented HIV infection. Cryptococcal meningitis 1-year mortality of 65% was previously reported from this cohort.2Patel RKK Leeme T Azzo C et al.High mortality in HIV-associated cryptococcal meningitis patients treated with amphotericin B-based therapy under routine care conditions in Africa.Open Forum Infect Dis. 2018; 5ofy267Crossref PubMed Scopus (19) Google Scholar Outside of Africa, linkage of multiple national datasets to improve the understanding of meningitis and other diseases happens more often;3Edge C Waight P Ribeiro S Borrow R Ramsay M Ladhani S Clinical diagnoses and outcomes of 4619 hospitalised cases of laboratory-confirmed invasive meningococcal disease in England: linkage analysis of multiple national databases.J Infect. 2016; 73: 427-436Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 4Polkowska A Toropainen M Ollgren J Lyytikäinen O Nuorti JP Bacterial meningitis in Finland, 1995–2014: a population-based observational study.BMJ Open. 2017; 7e015080Crossref PubMed Scopus (37) Google Scholar it is exciting to now see this powerful epidemiological method in use with African datasets, in this report and others.5Nanoo A Izu A Ismail NA et al.Nationwide and regional incidence of microbiologically confirmed pulmonary tuberculosis in South Africa, 2004–12: a time series analysis.Lancet Infect Dis. 2015; 15: 1066-1076Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Collection of large-scale, high-quality, routine data in electronic databases has great potential to enhance epidemiological assessment of common diseases, diagnostic and management practices, and outcomes, and to direct and prioritise interventions and inform policy, practice, and research. The high mortality reported by Tenforde and colleagues1Tenforde MW Mokomane M Leeme TB et al.Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.Lancet Infect Dis. 2019; 19: 740-749Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar is similar to the mortality in other meningitis cohorts in Africa,6Cresswell F V Bangdiwala AS Bahr NC et al.Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda.Wellcome Open Res. 2018; 3: 64PubMed Google Scholar, 7Wall EC Cartwright K Scarborough M et al.High mortality amongst adolescents and adults with bacterial meningitis in sub-Saharan Africa: an analysis of 715 cases from Malawi.PLoS One. 2013; 8e69783Crossref PubMed Scopus (38) Google Scholar, 8Marais S Pepper DJ Schutz C Wilkinson RJ Meintjes G Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting.PLoS One. 2011; 6e20077Crossref PubMed Scopus (80) Google Scholar although the lack of details regarding presentation and management in this report (eg, clinical signs and symptoms on presentation, history of length of illness before presenting to hospital, antimicrobial therapy, length of treatment, use of adjuvant therapy) limits the ability to evaluate the major health system contributors. Late presentation, reduced access to optimal diagnostics and antimicrobial therapies, suboptimal acute care, and HIV co-infection have been implicated as major contributors in previous reports.7Wall EC Cartwright K Scarborough M et al.High mortality amongst adolescents and adults with bacterial meningitis in sub-Saharan Africa: an analysis of 715 cases from Malawi.PLoS One. 2013; 8e69783Crossref PubMed Scopus (38) Google Scholar, 9Loyse A Burry J Cohn J et al.Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.Lancet Infect Dis. 2019; 19: e143-e147Summary Full Text Full Text PDF PubMed Scopus (38) Google Scholar Of concern is that over the 12-year period covered by Tenforde and colleagues,1Tenforde MW Mokomane M Leeme TB et al.Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.Lancet Infect Dis. 2019; 19: 740-749Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar HIV was still associated with more than two-thirds of meningitis diagnoses and there was no reduction in meningitis mortality over time, despite the scale-up of antiretroviral therapy in Botswana. Reasons for patients continuing to present with complications of advanced HIV (such as meningitis) despite successful antiretroviral therapy programmes include delayed HIV diagnosis and disengagement from antiretroviral care.10Ford N Meintjes G Calmy A et al.Managing advanced HIV disease in a public health approach.Clin Infect Dis. 2018; 66: S106-S110Crossref PubMed Scopus (39) Google Scholar A surprising finding was the high mortality in patients with culture-negative meningitis, regardless of the presence of CSF pleocytosis. The authors postulate that this high mortality could be due to missed diagnoses. During the study, tuberculosis culture was done at the request of clinical providers at a central national tuberculosis reference laboratory on 1723 (9%) samples, with acid-fast bacilli microscopy done on 2524 (13%). Together with the low sensitivity of these tests and the suboptimal sample volumes often sent in routine clinical services, these results imply that a proportion of patients with culture-negative meningitis very likely had undiagnosed tuberculous meningitis. The proportion of patients who were treated for tuberculosis could not be established given the study methodology. Additionally, CSF cryptococcal antigen testing was largely unavailable during the study period, potentially resulting in missed diagnoses. Diagnoses of bacterial meningitis were likely also missed in patients who had received antibiotics before lumbar puncture, or due to technical limitations of culture. The indication for lumbar puncture in some patients might also have been prompted by delirium caused by fatal non-neurological infections (such as bacterial sepsis or disseminated tuberculosis), frequent in advanced HIV.11Paddick S-M Kalaria RN Mukaetova-Ladinska EB The prevalence and clinical manifestations of delirium in sub-Saharan Africa: a systematic review with inferences.J Neurol Sci. 2015; 348: 6-17Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar This may be particularly relevant for those without CSF pleocytosis. There is an urgent need for improved rapid diagnostics for meningitis in other low-income and middle-income countries in Africa. Use of better diagnostic modalities, including multipathogen molecular panels, has improved diagnostic yield among patients presenting with meningitis,12Nesher L Hadi CM Salazar L et al.Epidemiology of meningitis with a negative CSF Gram stain: under-utilization of available diagnostic tests.Epidemiol Infect. 2016; 144: 189-197Crossref PubMed Scopus (25) Google Scholar but there are conflicting opinions about the benefits of routine implementation.13Dien Bard J Alby K Point-counterpoint: meningitis/encephalitis syndromic testing in the clinical laboratory.J Clin Microbiol. 2018; 56 (pii e00018-18.)Crossref Scopus (45) Google Scholar Even with the implementation of such testing modalities, more than half of patients with meningitis might not have pathogens detected with available methods in high-income settings.12Nesher L Hadi CM Salazar L et al.Epidemiology of meningitis with a negative CSF Gram stain: under-utilization of available diagnostic tests.Epidemiol Infect. 2016; 144: 189-197Crossref PubMed Scopus (25) Google Scholar, 13Dien Bard J Alby K Point-counterpoint: meningitis/encephalitis syndromic testing in the clinical laboratory.J Clin Microbiol. 2018; 56 (pii e00018-18.)Crossref Scopus (45) Google Scholar In a Ugandan study,6Cresswell F V Bangdiwala AS Bahr NC et al.Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda.Wellcome Open Res. 2018; 3: 64PubMed Google Scholar implementation of routine liquid medium culture for tuberculosis and the Xpert MTB/Rif assay of CSF from adults with meningitis and negative CSF cryptococcal antigen did not change in-hospital mortality significantly. However, the sensitivity of the second-generation Xpert Ultra assay of CSF has significantly improved.14Bahr NC Nuwagira E Evans EE et al.Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study.Lancet Infect Dis. 2018; 18: 68-75Summary Full Text Full Text PDF PubMed Scopus (196) Google Scholar Better access to existing diagnostics and novel diagnostics alone are unlikely to change long-term outcomes,6Cresswell F V Bangdiwala AS Bahr NC et al.Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda.Wellcome Open Res. 2018; 3: 64PubMed Google Scholar unless coupled with interventions to ensure earlier presentation, adherence to evidence-based treatment guidelines, and availability of antimicrobials at the facilities where patients present. Adequately trained clinical staff in functional facilities are also required to make a positive impact on outcomes. As countries plan for improvements in health-care delivery, the focus should be on broadening coverage, but also on the key role of improved health services.15Kruk ME Gage AD Joseph NT Danaei G García-Saisó S Salomon JA Mortality due to low-quality health systems in the universal health coverage era: a systematic analysis of amenable deaths in 137 countries.Lancet. 2018; 392: 2203-2212Summary Full Text Full Text PDF PubMed Scopus (341) Google Scholar AvG has received grants and travel expenses from Pfizer and Sanofi. GM has research collaborations with Joe Jarvis, an author of the Article. Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort studyMortality 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. Full-Text PDF Open AccessCulture-negative cryptococcal meningitisWe read with interest the Article by Mark W Tenforde and colleagues1 describing clinical and laboratory predictors of mortality in adult patients with meningitis in Botswana. Using a nationwide patient information system, the authors observed high mortality and ongoing contributions of HIV co-infection on meningitis prevalence over 12 years. We applaud the systematic categorisation of patients included in the analyses, which provides strong justification for the development of improved diagnostics for meningitis in Africa. Full-Text PDF