Death and disability: the outcomes of tuberculous meningitis
The most feared consequence of infection with Mycobacterium tuberculosis in infants and young children is tuberculous meningitis. In the 1930s, researchers established that infants and young children are particularly susceptible to tuberculous meningitis, and that it is the major cause of tuberculosis-related childhood death (1, 2). The numbers of deaths due to tuberculous meningitis worldwide each year are unknown because of difficulties in diagnosis and under-reporting of tuberculosis in children, especially when infection causes early death. However, tuberculous meningitis is probably a major contributor to the estimated 200 or more child deaths every day due to tuberculosis worldwide (3). Furthermore, as other common causes of meningitis in infants and children become less common with the rollout of effective bacterial conjugate vaccines, M tuberculosis becomes relatively more important as a preventable and treatable pathogen causing death and disability due to bacterial meningitis in children (4—6).
In a systematic review and meta-analysis in The Lancet Infectious Diseases, Silvia Chiang and colleagues (7) highlight the catastrophic consequences of tuberculous meningitis in children. Their review included 1636 children diagnosed with and treated for tuberculous meningitis from ten countries, with reported outcomes spanning five decades. Overall, a fifth of children died during treatment (risk 19·3%, 95% CI 14·0—26·1) and half of survivors had neurological sequelae (risk 53·9%, 95% CI 42·6—64·9), with more advanced disease at presentation associated with worse outcomes. A wide variety of treatment regimens and durations were used and the review acknowledges important limitations of heterogeneity between studies. Although mortality in children seems to have improved slightly after the introduction of regimens based on rifampicin and pyrazinamide,8 the mortality and morbidity of this disease remains daunting.
Neonatal BCG vaccination is an effective and cost-effective intervention that protects against tuberculous meningitis and miliary tuberculosis (9). Although coverage is high in many tuberculosis-endemic countries, it was reportedly less than 85% (and as low as 47%) in half of the 22 high-burden tuberculosis countries worldwide in 2011 (10). Another protective strategy is preventive chemotherapy for infants and young children exposed to an infectious case of tuberculosis. Many children with tuberculous meningitis have been infected with M tuberculosis by a close contact. Similar to the epidemiology of tuberculous meningitis, evidence of the protective efficacy of preventive therapy against tuberculous meningitis has also been available for more than 50 years.2 Despite being almost universally recommended and potentially highly effective, screening to provide preventive therapy for eligible contacts is still rarely implemented in tuberculosis-endemic communities (11).
Accurate and early diagnosis of tuberculous meningitis remains challenging and most cases are diagnosed on the basis of clinical and cerebrospinal-fluid abnormalities without microbiological confirmation. Recognised features help to distinguish tuberculous meningitis from other causes of meningitis in children, but none are sufficiently sensitive or specific to adequately improve diagnostic certainty. Chiang and colleagues noted the low yield from standard microbiological techniques—9% positive on microscopy for acid-fast bacilli, and 35% positive on mycobacterial culture (7)—similar to proportions for the yield from sputum for children of all ages with pulmonary tuberculosis (12). More sensitive tests are needed that can also identify drug-resistant strains. Nonetheless, if improved outcomes are to be achieved, the decision to implement treatment for tuberculous meningitis will usually have to be made before confirmation of diagnosis is received.
Depressingly, outcomes have not substantially improved during the past 50 years (7). Clearly, there is an urgent need to assess novel dose regimens and combinations of antituberculosis drugs in infants and children that might reduce mortality and neurological sequelae (13), and address the problem of vasculitis that causes much of the morbidity. Corticosteroids seem to improve mortality in both adults and children, but do not substantially reduce neurological deficits in survivors (14, 15).
In view of the lack of progress and the ongoing burden of childhood deaths and disability due to tuberculous meningitis, research is clearly needed to improve timely and accurate diagnosis in addition to treatment outcomes. The full potential of preventive strategies is not being realised. Furthermore, important opportunities are being missed for improved surveillance, such as in the context of the ongoing surveillance for other common causes of bacterial meningitis in childhood. The incidence of tuberculous meningitis relates to the annual risk of infection, and a sound surveillance system documenting the occurrence of tuberculous meningitis in young children could improve estimates and monitoring of the tuberculosis burden and tuberculosis-related deaths in children (16).
We declare no competing interests.
References
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a Centre for International Child Health, The University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia
b International Union Against Tuberculosis and Lung Disease, Paris, France
c Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Treatment outcomes of childhood tuberculous meningitis: a
systematic review and meta-analysis
Source:
The Lancet Infectious Diseases
