Sequelae due to bacterial meningitis among African children: a systematic literature review

Bacterial meningitis is a serious, often disabling and potentially fatal infection resulting in 170,000 deaths worldwide each year [1]. Young children are particularly vulnerable to bacterial meningitis, and when exposed poor outcomes may occur due to the immaturity of their immune systems. Two thirds of meningitis deaths in low-income countries occur among children under 15 years of age [2]. The main bacterial pathogens causing meningitis beyond the neonatal period are Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae type b (Hib) and Neisseria meningitidis (meningococcus) [3–5]. Pneumococcal meningitis is associated with the highest case fatality ratios (CFRs) globally [6]. In Africa, pneumococcal meningitis CFRs attain 45% compared to 29% for Hib meningitis and 8% for meningococcal meningitis [3].

Serious, long-term neuropsychological sequelae further increase the population impact of paediatric meningitis. Sequelae comprise a range of findings with implications for child development and functioning and include such deficits as hearing loss, vision loss, cognitive delay, speech/language disorder, behavioural problems, motor delay/impairment, and seizures [7, 8]. Meningitis sequelae can present a long-term, serious hardship for families with limited means to care for a disabled child, especially in resource-poor settings.

Africa experiences a disproportionately large burden of meningitis due to its young population, epidemics in the meningitis belt and high rates of endemic disease. The incidence and CFRs associated with paediatric Hib and pneumococcal meningitis were highest in Africa compared to all other regions in a recent global review [9]. In addition, Africa is the only region with cyclic epidemics of meningitis that affect persons of all ages, with attack rates ranging from 100 to 800 per 100,000 population [10]. Epidemics of meningitis are mostly associated with meningococcus, but there is some evidence that increases in pneumococcal meningitis cases occur in parallel during the hot and dry season [11–13].

A safe and effective Hib conjugate vaccine is available and routinely used in most African countries. Pneumococcal vaccines are gradually being introduced with support from the Global Alliance for Vaccines and Immunisation (GAVI), and meningococcal vaccines will soon become available. Together with mortality, morbidity due to in-hospital and long-term neuropsychological sequelae must be incorporated into estimates of the burden of meningitis to evaluate the potential benefit of preventive efforts such as conjugate vaccines.

The objective of this paper is to present a systematic review of the sequelae following acute bacterial meningitis in African children between the ages of 1 month and 15 years. Several earlier reviews have examined mortality associated with bacterial meningitis [3, 9]. This review focuses on studies with primary data on neuropsychological sequelae due to bacterial meningitis.

In this review, we obtained comprehensive, up to date information on the burden of sequelae associated with bacterial meningitis in African children. We included 37 articles with sequelae data from 1980 to 2008, while an earlier review based sequelae estimates only on 10 articles published between 1970 and 2000 [3]. We estimated that the median risk of in-hospital sequelae was 25% for pneumococcal meningitis, 25% for Hib meningitis and 7% for meningococcal meningitis, while the median risk of post-discharge sequelae was 25% for all pathogens combined. These estimates are slightly lower than those found in the earlier African literature review [3], but the higher risk of sequelae for pneumococcal and Hib meningitis compared to meningococcal meningitis is consistent across the two reviews. The median CFR estimates in our review were 35% and 25% for pneumococcal and Hib meningitis, respectively, and thus slightly lower than the findings from two previous reviews [3, 9].

Few studies report on the nature of the neuropsychological deficit beyond vision loss, hearing loss, seizures and gross motor impairment. Our database included more detailed and subtle neuropsychological deficit categories in keeping with the World Health Organization (WHO) international classification of functioning, disability and health [7]. This highlighted gaps in knowledge for the population studied: particularly lacking are data on cognitive delay, speech/language problems and behavioural problems.

In the studies we included, children with meningitis were treated in hospital with antibiotics recommended by the WHO (third generation cephalosporins or ampicillin plus chloramphenicol), and in some cases steroids [18]. Our findings suggest that even with appropriate antibiotic treatment, up to half of all children affected by pneumococcal and Hib meningitis die or experience clinically evident sequelae prior to hospital discharge. Increasing resistance to penicillin and chloramphenicol among pneumococcal strains may contribute to worse outcomes in some cases where access to third generation cephalosporins is limited. In our review, 15 of the articles (41%) reported using third generation cephalosporins as a first-line antibiotic in at least some cases. There were no clear trends in in-hospital sequelae risk over time likely because of relatively little heterogeneity in first-line therapies during the time period studied. Updated WHO guidelines promote the use of ceftriaxone in epidemic and non-epidemic settings as the first-line therapy for bacterial meningitis in Africa [19].

Further, a small number of studies included in the review show an increased risk of death and a 25% risk of long-term disability subsequent to discharge in children hospitalised for bacterial meningitis. The median estimates for in-hospital and post-discharge sequelae in our review did not differ greatly even though some sequelae following bacterial meningitis are expected to resolve over time [20]. African children experience the highest incidence rates for pneumococcal and Hib meningitis globally [9]. The high incidence, case fatality and sequelae risk due to bacterial meningitis underscore the public health importance of this disease and its poor outcome among children in Africa.

The articles included in this review represent 21 of the 52 African countries. In all, 44% of children with in-hospital outcome data were from the western Africa meningitis belt region and 72% of those with post-discharge data were from the northern Africa region. There were no major regional differences for study estimates of in-hospital sequelae risk associated with each of the three main bacteria (Table 5). The post-discharge sequelae studies had very few subjects overall and represent only seven countries. Among the post-discharge studies, the two northern Africa studies found the lowest risk of sequelae associated with individual bacterial pathogens (Table 7).

Our strict case definition for confirmed bacterial meningitis led to the exclusion of 42 articles with data on neuropsychological sequelae (49% of 86 studies). This definition was selected to ensure that cases of viral meningitis, which are generally less severe, were excluded and to enable us to calculate pathogen-specific estimates for sequelae and mortality. However, this methodological choice limits the generalisibility of our findings, given the small number and regional provenance of the remaining studies.

Many African children have limited access to medical care. Our review includes only patients who were admitted to a hospital, of which 77% were tertiary referral or teaching hospitals, had diagnostic testing for bacterial meningitis and received appropriate antibiotic therapy. These children are likely to have improved outcomes compared to children treated in lower-level facilities, where antibiotics are not always available, and children who did not reach medical care. Thus, our review likely underestimates the overall burden of sequelae and mortality in African children with bacterial meningitis.

This review identified very few studies with data on post-discharge outcomes of bacterial meningitis among African children. High loss to follow-up in these studies may lead to biased results, while small sample sizes limit the precision of our findings. However, a post-discharge study of children with pneumococcal meningitis from Bangladesh found that 11% died and 49% had long-term sequelae detectable 12 to 24 months post infection [21]. This study had a low loss to follow-up rate of 11%, and the proportion of children affected was on par with a similar study from The Gambia [22]. A recent review of the global burden of meningitis sequelae was conducted and found the highest risk of long-term sequelae in Africa compared to all other regions (Karen Edmond, senior lecturer in infectious disease epidemiology, London School of Hygiene and Tropical Medicine, personal communication). Limited access to health care and poor health indicators make many African children highly susceptible to adverse outcomes following bacterial meningitis.

Further, the social and economic burden of survivors with neuropsychological sequelae is little studied in Africa. Most studies included in this review diagnosed sequelae based on clinical exam alone and thus represent profound deficits that would severely affect a child's developmental potential. In the absence of follow-up specialty services for affected children, major sequelae can result in lifelong disability. This in turn affects the disabled child's entire family, as caregivers must choose between caring for the disabled child, providing for siblings and working outside the home to supplement the family's income [21]. In a South African study following children with TB meningitis and their families, 35% of previously-employed mothers had to stop working and one in five families experienced a financial loss as a result of the child's illness; half of the schoolgoing children failed at least one school grade [23]. The societal burden of hearing loss is best documented, and in several countries meningitis has been consistently found to be a common cause of profound hearing loss [24–26].

Our review provides no information on the effect of HIV on meningitis outcomes. HIV may shift the relative frequencies of bacterial pathogens causing meningitis and contribute to childhood malnutrition, which was associated with worse prognosis in our risk factor analysis. A study from Malawi found a higher rate of mortality and recurrent disease in HIV-infected children with bacterial meningitis [27]. Another study from South Africa found a higher rate of pneumococcal meningitis and poor outcomes in HIV-infected children [28]. More research is needed on the effects of the HIV pandemic on bacterial meningitis outcomes, particularly in the high HIV prevalence areas of middle, southern and eastern Africa.

The three main bacterial causes of postneonatal childhood meningitis are all vaccine preventable. Even with appropriate treatment, pneumococcal and Hib meningitis kill approximately one third of affected children and cause clinically evident sequelae in a quarter of survivors prior to hospital discharge. Hib conjugate vaccine use has nearly eliminated Hib meningitis in many African countries [29, 30]. In Uganda, it was estimated that the vaccine prevents 1,000 cases of severe meningitis sequelae each year in the country's population of 5.3 million children under 5 years of age [29]. Pneumococcal conjugate vaccines (PCVs) are effective against invasive pneumococcal disease in African children, including meningitis [31]. In light of the high incidence of pneumococcal disease and its poor outcomes, these vaccines could prevent substantial numbers of meningitis-associated disabilities and deaths. PCV introduction into GAVI-eligible countries is underway and subsequent health and economic benefits will be closely monitored. Finally, though mortality and sequelae risk following meningococcal meningitis are not as high as with pneumococcal or Hib meningitis, the absolute numbers of sequelae and deaths occurring during meningococcal meningitis epidemics are tremendous. The epidemic potential of meningococcal meningitis has focused much attention on the introduction of meningococcal polysaccharide and conjugate vaccines in countries of the African meningitis belt. In addition, the related clinical syndrome of meningococcal sepsis, a fulminant disease that has been associated with CFRs of up to 80%, could decrease with the expanded use of meningococcal vaccine [32].

Evaluations of the health impact and cost effectiveness of conjugate vaccines should incorporate the economic and social impact of meningitis morbidity and mortality on families, many of which have little financial reserve to care for a child with a long-term disability. This review mainly includes children treated at tertiary care facilities and therefore underestimates the sequelae and mortality risk associated with bacterial meningitis. Thus, the true cost of meningitis and the true benefit of bacterial conjugate vaccines are likely to be tremendous.

Bacterial meningitis is a serious infection that has high risk of sequelae as well as mortality in African children. Even with appropriate treatment, pneumococcal and Hib meningitis kill approximately one third of affected children and cause clinically evident sequelae in a quarter of survivors prior to hospital discharge. The three leading causes of bacterial meningitis in childhood are vaccine preventable, and the regular use of these conjugate vaccines would reduce the high burden of morbidity and mortality in both epidemic and endemic settings.