Background
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.
Methods
Literature search strategy
We conducted a systematic literature search for articles published between January 1980 and August 2008 containing information on bacterial meningitis among children from continental Africa. Professional librarians searched eight databases: PubMed/Medline, Global Health Database, Embase, Biological Abstracts, Pascal, Current Contents, the Cochrane Library, and African Index Medicus. Search terms were based on the key words 'meningitis' and at least one of the following: bacteria, bacteraemia,
Streptococcus pneumoniae,
Haemophilus influenzae type b, or
Neisseria meningitidis (see Additional file
1 for full search strategy). We also screened the reference lists of two global reviews for articles with published or unpublished data [
5,
9]. Citations were uploaded into an EndNote XI library (EndNote, Carlsbad, CA, USA) and de-duplicated.
Citation screening
Two screeners reviewed each citation by preset inclusion and exclusion criteria; discrepancies were resolved through a weekly conference call. We only included articles with original sequelae data on at least 30 paediatric cases of laboratory-confirmed bacterial meningitis from 1 or more African countries. Laboratory-confirmed bacterial meningitis was defined as bacterial identification in cerebrospinal fluid (CSF) by culture, Gram stain, rapid antigen test (such as the Binax NOW test (Binax Inc., Scarborough, ME, USA)), latex agglutination or polymerase chain reaction, or bacterial isolation from blood culture accompanied by CSF abnormalities such as high white blood cell count, low glucose or high protein. We accepted the article definitions of CSF abnormalities, including CSF white blood cell count greater than 10 to 100 cells/mm3, protein greater than 0.3 to 2 g/l, and CSF glucose less than 0.2 g/l or CSF glucose: blood glucose ratio lower than 0.5. Articles had to present sequelae data separately for children or have a majority of their subjects between the ages of 1 month and 15 years. Articles in all languages were considered for inclusion.
Detailed information on neuropsychological sequelae was collected and entered into a Microsoft Access database (Microsoft, Redmond, WA, USA). Sequelae included hearing loss, vision loss, cognitive delay (including mental retardation and learning disability), speech/language disorder, behavioural problems, motor delay/impairment (including gross motor and fine motor impairment, impaired activities of daily living, hypertonia, and paralysis), seizures, and other neurological sequelae. In-hospital sequelae and deaths were defined as events that occurred after the initiation of treatment and prior to discharge, exclusive of complications observed at the time of admission. Post-discharge sequelae and deaths were defined as events that occurred or persisted after discharge as detected upon follow-up tracing of patients. Unless there was specific mention of patient follow-up after discharge, we assumed that sequelae were assessed in hospital.
We examined articles for overlaps in study population and outcomes: when these occurred, one article in the overlapping group was excluded or the outcomes partially extracted to avoid double counting cases. We also evaluated the consistency of papers by verifying that the numbers presented in the results section added up to the total subjects and total meningitis cases. If there were major or numerous inconsistencies in a paper, it was excluded from the final analysis.
Data analysis
The final database was transferred into Stata 10.0 for analysis (Stata, College Station, TX, USA). Outcomes of interest included risk of sequelae among survivors (both in hospital and post discharge) and case fatality ratios (in hospital and post discharge). Sequelae and mortality were calculated separately for pneumococcal, Hib, and meningococcal meningitis, and then for all laboratory-confirmed bacterial meningitis. For in-hospital sequelae prevalence, the denominator included all children surviving until discharge and evaluated for sequelae; for post-discharge sequelae prevalence, the denominator included children surviving until the follow-up visit and evaluated for sequelae. Case fatality ratios were calculated only for articles with at least 25 cases of confirmed bacterial meningitis and sequelae risks were calculated only for articles that assessed at least 25 survivors of bacterial meningitis.
African countries were grouped into regions to match the Global Burden of Disease analysis [
9]: eastern Africa meningitis belt, middle Africa meningitis belt, western Africa meningitis belt, eastern Africa, middle Africa, western Africa, northern Africa and southern Africa (Table
1).
Table 1
List of countries by African region
Africa Eastern Meningitis Endemic | Eritrea, Ethiopia, Kenya, Sudan, Uganda |
Africa Middle Meningitis Endemic | Cameroon, Central African Republic, Chad |
Africa Western Meningitis Endemic | The Gambia, Ghana, Senegal, Togo, Benin, Burkina Faso, Cote d'Ivoire, Guinea, Guinea-Bissau, Mali, Mauritania, Niger, Nigeria |
Africa Eastern | Mauritius, Seychelles, Comoros, Djibouti, Madagascar, Zimbabwe, Burundi, Malawi, Mozambique, Rwanda, Somalia, United Republic of Tanzania, Zambia |
Africa Middle | Congo, Gabon, Angola, Democratic Republic of Congo, Equatorial Guinea |
Africa Western | Cape Verde, Sao Tome and Principe, Liberia, Sierra Leone |
Africa Northern | Libya, Tunisia, Algeria, Egypt, Morocco |
Africa Southern | Namibia, South Africa, Botswana, Lesotho, Swaziland |
Discussion
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.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MR managed the review team, screened citations for inclusion or exclusion, reviewed the data analysis, drafted and revised the manuscript. AU screened citations, helped manage the review team, reviewed the data analysis and helped draft the manuscript. LS designed, managed and cleaned the database, conducted the data analysis and created the results tables. JM contributed to study design, oversaw database management and analysis and edited the manuscript. FW provided technical input to the process. OL conceived of the project and provided technical oversight to design and execute the review. All authors read and approved the final manuscript.