Bacterial Meningitis and Haemophilus influenzae Type b Conjugate Vaccine, Malawi

A retrospective database review showed that Haemophilus influenzae type b conjugate vaccine decreased the annual number of cases of H. influenzae type b meningitis in children in Blantyre, Malawi. Among young bacterial meningitis patients, HIV prevalence was high (36.7% during 1997–2009), and pneumococcus was the most common etiologic agent (57% in 2009).

A cute bacterial meningitis (ABM) is a major cause of illness and death in children in sub-Saharan Africa (1,2). Neisseria meningitidis is the most common cause of ABM in the meningitis belt (sub-Saharan Africa), and Streptococcus pneumoniae and Haemophilus infl uenzae type b (Hib) are the most common causes in southern and eastern Africa (1)(2)(3)(4). Of 114 case-patients with meningitis and positive cerebrospinal fl uid (CSF) cultures who came to the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi (southeastern Africa), during 1996-1997, more than half of these cases were caused by S. pneumoniae, Hib, or Salmonella spp. (5).
In February 2002, Malawi introduced Hib conjugate vaccine in a pentavalent formulation that includes vaccine against diphtheria, pertussis, tetanus, and hepatitis B. There was no mass campaign or catch-up program. This vaccine is given routinely to patients at 6, 10, and 14 weeks of age; vaccination coverage has been ≈90% since 2002 (http://apps.who.int/immunization_monitoring/en/ globalsummary/countryprofi leresult.cfm). Incidence of Hib meningitis decreased but the long-term effect of the vaccination program remains unclear (6). We examined the effectiveness of Hib conjugate vaccine by conducting a retrospective database review of children with ABM who came to QECH in Blantyre, Malawi during 1997Malawi during -2009.

The Study
QECH is the district hospital for Blantyre District and a major referral center serving southern Malawi. We aggregated data from 3 studies of childhood ABM at QECH, where patients 2 months to 15 years of age with suspected ABM were treated (7; E.M. Molyneux, unpub. data). A patient with ABM was defi ned as a person whose CSF sample at the time of hospital admission contained >100 leukocytes/high-power microscopic fi eld or demonstrable organisms by Gram stain or culture.
Data collection began in July 1997 and continued through December 2009. We multiplied the observed number of cases in 1997 by 2 to estimate the total number of cases for 1997. No data were collected during October 2000-October 2001; data from 2001 were excluded from analysis. Total number of cases in 2000 was estimated by multiplying the observed number of cases in 2000 by 1.25. S. pneumoniae and Hib had mild seasonal variations that did not affect the results, and we conclude that this estimation enables valid comparisons. We did not ascertain vaccination status of study participants.
Data were analyzed by using STATA 10.1 SE (Stata Corp LP, College Station, TX, USA). A 2-tailed t-test was used to compare mean case counts, and 2-tailed z tests were used to compare proportions. All studies were reviewed and approved by the College of Medicine Research and Ethics Committee in Blantyre, Malawi. CSF samples were obtained aseptically before administration of antimicrobial drugs, labeled, and immediately sent to the laboratory. These specimens were cultured onto blood and chocolate agar plates and incubated at 37°C for 72 hours. Isolates were identifi ed by using standard procedures (8). Commercial slide agglutination tests were used to serotype H. infl uenzae isolates (MAST Diagnostics, Bootle, UK). If CSF specimens were culture negative and gram negative after 2 days, they were tested for 5 common bacterial antigens (Hib, S. pneumoniae, N. meningitidis, group B streptococci, and Escherichia coli) by using latex agglutination reagents (Murex, Kent, UK) according to the manufacturer's instructions.
Serum samples were tested for HIV by using >2 of the following tests: Serodia-HIV particle agglutination (Fujirebio Inc., Tokyo, Japan and Mast Diagnostics), HIVSPOT (Genelabs Diagnostics, Singapore),  (9). Census data show that there were 6,749,800 children <15 years of age in Malawi in 2009 (10). We estimate that 1.65% of children in Malawi are HIV seropositive. The proportion of HIV-seropositive children was signifi cantly higher in our study population than in the general population (p<0.0001).
The number of annual cases for each causative agent of ABM changed dramatically during 1997-2009 (Figure). Before Hib vaccine was available (1997-2002), Hib was responsible for 53.2 annual cases of bacterial meningitis. After introduction of the vaccine, mean number of annual cases decreased to 9.7 (p<0.0001; Table)

Conclusions
Cases of Hib meningitis in children decreased substantially in Blantyre in the postvaccination era but causes of residual disease remain unclear. We hypothesize that Hib meningitis affects mainly those not fully immunized, those with HIV, and those vaccinated before introduction of pentavalent vaccine. However, without data on vaccination status of participants, we cannot address this hypothesis and recommend more intensive research. These results complement and extend those of a previous study and provide evidence of ongoing effectiveness of the Hib conjugate vaccination program in a population with high HIV seroprevalence (6). Hib conjugate vaccine is not equally effective among HIV-positive patients, and the high prevalence of HIV infection may be associated with persistence of Hib meningitis (11). Most Hib disease is seen as pneumonia, and estimates of Hib disease incidence based on meningitis data consequently underestimate the true incidence in the general population (2,12). Pneumococcal meningitis occurred more frequently in HIV-seropositive children than in the general population, suggesting that HIV infection is a predisposing factor. This fi nding has been widely reported elsewhere (13). Approximately 65% of children in South Africa with pneumococcal meningitis were HIV seropositive; the larger proportion of HIV co-infection in this population may be caused by the higher HIV prevalence in children in South Africa (4.5% vs. 1.7%) (14). Pneumococcal meningitis remains the leading cause of ABM in children in Malawi and we strongly recommend introducing the pneumococcal conjugate vaccine to reduce the incidence of ABM in this population.