Incidence, Seasonality, Age Distribution, and Mortality of Pneumococcal Meningitis in Burkina Faso and Togo

Transcription

1 SUPPLEMENT ARTICLE Incidence, Seasonality, Age Distribution, and Mortality of Pneumococcal Meningitis in Burkina Faso and Togo Yves Traore, 1 Tsidi Agbeko Tameklo, 4 Berthe-Marie Njanpop-Lafourcade, 5 Mathilde Lourd, 5 Seydou Yaro, 2 Dominique Niamba, 3 Aly Drabo, 2 Judith E. Mueller, 5 Jean-Louis Koeck, 6 and Bradford D. Gessner 5 1 Université de Ouagadougou, Ouagadougou, and 2 Centre Muraz and 3 Centre Hospitalier Universitaire Souro Sanou, Bobo-Dioulasso, Burkina Faso; 4 Ministère de la Santé Publique du Togo, Lomé, Togo; and 5 Agence de Médecine Préventive, Paris, and 6 Laboratoire de Biologie Clinique, Hôpital d Instruction des Armées Robert Picqué, Bordeaux, France Streptococcus pneumoniae causes a substantial proportion of meningitis cases in the African meningitis belt; however, few reports exist to quantify its burden and characteristics. We conducted population-based and sentinel hospital surveillance of acute bacterial meningitis among persons of all ages in Burkina Faso and Togo in S. pneumoniae and other organisms were identified by culture, polymerase chain reaction, or detection of antigen in cerebrospinal fluid (CSF). Information was collected on 2843 patients with suspected acute bacterial meningitis. CSF specimens were collected from 2689 (95%) of the patients; of these 2689, 463 (17%) had S. pneumoniae identified, 234 (9%) had Haemophilus influenzae type b identified, and 400 (15%) had Neisseria meningitidis identified. Of the 463 cases of S. pneumoniae meningitis, 99 (21%) were aged!1 year, 71 (15%) were aged 1 4 years, 95 (21%) were aged 5 14 years, and 189 (41%) were aged 15 years (age was unknown for 9 [2%]). In Burkina Faso, the annual incidence rate of pneumococcal meningitis was 14 cases per 100,000 persons, with annual incidence rates of 77, 33, 10, and 11 cases per 100,000 persons aged!1 year,!5 years, 5 14 years, and 15 years, respectively. The case-fatality ratio for S. pneumoniae meningitis was 47% (range for age groups, 44% 52%), and 53% of deaths occurred among those aged 15 years. S. pneumoniae meningitis had an epidemic pattern similar to that of N. meningitidis meningitis. Of 48 isolates tested for serotype, 18 were from children aged!5 years; of these 18, 3 isolates (17%) each were serotypes 1, 2, and 5, and 5 isolates (28%) were serotype 6A. The 7-, 10-, and 13-valent pneumococcal conjugate vaccines would cover 6%, 39%, and 67% of serotypes identified among children aged!5 years, respectively. Of the 30 serotypes identified for patients aged 5 years, 18 (60%) were serotype 1, whereas no other serotype constituted 110%. The 7-, 10-, and 13- valent vaccines would cover 7%, 70%, and 77% of serotypes. Epidemic pneumococcal meningitis in the African meningitis belt countries of Burkina Faso and Togo is common, affects all age groups, and is highly lethal. On the basis of a modest number of isolates from a limited area that includes only meningitis cases, 7-valent pneumococcal conjugate vaccine might have only a limited and short-term role. By contrast, the proposed 10- and 13-valent vaccines would cover most of the identified serotypes. To better inform vaccine policy, continued and expanded surveillance is essential to document serotypes associated with pneumonia, changes in serotype distribution across time, and the impact of vaccine after vaccine introduction. Faso, and Ghana, all countries in the African meningitis belt, have observed that pneumococcal meningitis has seasonal epidemics that mirror those of meningococcal meningitis, epidemics of serotype 1 can occur, casefatality ratios among hospitalized patients may exceed 50%, and a significant disease burden exists among older children and working-age adults [1 3]. The rea- Studies of pneumococcal meningitis in Niger, Burkina Reprints or correspondence: Dr. Bradford D. Gessner, Agence de Médecine Préventive, Institut Pasteur, 28 rue du Docteur Roux, 75015, Paris, France ( @compuserve.com). Clinical Infectious Diseases 2009; 48:S by the Infectious Diseases Society of America. All rights reserved /2009/4805S2-0020$15.00 DOI: / Pneumococcal Meningitis in Burkina Faso and Togo CID 2009:48 (Suppl 2) S181

2 sons for these features remain unknown, and the degree to which the information represents the situation in the entire meningitis belt remains in question. The current study presents an update to data previously published for Burkina Faso [3] and adds data from neighboring Togo. METHODS Surveillance sites. With use of a methodology described elsewhere [3], surveillance of acute bacterial meningitis was initiated in April 2002 in Bobo-Dioulasso, Burkina Faso, and its surroundings, including the mainly urban district 15 and the rural districts 22 and Houndé (total 2002 population, 880,000, including 140,000 children aged!5 years). Age-specific populations were derived by applying estimates for all of Burkina Faso to the study population [4]. Population-based surveillance was conducted at the regional referral hospital and at all 59 local health care centers from April 2002 through April 2003 and again from March 2004 through February 2005 (activities were halted midstudy because of funding limitations). Additionally, we conducted surveillance from March through July 2005 and from May through July 2006; for these 2 periods, however, case identification was limited to hospitalized cases at the regional referral hospital only. In Togo, sentinel hospital surveillance was conducted from November 2003 through December 2006, with the exception that no patients were enrolled from June through November Case enrollment began during November 2003 at the local hospitals in Sotouboua (in central Togo; 2003 census population estimate, 20,000) and Dapaong (in northern Togo, along the border with Burkina Faso; 2003 census population estimate, 49,000). Starting in February 2004, we added the regional referral hospital in Sokode (central Togo; 2003 census population estimate, 101,000). Case identification. A case of suspected meningitis was defined by rapid onset of fever (temperature, 38.5 C rectal or 38.0 C axillary) and 1 of the following symptoms: stiff neck, altered consciousness, petechial or purpuric rash, or other signs of meningitis. For infants, fever with bulging fontanelle was also included in the case definition. Although this case definition was provided to them, providers were free to use their clinical judgment to identify patients with suspected bacterial meningitis. A lumbar puncture was performed for the majority of patients with suspected acute bacterial meningitis, regardless of age. At all study sites, patients usually underwent lumbar puncture and received treatment before being transferred from a health care center or local hospital to a reference hospital. For each patient with suspected meningitis, an aliquot of CSF and a clinical case report form were transported to the reference laboratory in Bobo-Dioulasso. For specimens from Burkina Faso, all diagnostic tests were performed at the reference laboratory. For specimens from Togo, latex agglutination and culture were performed locally, and PCR testing was performed in Bobo-Dioulasso. Purulent CSF was defined by visual turbulence or a WBC count 100 cells/mm 3. For a subset of patients from Burkina Faso who were enrolled during (the period of population-based surveillance), we performed additional analyses, comparing this definition to other definitions of purulence. These other definitions included WBC count 100 cells/mm 3 or visual turbulence, but visual turbulence only if CSF WBC count was missing; WBC count 100 cells/mm 3 regardless of visual appearance; visual appearance regardless of CSF WBC count; and CSF WBC count of cells/mm 3. The season of epidemic meningitis in the African meningitis belt may vary, depending on the year and the region. For the purposes of the current evaluation, we defined this season as December of one year through April of the next year. Laboratory methods. In Burkina Faso, the study protocol required PCR testing of CSF specimens from all suspected meningitis cases, culture of CSF specimens for which the time from collection to arrival at the reference laboratory was!2h,and latex agglutination testing for CSF specimens that were visibly cloudy. Togo implemented a similar methodology, except that CSF specimens were kept frozen until sent, at ambient temperature, to the laboratory in Bobo-Dioulasso for PCR testing. PCR is generally considered the most sensitive assay for detection of a bacterial etiology of meningitis; in this setting, however, there were occasional transport delays, which may have reduced PCR sensitivity. Isolates were cultured using standard methodology [5]. Latex agglutination testing was performed using Pastorex (Biorad) in accordance with the manufacturer s instructions. PCR of CSF specimens was performed at the Centre Muraz laboratory in Bobo-Dioulasso, with identification on the basis of gene amplification of lyta for Streptococcus pneumoniae [6], crga for Neisseria meningitidis [7], and bexa for Haemophilus influenzae type b (Hib) [6]. A suspected case of meningitis was considered to have a confirmed etiology when an organism was identified by PCR, culture, or latex agglutination from the CSF specimen. As reported previously [3], 48 isolates collected from Burkina Faso during were available for serotype evaluation. Testing was performed at the Army Medical Biology Laboratory Robert Picqué (Bordeaux, France) with use of Pneumotest- Latex kits (Statens Serum Institute), which can detect 90% 95% of serogroups and/or serotypes of invasive pneumococci [8]. The tested isolates came from all 3 surveillance districts in Burkina Faso, whereas no isolates from Togo were available for serotyping. Local sites performed antibiotic-resistance evaluation for penicillin, sulfamethoxazole, ceftriaxone, and chloramphenicol by using the disk-diffusion method and standard breakpoints S182 CID 2009:48 (Suppl 2) Traore et al.

3 [9]. Erythromycin-susceptibility testing was not performed, because this antibiotic was rarely used in the study area. The 48 isolates sent to France were evaluated by E-test (AB Biodisk) to calculate MIC values for penicillin, ampicillin, and ceftriaxone. Study approval. This surveillance project was approved by the ethics review board of Centre Muraz in Burkina Faso and was supported by the ministries of health of Burkina Faso and Togo. RESULTS Case characteristics and mortality. There were 2843 patients identified with suspected acute bacterial meningitis, including 2223 from Burkina Faso (in ) and 620 from Togo (in ). Of these patients, 2689 (95%) had CSF specimens collected. Purulent CSF (turbid appearance or WBC count 100 cells/mm 3 ) was identified for 1063 patients (40% of those with CSF specimens collected); 897 were from Burkina Faso, and 166 were from Togo. Of the 2689 patients with CSF collected, 463 (17%) had S. pneumoniae identified, 234 (9%) had Hib identified, and 400 (15%) had N. meningitidis identified. Of the 1097 cases with an identified etiology, 42% overall (table 1), 42% in Burkina Faso, and 43% in Togo had S. pneumoniae. Both countries had similar etiology-specific age-group distributions; among children aged!1 year, Hib predominated, whereas pneumococcus was the most common etiology among persons aged 15 years. N. meningitidis caused 57% of meningitis cases with etiological confirmation among persons aged 5 14 years in Burkina Faso but caused only 11% of such cases in Togo. In Burkina Faso, 59% of pneumococcal meningitis cases and 58% of all etiologyconfirmed meningitis cases occurred among males, whereas, in Togo, these values were both 54%. S. pneumoniae case-fatality ratios were high among all age groups, with an overall ratio of 42% (range for age groups, 44% 52%). Case-fatality ratios were lower for N. meningitidis meningitis (overall, 14%; range for age groups, 11% 18%) and H. influenzae (overall, 27%; range for age groups, 22% 33%). Figure 1. Proportion of the total number of deaths due to acute bacterial meningitis attributable to particular etiologies, by age group, in Burkina Faso ( ) and Togo ( ). S. pneumoniae caused 65% of all deaths due to acute bacterial meningitis and caused the most deaths in every age group evaluated (table 1 and figure 1). Patterns of case-fatality ratios did not differ between countries. Testing results. Of the 463 pneumococcal meningitis cases, 101 (22%) had pneumococci identified by all 3 testing methods: PCR, latex agglutination, and culture. A total of 124 cases (27%) had pneumococci identified by 2 methods 61 (13%) had positive results of PCR and latex agglutination, 50 (11%) had positive results of culture and PCR, and 13 (3%) had positive results of culture and latex agglutination. A total of 238 cases (51%) had pneumococci identified by 1 method 125 (27%) had positive results of PCR only, 71 (15%) had positive results of latex agglutination only, and 42 (9%) had positive results of Table 1. Etiologies and case-fatality ratios for acute bacterial meningitis, by patient age group, in Burkina Faso ( ) and Togo ( ). Age group, years No. of cases with known etiology Streptococcus pneumoniae No. (%) of cases, by etiology Haemophilus influenzae type b Neisseria meningitidis No. of deaths/no. of cases with known outcome (case-fatality ratio, %), by etiology S. pneumoniae H. influenzae type b N. meningitidis! (35) 133 (47) 51 (18) 41/79 (52) 29/118 (25) 6/46 (13) (32) 59 (26) 94 (42) 29/58 (50) 14/47 (30) 14/79 (18) (33) 27 (10) 162 (57) 36/80 (45) 7/21 (33) 14/122 (11) (66) 12 (4) 86 (30) 64/145 (44) 2/9 (22) 6/56 (11) Unknown 19 9 (47) 3 (16) 7 (37) 1/1 (100) 0/0 (0) 2/3 (67) Total (42) 234 (21) 400 (36) 171/363 (47) 52/195 (27) 42/306 (14) Pneumococcal Meningitis in Burkina Faso and Togo CID 2009:48 (Suppl 2) S183

4 culture only. Overall, 337 (73%) of the 463 cases had pneumococci identified by PCR, 246 (53%) by latex agglutination, and 206 (44%) by culture. Seasonality and yearly trends. A complete description of seasonality and yearly trends was complicated by the interruptions in surveillance that were experienced at all sites. In general, pneumococcal meningitis occurred in a pattern indistinguishable from that observed for meningococcal meningitis. In Burkina Faso, with population-based surveillance from April 2002 through February 2005, the peak case counts for pneumococcal meningitis were as high as those seen for meningococcal meningitis (figure 2A). The months of the epidemic season include December through April. No epidemic of disease caused by N. meningitidis serogroup A occurred in the study area during the study period. However, a large epidemic caused by N. meningitidis serogroup W135 epidemic occurred in the Bobo-Dioulasso region during the epidemic season (including the first month of surveillance for the current study) and again during the epidemic season. In Togo, peak case counts for pneumococcal meningitis were not as high as the peak case counts seen for meningococcal meningitis (figure 2B). However, during the epidemic season, pneumococci caused the majority of identified cases. The contribution of pneumococcus to acute bacterial meningitis during the epidemic meningitis season increased during the study period in both Burkina Faso and Togo. In Burkina Faso, population-based surveillance using a consistent design occurred during all or parts of 4 epidemic seasons. Excluding the season (during which surveillance included only the month of April), the percentage of cases due to pneumococci increased from 36% to 45% to 53% (x 2 for linear trend, 6.9; P p.0084) from the to the to the seasons. Despite this increasing percentage of cases due to pneumococci, during the same periods the total number Figure 2. No. of cases of acute bacterial meningitis due to Streptococcus pneumoniae and Neisseria meningitidis among persons of all ages, by year and month, in the Bobo-Dioulasso region, Burkina Faso (A), and in central and northern Togo (B). S184 CID 2009:48 (Suppl 2) Traore et al.

5 Table 2. Incidence and number of cases of Streptococcus pneumoniae meningitis, on the basis of surveillance conducted during April 2002 April 2003 and March 2004 February 2005 in the Bobo- Dioulasso area, Burkina Faso. Age group No. of cases Percentage of all cases ( n p 248) Incidence, cases per 100,000 persons (95% CI)!3 months ( ) 3 5 months ( ) 6 11 months ( ) months ( ) 2 4 years ( ) 5 9 years ( ) years ( ) years ( ) years ( ) years ( ) years ( ) years ( ) 60 years ( ) Figure 3. Annualized incidence rates for disease caused by Streptococcus pneumoniae and Neisseria meningitidis (Nm) serogroups A and W135, by year of occurrence, for the recorded peak months of 4 meningitis epidemics in the Bobo-Dioulasso region, Burkina Faso. of pneumococcal meningitis cases decreased from 86 to 52 to 41. Burkina Faso and Togo both introduced Hib conjugate vaccine into routine infant immunization programs after 2005; thus, this would not have affected the results presented here. In Togo, a similar pattern was seen: during the , , and epidemic seasons, the percentage of acute bacterial meningitis cases due to pneumococci increased from 42% to 41% to 66%. However, because the Togo surveillance sites were not population based and because an additional site was added during the study period, inferences about changes in the contribution of pneumococcus to the overall burden of acute bacterial meningitis cannot be made. Incidence. Incidence could be calculated for the periods during which population-based surveillance was conducted in Burkina Faso, limiting analysis to 2 periods of 12 consecutive months each. The overall annualized incidence rate of pneumococcal meningitis was 14 cases per 100,000 persons, with incidence rates of 77 cases per 100,000 persons aged!1 year, 14 cases per 100,000 persons aged 1 4 years, 10 cases per 100,000 persons aged 5 14 years, and 11 cases per 100,000 persons aged 15 years. Incidence was remarkably stable among relatively specific age categories older than 2 years (table 2). To evaluate changes in the incidence of S. pneumoniae meningitis compared with N. meningitidis meningitis, for 4 consecutive years we compared incidence rates during the 2 peak months (except only April was available for 2002) of the 4 epidemic meningitis seasons (figure 3). Incidence patterns for pneumococcal and meningococcal serogroup A meningitis were similar, whereas meningococcal serogroup W135 meningitis had a distinct pattern. Serotypes and antibiotic resistance. For the Bobo-Dioulasso region in , 85 pneumococcal meningitis cases had a positive culture result. Among these, 48 isolates (24 from and 24 from ) were successfully prepared and arrived uncontaminated at the reference laboratory in France. Of the isolates tested for serotype, 24%, 65%, and 11% were from districts 15, 22, and Houndé, respectively, compared with 25%, 47%, and 27% of all pneumococcal cases. Eighteen isolates were from children aged!5 years; 3 isolates (17%) each were serotypes 1, 2, and 5, and 5 isolates (28%) were serotype 6A (figure 4). Of the 30 tested isolates from older subjects, 18 (60%) were serotype 1, whereas no other serotype contributed 110%. Little overlap existed in serotypes among isolates collected from patients aged!5 years and those collected from patients aged 5 years. The currently licensed 7-valent pneumococcal conjugate vaccine contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, whereas the proposed 10-valent vaccine also includes serotypes 1, 5, and 7F, and the proposed 13-valent vaccine also includes serotypes 1, 3, 5, 6A, 7F, and 19A. Among children aged!5 years, the 7-, 10-, and 13-valent conjugate vaccines would cover 6%, 39%, and 67% of serotypes (coverage including cross-reactive serotype 6A, 33%, 67%, and 67%, respectively). Among older patients, the 7-, 10-, and 13-valent vaccines would cover 7%, 70%, and 77% of serotypes. The 23-valent polysaccharide vaccine, which is recommended for use among elderly adults and children aged 12 years who have underlying medical conditions, includes 76% of the serotypes causing meningitis among persons aged 2 years (coverage including serotype 6A, 79%), on the basis of the determination of 34 serotypes for this age group. No persons age 65 years had isolates with serotype evaluated, and only 27 persons aged 65 years presented with meningitis, including 3 who had pneumococci identified. Pneumococcal Meningitis in Burkina Faso and Togo CID 2009:48 (Suppl 2) S185

6 a CSF WBC count 100 cells/mm 3. Although visual turbulence was more common as the CSF WBC count increased, it was noted even at low WBC counts. Figure 4. Serotype distribution of pneumococcal isolates for the age groups!5 years and 5 years in the Bobo-Dioulasso region, Burkina Faso, NT, nontypeable. By the disk-diffusion method, resistance to sulfamethoxazole was identified among 95 (57%) of 166 pneumococcal isolates tested (45 [70%] of 64 in Burkina Faso; 50 [49%] of 102 in Togo), resistance to chloramphenicol among 10 (5%) of 185 tested isolates (4 [4%] of 99 in Burkina Faso; 6 [7%] of 86 in Togo), and resistance to ceftriaxone among 3 (1%) of 201 tested isolates (1 [1%] of 99 in Burkina Faso; 2 [2%] of 102 in Togo). Resistance to penicillin was identified among 31 (17%) of 180 pneumococcal isolates tested (21 [22%] of 94 in Burkina Faso; 10 [12%] of 86 in Togo). However, of the 48 isolates from Burkina Faso tested for resistance to oxacillin in a reference laboratory, 2 had reduced susceptibility, and neither was resistant to penicillin or ampicillin by E-test. Among the 48 isolates from Burkina Faso that were shipped to the reference laboratory in France, we found that 4 of the 21 isolates of serotype 1 had resistance to sulfamethoxazole, whereas none were resistant to the other antibiotics. Both of the 2 isolates of serotype 14 were resistant to sulfamethoxazole and demonstrated reduced susceptibility to oxacillin. Of the 6 isolates of serotype 6A/6B, 3 had reduced susceptibility to sulfamethoxazole, as did both of the isolates of serotype 12A/12B. None of the 48 isolates had resistance to ceftriaxone, and one isolate (serotype 12B) had resistance to chloramphenicol. Purulent CSF. From 2002 to 2005, we identified 249 cases of pneumococcal meningitis. Among these, the visual appearance of CSF specimens was reported for 238 (96%), and the CSF WBC count was reported for 207 (83%) (all 207 had visual appearance reported). Of the 238 cases with information available, 222 (93%) met the standard definition for purulence (visual turbulence or CSF WBC count 100 cells/mm 3 ), of which 208 were visibly turbid (table 3). Only 142 (60%) met the definition of purulence when visual turbulence was allowed as a criterion only if the CSF WBC count was missing, and 113 (47%) met the definition when purulence was defined only by DISCUSSION The current study extends data on pneumococcal meningitis in Burkina Faso presented previously [3], adds results from central and northern Togo, and confirms the presence of highly lethal pneumococcal meningitis that has epidemiological characteristics similar to those seen for meningococcal serogroup A meningitis in the African meningitis belt. In Togo and Burkina Faso, and in the absence of a major outbreak of N. meningitidis serogroup A meningitis, S. pneumoniae may predominate during the epidemic season. Moreover, during the study period, pneumococcus was, by far, the most common cause of death due to acute bacterial meningitis. Although we did not measure sequelae, previous studies have confirmed that pneumococcal meningitis in Africa may cause substantial disability among survivors [10], as have more recent studies from other areas of the world [11]. Seasonal pneumococcal meningitis has been reported for at least several decades [1, 12]. However, the current study and studies from Ghana and Burkina Faso [2, 3] differ from the earlier studies in the extent to which pneumococcus contributed to the overall meningitis burden. In our study, pneumococcus was the most common cause of meningitis identified, despite the presence of a major epidemic of N. meningitidis serogroup W135 meningitis during , the lack of Hib conjugate vaccine, and a relatively low prevalence of HIV infection, compared with that reported in central and southern African countries. The virtually identical seasonal patterns for pneumococcal and meningococcal meningitis suggest that they share some risk factors for becoming epidemic. We also found that the age distribution across time of pneumococcal meningitis cases resembled that for N. meningitidis serogroup A meningitis cases much more closely than that for N. meningitidis serogroup W135 meningitis cases, indicating that the Table 3. WBC counts in CSF specimens, according to visual appearance of turbidity, for 249 cases of pneumococcal meningitis in Burkina Faso, CSF WBC count, cells/mm 3 Turbid Nonturbid Turbidity not recorded NA NOTE. NA, not available (CSF WBC count was not performed). S186 CID 2009:48 (Suppl 2) Traore et al.

7 observed similarities do not simply reflect risk factors common to all forms of acute bacterial meningitis [13]. We found that the highest incidence of pneumococcal meningitis occurred among infants, as shown previously in the United States and elsewhere [14]. Nevertheless, most cases and the majority of deaths occurred among older children and working-age adults. Unlike among infants and young children, death and disability among working-age adults may impoverish entire extended families and erode the economic productivity of communities. Our data thus support the extension of the use of pneumococcal vaccines beyond the age group of!5 years, at least in the African meningitis belt. We determined serotypes for a modest number of cases that presented only with meningitis (and not pneumonia) from a relatively limited area of 1 country. Additional evaluation is necessary to confirm the representativeness of our results. Nevertheless, these data make up one of the few reports on serotype distribution in the African meningitis belt. If our data are confirmed by others, they suggest that, although pneumococcal conjugate vaccines are clearly needed for primary infant immunization, pneumococcal vaccines also may have a role in older children and working-age adults in the meningitis belt. For example, mass catch-up campaigns among those aged 2 29 years with pneumococcal conjugate vaccines containing serotype 1 would have an immediate impact on pneumococcal disease burden. Given that most pneumococcal meningitis disease and mortality in Burkina Faso and elsewhere in the meningitis belt [1 3] appear to occur after age 5 years, the shortterm and midterm benefits of a catch-up campaign may be as great as those from primary infant immunization. The 23- valent polysaccharide vaccine also may have a role, although it has rarely been tested among healthy nonelderly older children and adults [15 17]. This vaccine also may have a role as a booster dose following primary vaccination with pneumococcal conjugate vaccines, particularly because polysaccharide vaccine may be highly immunogenic for serotype 1 [18]. Etiological determination of acute bacterial meningitis cases is problematic because of transportation and laboratory limitations. Under these circumstances, identification of purulent meningitis may assist in estimation of pneumococcal meningitis burden. Data from Burkina Faso demonstrate that estimates of bacterial meningitis disease burden, determined on the basis of CSF purulence, are highly sensitive to the definition of purulence that is used. Because CSF specimens from confirmed pneumococcal cases was frequently visually turbid despite a low WBC count, definitions that minimize the importance of or ignore visual appearance may miss many cases of potential pneumococcal meningitis. The reason for the moderate disassociation between CSF WBC count and visual appearance in our study is not clear. It may reflect the circumstance that visual appearance was determined immediately, whereas WBC count determination may have occurred after a substantial delay, or it may reflect laboratory limitations. Regardless of the reason, our data suggest that visual turbulence should be regarded as an indicator of purulence that is equally important as CSF WBC count. Pneumococcal antibiotic resistance was infrequent, although, again, our data are derived from a limited number of isolates from a single region. Despite the low prevalence of resistance, almost half of the patients with pneumococcal meningitis died after presentation to a health care center. Treatment strategies in the meningitis belt have relied on the use of 1 or 2 doses of oily chloramphenicol (a long-acting preparation of chloramphenicol in an oil suspension) for empirical therapy during the epidemic meningitis season, on the basis of the assumption that most meningitis cases result from meningococcal infection [19, 20]. This treatment is likely inadequate for pneumococcal meningitis and may explain partially the observed high casefatality ratios. It cannot explain all the mortality, however, because many patients died rapidly after presentation to a health care facility. Moreover, a recent study from Malawi documented a case-fatality ratio of 46%, despite the use of third-generation cephalosporins as first-line therapy [21]. In Burkina Faso, many clinicians have switched to using ceftriaxone for confirmed cases of pneumococcal meningitis, and continued surveillance may indicate whether this strategy contributes to an improvement in case-fatality ratios. The various epidemiological outcomes of pneumococcal meningitis can be influenced by access to care, the prevalences of HIV infection and malnutrition, and the use of Hib conjugate vaccine. We did not directly measure these variables in our study. Access to care for patients with meningitis will depend on factors such as proximity to health care centers, availability of transportation, financial limitations, size of the yearly meningitis epidemic, and related factors such as drought and malnutrition. UNICEF reports that, in Burkina Faso and Togo, respectively, 36% and 30% of children aged!5 years with acute respiratory illness are taken to a health care provider [22]. These data suggest the possibility that some or even many patients with meningitis do not present for care to a modern health care facility. In Burkina Faso and Togo, the 2003 prevalence rates of HIV infection among adults were 4.2% and 4.1%, respectively [23]. If these rates increase, it will likely increase the burden of pneumococcal meningitis. Moderate or severe malnourishment during 2003 occurred among 38% and 25% of children aged!5 years in Burkina Faso and Togo, respectively [21]. Burkina Faso implemented routine infant vaccination with Hib conjugate vaccine during January 2006, whereas Togo had not yet implemented the vaccine by the end of the study. The GAVI Alliance will make the 7-valent pneumococcal conjugate vaccine available to eligible countries at a cost to the country of US$0.10 $0.30 per dose. In the Bobo-Dioulasso Pneumococcal Meningitis in Burkina Faso and Togo CID 2009:48 (Suppl 2) S187

8 region of Burkina Faso, this vaccine would have covered only 33% and 10% of serotypes identified in pediatric and adult meningitis cases, respectively. Additional data will be needed to determine whether our results based on limited serotype testing apply to other areas of the meningitis belt, whether serotype distribution changes across time, and whether serotype distribution among pneumonia cases differs from that among meningitis cases. Until these data are available, decision makers in Burkina Faso, Togo, and other countries in the region must decide whether to introduce the 7-valent vaccine on the basis of relatively limited data or whether to await further data and the arrival of the 10-valent or 13-valent vaccine. For several reasons, Burkina Faso and Togo may benefit from vaccine introduction now. Pneumonia causes the major burden of pneumococcal disease. Serotypes causing pneumonia were not measured in our study and may differ from those causing meningitis [23]. Additionally, as we have reported previously [3], pneumococcal serotypes varied greatly even between 2 epidemic seasons, with serotype 1 being less common during the more recent epidemic. Lastly, a relatively high incidence of pneumococcal meningitis in combination with a case-fatality ratio of almost 50% and high morbidity rates among survivors argue that even a modest reduction in incidence may make vaccination an attractive option. If countries choose to adopt use of the 7-valent vaccine, funding must be available to establish high-quality surveillance at least at a regional level that includes monitoring of serotype distribution and changes across time among isolates collected from both meningitis and pneumonia cases. Among the countries in the meningitis belt, Burkina Faso, central and northern Togo, Niger, and northern Ghana have documented an extensive burden of pneumococcal meningitis disease and a high associated mortality that affects people of all ages. Other countries in the region have documented high burdens of pediatric pneumococcal meningitis and pneumonia [24, 25]. The currently available conjugate and polysaccharide vaccines are not optimal for the region but nevertheless may provide substantial benefit. Countries that introduce the vaccines should ensure that adequate surveillance systems exist before or begin concurrent with the vaccine introduction, at least at the regional level. Acknowledgments For care of patients and assistance with parts of the study, we thank the numerous clinical and laboratory staff of Centre Muraz; Centre Hospitalier Universitaire Souro Sanou; peripheral health centers in Burkina Faso; and the Sotouboua, Dapaong, and Sokode hospitals in Togo. We thank A. Leblond, R. Idohou, and S. Kroman of Agence de Médecine Préventive for coordination, follow-up, monitoring, and quality control of clinical and laboratory activities. Financial support. Sanofi-Pasteur; Institut Pasteur; the Bill & Melinda Gates Foundation; and PneumoADIP. Supplement sponsorship. This article was published as part of a supplement entitled Coordinated Surveillance and Detection of Pneumococcal and Hib Disease in Developing Countries, sponsored by the GAVI Alliance s PneumoADIP of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Potential conflicts of interest. B.-M.N.-L., M.L., J.E.M., and B.D.G. were employees of Agence de Médecine Préventive, which receives substantial financial support from Sanofi-Pasteur, one of the financial supporters of the study and a manufacturer of pneumococcal vaccines. J.L.K. receives funding from Sanofi-Pasteur. All other authors: no conflicts. References 1. Campagne G, Schuchat A, Djibo S, et al. Epidemiology of bacterial meningitis in Niamey, Niger, Bull World Health Organ 1999; 77: Leimkugel J, Adams Forgor A, Gagneux S, et al. An outbreak of serotype 1 Streptococcus pneumoniae meningitis in northern Ghana with features that are characteristic of Neisseria meningitidis meningitis epidemics. J Infect Dis 2005; 192: Yaro S, Lourd M, Traore Y, et al. Epidemiological and molecular characteristics of a highly lethal pneumococcal meningitis epidemic in Burkina Faso. Clin Infect Dis 2006; 43: US Census Bureau. International data base: data tables by country. Available at: Accessed 9 January WHO. Laboratory methods for the diagnosis of meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. World Health Organization communicable disease surveillance and response. Document WHO/CDS/CSR/EDC/99.7. Geneva: World Health Organization, Hassan-King M, Baldeh I, Adegbola R, et al. Detection of Haemophius influenzae and Streptococcus pneumoniae DNA in blood culture by a single PCR assay. J Clin Microbiol 1996; 34: Taha MK. Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis. J Clin Microbiol 2000; 38: Slotved HC, Kaltoft M, Skovsted IC, Kerrn MB, Espersen F. Simple, rapid latex agglutination test for serotyping of pneumococcus (Pneumotest-Latex). J Clin Microbiol 2004; 42: Members of the SFM Antibiogram Committee. Comite de l Antibiogramme de la Société Française de Microbiologie report Int J Antimicrob Agents 2003; 21: Peltola H. Burden of meningitis and other severe bacterial infections of children in Africa: implications for prevention. Clin Infect Dis 2001; 32: Saha SK, Khan NZ, Ahmed ASMNU, et al. Neurodevelopmental sequelae in pneumococcal meningitis cases in Bangladesh: a comprehensive follow-up study. Clin Infect Dis 2009; 48(Suppl 2):S90 6 (in this supplement). 12. Tugwell P, Greenwood BM, Warrell DA. Pneumococccal meningitis: a clinical and laboratory study. Q J Med 1976; 45: Greenwood B. Pneumococcal meningitis epidemics in Africa. Clin Infect Dis 2006; 43: Robinson KA, Baughman W, Rothrock G, et al. Epidemiology of invasive Streptococcus pneumoniae infections in the United States, : opportunities for prevention in the conjugate vaccine era. JAMA 2001; 285: Mangtani P, Cutts F, Hall AJ. Efficacy of polysaccharide pneumococcal vaccine in adults in more developed countries: the state of the evidence. Lancet Infect Dis 2003; 3: Cornu C, Yzebe D, Leophonte P, Gaillat J, Boissel JP, Cucherat M. Efficacy of pneumococcal polysaccharide vaccine in immunocompetent adults: a meta-analysis of randomized trials. Vaccine 2001; 19: French N, Nakiyingi J, Carpenter LM, et al. 23-Valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: doubleblind, randomised and placebo controlled trial. Lancet 2000;355: S188 CID 2009:48 (Suppl 2) Traore et al.

9 18. Shann F. Pneumococcal vaccine: time for another controlled trial. Lancet 1998; 351: Lewis RF, Dorlencourt F, Pinel J. Long-acting oily chloramphenicol for meningococcal meningitis. Lancet 1998; 352: World Health Organization. Meningococcal meningitis. Fact sheet no Revised May Available at: factsheets/2003/fs141/en/. Accessed 15 July Molyneaux E, Riordan AI, Walsh A. Acute bacterial meningitis in children presenting to the Royal Liverpool Children s Hospital, Liverpool, UK and the Queen Elizabeth Central Hospital in Blantyre, Malawi: a world of difference. Ann Trop Paediatr 2006; 26: UNICEF. The state of the world s children 2006: statistics. Available at: Accessed 10 April Hausdorff WP, Bryant J, Kloek C, Paradiso PR, Siber GR. The contribution of specific pneumococcal serogroups to different disease manifestations: implications for conjugate vaccine formulation and use, part II. Clin Infect Dis 2000; 30: Cutts FT, Zaman SM, Enwere G, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebocontrolled trial. Lancet 2005; 365: Campbell JD, Kotloff KL, Sow SO, et al. Invasive pneumococcal infections among hospitalized children in Bamako, Mali. Pediatr Infect Dis J 2004; 23: Pneumococcal Meningitis in Burkina Faso and Togo CID 2009:48 (Suppl 2) S189