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The epidemiology of Neisseria meningitidis meningitis in Togo during 2003–2005
Vaccine 25S (2007) A47–A52
The epidemiology of Neisseria meningitidis meningitis in Togo during 2003–2005 Kokou-Louis-Sewonou Adjogble a , Mathilde Lourd b , Berthe-Marie Njanpop-Lafourcade b , Yves Traor´e c , Avoko Fidelia Sitti Hlomaschi d , K. Agbenon Amegatse e , Kodjo Agbenoko e , Oumarou Sanou f , Kroman Sita b , Judith E. Mueller b , Bradford D. Gessner b,∗ a
Minist`ere de la Sante Publique du Togo, Lom´e, Togo Agence de M´edecine Pr´eventive (AMP), Paris, France c Universit´ e de Ouagadougou, Ouagadougou, Burkina Faso National Reference Laboratory for Meningitis, Institut National d’Hygi`ene,Minist`ere de la Sante Publique, Lom´e, Togo e CHR Dapaong, Dapaong, Togo f Centre-Muraz-AMP PCR Laboratory, Centre Muraz Bobo-Dioulasso, Burkina Faso b
d
Available online 7 May 2007
Abstract Few reports documenting the epidemiology of Neisseria meningitidis (Nm) serogroup W135 exist, and none from Togo. During 2003–2005, we conducted acute bacterial meningitis surveillance at three major reference hospitals in Togo. Of 116 Nm identified, 83 (71%) were NmA, 23 (20%) were NmW135, and 10 (9%) did not have a serogroup identified. Nine percent of NmW135 cases and 35% of NmA cases occurred among those aged 15 years or older. The two hospitals in central Togo reported 23% of all Nm cases and 78% of NmW135 cases. Twelve of the 23 NmW135 cases occurred during February–March 2003, while the remaining 11 occurred sporadically over the remaining 18 months of the study. NmW135 meningitis showed pronounced temporal and geographic clustering and occurred almost exclusively among those younger than 15 years old. By the 2004–2005 epidemic season, NmW135 had largely disappeared from Togo for unknown reasons. © 2007 Elsevier Ltd. All rights reserved. Keywords: Epidemiology; Meningitis; Meningococcus; Neisseria meningitidis; Serogroup; Togo
1. Introduction Historically, most meningitis epidemics in the meningitis belt of Sub-Saharan Africa have been caused by Neisseria meningitidis (Nm) serogroup A [1]. Recently, however, large epidemics due to NmW135 have occurred in Burkina Faso [2–4]. Other countries have also reported an increase in disease due to NmW135 [5–7] but this has infrequently been based on systematic evaluation. Since 2005, reports of NmW135 to the World Health Organization have decreased [8] for unknown reasons. Because of the importance of the presence of NmW135 and other epidemic serogroups in the meningitis belt for ∗ Corresponding author at: 25, due du Dr. Roux, 75724 Paris cedex 15, France. Tel.: +33 1 5386 8920; fax: +33 1 5386 8939. E-mail address: [email protected] (B.D. Gessner).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.04.040
vaccine policy, we established surveillance for acute bacterial meningitis during 2003–2005 at three sites in Togo, an African meningitis belt country that borders Burkina Faso. The current report presents initial results from this effort.
2. Materials and methods Based on our previous experience at Centre Muraz in Bobo-Dioulasso, Burkina Faso [2], we developed a regional system to enhance sentinel site surveillance of bacterial meningitis at three major referral hospitals in central and northern Togo (Fig. 1). Surveillance was conducted from October 2003 to May 2004 and from January to December 2005 at Sotouboua in central Togo and at Dapaong in Northern Togo (along the border with Burkina Faso). Surveil-
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Fig. 1. Togo map. Sentinel hospitals were in Tone, Soutouboua, and Tchaoudjo districts.
K.-L.-S. Adjogble et al. / Vaccine 25S (2007) A47–A52
lance was also conducted at Sokode (Tchaoudjo District in central Togo) during the same period except that it only started in February 2004. During the study period, none of the study districts passed the World Health Organization epidemic threshold of 10 suspected bacterial meningitis cases per 100,000 per week and no mass meningococcal vaccination campaigns were conducted. The Togolese Ministry of Health meningitis case management policy required referral to a local or regional hospital for all suspected acute bacterial meningitis cases. Using their clinical judgment, health care providers at study hospitals identified patients with suspected acute bacterial meningitis and performed lumbar punctures. The study did not interfere with patient referral, access, or treatment. Gram stain was performed at each sentinel hospital and culture at the two regional hospitals in Dapaong and Sokode. Latex agglutination tests occasionally were performed at the regional hospitals based on limited test availability. For each patient, an aliquot of cerebrospinal fluid and clinical and bacteriological case report forms were transported to the National Reference Laboratory at the National Institute of Hygiene in Togo. Once every 2 months, specimens were transported to Centre Muraz in Bobo-Dioulasso, Burkina Faso for polymerase chain reaction (PCR) testing [2]. Most specimens were kept at sentinel hospital laboratories for up to 2 weeks and then transported at between +3 ◦ C and +8 ◦ C. Specimens were frozen at −20 ◦ C at the National Reference Laboratory before sending at room temperature to the PCR laboratory in Burkina Faso. At the Centre Muraz laboratory, culture, Gram stain identification and latex agglutination tests were performed according to World Health Organization recommendations [9]. PCR diagnosis of Nm was based on crgA gene amplification [10,11]. For meningococcal serogroup prediction (genogrouping), a multiplex PCR was developed that simultaneously used oligonucleotides for siaD (for genogroups B, C, Y, X, and W135) and mynB (for genogroup A) [10]. PCR diagnosis of Haemophilus influenzae was based on the bexA gene [12] and that of Streptococcus pneumoniae on the lytA gene [13]. PCR results were considered the gold standard. When these were missing or negative, culture results were used. When culture results also were missing or negative, Gram stain results were used, with Gram negative diplococci indicating N. meningitidis, Gram negative bacilli indicating H. influenzae, and Gram positive cocci indicating S. pneumo-
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niae. PCR provided serotypes for most meningococcal cases since latex agglutination was infrequently performed. While most cases of H. influenzae meningitis were identified by PCR and thus were confirmed as type b, other cases were identified by culture or Gram stain and thus serotype could not be assigned. This surveillance support project was approved and supported by the Ministry of Health of Togo. The Togolese Epidemiology Department within the Ministry of Health assisted with field activities and project coordination.
3. Results 3.1. All etiologies Of 453 CSF samples collected during the study, a bacterial etiology was identified for 327, including 126 S. pneumoniae (39%), 116 N. meningitidis (35%) and 85 H. influenzae (26%). PCR alone or in combination with culture or Gram stain was positive for 56 (65%) H. influenzae, 84 (67%) S. pneumoniae, and 108 (93%) N. meningitidis. Most of the isolates came from Dapaong (n = 270; 83%) followed by Sotouboua (n = 42; 13%) and Sokode (n = 15; 5%). H. influenzae was the most common etiology among children less than 5 years old while meningococcus was more common among older children and pneumococcus among older adults (Table 1). Meningococcal meningitis peaked during February–April for both years, while S. pneumoniae and H. influenzae meningitis showed a less marked seasonal variation (Fig. 2). 3.2. Neisseria meningitidis Of the 116 meningococcal meningitis cases identified, NmA was identified in 83 (72%) and NmW135 in 23 (20%). PCR results were indeterminate for four cases and PCR was not performed for six cases. Latex agglutination identified three NmA and one NmW135 cases not detected by PCR. Dapaong reported 89 of the meningococcal meningitis cases, of which 77 (87%) were confirmed as NmA and 5 (6%) were confirmed as NmW135. Sotouboua reported 19 Nm cases of which 5 (26%) were confirmed as NmA and 12 (63%) were confirmed as NmW135. Sokode reported eight Nm cases of which one (13%) was NmA and six (75%) were
Table 1 Etiology of acute bacterial meningitis by age group; Central and Northern Togo, 2003–2005 Etiology Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae Total
<5 years
5–14 years
15–29 years
30+ years
Total
59 (80%/47%) 27 (24%/21%) 40 (34%/32%)
10 (14%/13%) 51 (46%/65%) 17 (14%/22%)
3 (4%/5%) 25 (23%/45%) 27 (23%/49%)
2 (3%/4%) 8 (7%/18%) 35 (29%/78%)
74 (100%/25%) 111 (100%/37%) 119 (100%/39%)
126 (41%/100%)
78 (26%/100%)
55 (18%/100%)
45 (15%/100%)
304 (100%/100%)
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Fig. 2. Case counts by month for etiological agents of acute bacterial meningitis among persons of all ages presenting to one of the three sentinel hospitals. Table 2 Serogroup distribution of 111 Neisseria meningitidis (Nm) meningitis by age group in years; Central and Northern Togo, 2003–2005 Etiology
<5 years
5–14 years
15–29 years
NmA NmW135 Nm serogroup unknown
16 (20%/59%) 7 (32%/26%) 4 (44%/15%)
36 (45%/71%) 13 (59%/25%) 2 (22%/4%)
22 (28%/88%) 2 (9%/8%) 1 (11%/4%)
Total
27 (24%/100%)
51 (46%/100%)
25 (23%/100%)
NmW135. In summary, Sokode and Sotouboua reported 23% of all Nm cases and 78% of NmW135 cases. Age was known for 111 cases. Serogroup W135 cases were more likely to occur among younger persons than serogroup A cases (Table 2). Of 80 NmA cases, 28 (35%) occurred among those age 15 years or older compared to 2 of 22 NmW135 cases (9%) (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.0–34). One of the 80 (1.3%) NmA
30+ years
Total
6 (8%/75%) 0 (0%/0%) 2 (22%/25%)
80 (100%/72%) 22 (100%/20%) 9 (100%/7.2%)
8 (7.2%/100%)
111 (100%/100%)
cases occurred to a child less than age 1 year compared to 4 of 22 (18%) NmW135 cases (OR, 0.07; 95% CI, 0.0–0.71); by contrast, 15 of 80 (19%) NmA and 4 of 22 (18%) NmW135 cases occurred from age 1 to <5 years. Of the 23 NmW135 cases, 12 (52%) occurred during February or March 2004 (Fig. 3) while the remainder occurred sporadically before and after that period, including during the non-epidemic season. By contrast, substantial
Fig. 3. Case counts by month for meningococcal serogroups associated with meningitis among persons of all ages presenting to one of the three sentinel hospitals.
K.-L.-S. Adjogble et al. / Vaccine 25S (2007) A47–A52
peaks in NmA incidence occurred during both the 2004 and 2005 epidemic seasons.
4. Discussion During a period in which no meningitis epidemic was declared, Togo had a substantial proportion of cases caused by Nm serogroup W135 and these cases were concentrated in two districts and for only one season. Burkina Faso has had the largest reported outbreak of NmW135 to date [2–5,8]; however, in our study the northern Togolese district immediately adjacent to Burkina Faso reported the lowest proportion and lowest absolute number of NmW135 cases. These findings emphasize the localized nature of the recent increases in NmW135 meningitis [7,14], a finding previously reported for NmA [15]. Cases of NmW135 have occurred sporadically across the meningitis belt since at least 1981 [16] with isolates of the epidemic phenotype W135:2a:P1.5,2 belonging to the ST-11 clonal complex identified since 1985 [17]. The reasons for the increase in incidence beginning with the 2000 Hajj [18] and the 2000–2001 epidemic meningitis season in Burkina Faso [4] remain unknown. In theory, widespread meningococcal A/C polysaccharide vaccine for epidemic control could have led to clonal expansion in carriage of a non-vaccine strain. This however seems unlikely for various reasons. For example, we found that an area of Togo with no recent history of vaccination experienced an increase in NmW135 meningitis contemporaneous with increases seen in other areas of the meningitis belt. It is more likely that slight alterations in the strain structure, in combination with changes in ecological or social conditions, led to increases in transmission and virulence and decreases in strain-specific population immunity. Similarly, the reasons for the decrease in NmW135 meningitis documented here and elsewhere [8] remain unknown. NmA outbreaks usually involve a shift in age distribution from young children to older persons [1,15]. Age distribution among NmW135 cases has been reported infrequently, but at least one study found a shift towards younger children, including infants [2]. Data presented here from Togo confirm a younger age distribution for NmW135 than NmA, including increased occurrence among infants. This occurrence of NmW135 among younger children supports the hypothesis that one contributing mechanism towards the increase in NmW135 meningitis may be changes in population susceptibility to carriage and invasive disease. The current study had substantial limitations. Changes in technical, material, and financial supports provided to sites during the 3-year study period likely influenced case ascertainment, so that it is difficult to draw firm conclusions regarding the relative number of cases identified over time. Also, this was a sentinel hospital-based surveillance system and thus disease incidence could not be estimated. Records
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were not kept for all patients presenting for acute bacterial meningitis, preventing us from estimating the proportion of cases from which an etiologic agent was identified. Lastly, not all persons had all tests performed. This well illustrates the inherent difficulty with establishing an efficient surveillance system in the field. The Meningitis Vaccine Project has led efforts to develop a monovalent conjugate NmA vaccine for Africa ([19] and Laforce et al., this volume). The presence of substantial amounts of NmW135 meningitis in Togo and elsewhere raises the question of whether a multivalent vaccine would be more appropriate. The rapid decrease in NmW135 disease and the infrequent occurrence of outbreaks due to this serogroup and other serogroups [20] lends support to use of monovalent vaccine as a short-term strategy. Because of the continued circulation of strains with epidemic potential, however, the eventual use of multivalent vaccines or vaccines using antigens found across serogroups will likely prove of substantial benefit to countries of the meningitis belt.
Acknowledgements We would like to acknowledge the assistance provided by clinical and laboratory staff at the three sentinel hospitals, Regina Idohou and Annie Leblond for their assistance in the field methodology preparation and implementation, M. Prince-David Mireille, BIOLIM Lom´e for assistance in establishing the surveillance system, and Dr. Isabelle Parent du Chˆatelet of Agence de M´edecine Pr´eventive for the conception of the project. Conflict of interest: None of the authors have a commercial interest in any products that might be affected by the results of this investigation. Six authors were employees of Agence de M´edecine Pr´eventive, which receives substantial financial support for all of its activities from Sanofi-Pasteur, one of the funders of the study and a manufacturer of meningococcal vaccines. Funding sources: Sanofi-Pasteur, Institut Pasteur, the Bill and Melinda Gates Foundation, PneumoADIP.
References [1] Moore PS. Meningococcal meningitis in sub-Saharan Africa: a model for the epidemic process. Clin Infect Dis 1992;14:515–25. [2] Parent du Chatelet I, Traore Y, Gessner BD, Antignac A, Naccro B, Njanpop-Lafourcade BM, et al. Bacterial meningitis in Burkina Faso: surveillance using field-based polymerase chain reaction testing. Clin Infect Dis 2005;40:17–25. [3] Decosas J, Koama JBT. Chronicle of an outbreak foretold: meningococcal meningitidis W135 in Burkina Faso. Lancet 2002;2:763–5. [4] Taha MK, Parent Du Chatelet I, Schlumberger M, Sanou I, Djibo S, de Chabalier F, et al. Neisseria meningitidis serogroups W135 and A were equally prevalent among meningitis cases occurring at the end of the 2001 epidemics in Burkina Faso and Niger. J Clin Microbiol 2002;40:1083–4. [5] WHO. Epidemic meningitis: surveillance and response activities during the 2002–2003 season in the countries of the African meningitis belt.
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K.-L.-S. Adjogble et al. / Vaccine 25S (2007) A47–A52 Report on an informal WHO consultation. WHO, Geneva 24–25 2003. WHO/CDS/CSR/GAR/2003.13; 2003. Forgor AA, Leimkugel J, Hodgson A, Bugri A, Dangy JP, Gagneux, et al. Emergence of W135 meningococcal meningitis in Ghana. Trop Med Int Health 2005;10:1229–34. Boisier P, Djibo S, Sidikou F, Mindadou H, Kairo KK, Djibo, et al. Epidemiological patterns of meningococcal meningitis in Niger in 2003 and 2004: under the threat of N. meningitidis serogroup W135. Trop Med Int Health 2005;10:435–43. WHO. Enhanced surveillance of epidemic meningococcal meningitis in Africa: a three-year experience. Wkly Epidemiol Rep 2005;37:313–20. WHO. Laboratory methods for the diagnosis of meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. WHO communicable disease surveillance and response. WHO/CDS/CSR/EDC/99.7, 1999. Taha MK. Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis. J Clin Microbiol 2000;38:855–7. Deghmane AE, Giogini D, Larribe M, Alonso JM, Taha MK. Down regulation of pili and capsule of Neisseria meningitidis upon contact with epithelial cells is mediated by CrgA regulatory protein. Mol Microbiol 2002;43:1555–64. Corless CE, Guiver M, Borrow R, Edwards-Jones V, Fox AJ, Kaczmarski EB. Simultaneous detection of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae in suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol 2001;39:1553–8.
[13] Hassan-King M, Baldeh I, Adegbola R, Omosigho C, Usen SO, Oparaugo A, et al. Detection of Haemophilus influenzae and Streptococcus pneumoniae DNA in blood culture by a single PCR assay. J Clin Microbiol 1996;34:2030–2. [14] Sidikou F, Djibo S, Taha MK, Alonso JM, Djibo A, Kairo KK, et al. Polymerase chain reaction assay and bacterial meningitis surveillance in remote areas. Niger Emerg Infect Dis 2003;9:1486–8. [15] Greenwood B. Manson Lecture. Meningococcal meningitis in Africa. Trans R Soc Trop Med Hyg 1999;93:341–53. [16] Denis F, Rey JL, Amadou A, Saliou P, Prince-David M, M’Boup S, et al. Emergence of meningococcal meningitis caused by W135 subgroup in Africa. Lancet 1982;2:1335–6. [17] Mayer LW, Reeves MW, Al-Hamdan N, Sacchi Ct, Taha Mk, Ajello GW, et al. Outbreak of W135 meningococcal disease in 2000: not emergence of a new W135 strain but clonal expansion within the electrophoretic type 37 complex. J Infect Dis 2002;185:1596– 605. [18] Taha MK, Achtman M, Alonso JM, Greenwood B, Ramsay M, Fox A, et al. Serogroup W135 meningococcal disease in Hajj pilgrims. Lancet 2000;356:2159. [19] Jodar L, LaForce FM, Ceccarini C, Aguado T, Granoff DM. Meningococcal conjugate vaccine for Africa: a model for development of new vaccines for the poorest countries. Lancet 2003;361:1902– 4. [20] Djibo S, Nicolas P, Alonso JM, Djibo A, Couret D, Riou JY, et al. Outbreaks of serogroup × meningococcal meningitis in Niger 1995–2000. Trop Med Int Health 2003;8:1118–23.
The epidemiology of Neisseria meningitidis meningitis in Togo during 2003–2005 Kokou-Louis-Sewonou Adjogble a , Mathilde Lourd b , Berthe-Marie Njanpop-Lafourcade b , Yves Traor´e c , Avoko Fidelia Sitti Hlomaschi d , K. Agbenon Amegatse e , Kodjo Agbenoko e , Oumarou Sanou f , Kroman Sita b , Judith E. Mueller b , Bradford D. Gessner b,∗ a
Minist`ere de la Sante Publique du Togo, Lom´e, Togo Agence de M´edecine Pr´eventive (AMP), Paris, France c Universit´ e de Ouagadougou, Ouagadougou, Burkina Faso National Reference Laboratory for Meningitis, Institut National d’Hygi`ene,Minist`ere de la Sante Publique, Lom´e, Togo e CHR Dapaong, Dapaong, Togo f Centre-Muraz-AMP PCR Laboratory, Centre Muraz Bobo-Dioulasso, Burkina Faso b
d
Available online 7 May 2007
Abstract Few reports documenting the epidemiology of Neisseria meningitidis (Nm) serogroup W135 exist, and none from Togo. During 2003–2005, we conducted acute bacterial meningitis surveillance at three major reference hospitals in Togo. Of 116 Nm identified, 83 (71%) were NmA, 23 (20%) were NmW135, and 10 (9%) did not have a serogroup identified. Nine percent of NmW135 cases and 35% of NmA cases occurred among those aged 15 years or older. The two hospitals in central Togo reported 23% of all Nm cases and 78% of NmW135 cases. Twelve of the 23 NmW135 cases occurred during February–March 2003, while the remaining 11 occurred sporadically over the remaining 18 months of the study. NmW135 meningitis showed pronounced temporal and geographic clustering and occurred almost exclusively among those younger than 15 years old. By the 2004–2005 epidemic season, NmW135 had largely disappeared from Togo for unknown reasons. © 2007 Elsevier Ltd. All rights reserved. Keywords: Epidemiology; Meningitis; Meningococcus; Neisseria meningitidis; Serogroup; Togo
1. Introduction Historically, most meningitis epidemics in the meningitis belt of Sub-Saharan Africa have been caused by Neisseria meningitidis (Nm) serogroup A [1]. Recently, however, large epidemics due to NmW135 have occurred in Burkina Faso [2–4]. Other countries have also reported an increase in disease due to NmW135 [5–7] but this has infrequently been based on systematic evaluation. Since 2005, reports of NmW135 to the World Health Organization have decreased [8] for unknown reasons. Because of the importance of the presence of NmW135 and other epidemic serogroups in the meningitis belt for ∗ Corresponding author at: 25, due du Dr. Roux, 75724 Paris cedex 15, France. Tel.: +33 1 5386 8920; fax: +33 1 5386 8939. E-mail address: [email protected] (B.D. Gessner).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.04.040
vaccine policy, we established surveillance for acute bacterial meningitis during 2003–2005 at three sites in Togo, an African meningitis belt country that borders Burkina Faso. The current report presents initial results from this effort.
2. Materials and methods Based on our previous experience at Centre Muraz in Bobo-Dioulasso, Burkina Faso [2], we developed a regional system to enhance sentinel site surveillance of bacterial meningitis at three major referral hospitals in central and northern Togo (Fig. 1). Surveillance was conducted from October 2003 to May 2004 and from January to December 2005 at Sotouboua in central Togo and at Dapaong in Northern Togo (along the border with Burkina Faso). Surveil-
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Fig. 1. Togo map. Sentinel hospitals were in Tone, Soutouboua, and Tchaoudjo districts.
K.-L.-S. Adjogble et al. / Vaccine 25S (2007) A47–A52
lance was also conducted at Sokode (Tchaoudjo District in central Togo) during the same period except that it only started in February 2004. During the study period, none of the study districts passed the World Health Organization epidemic threshold of 10 suspected bacterial meningitis cases per 100,000 per week and no mass meningococcal vaccination campaigns were conducted. The Togolese Ministry of Health meningitis case management policy required referral to a local or regional hospital for all suspected acute bacterial meningitis cases. Using their clinical judgment, health care providers at study hospitals identified patients with suspected acute bacterial meningitis and performed lumbar punctures. The study did not interfere with patient referral, access, or treatment. Gram stain was performed at each sentinel hospital and culture at the two regional hospitals in Dapaong and Sokode. Latex agglutination tests occasionally were performed at the regional hospitals based on limited test availability. For each patient, an aliquot of cerebrospinal fluid and clinical and bacteriological case report forms were transported to the National Reference Laboratory at the National Institute of Hygiene in Togo. Once every 2 months, specimens were transported to Centre Muraz in Bobo-Dioulasso, Burkina Faso for polymerase chain reaction (PCR) testing [2]. Most specimens were kept at sentinel hospital laboratories for up to 2 weeks and then transported at between +3 ◦ C and +8 ◦ C. Specimens were frozen at −20 ◦ C at the National Reference Laboratory before sending at room temperature to the PCR laboratory in Burkina Faso. At the Centre Muraz laboratory, culture, Gram stain identification and latex agglutination tests were performed according to World Health Organization recommendations [9]. PCR diagnosis of Nm was based on crgA gene amplification [10,11]. For meningococcal serogroup prediction (genogrouping), a multiplex PCR was developed that simultaneously used oligonucleotides for siaD (for genogroups B, C, Y, X, and W135) and mynB (for genogroup A) [10]. PCR diagnosis of Haemophilus influenzae was based on the bexA gene [12] and that of Streptococcus pneumoniae on the lytA gene [13]. PCR results were considered the gold standard. When these were missing or negative, culture results were used. When culture results also were missing or negative, Gram stain results were used, with Gram negative diplococci indicating N. meningitidis, Gram negative bacilli indicating H. influenzae, and Gram positive cocci indicating S. pneumo-
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niae. PCR provided serotypes for most meningococcal cases since latex agglutination was infrequently performed. While most cases of H. influenzae meningitis were identified by PCR and thus were confirmed as type b, other cases were identified by culture or Gram stain and thus serotype could not be assigned. This surveillance support project was approved and supported by the Ministry of Health of Togo. The Togolese Epidemiology Department within the Ministry of Health assisted with field activities and project coordination.
3. Results 3.1. All etiologies Of 453 CSF samples collected during the study, a bacterial etiology was identified for 327, including 126 S. pneumoniae (39%), 116 N. meningitidis (35%) and 85 H. influenzae (26%). PCR alone or in combination with culture or Gram stain was positive for 56 (65%) H. influenzae, 84 (67%) S. pneumoniae, and 108 (93%) N. meningitidis. Most of the isolates came from Dapaong (n = 270; 83%) followed by Sotouboua (n = 42; 13%) and Sokode (n = 15; 5%). H. influenzae was the most common etiology among children less than 5 years old while meningococcus was more common among older children and pneumococcus among older adults (Table 1). Meningococcal meningitis peaked during February–April for both years, while S. pneumoniae and H. influenzae meningitis showed a less marked seasonal variation (Fig. 2). 3.2. Neisseria meningitidis Of the 116 meningococcal meningitis cases identified, NmA was identified in 83 (72%) and NmW135 in 23 (20%). PCR results were indeterminate for four cases and PCR was not performed for six cases. Latex agglutination identified three NmA and one NmW135 cases not detected by PCR. Dapaong reported 89 of the meningococcal meningitis cases, of which 77 (87%) were confirmed as NmA and 5 (6%) were confirmed as NmW135. Sotouboua reported 19 Nm cases of which 5 (26%) were confirmed as NmA and 12 (63%) were confirmed as NmW135. Sokode reported eight Nm cases of which one (13%) was NmA and six (75%) were
Table 1 Etiology of acute bacterial meningitis by age group; Central and Northern Togo, 2003–2005 Etiology Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae Total
<5 years
5–14 years
15–29 years
30+ years
Total
59 (80%/47%) 27 (24%/21%) 40 (34%/32%)
10 (14%/13%) 51 (46%/65%) 17 (14%/22%)
3 (4%/5%) 25 (23%/45%) 27 (23%/49%)
2 (3%/4%) 8 (7%/18%) 35 (29%/78%)
74 (100%/25%) 111 (100%/37%) 119 (100%/39%)
126 (41%/100%)
78 (26%/100%)
55 (18%/100%)
45 (15%/100%)
304 (100%/100%)
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Fig. 2. Case counts by month for etiological agents of acute bacterial meningitis among persons of all ages presenting to one of the three sentinel hospitals. Table 2 Serogroup distribution of 111 Neisseria meningitidis (Nm) meningitis by age group in years; Central and Northern Togo, 2003–2005 Etiology
<5 years
5–14 years
15–29 years
NmA NmW135 Nm serogroup unknown
16 (20%/59%) 7 (32%/26%) 4 (44%/15%)
36 (45%/71%) 13 (59%/25%) 2 (22%/4%)
22 (28%/88%) 2 (9%/8%) 1 (11%/4%)
Total
27 (24%/100%)
51 (46%/100%)
25 (23%/100%)
NmW135. In summary, Sokode and Sotouboua reported 23% of all Nm cases and 78% of NmW135 cases. Age was known for 111 cases. Serogroup W135 cases were more likely to occur among younger persons than serogroup A cases (Table 2). Of 80 NmA cases, 28 (35%) occurred among those age 15 years or older compared to 2 of 22 NmW135 cases (9%) (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.0–34). One of the 80 (1.3%) NmA
30+ years
Total
6 (8%/75%) 0 (0%/0%) 2 (22%/25%)
80 (100%/72%) 22 (100%/20%) 9 (100%/7.2%)
8 (7.2%/100%)
111 (100%/100%)
cases occurred to a child less than age 1 year compared to 4 of 22 (18%) NmW135 cases (OR, 0.07; 95% CI, 0.0–0.71); by contrast, 15 of 80 (19%) NmA and 4 of 22 (18%) NmW135 cases occurred from age 1 to <5 years. Of the 23 NmW135 cases, 12 (52%) occurred during February or March 2004 (Fig. 3) while the remainder occurred sporadically before and after that period, including during the non-epidemic season. By contrast, substantial
Fig. 3. Case counts by month for meningococcal serogroups associated with meningitis among persons of all ages presenting to one of the three sentinel hospitals.
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peaks in NmA incidence occurred during both the 2004 and 2005 epidemic seasons.
4. Discussion During a period in which no meningitis epidemic was declared, Togo had a substantial proportion of cases caused by Nm serogroup W135 and these cases were concentrated in two districts and for only one season. Burkina Faso has had the largest reported outbreak of NmW135 to date [2–5,8]; however, in our study the northern Togolese district immediately adjacent to Burkina Faso reported the lowest proportion and lowest absolute number of NmW135 cases. These findings emphasize the localized nature of the recent increases in NmW135 meningitis [7,14], a finding previously reported for NmA [15]. Cases of NmW135 have occurred sporadically across the meningitis belt since at least 1981 [16] with isolates of the epidemic phenotype W135:2a:P1.5,2 belonging to the ST-11 clonal complex identified since 1985 [17]. The reasons for the increase in incidence beginning with the 2000 Hajj [18] and the 2000–2001 epidemic meningitis season in Burkina Faso [4] remain unknown. In theory, widespread meningococcal A/C polysaccharide vaccine for epidemic control could have led to clonal expansion in carriage of a non-vaccine strain. This however seems unlikely for various reasons. For example, we found that an area of Togo with no recent history of vaccination experienced an increase in NmW135 meningitis contemporaneous with increases seen in other areas of the meningitis belt. It is more likely that slight alterations in the strain structure, in combination with changes in ecological or social conditions, led to increases in transmission and virulence and decreases in strain-specific population immunity. Similarly, the reasons for the decrease in NmW135 meningitis documented here and elsewhere [8] remain unknown. NmA outbreaks usually involve a shift in age distribution from young children to older persons [1,15]. Age distribution among NmW135 cases has been reported infrequently, but at least one study found a shift towards younger children, including infants [2]. Data presented here from Togo confirm a younger age distribution for NmW135 than NmA, including increased occurrence among infants. This occurrence of NmW135 among younger children supports the hypothesis that one contributing mechanism towards the increase in NmW135 meningitis may be changes in population susceptibility to carriage and invasive disease. The current study had substantial limitations. Changes in technical, material, and financial supports provided to sites during the 3-year study period likely influenced case ascertainment, so that it is difficult to draw firm conclusions regarding the relative number of cases identified over time. Also, this was a sentinel hospital-based surveillance system and thus disease incidence could not be estimated. Records
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were not kept for all patients presenting for acute bacterial meningitis, preventing us from estimating the proportion of cases from which an etiologic agent was identified. Lastly, not all persons had all tests performed. This well illustrates the inherent difficulty with establishing an efficient surveillance system in the field. The Meningitis Vaccine Project has led efforts to develop a monovalent conjugate NmA vaccine for Africa ([19] and Laforce et al., this volume). The presence of substantial amounts of NmW135 meningitis in Togo and elsewhere raises the question of whether a multivalent vaccine would be more appropriate. The rapid decrease in NmW135 disease and the infrequent occurrence of outbreaks due to this serogroup and other serogroups [20] lends support to use of monovalent vaccine as a short-term strategy. Because of the continued circulation of strains with epidemic potential, however, the eventual use of multivalent vaccines or vaccines using antigens found across serogroups will likely prove of substantial benefit to countries of the meningitis belt.
Acknowledgements We would like to acknowledge the assistance provided by clinical and laboratory staff at the three sentinel hospitals, Regina Idohou and Annie Leblond for their assistance in the field methodology preparation and implementation, M. Prince-David Mireille, BIOLIM Lom´e for assistance in establishing the surveillance system, and Dr. Isabelle Parent du Chˆatelet of Agence de M´edecine Pr´eventive for the conception of the project. Conflict of interest: None of the authors have a commercial interest in any products that might be affected by the results of this investigation. Six authors were employees of Agence de M´edecine Pr´eventive, which receives substantial financial support for all of its activities from Sanofi-Pasteur, one of the funders of the study and a manufacturer of meningococcal vaccines. Funding sources: Sanofi-Pasteur, Institut Pasteur, the Bill and Melinda Gates Foundation, PneumoADIP.
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