Background
Neisseria meningitidis (
N. meningitidis) is a gram-negative, encapsulated
β-proteobacterium and the leading cause of epidemic meningitis. Globally,
N. meningitidis causes an estimated 1.2 million cases and 135,000 deaths each year [
1‐
3]. In Africa,
N. meningitidis is the leading cause of severe, life-threatening meningitis and is responsible for thousands of cases and scores of deaths across sub-Saharan “meningitis belt” countries [
4‐
7]. Moreover,
N. meningitidis serogroups A and W-135 have been exported from Asia to other regions [
8]. Previous studies suggest that these meningococcal serogroups were carried to the Middle East/Mediterranean region where meningococcal disease outbreaks subsequently occurred among Hajj pilgrims and across sub-Saharan African countries [
4,
9‐
12].
In Asia, meningitis outbreaks have been reported in child-care settings, schools, college dormitories, military camps, and among returning Hajj pilgrims [
8,
10,
12‐
15]. Despite these reports documenting sporadic and epidemic meningococcal disease, there are large gaps in our knowledge of meningococcal disease patterns across large populations of Asia. It is believed that vaccine introduction against meningococcal disease may have been an important factor leading to the control of meningococcal epidemics [
16,
17], yet there is limited introduction of vaccines against meningococcal meningitis in Asian countries [
13]. In addition, the serogroup distribution of meningococcus in Asia is scarce, in part, due to the limited availability of appropriate diagnostic tests including molecular assays [
13,
18]. Here, through the application of molecular analyses, we provide new evidence of meningococcal meningitis among hospitalized children < 5 years of age who were identified during prospective, population-based surveillance in China, South Korea, and Vietnam.
Discussion
This is the first and largest collection of CSF specimens obtained during population-based studies in representative populations of Asian children that provides laboratory-confirmed meningococcal meningitis incidence rates based on molecular diagnostic technologies. The application of modern molecular diagnostics for N. meningitidis identified case clusters of meningococcal serogroup B meningitis and an additional high number of serogroup X and Y meningococcal meningitis that had been previously unrecognized when CSFs were tested only by culture and antigen detection methods alone during the original surveillance study periods. Our findings suggest that retrospective molecular analyses of well-preserved clinical specimens in a biorepository provide novel insights into causes of childhood meningitis that are potentially vaccine-preventable diseases, particularly among patients who may commonly use antibiotics.
Based on the combined testing of CSFs by bacterial culture and PCR, this study demonstrated that 75.6% of the children identified with
N. meningitidis in CSF were less than 2 years of age: this occurred particularly among infants less than 6 months of age and even in neonates. Previous incidence studies of
N. meningitidis among children have demonstrated a sizable disease burden. For example, among children under 4 years of age in the United Kingdom [
28], rates of serogroup B meningococcal infections peaked among infants aged less than one year of age with, accounting for almost 90% of laboratory confirmed cases. There is still no licensed vaccine available to protect against serogroup B disease and Active Bacterial Core surveillance (ABCs) data in the United States estimated that infants aged < 1 year had the highest rates of meningococcal disease at 5.38 cases per 100,000 population in 1998–2007 [
29]. In Romania, children aged < 5 years old were found to have a meningococcal meningitis incidence rate of 22 per 100,000 annually based on prospective population-based surveillance in 2000–2002 [
30].
In spite of reports of sporadic or outbreak-associated meningococcal disease in Asia, there are limited data on meningococcal incidence rates and on
N. meningitidis serogroup distribution. In Korea, there is an estimated annual incidence of 2.2 per 100,000 among 550,000 soldiers [
14]; a nationwide study among 17 university hospitals also reported bacteria-proven meningococcal meningitis in 125 cases from 1996 to 2005. Of these, two (1.6%) were less than one month of age [
31]. Available study identified outbreaks of
N. meningitidis in southern province in Vietnam [
32].
Our findings describing the meningococcal serogroup distribution are inconsistent with previous studies. For example, there have been no reports on serogroup X in Asia in the past 50 years [
13]. There is also a recent increase in serogroup B, C, and Y predominating in Europe, the United States, and Australia, whilst serogroup A is prevalent in Africa and Asia [
12,
13,
33]. All of the bacterial isolates in Vietnam from our analysis were serotype B, which is the most commonly identified serogroup in infants in endemic settings. Prolonged outbreaks of serogroup B disease in some countries have also caused substantial morbidity and mortality [
34,
35] and there is presently no available vaccine against this serogroup [
2,
30,
36]. The occurrence of a cluster of serogroup B meningococcal meningitis in Vietnam underscores the need for further investigation of epidemiologic factors and transmission dynamics that drive circulation of meningococcal serogroups. In addition, a substantial number of serogroup X and Y in China and Korea was identified in the present study, suggesting that serogroup X may have been previously under-detected due to limited surveillance or limited availability of assays capable of detecting serogroup X. Among the three countries,
N. meningitidis was responsible for very large epidemics in China, leading to the development and introduction of serogroup A and C meningococcal polysaccharide vaccines for children starting in the 1980s [
37]. Nonetheless and in spite of the vaccine having been introduced in China, there have been sporadic outbreaks and increased cases of circulating serogroup A and C infections in 2003–2006 [
38]. There have also been continuous reports of serogroup B infections, which have been confirmed with modern molecular diagnostics [
37‐
39]. In Korea, our results showed a unique serogroup distribution (serogroup X [9/16], Y [6/16] and C [1/16]), relative to a previous study that reported serogroup Y as the most frequently detected serogroup (9/11 isolates). Another study found one serogroup A and two serogroup C strains among ten
crg A PCR positive specimens [
14,
40]. Current available vaccines target serogroups A, B, C, and W-135 [
12,
41], but do not cover serogroups X and Y. The results from our analysis suggest that existing knowledge gaps may be filled through the application of systematic surveillance that applies molecular diagnostic techniques for detection of
N. meningitidis. The application of molecular testing for meningococcus has had a substantial impact in our understanding epidemiologic patterns of meningococcus in Asia and the potential role of contemporary available meningococcal vaccines.
Clinically, our CSF analysis confirms that infants and young age groups were particularly vulnerable to meningococcal meningitis, suffering severe signs and symptoms, including sepsis, seizure, coma and lethargy, and vomiting. Our findings are intriguing given the limited number of previous studies that have reported
N. meningitidis infection in neonates and young infants [
33,
42,
43]. These new results suggest the need to improve surveillance for meningitis among infants and to consider the role of meningococcal vaccines among infants [
12,
41].
Although this study provides one of the largest CSF analyses to describe N. meningitidis in Asian countries, there are some limitations. For example, 84.1% of the N. meningitidis positive CSF specimens could not be serogrouped and may have resulted from partial degradation of pathogen components during storage. In addition, some specimen testing may have been limited by prolonged storage that was associated with diminution of specimen volume through evaporation or prolonged storage. Second, although original studies were done in representative populations, rates of meningococcal meningitis among children in other parts of each country and in other countries in Asia may differ from those found in this analysis. Third, overall reduced detection of bacterial pathogens, including common invasive species causing meningitis in children, may, at least in part, be the result of widespread antibiotic overuse that was observed throughout each study site in China, Korea and Vietnam. In spite of the easy access to antibiotics in these three countries, an 11.6% fatality prevailed and remains poorly understood.
Conclusions
The burden of N. meningitidis-associated meningitis among Asian children aged < 5 years old was found to be substantially higher than previously reported. Incidence rates among neonates and infants suggest that meningococcal meningitis may be affecting a younger age range of patients than previously understood. By understanding the dynamics of N. meningitidis, with incorporation of routine PCR methods for detection of N. meningitidis and the use of standardized surveillance methods for meningococcal meningitis, many countries will have the capacity to more accurately describe and mitigate invasive meningococcal disease. This may be of patients particularly true in areas with high antimicrobial usage in developing or middle income countries, where laboratory culture capacity may be limited. To date, more than a decade after the original prospective surveillance studies were completed, there have been few improvements in surveillance for N. meningitidis across Asia. In addition, given these observations, it is likely that new surveillance may uncover additional serogroups, including those identified in the results presented here. Therefore, we strongly advocate for a pan-Asian surveillance strategy focused on meningococcal meningitis to better understand the epidemiology and to implement prevention strategies (e.g., vaccines) in this region.
Acknowledgements
We thank Dr. Batmunkh Nyambat for his technical assistance in accessing patient and laboratory databases assembled for each of the prospective surveillance systems in China, Korea and Vietnam. We also thank Eunjin Kim for her technical assistance in the laboratory testing of the CSF and bacterial isolates at the IVI. We specially thank Dr. Mirna Robert– Du Ry van Beest Holle, Novartis Vaccines and Diagnostics, Global Epidemiology, The Netherlands, for epidemiologic insights and Dr. Maurizio Comanducci, Laboratory Head, Novartis Vaccines and Diagnostics, for his inputs on particular laboratory tests and interpretations. We thank Drs. Kenneth Zangwell and Swei-Ju Chang for their collaboration in the preservation of CSF specimens. We thank the Communications & Advocacy Unit at IVI for editorial review and Lisa DeTora, at the Medical Publication Lead in Novartis Vaccines and Diagnostics, for her editorial comments during preparation of this manuscript.
Financial support
This work was supported by an unrestricted funding to the International Vaccine Institute from the government of South Korea, and Sweden. Additional support for this project was provided by Novartis Vaccines and Diagnostics, Global Epidemiology, The Netherlands. Results reported in this manuscript were presented in part at The 7th World Congress of the World Society for Pediatric Infectious Diseases (WSPID), Melbourne, Australia. November 16-19, 2011.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SAK and PEK carried out study design, data collection and analysis, and drafted the manuscript. DWK performed study design and conducted molecular laboratory test and drafted the manuscript. BQD, JSK and DDA participated in its design and helped to draft the manuscript. All authors read and approved the final manuscript.