Abstract

Background

Japanese encephalitis (JE), a mosquito-borne viral infection, has a high case-fatality rate (10%–30%) [1,2] with 30%–50% of survivors left with long-term neurological disability [3,4]. Some 35,000 to 50,000 cases of JE are reported annually [1-4], a likely underestimate given that JE is not a notifiable disease in most Asian countries. Following the successful control of poliomyelitis, JE has become a major cause of neurological disability among Asian children.

Culex tritaeniorhynchus, the major mosquito vector of JE virus (JEV), breeds by laying eggs in wet rice fields [1]. JEV is transmitted by mosquito vectors to a variety of mammals and birds [1,5]. Pigs are the most efficient amplifying hosts for dissemination of JEV, capable of exhibiting up to 9 logs of viremia [6,7]. Thus, rural areas with both rice fields and pigpens provide the best habitats for propagation and transmission of JEV. Children remain the main victims of the disease [2,8]. Most JE infections are asymptomatic, and the ratio of symptomatic to asymptomatic infections ranges from 1 in 300 to 1 in 1,000 [9-12].

JE incidence declined dramatically in Japan, Korea, China and Thailand after JE vaccine was mandated in routine childhood immunization programs [13]. Most other Asian countries have not implemented JE vaccination programs, owing partly to inadequate documentation of JE risk. For example, in Indonesia, Malaysia and the Philippines, only 284 JE cases were reported between 1986 and 1996, compared with thousands of cases during the same period in the neighboring countries of Thailand and Vietnam, which share similar natural ecological conditions [14]. We believed the low JE incidence in Malaysia, Indonesia and the Philippines probably reflected an underestimate due to lack of JE surveillance activities and diagnostic capabilities. To determine the potential high risk of JE in this region, we conducted a prospective hospital-based surveillance in Bali, Indonesia, from July 2001 through December 2003.

Methods

Results

Distribution of JE cases by month

As shown in Figure ​Figure1,1, no calendar month consistently lacked reports of JE cases throughout the 2.5-year study period, though several calendar months showed at least one JE case in one year but not in the other. For instance, JE cases were reported during February and March in 2002, but not in 2003; no case was reported in September and October of 2001, but 4 and 8 cases were reported in these 2 calendar months in 2002 and 2003 respectively. Hence, unlike the strict summer seasonality in temperate JE-endemic countries [1,2], JEV appears to be transmitted year-round in Bali. Seventy percent of JE cases were detected between December and May, a typical 1-month lag behind the usual rainy season (November-April), which is required for JEV incubation and dissemination.

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Figure 1

Average monthly hospital admission of children with Japanese encephalitis (JE) in Bali, Indonesia, July 2001 through December 2003

Discussion

Tropical countries of eastern Asia (Indonesia, Malaysia and the Philippines) have conventionally been considered to have low JE risk [2]. In Indonesia, for example, only 41 JE cases were reported for the whole country during the 11 years from 1986 through 1996 [14]. Although JEV was isolated from the mosquito vector in 1972 and serological surveys confirmed the prevalence of JEV infections in endemic wild birds and domestic animals, only sporadic human JE cases have been reported in Indonesia [20-22]. Previously, this low JE-risk to humans was attributed to a less virulent JEV circulating in the region [23]. Our study results suggest the contrary. In Bali alone we identified 90 JE cases in humans within just 2.5 years. Even this may be an underestimate given that 135 of the 239 suspected JE cases provided only acute-phase CSF samples within the 1^st week of illness onset, of which only 32 JE cases were detected. If we assume that 30% of JE cases were undiagnosed in the acute-phase-only CSF group, approximately 14 additional JE cases would have been detected if a convalescence CSF sample had been available, making the total confirmed and probable JE cases 104. The annualized JE incidence rate among children under 10 years of age could then be adjusted from 7.1 to 8.2 per 100,000. Thus, the data obtained through comprehensive surveillance indicate that JEV is hyperendemic in Bali, that it causes substantial human illness, and that it circulates year-round. Our findings in a tropical country that was presumed to have low risk of JE may necessitate more intensive surveillance to assess JE-risk fully in other countries of tropical Asia.

Most evaluations of JE disease burden have been based on clinical reports of acute viral encephalitis without laboratory confirmation. Accurate estimation of age-specific incidence of JE is rare. The pre-adjusted annual incidence rates of 9.1 per 100,000 in children 0–4 years of age and 7.1 per 100,000 in children 0–9 years in Bali are similar to the incidence rates of 7–11 per 100,000 among children aged 0–9 years living in high-risk provinces of northern Thailand and 6.0 per 100,000 in children aged 0–9 years in endemic areas of Taiwan [3,24,25]. Age-specific incidence rates in placebo groups observed during vaccine trials in Asian countries have fluctuated between 15 and 25 per 100,000 [14]. However, the study populations for vaccine trials are selected from high-risk areas, and JE incidence in such studies is measured more rigorously using advanced technologies.

JE in temperate and subtropical Asian countries (China, Japan, Korea, Nepal, northern Vietnam and northern Thailand) is characterized by cyclic epidemics and JE outbreaks every 5–15 years [26]. During the inter-epidemic years, JE incidence rates significantly decline [2,4]. In contrast, in Bali, we observed consistent JE incidence rates of about 7.1 per 100,000 over 2.5 consecutive years. Further studies are needed to assess the validity of this finding over longer periods of time and to determine whether cyclic epidemics occur in Bali. In temperate JE-epidemic regions, a strict summer seasonality of JE has been observed; the mechanism of over-wintering of the virus in the winter and spring is unclear [1,4,5]. In Bali, where JEV appears to circulate year-round, this mechanism may not apply.

In the northern regions of Thailand and Vietnam, the highest JE attack rates are in children aged 5–9 years [27-29]. In Bali, however, 70% of the JE cases were children under 5 years of age (Table ​(Table1).1). This suggests a greater intensity of transmission that exposes children to JEV at a younger age. Similar to findings elsewhere, our study suggests that amongst children above the age of 1 year, males have a greater predilection to JE than females. This may be related to boys engaging in more outdoor activities than girls, leading to greater exposure to JE-infected mosquitoes [3,4]. Also consistent with other studies, no clustering of JE cases was evident [3,4]. Though emergency yellow fever immunization in response to yellow fever outbreaks is effective in ameliorating the person-to-person transmission involving domicile mosquitoes [30], such a strategy of emergent JE vaccination in response to identification of an initial JE case would be ineffective.

The transmission cycle of JEV relies solely on the mosquito vector and the amplifying non-human host (primarily the pig). Humans are accidental hosts and are not required for virus transmission. Bali represents an interesting, but not necessarily unique, ecological setting wherein both pig raising and rice farming take place year-round, representing ideal conditions for consistent JEV propagation. As Balinese are predominantly Hindu (unlike other Indonesians, who are predominantly Muslim), pork is a major food item with a pig-to-human population ratio of approximately 1:2. We found that 280 (70%) of 400 pigs in Bali showed hemagglutination inhibition antibody against JEV (unpublished data). Consequently, pigs probably serve as the primary amplifying hosts of JEV in Bali. Rice cultivation in Bali is not seasonal. Therefore, only parts of rice fields are filled with water at any given time and they are periodically drained as part of intermittent irrigation practice [31]. As a result, the rainy season appears to facilitate water filling and mosquito breeding within the rice fields. Hence, the tropical climate and agricultural practices in Bali work in concert to accelerate the year-round transmission of JEV via the animal-mosquito cycle.

We note certain study limitations. First, JE infections were found in children presenting with acute flaccid paralysis (AFP) in southern Vietnam [32]. In retrospect, we found that we failed to include 14 AFP cases documented within Bali whose ages were within the case definition of our surveillance. Second, our surveillance approach targeted children seeking medical attention and missed JE cases that may have led to early pre-hospital deaths. Likewise, mild JE cases manifesting only by febrile convulsions may have been missed. These omissions may have contributed further to the underestimation of true JE incidence in our study.

Conclusion

Given the particular social and ecological setting, the data obtained from Bali may or may not be applicable to the rest of Indonesia. However, our findings clearly suggest that countries previously classified as at low JE risk may be so only because of insufficient surveillance data. Additional studies are warranted in areas presumed to have low JE risk.

Current JE vaccines are safe, effective and cost-effective [33-35]. By any standard, JE is a major public health problem in Bali and will remain so given that humans are accidental (not required) hosts in the vector-animal (pig) transmission cycle. Effective JE vaccination programs provide the only solution to the ongoing threat of JE to endemic populations such as those on Bali.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Dr. Komang Kari and Dr. Kompiang Gautama established and monitored the surveillance activities, and enrolled and evaluated the patients. Dr. Wei Liu tested specimens, collected, checked and analyzed surveillance data, and wrote and edited text for the manuscript. Dr. Mammen P. Mammen Jr. and Dr. Ananda Nisalak provided expertise on JE diagnosis and edited the manuscript. Dr. John D. Clemens provided guidance and critique during data analysis and helped with writing and editing the manuscript. Dr. Ketut Subrata and Ms. Hyei Kyung Kim contributed to data collection and data analysis. Dr. Zhi-Yi Xu designed the study, guided data collection and statistical analysis, and wrote and edited the manuscript text.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1741-7015/4/8/prepub

Acknowledgements

References