Jpn. J. Infect. Dis., 61, 333-338, 2008
Review Japanese Encephalitis: Surveillance and Elimination Effort in Japan from 1982 to 2004 Satoru Arai, Yasuko Matsunaga, Tomohiko Takasaki1, Keiko Tanaka-Taya, Kiyosu Taniguchi, Nobuhiko Okabe, Ichiro Kurane1* and Vaccine Preventable Diseases Surveillance Program of Japan** Infectious Disease Surveillance Center and 1Department of Virology 1, National Institute of Infectious Diseases, Tokyo 162-8640, Japan (Received May 21, 2008. Accepted July 28, 2008) CONTENTS: 1. Introduction 7. JE vaccination histories 2. Surveillance of JE in Japan 8. Prognoses of the cases 3. Annual numbers of confirmed human JE cases 9. Prevalence of JE antibody among general popu- 4. Sex and age distribution of the JE cases lations in Japan 5. Geographical distribution of JE in Japan 10. JE virus infection of sentinel pigs 6. Monthly occurrence of JE 11. Discussion SUMMARY: Japanese encephalitis (JE) surveillance has been conducted since 1965 as a part of the National Epidemiological Surveillance of Vaccine Preventable Diseases in Japan. Over 1,000 JE cases were reported annually in the late 1960s. The number of JE cases has since markedly decreased, with less than 10 cases reported annually from 1992 to 2004. A total of 361 JE cases were reported between 1982 and 2004. Prognosis was available for 320 cases; 58 (18%) died, 160 (50%) recovered with neuropsychiatric sequelae, and 102 (32%) completely recovered. Seventy-eight percent of these cases were 40 years old or over with a peak age group of 60-69 years old. JE predominantly occurred in unvaccinated populations. A high seroconversion rate among sentinel pigs was recorded every year. This suggests the presence of JE virus-infected mosquitoes during the summer in most areas of Japan, including the northern districts where no JE cases were reported from 1982 to 2004. Although JE cases have been reported in single figures since 1992, the risk of JE virus infection is still present. Thus, high immunization rates of JE vaccine should be maintained in Japan.
(5). The surveillance includes (i) confirmation of notified JE Introduction cases, (ii) prevalence of JE antibodies among general popu- Japanese encephalitis (JE) is a serious viral encephalitis lations, and (iii) seroconversion rates of sentinel pigs nation- with a high mortality rate and a high percentage of neuro- wide. Laboratory confirmation of JE has been performed by psychiatric sequelae (1,2). JE occurs in annual epidemics in hemmagglutination inhibition (HI) or complement fixation many Asian countries (3). Approximately 50,000 cases have (CF) tests, according to the guidelines established in 1965. been reported annually worldwide (4). However, the actual The cases were confirmed to be JE when HI or CF antibody number of JE cases is considered to be significantly greater titers were increased by 4 times or more in convalescent phase because JE surveillance systems are not effectively imple- serum samples when compared to acute phase samples. In mented in many developing countries. The epidemiological cases where only single patient samples were available, HI features of JE have dramatically changed over the past 3 titers of 1:160 or greater and CF titers of 1:8 or greater were decades in Japan, with a virtual elimination of clinical cases. considered to be confirmatory laboratory data. Neutralization In this paper, we analyze the records of JE surveillance in assay, polymerase chain reaction (PCR) and enzyme-linked Japan from 1982 to 2004 and describe control measures taken immunosorbent assay (ELISA) have also been used recently in recent years. for laboratory confirmation.
Surveillance of JE in Japan Annual numbers of confirmed human JE cases JE surveillance was first implemented in 1965 through the The annual numbers of confirmed JE cases from 1965 to National Epidemiological Surveillance of Vaccine Prevent- 2004 are shown in Figure 1. More than 1,000 JE cases were able Diseases by the Ministry of Health and Welfare (cur- reported annually in the late 1960s. Since then, the number rently the Ministry of Health, Labour and Welfare [MHLW]) of cases dramatically decreased, with 20 to 90 cases reported annually from 1978 to 1991, and less than 10 cases reported annually from 1992 to 2004. A total of 361 confirmed JE *Corresponding author: Mailing address: Department of Virol- ogy 1, National Institute of Infectious Diseases, 1-23-1 Toyama, cases were reported between 1982 and 2004. Shinjuku-ku, Tokyo 162-8640, Japan. Tel & Fax: +81-3-5285- 1169, E-mail: [email protected] Sex and age distribution of the JE cases **Members of the Vaccine Preventable Diseases Surveillance Pro- gram of Japan are listed in the Appendix. Of 361 confirmed JE cases, 184 cases were male and 177
333 Fig. 1. Annual incidences of JE from 1965 to 2004 in Japan. Records of JE cases were collected using individual report cards by the Ministry of Health, Labour and Welfare, Japan. These reported cases included Fig. 2. Sex and age distribution of JE cases from 1982 to 2004 in fatal cases and serologically and/or virologically confirmed survival Japan. A total of 361 JE cases are shown based on ages at the devel- cases. opment of symptoms.
Table 1. Number of confirmed cases of JE in Japan during from 1982 to 2004, by sex, prognosis, and history of vaccination Sex Prognosis History of vaccination No. of Year Complete Incomplete cases Male Female Sequelae Fatal Unknown Vaccinee Non-vaccinee Unknown recovery vaccinee 1982 21 12 9 8 9 4 0 0 2 14 5 1983 32 14 18 6 18 8 0 0 1 19 12 1984 27 16 11 12 9 5 1 0 0 22 5 1985 39 26 13 11 20 8 0 0 2 30 7 1986 26 12 14 9 14 3 0 4 0 13 9 1987 37 14 23 16 14 7 0 0 1 20 16 1988 32 17 15 6 18 4 4 0 0 18 14 1989 27 12 15 11 11 4 1 0 4 11 12 1990 54 29 25 15 27 8 4 0 2 25 27 1991 13 9 4 2 6 4 1 0 1 3 9 1992 2 1 1 0 1 0 1 0 0 1 1 1993 4 2 2 1 2 1 0 0 1 2 1 1994 4 1 3 1 2 0 1 0 0 0 4 1995 2 1 1 0 2 0 0 0 0 2 0 1996 4 1 3 1 3 0 0 0 0 1 3 1997 4 2 2 2 2 0 0 0 0 0 4 1998 2 1 1 0 2 0 0 0 0 1 1 1999 5 4 1 0 0 0 5 0 0 0 5 2000 7 1 6 0 0 1 6 0 0 0 7 2001 5 3 2 0 0 0 5 0 0 0 5 2002 8 4 4 0 0 0 8 1 0 1 6 2003 2 0 2 1 0 0 1 0 1 0 1 2004 4 2 2 0 0 1 3 0 0 0 4 Total 361 184 177 102 160 58 41 5 15 183 158 Rate 51% 49% 28% 44% 16% 11% 1% 4% 51% 44% were female (Table 1). Seventy-eight percent of the total cases Geographical distribution of JE in Japan were 40 years old or older with a peak in the 60-69 year age group (Figure 2). These data indicate that JE occurred mainly Japan is geographically divided into 8 districts: Kyushu (the among elderly populations. The highest incidence rates were southernmost district including Okinawa Prefecture), Shikoku, in the 50-59 year age group among males and in the 60-69 Chugoku, Kinki, Chubu, Kanto, Tohoku, and the northernmost year age group among females. district of Hokkaido (Figure 3). Of 361 JE cases, 165 cases Although JE occurred mainly in elderly populations from (46%) were reported in the Kyushu district, 40 cases (11%) 1982 to 2004, there were a small number of JE cases in indi- in Shikoku, 40 cases (11%) in Chugoku, 64 cases (18%) in viduals younger than 10 years old (Figure 2). These cases Kinki, 24 cases (7%) in Chubu, and 28 cases (8%) in Kanto accounted for 12% of the total JE cases. (Figure 3). There were no confirmed JE cases in the northern districts of Tohoku and Hokkaido between 1982 and 2004. Therefore, JE occurred mainly in the southern districts of Japan.
334 Fig. 3. Geographical distribution of JE cases from 1982 to 2004 in Japan. Japan is geographically divided into 8 districts: from south to north, Kyushu (Fukuoka, Saga, Nagasaki, Kumamoto, Oita, Miyazaki, Kagoshima, and Okinawa Prefectures), Shikoku (Tokushima, Kagawa, Ehime, and Kochi Prefectures), Chugoku (Tottori, Shimane, Okayama, Hiroshima, and Yamaguchi Prefectures), Kinki (Osaka, Hyogo, Kyoto, Shiga, Nara, and Wakayama Prefectures), Chubu (Niigata, Toyama, Ishikawa, Fukui, Yamanashi, Nagano, Gifu, Shizuoka, Aichi, and Mie Prefectures), Kanto (Tokyo, Kanagawa, Saitama, Chiba, Ibaraki, Tochigi, and Gunma Prefectures), Tohoku (Aomori, Iwate, Miyagi, Akita, Yamagata, and Fukushima Prefectures), and Hokkaido. Records of 145 cases from 1982 to 1986, 163 cases from 1987 to 1991, 16 cases from 1992 to 1996, 23 cases from 1997 to 2001, and 14 cases from 2002 to 2004 were used for the analysis.
Fig. 5. Prevalence of the JE antibody among general populations in Fig. 4. Date of the onset of JE cases from 1982 to 2004. A total of 361 2004. Percent anti-JE virus antibody positive rates are shown based JE cases were analyzed for the date of the onset of symptoms. The on the ages. Populations with neutralizing antibody titers equal to or southern districts (Kyushu, Shikoku, Chugoku, and Kinki districts) greater than 1:10, equal to or greater than 1:40, and equal to or greater and the northern districts (Chubu, Kanto, Tohoku, and Hokkaido than 1:160 are separately shown. districts) were separately analyzed.
Monthly occurrence of JE (Table 1). One hundred and eighty-three of the 203 cases were unvaccinated, and only 20 cases were vaccinated in full (5 All the JE cases were reported during a 5-month span, from times) or on partial vaccination schedules. The data suggest July to November. The earliest onset of the disease was on that JE predominantly occurred in the unvaccinated popula- July 12 in 2001 and the latest on November 1 in 2002. The tions. majority of JE cases were reported in August and September with a peak in late August (Figure 4). When southern dis- tricts (Kyushu, Shikoku, Chugoku, and Kinki) and northern Prognoses of the cases districts (Chubu and Kanto) are analyzed separately, a differ- Prognoses were available for 320 of the 361 cases. Of the ence in monthly JE inception is observed. JE occurred from 320 cases, 58 (18%) died, 160 (50%) recovered with neuro- mid-July to early November with a peak in late August in psychiatric sequelae, and 102 (32%) completely recovered the southern districts, while it occurred from early August to (Table 1). Prognosis was analyzed in 2 groups: cases younger late October with a peak in early September in the northern than 40 years old and cases 40 years old or older. The percent- districts. ages of JE cases with fatal outcomes and complete recoveries were 9% (7/78) and 38% (38/78), respectively, in the younger JE vaccination histories group, and 18% (51/283) and 29% (72/283), respectively, in the older group. Records of JE vaccinations were available for 203 cases
335 Fig. 6. The seroconversion rate among sentinel pigs in each prefecture. Serum samples were collected from 6- to 8-month-old pigs every 10 days. HI antibody was tested, and percent positive rates were calculated. The results are presented in each attending prefecture at the end of July, August, and October in 1982, 1986, 1990, 1994, 1998, 2001, and 2004.
Prevalence of JE antibody among general populations Discussion in Japan JE is an acute viral encephalitis transmitted by infected JE antibody prevalence was surveyed among general popu- mosquitoes. Culex tritaeniorhynchus is the main vector in lations in the National Epidemiological Surveillance of Vac- Japan. The ratio of asymptomatic to symptomatic infections cine Preventable Diseases. The data for 2004 are shown in is estimated to be 100:1-1,000:1 (3). Mouse-brain-derived, Figure 5. Neutralizing antibody titers equal to or greater than inactivated JE vaccine is available and internationally ac- 1:10 were considered to be positive in the analysis. Antibody cepted (6,7). JE is, therefore, a vaccine preventable disease; prevalence differed between age groups. The JE antibody- however, this vaccine has not been used regularly in all the positive population was less than 50% for ages 3 years and JE epidemic or endemic countries in Asia, mainly due to its younger, greater than 70% for ages 4-24 and 65-69, and high cost and to limitations in production capacity. The epi- between 20 and 70% for ages 25-64 and 70 years or more. It demic and endemic areas are located in East Asia, South Asia, should be noted that the JE antibody-positive rate was also and Southeast Asia (3,8). Approximately 1 billion children are low in the population aged 45-49. believed to be at risk for JE virus infection in these areas. Additionally, JE cases have been reported in Papua New Guinea and Australia (9-12). JE is therefore no longer restricted to JE virus infection of sentinel pigs only Asian countries. The seroconversion rates among sentinel seronegative pigs JE was a serious cause of morbidity and mortality in Japan were checked annually in most prefectures. Swine are known for many years. There were more than 1,000 JE cases re- to be an amplifier of JE virus, and it is generally accepted ported annually in the late 1960s. The number of JE cases that the seroconversion rates of sentinel pigs reflect the preva- has decreased dramatically, and less than 10 cases have been lence of JE virus in the area. Local public health institutes in reported annually since 1992 (Figure 1). The majority of the most of the 47 prefectures surveyed pigs, which were brought cases were in the elderly population with a peak in the 60-69 to slaughterhouses, for positive rates of HI antibodies. Data year age group. The JE antibody-positive percentage, how- in the representative 7 years including 1982, 1986, 1990, 1994, ever, is not lower in the elderly population than in the younger 1998, 2001, and 2004 are presented in Figure 6. Seroconversion population. We assume that the high incidence of JE among usually began in May in Okinawa Prefecture and in July in the elderly population is mainly due to impaired immune other southern prefectures (data not shown). Seroconversion responses. However, it should be noted that the age distribu- in the sentinel pigs moved to the north and occurred in all the tion of JE patients in Table 1 is a sum from 1982 to 2004, and prefectures by October with the exception of Hokkaido in the antibody positive rate in Figure 5 is that observed in 2004. some years. Seroconversion rates were somewhat lower in Thus, a direct comparison between these two data may not the northern prefectures. be appropriate. Although the percentage was low, there were
336 JE cases among children younger than 10 years old. In Japan, Prefecture (23). It was also reported that anti-JE virus NS1 primary JE vaccination is to be given twice at 1 - 4 week antibody was detected in 0.2 to 3.4% of the residents in 8 intervals between 6 and 90 months of age, and the current prefectures (24). Additionally, anti-JE virus NS1 antibody was standard schedule usually starts at 3 years old. The first booster detected among racehorses nationwide (25). Anti-JE virus immunization is given 1 year after the primary vaccination NS1 antibody is induced only by JE virus infection, not by (usually at the age of 4 years), and the 2nd and 3rd booster immunization with inactivated JE vaccine. These results immunizations are given at ages 9-13 years and 14-15 years, indicate that humans and horses are naturally infected with respectively. (The 3rd booster immunization was terminated JE virus at low but significant levels today. Therefore, JE as of July 29, 2005.) The small cluster of cases between vaccination is still recommended throughout Japan. For the ages of 0 and 4 years most likely reflects lower levels many countries that have been suffering from serious JE of antibody prevalence among this age population. Thus, epidemics, the Japanese experience is a good example of immunization at ages younger than 3 years old should be con- successfully fighting the battle against this devastating disease. sidered in order to prevent JE in children aged 3 years old and younger. The JE antibody-positive rate was also low in ACKNOWLEDGMENTS the population 45 - 49 years of age. It is possible that this We wish to thank Dr. Isao Arita of the Agency for Cooperation in Inter- population was not vaccinated with JE vaccine at a high rate national Health, Kumamoto, Japan for critical reading of the manuscript. and was not naturally infected at a high rate as in the elderly This study was supported by the vaccine preventable diseases surveil- populations. lance program of the Ministry of Health, Labour and Welfare, Japan. There have been reports of acute disseminated encephalo- myelitis (ADEM) after immunization with mouse brain- APPENDIX derived JE vaccine. The MHLW of Japan halted the recom- The member of Vaccine Preventable Diseases Surveillance Program of mendation of JE vaccination as of May 30, 2005, because of Japan (VPDSJ) have been constructed with researchers from the Hokkaido the occurrence of severe ADEM. However, the JE vaccina- Institute of Public Health, Aomori Prefectural Institute of Public Health and tion system has not been changed, and JE vaccine is avail- Environment, Research Institute for Environmental Sciences and Public Health of Iwate Prefecture, Miyagi Prefectural Institute of Public Health able for those who request the vaccination. The incidence of and Environment, Akita Prefectural Institute of Public Health, Yamagata ADEM is estimated to be less than one case per 1 million Prefectural Institute of Public Health, Fukushima Institute for Public Health, doses ([13] and data not shown), and this rate is not higher Ibaraki Prefectural Institute of Public Health, Tochigi Prefectural Institute than those induced by other vaccines. Further investigation of Public Health and Environmental Science, Gunma Prefectural Institute of Public Health and Environmental Sciences, Saitama Institute of Public Health, is needed to define the relationship between JE vaccine and Chiba Prefectural Institute of Public Health, Tokyo Metropolitan Institute ADEM. The development of Vero cell-derived JE vaccine is of Public Health, Kanagawa Prefectural Institute of Public Health, Niigata underway (14). Prefectural Institute of Public Health and Environmental Sciences, Toyama Extensive vaccination with mouse brain-derived, inacti- Institute of Health, Ishikawa Prefectural Institute of Public Health and vated vaccine is considered to be the main factor in the signifi- Environmental Science, Fukui Prefectural Institute of Public Health and Environmental Science, Yamanashi Institute for Public Health, Nagano cant decrease in the number of JE cases in Japan. The JE virus Environmental Conservation Research Institute, Gifu Prefectural Institute Nakayama strain was originally used for vaccine production of Health and Environmental Sciences, Shizuoka Institute of Environment in Japan, but since 1989 the Beijing-1 strain has been used and Hygiene, Aichi Prefectural Institute of Public Health, Mie Prefectural instead. The protective efficacy of the vaccine was evaluated Science and Technology Promotion Center, Shiga Prefectural Institute of Public Health and Environmental Science, Kyoto Prefectural Institute of in placebo-controlled studies. The efficacy was estimated to Hygienic and Environmental Sciences, Osaka Prefectural Institute of Public be 80% in Taiwan in 1965 (15) and 91% in Thailand in 1988 Health, Hyogo Prefectural Institute of Public Health and Environmental (16). Neutralizing antibody titers of 1:10 or greater, which Sciences, Nara Prefectural Institute for Hygiene and Environment, Wakayama are generally considered to be protective levels, were main- Prefectural Research Center of Environment and Public Health, Tottori tained for at least 3-4 years after the first booster immuniza- Prefectural Institute of Public Health and Environmental Science, Shimane Prefectural Institute of Public Health and Environment Science, Okayama tion (17-20). Prefectural Institute for Environmental Science and Public Health, Hiroshima It is believed that in addition to extensive JE vaccination, Prefectural Health Environment Center, Yamaguchi Prefectural Research there are other multiple factors which also contributed to the Institute of Public Health, Tokushima Prefectural Institute of Public Health decrease in the number of JE cases in Japan. These factors and Environmental Sciences, Kagawa Prefectural Research Institute for Environmental Sciences and Public Health, Ehime Prefectural Institute of include a decrease in the areas of the irrigation fields where Public Health and Environmental Science, The Public Health Institute of Cx. tritaeniorhynchus breed and changes in rice cultivation Kochi Prefecture, Fukuoka Institute of Health and Environmental Sciences, methods. These changes decreased the population of Cx. Saga Prefectural Institute of Public Health and Pharmaceutical Research, tritaeniorhynchus (21). Other factors also include the segrega- Nagasaki Prefectural Institute of Public Health and Environmental Sciences, tion of pigs, which are amplifiers of JE virus, from residential Kumamoto Prefectural Institute of Public Health and Environmental Science, The Oita Prefectural Institute of Health and Environment, The Miyazaki areas (21) and fewer pig farms (22). Due to these factors, JE Prefectural Institute for Public Health and Environment, Kagoshima Prefec- virus-infected mosquitoes have fewer chances to bite humans. tural Institute for Environmental Research and Public Health, Okinawa A high seroconversion rate among sentinel pigs is consist- Prefectural Institute of Health and Environment and National Institute of ent with the occurrence of JE cases in southern districts (Fig- Infectious Diseases since 1965. ure 4). It should, however, be noted that sentinel pigs are seroconverted even in northern districts with the exception REFERENCES of Hokkaido in some years. The data suggest that JE virus- 1. Hoke, C.H., Jr. (1992): Encephalitis viruses belonging to the families infected mosquitoes are present during the summer in most Flaviviridae, Togaviridae, and Bunyaviridae. p. 1835-1842. In Gorbach, areas of Japan, including the northern districts where no JE S.L., Bartlett, J.G. and Blackow, N.R. (ed.), Infectious Diseases. W. B. 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