Control of Japanese Encephalitis — Within Our Grasp?
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《新英格兰医药杂志》
The second half of 2005 saw one of the largest outbreaks of Japanese encephalitis that has occurred in northern India in recent years. Cases were first reported in the state of Uttar Pradesh in July 2005; by November, there had been nearly 5000 cases and 1300 deaths, as well as outbreaks in neighboring Nepal. At the height of the outbreak, some hospitals had no beds available, and even their corridors were full of patients.1
Although the number of cases was especially high for this part of India, for Asia as a whole, the outbreak was nothing new. Unusual outbreaks of "summer encephalitis" were first described in Japan in the 1870s; in just six weeks in 1924, there were more than 6000 cases and 3000 deaths. The disease was initially called Japanese B encephalitis, to distinguish it from von Economo's encephalitis (encephalitis lethargica), which was labeled type A; the virus was first isolated from a human brain in the 1930s. It is estimated that 30,000 to 50,000 cases occur each year, causing 10,000 to 15,000 deaths, but these may be underestimates.2 Whether there will be large outbreaks in 2006 and where they might occur are hard to predict.
Japanese encephalitis virus is a mosquito-borne member of the genus flavivirus (of the Flaviviridae family). West Nile virus and St. Louis encephalitis virus, which were also isolated during the 1930s (in Uganda and the United States, respectively), are genetically close to Japanese encephalitis virus and have similar ecologic and clinical features.3 Dengue virus and tick-borne encephalitis virus are less closely related flaviviruses.
Japanese encephalitis virus is an arbovirus transmitted in an enzootic cycle involving birds, particularly wading ardeids, such as herons and egrets. Pigs can become infected and act as amplifying hosts, bringing the virus closer to human habitats — especially in parts of Asia where pigs are kept near homes. Many mosquito species are potential vectors, but culex species such as Culex tritaeniorhynchus and C. vishnui, which breed in rice paddies and other dirty water, are especially important. Humans become infected when they are bitten by infected mosquitoes, but because they have transient and low-level viremia, they are "dead-end" hosts that do not normally transmit the virus.
There are at least four genotypes of Japanese encephalitis virus (distinguished by approximately 10 percent divergence at the nucleotide level). Whether they vary in terms of neurovirulence in humans is debated. For unknown reasons, genotype III has spread most widely. Most countries in South Asia, Southeast Asia, and the Asian Pacific Rim have now been affected (see map), and a complex interplay of ecologic, environmental, climatic, and human behavioral factors has been implicated in the virus's spread. For example, as the regional economy grows, the introduction of irrigation schemes for developing the rice industry may increase the risk of disease, both by attracting migrating birds that introduce the virus and by providing breeding grounds for the mosquitoes that transmit it. Wind-blown mosquitoes are thought to have been important in the virus's spread, in the mid-1990s, from Papua New Guinea to the Torres Strait islands and the Australian mainland.
Approximate Geographic Area Affected by Japanese Encephalitis Virus.
Because the virus and its vectors and hosts are ubiquitous in rural Asia, most of the population is exposed during childhood, as shown by serologic studies, though disease develops in only a small proportion of infected persons. The effects range from a nonspecific febrile illness to severe meningoencephalitis, characterized by a reduced level of consciousness, seizures, parkinsonian movement disorders, and acute flaccid paralysis. Pathological and imaging studies have shown that some of these clinical features reflect the anatomical sites of damage, such as the basal ganglia or the anterior horns of the spinal cord. How the virus crosses the blood–brain barrier and why it targets particular regions of the central nervous system are not known.
There is no established treatment for the disease, but an understanding of the pathogenesis may point the way toward therapies. Typically, 20 to 30 percent of patients with Japanese encephalitis die, and approximately half the survivors have severe neuropsychiatric sequelae. Treatment efforts are directed at controlling both the immediate complications of infection, including seizures and increased intracranial pressure, and the longer-term consequences of neurologic impairment, such as limb contractures and bed sores.
Various measures have been used to try to control the spread of the virus. Larvicides and insecticides have largely proved to be ineffectual in the restriction of mosquito breeding in rice paddies; more ecologically friendly methods — such as the application of neem cake (a natural larvicide and fertilizer made from crushed neem nuts), the placing of larvivorous fish in rice paddies, and the intermittent draining of paddies — have been shown to reduce the mosquito population and thus might reduce the rate of disease. Vaccination of pigs has been used but has not been shown to consistently reduce mosquito and human infections and is not cost-effective in most settings. Moving pigs away from human habitats also makes sense, though the animals probably need to be moved at least 5 km (3.1 mi) away, and the benefit has not been proved. Since culex mosquitoes preferentially feed on cattle, which are dead-end hosts for the virus, it has been suggested that cattle be used to divert infected mosquitoes from humans and swine. Measures to reduce the risk of being bitten by infected mosquitoes include minimizing the time spent outdoors in the evening, wearing clothing that leaves minimal skin exposed, and using insect repellents. Still, the best hope for controlling Japanese encephalitis lies in vaccination.
Soon after the virus was discovered, crude vaccines were produced by the Japanese and others by growing the virus in mouse brain and inactivating it in formalin. Production was refined, and the vaccine's efficacy was demonstrated in large, placebo-controlled trials in Taiwan in the 1960s and in Thailand in the 1980s. The vaccine became available in the United States in the 1980s, following the campaign of a Washington, D.C., lawyer whose son had died of Japanese encephalitis after contracting the infection in China.
The vaccine developed a bad reputation in the 1990s, however, owing to occasional urticarial reactions, which typically occurred four days after vaccination. In addition, because it is derived from mouse brain, there has been concern about possible adverse neurologic effects, though the risk of such effects is about 1 per million vaccinations — similar to that associated with measles vaccine. The high production costs and the need for two or three doses plus boosters have limited the vaccine's use among travelers and residents of areas where the virus is endemic. Opinions vary as to whether all travelers to Asia should be vaccinated or only those staying for extended periods in high-risk areas.4,5
There is a stronger case for vaccinating residents of these regions, but the proposition is complicated by issues of disease burden, cost, and competing health care priorities. In most Asian countries, it is difficult to estimate the disease burden because of questions about the case definition of acute encephalitis syndrome, challenges in confirming the diagnosis in rural hospitals, and problems in quantifying the disease outcome (because survivors with sequelae probably impose a greater burden on the community than do fatal cases).
Accurate diagnosis is essential, as was demonstrated by the recent outbreaks of Nipah virus in Malaysia and Bangladesh and of Chandipura virus in southern India, all of which were initially thought to be outbreaks of Japanese encephalitis. Diagnostic problems are being addressed with the introduction of simple enzyme-linked immunosorbent assays. Good data on the disease burden and cost-effectiveness analyses are critical for countries that need to weigh Japanese encephalitis vaccination against other health care priorities.
Nevertheless, in wealthier Asian countries such as Japan, Taiwan, and Korea, where mass vaccination with the inactivated vaccine has been practiced for years, the incidence of Japanese encephalitis has diminished considerably. The vaccine confers no herd immunity because humans are not the primary hosts. The introduction of vaccination into the Expanded Program on Immunization of the World Health Organization has also been associated with reduced disease in Thailand.
Moreover, newer inactivated and live attenuated vaccines are becoming available. The mouse-brain–derived vaccine is being replaced by an inactivated vaccine derived from cell culture, which should be cheaper and safer. In 1988, the Chinese licensed a live attenuated vaccine that had been developed empirically, by passage through a range of cell lines; more than 200 million doses have been given in China, and the safety and efficacy have been excellent. The vaccine's use outside China has been limited, initially because of questions about the novel cell line that is used (primary hamster kidney cell); however, these issues have been resolved, and the vaccine has now been licensed in Nepal, Sri Lanka, South Korea, and most recently, India. A new chimeric vaccine based on the yellow fever 17D vaccine also looks promising. Currently, all vaccines are based on genotype III viruses, but they appear to be effective against all genotypes of the virus.
Whether these vaccines will translate into a reduced disease burden remains to be seen. The signs are encouraging, with increasing use of vaccine in many Asian countries. Unfortunately, the complex ecology of Japanese encephalitis virus, involving multiple vertebrate hosts and mosquito vectors, means that the virus — unlike poliovirus and smallpox — is unlikely to disappear.
Source Information
Dr. Solomon is a United Kingdom Medical Research Council senior clinical fellow. He is also a senior lecturer in neurology, medical microbiology, and tropical medicine and head of the Viral Brain Infections Group at the University of Liverpool and the Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom.
References
India encephalitis toll hits 175. BBC News Online. August 24, 2005. (Accessed August 10, 2006, at http://news.bbc.co.uk/2/hi/south_asia/4179760.stm.)
Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15 October 1998. Vaccine 2000;18:Suppl 2:1-25.
Solomon T. Flavivirus encephalitis. N Engl J Med 2004;351:370-378.
Ostlund MR, Kan B, Karlsson M, Vene S. Japanese encephalitis in a Swedish tourist after travelling to Java and Bali. Scand J Infect Dis 2004;36:512-513.
Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis 2002;35:183-188.(Tom Solomon, M.R.C.P., D.)
Although the number of cases was especially high for this part of India, for Asia as a whole, the outbreak was nothing new. Unusual outbreaks of "summer encephalitis" were first described in Japan in the 1870s; in just six weeks in 1924, there were more than 6000 cases and 3000 deaths. The disease was initially called Japanese B encephalitis, to distinguish it from von Economo's encephalitis (encephalitis lethargica), which was labeled type A; the virus was first isolated from a human brain in the 1930s. It is estimated that 30,000 to 50,000 cases occur each year, causing 10,000 to 15,000 deaths, but these may be underestimates.2 Whether there will be large outbreaks in 2006 and where they might occur are hard to predict.
Japanese encephalitis virus is a mosquito-borne member of the genus flavivirus (of the Flaviviridae family). West Nile virus and St. Louis encephalitis virus, which were also isolated during the 1930s (in Uganda and the United States, respectively), are genetically close to Japanese encephalitis virus and have similar ecologic and clinical features.3 Dengue virus and tick-borne encephalitis virus are less closely related flaviviruses.
Japanese encephalitis virus is an arbovirus transmitted in an enzootic cycle involving birds, particularly wading ardeids, such as herons and egrets. Pigs can become infected and act as amplifying hosts, bringing the virus closer to human habitats — especially in parts of Asia where pigs are kept near homes. Many mosquito species are potential vectors, but culex species such as Culex tritaeniorhynchus and C. vishnui, which breed in rice paddies and other dirty water, are especially important. Humans become infected when they are bitten by infected mosquitoes, but because they have transient and low-level viremia, they are "dead-end" hosts that do not normally transmit the virus.
There are at least four genotypes of Japanese encephalitis virus (distinguished by approximately 10 percent divergence at the nucleotide level). Whether they vary in terms of neurovirulence in humans is debated. For unknown reasons, genotype III has spread most widely. Most countries in South Asia, Southeast Asia, and the Asian Pacific Rim have now been affected (see map), and a complex interplay of ecologic, environmental, climatic, and human behavioral factors has been implicated in the virus's spread. For example, as the regional economy grows, the introduction of irrigation schemes for developing the rice industry may increase the risk of disease, both by attracting migrating birds that introduce the virus and by providing breeding grounds for the mosquitoes that transmit it. Wind-blown mosquitoes are thought to have been important in the virus's spread, in the mid-1990s, from Papua New Guinea to the Torres Strait islands and the Australian mainland.
Approximate Geographic Area Affected by Japanese Encephalitis Virus.
Because the virus and its vectors and hosts are ubiquitous in rural Asia, most of the population is exposed during childhood, as shown by serologic studies, though disease develops in only a small proportion of infected persons. The effects range from a nonspecific febrile illness to severe meningoencephalitis, characterized by a reduced level of consciousness, seizures, parkinsonian movement disorders, and acute flaccid paralysis. Pathological and imaging studies have shown that some of these clinical features reflect the anatomical sites of damage, such as the basal ganglia or the anterior horns of the spinal cord. How the virus crosses the blood–brain barrier and why it targets particular regions of the central nervous system are not known.
There is no established treatment for the disease, but an understanding of the pathogenesis may point the way toward therapies. Typically, 20 to 30 percent of patients with Japanese encephalitis die, and approximately half the survivors have severe neuropsychiatric sequelae. Treatment efforts are directed at controlling both the immediate complications of infection, including seizures and increased intracranial pressure, and the longer-term consequences of neurologic impairment, such as limb contractures and bed sores.
Various measures have been used to try to control the spread of the virus. Larvicides and insecticides have largely proved to be ineffectual in the restriction of mosquito breeding in rice paddies; more ecologically friendly methods — such as the application of neem cake (a natural larvicide and fertilizer made from crushed neem nuts), the placing of larvivorous fish in rice paddies, and the intermittent draining of paddies — have been shown to reduce the mosquito population and thus might reduce the rate of disease. Vaccination of pigs has been used but has not been shown to consistently reduce mosquito and human infections and is not cost-effective in most settings. Moving pigs away from human habitats also makes sense, though the animals probably need to be moved at least 5 km (3.1 mi) away, and the benefit has not been proved. Since culex mosquitoes preferentially feed on cattle, which are dead-end hosts for the virus, it has been suggested that cattle be used to divert infected mosquitoes from humans and swine. Measures to reduce the risk of being bitten by infected mosquitoes include minimizing the time spent outdoors in the evening, wearing clothing that leaves minimal skin exposed, and using insect repellents. Still, the best hope for controlling Japanese encephalitis lies in vaccination.
Soon after the virus was discovered, crude vaccines were produced by the Japanese and others by growing the virus in mouse brain and inactivating it in formalin. Production was refined, and the vaccine's efficacy was demonstrated in large, placebo-controlled trials in Taiwan in the 1960s and in Thailand in the 1980s. The vaccine became available in the United States in the 1980s, following the campaign of a Washington, D.C., lawyer whose son had died of Japanese encephalitis after contracting the infection in China.
The vaccine developed a bad reputation in the 1990s, however, owing to occasional urticarial reactions, which typically occurred four days after vaccination. In addition, because it is derived from mouse brain, there has been concern about possible adverse neurologic effects, though the risk of such effects is about 1 per million vaccinations — similar to that associated with measles vaccine. The high production costs and the need for two or three doses plus boosters have limited the vaccine's use among travelers and residents of areas where the virus is endemic. Opinions vary as to whether all travelers to Asia should be vaccinated or only those staying for extended periods in high-risk areas.4,5
There is a stronger case for vaccinating residents of these regions, but the proposition is complicated by issues of disease burden, cost, and competing health care priorities. In most Asian countries, it is difficult to estimate the disease burden because of questions about the case definition of acute encephalitis syndrome, challenges in confirming the diagnosis in rural hospitals, and problems in quantifying the disease outcome (because survivors with sequelae probably impose a greater burden on the community than do fatal cases).
Accurate diagnosis is essential, as was demonstrated by the recent outbreaks of Nipah virus in Malaysia and Bangladesh and of Chandipura virus in southern India, all of which were initially thought to be outbreaks of Japanese encephalitis. Diagnostic problems are being addressed with the introduction of simple enzyme-linked immunosorbent assays. Good data on the disease burden and cost-effectiveness analyses are critical for countries that need to weigh Japanese encephalitis vaccination against other health care priorities.
Nevertheless, in wealthier Asian countries such as Japan, Taiwan, and Korea, where mass vaccination with the inactivated vaccine has been practiced for years, the incidence of Japanese encephalitis has diminished considerably. The vaccine confers no herd immunity because humans are not the primary hosts. The introduction of vaccination into the Expanded Program on Immunization of the World Health Organization has also been associated with reduced disease in Thailand.
Moreover, newer inactivated and live attenuated vaccines are becoming available. The mouse-brain–derived vaccine is being replaced by an inactivated vaccine derived from cell culture, which should be cheaper and safer. In 1988, the Chinese licensed a live attenuated vaccine that had been developed empirically, by passage through a range of cell lines; more than 200 million doses have been given in China, and the safety and efficacy have been excellent. The vaccine's use outside China has been limited, initially because of questions about the novel cell line that is used (primary hamster kidney cell); however, these issues have been resolved, and the vaccine has now been licensed in Nepal, Sri Lanka, South Korea, and most recently, India. A new chimeric vaccine based on the yellow fever 17D vaccine also looks promising. Currently, all vaccines are based on genotype III viruses, but they appear to be effective against all genotypes of the virus.
Whether these vaccines will translate into a reduced disease burden remains to be seen. The signs are encouraging, with increasing use of vaccine in many Asian countries. Unfortunately, the complex ecology of Japanese encephalitis virus, involving multiple vertebrate hosts and mosquito vectors, means that the virus — unlike poliovirus and smallpox — is unlikely to disappear.
Source Information
Dr. Solomon is a United Kingdom Medical Research Council senior clinical fellow. He is also a senior lecturer in neurology, medical microbiology, and tropical medicine and head of the Viral Brain Infections Group at the University of Liverpool and the Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom.
References
India encephalitis toll hits 175. BBC News Online. August 24, 2005. (Accessed August 10, 2006, at http://news.bbc.co.uk/2/hi/south_asia/4179760.stm.)
Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15 October 1998. Vaccine 2000;18:Suppl 2:1-25.
Solomon T. Flavivirus encephalitis. N Engl J Med 2004;351:370-378.
Ostlund MR, Kan B, Karlsson M, Vene S. Japanese encephalitis in a Swedish tourist after travelling to Java and Bali. Scand J Infect Dis 2004;36:512-513.
Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis 2002;35:183-188.(Tom Solomon, M.R.C.P., D.)