Definition
Japanese encephalitis (JE) is an arthropod-borne virus disease
affecting the central nervous system (CNS) of human beings and, less frequently, horses.
The infection also results in the birth of litters of pigs with a high percentage of
stillbirths or pigs affected with encephalitis.
Etiology
The JE virus is a member of the family Flaviviridae and is in the
genus Flavivirus. Host range and other characteristics are described in detail in
the International Catalogue of Arboviruses (1).
Host Range
People and horses are victims of the JE virus infection but appear
to be dead-end hosts from an epidemiologic standpoint. Viremia levels in infected human
beings and equine species are generally too low to provide potential mosquito vectors with
an infective blood meal. Under experimental conditions, however, Gould et al. (9)
demonstrated horse to horse transmission by Culex tritaeniorhynchus. Cattle are
frequently infected in enzootic areas (24) but do not develop sickness or viremia (14).
Swine in Japan and Taiwan are both victims of disease as well as
amplifiers of infection in nature. This is particularly true when swine are bred to farrow
at a time when infected mosquitoes make their first appearance. This type of breeding
program is practiced in Japan where, because of immunity or natural seasonal lows in
transmission, gilts resist infection during pregnancy, and thus losses due to abnormal
litters resulting from JE infection are reduced. However, normal newborn piglets soon lose
maternally acquired antibody and are fully susceptible to infection from arthropod
vectors.
Although JE infection in shoats is subclinical, viremias are
sufficiently high to provide emerging broods of Cu. tritaeniorhynchus, which feed
readily on swine, with a plentiful source of virus-containing blood. Following a period of
extrinsic incubation of virus, the mosquitoes are able to transmit the infection to
susceptible vertebrate hosts.
In Japan, herons and egrets play a role in the spread of infection
to man and other vertebrates and may be responsible for carrying the virus from rural to
urban areas. Cu. tritaeniorhynchus feeds readily on herons and egrets and ranges
sufficiently high off the ground to feed on the young nesting birds.
Geographic Distribution
Human encephalitis in Japan was recognized as early as 1871, and
Japanese encephalitis in epidemic form has been known since 1924 when 4,000 human deaths
were recorded in Japan. The epidemiology of the disease was studied extensively after
World War II in Japan by scientists of the U.S. Army's 406th Medical General Laboratory
(2). Concurrent with vaccination of people and extensive use of agricultural pesticides in
the last three decades, the disease has practically disappeared from Japan.
Japanese encephalitis virus infection is widespread throughout
temperate and tropical Asia; increasing numbers of human and equine cases have appeared in
India, Nepal, China, Philippines, Sri Lanka, and northern Thailand. The disease in humans
is sporadic in Indonesia and northern Australia but is not known in the rest of the world.
Transmission
The virus is maintained in nature in a cycle involving Culex
mosquitoes of the genera tritaeniorhynchus, annulus, fuscocephala, gelidus, and vishnui complex. Mosquitoes transmit the virus to many species
of birds and to swine (2,25).
The sequence of events in temperate Asia is initiated by
appearance of virus in mosquitoes in late spring followed by the infection and disease in
susceptible horses and swine. This is followed by the appearance of disease in man in
August and September. In tropical and semitropical areas of Asia, the seasonal nature of
the disease is less marked.
Basically, however, it appears the Culex mosquitoes and
birds are common factors in the epidemiology of JE, regardless of the region of
occurrence, and that swine are involved where they are numerous in Asia (15).
The mechanism of maintaining the virus over the winter in
temperate areas has not been elucidated. Overwintering in mosquitoes is a possibility
either in infected hibernating mosquitoes or by transovarial passage (23). It is also
possible that bats may carry the virus for prolonged periods (18,6).
Incubation Period
In horses, the incubation period is 8 to 10 days. The time between
exposure of pregnant swine to an infectious dose of JE virus and delivery of abnormal
litters does not seem to be clearly established, although exposure early in gestation
appears more likely to result in abnormal litters than later exposure.
Clinical Signs
In horses, initial signs are fever, impaired locomotion, stupor,
and grinding of teeth. Blindness, coma, and death follow in more severe cases. Although
the clinical signs resemble those seen in horses with Western equine encephalomyelitis and
Eastern equine encephalomyelitis, mortality is relatively low. Inapparent or subclinical
infections in horses are far more common than cases of recognizable encephalitis.
The principal manifestation of disease in swine is the expulsion
of litters of stillborn or mummified fetuses, usually at term. Viable piglets frequently
die shortly after birth and exhibit tremor and convulsions before expiring. Experimental
infection of boars leads to diminished sperm count and decreased mobility of sperm. Virus
has been transmitted to gilts by way of infected semen (11).
Gross Lesions
In horses, gross lesions are similar to those observed in animals
dying from Eastern equine encephalomyelitis and Western equine encephalomyelitis virus
infections and are not specific enough to establish an etiologic diagnosis. Litters from
infected pigs contain fetuses that are mummified and dark in appearance (24,4).
Hydrocephalus, cerebellar hypoplasia, and spinal hypomyelinogenesis have been noted (20).
Morbidity and Mortality
The equine mortality caused by JE has been reported at about 5
percent in Japan and may actually be less than this in Southeast Asia. Mortality in adult
pigs is close to zero. Litters of pigs from infected sows may be dead at delivery or, if
living, may be quite weak and apt to succumb to encephalitis shortly after birth.
Diagnosis
Field Diagnosis
Presumptive diagnosis can be made in horses that manifest CNS
disease accompanied by fever, particularly in an epizootic period. It has been observed
that illness in horses at race tracks in Malaysia is frequently due to JE infection. The
infection is manifested only by fever and a short period of lethargy (16,12,22). In
temperate zones, the disease appears during late summer and early fall.
A presumptive diagnosis in swine is based on the birth of litters
with a high percentage of stillborn or weak piglets.
Specimens for Laboratory
One half of a brain from animals having signs of encephalitis
should be submitted unfixed and the other half fixed in 10 percent formalin. Paired serum
samples collected at least 14 days apart should be submitted from animals that survive.
Cerebrospinal fluid from horses with CNS signs should be submitted for detection of
JE-specific IgM.
Laboratory Diagnosis
Confirmation of JE can be accomplished by demonstrating
seroconversion in animals that survive long enough to yield properly spaced blood samples.
Neutralization, complement fixation, hemagglutination inhibition, immunofluorescence, and
enzyme-linked immonosorbent assay tests are used to show a rise in titer from the acute
stage to death or recovery. Reliance on seroconversion or IgM as a means of diagnosis in
horses is not definitive because seroconversion may have resulted from exposure to another
nonpathogenic Flavivirus.
Demonstration of JE-specific IgM in serum of an encephalitic
equine is presumptive evidence of the diagnosis.
Further confirmation of JE in horses can be obtained by
examination of the cerebrospinal fluid and the brain. Specific IgM in the spinal fluid is
excellent evidence of CNS infection. Although microscopic lesions of the brain are of
value, definitive confirmation is based on isolation and identification of the virus from
the brain. Virus isolations are more likely to be successful from brains of animals that
died after a short course of the disease.
Confirmation of JE in diseased litters of pigs is accomplished by
isolation of the virus from fetal brains or brains of piglets that die after manifesting
signs of encephalitis. Demonstration of antibody increase in dams bearing affected litters
is probably not a reliable measure because seroconversion in such animals would probably
have occurred earlier in infection.
Differential Diagnosis
The disease in horses must be differentiated from other viral
encephalitides. In Asia, JE is the only recognized arboviral infection causing
encephalitis in horses. Because there are many mild or subclinical infections, laboratory
confirmation is essential.
Various forms of toxic encephalitis must be considered in
differential diagnosis. In temperate-zone Asia, the midsummer seasonal occurrence of JE in
horses aids in differential diagnosis.
Japanese encephalitis in pigs must be differentiated from a
hemagglutinating DNA virus infection that appears to be as commonplace in Japan as JE (21)
and causes the same pattern of disease. There is evidence that the DNA virus infection is
established in gilts in the middle or last trimester of pregnancy. Seasonal patterns of
DNA virus infection need more complete study, but the disease does appear concurrently
with Japanese encephalitis and therefore requires laboratory tests for differentiation.
Another hemagglutinating virus, myxovirus parainfluenza 1
(Sendai), has been shown capable of producing stillbirth in swine under experimental
conditions (20). Encephalitis in neonatal pigs is also associated with a coronavirus
infection. This agent is known to cause encephalitis in piglets in at least North America
and Europe (19).
Vaccination
A live attenuated vaccine produced in hamster kidney tissue
culture is in widespread use in horses in China (13). This vaccine reduced disease by
about 85 percent. An inactivated vaccine prepared in mouse brain is licensed in Japan,
Korea, Taiwan, India, and Thailand for use in humans. A similar inactivated product made
in hamster kidney tissue culture has been used to immunize children annually in China
since 1965. Live attenuated vaccines are used to immunize pigs in Japan and Taiwan (8) and
humans in China (13A).
Control and Eradication
Options for control include elimination of the vectors, prevention
of amplification of the infection cycle in birds and pigs, or immunization of horses,
pigs, and people. Although some success in vector control was achieved by modification of
irrigation methods to minimize breeding of Cu. tritaeniorhynchus in Southeast Asia
and coincidentally by the use of agricultural pesticides, vector control has never been
more than marginally successful. Reduction of the avian reservoir hosts does not appear
feasible.
The most promising approach to reducing livestock losses and at
the same time reducing the totality of infection in nature is widespread immunization of
swine. Live attenuated vaccines are in use in Japan and Taiwan (8). Immunization of shoats
prevents infection in vaccinees and neutralizes their role as amplifiers of infection in
nature. It is anticipated that those animals retained for breeding will remain immune,
and, because of immunity or natural seasonal lows in transmission resist infection during
pregnancy and therefore bear normal litters. Although controlling the disease in swine
dampens the spread of infection in nature, there is a continued threat to horses and human
beings from other sources.
The introduction of JE virus into the United States is always a
possibility, but whether the infection, once introduced, would become established in
nature is difficult to assess. Animal health authorities must continue to be alert to
detecting and identifying agents associated with encephalitis in horses and with abnormal
litters of pigs. The means for rapid diagnosis and identification of JE are available,
although it is doubtful that control of the disease in Asia will be achieved in the near
future.
Public Health
Japanese encephalitis can cause an explosive, highly fatal form of
human encephalitis.
GUIDE TO THE LITERATURE
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Robert E. Shope, M..D., Center for Tropical Diseases, University
of Texas Medical Branch, Galveston, TX 77555
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