Japanese Encephalitis

Japanese encephalitis (JE) is an acute disease of the central nervous system caused by infection with Japanese encephalitis virus (JEV). JEV is a mosquito-borne Flavivirus that is closely related to the West Nile Virus and St. Louis Encephalitis virus. JEV infection occurs throughout most of Asia and is the most common cause of encephalitis in that region. Symptoms may include fever, headache, gastrointestinal symptoms, weakness and neurological changes. Symptoms may be mild or severe. Many people affected by the virus have no symptoms.



Signs and Symptoms
The majority of human infections with JEV are asymptomatic. Encephalitis (an acute infection of the brain, usually caused by a virus) is the most common clinical manifestation of JEV infection. JEV infection leads to encephalitis in only 1 of 20 to 1,000 cases.

The incubation period of JEV is 5 to 15 days. Illness usually begins with sudden onset of fever with gastrointestinal symptoms and headache. Mental status or behavioral changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days. Seizures are very common among children. Milder forms of disease such as aseptic meningitis or fever with headache can occur, more commonly among adults.

Causes
The Japanese encephalitis virus has a life cycle involving domestic pigs and a specific type of mosquito, Culex tritaeniorhynchus, that lives in rural rice-growing and pig-farming regions. The mosquito breeds in flooded rice fields, marshes, and standing water around planted fields. The virus can infect humans, most domestic animals, birds, bats, snakes, and frogs through the bite of the mosquito. After infection, the virus invades the central nervous system, including the brain and spinal cord.

Exams and tests
Laboratory findings of JE include moderate leukocytosis (elevated white blood cell) count, mild anemia, hyponatremia (low sodium), and an increased cell count in the cerebrospinal fluid (CSF) (especially white blood cells). Laboratory diagnosis of JEV infection should be performed by using JE-specific IgM-capture enzyme-linked immunosorbent assay (ELISA) on CSF or serum. JE-specific IgM antibodies will be present in the CSF or blood of almost all patients 7 days following onset of symptoms. The Centers for Disease Control or local health department can help with diagnosis.

Treatment
There is no specific antiviral treatment for JE; therapy consists of supportive care and management of complications.

Prevention
An inactivated mouse-brain JE vaccine (JE-VAX) has been licensed for use in the U.S. civilian population since 1992. This vaccine is manufactured by Biken (Osaka, Japan) and distributed in the United States by Sanofi Pasteur. Although production of the mouse brain-derived vaccine was discontinued in 2006, stockpiles of the vaccine will be available for use in U.S. travelers for several more years. An inactivated cell culture-derived JE vaccine has been evaluated in the United States and other countries, and will likely also be approved for use in the United States in the next 1-3 years. Other inactivated and live attenuated JE vaccines are manufactured and used in Asia but not licensed for use in the United States.

Vaccination should be considered for persons who plan to live in areas where JE is endemic or epidemic, and for travelers whose activities include trips into rural farming areas. Short-term travelers, especially those whose visits are restricted to major urban areas, are at lower risk for infection and generally do not require the vaccine. Evaluation of an individual traveler’s risk should take into account itinerary and activities, and best-available information on the current level of JE activity in the travel area.

The recommended primary immunization series is three doses of 1.0 mL each, administered subcutaneously on days 0, 7, and 30. An abbreviated schedule (days 0, 7, and 14) can be used when the longer schedule is impractical. The last dose should be administered at least 10 days before beginning travel to ensure an adequate immune response and access to medical care in the event of any delayed adverse reactions.

Immunization routes and schedules for children 1-3 years of age are identical except that 0.5-mL doses should be administered. No data are available on vaccine safety and efficacy in infants younger than 1 year.

Preliminary data indicate that neutralizing antibodies persist for at least 2 years after a three-dose primary series. Booster doses of 1.0 mL (0.5 mL for children younger than 3 years of age) may be administered 2 years after the primary series. The duration of immunity after serial booster doses has not been well established.

Although JE vaccination is very effective against developing infection, travelers should still avoid mosquito bites to reduce the risk of other vector-borne infectious diseases (e.g., malaria, dengue, and chikungunya fever).

Vaccine side effects
Inactivated mouse brain-derived JE vaccine has been associated with localized erythema, tenderness, and swelling at the injection site in about 20% of recipients. Mild systemic side effects (e.g., fever, chills, headache, rash, myalgia, and gastrointestinal symptoms) have been reported in approximately 10% of vaccinees. More serious allergic hypersensitivity reactions including generalized urticaria and angioedema of the extremities, face, and oropharynx have been reported at a rate of 180 to 640 cases per 100,000 vaccinees. Accompanying bronchospasm, respiratory distress, and hypotension was also reported in several of these patients. Most of these allergic reactions were treated successfully with antihistamines or corticosteroids; however, up to 10% of vaccinees with these reactions were hospitalized. One death possibly associated with JE vaccine has been reported in a person with a history of recurrent hypersensitivity reactions and anaphylaxis.

Vaccine precautions
Vaccine recipients should be observed for a minimum of 30 minutes after immunization and warned about the possibility of delayed allergic reactions. The full course of immunization should be completed at least 10 days before departure, and vaccinees should be advised to remain in areas with access to medical care.

Persons with multiple allergies or with a history of urticaria or angioedema for any reason may be at higher risk for allergic complications from the JE vaccine. This history should be considered when weighing the risks and benefits of the vaccine for an individual patient.

No specific information is available on the safety of JE vaccine in pregnancy. Therefore, the vaccine should not be routinely administered during pregnancy. Pregnant women who must travel to an area where risk of JE is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection.

Chances of Developing
According to the Centers for Disease Control (CDC): Japanese encephalitis is the leading cause of viral encephalitis in Asia, where 30,000 to 50,000 cases are reported each year. The disease is very rare, however, in U.S. travelers to Asia.

The chance that a traveler to Asia will get Japanese encephalitis is very small: 1) only certain mosquito species can spread Japanese encephalitis; 2) in areas infested with mosquitoes, only a small portion of the mosquitoes are usually infected with Japanese encephalitis virus; 3) among persons who are infected by a mosquito bite, only 1 in 50 to 1 in 1,000 will develop an illness. As a result, fewer than 1 case per year is reported in U.S. civilians and military personnel traveling to and living in Asia. Only 5 cases among Americans traveling or working in Asia have been reported since 1981.

Risk factors
The risk to short-term travelers and those who confine their travel to urban centers is very low. Expatriates and travelers living for prolonged periods in rural areas where JE is endemic or epidemic are at greater risk. Travelers with extensive outdoor, evening, and nighttime exposure in rural areas, such as might be experienced while bicycling, camping, working outdoors, or sleeping in unscreened structures without bed nets, may be at high risk even if their trip is brief.

How is Spread
JE transmission mostly occurs in rural agricultural locations where flooding irrigation is practiced. In many areas of Asia, these ecologic conditions may occur near, or occasionally within, urban centers. Transmission is seasonal and occurs in the summer and autumn in the temperate regions of China, Japan, Korea, and eastern Russia. Elsewhere, seasonal patterns of disease may be extended or vary with the rainy season and irrigation practices. Thus, the risk of JE transmission varies by season and geographic area.

Culex tritaeniorhynchus is the principal vector for transmission of JE and feeds outdoors from dusk to dawn. Larvae are found in flooded rice fields, marshes, and other small stable collections of water found around cultivated fields. In temperate zones, this vector is present in greatest density from June through September; it is inactive during winter months. In tropical parts of Asia, other mosquito species that breed in rice paddies may also be important vectors, and JEV transmission may occur over a longer season or even throughout the year.

Clinical Trials
A list of ongoing clinical trials is available at ClinicalTrials.gov: Japanese encephalitis trials.

Recent discoveries

 * The epidemiology, clinical features and long-term outcome of Japanese encephalitis survivors was studied.
 * The Japanese encephalitis vaccine was found to be cost-effective in Indonesia.
 * Japanese encephalitis vaccine is currently restricted to travelers who have a relatively high likelihood of contracting the virus. As the vaccine becomes more widely available, the vaccination guidelines may need to be revisited.

Future research

 * The safety of administration of live attenuated JE vaccine together with the measles vaccine was studied.
 * An evaluation of the long-term efficacy of the JE vaccine.

Epidemiology
Japanese encephalitis outbreaks are usually circumscribed and do not cover large areas. They usually do not last more than a couple of months, dying out after the majority of the pig amplifying hosts have become infected. Birds are the natural hosts for Japanese encephalitis. Epidemics occur when the virus is brought into the peridomestic environment by mosquito bridge vectors where there are pigs, which serve as amplification hosts, infecting more mosquitoes which then may infect humans. Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Viet Nam, Cambodia, Myanmar, India, Nepal, and Malaysia.