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John D. Wilson, M.D.
1200 Hilyard St. Ste. 560
mailing address: POB 5337
Eugene, Oregon 97405 USA
fax 541.485.7702
www.TravelClinicOregon.com
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JAPANESE ENCEPHALITIS
(chapter from the 2012 Yellow Book)  
 

INFECTIOUS AGENT: Japanese encephalitis virus (JEV) is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile and Saint Louis encephalitis viruses. JEV is transmitted to humans through the bite of an infected mosquito, primarily Culex species. The virus is maintained in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. Humans are incidental or dead-end hosts, because they usually do not develop a level or duration of viremia sufficient to infect mosquitoes.

EPIDEMIOLOGY: JEV is the most common vaccine-preventable cause of encephalitis in Asia, occurring throughout most of Asia and parts of the western Pacific (Map 3-08). Local transmission of JEV has not been detected in Africa, Europe, or the Americas. Transmission principally occurs in rural agricultural areas, often associated with rice cultivation and flooding irrigation. In some areas of Asia, these ecologic conditions may occur near, or occasionally within, urban centers. In temperate areas of Asia, transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, seasonal transmission varies with monsoon rains and irrigation practices and may be extended or even occur year-round. In endemic countries, Japanese encephalitis (JE) is primarily a disease of children. However, travel-associated JE can occur among people of any age. The risk for JE for most travelers to Asia is extremely low but varies based on destination, duration, season, and activities. From 1973 through 2008, there were 55 published reports of travel-associated JE among travelers from nonendemic countries. Only 4 cases among people from the United States have been reported since 1992, when a JE vaccine was first licensed in the United States. The overall incidence of JE among people from nonendemic countries traveling to Asia is estimated to be less than 1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission are likely at similar risk as the susceptible resident population (5–50 cases per 100,000 children per year). Travelers on even brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Short-term (<1 month) travelers whose visits are restricted to major urban areas are at minimal risk for JE. In endemic areas there are few human cases among residents because of vaccination or natural immunity. JEV is often still maintained in an enzootic cycle between animal and mosquitoes. Therefore, susceptible visitors may be at risk for infection.

CLINICAL PRESENTATION: Most human infections with JEV are asymptomatic; <1% of people infected with JEV develop clinical disease. Acute encephalitis is the most commonly recognized clinical manifestation of JEV infection. Milder forms of disease, such as aseptic meningitis or undifferentiated febrile illness, can also occur. The incubation period is 5–15 days. Illness usually begins with sudden onset of fever, headache, and vomiting. Mental status changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days. The classical description of JE includes a parkinsonian syndrome with masklike facies, tremor, cogwheel rigidity, and choreoathetoid movements. Acute flaccid paralysis, with clinical and pathological features similar to those of poliomyelitis, has also been associated with JEV infection. Seizures are common, especially among children. Clinical laboratory findings might include a moderate leukocytosis, mild anemia, and hyponatremia. Cerebrospinal fluid (CSF) typically has a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal ratio of CSF to plasma glucose. The case-fatality ratio is approximately 20%–30%. Among survivors, 30%–50% have significant neurologic, cognitive, or psychiatric sequelae.

DIAGNOSIS: JE should be suspected in a patient with evidence of a neurologic infection (such as encephalitis, meningitis, or acute flaccid paralysis) who has recently traveled to or resided in an endemic country in Asia or the western Pacific. Laboratory diagnosis of JEV infection should be performed by using a JEV-specific IgM-capture ELISA on CSF or serum. JEV-specific IgM can be measured in the CSF of most patients by 4 days after onset of symptoms and in serum by 7 days after onset. A ≥4-fold rise in JEV-specific neutralizing antibodies between acute- and convalescent-phase serum specimens may be used to confirm the diagnosis. Vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographic area that may cross-react in serologic assays need to be considered when interpreting results.
Humans have low levels of transient viremia and usually have neutralizing antibodies by the time distinctive clinical symptoms are recognized. Virus isolation and nucleic-acid amplification tests are insensitive in detecting JEV or JE viral RNA in blood or CSF and should not be used for ruling out a diagnosis of JE. Clinicians should contact their state or local health department or CDC’s Division of Vector-Borne Diseases at 970-221-6400 for assistance with diagnostic testing.

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

PREVENTIVE MEASURES FOR TRAVELERS: One JE vaccine is licensed and available in the United States—an inactivated Vero cell culture–derived vaccine (Ixiaro). Ixiaro, manufactured by Intercell and distributed by Novartis Vaccines, was approved in March 2009 for use in people aged ≥17 years. Pediatric clinical trials are being conducted to enable licensure of Ixiaro for use in children. Other inactivated and live attenuated JE vaccines are manufactured and used in Asia but are not licensed for use in the United States.

EFFICACY AND IMMUNOGENICITY: There are no efficacy data for Ixiaro. The vaccine was licensed in the United States on the basis of its ability to induce JEV neutralizing antibodies as a surrogate for protection, as well as safety evaluations in almost 5,000 adults. In the pivotal noninferiority immunogenicity study, 96% of adults developed protective neutralizing antibodies after receiving a primary immunization series of 2 doses administered 28 days apart.

DOSAGE AND ADMINISTRATION: The primary immunization schedule for Ixiaro is 2 doses administered intramuscularly on days 0 and 28. The dose is 0.5 mL for people aged ≥17 years, and the 2-dose series should be completed ≥1 week before travel.

BOOSTER DOSES: The full duration of protection after primary immunization with Ixiaro is unknown. In one study, 83% of people who received two doses of Ixiaro maintained protective levels of antibodies at 12 months after the first vaccine dose, and in a second study, 58% and 48% of people had protective antibodies at 12 and 24 months, respectively. If the primary series of Ixiaro was administered ≥1 year previously, a booster dose should be given prior to potential reexposure or if there is a continued risk for JEV infection. Data on the response to a booster dose administered ≥2 years after the primary series are not available. Data on the need for and timing of additional booster doses are also not available.
There are no data on the use of Ixiaro as a booster dose after a primary series with JE-Vax. People who have received JE-Vax previously and require further vaccination against JEV should receive a 2-dose primary series of Ixiaro.

Vaccine safety and adverse reactions: Pain and tenderness were the most commonly reported symptoms in a safety study with 1,993 participants who received 2 doses of Ixiaro. Systemic side effects, including headache, myalgia, fatigue, and an influenzalike illness, were each reported at a rate of >10%. Because Ixiaro was licensed after study in <5,000 recipients, the possibility of rare serious adverse events cannot be excluded. Postlicensure studies and surveillance are further evaluating the safety of Ixiaro in a larger population.

Indications for use of JE vaccine in travelers: When making recommendations regarding the use of JE vaccine for travelers, clinicians must weigh the overall low risk of travel-associated JEV disease, the high rate of death and disability when JE occurs, the low probability of serious adverse events after immunization, and the cost of the vaccine. Evaluation of an individual traveler’s risk should take into account the planned itinerary, including travel location, duration, activities, and seasonal patterns of disease in the areas to be visited (see Table 3-08). The data in the table should be interpreted cautiously, because JEV transmission activity varies within countries and from year to year.

The Advisory Committee on Immunization Practices recommends JE vaccine for travelers who plan to spend ≥1 month in endemic areas during the JEV transmission season. This includes long-term travelers, recurrent travelers, or expatriates who will be based in urban areas but are likely to visit endemic rural or agricultural areas during a high-risk period of JEV transmission. Vaccine should also be considered for the following:

  • Short-term (<1 month) travelers to endemic areas during the JEV transmission season, if they plan to travel outside an urban area and their activities will increase the risk of JEV exposure. Examples of higher-risk activities or itineraries include: 1) spending substantial time outdoors in rural or agricultural areas, especially during the evening or night; 2) participating in extensive outdoor activities (such as camping, hiking, trekking, biking, fishing, hunting, or farming); and 3) staying in accommodations without air conditioning, screens, or bed nets.
  • Travelers to an area with an ongoing JE outbreak.
  • Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel.
    JE vaccine is not recommended for short-term travelers whose visits will be restricted to urban areas or times outside a well-defined JEV transmission season.


Precautions and Contraindications of Ixiaro: A severe allergic reaction after a previous dose of Ixiaro is a contraindication to administration of further doses. Ixiaro contains protamine sulfate, a compound known to cause hypersensitivity reactions in some people. The safety and effectiveness of Ixiaro among children aged ≤16 years have not yet been determined. Limited data on the use of Ixiaro in people aged ≥65 years suggest safety and immunogenicity are similar to that among younger people, but further data are needed. No studies of Ixiaro in pregnant women have been conducted. Therefore, administration of Ixiaro to pregnant women usually should be deferred. However, pregnant women who must travel to an area where risk for JEV infection is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection. (Updated September 1. 2011)

Personal Protection Measures: The best way to prevent mosquitoborne diseases, including JE, is to avoid mosquito bites (see Chapter 2, Protection against Mosquitoes, Ticks and Other Insects and Arthropods).

 
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  John D. Wilson, M.D. 1999-2016; Last Update 4/23/2016