Japanese encephalitis

INTRODUCTION — Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the most important cause of viral encephalitis in Asia based on its frequency and severity. With the near eradication of poliomyelitis, JEV is now the leading cause of childhood viral neurological infection and disability in Asia [1]. JEV is closely related to West Nile, St. Louis encephalitis, and Murray Valley encephalitis viruses [2].

About 68,000 cases of Japanese encephalitis (JE) are estimated to occur each year. JEV is endemic throughout most of Asia and parts of the western Pacific. For travelers to Asia, the risk of JE is very low but varies based on season, destination, duration, and activities [3]. The estimated incidence of JE among travelers to Asia from nonendemic countries is <1 case per 1 million travelers. Risk is likely to be higher for individuals with longer duration of travel or whose plans include extensive outdoor activities in rural areas [3]. Between 1973 and 2020, 88 cases of JE among individuals from nonendemic countries were reported [3]. Since a JE vaccine became available in the United States in 1993, only 13 cases of JE were reported among United States travelers through 2020 [4,5].

Most human JEV infections are asymptomatic or cause a nonspecific febrile illness. Fewer than 1 percent of JEV infections results in symptomatic neuroinvasive disease [6]. However, when neurologic disease does occur, it is usually very severe with a high case-fatality rate; among survivors, neurological sequelae are common. All travelers to JEV-endemic countries should be given advice on measures to prevent JE, and JE should be considered among the differential diagnoses for patients with suspected neurological infection who have returned from recent travel in a JEV-endemic country in Asia or the Western Pacific region.

EPIDEMIOLOGY — JE is endemic throughout most of Asia and parts of the Western Pacific region (figure 1). During 2022, cases were reported for the first time in eastern and southern states of Australia, much further south than where JEV transmission had previously been detected [7]. Within the JE-endemic region, there are two typical patterns of transmission:

●In areas with temperate climates (including China, Japan, South Korea, Nepal, northern Vietnam, and northern India), most cases occur over a period of several months when the weather is warmest, usually after the monsoons begin or associated with heavy rainfall [2,8,9]. The peak months of transmission and the length of the season vary from place to place. There are sometimes large, explosive outbreaks.

●In areas with tropical climates (including Cambodia, Indonesia, southern Vietnam, and southern Thailand), there is year-round transmission. An increase in cases may be observed during the rainy season [10,11].

In endemic areas, JE typically affects children <15 years of age; by early adulthood, the majority of the population has protective immunity following natural exposure to JEV as a result of ongoing environmental transmission [12]. However, when the virus enters new geographic areas where there is no immunity, JE affects both adults and children [10]. In regions where childhood immunization programs have been introduced, the age distribution of disease shifts to older ages [9,13]. Among immunologically naïve travelers visiting JEV-endemic regions, the disease can affect individuals at any age [5].

TRANSMISSION — JEV is transmitted in an enzootic cycle involving mosquitoes and vertebrate amplifying hosts, primarily pigs and wading birds. Humans are incidental and dead-end hosts in the JEV transmission cycle as they do not develop sufficiently high viremia to infect feeding mosquitoes. Therefore, mosquitoes do not transmit the virus directly from one person to another person.

Mosquitoes of the Culex vishnui subgroup, particularly Culex tritaeniorhynchus, are the major vectors of JEV, although JEV has been isolated from over 30 mosquito species [14]. C. tritaeniorhynchus commonly breeds in rice fields, marshes, and other shallow pools of water. It is an evening and night-time biting mosquito and mainly feeds outdoors, preferentially on large animals and birds and only infrequently on humans.

Pigs and wading birds, such as herons and egrets, are the most important hosts for maintenance and amplification of JEV. Pigs are a key host as they develop high levels of viremia, and in Asia, large numbers of pigs are frequently kept near human dwellings. In addition, the population of susceptible pigs is replenished regularly because of commercial slaughtering [10]. JEV infection in pigs is usually subclinical, but gestational infection can result in abortions and stillbirths [6]. The strong epidemiological link with pigs in the JEV transmission cycle has sometimes led to the misconception that areas without pigs are likely to be free of disease. However, transmission in such areas has also been documented, likely secondary to infection in wading birds [11].

The risk for JEV infection is highest in rural, agricultural areas of Asia, as all the elements of the enzootic transmission cycle are in close proximity to humans. However, Japanese encephalitis cases are occasionally reported from urban or peri-urban areas [15]. A small number of cases of transmission via non-mosquito-borne routes have been reported; these include transplacental transmission, transfusion, laboratory exposure, and possibly organ transplantation [16-18].

CLINICAL MANIFESTATIONS — The most commonly recognized clinical presentation of JEV infection is acute encephalitis. Milder forms of disease such as aseptic meningitis or nonspecific febrile illness with headache also occur [1]. After an incubation period of 5 to 15 days, initial symptoms are usually nonspecific and may include fever, diarrhea, and rigors followed by headache, vomiting, and generalized weakness. Over the next few days, mental status changes, focal neurologic deficits (including paresis, hemiplegia, tetraplegia, or cranial nerve palsies), and/or movement disorders develop [6,19]. Many patients lapse into coma and some require ventilatory assistance.

In some patients, the initial presentation may consist of abnormal behavior or acute psychosis, leading to potential misdiagnosis. For example, during the Korean War in the 1950s, some American soldiers presenting with JE were thought initially to have "war neurosis" [20].

Seizures (usually generalized tonic-clonic) are very common, especially among children. In some children, subtle motor seizures occur and may present with twitching of a digit, eye deviation, or irregular breathing. These may be missed without electroencephalogram monitoring [21]. A very distinctive clinical presentation of JE is a Parkinsonian syndrome resulting from extrapyramidal involvement; findings include dull, flat, mask-like facies with unblinking eyes, tremor, and cogwheel rigidity [19].

In some patients with JEV infection, the presentation may be with a poliomyelitis-like acute flaccid paralysis due to anterior horn cell damage, without any alteration in consciousness [22,23]. After a brief febrile illness, paralysis occurs in one or more limbs, usually asymmetric and more common in the lower than upper limbs. In these patients, encephalitis develops subsequently in about 30 percent [19]. Patients with JEV infection can also present with Guillain Barré syndrome [24].

Clinical signs associated with a poor prognosis include multiple prolonged seizures and raised intracranial pressure. Changes in the respiratory pattern, flexor and extensor posturing, and abnormalities of the pupillary and oculocephalic reflexes are also poor prognostic signs and may reflect brainstem encephalitis with or without transtentorial herniation [21,25].

DIAGNOSIS

Laboratory findings — The white blood cell count is moderately elevated in most patients, and hyponatremia may be observed due to the syndrome of inappropriate antidiuretic hormone secretion. Thrombocytopenia, mild anemia, and elevated hepatic enzymes may also occur but are relatively nonspecific laboratory features.

The cerebrospinal fluid (CSF) opening pressure is elevated in about 50 percent of patients. CSF findings are typically a mild to moderate pleocytosis of 10 to several hundred white blood cells/mm³ with lymphocytic predominance, slightly elevated protein, and normal CSF to plasma glucose ratio. Early in disease, there may be no pleocytosis or neutrophils may predominate.

Imaging — Magnetic resonance imaging is more sensitive than computed tomography scanning for detecting JEV-associated abnormalities such as changes in the thalamus, basal ganglia, midbrain, pons, and medulla [26,27]. Thalamic lesions are the most commonly described abnormality; although these can be highly specific for JE in the appropriate clinical context, they are not a very sensitive marker of JE (image 1) [28].

Electroencephalogram abnormalities may include theta and delta coma, burst suppression, epileptiform activity, and occasionally alpha coma [19].

Diagnostic testing — JE is diagnosed serologically by detection of JEV-specific immunoglobin (Ig)M antibodies in CSF or serum by an enzyme-linked immunosorbent assay (ELISA). The presence of JEV-specific IgM antibodies in CSF confirms recent central nervous system infection. IgM antibody in serum is suggestive of JE but could indicate asymptomatic infection or recent JEV vaccination.

On admission to hospital, CSF antibodies are detectable in 70 to 90 percent of JE patients; JEV IgM is detectable in most CSF samples collected five to eight days after symptom onset. On admission to hospital, serum antibodies are detectable in about 60 to 70 percent of patients; serum antibodies are detectable in nearly all serum samples collected at least nine days after symptom onset [29-32]. If JE is suspected and acute samples are negative, a convalescent serum sample should be collected.

Important considerations for interpretation of serology results include vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographical area that may cross-react in serologic assays (such as dengue, Murray Valley encephalitis, or West Nile viruses). As serodiagnosis of flaviviral infections is not straightforward and cross-reactivity is common, samples positive by ELISA should be referred to a reference laboratory for confirmatory plaque reduction neutralization testing.

Virus isolation or detection of viral ribonucleic acid (RNA) with a nucleic acid amplification test (NAAT) can provide a definitive diagnosis, but positive results from CSF or blood are rare [21,33,34]. Because humans have low levels of transient viremia and high levels of neutralizing antibodies by the time distinctive clinical symptoms are recognized, virus isolation and NAATs are insensitive for the detection of JEV or JE viral RNA in blood or CSF. JEV isolates have been obtained postmortem from brain tissue [31].

United States health care providers should contact their state or local health department or the United States Centers for Disease Control and Prevention's (CDC's) Division of Vector-Borne Diseases in Colorado for assistance with diagnostic testing (telephone: 970-221-6400).

Differential diagnosis — The differential diagnosis of JE includes other viral encephalitides, other central nervous system infections, para- or postinfectious causes, and noninfectious diseases [25,35]. Domestic arboviral infections should be considered if the patient could have been exposed to local arboviruses during the incubation period. In the United States, this may include La Crosse, St. Louis encephalitis, Eastern equine encephalitis, or Powassan viruses, among other arboviruses [36]. (See related topics.)

TREATMENT — Treatment of JE consists of supportive care with emphasis on control of intracranial pressure, maintenance of adequate cerebral perfusion pressure, seizure control, and prevention of secondary complications [37].

There is no specific antiviral treatment for JE. A randomized, placebo-controlled trial of oral ribavirin in 153 Indian children did not show any difference in outcome between the treatment and control groups [38]. Corticosteroids and interferon-alfa-2a did not improve outcome in controlled clinical trials [39,40]. Work is ongoing to investigate other potential antiviral agents [41,42].

OUTCOME — Mortality among hospitalized patients is about 20 to 30 percent. Some deaths come after a short fulminant course while others occur after a prolonged period of coma [1].

Among JE survivors, long-term sequelae occur in at least 30 to 50 percent. Although the clinical condition of many JE patients improves after hospital discharge, deterioration in the months following acute illness may be observed in about 20 percent of patients [15]. The most common sequelae are upper and lower motor neuron weakness and cerebellar and extrapyramidal signs. Severe cognitive or language impairment, psychiatric problems, and recurrent seizures also occur. Among patients who appear to have recovered well, subtle sequelae such as learning or behavioral problems may be observed in about 50 percent [19].

There is limited information on JEV infection in pregnancy. In India, four miscarriages were reported among nine infected pregnant women; all of the women were in the first or second trimester of pregnancy [17,43]. JEV was isolated from one of the four aborted fetuses, suggesting that intrauterine transmission of JEV can occur.

Infection with JEV is thought to produce lifelong immunity.

PREVENTION — Personal protective measures to prevent mosquito bites are important to reduce the risk of JE among travelers to endemic regions. In addition, JE vaccine provides substantial additional protection for travelers to high-risk settings (based on location, duration, season, accommodations, and activities) [3].

Personal protective measures — Measures include using insect repellent, permethrin-impregnated clothing, staying in screened or air-conditioned rooms, or sleeping under a bed net. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Vaccination — One JE vaccine is available in the United States: an inactivated Vero cell culture-derived vaccine (JE-VC; IXIARO) (table 1). JE-VC was licensed in 2009 for use in individuals ≥17 years and in 2013 for use in children 2 months through 16 years of age. An inactivated mouse brain-derived vaccine (JE-MB; JE-VAX) was used in the United States for almost 20 years following its licensure in 1992, but it is no longer available.

Other JE vaccines are manufactured and used in other countries but are not licensed for use in the United States. These include a live-attenuated chimeric virus vaccine, the live-attenuated SA 14-14-2 JE vaccine, inactivated Vero cell culture-derived vaccines, and inactivated mouse brain-derived vaccines. The recommended number of doses and schedule vary by vaccine and country.

Whom to vaccinate — Most travelers to JE-endemic countries are at low risk for clinical JE. We are in agreement with the United States Advisory Committee on Immunization Practices (ACIP) which recommends JE vaccine for individuals moving to a JE-endemic country to take up residence, longer-term (eg, ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas (table 2). Vaccination should be considered for shorter-term travelers with an increased risk of JEV exposure [3]. JE vaccine is not recommended for travelers with very low-risk itineraries, such as shorter-term travel limited to urban areas or travel that occurs outside of a well-defined JEV transmission season.

For most travelers to JE-endemic countries, the risk of developing JE disease is very low. Factors that increase the risk for JEV exposure include:

●Longer duration of travel

●Travel during the JEV transmission season

●Spending time in rural areas

●Participating in extensive outdoor activities

●Staying in an accommodation without air conditioning, screens, or bed nets

Health care providers should assess each traveler’s risk for mosquito exposure and JEV infection on the basis of their planned itinerary. The decision whether to vaccinate should be individualized and predicated on the risks related to the specific travel itinerary, the likelihood of future travel to JE-endemic countries, the high morbidity and mortality of JE, the availability of an effective vaccine, the possibility (but low probability) of serious adverse events after vaccination, and patient preference.

Immunogenicity and safety — There are no efficacy data for JE-VC; the vaccine was licensed on the basis of its ability to induce JEV neutralizing antibodies as a surrogate for protection and safety evaluations [3]. JEV neutralizing antibody levels measured by plaque-reduction neutralization test are thought to be a reliable surrogate for efficacy.

Adults — In a noninferiority immunogenicity study comparing JE-VC (two-dose schedule; 365 adults) with JE-MB (three-dose schedule; 370 adults), seroconversion rates at 28 days after the last dose were comparable (96 versus 94 percent, respectively) [44,45]. Among adults aged ≥65 years, seroprotection rates are lower; 65 percent of individuals in this age group have seroprotection at 42 days after the two-dose primary series [46].

In one observational study evaluating long-term seroprotection among adults 6 years following a booster dose of JE-VC at 15 months, seroprotection was observed among 96 percent of individuals [47]. Seroprotection against JE-VC may be enhanced among individuals who are also vaccinated against tickborne encephalitis [48].

Studies evaluating individuals receiving JE-VC or placebo adjuvant have described comparable rates of local and systemic reactions [45,49]. In a study evaluating 2650 individuals who received JE-VC or placebo adjuvant, the frequency of injection site reaction was similar in both groups (about 55 percent overall; 3 percent severe) [45,49]. Pain and tenderness were the most common reactions. Overall, about 60 percent of subjects reported a systemic adverse event; headache, myalgias, fatigue, and an influenza-like illness were each reported at a rate of >10 percent. The rates of serious adverse events following immunization were also similar in the vaccine and the placebo groups (0.5 and 0.9 percent). A publication reporting findings from postmarketing surveillance data suggested a good safety profile for JE-VC, consistent with findings from prelicensure clinical trials [50].

Children — The largest pediatric trial of JE-VC was conducted in children aged 2 months through 17 years in the Philippines [51,52]. Among 385 children vaccinated with JE-VC and evaluated for seroprotection, 384 had protective antibodies 28 days following the second dose. At six months following completion of the series, protective antibodies were present in 88 percent (134 out of 152) of children aged two months to two years (CI 82-92 percent), and 95 percent (224 out of 237) of children aged 3 to 17 years (CI 91-97 percent) [3]. In another pediatric trial among 23 children in India aged between 1 and 3 years, 96 percent (CI 87-100 percent) had protective antibodies at 28 days after two doses of JE-VC [53]. In an observational study of children from nonendemic countries, all 62 children had protective neutralizing antibodies at 28 days [51,54].

The incidence of adverse events due to JE-VC appear to be similar to those observed with the comparison vaccines used in the clinical trials, including pneumococcal conjugate vaccine and hepatitis A vaccine [3]. In the clinical trial in the Philippines, 9 percent (122 out of 1411) of JE-VC recipients had fever (≥38°C) within seven days after the first dose, and 6 percent (84 out of 1405) had fever within seven days after the second dose. Fewer than 1 percent had urticaria, hypersensitivity reaction, or febrile seizures [3,51].

Dose and administration — For adults 18 to 65 years of age, the primary immunization schedule for JE-VC is two doses administered intramuscularly 7 to 28 days apart. For children 2 months to <18 years of age and for adults >65 years of age, the primary immunization schedule is two doses administered intramuscularly on days 0 and 28. The two-dose series should be completed at least one week prior to travel.

For adults and children ≥3 years, each dose is 0.5 mL; for children aged 2 months to 2 years of age, each dose is 0.25 mL. For adults and children, a booster dose should be given if the primary series of JE-VC was administered ≥1 year previously and ongoing exposure or re-exposure to JEV is expected [3]. No data are available on the response to a booster dose administered >2 years after the primary series.

A severe allergic reaction after a previous dose of JE-VC, any other JE vaccine, or any component of JE-VC is a contraindication to administration of a subsequent dose. JE-VC contains protamine sulfate, which is known to cause hypersensitivity reactions in some individuals; it does not contain gelatin or murine proteins [55]. The risk of hypersensitivity or neurologic adverse events with JE-VC is probably lower than that with JE-MB, although the possibility of rare adverse events cannot be excluded. No studies of JE-VC in pregnant women have been conducted. Therefore, administration of JE-VC 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 for immunization is outweighed by the risk for infection.

Data on use of JE-VC as a booster dose after a primary series with the mouse brain–derived inactivated JE vaccine (JE-MB) are limited. Three studies have investigated the use of JE-VC as a booster dose after a primary series with JE-MB; two studies were performed among United States military personnel and one was conducted at two European travel clinics [3,56,57]. In one United States military study and the European study, among adults previously vaccinated with a primary series of JE-MB, a single dose of JE-VC adequately boosted neutralizing antibody levels (measured at 4 to 8 weeks after the booster dose). A second study among United States military personnel investigated longer term protection, the immunologic response at 12 to 23 months following one dose of JE-VC in adults previously vaccinated with ≥3 doses of JE-MB was noninferior to the response following two doses of JE-VC in JE vaccine-naïve adults [3]. Among 19 European study participants available for longer-term follow up, 89 to 100 percent had protective neutralizing antibodies against different genotypes of JEV a mean of 2 years following the booster dose [58].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis" and "Society guideline links: Travel medicine".)

SUMMARY

●Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the most important cause of viral encephalitis in Asia based on its frequency and severity. (See 'Introduction' above.)

●About 68,000 cases of Japanese encephalitis are estimated to occur each year. However, for travelers, the risk is low. Fewer than 1 percent of JEV infections results in symptomatic neuroinvasive disease. However, when neurological disease does occur, it is usually a very severe disease with a high case-fatality rate and neurological sequelae in 30 to 50 percent of survivors. (See 'Introduction' above and 'Outcome' above.)

●In endemic areas, JE typically affects children <15 years of age; by early adulthood, the majority of the population has protective immunity following natural exposure to JEV as a result of ongoing environmental transmission. Among immunologically naïve travelers visiting endemic regions, the disease can affect individuals at any age. (See 'Epidemiology' above.)

●JEV is transmitted in an enzootic cycle involving mosquitoes and vertebrate-amplifying hosts, primarily pigs and wading birds. Humans are incidental and dead-end hosts in the JEV transmission cycle as they do not develop sufficiently high viremia to infect feeding mosquitoes. (See 'Transmission' above.)

●The most commonly recognized clinical presentation of JEV infection is acute encephalitis. Milder forms of disease such as aseptic meningitis or nonspecific febrile illness with headache also occur. Seizures (usually generalized tonic-clonic) are very common, especially among children. (See 'Clinical manifestations' above.)

●JE is diagnosed serologically by detection of JEV-specific immunoglobin (Ig)M antibody in cerebrospinal fluid (CSF) or serum by an enzyme-linked immunosorbent assay. The presence of JEV-specific IgM antibodies in CSF confirms recent central nervous system infection. IgM antibody in serum is suggestive of JE but could indicate asymptomatic infection or recent JE vaccination. (See 'Diagnostic testing' above.)

●There is no specific antiviral treatment for JE. Treatment consists of supportive care with emphasis on control of intracranial pressure, maintenance of adequate cerebral perfusion pressure, seizure control, and prevention of secondary complications. (See 'Treatment' above.)

●Precautions to reduce the risk of JE among travelers to endemic regions include personal protective measures to prevent mosquito bites. For some travelers who will be in a high-risk setting (based on location, duration, season, accommodations, and activities), JE vaccine may further reduce the risk of infection. (See 'Prevention' above.)

●One JE vaccine is available in the United States: an inactivated Vero cell culture-derived vaccine (JE-VC; IXIARO). (See 'Vaccination' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Marc Fischer, MD, MPH, who contributed to an earlier version of this topic review.