| Japanese encephalitis | |
|---|---|
| Other names | Japanese B encephalitis |
 | |
| The geographic distribution of Japanese encephalitis (dark green) | |
| Specialty | Infectious disease |
| Symptoms | Headache, fever, vomiting, confusion,seizures[1] |
| Usual onset | 5 to 15 days after infection[1] |
| Causes | Japanese encephalitis virus (spread by mosquitoes) |
| Diagnostic method | Blood orcerebrospinal fluid testing[2] |
| Prevention | Japanese encephalitis vaccine, avoiding mosquito bites[2] |
| Treatment | Supportive care[1] |
| Prognosis | Permanent neurological problems occur in up to half of survivors[2] |
| Frequency | 68,000[2] |
| Deaths | 17,000[2] |
Japanese encephalitis (JE) is an infection of thebrain caused by the Japanese encephalitis virus (JEV).[3] While most infections result in little or no symptoms, occasionalinflammation of the brain occurs.[3] In these cases, symptoms may include headache, vomiting, fever, confusion andseizures.[1] This occurs about 5 to 15 days after infection.[1]
JEV is generally spread bymosquitoes, specifically those of theCulex type.[2]Pigs and wild birds serve as a reservoir for the virus.[2] The disease occurs mostly outside of cities.[2] Diagnosis is based on blood orcerebrospinal fluid testing.[2]
Prevention is generally achieved with theJapanese encephalitis vaccine, which is both safe and effective.[2] Other measures include avoiding mosquito bites.[2] Once infected, there is no specific treatment, withcare being supportive.[1] This is generally carried out in a hospital.[1] Permanent problems occur in up to half of people who recover from JE.[2]
The disease primarily occurs inEast andSoutheast Asia as well as theWestern Pacific.[2] About 3 billion people live in areas where the disease occurs.[2] About 68,000 symptomatic cases occur a year, with about 17,000 deaths.[2] Often, cases occur inoutbreaks.[2] The disease was first described inJapan in1871.[2][4]
The Japanese encephalitis virus (JEV) has anincubation period of 2 to 26 days.[5] The vast majority of infections areasymptomatic.[6] Only 1 in 250 infections develop into encephalitis.[7]
Severe rigors may mark the onset of this disease in humans. Fever, headache, andmalaise are othernon-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs that develop during the acute encephalitic stage include neck rigidity,cachexia,hemiparesis, convulsions, and a raised body temperature between 38–43 °C (100.4–109.4 °F). The mortality rate of the disease is around 25% and is generally higher in children under five, the immuno-suppressed, and the elderly. Transplacental spread has been noted.Neurological disorders develop in 40% of those who survive with lifelong neurological defects such as deafness, emotional lability andhemiparesis occurring in those who hadcentral nervous system involvement.[8]
Increasedmicroglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the residentimmune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such asinterleukin-1 (IL-1) andtumor necrosis factor-alpha (TNF-α), which can cause toxic effects in the brain. Additionally, other soluble factors such asneurotoxins,excitatory neurotransmitters,prostaglandin,reactive oxygen, and nitrogen species are secreted by activated microglia.[9]
In amurine model of JE, it was found that in thehippocampus and thestriatum, the number of activated microglia was more than anywhere else in the brain, closely followed by that in thethalamus. In the cortex, the number of activated microglia was significantly less when compared to other regions of themouse brain. An overall induction of differential expression ofproinflammatory cytokines andchemokines from different brain regions during a progressive Japanese encephalitis infection was also observed.Shukla M, Garg A, Dhole TN, Chaturvedi R (2023)."Exaggerated levels of some specific TLRs, cytokines and chemokines in Japanese encephalitis infected BV2 and neuro 2A cell lines associated with worst outcome".Virol. J.20 (1) 16.doi:10.1186/s12985-023-01966-8.PMC 9881527.PMID 36707891.
Although the net effect of the proinflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a non-regenerating organ such as the brain, a dysregulated innate immune response would be deleterious. In JE the tight regulation of microglial activation appears to be disturbed, resulting in anautotoxic loop of microglial activation that possibly leads to bystander neuronal damage.[10] In animals, key signs include infertility and abortion in pigs, neurological disease in horses, and systemic signs including fever, lethargy and anorexia.[11]
It is a disease caused by themosquito-borneJapanese encephalitis virus (JEV).[12]
| Japanese encephalitis virus | |
|---|---|
 | |
| Flavivirus structure and genome | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Riboviria |
| Kingdom: | Orthornavirae |
| Phylum: | Kitrinoviricota |
| Class: | Flasuviricetes |
| Order: | Amarillovirales |
| Family: | Flaviviridae |
| Genus: | Orthoflavivirus |
| Species: | Orthoflavivirus japonicum |
JEV is a virus from the familyFlaviviridae, part of the Japanese encephalitis serocomplex of nine genetically andantigenically related viruses, some of which are particularly severe inhorses, and four of which, includingWest Nile virus, are known to infect humans.[13] The enveloped virus is closely related to theWest Nile virus and theSt. Louis encephalitis virus. The positive sense single-strandedRNA genome is packaged in thecapsid which is formed by the capsid protein. The outer envelope is formed by envelope protein and is the protective antigen. It aids in the entry of the virus into the cell. The genome also encodes several nonstructural proteins (NS1, NS2a, NS2b, NS3, N4a, NS4b, NS5). NS1 is also produced as a secretory form. NS3 is a putativehelicase, and NS5 is the viralpolymerase. It has been noted that Japanese encephalitis infects thelumen of theendoplasmic reticulum (ER)[14][15] and rapidly accumulates substantial amounts of viral proteins.
Based on the envelope gene, there are five genotypes (I–V). The Muar strain, isolated from a patient inMalaya in 1952, is the prototype strain of genotype V. Genotype V is the earliest recognized ancestral strain.[16] The first clinical reports date from 1870, but the virus appears to have evolved in the mid-16th century. Complete genomes of 372 strains of this virus have been sequenced as of 2024.[17]
Japanese encephalitis is diagnosed by commercially available tests detecting JE virus-specific IgM antibodies in serum and/orcerebrospinal fluid, for example by IgM captureELISA.[18]
JE virus IgM antibodies are usually detectable 3 to 8 days after onset of illness and persist for 30 to 90 days, but longer persistence has been documented. Therefore, positive IgM antibodies occasionally may reflect a past infection or vaccination. Serum collected within 10 days of illness onset may not have detectable IgM, and the test should be repeated on a convalescent sample. Patients with JE virus IgM antibodies should have confirmatory neutralizing antibody testing.[19]Confirmatory testing in the US is available only at the CDC and a few specialized reference laboratories. In fatal cases, nucleic acid amplification and virus culture of autopsy tissues can be useful. Viral antigens can be shown in tissues byindirect fluorescent antibody staining.[11]
Infection with Japanese encephalitis confers lifelongimmunity. There are currently threevaccines available: SA14-14-2, IXIARO (IC51, also marketed in Australia, New Zealand as JESPECT and India as JEEV[20]) and ChimeriVax-JE (marketed as IMOJEV).[21] All current vaccines are based on the genotype III virus.[citation needed]
Aformalin-inactivated mouse-brain-derived vaccine was first produced in Japan in the 1930s and validated for use in Taiwan in the 1960s and Thailand in the 1980s. The widespread use of vaccines andurbanization has led to control of the disease in Japan and Singapore. The high cost of this vaccine, which is grown in live mice, means that poorer countries could not afford to give it as part of a routine immunization program.[12]
The most common adverse effects are redness and pain at the injection site. Uncommonly, anurticarial reaction can develop about four days after injection. Vaccines produced from mouse brain have a risk ofautoimmune neurological complications of around 1 per million vaccinations.[22] However where the vaccine is not produced in mouse brains butin vitro usingcell culture there are few adverse effects compared toplacebo, the main side effects being headache andmyalgia.[23]
The neutralizingantibody persists in the circulation for at least two to three years, and perhaps longer.[24][25] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years,boosters are recommended every 11 months for people who remain at risk.[26] Some data are available regarding the interchangeability of other JE vaccines and IXIARO.[27]
There is no specific treatment for Japanese encephalitis and treatment is supportive,[28] with assistance given forfeeding,breathing orseizure control as required. Raisedintracranial pressure may be managed withmannitol.[29] There is notransmission from person to person and therefore patients do not need to be isolated.[citation needed]
A breakthrough in the field of Japanese encephalitis therapeutics is the identification ofmacrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement ofmonocyte andmacrophage receptorCLEC5A in severe inflammatory response in Japanese encephalitis infection of the brain. Thistranscriptomic study provides a hypothesis ofneuroinflammation and a new lead in development of appropriate therapies for Japanese encephalitis.[30][31]
The effectiveness ofintravenous immunoglobulin for Japanese encephalitis is unclear due to a paucity of evidence.[32] Intravenous immunoglobulin for Japanese encephalitis appeared to have no benefit.[32]
Japanese encephalitis (JE) is the leading cause of viral encephalitis inAsia, with up to 70,000 cases reported annually.[33] Of those with symptoms case-fatality rates range from 20% to 30%.[34] Rare outbreaks in U.S. territories in the Western Pacific have also occurred.[34] Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas.[34]
Countries that have had major epidemics in the past, but which have controlled the disease primarily by vaccination, includeChina,South Korea,Singapore,Japan,Taiwan andThailand. Other countries that still have periodic epidemics includeVietnam,Cambodia,Myanmar,India,Nepal, andMalaysia. Japanese encephalitis has been reported in theTorres Strait Islands, and two fatal cases were reported in mainland northernAustralia in 1998. There were reported cases inKachin State, Myanmar in 2013. There were 116 deaths reported in Odisha'sMalkangiri district of India in 2016.[citation needed]
In 2022, the notable increase in the distribution of the virus in Australia due toclimate change became a concern to health officials as the population has limited immunity to the disease and the presence of large numbers of farmed and feral pigs could act as reservoirs for the virus.[8] In February 2022, Japanese encephalitis was detected and confirmed inpiggeries in Victoria, Queensland and New South Wales. On 4 March, cases were detected in South Australia. By October 2022, the outbreak in eastern mainland Australia had caused 42 symptomatic human cases of the disease, resulting in seven deaths. In 2025, further cases and a fatality were recorded in south-eastern Australia.[35][36][37]
Humans, cattle, and horses are dead-end hosts as the disease manifests as fatal encephalitis. Pigs act as amplifying hosts and have a vital role in the epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows when abortion and fetal abnormalities are common sequelae. The most important vector isCulex tritaeniorhynchus, which feeds on cattle in preference to humans. The natural hosts of the Japanese encephalitis virus are birds, not humans, and many believe the virus will never be eliminated.[38] In November 2011, the Japanese encephalitis virus was reported inCulex bitaeniorhynchus inSouth Korea.[39]
Recently, whole genomemicroarray research ofneurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. Although this challenges the long-held belief that neurons are immunologically quiescent, an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.[40]
A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies in mice. None are currently advocated in treating human patients.
It is theorized that the virus may have originated from an ancestral virus in the mid-1500s in theMalay Archipelago region and evolved there into five different genotypes that spread across Asia.[47] The mean evolutionary rate has been estimated to be 4.35×10−4 (range: 3.49×10−4 to 5.30×10−4) nucleotide substitutions per site per year.[47]
The clinical recognition and recording of Japanese encephalitis (JE) trace back to the 19th century when recurring encephalitis outbreaks were noted during Japan’s summer months. The first clinical case of JE was documented in 1871 in Japan. However, it wasn’t until 1924, during a major outbreak involving over 6,000 cases, that JE’s severity and potential for widespread impact became apparent. Subsequent outbreaks in Japan were recorded in 1927, 1934, and 1935, each contributing to a deeper understanding of the disease and its transmission patterns. The spread of JE extended beyond Japan over the following decades, impacting numerous countries across Asia. On the Korean Peninsula, the first JE cases were reported in 1933, and mainland China documented its initial cases in 1940. The virus reached the Philippines in the early 1950s and continued its westward spread, with Pakistan recording cases in 1983, marking JE’s furthest westward extension. By 1995, JE cases had reached Papua New Guinea and northern Australia (specifically the Torres Strait), representing the virus's southernmost range. According to the World Health Organization (WHO), JE is also endemic to the Western Pacific Islands, but cases are rare, possibly due to an enzootic cycle that does not sustain continuous viral transmission. Epidemics in these islands likely occur only when the virus is introduced from other JE-endemic regions. In the early 2020s, JE had become endemic in the southern parts of Australia with locally contracted human fatalities from the disease being recorded in these areas for the first time.[48][49]
