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Japanese Encephalitis

Disease Details

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Description: Japanese encephalitis is a viral infection transmitted by mosquitoes that primarily affects the brain and can cause inflammation and severe neurological symptoms.
Type: Japanese encephalitis is a viral infection. It is not transmitted genetically; rather, it is transmitted through the bite of an infected mosquito, primarily the Culex species.
Signs And Symptoms: The Japanese encephalitis virus (JEV) has an incubation period of 2 to 26 days. The vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis.Severe rigors may mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38–41 °C (100.4–105.8 °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 and hemiparesis occurring in those who had central nervous system involvement.
Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident immune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α), which can cause toxic effects in the brain. Additionally, other soluble factors such as neurotoxins, excitatory neurotransmitters, prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain, closely followed by that in the thalamus. In the cortex, the number of activated microglia was significantly less when compared to other regions of the mouse brain. An overall induction of differential expression of proinflammatory cytokines and chemokines from different brain regions during a progressive Japanese encephalitis infection was also observed.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 nonregenerating 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 an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. In animals, key signs include infertility and abortion in pigs, neurological disease in horses, and systemic signs including fever, lethargy and anorexia.
Prognosis: Japanese Encephalitis Prognosis:

Japanese encephalitis (JE) can have a variable prognosis depending on several factors, including the age and health status of the patient, the timeliness and adequacy of medical treatment, and the severity of the neurological involvement. Here are some general points about the prognosis:

1. **Mild Cases:** Individuals with mild symptoms may recover completely without long-term effects.
2. **Severe Cases:** Those with severe neurological involvement, such as encephalitis, can experience significant complications, including long-term neurological deficits.
3. **Mortality Rate:** The mortality rate for severe JE cases can be as high as 20-30%, even with proper medical care.
4. **Long-term Effects:** Approximately 30-50% of survivors of severe JE may experience long-term neurological or psychiatric sequelae, including cognitive impairment, motor deficits, and seizures.

Early diagnosis and supportive care are crucial in improving the outcomes for those affected by Japanese encephalitis. Vaccination is the most effective preventive measure.
Onset: Japanese encephalitis typically has an incubation period of 5 to 15 days. Initial symptoms are non-specific, such as fever, headache, and general malaise. The illness can quickly progress to more severe symptoms including high fever, neck stiffness, disorientation, tremors, and convulsions. In some cases, it can lead to coma and even death. Initial non-specific symptoms make early diagnosis challenging, emphasizing the importance of preventative measures such as vaccination in endemic areas.
Prevalence: Japanese encephalitis is a mosquito-borne viral infection prevalent in many parts of Asia and the Western Pacific. The disease primarily affects rural and agricultural areas where rice paddies and standing water provide breeding grounds for mosquitoes. Prevalence varies by region, but it is estimated that there are approximately 68,000 clinical cases annually, with a significant portion occurring in children. The distribution and incidence can fluctuate due to factors like vaccination coverage, mosquito control measures, and environmental conditions.
Epidemiology: Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, with up to 70,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depend on the population and age. Rare outbreaks in U.S. territories in the Western Pacific have also occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas.Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, South Korea, Singapore, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported in the Torres Strait Islands, and two fatal cases were reported in mainland northern Australia in 1998. There were reported cases in Kachin State, Myanmar in 2013. There were 116 deaths reported in Odisha's Malkangiri district of India in 2016.In 2022, the notable increase in distribution of the virus in Australia due to climate 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. In February 2022, Japanese encephalitis was detected and confirmed in piggeries 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.Humans, cattle, and horses are dead-end hosts as the disease manifests as fatal encephalitis. Pigs act as an amplifying host and have a very important 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 is Culex 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 therefore never be eliminated. In November 2011, the Japanese encephalitis virus was reported in Culex bitaeniorhynchus in South Korea.Recently, whole genome microarray research of neurons 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.A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies upon mice. None are currently advocated in treating human patients.

The use of rosmarinic acid, arctigenin, and oligosaccharides with degree of polymerization 6 from Gracilaria sp. or Monostroma nitidum has been shown to be effective in a mouse model of Japanese encephalitis.
Curcumin has been shown to impart neuroprotection against Japanese encephalitis infection in an in vitro study. Curcumin possibly acts by decreasing cellular reactive oxygen species level, restoration of cellular membrane integrity, decreasing pro-apoptotic signaling molecules, and modulating cellular levels of stress-related proteins. It has also been shown that the production of infective viral particles from previously infected neuroblastoma cells is reduced, which is achieved by inhibition of the ubiquitin-proteasome system.
Minocycline in mice resulted in marked decreases in the levels of several markers, viral titer, and the level of proinflammatory mediators and also prevented blood–brain barrier damage.
Intractability: Japanese encephalitis is a viral disease transmitted primarily by mosquitoes. While there is no specific antiviral treatment for Japanese encephalitis, supportive care can help manage symptoms. Vaccination is an effective preventive measure. The disease is not considered completely intractable because preventive measures, such as vaccination and mosquito control, can significantly reduce the incidence of infection. However, once severe neurological complications arise, the damage can be irreversible, and they may require long-term care.
Disease Severity: Japanese encephalitis is a potentially severe viral disease. While many infections are asymptomatic, when symptoms do occur, they can range from mild fever and headache to severe neurological symptoms, including high fever, neck stiffness, seizures, and coma. Severe cases can lead to permanent neurological damage or even death.
Healthcare Professionals: Disease Ontology ID - DOID:10844
Pathophysiology: Japanese encephalitis is caused by the Japanese encephalitis virus (JEV), a flavivirus transmitted primarily by Culex mosquitoes. Pathophysiologically, the virus enters the bloodstream through the mosquito bite, leading to viremia. It then crosses the blood-brain barrier, infecting the central nervous system. The infection triggers inflammation of the brain (encephalitis), characterized by the infiltration of immune cells and release of cytokines. This can result in neuronal damage and subsequent neurological manifestations such as seizures, paralysis, and alterations in consciousness.
Carrier Status: Carrier status for Japanese encephalitis: The primary carriers of Japanese encephalitis are mosquitoes, particularly the Culex species, which transmit the virus from infected animals, mainly pigs and wading birds, to humans. Humans are considered dead-end hosts, meaning they do not develop high enough levels of the virus in their bloodstream to infect mosquitoes.
Mechanism: Japanese encephalitis (JE) is caused by the Japanese encephalitis virus (JEV), a flavivirus transmitted primarily by mosquitoes, mainly Culex species. Here are the mechanisms and molecular details:

**Mechanism:**
1. **Transmission**: JEV is primarily transmitted to humans through the bite of an infected mosquito.
2. **Entry and Replication**: Upon entering the human body, JEV initially infects and replicates in keratinocytes or Langerhans cells at the site of the mosquito bite. The virus then travels to local lymph nodes and enters the bloodstream (viremia).
3. **Central Nervous System (CNS) Invasion**: JEV crosses the blood-brain barrier (BBB) and infects neurons in the CNS. The virus propagates in the brain, leading to inflammation (encephalitis), neuronal damage, and neurological symptoms.

**Molecular Mechanisms:**
1. **Viral Structure**: JEV is a single-stranded RNA virus with a positive-sense RNA genome. The viral genome encodes three structural proteins (C, prM/M, E) and seven non-structural proteins (NS1-NS5).
2. **Immune Evasion**: The viral envelope protein (E) plays a critical role in binding to host cell receptors and mediating viral entry. The NS1 protein helps JEV evade the host immune response by antagonizing the complement system.
3. **Replication Cycle**: Upon entering the host cell, the viral RNA is translated into a single polyprotein, which is then cleaved by viral and host proteases into functional proteins. The viral RNA is replicated in the host cell's endoplasmic reticulum to form replication complexes.
4. **Inflammation and Neurotoxicity**: JEV infection triggers a strong immune response. Pro-inflammatory cytokines and chemokines are released, leading to an influx of immune cells into the CNS. This response can cause neuronal cell death and CNS damage.
5. **Apoptosis and Autophagy**: JEV can induce apoptosis (programmed cell death) in infected neurons through both intrinsic and extrinsic pathways. Additionally, JEV can modulate autophagy, a cellular degradation process, to promote its replication.

Understanding these mechanisms is crucial for developing targeted therapies and effective vaccines against Japanese encephalitis.
Treatment: There is no specific treatment for Japanese encephalitis and treatment is supportive, with assistance given for feeding, breathing or seizure control as required. Raised intracranial pressure may be managed with mannitol. There is no transmission from person to person and therefore patients do not need to be isolated.A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in Japanese encephalitis infection of the brain. This transcriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapies for Japanese encephalitis.The effectiveness of intravenous immunoglobulin for the management of encephalitis is unclear due to a lack of evidence. Intravenous immunoglobulin for Japanese encephalitis appeared to have no benefit.
Compassionate Use Treatment: For Japanese encephalitis, there is currently no specific antiviral treatment available. Supportive care is the mainstay of treatment, which includes hospitalization for observation, respiratory support, and management of complications such as seizures and increased intracranial pressure.

Regarding compassionate use, off-label, or experimental treatments:

1. **Compassionate Use**: In cases of severe Japanese encephalitis, some healthcare providers may request the use of experimental treatments under compassionate use protocols, but there are no widely recognized antiviral drugs specifically approved for this purpose.

2. **Off-Label Treatments**: Ribavirin, an antiviral medication, has been studied for off-label use but has not shown consistent efficacy. Similarly, intravenous immunoglobulins (IVIG) have been tried in some cases.

3. **Experimental Treatments**: Research is ongoing to explore potential antiviral therapies, including investigational drugs. Monoclonal antibodies and other antiviral agents are subjects of current clinical trials, but none have received approval for widespread use.

Continued efforts in vaccination and mosquito control are crucial for preventing Japanese encephalitis.
Lifestyle Recommendations: For Japanese encephalitis, lifestyle recommendations include:

1. **Vaccination**: Get vaccinated, especially if you are traveling to areas where Japanese encephalitis is common.

2. **Mosquito Protection**:
- Use insect repellent containing DEET, picaridin, or oil of lemon eucalyptus.
- Wear long-sleeved clothing and long pants to reduce skin exposure.
- Use bed nets treated with insecticide if staying in areas with high mosquito activity.

3. **Avoid Peak Mosquito Activity**: Try to stay indoors during dusk and dawn when mosquitoes are most active.

4. **Environmental Control**:
- Stay in accommodations with air conditioning, screens on windows and doors, or sleeping under a mosquito net.
- Eliminate standing water where mosquitoes can breed around your home or lodging.

5. **Travel Precautions**: Be aware of the risk of Japanese encephalitis in rural areas of Asia and avoid outdoor activities without protection during peak mosquito activity times.
Medication: Japanese encephalitis primarily relies on supportive care as there are no specific antiviral treatments for the virus. Preventative strategies include vaccination, mosquito control measures, and avoiding mosquito bites through the use of repellents and protective clothing.
Repurposable Drugs: Japanese Encephalitis (JE) is a viral disease spread by mosquitoes. As of now, there is no specific antiviral treatment for JE. Management primarily involves supportive care to relieve symptoms and stabilize the patient. However, some drugs have been investigated for potential repurposing to treat JE:

1. **Ribavirin**: An antiviral medication that has shown some efficacy in vitro but has limited clinical effectiveness.
2. **Interferons**: Proteins with antiviral properties; their effectiveness against JE is under investigation.
3. **Corticosteroids**: These have been explored to reduce brain inflammation but have not shown consistent benefits.

Research is ongoing, and vaccinations remain the most effective preventive measure against Japanese Encephalitis.
Metabolites: Japanese encephalitis (JE) primarily affects the central nervous system, and information about specific metabolites directly associated with the disease in a clinical context may not be widely documented. Research on metabolites related to JE might focus on inflammatory markers, immune response indicators, and neurological damage markers. There is no well-established single metabolite unique to JE that is used diagnostically or therapeutically at present. For detailed metabolic profiling, specialized studies and advanced diagnostic methods are required.
Nutraceuticals: Nutraceuticals are dietary supplements or food-based products with potential health benefits. There is no strong evidence to suggest that nutraceuticals have a significant impact on preventing or treating Japanese encephalitis. The most effective preventive measure for Japanese encephalitis is vaccination and avoiding mosquito bites.
Peptides: Peptides are being explored in the context of Japanese encephalitis for their potential roles in vaccine development and therapeutic interventions. Nanotechnology (nan) also offers promising advancements in diagnostics, drug delivery, and the development of more effective vaccines against Japanese encephalitis by improving the stability and delivery efficiency of antigens and therapeutic agents.