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JAPANESE BENCEPHALITIS

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Flaviviridae◦ Flavivirus

The name is derived from the Latin ‘flavus’ ◦ Flavus means “yellow”

Refers to yellow fever virus

Enveloped Single stranded RNA

virus Morphology not well

defined Center for Food Security and Public

Health Iowa State University - 2007

Japanese Encephalitis belongs to Genus Flavivirus

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Genus - Flavivirus Japanese B

encephalitis virus is Spherical, 40 – 60 nm

in diameter Contain a positive

sense Single stranded RNA, 11 kb in size

RNA genome is infectious

Several viruses in this group are related.

Dr.T.V.Rao MD 4

Japanese encephalitis ( previously known as Japanese B encephalitis is a disease caused by the mosquito-borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds are reservoirs of the virus; transmission to humans may occur

A Flavivirus

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The outer envelope is formed by envelope (E) protein and is the protective antigen. It aids in entry of the virus to the inside of the cell. The genome also encodes several non-structural proteins also (NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5). NS1 is produced as secretary form also. NS3 is a putative helicase, and NS5 is the viral polymerase.

Structure of Virus

1870s: Japan◦“Summer encephalitis” epidemics

1924: Great epidemic in Japan◦6,125 human cases; 3,797 deaths

1935: First isolated◦From a fatal human encephalitis case

1938: Isolated from Culex tritaeniorhynchus

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History

1940-1978◦Disease spread with epidemics in China, Korea, and India

1983: Immunization in South Korea◦Started as early as age 3◦Endemic areas started earlier

1983-1987: Vaccine available in U.S. on investigational basis

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History

Viruses (most common)◦ More than 100 different viruses

can cause acute encephalitis◦ Seasonal and geographic

distribution can help narrow differential diagnosis

◦ Examples of common viruses: Arbovirus Enter viruses Mumps, Varicella Herpes simplex virus Influenza Rabies

What causes encephalitis?

*Note: A large number of reported cases of encephalitis are due to an unspecified cause

First discovered and originally restricted to Japan. Now large scale epidemics occur in China, India and other parts of Asia.

Flavivirus, transmitted by culex mosquitoes. The virus is maintained in nature in a transmission cycle involving

mosquitoes, birds and pigs. Most human infections are subclinical: the in apparent to clinical cases is

 300:1 In clinical cases, a life-threatening encephalitis occurs. The disease is usually diagnosed by serology. No specific therapy is

available. Since Culex has a flight range of 20km, all local control measures will fail.

An effective vaccine is available.

Japanese Encephalitis

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Infection is caused by a flavivirus, a single stranded RNA virus. It is transmitted by the bite of the Culex tritaeniorhynchus mosquito. The virus multiplies at the site of the bite and in regional lymph nodes before viraemia develops. Viraemia can lead to inflammatory changes in the heart, lungs, liver, and reticuloendothelial system.

Japanese B virus Infection

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Japanese encephalitis is the leading cause of viral encephalitis in Asia, with 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on age.

A leading cause of viral Encephalitis

Animal-Arthropod-Man Cycle

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Cycle of Infection in Japanese B Viral Infection

Vector-borne disease Enzootic cycle

◦Mosquitoes: Culex species Culex tritaeniorhynchus

◦Reservoir/Amplifying hosts Pigs, bats Ardeid (wading) birds Possibly reptiles and amphibians

◦Incidental hosts Horses, humans, others

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Transmission

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A Vector born- Arbovirus Infection

Culex tritaeniorhynchus a rural Mosquito that breeds in rice fields, is the principle vector.

In India in 1955 the virus were isolated from Culex vishnui mosquitoes in Vellore region in Tamil Nadu

Most important global cause of arboviral encephalitis with > 50,000 cases and 15,000 deaths reported each year.

Only about 1 in 250 JE infections result in symptomatic illness.

Primarily affects children 1 to 15 years of age.

Incubation period is 5 to 14 days.

Japanese Encephalitis (JE)

• If unrecognized, mortality is up to 30% with half of survivors sustain severe neurological sequelae.

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Leading cause of viral encephalitis in Asia with 30-50,000 cases reported annually

Fewer than 1 case/year in U.S. civilians and military personnel travelling to and living in Asia

Rare outbreaks in U.S. territories in Western Pacific

INCIDENCE

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Cycle of Events in Japanese B Encephalitis

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Pass through two prominent Hosts Herons act as

reservoir hosts and pigs as amplifier hosts.

Human infection is a tangential ‘dead end’ and infections are spread when the infected mosquitoes reach high density.

Subcutaneous injection

Regional lymph nodes

Extraneural Tissues Connective tissue Striated muscle Pancreas Adrenal Smooth muscle

Efferent lymphaticsThoracic duct

Plasma ViremiaReticuloendothelialcell clearance

Humoral antibody

Olfactory epitheliumVascular endothelium

Neural Parenchyma

Neurons, Glia(?)

CNS antibody

lymphocytes, macrophage

Cellular dysfunction Cellular lysisInflammation

?

?

Pathogenesis of Flavivirus Infections

Fields Virology, Vol 1, Fourth Edition. Lippincott-Williams & Wilkins (Philadelphia), pp 1057, 2001

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The incubation period is 6 to 16 days. There is a prodrome of fever, headache,

nausea, diarrhoea, vomiting, and myalgia, which may last for several days.

This may be followed by a spectrum of neurological disease ranging from mild confusion, to agitation, to overt coma.

Two thirds of patients have seizures. It is more common in children, while headache and meningism are more common in adults.

Clinical Manifestations

LethargySudden fever

Vomiting and diarrhea

Tremors or convulsions

Headache Change in consciousness

Irritability or restlessness

Common symptoms of encephalitis

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Tremor or other involuntary movements are common.

Mutism has been described as a presenting symptom. So has a syndrome of acute flaccid paralysis.

Fever resolves by the second week, and choreoathetosis or extra pyramidal symptoms develop as the other neurological symptoms disappear.

Can lead to Neurological damage

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The isolation of virus from Blood, CSF, or tissues.

Detection of Arbovirus specific RNA in blood,CSF, or Tissue

However very few reference laboratories can perform the isolation in view of the biosafety considerations

Diagnosis of Japanese B Encephalitis

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IgM capture enzyme-linked immunoassay (ELISA) of serum or CSF is the standard diagnostic test. Sensitivity is nearly 100% when both serum and CSF are tested. False-negatives may result if the samples are tested too early, as in the first week of illness.

New IgM dot enzyme immunoassays for CSF and serum are portable and simple tests that can be used in the field. Compared with ELISA as the gold standard, the sensitivity and specificity are around 98 and 99% respectively.

Serology by ELISA

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Viral RNA is extracted from serum or from suspected tissues of the patients or mosquito homogenates.

The product is amplified by RTPCR and the products analyzed by restriction digestion and determined by nucleotide sequence of PCR product.

The identified sequence is compared with nucleotide sequence found in Gene bank or other data bases

Arbovirus Specific RNA detection

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There is some cross-reactivity with other flavivirus and from Japanese encephalitis and yellow fever vaccinations.

False Positive Tests

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Japanese Encephalitis B Vaccine has been produced since 1992. The vaccine is effective but not without risks and the substantial risks of the disease and the risks of the vaccine have to be balanced, especially for stays of brief duration. These are discussed more fully in the article on that subject.As with malaria, prophylaxis must be supplemented by techniques to avoid being bitten by mosquitoes.

Japanese Encephalitis B Vaccine

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Preventive measures include mosquito control and locating piggeries away from human dwellings

A formalin inactivated mouse brain vaccine using the Nakayama strain has been employed in human immunization in Japan – Two doses at two week’s interval followed by a booster 6 – 12 months later constitute a full course.

However the immunity was short lived

Preventive measures

Two vaccines are manufactured and distributed exclusively in People’s Republic of China◦ Inactivated vaccine grown in primary hamster

kidney cells◦ Live attenuated vaccine (SA14-14-2) grown in

hamster kidney cells The third is manufactured in Japan and

distributed abroad by arrangement with Sanofi-Pasteur◦ Licensed as JE-VAXR and is the only FDA

approved vaccine for use in the U.S.◦ Has been in wide use worldwide since the

1960’s◦ Three subcutaneous injections over a month

with a booster at 3 years◦ 91% efficacy in a large field trial in Thailand

Emerging Vaccines for JE virus

Live attenuated vaccine◦Used in equine and swine◦Successful for reducing incidence

Inactivated vaccine (JE-VAX) Used for humans Japan, Korea, Taiwan, India, Thailand Used for endemic or epidemic areas

◦Recommended for travelers Visiting endemic areas for > 30 days

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Vaccination

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A live attenuated vaccine has been developed in China from JE strain SA 14-14-2, passed through weanling mice

The vaccine is produced in primary bay hamster kidney cells.

Administered in two doses, one year apart, the vaccine has been reportedly effective in preventing clinical disease

Later vaccines

Side effects “Generally inconsequential.” Local tenderness or mild systemic symptoms in 10-30% - Field’s virology

No neurologic events in Japanese surveillance Infrequent allergic reactions in adult travelers

◦ Urticaria, angioedema, bronchospasm, erythema nodosum and e. multiforme

Incidence varies in different reports: 2/1000 to 1%

14,000 US Marines, 11 pruritus, 26 urticaria◦ History of urticaria after hymenoptera envenomation

or other provocations caused a relative risk increase of 9.1

◦ None of the reactions were severe or life threatening Case control study in Australia identified

increased reaction risk if excessive alcohol consumption in 48 hours after vaccination (p= 0.005)

Safety of Current JE Vaccine

Vector control◦Eliminate mosquito breeding areas◦Adult and larvae control

Vaccination◦Equine and swine◦Humans

Personal protective measures◦Avoid prime mosquito hours◦Use of repellants containing DEET

Center for Food Security and Public Health Iowa State University - 2007

Prevention

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Facilitate implementation of attenuated vaccine in unvaccinated populations in endemic areas

Develop improved vaccines Identify risk factors for progression to symptomatic encephalitis and viral persistence

Describe clinical features of JE in AIDS and determine its potential as an opportunistic infection

RESEARCH PRIORITIES

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