JAPANESE B Encephalitis

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JAPANESE B Encephalitis

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JAPANESE B ENCEPHALITIS:

JAPANESE B ENCEPHALITIS Dr.T.V.Rao MD Dr.T.V.Rao MD 1

Japanese Encephalitis belongs to Genus Flavivirus:

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

Genus - Flavivirus:

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 3

A Flavivirus:

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 Dr.T.V.Rao MD 4 A Flavivirus

Structure of Virus:

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. Dr.T.V.Rao MD 5 Structure of Virus

History:

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

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

What causes encephalitis?:

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

Japanese Encephalitis:

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

Japanese B virus Infection:

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. Dr.T.V.Rao MD 10 Japanese B virus Infection

A leading cause of viral Encephalitis:

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. Dr.T.V.Rao MD 11 A leading cause of viral E ncephalitis

Animal-Arthropod-Man Cycle:

Animal-Arthropod-Man Cycle

Cycle of Infection in Japanese B Viral Infection:

Dr.T.V.Rao MD 13 Cycle of Infection in Japanese B Viral Infection

Transmission:

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

A Vector born- Arbovirus Infection:

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 Nad u Dr.T.V.Rao MD 15

Japanese Encephalitis (JE):

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.

INCIDENCE :

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 Dr.T.V.Rao MD 17 INCIDENCE

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Dr.T.V.Rao MD 18

Cycle of Events in Japanese B Encephalitis:

Dr.T.V.Rao MD 19 Cycle of Events in Japanese B E ncephalitis

Pass through two prominent Hosts:

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. Dr.T.V.Rao MD 20

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Subcutaneous injection Regional lymph nodes Extraneural Tissues Connective tissue Striated muscle Pancreas Adrenal Smooth muscle Efferent lymphatics Thoracic duct Plasma Viremia Reticuloendothelial cell clearance Humoral antibody Olfactory epithelium Vascular endothelium Neural Parenchyma Neurons, Glia (?) CNS antibody lymphocytes, macrophage Cellular dysfunction Cellular lysis Inflammation ? ? Pathogenesis of Flavivirus Infections Fields Virology, Vol 1, Fourth Edition. Lippincott-Williams & Wilkins (Philadelphia), pp 1057, 2001

Clinical Manifestations:

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. Dr.T.V.Rao MD 22 Clinical Manifestations

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Lethargy Sudden fever Vomiting and diarrhea Tremors or convulsions Headache Change in consciousness Irritability or restlessness Common symptoms of encephalitis

Can lead to Neurological damage:

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. Dr.T.V.Rao MD 24 Can lead to Neurological damage

Diagnosis of Japanese B Encephalitis:

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 Dr.T.V.Rao MD 25 Diagnosis of Japanese B Encephalitis

Serology by ELISA:

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. Dr.T.V.Rao MD 26 Serology by ELISA

Arbovirus Specific RNA detection:

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 Dr.T.V.Rao MD 27 Arbovirus Specific RNA detection

False Positive Tests:

There is some cross-reactivity with other flavivirus and from Japanese encephalitis and yellow fever vaccinations. Dr.T.V.Rao MD 28 False Positive Tests

Japanese Encephalitis B Vaccine:

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 . Dr.T.V.Rao MD 29 Japanese Encephalitis B Vaccine

Preventive measures:

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 Dr.T.V.Rao MD 30 Preventive measures

Emerging Vaccines for JE virus:

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-VAX R 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

Vaccination:

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

Later vaccines:

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 Dr.T.V.Rao MD 33 Later vaccines

Safety of Current JE Vaccine:

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

Prevention:

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

RESEARCH PRIORITIES :

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 Dr.T.V.Rao MD 36 RESEARCH PRIORITIES

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Created by Dr.T.V.Rao MD for Medical and Paramedical Professionals in Developing World Email doctortvrao@gmail.com Dr.T.V.Rao MD 38