JAPANESE ENCEPHALITIS:EPIDEMIOLOGY AND PUBLIC HEALTH IMPORTANCE

ASHWIN PATIL

Framework of seminar
Definition History. JE virus morphology.

Mode of transmission.
Stages of clinical manifestation. Clinical spectrum of JE.

JE case classification.
Differential diagnosis. Investigations.

Prognosis.
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Continued.
Burden and Distribution of JE globally and in India. Major JE outbreaks In India. JE surveillance. Prevention and control strategy. Challenges and gaps in implementation. Case study and newspaper article. Current research. Acknowledgment. Key messages. References. Question/doubt/feedback/guidance
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Definition of JE

"A mosquito-borne encephalitis caused by the Japanese B encephalitis virus occurring throughout Eastern Asia and Australia. The majority of infections occur in children and are subclinical or have features limited to transient fever and gastrointestinal symptoms. Inflammation of the brain, spinal cord, and meninges may occur and lead to transient or permanent neurologic deficits (including a POLIOMYELITISlike presentation); SEIZURES; COMA; and death.

(From Adams et al., Principles of Neurology, 6th ed, p751; Lancet 1998 Apr 11;351(9109):1094-7)
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History
1871-Described clinically
1935- JEV isolated from a post-mortem Of human brain in Japan 1938- Mosquito transmission was proven. 1952 - First evidence of JE viral activity by VRC (NIV) during sero-surveys for arbo-viruses. 1955 - First clinically diagnosed human case of JE.at Vellore, North Arcot district of Tamil Nadu. 1958 - First viral isolation from JE case.

1973 - First outbreak- Bankura and Burdwan in West Bengal.

1976 - Repeat outbreak in Burdwan.
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Continued

1978
Widespread occurrence of suspected JE cases. National level monitoring initiated by NMEP in 1978.

Initiation of immunization using inactivated mouse brain vaccine

Molecular virological studies -all flaviviruses originated from a common ancestor 10-20 000 years ago. originated from its ancestral virus in the mid 1500s in the IndonesiaMalaysia region.
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International classification of diseases (ICD)

Encephalitis A83 Mosquito-borne viral encephalitis A83.5 California encephalitis California meningo - encephalitis La Crosse encephalitis

A83.0
A83.1 A83.2 A83.3 A83.4 7

Japanese encephalitis
Western equine encephalitis Eastern equine encephalitis St Louis encephalitis Australian encephalitis

A83.6
A83.8 A83.9

Rocio virus disease

Other mosquito-borne viral encephalitis Mosquito-borne viral encephalitis, unspecified

JE virus morphology
Group: Group IV (ssRNA) Family: Flaviviridae Genus: Flavivirus (Arbovirus) Species: Japanese encephalitis virus Closely related to Murray Valley virus, west nile and st. Louis encephalitis viruses,dengue virus.

It has three proteins

A) envelope protein B) core protein

C) & membrane protein

Small (50 nm) lipoprotein envelope surrounding a nucleocapsid comprising of core protein and 11 kb single stranded RNA (3800 kd) At least four genotypes- Asia.
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VECTORS
major vectors in India - Culex vishnui and Cx. pseudovishnui .

JEV - isolated from 16 species of mosquitoes,

majority of the isolations are from Cx. vishnui complex- breed in rice eco system. birds (egrets, pond herons, paddy birds) -close link with rice fields and water. cattle populations do not circulate the virus . Establishment of pig forms Building reservoirs and canals for agricultural purpose
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Species inhabitant to area.

Cx. tritaeniorhynchus -TN, KA, KL Cx. vishnui - TN, KA, WB Cx. Pseudovishnui - KA, GOA Cx. bitaeniorhynchus - KA, WB Cx. epidesmus - WB Cx. fuscocephala - TN, KA Cx. gelidus - TN, KA Cx. quinquefasciatus - KA Cx. whitmorei - TN,KA, AP, WB An. barbirostris - WB An. paeditaeniatus - KA An. Subpictus - TN, KA, KL Ma. annulifera - KL, ASSAM Ma. indiana - KL 10 Ma. uniformis - KA, KL

Culex mosquito laying eggs.

FEMALE CULEX QUINQUE FASCIATUS

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Culex mosquito biting human.

Dead end Host : Horses, oxen, cows, bulls, human

Ardeid birds:Herons and Egrets

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MODE OF TRANSMISSION

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Dynamics of JE transmission

Man to man transmission is not possible

Environment

Vector Mosquito

Ardeid bird/pig/ducklingmosquitopig/duckling/Ardeid bird

Victim-Accidental

incidental and dead-end host

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Host Carrier Host - Amplifying main animal reservoir Full Recovery

Recovery with residual complications

Death

CLINICAL MANIFESTATION

only 1 in 200 infections results symptomatic illness

Most infections asymptomatic.

Incubation period - 5-15 days. Extrinsic incubation period in vector mosquitoes - 9-12 days. ~ 25-30% - cases fatality ratio.( High as 60 %) 30%50% survivors :- neurologic, psychiatric,cognitive and physical complications majority of cases occur in people under the age of 15.

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Common symptoms of encephalitis

Sudden fever Lethargy

Headache

Change in consciousness

Irritability or restlessness Tremors or convulsions

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Vomiting and diarrhea

Three stages Of manifestations

1) Prodromal Stage 2) Acute encephalitic Stage 3) late stage

1) Prodromal Stage:-

Sudden onset of -

Fever
Rigors Headache

Nausea
Vomiting
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Last for 1 to 6 hours.

Acute Encephalitic Stage

Most commonly recognized clinical manifestation. Stiff Neck Muscular Rigidity Tremors in fingers, tongue, eyelids and eyes. Abnormal movements of limbs Speech impairment
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Aseptic meningitis or

undifferentiated febrile illness

Convulsions Altered sensorium,

unconsciousness, coma
Mask like face Parkinsonian syndrome with mask like facies, cogwheel rigidity, and choreoathetoid movements. Acute flaccid paralysis, Seizures common.

Last for 6-24 hours.

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Late Stage
Persistance of signs of CNS injury such as, Mental impairment.

Increased deep Tendon reflexes

Paresis either of the upper or lower motor neuron type. speech impairment

Epilepsy, Abnormal movements, Behaviour abnormalities

Vary from few weeks to several months.

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Differential Diagnosis
Cerebral Malaria Meningitis Febrile Convulsions Reys Syndrome Rabies

Toxic Encephalopathy.
Poliomyelitis.
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Clinical spectrum of JE infection

Severe

Die

Moderate Mild

Asymptomatic

For every symptomatic JE case, there are likely to be about 300 1000 people infected with JE virus but without any clinical manifestation But people of any age can be infected. Adult infection most often occurs in areas where the disease is newly introduced.

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Prognosis

Depends on cause and severity of illness and patients age. Mild cases recover in 2 to 4 weeks with supportive care. Severe encephalitis can lead to numerous complications.
Hearing and/or speech loss, blindness, permanent brain and nerve damage, behavioral changes, cognitive disabilities, lack of muscle control, seizures, memory loss.
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Laboratory investigation

Peripheral blood picture - leucocytosis ,neurophilia mild anemia. CSF analysis: lymphocytic pleocytosis is typical. CSF protein -elevated in 50% of cases. Hypo natremia, Serological tests: to detect antibodies to viral antigens, 1) Plaque reduction virus neutralization test, 2) Hem-agglutination inhibition,

3) Complement fixation:- significant rise in titer

Virus isolation from CSF by inoculating into 2-4 day old mice and the virus is identified by haem-agglutination inhibition.
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Burden of JE

Leading cause of viral encephalitis in Asia : 30000-50000 cases annually.

~ 3 billion people and 60% of the world's population live in endemic region 50,000 cases with 10,000 deaths notified annually - WHO India - rise in 1980s and has dropped and maintained till 1995

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DISTRIBUTION OF JE - GLOBALLY

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JE ENDEMIC AREAS IN INDIA

Andhra Pradesh Assam Bihar Haryana Kerala Karnataka Maharashtra Manipur

Nagaland
Tamil Nadu Uttar Pradesh
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Number of endemic districts: 135; Population: 330 million

West Bengal

Frequency of Japanese Encephalitis episodes in India (1996-2007)

No. of States with reported JE cases: 15

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10 Times 8-9 Times 5-7 Times 2-4 Times 1 Time

JE CASES & DEATHS IN INDIA (1980 2007)

8000

7000

6000

5000

4000

3000

2000

1000

JE ASSOCIATED HEALTH INDICATORS Morbidity (2001 2007) (No. of suspected cases): Annual cases (1695 to 6587) 29 Case Fatality Rate (2001 2007) : 22% 28% Proportion of sequelae : [30 -40%] out of survivors

19 80 19 81 19 82 19 83 19 84 19 85 19 86 19 87 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07

Cases

Deaths

CFR (in %)
10.0 20.0 30.0 40.0 50.0 60.0 0.0
41.3 30.0 35.9 33.9 41.7 36.8 35.0 38.3 35.0 37.3 44.3 37.6 36.5 40.3 51.5 31.7 26.4 25.1 23.9 19.8

19

30
21.4 23.2 26.4 27.5 21.7 25.2 23.6 24.6

19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 99 00 01 02 03 04 05 06 07 98 97 96 95 94 93 92 91 90 89 88 87 86 85 84 83 82 81

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CASE FATALITY RATE (CFR) OF JE (1980-2007)

YEAR

Contribution of AES/JE cases by the States - 2007

0.75% 0.75% 1.81% 2.98%

Uttar Pradesh Bihar

10.40%

Assam Haryana Karnataka

8.31%

Tamil Nadu Others

75%

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Age-wise Cases & Deaths during 2007

45 40 35.1 35
Percentage (%)

41.8 Cases Deaths

30 25 20 16.3 15 10 5.7 5 0 <1 15 610 Age 1115 >15 3 14 14.7 23.8 23.3 22.3

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Sexwise and Agewise CFR% 25

Percentage(%)

21.7

20 15 10.3 10 5.5 5 0 <1 15 610 Age 1115 >15 13.8 10.5 7.8 6.1 6.1 7.2 11 Male Female

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AREA OF HIGH OCCURRENCE IN INDIA

The three southern states of India- Tamil Nadu (TN), Andra Pradesh(AP), Karnataka (KA)- higher incidence.

JE is emerging as a public health problem - Kerala

known JE-endemic area -(Chidambaram, Virudhachalam, Thittakudi) -

villages of Cuddalore district of Tamil Nadu.

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RISK FACTORS FOR JE OUTBREAK IN AN AREA

Increase in susceptible population High density of Culex mosquitoes Presence of amplifying hosts such as pigs, water birds etc. Paddy cultivation

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JE OUTBREAK INDIA

Nagpur (1954-1955)

North Arcot , Madras (1955)

Agra,Uttar Pradesh - 1958 West Bengal 1973

TN, KA,WB,AP,Bihar,Assam,&U.P-1977-1979
Goa, Kerala, Haryana (samuel et.al.2000) . 1145 cases of Japanese encephalitis have been reported from 14 districts of Uttar Pradesh Province, India from 29 July to 30 August 2005. About onefourth of these (n=296) have died. 90 cases from the adjoining districts of Bihar have also been admitted to the hospitals in Uttar Pradesh.
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Doctors look at a child who is being treated for Japanese Encephalitis at a hospital in Lucknow, India, Thursday, Sept. 8, 2005. The death toll from an outbreak of Japanese Encephalitis in northern India has reached nearly 600, as another 53 people died overnight.

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A man rushing his child to a hospital in Ghorakpur, Uttar Pradesh.)

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Children romp in a rice field near Rakshwapar village in the northern Indian state of Uttar Pradesh, a bowl-shaped breeding ground for mosquitos that spread Japanese encephalitis. This year has been exceptionally rainy, leaving mosquito-friendly pools of water everywhere. At least 850 people, mostly children, have already died

from the incurable disease.

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Comparative Statement of JE positive cases between 2005,2006,2007- UP

Total Sampls tested Positive for JE Percentage

2005

3040

1091

35.88%

2006

1127

158

14.2%

2007
40

1855

243

13%

Japanese encephalitis in children in Bellary Karnataka. Kamala CS, Rao MV, George S, Prasanna NY.

One hundred and fifty cases of Japanese encephalitis (JE) in children below 12 years of age admitted to the Headquarters Hospital, Bellary Medical College during October, 1986 to January, 1987 were studied
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TAMILNADU
In the early 1980s cases- reported from

Tamilnadu in the following revenue districts

Tiruvannamalai, Dharmapuri, Namakkal, Trichirapalli, Dindigul, Theni, Madurai,Virdhunagar, Tirinelveli, and Tuticorin. However for the past 5 years sporadic cases are

reported from Villupuram, Cuddalore,and

Perambalur districts only.
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Incidence of JE - Tamil Nadu

YEAR CASES DEATH

1995 1996
1997 1998

115 111
89 25

57 53
42 14

1999 2000
2001 2002
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14 116
119 126

05 17
18 28

2003 2004

163 82

36 09

JE SURVEILLANCE
Epidemiological surveillance for Acute
Encephalitis Syndrome (AES)

Epidemiological surveillance for Acute Encephalitis Syndrome (AES). Entomological surveillance. Veterinary based surveillance. 44

Epidemiological surveillance for Acute Encephalitis Syndrome (AES)

1) Case definition of Acute Encephalitis Syndrome (AES): Clinically, a case of AES is defined as a person of any age, at any time of year with the acute onset of fever and a change in mental status (including symptoms such as confusion, disorientation, coma, or inability to talk ) AND/OR new onset of seizures (excluding simple febrile seizures ). Other early clinical findings may include an increase in irritability, somnolence or abnormal behavior greater than that seen with usual febrile illness. 2) SUSPECT: A case that is compatible with the clinical description. Acute onset of fever ( 7 days) change in mental status With/ without New onset of seizures (excluding

febrile seizures)
Other early clinical findings :-irritability, somnolence or abnormal behavior greater than that seen with usual febrile illness) 45

3) PROBABLE: A suspect case with presumptive laboratory results.

Suspected case in close geographic and temporal relationship to a laboratory-confirmed case of JE in an outbreak.
4) CONFIRMED: A suspected case that is laboratory confirmed with any one of the following markers:

Presence of Ig M antibody in serum and/ or CSF

Four fold difference in Ig M antibody titer in paired sera Virus isolation from brain tissue

Antigen detection by immunofluroscence

Nucleic acid detection by PCR
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5) AES (due to other agent): A suspected case in which diagnostic testing is performed and an etiological agent other than JE virus is identified. 6) AES (due to unknown agent) A suspected case in which no diagnostic testing is performed or in which testing was performed but no etiological agent was identified or in which the test results were indeterminate.

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JE and AES Surveillance

Sentinel Surveillance Sites with laboratory facilities
referral hospital with laboratory capacity to diagnose JE. medical colleges, regional/district hospitals and private hospitals with laboratories facilities.

Sentinel Surveillance Sites without laboratory facilities

Referral hospital without laboratory capacity to diagnose JE. District hospitals, CHCs, PHCs

Other Informer Units

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smaller health facilities or clinicians Pediatricians and GP.

INFORMATION FLOW DIAGRAM

AESF1/1A = AES Cases & JE cases reporting Form from the States SSSL = Sentinel Surveillance Sites with laboratory facilities SSS = Sentinel Surveillance Sites without laboratory facilities IU = Informer Unit AESF2/2A = AES Cases & JE cases reporting Form from the Districts AESF3 = Line listing Form AESF4 = Case Investigation Form AESF5 = Laboratory Report Form I
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Components of Laboratory based serological surveillance

Laboratory confirmation of JE cases

identified sentinel laboratories. IgM C a p t u r e EL I S A

Blood (serum) and Cerebrospinal fluid (CSF). Equipment for collection of serum/CSF.Collection procedure. Transportation of blood/serum /CSF specimens. rejection of CSF/ Serum samples

Specimen collection and transportation

Networking of JE testing Laboratories Identification and notification of Laboratories for sero surveillance

strengthening of laboratory for sero-diagnosis Regional Sentinel surveillance laboratories/WHO designated laboratories District Sentinel Surveillance Laboratories Laboratories are accredited by WHO. 100% proficiency score in test panels & yearly on-site review by trained WHO virologist To match virus strain of post-vaccinated children with vaccination strain.

Quality assurance

50 Sero-Surveillance in vaccinated Children

Entomological Surveillance
Larval surveys
Larval density & Mapping of breeding sites JEF- 6 form for breeding survey Indoor / Outdoor resting collection and the Dusk Collection by hand catch method using suction tubes. Per Man Hour Density (PMHD). JEF- 7. ELISA method to know the source of blood.

Adult surveys
Blood meal analysis
Susceptibility of JE vector mosquitoes & larvae Collection & transportation of mosquitoes for isolation of JE virus

Malathion. Format JEF-9 for reporting susceptibility/resistance status

collected in a screw-capped clean test tube and sent to the laboratory at NIV/CRME. NIV Pune, CRME Madurai, NICD Delhi.

51 Laboratory Support

Veterinary Based Surveillance

Natural Reservoirs of JE virus:Birds:- pond herons, pultry birds, cattle egrets,ducks, sparrows, migratory birds.

Cattle: Pigs.

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JE prevention and control

Clinical management: No specific antiviral treatment

Only supportive care.

Management of complication. No antibiotics work on viruses.

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Management of at Community Level

Community Level Danger Signs Fever with any one of the following: Lethargy/ Unconsciousness Convulsions

Pre Referral Care:Sponging with tap water if fever is present Patients position - head on side Nothing to be given orally Referral to nearest FRU 54

Integrated Vector Management (IVM) : A process for managing vector populations in such a way as to reduce or interrupt transmission of disease.
A rational decision-making process for the optimal use of resources for vector control

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Environmental Management
Environmental modification
Long lasting physical transformation of vector habitats. Environmental manipulation

Temporary changes to vector habitats . Management of ssentialand non-essential e containers Removal of aturalbreeding sites n
Changes in human habitations
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Reduce man-virus contact

Environmental modification

Changes in human habitations

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Environmental manipulation
Reduction of Breeding Source for Larvae
Water management system with intermittent irrigation system (alternate drying and wetting water management system in the rice fields.). Incorporation of Neem products in rice fields Introduction of composite fish culture for mosquito control in rice fields. Draining mosquito habitats.

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Personal Protection

Protective clothing and repellents. Household insecticide products:- mosquito coils, pyrethrum space spray and aerosols

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Biological Control
Larvivorous fish: Endotoxin-producing bacteria, Bacillus thuringiensis serotype H-14 (Bt H14)
GUPPY FISHES GAMBUSIA FISHES

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Chemical Control

Larvicide :-Temephos (1 mg per liter of water) Adulticide :1) Pyrethrum spray:- IRS Concentration :- 0.1% - 0.2% @ 30-60 ml/1000 cu. ft. Ready -to-spray. Formulation:- 1 lit.of 2% pyrethrum extract is diluted by kerosene into 20 lt.to make 0.1% pyrethrum formulation.
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Malathion fogging/Ultra Low Volume(ULV)spray:Most cost-effective than thermal fogging. 95% or pure technical malathion.

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Legislative measures
Model civic byelaws Model civic byelaws

Building Construction Regulation Act

Legislation

Health Impact Assessments

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Environmental Health Act (HIA)

Health education

continuous dialogue between health personnel and the community.

Behavior Change Communication (BCC) campaign.

Information Education Communication (IEC)

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 PIG CONTROL Segregation Slaughtering , Vaccination. Piggeries 4-5 kms away from human dwellings.

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JE VACCINE Three types of JE vaccine are produced and used worldwide.

1) INACTIVATED MOUSE BRAIN VACCINE expensive, complicated dosing schedule, side effect.effective,high cost, low availability. Inactivated (formaldehyde)Mouse brain vaccine. Dose:- 3

Route of administration :- subcutaneous.

Interval :- 7- 14 days Booster:- Every 3 year

3-5 US $ /dose
9 15 US $ /per child
66 prepared by killing populations of mice. Manufactured by Central Research Institute, Kasauli.

2) Inactivated hamster kidney cell vaccine3) LIVE ATTENUATED hamster kidney cell VACCINE SA 14 - 14-2 Chinese live attenuated vaccine

affordable cost, safe, effective.

developed in China and used there since 1988. licensed and used in South Korea and Nepal and licensed in Sri Lanka.

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Schedule for JE vaccine

Age group Doses (Subcutaneous) 0.5 ml 0.5 ml 0.5ml No. of doses

Below 1 year Primary dose 1-2 years

Vaccination should not be given 1 dose 2nd at interval of 4 wks 3rd at interval of 6th month

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Booster dose

If the child is above 2 years then, instead of 0.5 ml give 1 ml.

4th year 8th year 11th year 1ml 1ml 1ml 1st booster 2nd booster 3rd booster

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PREVENTIVE MEASURES FOR TRAVELERS

Ixiaro: licensed and available in the United States 0.5 ml IM on 0 and 28th days. For people aged 17 years.

full duration of protection after primary immunization is unknown.

Pediatric clinical trials are being conducted to get licence. Adverse reactions:-

Pain, tenderness, headache,myalgia,ILI,fatigue,hypersensitivity.

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The steps taken by Govt. of India towards prevention and Control of AES/JE
JE vaccination campaign was launched during 2006 . During 2009-2010 an amount of Rs.2.90 crores was allocated to the JE endemic states. Re-orientation training course on AES/JE case management . Diagnostic facilities strengthened at 50 sentinel and 13 Apex Referral Laboratories (15 sentinel sites in UP). The diagnostic kits are supplied free of cost from National Institute of Virology (NIV), Pune. Establishment of Physical, Medicine & Rehabilitation (PMR) department at BRD Medical College for treating physical disabilities due to AES/JE. One Vector Borne Disease Surveillance Unit (VBDSU) and one JE sub-office was established at BRD Medical College, Gorakhpur, Uttar Pradesh. One Vector Borne Disease Surveillance Unit (VBDSU) and one JE sub-office was established at BRDMC. establishing 50 bedded AES/JE treatment facilities at BRDMC an amount of Rs.5.88 crores 71 released under NRHM during 2009-10.

Challenges in prevention and control of JE

Scattered distribution of cases spread over relatively large areas Role of different reservoir hosts Specific vectors for different geographical and ecological areas

Immune status of various population groups is not known making it difficult to delineate vulnerable population groups.
Diverse eco-epidemiological situation Epidemic forecasting & preparedness

Quality control of diagnostic tools

Variation in vector bionomics Supervision & monitoring Inter-sectoral convergence Community participation JE immunization programme - supply problems, cost factor, coverage
72 Political commitment

Current research
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 [1]

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Acknowledgment

Dr. R. Kamath Dr. L. Macchado

Dr. S. Pattanshetty.
Dr. Rohini Madam (DSO, Udupi)

Staff of IDSP department (District Hospital)

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Key messages

VIRAL MOSQUITO born ZOONOTIC disease.

AES is a medical emergency. Any patient presenting with fever and impaired mental status or neurological exam should be evaluated for encephalitis. All suspected cases of encephalitis should be reported to local authorities. No specific treatment to JE. Killed JE vaccine is not recommended for control of outbreak.

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References:
http://www.diseasesdatabase.com/umlsdef.asp?glngUserChoice=7036 Japanese Encephalitis. Dengue, Japanese encephalitis and other arbovirus infection, M.E.Yeolekar.7th Edition, revised reprint: API textbook of medicine. Accessed on 23th September 2011. www.who.int/immunization monitoring/Manual lab_diagnosisJE.pdf. http://apps.who.int/classifications/apps/icd/icd10online/?ga80.htm+a830. http://nvbdcp.gov.in/sitemap.html. http://www.cdc.gov/ncidod/dvbid/jencephalitis/index.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5901a1.htm
[1]

http://www.cdc.gov/ncidod/dvbid/jencephalitis/facts.htm

http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-totravel/japanese-encephalitis.htm.

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PUBLIC HEALTH IS TEAM WORK

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