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Arboviruses

Arthropod-Borne Viruses
Dr.T.V.Rao MD

Part 1

Dr.T.V.Rao MD

What Is An Arbovirus?
Arbovirus = arthropod-borne viruses Arboviruses are maintained in nature through biological transmission between susceptible vertebrate hosts by blood-feeding arthropods Vertebrate infection occurs when the infected arthropod takes a blood meal
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Arboviral Infections.
100s of Arbovirus, Around 100 are Human pathogens, Prevalent in Temperate and Tropical areas. Most common in tropics, Out of Many 10 are very important.
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Arthropod-borne Viruses
Arthropod-borne viruses (arbovirus) are viruses that can be transmitted to man by arthropod vectors.

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The WHO definition is as follows


Viruses maintained in nature principally, or to an important extent, through biological transmission between susceptible vertebrate hosts by haematophagus arthropods or through trans ovarian and possibly venereal transmission in arthropods.
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Arbovirus belong to
Arbovirus belong to three families 1. Toga viruses e.g. EEE, WEE, and VEE 2. Bunya viruses e.g. Sandfly Fever, Rift Valley Fever, Crimean-Congo Haemorrhagic Fever 3. Flavivirus e.g. Yellow Fever, dengue, Japanese Encephalitis
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Disease Mechanisms of Toga viruses and Flavivirus


Viruses are cytolytic, except for rubella. Viruses establish systemic infection and viremia. Viruses are good inducers of interferon, which can account for the flulike symptoms of infection. Viruses, except rubella and hepatitis C, are arboviruses. Flavivirus can infect cells of the monocyte-macrophage lineage. Nonneutralizing antibody can enhance Flavivirus infection via Fc receptors on the macrophage.
Flulike Syndrome Encephalitis Hepatitis Hemorrhage Shock

Dengue Yellow fever St. Louis encephalitis West Nile encephalitis Venezuelan encephalitis Western equine encephalitis Eastern equine encephalitis Japanese encephalitis

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Man-Arthropod-Man Cycle

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Animal-Arthropod-Man Cycle

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INDIAN SCENARIO

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Arboviral are Basically Zoonotic


All arboviral encephalitis's are zoonotic, being maintained in complex life cycles involving a nonhuman primary vertebrate host and a primary arthropod vector. These cycles usually remain undetected until humans encroach on a natural focus, or the virus escapes this focus via a secondary vector or vertebrate host as the result of some ecologic change
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Arthropod Vectors
Mosquitoes
Japanese encephalitis, dengue, yellow fever, St. Louis encephalitis, EEE, WEE, VEE etc.

Ticks
Crimean-Congo hemorrhagic fever, various tickborne encephalitis's etc.

Sandflies
Sicilian sandfly fever, Rift valley fever.
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Examples of Arthropod Vectors

Aedes Aegyti

Assorted Ticks

Culex Mosquito

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Phlebotmine Sandfly

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Animal Reservoirs
In many cases, the actual reservoir is not known. The following animals are implicated as reservoirs

Birds
encephalitis, Pigs Monkeys Rodents encephalitis

Japanese

encephalitis,

St

Louis

EEE, WEE Japanese encephalitis Yellow Fever VEE, Russian Spring-Summer


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Major Arboviral Diseases


1.Yellow fever

2.Dengue,
3.Japanese B Encephalitis,
4.St Louis Encephalitis, 5.Russian spring summer encephalitis. 6.Eastren Equine Encephalitis, 7.West Nile Fever, 8.Sand fly Fever
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Major Arboviruses That Cause Encephalitis


Flaviviridae
Japanese encephalitis St. Louis encephalitis West Nile

Togaviridae
Eastern equine encephalitis Western equine encephalitis

Bunyaviridae
La Crosse encephalitis
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17 http://www.cdc.gov/ncidod/dvbid/arbor/schemat.pdf

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St. Louis Encephalitis

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St. Louis Encephalitis


Flavivirus Most common mosquitotransmitted human pathogen in the US Leading cause of epidemic flaviviral encephalitis

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Eastern Equine Encephalitis


Toga virus Caused by a virus transmitted to humans and horses by the bite of an infected mosquito. 200 confirmed cases in the US 1964-present Average of 4 cases per year States with largest number of cases Florida, Georgia, Massachusetts, and New Jersey. Human cases occur relatively infrequently, largely because the primary transmission cycle takes place in swamp areas where populations tend to be limited.
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Western Equine Encephalitis


Toga virus Mosquito-borne 639 confirmed cases in the US since 1964 Important cause of encephalitis in horses and humans in North America, mainly in the Western parts of the US and Canada
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La Crosse Encephalitis
Bunyaviruses On average 75 cases per year reported to the CDC Most cases occur in children under 16 years old Zoonotic pathogen that cycles between the daytime biting tree hole mosquito, and vertebrate amplifier hosts (chipmunk, tree squirrel) in deciduous forest habitats Most cases occur in the upper Midwestern state, but recently cases have been reported in the MidAtlantic region and the Southeast 1963 isolated in La Crosse, WI from the brain of a child who died from encephalitis

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Togaviridae

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Togaviridae
The name Togaviridae derived from Toga meaning roman mantle or clack refers to the viral surface
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TOGAVIRIDAE Chikungunya virus Infection

1952 Epidemic in Tanzania. Manifest as Bend Up with Severe Joint pains. Spread from wild primates Mosquito-Man Appears , reappears,
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Indian outbreaks
The virus first appeared in India in 1958 the virus caused large epidemics in Thailand In 1963 India Chikungunya outbreaks occurred at irregular intervals along the east coast of India and in Maharashtra
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Viral Morphology
Spherical 50 - 70 nm Bears the Nucleocapsid, 42 capsomeres Positive sense ss stranded RNA
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Prevalence of Chikungunya

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Transmission of Infection

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Man to Man infection with Mosquito bites


Chikungunya virus requires an agent for transmission and hence direct human to human transmission is not possible. Usually transmission occurs when a mosquito bites an infected person and then later bites a non infected person.
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Clinical Manifestations Crippling Joint pains Conjunctivitis


Lymphadenopathy

Hemorrhagic tendencies.
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Diagnosis
Isolation of viruses, Serology Ig M Nt and HI tests,
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Control and Prevention.


Mosquito control No vaccines, Other diseases like Chikungunya 1 Onyong Nyong Viruses 2 Simliki Forest Viruses
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Japanese B Encephalitis

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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

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Flaviviridae Genus Flavivirus,


Important Diseases,

1. St Louis encephalitis, 2.Ilheus virus 3.West Nile Virus, 4.Murray valley encephalitis, 5.Japanese B encephalitis,
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Japanese Encephalitis
First discovered and originally restricted to Japan. Now large scale epidemics occur in China, India and other parts of Asia. Flavivirus, mosquitoes. transmitted by culex

The virus is maintained in nature in a transmission cycle involving mosquitoes, birds and pigs.
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Japanese Encephalitis
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.
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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


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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.

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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.
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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 nonstructural proteins also (NS1,NS2a,NS2b,NS3,N4a,N S4b,NS5). NS1 is produced as secretary form also. NS3 is a putative helicase, and NS5 is the viral polymerase.
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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
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INDIAN SCENARIO
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
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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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A leading cause of viral Encephalitis


Japanese encephalitis is the leading cause of viral encephalitis in Asia, with 30,00050,000 cases reported annually. Casefatality rates range from 0.3% to 60% and depends on the

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Animal-Arthropod-Man Cycle

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Cycle of Infection in Japanese B Viral Infection

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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
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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
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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 If unrecognized, mortality is up 1 to 30% with half of survivors sustain severe neurological sequelae. to 15 years of age. Incubation period is 5 to 14 days.
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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
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Many poor people are Infected

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Cycle of Spread of Japanese Encephalitis

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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.

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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.
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Common symptoms of encephalitis


Sudden fever Headache Lethargy Change in consciousness

Irritability or restlessness
Tremors or convulsions Vomiting and diarrhea

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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.
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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
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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.

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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
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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.
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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 weeks interval followed by a booster 6 12 months later constitute a full course. However the immunity was short lived
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Emerging Vaccines for JE virus


Two vaccines are manufactured and distributed exclusively in Peoples 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 1960s Three subcutaneous injections over a month with a booster at 3 years 91% efficacy in a large field trial in Thailand Dr.T.V.Rao MD 67

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
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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
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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
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Yellow Fever, Flaviviridae - Family

Mosquito Borne disease Present in Africa, Central and South America. Absent in India.
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Flavivirus
Spherical 40-60 nm in diameter glycosylated. Diameter, Ss-RNA positive sense Three or Four structural polypeptides, Two are glycosylated. Replicates in Cytoplasm. Produces Councilman bodies
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Pathogenesis and Pathology


Mosquito ( Ades aegypti )Through skinLymphatic's, Lymph nodes, circulation liver, Spleen, Kidney, Bone marrow, Lymph glands. Necrotic lesions in liver , kidney, Mid zone liver Fatty degeneration kidney, Hemorrhages/Circulatory collapse. Injury to Myocardium
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Clinical Features
Incubation period 3-6 days, Fever, chills, Intoxication, Fever, Jaundice Clotting disorders, Mortality > 20% May recover totally
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Laboratory Diagnosis
Intracerebral inoculation, Mosquito cell lines, PCR Serology ELISA Ig M Raise of titers,
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Immunity and Epidemiology


Nt Antibodies protects, Epidemiology Urban yellow fever, Jungle yellow fever. Monkey, Not Invaded Asia Not present in India.
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Treatment and Prevention.


No Antiviral drugs, Mosquito control Vaccine 17 D strain of yellow fever vaccine. A single dose protect 95% of vaccinated. Not to be given in infants < 9 months age.
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