Arthropod-borne Viral Infections

Dr.T.V.Rao MD

21-01-2018 Dr.T.V.Rao MD 1

• VECTOR BORNE VIRAL INFECTIONS - Vector-borne diseases are infections transmitted by the bite of infected arthropod species, such as mosquitoes, ticks, triatomine bugs, sandflies, and blackflies (. Arthropod vectors are cold-blooded (ectothermic) and thus especially sensitive to climatic factors. Weather influences survival and reproduction rates of vectors in turn influencing habitat suitability, distribution and abundance; intensity and temporal pattern of vector activity (particularly biting rates) throughout the year; and rates of development, survival and reproduction of pathogens within vectors. However, climate is only one of many factors influencing vector distribution, such as habitat destruction, land use, population migration to Urban areas, pesticide application, and host density. Vector-borne diseases are widespread in Europe. Majority of Asian countries and African continent continue to suffer the most and are the best studied diseases associated with climate change, which is presented in this program file Many vector borne diseases are associated with Viral infections, Many physicians miss the maters in the early stages as the manifestation looks alike Bacterial infection treat with new generation of antibiotics Hope a basic understanding on the diseases which prevail in many regions of the world, a great priority

• Dr.T.V.Rao MD

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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 Hemorrhagic 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.

Flaviviruses can infect cells of the monocyte-macrophage lineage. Non-

neutralizing 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 + +21-01-2018 Dr.T.V.Rao MD 8

Man-Arthropod-Man Cycle

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Animal-Arthropod-Man Cycle

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INDIAN SCENARIO

Dr.T.V.Rao MD 1121-01-2018

Arthropod Vectors

Mosquitoes

Japanese encephalitis, dengue, yellow fever, St.

Louis encephalitis, EEE, WEE, VEE etc.

Ticks

Crimean-Congo hemorrhagic fever, various tick-

borne encephalitis's etc.

Sandflies

Sicilian sandfly fever, Rift valley fever.

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Examples of Arthropod Vectors

Aedes AegytiAssorted Ticks

Phlebotmine SandflyCulex Mosquito21-01-2018 Dr.T.V.Rao MD 13

Animal Reservoirs

In many cases, the actual reservoir is not known. The

following animals are implicated as reservoirs

Birds Japanese encephalitis, St Louis

encephalitis,

EEE, WEE

Pigs Japanese encephalitis

Monkeys Yellow Fever

Rodents VEE, Russian Spring-Summer

encephalitis

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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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http://www.cdc.gov/ncidod/dvbid/arbor/schemat.pdf

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http://www.cdc.gov/ncidod/dvbid/arbor/worldist.pdf

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St. Louis Encephalitis

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St. Louis Encephalitis

• Flavivirus

• Most common mosquito-transmitted human pathogen in the US

• Leading cause of epidemic flaviviralencephalitis

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Eastern Equine Encephalitis

• Togavirus• 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

• Togavirus

• 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• Bunyavirus• 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 treehole 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 Mid-Atlantic 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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TOGAVIRIDAEChikungunya 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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FlaviviridaeGenus – 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, 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.

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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 tritaeniorhynchusmosquito. 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 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.

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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 virusfrom 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 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on

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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 1 to 15 years of age.

• Incubation period is 5 to 14 days.

• If unrecognized, mortality is up to 30% with half of

survivors sustain severe neurological sequelae.

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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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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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LethargySudden fever

Vomiting and

diarrhea

Tremors or

convulsions

Headache Change in

consciousness

Irritability or

restlessness

Common symptoms of encephalitis

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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 week’s interval followed by a booster 6 – 12 months later constitute a full course.

• However the immunity was short livedDr.T.V.Rao MD 6321-01-2018

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-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 Thailand21-01-2018 Dr.T.V.Rao MD 64

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 daysDr.T.V.Rao MD 21-01-2018 65

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 skin-

Lymphatic'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,

• P C R

• 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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Viral Hemorrhagic Fevers

CDC, AFIP

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Viral Hemorrhagic Fevers

• Diverse group of illnesses caused by RNA viruses from 4 families:– Arenaviridae, Bunyaviridae, Filoviridae, Flaviridae

– Differ by geographic occurrence and vector/reservoir

– Share certain clinical and pathogenic features

• Potential for aerosol dissemination, with human infection via respiratory route (except dengue)

• Target organ: vascular bed

• Mortality 0.5 - 90%, depending on agent

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Viral Hemorrhagic Fevers

• Category A agents – Filoviruses

– Arenaviruses

• Category C agents – Hantaviruses

– Tick-borne hemorrhagic fever viruses

– Yellow fever

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Tick Borne Encephalitis

• Russian spring summer encephalitis,

• Contact with sheep

• Produces mild aseptic meningitis,

• Bite of Ixodid Ticks,

• Avoid Tick bites,21-01-2018 Dr.T.V.Rao MD 80

Viral Hemorrhagic Fevers Transmission

• Zoonotic diseases– Rodents and arthropods main reservoir

– Humans infected via bite of infected arthropod, inhalation of rodent excreta, or contact with infected animal carcasses

• Person-to-person transmission possible with several agents– Primarily via blood or bodily fluid exposure

– Rare instances of airborne transmission with arenaviruses and filoviruses

• Rift Valley fever has potential to infect domestic animals following a biological attack

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Viral Hemorrhagic FeversClinical Presentation

• Clinical manifestations nonspecific, vary by agent

• Incubation period 2-21 days, depending on agent

• Onset typically abrupt with filoviruses, flaviviruses, and Rift Valley fever

• Onset more insidious with arenaviruses

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Viral Hemorrhagic FeversInitial Symptoms

– High fever

– Headache

– Malaise

– Weakness

– Exhaustion

– Dizziness

– Muscle aches

– Joint pain

– Nausea

– Non-bloody diarrhea

Prodromal illness lasting < 1 week may include:

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VHF Surveillance: Clinical Identification of Suspected Cases

• Clinical criteria: – Temperature 101 F(38.3 C) for <3 weeks

– Severe illness and no predisposing factors for hemorrhagic manifestations

– 2 or more of the following:• Hemorrhagic or purple rash

• Epistaxis

• Hematemesis

• Hemoptysis

• Blood in stools

• Other hemorrhagic symptoms

• No established alternative diagnosis

JAMA 2002;287Adapted from WHO

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Viral Hemorrhagic FeversTreatment

• Supportive care

• Correct coagulopathies as needed

• No antiplatelet drugs or IM injections

• Investigational treatments, available under protocol:

– Ribavirin x 10 days for arenaviridae and bunyaviridae

– Convalescent plasma w/in 8d of onset for AHF

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Viral Hemorrhagic Fevers Management of Exposed Persons

• Medical surveillance for all potentially exposed persons, close contacts, and high-risk contacts (i.e., mucous membrane or percutaneous exposure) x 21 days – Report hemorrhagic symptoms (slide 47)

– Record fever 2x/day

• Report temperatures 101F(38.3C) Initiate presumptive ribavirin therapy

• Percutaneous/mucocutaneous exposure to blood or body fluids of infected: – Wash thoroughly with soap and water, irrigate mucous membranes with

water or saline

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Viral Hemorrhagic FeversInfection Control

• Airborne & contact precautions for health care, environmental, and laboratory workers

• Negative pressure room, if available

– 6-12 air changes/hour

– Exhausted outdoors or through HEPA filter

• Personal protective equipment

– Double gloves

– Impermeable gowns, leg and shoe coverings

– Face shields and eye protection

– N-95 mask or PAPR21-01-2018 Dr.T.V.Rao MD 87

Tick Borne Hemorrhagic Fevers

• Kyasanur Forest Disease,

• ( Karnataka India )

• Like Russian Spring Summer Encephalitis,

• Present with

Fever, Headache, Conjunctivitis,

Myalgia, Severe prostration,

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Viral Hemorrhagic FeversInfection Control

• Dedicated medical equipment for patients

• If available, point-of-care analyzers for routine laboratory analyses – If unavailable, pretreat serum w/Triton X-100

– Lab samples double-bagged & hand-carried to lab

• Prompt burial or cremation of deceased with minimal handling – Autopsies performed only by trained personnel with

PPE

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Viral Hemorrhagic FeversSummary of Key Points

• A thorough travel and exposure history is key to distinguishing naturally occurring from intentional viral hemorrhagic fever cases.

• Viral hemorrhagic fevers can be transmitted via exposure to blood and bodily fluids.

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Pathogenesis.

• Enters through the bite of Insect vector,

• Multiply in RES.

• Target the organ

CNS Encephalitis,

Liver Yellow fever,

Capillary endothelium in

Hemorrhagic fevers.

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Kyasanur Forest Fever ( cont )

• Also called as Monkey fever,

• Associated with felling of virgin forests,

• Tick Bite – Vector – Haemaphysalis spinigera spread the disease

• Vaccine on trail

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Rodent Borne Hemorrhagic Fevers,

•Hanta Virus, Produces pulmonary infections in USA

•Belong to Bunya Virus –Hanta Viruses

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Hanta Viruses,

• Human disease Hemorrhagic fever with renal syndrome

• Hanta virus pulmonary syndrome.

• Spread by inhalation of Aerosols of Rodent Excreta,

• Renal Involvement and failure

• Lead to Hemorrhagic shock, Korea

• Spread by Rats carried in ships,

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Laboratory Diagnosis

• Detection of viral nucleic acid,

• Grown in culture lines,

• PCR, Rodent control

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Filoviruses,African Hemorrhagic Fevers.

• Most important Diseases are

• Marburg and Ebola.

• The nature of Viruses are 80 nm Filamentous threads,

• Produce Internal and external Bleeding.

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Filoviruses. Marburg

• Marburg 1967 African Green Monkey,

• Bat – Rodent – Host Human.

• East Africa Monkey – Humans.

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Filoviruses - Ebola

• Incubation 2-21 days

• Carries 80% mortality.

• Barrier Nursing Most essential.

• ELISA test

• Culturing Hazardous.

• RT-PCR

• Transporting and carrying Primates is Hazardous

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• Program created by Dr.T.V.Rao MD for

Medical and Paramedical students in

the Developing World

• Email

• doctortvrao@gmail.com

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