ARBOVIRUSES Arthropod-borne Viruses

ARBOVIRUSES
The WHO definition is as follows

Viruses maintained in nature principally or to an important extent:

Through biological transmission between vertebrate hosts by haematophagus arthropods

susceptible

Through transovarian and possibly venereal transmission in arthropods

ARBOVIRUSES

Arthropod borne viruses (Arboviruses) are transmitted from one host to another through blood sucking arthropods

(Mosquitoe, ticks, fleas etc.)

They are most prevalent in tropical rain forest with abundance of animals and arthropods

There are more than 450 arboviruses, out of these 100 are infective to humans
Arboviruses may belong to families that includes Togaviridae, Flaviviridae and Bunyaviruses. Families are enveloped, RNA viruses
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ARBOVIRUSES contd

The infection is zoonotic, with humans act as accidental hosts. Humans do not play any role in maintenance or transmission cycle of virus.

Exceptions are urban yellow fever and dengu

Classification

Togaviridae Arterivirus

consists

of

Alphaviruses,

Rubivirus

and

Only Alphaviruses and Rubivirus are important in causing human disease Rubivirus that consists of Rubella transmitted by arthropod vectors. Alphaviruses include

virus

is NOT

Sindbis virus, Semliki encephalitis virus (VEE)

forest

virus,

Venezuelan

equine

Eastern equine encephalitis virus (EEE), Western equine encephalitis virus (WEE) and chikungunya virus
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Classification contd..

Flaviviridae consists of Flaviviruses, Hepaciviruses (Hepatitis C Virus)

Pestiviruses

and

Flaviviruses are transmitted through arthropods. Dengue virus Yellow fever virus Japanese B encephalitis virus West Nile encephalitis virus, St. Louis encephalitis virus Russian spring summer encephalitis virus Powassan encephalitis virus.
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Important Flaviviruses include

Classification contd..

Bunyaviruses e.g. Sandfly Fever, Rift Valley Fever, CrimeanCongo Haemorrhagic Fever

Naming of Arboviruses

Some arboviruses are named after a disease (dengue, yellow fever) Geographic area where virus was first isolated (St.Louis encephalitis, West Nile fever)

Transmission Cycles

Man - arthropod -man

E.g. dengue, urban yellow fever.

Reservoir may be in either man or arthropod vector. In the arthropod vector transovarial transmission may take place. E.g. Japanese encephalitis, EEE, WEE, jungle yellow fever. The reservoir is in an animal. The virus is maintained in nature in a transmission cycle involving the arthropod vector and animal. Man becomes infected incidentally.

Animal - arthropod vector - man

Both cycles may be seen with some arboviruses such as yellow fever.
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Man-Arthropod-Man Cycle

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Animal-Arthropod-Man Cycle

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Arthropod Vectors
Mosquitoes
Japanese encephalitis, dengue, yellow fever, St. Louis encephalitis, EEE, WEE, VEE, Rift valley fever etc.

Ticks
Crimean-Congo haemorrhagic fever, various tick-borne encephalitides etc.

Sandflies
Sicilian sandfly fever
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Examples of Arthropod Vectors

Aedes Aegyti

Assorted Ticks

Culex Mosquito

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 Pigs Monkeys Rodents Japanese encephalitis, St Louis encephalitis, EEE, WEE Japanese encephalitis Yellow Fever VEE, Russian Spring-Summer encephalitis

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Diseases Caused

Fever and rash - this is usually a non-specific illness resembling a number of other viral illnesses

Such as influenza, rubella, and enterovirus infections. The patients may go on to develop encephalitis or haemorrhagic fever.

Encephalitis - e.g. EEE, WEE, St Louis encephalitis, Japanese encephalitis.

Haemorrhagic fever - e.g. yellow fever, dengue, CrimeanCongo haemorrhagic fever. Some arboviruses may be associated with more than one syndrome, eg, dengue
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Diagnosis

Serology - usually used to make a diagnosis of arbovirus infections.

Culture - a number of cell lines may be used, including mosquito cell lines.

However, it is rarely carried out since many of the pathogens are group 3 or 4 pathogens.
Direct detection tests - e.g detection of antigen and nucleic acids are available but again there are safety issues.

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Prevention

Surveillance - of disease and vector populations Control of vector - pesticides, elimination of breeding grounds Personal protection - screening of houses, bed nets, insect repellants Vaccination - available for a number of arboviral infections e.g. Yellow fever, Japanese encephalitis, Russian tick-borne encephalitis

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Alphaviral diseases

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Sindbis

Vector is Aedes and other mosquitoes

Natural host are birds

Prevalent in Africa, Australia and India Disease is manifested from subclinical infection to febrile illness with or without rash

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Semliki Forest

Vector is Aedes and other mosquitoes. Natural host are birds Prevalent in East and West Africa Disease is manifested from subclinical infection to febrile illness with or without rash

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Venezuelan equine encephalitis (VEE)

Vectors are Aedes and Culex

Natural host are Rodents and horses

Prevalent in north, south and central America The disease may range from mild systemic to severe encephalitis.

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Eastern Equine encephalitis (EEE):

Vectors are Aedes and Culex

Natural host are birds and horses

Prevalent in north and south America The disease may range from mild systemic to severe encephalitis

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Western equine encephalitis (WEE)

Vectors are Culex, Culista

Natural host include birds and horses.

Prevalent in North and south America Disease may range from mild systemic to encephalitis

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Chikungunya:

Vector is Aedes. Natural host include humans and monkeys Prevalent in Africa and Asia Disease manifestation include fever, arthralgia and arthritis

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Flaviviruses

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Yellow Fever

It is an acute, febrile, mosquito-borne illness

Severe cases are characterized by jaundice, proteinuria, and hemorrhage

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Pathogenesis & Pathology

Virus is introduced by mosquito through skin and spreads to local lymph nods, where it multiplies From lymph nodes, it enters circulating blood and becomes localized in liver, spleen, kidney, bone marrow and lymph glands Lesions of yellow fever are due to localization and multiplication of virus in a particular organ Death may result from necrotic lesions in liver and kidney Most frequent site of hemorrhage is mucosa at pyloric end of stomach Degenerative changes also occur in spleen, lymph nodes and heart.
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Clinical features

Classically Yellow Fever at the onset, patient has fever,

chills, headache, backache, nausea, vomiting fever and moderate jaundice with high

In severe cases, increased proteinuria and hemorrhagic manifestations appear and develop bradycardia (Faget's sign) Vomitus may be black with altered blood

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Clinical features contd.

50% of patients with frank YF will develop fatal disease characterized by severe haemorrhagic manifestations, oliguria and hypotension

Some patients may experience an asymptomatic infection or a mild undifferentiated febrile illness

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Laboratory diagnosis
Isolation of virus

From patients blood virus can intracerebral inoculation of mice

be

recovered

by

It is identified by neutralization test with specific antiserum( by serology)

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Epidemiology

Flavivirus, mainly found in West Africa and S America Yellow fever occurs in 2 major forms:

Urban and jungle (sylvatic) yellow fever.

Jungle YF is the natural reservoir of the disease in a cycle involving nonhuman primates and forest mosquitoes

Man may become incidentally infected on venturing into jungle areas.

The urban form is transmitted between humans by the Aedes aegypti mosquito
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Treatment and prevention

There is no specific antiviral treatment An effective live attenuated vaccine is available against yellow fever

And is used for persons living in or traveling to endemic areas

17D strain of yellow fever virus is an excellent attenuated live virus vaccine

Control involves mosquito control to prevent urban yellow fever

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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 inapparent to clinical cases is 300:1

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Japanese Encephalitis

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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Dengue (Breakbone Fever )

Dengue is the biggest arbovirus problem in the world today with over 2 million cases per year
Dengue is found in SE Asia, Africa and the Caribbean and S America.

Flavivirus, 4 mosquitoes

serotypes,

transmitted

by

Aedes

Which reside in water-filled containers.

Human infections arise from a human-mosquitoehuman cycle

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Characteristics of the Aedes Mosquito

One distinct physical feature black and white stripes on its body and legs.

Bites during the day.

Lays its eggs in clean, stagnant water.

Close-up of an Aedes mosquito

Genome

Positive-sense genome

RNA

Approximately 10.6 kb long

Composed of a one open reading frame Genes encoding structural and non-structural proteins Four major serotypes

The outer surface of the mature virus particle consists of a flat array of E glycoprotein homodimers

DENV-1, DENV-2, and DENV-4

DENV-3,

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Distribution of Dengue

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Dengue (Breakbone Fever )

Classically, dengue presents with a high fever, lymphadenopathy, myalgia, bone and joint pains, headache, and a maculopapular rash

Dengue should be considered in the differential diagnosis of all febrile patients

Severe cases may present with haemorrhagic fever and shock with a mortality of 5-10%. (Dengue haemorrhagic fever or Dengue shock syndrome.)

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Dengue (Breakbone Fever )

Dengue haemorrhagic fever and shock syndrome appear most often in patients

Previously infected by a different serotype of dengue, Suggesting an immunopathological mechanism.

Diagnosis is made by serology.

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Dengue (Breakbone Fever )

Encourage bed rest and maintenance of fluids to prevent dehydration while the patient is febrile Control fever No specific antiviral therapy is available.

Prevention of dengue in endemic areas depends on mosquito eradication.

The population should remove all containers from their premises which may serve as vessels for egg deposition.

A live attenuated vaccine is being tried in Thailand with encouraging results.

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West Nile Fever

It is transmitted by Culex mosquitoes a

Produces viremia and acute, mild febrile disease with lymphadenopathy and rash.
Transitory meningeal involvement occurs during acute stage. Virus may produce fatal encephalitis in older people Virus can be recovered from culex mosquitoes, birds and patient blood in the acute stage

Demonstration of rise in antibody titer between acute and convalescent stage may be diagnostic
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Bunyaviruses

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Sand Fly Fever (Phlebovirus)

It is a mild insect-borne disease transmitted by female sand fly (Phlebotomus) In endemic areas, infection is common in childhood Disease begins after 3-6 days of incubation period Clinical features include

Head ache, malaise, nausea, fever, photophobia, stiffness of the neck and back, abdominal pain and leucopenia

There is no specific treatment

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Rift Valley Fever

Infects sheep and domestic animals

Humans are secondarily infected as zoonisis

Disease in humans is mild febrile illness that is short lived and recovery is complete Some cases ire may lead to encephalitis or hemorrhagic fever

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Rift Valley Fever contd

Permanent loss of vision may occur

Virus may be isolated from blood early in the disease. Neutralizing and hemagglutination inhibiting antibodies develop and persist for years Epizootics occur following heavy rains that allow breeding of primary vector and reservoir (Aedes)
Viremia in animals leads to infection of other vectors and transmission to humans

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ROBOVIRUS Rodent Borne Viruses Rodent Borne Hemorrhagic Fevers

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ROBOVIRUS

Zoonotic rodent borne hemorrhagic fevers include

Hantaan virus
Junin Machupo viruses Lassa fevers Marburg

Ebola viruses
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Hantaviruses

Forms a separate genus in the Bunyavirus family Unlike under bunyaviridae, its transmission does not involve an arthropod vector. Enveloped ssRNA virus. Virions 98nm in diameter with a characteristic square grid-like structure Genome consists of three RNA segments: L, M, and S.
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History

Haemorrhagic Fever with Renal Syndrome (HFRS: later renamed hantavirus disease)
First came to the attention of the West during the Korean war when over 3000 UN troops were afflicted. It transpired that the disease was not new and had been described by the Chinese 1000 years earlier.

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History

In 1974, the causative was isolated from the Korean Stripped field mice and was called Hantaan virus In 1995, a new disease entity called hantavirus

Pulmonary syndrome was described in the four corners region of the U.S

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Some Subtypes of hantaviruses associated with human disease

Hantaan, Porrogia and related viruses - This group is found in China, Eastern previous USSR, and some parts of S. Europe

It is responsible for the severe classical type of hantavirus disease. It is carried by stripped field mice. (Apodemus agrarius)

Seoul type - associated with moderate hantavirus disease

It is carried by rats and have a worldwide distribution It has been identified in China, Japan, Western previous USSR, USA and S.America.
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Some Subtypes of hantaviruses associated with human disease contd..

Puumala type - mainly found in Scandinavian countries, France, UK and the previous Western USSR It is carried by bank voles (Clethrionomys glareolus)

Causes mild hantavirus disease (nephropathia epidemica).

Sin Nombre - found in many parts of the US, Canada and Mexico

Carried by the Deer Mouse (Peromyscus maniculatus) and causes hantavirus pulmonary syndrome. 55

Rodent Carriers of Hantaviruses

Stripped field mouse (Apodemus agrarius) Bank vole (Clethrionomys glareolus)

Deer Mouse (Peromyscus maniculatus)

Rat (Rattus)
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Transmission

Virus infections in rodents are life long and without deleterious effects To human transmission by inhaling aerosols of rodent excreta

Urine, feces, saliva

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Clinical Features of Hantavirus Disease

Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome (HPS) The multisystem pathology of HVD is characterized by

Damage to capillaries and small vessel walls, resulting in vasodilation and congestion with hemorrhages

Classically, hantavirus disease consists of 5 distinct phases

These phases may be blurred in moderate or mild cases.

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Clinical Features of Hantavirus Disease contd..

Febrile phase - abrupt onset of a severe flu-like illness with a

erythematous rash after an incubation period of 2-3 days.

Hypotensive phase - begins at day 5 of illness Oliguric phase - begins at day 9 of illness.

The patient may develop acute renal failure and shock. Haemorrhages are usually confined to petechiae The majority of deaths occur during the hypotensive and oliguric phases

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Clinical Features of Hantavirus Disease contd..

Diuretic phase - this occurs between days 12-14 . Convalescent phase - this may require up to 4 months.

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Comparative Clinical Features of Recognized Hantavirus Disease (HVD)

Nephropathia Epidermica Virus type Overall Severity Multiphasic Disease Renal Abnormalities Hepatic abnormalities Haemorrhagic phenomenon Mortality Score = 0 to 4 Puumala 1-2 occasionally 1-2 0 0-1 <1% Far Eastern HVD Hantaan 2-4 Yes 4 0-1 1-4 5-10% Rat-bourne HVD Seoul 1-3 Blurred 1-2 1-3 1-2 1% Balkan HVD Porogia 2-4 Yes 4 0-1 1-4 5-35%

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Hantavirus Pulmonary Syndrome (HPS)

More than 250 cases of HPS have been reported throughout North and South America with a mortality rate of 50% In common with classical HVD, HPS has a similar febrile phase. However, the damage to the capillaries occur predominantly in the lungs rather than the kidney.
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Hantavirus Pulmonary Syndrome (HPS) contd.

Shock and cardiac complications may lead to death. The majority of HPS cases are caused by the Sin Nombre virus The other cases are associated with a variety of other hantaviruses

E.g. New York and Black Creek Canal viruses.

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Diagnosis

Serological diagnosis - a variety of tests including IF, HAI, SRH, ELISAs have been developed for the diagnosis of HVD and HPS. Direct detection of antigen - this appears to be more sensitive than serology tests in the early diagnosis of the disease The virus antigen can be demonstrated in the blood or urine. RT-PCR - found to of great use in diagnosing hantavirus pulmonary syndrome.

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Diagnosis contd.

Virus isolation - isolation of the virus from urine is successful early in hantavirus disease. Isolation of the virus from the blood is less consistent Sin Nombre virus has never been isolated from patients with HPS. Immunohistochemistry - useful in diagnosing HPS.

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Treatment and Prevention

Treatment of HVD and HPS depends mainly on supportive measures. Ribavirin - reported to be useful if given early in the course of hantavirus disease. Its efficacy is uncertain in hantavirus pulmonary syndrome. Vaccination - an inactivated vaccine is being tried out in China. Other candidate vaccines are being prepared.

Rodent Control - control measures should be aimed at reducing contact between humans and rodents.

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Treatment and Prevention

Treatment of HVD and HPS depends mainly on supportive measures. Ribavirin - reported to be useful if given early in the course of hantavirus disease. Its efficacy is uncertain in hantavirus pulmonary syndrome. Vaccination - an inactivated vaccine is being tried out in China. Other candidate vaccines are being prepared.

Rodent Control - control measures should be aimed at reducing contact between humans and rodents.

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Arenaviruses

Lassa fever virus particles budding from the surface of an infected cell. (Source: CDC)

Enveloped ssRNA viruses virions 80-150nm in diameter genome consists of 2 pieces of ambisense ssRNA. 7-8 nm spikes protrude from the envelope. host cell ribosomes are usually seen inside the outer membrane but play no part in replication. Members of arenaviruses include Lassa fever, Junin and 68 Macupo viruses.

Lassa Fever

Found predominantly in West Africa, in particular Nigeria, Sierra Leone and Liberia.
The natural reservoir is multimammate rat (Mastomys) Man may get infected through contact with infected urine and faeces.
Mastomys

Man to man transmission can occur through infected bodily fluids

Lassa fever had caused welldocumented nosocomial outbreaks.
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Clinical Manifestations

Incubation period of 3-5 days.

Insidious onset of non-specific symptoms such as fever, malaise, myalgia and a sore throat.

Typical patchy or ulcerative pharyngeal lesions may be seen.

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Clinical Manifestations

Severe cases may develop the following:

Myocarditis Pneumonia Encephalopathy Haemorrhagic manifestations Shock The reported mortality rate for hospitalized cases of Lassa fever is 25% It carries a higher mortality in pregnant women

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Laboratory Diagnosis
Lassa fever virus is a Group 4 Pathogen. Laboratory diagnosis should only be carried out in specialized centers.

Detection of Virus Antigen - the presence of viral antigen in sera can be detected by EIA. The presence of viral antigen precedes that of IgM.

Serology - IgM is detected by EIA. Using a combination of antigen and IgM antibody tests, it was shown that virtually all Lassa virus infections can be diagnosed early.
Virus Isolation - virus may be cultured from blood, urine and throat washings. Rarely carried out because of safety concerns. RT-PCR - being used experimentally.

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Treatment and Prevention

Good supportive care is essential. Ribavirin - had been shown to be effective against Lassa fever with a 2 to 3 fold decrease in mortality in high risk Lassa fever patients. Must be given early in the illness. Hyperimmune serum - the effects of hyperimmune serum is still uncertain although dramatic results have been reported in anecdotal case reports. Postexposure Prophylaxis - There is no established safe prophylaxis. Various combinations of hyperimmune immunoglobulin and/or oral ribavirin may be used. There is no vaccine available, prevention of the disease depends on rodent control.

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Junin and Macupo Viruses

Junin and Macupo viruses are the causative agents of Argentine and Bolivian Haemorrhagic fever respectively.
Calomys musculinis and C callosus are the rodent vectors. The clinical presentations are similar to that of Lassa fever. Neurological signs are much more prominent than in Lassa fever. Unlike Lassa virus, no secondary human to human spread had been recorded. Hyperimmune serum and ribavirin had been shown to be effective in treatment.
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