Published on March 9, 2014
Arboviruses Dr. Pendru Raghunath Reddy
Arthropod-borne viruses (arboviruses) are viruses that can be transmitted to man by arthropod vectors The WHO definition Viruses that are maintained in nature principally, or to an important extent, through biological transmission between susceptible vertebrate host by hematophagous arthropods or through transovarian and possibly venereal transmission in arthropods”
They can multiply in the tissues of the arthropod without evidence of disease or damage The vector acquires a lifelong infection through the ingestion of blood from a viremic vertebrate All arboviruses have an RNA genome, and most have a lipid-containing envelope and consequently are inactivated by ether or sodium deoxycholate Inclusion in this group is based on ecological and epidemiological considerations and hence it contains viruses of diverse physical and chemical properties Though taxonomically unacceptable, the name “arbovirus” is a useful biological concept
Classification Togaviridae Genus Alphavirus Flaviviridae Genus Flavivirus Bunyaviridae Genus Bunyavirus Reoviridae Genus Orbivirus Rhabdoviridae Genus Vesiculovirus Orthomyxoviridae Approximately 80 arboviruses known to cause human disease
Arboviruses prevalent in India Virus Reservoir Vector Disease Chikungunya Monkeys Mosquito Chikungunya fever Dengue Monkeys, Man Mosquito Dengue haemorrhagic fever Japanese B encephalitis Wild birds, pigs Mosquito Encephalitis Kyasanur forest disease Forest birds, animals Tick Haemorrhagic fever Sindbis - Mosquito Sindbis fever
General properties The arboviruses share some common biological properties 1. All members produce fatal encephalitis in suckling mice after intracerebral inoculation 2. They possess haemagglutinin and agglutinate erythrocytes of goose or day-old chicks 3. They can be grown in tissue cultures of primary cells like chick embryo fibroblasts or continuous cell lines like vero, and in cultures of appropriate insect tissues 4. They may also be isolated in the yolk sac or CAM of chick embryo 5. In general, arboviruses are readily inactivated at room temperature and by bile salts, ether and other lipid solvents
Arthropod Vectors Mosquitoes Japanese encephalitis, dengue, yellow fever, Rift valley fever St. Louis encephalitis, EEE, WEE, VEE etc Ticks Crimean-Congo haemorrhagic fever, Kyasanur forest disease and various tick-borne encephalitis etc. Sandflies Sicilian sandfly fever
Examples of Arthropod Vectors Aedes aegyti Culex Mosquito Ixodid Ticks Phlebotomine Sandfly
Animal Reservoirs In many cases, the actual reservoir is not known. The following animals are implicated as reservoirs Birds encephalitis, Japanese B encephalitis, St Louis EEE, WEE Pigs Japanese B encephalitis Monkeys Yellow Fever Rodents VEE, Russian Spring-Summer encephalitis
Pathogenesis When an infected vector bites a suitable host, the virus is injected into the capillary circulation Virus comes in contact with susceptible target cells such as endothelial cells of capillaries, monocytes, macrophages and cells of RES After replication in endothelial cells and RE cells, a secondary viraemia usually results leading to infection of target organs such as brain, skin, musculature and liver, depending on the tissue tropism The virus reaches the brain by infecting small blood vessels of the brain or choroid plexus
Diseases Caused Fever with or without 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 B encephalitis Haemorrhagic fever - e.g. yellow fever, dengue, Crimean-Congo haemorrhagic fever All arbovirus infections occur with varying degree of severity, subclinical infections being common
Structure of Alphaviruses
Principal medically important alphaviruses Virus Clinical Syndrome Vector Host Distribution Eastern equine encephalitis Encephalitis (EEE) Mosquito Birds Americas Western equine encephalitis Encephalitis (WEE) Mosquito Birds North America Venezuelan equine encephalitis Febrile illness, encephalitis (VEE) Mosquito Rodents, horses Americas
Virus Clinical Syndrome Vector Host Distribution Febrile illness, rash, arthralgia Mosquito humans Africa, India, Southeast Asia O’nyongFebrile nyong (ONN) illness, rash, arthralgia Mosquito Primates Africa Sindbis (SIN) Febrile illness, rash, arthralgia Mosquito Birds Nothern Europe, Africa, Asia, Australia Semliki Forest Febrile illness, rare encephalitis Mosquito Birds Africa Chikungunya (CHIK)
Chikungunya virus The virus is transmitted by Aedes aegypti Full-blown disease is most common in adults Incubation period - 2-3 days The disease is chracterised by fever, crippling joint pains, lymphadenopathy, conjunctivitis and rash Migratory polyarthritis mainly affects the small joints of the hands and wrists The fever is typically biphasic with a period of remission after 1-6 days
A maculopapular rash is common and most intense on the trunk and limbs that may desquamate Haemorrhagic manifestations are seen in some patients Chickungunya is the native word for the disease in which the patient lies ‘doubled up’ due to severe joint pains The virus first appeared in India in 1963 when it caused extensive epidemics in calcutta, Madras and other areas There is no animal reservoir for the virus No vaccine is available
Structure of Flaviviruses
Principal medically important flaviviruses Virus Clinical Syndrome Vector Host Distribution Dengue (DEN) Febrile illness, rash, hemorrhagic fever, shock syndrome Mosquito Humans Tropics, worldwide Yellow fever Hemorrhagic fever, (YF) hepatitis Mosquito Primates, humans Africa, South America Birds Americas St. Louis encephalitis (SLE) Encephalitis Mosquito
Principal medically important flaviviruses Virus Clinical Syndrome Vector Host Distribution Japanese encephalitis (JE) Encephalitis Mosquito Pigs, birds India, China, Japan, South-East Asia West Nile Febrile illness Mosquito Birds Africa, Middle East, Europe Tick-borne encephalitis (TBE) Encephalitis Tick Rodent Europa, Asia
Principal medically important flaviviruses Virus Clinical Syndrome Vector Host Distribution Omsk hemorrhagic fever Hemorrhagic fever Tick Muskrats Siberia Kyasanur Forest disease (KFD) Hemorrhagic fever Tick Rodents India
Human infection with both mosquito-borne and tick-borne flaviviruses is initiated by deposition of virus through the skin via the saliva of an infected arthropod (Fig). Figure. Pathogenesis of flaviviruses.
Japanese B encephalitis First discovered and originally restricted to Japan. Now large scale epidemics occur in China, India and other parts of Asia The virus was named Japanese B encephalitis virus to distinguish it from Japanese A encephalitis virus Transmitted by Culex tritaeniorhynchus mosquitoes The virus is maintained in nature in a transmission cycle involving mosquitoes, birds (reservoirs) and pigs (amplifier hosts) Herons act as reservoir host and pigs as amplifier hosts
Clinical features Most human infections are subclinical: the inapparent to clinical cases is 500-1000:1 Incubation period: 5-15 days The course of the disease in man may be divided into three stages 1.Prodromal stage 2.Acute encephalitic stage 3.Late stage and sequelae
Prodromal stage The onset of illness is usually acute and symptoms include fever, headache and vomiting Acute encephalitic stage After 1-6 days, signs of encephalitis characterised by neck rigidity, convulsions, altered sensorium and coma appear Late stage and sequelae Convalescence may be prolonged and residual neurological deficits may not be uncommon Case fatality rate varies between 20-40%, but it may reach 58% and over in some epidemics Residual neurological damage may persist in about 50% of survivors
The disease is usually diagnosed by serology No specific therapy is available Prevention Preventive measures include mosquito control and establishment of piggeries away from residential areas A formalin inactivated mouse brain vaccine using the Nakayama strain has been employed for human immunisation A live attenuated vaccine prepared in hamster kidney cell line is also available
Yellow Fever Yellow fever is a mosquito-borne accompanied by hepatic necrosis acute febrile illness It occurs mainly in tropical Africa and Latin America It does not exist in India The name has been derived from ‘yellow quarantine flag’ used by the ships during 17th century to warn the presence, on board of this infection Yellow fever occurs in 2 major forms: urban and jungle (sylvatic) cycle
In the urban cycle, man serves both as reservoir and as definitive host, the virus being transmitted by Aedes aegypti mosquito In the forest or sylvatic cycle, wild monkeys act as reservoirs and several species of forest mosquitos are vectors. Human cases occur only when humans trespass into the forest or when monkeys raid villages
Pathogenesis After introduction into the skin by the mosquito-bite, the virus multiplies locally and spreads to the local lymphnodes where it multiplies From the lymphnodes, it enters the circulating blood. The virus starts appearing in blood 3-6 days after the bite of infected mosquito and viraemia lasts for 4-5 days From blood, the virus becomes localised in the liver, spleen, kidney, bonemarrow and myocardium, where it may persist for days The lesions of yellow fever are due to the localization and propagation of the virus in a particular organs
Clinical features After an incubation period of 3-6 days, patient develops fever with chills, headache, myalgia and vomiting Most cases are mild in nature, especially in the endemic areas, in whom the disease may present as undifferentiated fever without jaundice The pulse is usually slow despite a high temperature In 15-20% of cases, the disease progresses to a more serious form with jaundice, albuminuria, renal failure and haemorrhagic manifestations and the patient may die of hepatic and renal failure
Laboratory diagnosis Diagnosis is usually clinical; laboratory diagnosis is made for confirmation 1.Detection of viral antigen 2.Isolation of virus 3.Postmortem diagnosis 4.Serology
Detection of viral antigen Viral antigen or nucleic acid can be detected in tissue specimen using ELISA, PCR, and immunohistochemistry Isolation of virus Virus can be isolated from blood in the first 4 days after onset or from postmortem tissue by intracerebral inoculation of mice or inoculating cell lines
Postmortem diagnosis Can be made histologically There is severe midzonal degeneration, necrosis and acidophilic inclusion bodies seen in the liver Serology During first week of illness, IgM antibody can be detected by ELISA
Prophylaxis There is no antiviral drug against yellow fever The control of urban yellow fever can be achieved by eradicating the vector mosquito Two vaccines have been developed for human use 1. The french neurotropic vaccine (Dakar) produced from infected mouse brain 2. 17D vaccine developed by Theiler in 1937 by passaging the Asibi strain serially in mouse embryo and whole chick embryo tissues and then in chick embryo tissue from which the central nervous tissue has been removed
Dengue The word dengue is derived from the Swahili Ki denga pepo meaning a sudden seizure by a demon Dengue fever is clinically similar to the illness caused by the chikungunya and O’nyong-nyong viruses Dengue virus is widely distributed in the Caribbean region, south east asia In India first outbreak of dengue was recorded in 1812 In New Delhi, outbreaks of dengue fever reported in 1967,1970,1982, &1996
Distribution of Dengue
Morphology of Dengue virus Dengue virion are spherical particles approximately 50 nm in diameter Contains a single plus strand of RNA. surrounded by a lipid bilayer Mature virions are composed of 6% RNA, 9% carbohydrate, and 17% lipid Because of the lipid envelope, flavviviruses are readily inactivated by organic solvents and detergents
Three viral proteins are associated with virions The E (envelope), M (membrane) and C (capsid) proteins
The E protein is the major surface protein of the viral particle and mediates virus-cell membrane fusion. Antibodies that neutralize virus infectivity usually recognize this protein and mutations in E can affect virulence M protein is a small proteolytic fragment which is important for maturation of the virus into an infectious form C protein is a component nucleocapsid
Etiology types Four distinct antigenically related serotypes ( 1to 4) of dengue virus of the family flaviviridae are etiologically responsible Infection in human by one serotypes produces life long immunity against re-infection by the same serotype All 4 types of dengue viruses are present in India, more than one type of dengue virus has been occasionally recovered from a patient Subsequent infection with other serotypes may result in a severe illness i. e., dengue haemorrhagic fever or dengue shock syndrome Some genetic variants within each serotype appear to be more virulent or have greater epidemic potential
The most common epidemic vector of dengue in the world is the Aedes aegypti mosquito. It can be identified by the white bands or scale patterns on its legs and thorax.
Aedes aegypti • Dengue transmitted by infected female mosquito • Primarily a daytime feeder • Lives around human habitation • Lays eggs and produces larvae preferentially in artificial containers
Pathogenesis 1.The virus is inoculated into humans with the mosquito saliva 2.The virus localizes and replicates in various organs, for example, local lymph nodes, liver, spleen and the thymus 3.The virus is then released from these tissues into the blood 4.Via the blood, the virus spreads throughout the body to infect other lymphatic tissues and organs, which is accompanied by symptoms
5.The mosquito ingests blood containing the virus 6.The virus replicates in the mosquito midgut, the ovaries, nerve tissue and fat body. It then escapes into the body cavity, and later infects the salivary glands 7.The virus replicates in the salivary glands and when the mosquito bites another human, the cycle continues
Clinical features The disease may occur in two forms 1. Classical dengue fever (break-bone fever) 2. Dengue in more serious forms with haemorrhagic manifestations (DHF/DSS)
Classical dengue fever This usually affects older children and adults It has relatively benign course with fever, headache, retrobulbar pain, conjunctival infection, pain in muscles and bones, lymphadenopathy and maculopapular rash The fever is typically biphasic (saddle back) Incubation period is 5 – 8 days A maculopapular rash generally appears on 3rd or 4th day The febrile illness lasts for about 10 days after which recovery is generally complete. It is rarely fatal
Other manifestations Dengue may also occur in more serious forms, with haemorrhagic manifestations or with shock DHF/DSS remains mostly confined among children of 5 -10 years age group in area where multiple dengue viruses cause disease It appers to be hyperimmune response On reinfection with a different serotype of dengue virus, antibody formed against the first virus reacts with the second serotype virus forming immune complexes (virus-antibody complex)
In DHF/DSS, initial symptoms are like those of dengue fever but associated with haemorrhagic rash, thrombocytopenia and shock The moratality rate is 5 -10 % The disease is more often found in epidemic form in Thailand, South -East Asia and India where dengue serotypes are regularly present All four types of dengue virus are present in India
Clinical Case Definition for Dengue Fever Classical Dengue fever or Break bone fever is an acute febrile viral disease frequently presenting with headaches, bone or joint pain, muscular pains,rash,and leucopenia Clinical Case Definition for Dengue Hemorrhagic Fever 4 Necessary Criteria: 1. Fever, or recent history of acute fever 2. Hemorrhagic manifestations 3. Low platelet count (100,000/mm3 or less) 4. Objective evidence of “leaky capillaries:” • elevated hematocrit (20% or more over baseline) • low albumin • pleural or other effusions
Clinical Case Definition for Dengue Shock Syndrome 4 criteria for DHF + Evidence of circulatory failure manifested indirectly by all of the following •Rapid and weak pulse •Narrow pulse pressure hypotension for age (< 20 mm •Cold, clammy skin and altered mental status •Frank shock is direct evidence of circulatory failure Hg) OR
Hemorrhagic Manifestations of Dengue •Skin petechiae, purpura, ecchymoses hemorrhages: •Gingival bleeding •Nasal bleeding •Gastrointestinal Hematemesis, melena, hematochezia •Hematuria •Increased menstrual flow bleeding:
Laboratory diagnosis Specimens 1) For antibody detection – serum 2) For antigen detection – serum 3) For isolation of virus and PCR a) Serum b) Plasma c) Whole blood (washed buffy coat) d) Autopsy tissues e) Mosquitoes collected in nature
Haematological diagnosis Thrombocytopenia (1,00,000 cells or less per mm3) Haemoconcentration (> 20 % rise in haematocrit) Microbiological diagnosis Isolation of virus is difficult hence serology plays a major role in diagnosis 1. Detection of antibody Demonstration of IgM antibody in serum provides early diagnosis IgM antibody appears 5 days after onset of symptoms and persists for one to three months Detection of four fold rise in IgG titre in paired sera taken at an interval of ten days or more is confirmatory
2. Detection of NS1 antigen Immunochromatographic test is available for detection of NS1 antigen (nonstructural protein 1) It is a rapid test and detects antigen on the first day of fever 3. Isolation of virus Virus isolation can be done by inoculating clinical specimen into mosquitoes, mosquitoes cell lines (C6/36 or AP-61 cells) or suckling mice 4. PCR Viral RNA can be detected in clinical specimens by RT-PCR
Dengue fever Management There is no specific antiviral treatment The management is essentially supportive and symptomatic The key to success is frequent monitoring and changing strategies depending on clinical and laboratory evaluations Bed rest is advisable during the acute febrile phase Antipyretics or cold sponging should be used to keep the body temperature < 400C Analgesics and mild sedation may be required to control pain
Prophylaxis Control measures include elimination of mosquitoes No effective vaccine is available In order to avoid the DHF/DSS in immunised persons, a live attenuated vaccine containing all four dengue serotypes is under clinical trials
Tick-borne Flaviviruses 1.Tick-borne encephalitis viruses a) Russian spring-summer encephalitis b) Powassan virus 2. Tick-borne haemorrhagic fevers a) Kyasanur Forest Disease (KFD) b) Omsk haemorrhagic fever
Kyasanur Forest Disease (KFD) Febrile disease associated with hemorrhages that appeared in Kyasanur Forest of Karnataka in 1957 as a fatal epizootic affecting monkeys, along with a severe prostrating illness in some of the villagers in the area Antigenically related to the RSSE virus Birds and small mammals are believed to be the reservoirs of the virus Virus is transmitted by bite of tick (Haemaphysalis spinigera) Ticks may also act as the reservoir hosts as virus is transmitted transovarially in them Monkeys act as amplifier hosts
Clinical features Incubation period varies from 3 – 7 days Patient develops fever of sudden onset with headache, vomiting, conjunctivitis, myalgia and severe prostration Some patients also develop haemorrhages into the skin, mucosa, alimentary canal, chest cavity and also in viscera Epistaxis may occur in some cases Case fatality is about 5 %
Control Control of ticks The population at risk should be vaccinated with killed KFD vaccine Personnel protection – protection of individuals by adequate clothing and insect repellents
Bunyaviridae is a family of arthropod-borne or rodent-borne, spherical, enveloped RNA viruses. Bunyaviruses are responsible for a number of febrile diseases in humans and other vertebrates. They have either a rodent host or an arthropod vector and a vertebrate host
Human diseases Caused by Viruses of the Family Bunyaviridae Genus and Group Virus Disease Vector Distributi on Bunyavirus Bunyamwera Bunyamwera Bwamba Bwamba California California encephalitis Simbu Shuni Fever Mosquito Africa Fever , Mosquito Rash Africa Encep Mosquito North ha-litis America Fever Mosquito Africa, Asia
Human diseases Caused by Viruses of the Family Bunyaviridae Genus and Group Virus Disease Vector Distribution Phlebovirus Phlebotomus fever Fever Sand fly Europe, Africa, Asia Naples Rift Valley Fever Sicilian Fever Sand fly Europe, Asia, Africa Rift Valley Fever Fever, encephalitis, hemorrhagic fever, blindness Mosquito Africa
Human diseases Caused by Viruses of the Family Bunyaviridae Genus and Group Virus Disease Vector Distribution Tick Africa, Asia Tick Africa, Asia Nairovirus CrimeanCongo Nairobi sheep disease Crimean- Hemorrhagic Congo fever hemorrhagi c fever Nairobi sheep disease Fever
Human diseases Caused by Viruses of the Family Bunyaviridae Genus and Group Virus Disease Reservoir Distribution host Hantavirus Hanntavirus Hantaan HFPS (hantavirus pulmonary syndrome), HFRS Rodent Asia Puumala HFPS, HFRS Rodent Asia Seoul HFPS, HFRS Rodent Asia, Europe
Human diseases Caused by Viruses of the Family Bunyaviridae Genus and Group Virus Disease Vector Distribution Genus unassigned Bangui Fever, rash Unknown Africa Bhanja Fever, encephalitis Tick Africa, Europa, Asia Issk-kul Kasokero Fever Fever Tick Unknown Asia Africa Nyando Tataguine Fever Fever Mosquito Mosquito Africa Africa Wanowri Fever, hemorrhage Tick Middle East, Asia
FIGURE. Pathogenesis of bunyavirus infections. Humans are dead-end hosts of most bunyaviruses; however, the blood of Crimean-Congo hemorrhagic fever patients may be highly infectious
Signs of Crimean-Congo Hemorrhagic Fever
Laboratory diagnosis of arboviruses Specimens Blood, CSF, brain tissue may be used for isolation of virus 1. Virus isolation a) Suckling mice Specimens are inoculated intracerebrally into suckling mice The animal develops fatal encephalitis Most sensitive method for isolation of arboviruses
b) Tissue culture Vero, BHK-21 and mosquito cell lines are inoculated with specimens Growth of virus in cell cultures is identified by immunofluorescence, haemagglutination inhibition, CFT, ELISA or neutralisation tests 2. Serology Usually used to make a diagnosis of arbovirus infections 3. Direct detection tests Methods for detection of antigen and nucleic acids are available
Prevention of arbovirus infections Surveillance - of disease and vector populations Control of vector - pesticides, elimination of breeding grounds Personal protection - screening of houses, bed nets, insect repellants. When possible, wear protective clothing while outdoors Vaccination - available for a number of arboviral infections e.g. Yellow fever, Japanese encephalitis, Russian tick-borne encephalitis
Treatment of arbovirus infections No specific therapy Arboviral encephalitis treated by hospitalization, intravenous fluids, respiratory support, prevention of secondary infections, and good nursing care
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