Arthropod-borne Viruses Part II

Dr.T.V.Rao MD

Dr.T.V.Rao MD

Arthropod-borne Viruses
Arboviruses belong to three families 1. Togaviruses e.g. EEE, WEE, and VEE 2. Bunyaviruses e.g. Sandfly Fever, Rift Valley Fever, Crimean-Congo Haemorrhagic Fever

Flavivirus e.g. Yellow Fever, Dengue, Japanese Encephalitis

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DENGUE FEVER

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Arboviruses
The Arbovirus are also called as Arthropod borne viruses, represent an ecological grounding of viruses with complex transmission cycles involving Arthropods These viruses have diverse physical and chemical properties and are classified in several virus families. Dengue infection is caused by Arbovirus
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Man-Arthropod-Man Cycle

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History - Dengue
This disease was first described 1780, and the virus was isolated by Sabin 1944. Dengue virus infection is the most common arthropod-borne disease worldwide with an increasing incidence in the tropical regions of Asia, Africa, and Central and South America.
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Over view of Dengue

With more than one-third of the worlds population living in areas at risk for transmission, dengue infection is a leading cause of illness and death in the tropics and subtropics. As many as 100 million people are infected yearly. Dengue is caused by any one of four related viruses transmitted by mosquitoes
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Dengue
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 serotypes, transmitted by Aedes mosquitoes which reside in water-filled containers.

Human infections arise from a human-mosquitoehuman cycle .
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Current Trends
In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of dengue fever in 1994..
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Distribution of Dengue

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Dengue Infection and Implications

Dengue virus (DENV) infects 50 million (WHO) to 100 million (NIH) people annually. Forty per cent of the worlds population, predominately in the tropics and sub-tropics, is at risk for contracting dengue virus. DENV infection can cause dengue fever, dengue haemorrhagic fever, dengue shock syndrome, and death.
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Dengue Mosquito transmitted Viral Infection

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What causes Dengue

Dengue (DF) and dengue haemorrhagic fever (DHF) are caused by one of four closely related, but antigenic ally distinct, virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the genus Flavivirus. Infection with one of these serotypes provides immunity to only that serotype for life,
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Aedes aegypti Vector

Aedes aegypti, a
domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species. Infections produce a spectrum of clinical illness ranging from a nonspecific viral syndrome to severe and fatal haemorrhagic disease. Other species of Aedes can also transmit.
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Dengue Virus A Flavivirus

Flavivirus are spherical and 40- 60 mm in diameter. Genome Positive sense, single sense RNA,11kb in size Genome RNA infectious Enveloped virus Three structural polypeptides two are glycosylated Replication in cytoplasm
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How Mosquitos spread the infection

The disease starts during the rainy season, when vector Mosquito Aedes aegypti is abundant The Aedes breeds in the tropical or semitropical climates in water holding receptacles or in plants close to human dwellings A female Aedes acquires the infection feeding upon a viremic human. After a period of 8 14 days mosquitoes are infective and remain infective for life. ( 1- 3 ) months.
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Pathogenesis
Presence of existing Dengue antibody, associated with fresh viral infection with new serotype complexes and forms within few days of the second dengue infection. Non neutralizing enhancing antibodies promote infection of higher number of Mononuclear cells.
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Immunology Dengue
Four serotypes exist distinguished by Molecular basis and Nt tests Infection confers life long immunity But cross protection between serotypes is of short duration. Reinfection with different serotype after primary attack is more dangerous causes Dengue hemorrhagic fever.
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Clinical Manifestations
Any or few of the following events can occur. Fever, Severe head ache Muscle and joint pains Nausea, vomiting, Eye pain
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How Dengue Infection starts and manifests

Incubation period 4 7 days ( 3 14 days) Fever may start with, Malise,chills,head ache Soon leads to severe back ache, joint pains, muscular pain, pain in the eye ball. Temperature may persist for 3 -5 days. On some occasions once again raises in about 5 8 days ( Saddle back fever ) Myalgia may be severe with deep bone pain ( Break bone fever ) characteristic of the Disease

On majority of the occasions a self limited condition, Subside on its own Death is a rare event.
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Dengue with Rashes

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Dengue Hemorrhagic Fever

DHF was first recognized in the 1950s during the dengue epidemics in the Philippines and Thailand. Today emerging DHF cases are causing increased dengue epidemics in the Americas, and in Asia, where all four dengue viruses are endemic, DHF has become a leading cause of hospitalization and death among children in several countries. ( WHO )
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Dengue Hemorrhagic Fever

Common in children. In children passively acquired contributed by the maternal antibodies transferred to the fetus. In other ( Adults ) the presence of antibodies due to previous infection with different serotype Initially presents like classical Dengue infection But patients condition abruptly worsens, an important cause of morbidity and mortality in Dengue
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Basic Understanding of Dengue Hemorrhagic Fever

Dengue Hemorrhagic Fever is a probable case of dengue and hemorrhagic tendency evidenced by one or more of the following: Positive tourniquet test Petechial, ecchymosis or purpura Bleeding from mucosa (mostly epistaxis or bleeding from gums), injection sites or other sites Haematemesis or melena
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How to do a Tourniquet test

The tourniquet test is performed by inflating a blood pressure cuff to a point mid-way between the systolic and diastolic pressures for five minutes. A test is considered positive when 10 or more petechiae per 2.5 cm2 (1 inch) are observed. In DHF, the test usually gives a definite positive result (i.e. >20 petechiae). The test may be negative or mildly positive during the phase of profound shock.

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What Happens in Dengue Hemorrhagic Fever

Thrombocytopenia (platelets 100,000/cu.mm or less) and Evidence of plasma leakage due to increased capillary permeability manifested by one or more of the following: A >20% rise in hematocrit for age and sex A >20% drop in hematocrit following treatment with fluids as compared to baseline Signs of plasma leakage (pleural effusion, ascites or hypoproteinaemia).
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Risk factor for DHF

Important risk factors for DHF include the strain of the infecting virus, as well as the age, and especially the prior dengue infection history of the patient
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Dengue Hemorrhagic Syndrome

Chateresied by shock and hemoconcentration Contributed by circumstantial evidence suggests secondary infection with Dengue type 2 following type 1 infection in the past.

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Dengue hemorraghigic Syndrome

DHS is caused due to release of, 1 Release of cytokines 2 Vasoactive mediators. 3 Procoagulants

Manifest with disseminated intravascular coagulation

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Diagnosis
In resource rich establishments
1 Reverse transcriptase polymerase chain reaction methods help rapid identification 2 Isolation of virus is difficult 3 The current favored approach is inoculation of mosquito cell line with patient serum coupled with nucleic acid assay to identify a recovered virus.
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Dengue Serology
The serology is limited with cross reactivity of IgG antibodies to heterologous Flavivirus antigens Most commonly used methods are Viral protein specific capture IgM or IgG by ELISA IgM antibodies develop within few days of illness
Neutralizing anti Haemagglutination inhibiting antibodies appear within a week after onset of Dengue fever Dr.T.V.Rao MD
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Importance of paired sample testing in Serology

Testing one sample for serum and reporting a negative test is fallacious

Analysis of paired acute and convalescent sera to show significant rise in antibody titer is the most reliable evidence of an active dengue infection.
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Newer Diagnostic Methods RT - PCR

RT PCR is a highly sensitive tool in Diagnosis, with established high sensitivity in Diagnosis in Puzzles Developing world lacks resources to implement and utilize the Scientific advances
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Treatment
No Anti viral therapy available Symptomatic management in Majority of cases Dengue Hemorrhagic fever to be treated with suitable fluid replacement No Vaccine available, difficult in view of four serotypes.

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Control of Dengue
Control of Mosquito breeding places. Anti mosquito measures Use of Insecticides. Screened windows and doors can reduce exposure to vectors.
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Epidemiology - Dengue
Dengue virus are distributed world wide in tropical regions. Where the Aedes vectors exist, are endemic areas Changing and increasing incidences are associated with rapid urban population growth, over crowding and lax mosquito control measures
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Viral Hemorrhagic Fevers

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Viral Haemorrhagic Fevers

Acute infection: fever, myalgia, malaise; progression to prostration Small vessel involvement: increased permeability, cellular damage Multisystem compromise (varies with pathogen) Hemorrhage may be small in volume (indicates small vessel involvement, thrombocytopenia) Poor prognosis associated with: shock, encephalopathy, extensive hemorrhage
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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 Fever viruses

Filoviruses
Ebola Hemorrhagic fever (EHF) Marburg virus

Arenaviruses
Bunyaviruses

Lassa fever New World Arenaviruses

Rift Valley fever (RVF) Crimean Congo Hemorrhagic fever (CCHF)

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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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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 Fevers

Clinical 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 Fevers

Initial Symptoms
Prodromal illness lasting < 1 week may include:
High fever Headache Malaise Weakness Exhaustion
Dizziness Muscle aches Joint pain Nausea Non-bloody diarrhea

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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
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JAMA 2002;287 Adapted from WHO

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Viral Hemorrhagic Fevers

Treatment
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 Fevers

Infection 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 PAPR
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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 Fevers

Infection 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 Fevers

Summary 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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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,

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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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Ebola Outbreaks 1979, 2004

Ivory Coast
1994

Sudan Gabon
1976, 1979, 2004

1994, 1996, 1996 Congo 2003 DRC

(formerly Zaire)

Uganda
2000

1976, 1995
0 2,000 kilometers
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4,000

South Africa
1996*

*Doctor returning from Gabon

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Bunya viruses Rift Valley fever Crimean Congo hemorrhagic fever

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Rift Valley Fever

Disease of sheep and cattle Humans: Asymptomaticto-mild Rare VHF, encephalitis, retinitis

Rift Valley Fever

Mosquito-borne (Aedes spp.)

vertical transmission in mosquitos

Transmission: Animal contact (birthing or blood) Laboratory aerosol Mortality 1% overall Therapy: Ribavirin? Live-attenuated vaccine (MP-12) undergoing trials
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Rift Valley Fever: Clinical features

3-7 day incubation, 3-5 day duration Asymptomatic or mild illness Fever, myalgia, weakness, weightloss Photophobia, conjunctivitis Encephalitis <5% hemorrhagic fever 1-10% vision loss (retinal hemorrhage, vasculitis)
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CRIMEAN CONGO HEMORRHAGIC FEVER (CCHF)

Extensive geographic distribution (Africa, Balkans, and western Asia) Transmission: Tick-borne (Hyalomma spp.) Contact with animal blood or products Person-to-person transmission by contact with infectious body fluids Laboratory worker transmission documented

Mortality 15-40% Therapy: Ribavirin Dr.T.V.Rao MD

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CCHF: Pathogenesis
Viremia present throughout disease

IFA becomes positive in patients destined to survive days 4-6, often simultaneously with viremia
Recovery may be due to CMI or neutralizing antibodies

Patients that die usually still viremic

Virus grows in macrophages and other cells DIC often present

Poor prognosis signaled by early elevated AST and clotting

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CCHF: Clinical features

4-12 day incubation after tick exposure 2-7day incubation after direct contact with infected fluids Abrupt onset fever, chills, myalgia, severe headache Malaise, GI symptoms, anorexia Leukopenia, thrombocytopenia, hemoconcentration, proteinuria, elevated AST Hemorrhages may be profuse (hematomas, ecchymoses)
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PREVENTION OF CCHF
DEET repellents for skin Permethrin repellents for clothing
(0.5% permethrin should be applied to clothing ONLY)

Check for and remove ticks at least twice daily. If a tick attaches, do not injure or rupture the tick.
Remove ticks by grasping mouthparts at the skin surface using forceps and apply steady traction.
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Guanarito (Venezuelan Hemorrhagic Fever)

Venezuela, central plains Rodent borne (Zygodontomys brevicauda) Person-to-person transmission not documented Mortality 20-30% Therapy: Ribavirin(?)
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South American Hemorrhagic Fevers: Clinical features

1-2 week incubation Gradual onset fever, malaise, myalgias, anorexia Headache, abdominal pain, nausea, vomiting, orthostasis Petechiae (axillae, palate), gingival hemorrhage Neurologic signs (hyporeflexia, tremor, lethargy, hyperesthesia) Leukopenia, thrombocytopenia, proteinuria

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South American Hemorrhagic Fevers: Clinical features

70% Recovery in 7-8 days without sequelae, prolonged fatigue and weakness common. Severe disease
Severe hemorrhage Delerium, coma, convulsions Combined hemorrhagic/neurologic disease High mortality
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VHF: Supportive therapy

Rule out or treat febrile illnesses: malaria, rickettsia, leptospirosis, typhoid, dysentery Early hospitalization Distant medical evacuation associated with high mortality
Cautious sedation and analgesia

Careful hydration
Pressors, cardiotonic drugs Support of coagulation system
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Ribavirin
Guanosine nucleoside analog:
blocks viral replication by inhibiting IMP dehydrogenase

Licensed for treatment of RSV and HCV

Potential adverse effects:
Dose dependent reversible anemia

Pancreatitis Teratogen in rodents

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Ribavirin: toxicities
Teratogenic Extravascular hemolysis Bone marrow suppression
Rigors with abrupt iv administration Reversible hyperbilirubinemia, hyperuricemia with oral administration Pruritus, nausea, depression, cough
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 Programme Created By Dr.T.V.Rao MD for Medical and Paramedical Students in Developing World
Email doctortvrao@gmail.com

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