Viral Hemorrhagic
Fever
Overview
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Organism
History
Epidemiology
Transmission
Disease in Humans
Disease in Animals
Prevention and Control
What is Viral Hemorrhagic Fever?
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Severe multisystem syndrome
Diffuse Damage to overall vascular system
Symptoms often accompanied by
hemorrhage
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Rarely life threatening in itself
Includes conjunctivitis, petechia, echymosis
Relatively high mortality
Quick Overview: Who are they?
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VHFs are:
Enveloped Lipid-encapsulated
 Single-strand RNA
 Zoonotic (animal-borne)
 Geographically restricted by host
 Persistent in nature (rodents, bats,
mosquitoes, ticks, livestock,
monkeys, and primates)
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Survival dependent on an animal or
insect host, for the natural reservoir
Quick Overview: Who are they?
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Arenaviridae
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Lassa Fever
Argentine HF (Junin)
Bolivian HF (Machupo)
Brazilian HF (Sabia)
Venezuelan HF (Guanarito)
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Filoviridae
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Flaviviridae
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Bunyaviridae
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Rift Valley Fever (RVF)
Crimean Congo HF (CCHF)
Hantavirus (Hemorrhagic Fever
with Renal Syndrome (HFRS))
Hantavirus Pulmonary
Syndrome (HPS)
Marburg
Ebola
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Yellow Fever
Dengue Fever
Omsk HF
Kyasanur Forest Disease
Quick Overview: How do we get
infected?
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Rodents & Arthropods, both reservoir &
vector
Bites of infected mosquito or tick
 Inhalation of rodent excreta
 Infected animal product exposure
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Person-to-Person
Blood/body fluid exposure
 Airborne potential for some arenaviridae, filoviridae
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Arenaviridae
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Junin virus
Machupo virus
Guanarito virus
Lassa virus
Sabia virus
Arenaviridae History
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First isolated in 1933
1958: Junin virus - Argentina
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1963: Machupo virus – Bolivia
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First to cause hemorrhagic fever
Argentine hemorrhagic fever
Bolivian hemorrhagic fever
Guanarito (Venezuela)
Sabia (Brazil)
1969: Lassa virus – Nigeria
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Lassa fever
Arenavirus Structure
Single-stranded, bi-segmented RNA
genome
 Large segment (7200nt), small one
(3500nt)
 Lipid envelope with
8-10nm club-shaped
projections
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Arenaviridae Transmission
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Virus transmission and amplification
occurs in rodents
Shed virus through urine, feces, and other
excreta
Human infection
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Contact with excreta
Contaminated materials
Aerosol transmission
Person-to-person transmission
Arenaviridae in Humans
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Incubation period 10–14 days
Fever and malaise 2–4 days
Hemorrhagic stage
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Hemorrhage, leukopenia, thrombocytopenia
Neurologic signs
Arenaviridae: Lassa Fever
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First seen in Lassa, Nigeria in 1969.
Now in all countries of West Africa
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5-14% of all hospitalized febrile illness
Rodent-borne (Mastomys natalensis)
Interpersonal transmission
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Direct Contact
Sex
Breast Feeding
Lassa Fever Virus
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Background
Discovered in 1969 when
two missionary nurses died
in Lassa, Nigeria, W. Africa
 It expands to Guinea,
Liberia, Sierra Leone
 100 to 300 thousand
cases per year with approx.
5,000 deaths
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Lassa Fever
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Distinguishing Features
 Gradual onset
 Retro-sternal pain
 Exudative pharyngitis
 Hearing loss in 25% may be persistent
 Spontaneous abortion
Mortality 1-3% overall (up to 50% in
epidemics)
Therapy: Ribavirin
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Bunyaviridae
Rift Valley Fever virus
Crimean-Congo Hemorrhagic Fever virus
Hantavirus
L-segment codes for an Lprotein (the RNA dependent
RNA polymerase);
M segment codes for two
surface glycoproteins G1 and G2
which form the envelope spikes;
S segment codes for an Nprotein (nucleocapsid protein).
Bunyaviridae
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Rift Valley Fever (RVF)
Crimean-Congo Hemorrhagic Fever (CCHF)
Hantavirus
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Old World: Hemorrhagic fever with renal
syndrome (HFRS)
New World: Hantavirus pulmonary syndrome
(HPS)
5 genera with over 350 viruses
Bunyaviridae Transmission
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Arthropod vector
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Exception – Hantaviruses
RVF – Aedes mosquito
CCHF – Ixodid tick
Hantavirus – Rodents
Less common
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Aerosol
Exposure to infected animal tissue
Bunyaviridae
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Transmission to humans
 Arthropod vector (RVF, CCHF)
 Contact with animal blood or products of
infected livestock
 Rodents (Hantavirus)
 Laboratory aerosol
 Person-to-person transmission with CCHF
Rift Valley Fever
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Predominantly a disease of sheep and
cattle
1930: First identified in an infected
newborn lamb in Egypt
In livestock:
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~100% abortion
90% mortality in young
5-60% mortality in adults
Rift Valley Fever
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Asymptomatic or mild illness in humans
Distinguishing Characteristics
 Hemorrhagic complications rare (<5%)
 Vision loss (retinal hemorrhage,
vasculitis) in 1-10%
Overall mortality 1%
Therapy: Ribavirin?
Crimean-Congo Hemorrhagic
Fever
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Distinguishing features
Abrupt onset
 Most humans infected will develop
hemorrhagic fever
 Profuse hemorrhage
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Mortality 15-40%
 Therapy: Ribavirin
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Bunyaviridae: Crimean-Congo
HF
 Transmission to humans:
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Ixodid, Hyalomma spp. ticks
Contact with animal blood/products
Person-to-person
Laboratory aerosols
Extensive geographical distribution
Bunyaviridae: Hantaviruses
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Transmission to humans:
 Exposure to rodent saliva and excreta
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Inhalation
Bites
Ingestion in contaminated food/water (?)
Person-to-person (Andes virus in
Argentina)
Hemorrhagic Fever with
Renal Syndrome (HFRS)
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Distinguishing Features
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Insidious onset
Intense headaches,
Blurred vision
kidney failure
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(causing severe fluid overload)
Mortality: 1-15%
Bunyaviridae Humans
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RVF
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CCHF
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Incubation period – 2-5 days
0.5% - Hemorrhagic Fever
Incubation period – 3-7 days
Hemorrhagic Fever - 3–6 days
following clinical signs
Hantavirus
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Incubation period – 7–21 days
HPS and HFRS
Filoviridae
Ebola
 Ebola-Zaire
 Ebola-Sudan
 Ebola-Ivory Coast
 Ebola-Bundibugyo
 (Ebola-Reston)
 Marburg
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Ebola
Marburg
Filoviridae History
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1967: Marburg, Frankfurt, Belgrade
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1976: Ebola virus
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Ebola Zaire
Ebola Sudan
1989 and 1992: Ebola Reston
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European laboratory workers
USA and Italy
Imported macaques from Philippines
1994: Ebola Côte d'Ivoire
Filoviridae Transmission
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Reservoir is UNKNOWN
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Intimate contact
Nosicomial transmission
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Bats implicated with Marburg
Reuse of needles and syringes
Exposure to infectious tissues, excretions, and
hospital wastes
Aerosol transmission
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Primates
Filoviridae: Ebola
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Rapidly fatal febrile hemorrhagic illness
Transmission:
 bats implicated as reservoir
 Person-to-person
 Nosocomial
Five subtypes
 Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast,
Ebola-Bundibugyo, Ebola-Reston
 Ebola-Reston imported to US, but only causes
illness in non-human primates
Human-infectious subtypes found only in Africa
Filoviridae: Ebola
 Distinguishing
features:
Acute onset
 Weight loss/protration
 25-90% case-fatality
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Filoviridae: Marburg
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Transmission:
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Animal host unknown
Person-to-person
infected animal blood/fluid exposure
Indigenous to Africa
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Uganda
Western Kenya
Zimbabwe
Democratic Republic of Congo
Angola
Filoviridae: Marburg
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Distinguising features
 Sudden onset
 Chest pain
 Maculopapular rash on trunk
 Pancreatitis
 Jaundice
21-90% mortality
Filoviridae Humans
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Most severe hemorrhagic fever
Incubation period: 4–10 days
Abrupt onset
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Fever, chills, malaise, and myalgia
Hemorrhage and DIC
Death around day 7–11
Painful recovery
Flaviviridae
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Dengue virus
Yellow Fever virus
Omsk Hemorrhagic Fever virus
Kyassnur Forest Disease virus
Flaviviridae History
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1648 : Yellow Fever described
17th–20th century
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Yellow Fever and Dengue outbreaks
1927: Yellow Fever virus isolated
1943: Dengue virus isolated
1947 Omsk Hemorrhagic Fever virus
isolated
1957: Kyasanur Forest virus isolated
Flaviviridae Transmission
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Arthropod vector
Yellow Fever and Dengue viruses
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Sylvatic cycle
Urban cycle
Kasanur Forest Virus
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Aedes aegypti
Ixodid tick
Omsk Hemorrhagic Fever virus
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Muskrat urine, feces, or blood
Flaviviridae Epidemiology
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Yellow Fever Virus – Africa and Americas
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Dengue Virus – Asia, Africa, Australia, and
Americas
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Case fatality rate – 1-10%
Kyasanur Forest virus – India
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Case fatality rate – varies
Case fatality rate – 3–5%
Omsk Hemorrhagic Fever virus – Europe
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Case fatlity rate – 0.5–3%
Flaviviridae Humans
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Yellow Fever
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Dengue Hemorrhagic Fever
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Incubation period – 3–6 days Short remission
Incubation period – 2–5 days
Infection with different serotype
Kyasanur Forest Disease
Omsk Hemorrhagic Fever Lasting sequela
Yellow Fever
 Distinguishing
features
 Biphasic infection
 Common hepatic involvement
& jaundice
 Mortality: 15-50%
Flaviviridae: Dengue
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Dengue Fever (DF) /Fatality: <1%
Dengue Hemorrhagic Fever (DHF)/ Fatality: 5-6%
Dengue Shock Syndrome (DSS) /Fatality 12-44%
Four distinct serotypes
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Distinguishing Features
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DEN-1, DEN-2, DEN-3, DEN-4
Sudden onset
Eye pain
Rash
Complications/sequelae uncommon
Illness less severe in younger children
Omsk Hemorrhagic Fever
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Distinguishing Features
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Acute Onset
Biphasic infection
Complications
Hearing loss
 Hair loss
 Psycho-behavioral difficulties
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Mortality: 0.5 – 3%
Flaviviridae: Kyanasur Forest
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Distribution: limited to Karnataka
State, India
Distinguishing Features
 Acute onset
 Biphasic
Case-fatality: 3-5% (400-500 cases
annually)
Symptoms/Signs vary
with the type of VHF
Common Pathophysiology
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Small vessel involvement
 Increased vascular permeability
 Multiple cytokine activation
 Cellular damage
 Abnormal vascular regulation:
 Early -> mild hypotension
 Severe/Advanced -> Shock
Viremia
 Macrophage involvement
 Inadequate/delayed immune response
Common Pathophysiology
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Multisystem Involvement
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Hematopoietic
Neurologic
Pulmonary
Hepatic (Ebola, Marburg, RVF, CCHF, Yellow Fever)
Renal (Hantavirus)
Hemorrhagic complications
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Hepatic damage
Consumptive coagulopathy
Primary marrow injury to megakaryocytes
Common Clinical Features:
Early/Prodromal Symptoms
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Fever
Myalgia
Malaise
Fatigue/weakness
Headache
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Dizziness
Arthralgia
Nausea
Non-bloody diarrhea
Common Clinical Features:
Progressive Signs
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Conjunctivitis
Facial & thoracic flushing
Pharyngitis
Exanthems
Periorbital edema
Pulmonary edema
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Hemorrhage
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Subconjunctival
hemorrhage
Ecchymosis
Petechiae
But the hemorrhage
itself is rarely lifethreatening.
Symptoms
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Incubation period of 6-21 days
80% of human infections are asyptomatic
Onset is slow: fever, weakness, & malaise
Few days: headache, pharyngitis, muscle pain,
retrostinal & abdominal pain, nausea, vomiting,
conjunctivitis, diarrhea, cough, & proteinuria
Severe cases:
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facial swelling, lung cavity fluid, hemorrhaging, hyopotension,
Neurological problems: tremors, encephalitis, hair loss, gait
disturbance, deafness
95% death rate among pregnant women & spontaneous
abortion
Common Clinical Features:
Severe/End-stage
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Multisystem compromise
Profuse bleeding
Consumptive coagulopathy/DIC
Encephalopathy
Shock
Death
Clinical Symptoms
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More severe
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Bleeding under skin
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Petechiae, echymoses, conjunctivitis
Bleeding in internal organs
Bleeding from orifices
Blood loss rarely cause of death
Major antiviral cells in early phrase
Plasmcytoid DC2
1.A major IFNα producer after viral infection
2. Toll-like receptor -3
< 2 days after viral infection
1.Cytolysis by perforin-granzyme
2.IFN γ: protect uninfected cells
and activate macrophages
3.Mediate ADCC
IFNγ
1. Phagocytosis of virus and virus-infected cells
2. Kill virus-infected cells
3. Produce antiviral molecules: TNFα, NO, IFNα
Adaptive (specific) immune response to viral infection
9
7
5
6
8
IFNγ
IFNα and IFNβ
Neighboring
uninfected
cells
1
3
4
2
Protection
Killing
Innate & Adaptive Immunity Timeline
Cambridge University Immunology Lectures (www)
Lab studies
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Complete Blood Count
 Leucopenia, leucocytosis, thrombocytopenia,
hemoconcentration, DIC
Liver enzymes Alb
Proteinuria universal
Serological tests – Ab not detected acute phase; Direct
examination blood/tissues for viral Ag enzyme
immunoassay.
Immunohistochemical staining liver tissue
Virus isolation in cell culture
RT-PCR sequencing of virus
Electron microscopy specific and sensitive
Treatment
 Supportive care:
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Fluid and electrolyte management
Hemodynamic monitoring
Ventilation and/or dialysis support
Steroids for adrenal crisis
Anticoagulants, IM injections,
Treat secondary bacterial infections
Treatment
 Manage severe bleeding complications
• Cryoprecipitate (concentrated clotting factors)
• Platelets
• Fresh Frozen Plasma
• Heparin for DIC
 Ribavirin in vitro activity vs.
• Lassa fever
• New World Hemorrhagic fevers
• Rift Valley Fever
• No evidence to support use in Filovirus or
Flavivirus infections
Prevention and
Control
Prevention
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Nosocomial: Complete equipment
sterilization & protective clothing
House to house rodent trapping
Better food storage & hygiene
Cautious handling of rodent if used as food
source
If human case occurs
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Decrease person-to-person transmission
Isolation of infected individuals
Prevention and Control
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Avoid contact with host species
 Rodents
Control rodent populations
 Discourage rodents from entering or living in human
populations
 Safe clean up of rodent nests and droppings
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Insects
Use insect repellents
 Proper clothing and bed nets
 Window screens and other barriers to insects
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Vaccination
 Argentine and Bolivian HF
• PASSIVE IMMUNIZATION
Treat with convalescent serum containing
neutralizing antibody or immune globulin
 Yellow Fever
• ACTIVE IMMUNIZATION
Travelers to Africa and South America
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Experimental vaccines under study
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Argentine HF, Rift Valley Fever, Hantavirus
and Dengue HF
VHF Personal Protective Equipment
 Airborne and Contact isolation for patients with respiratory
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symptoms
• N-95 or PAPR mask
• Negative pressure isolation
• Gloves
• Gown
• Fitted eye protection and shoe covers if going to be exposed to
splash body fluids
Droplet and Contact isolation for patients without respiratory
symptoms
• Surgical mask
• Gloves
• Gown
• Fitted eye protection and shoe covers if going to be exposed to
splash body fluids
Environmental surfaces
• Cleaned with hospital approved disinfectant
• Linen incinerated, autoclaved, double-bagged for wash
Why do VHFs make good
Bioweapons?
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Disseminate through aerosols
Low infectious dose
High morbidity and mortality
Cause fear and panic in the public
No effective vaccine
Available and can be produced in large quantity
Research on weaponization has been conducted