Viral Hemorrhagic
Fever
Overview Organism
History
Epidemiology
Transmission
Disease in Humans
Disease in Animals
Prevention and Control
What is Viral Hemorrhagic Fever?
Severe multisystem syndrome
Diffuse Damage to overall vascular system
Symptoms often accompanied by hemorrhage
Rarely life threatening in itself
Includes conjunctivitis, petechia, echymosis
Relatively high mortality
Quick Overview: Who are they? 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)
Survival dependent on an animal or insect host, for the natural reservoir
Quick Overview: Who are they? Arenaviridae
Lassa Fever
Argentine HF (Junin)
Bolivian HF (Machupo)
Brazilian HF (Sabia)
Venezuelan HF (Guanarito)
Bunyaviridae Rift Valley Fever (RVF)
Crimean Congo HF (CCHF)
Hantavirus (Hemorrhagic Fever
with Renal Syndrome (HFRS))
Hantavirus Pulmonary
Syndrome (HPS)
Filoviridae Marburg
Ebola
Flaviviridae Yellow Fever
Dengue Fever
Omsk HF
Kyasanur Forest Disease
Quick Overview: How do we get
infected?
Rodents & Arthropods, both reservoir &
vector
Bites of infected mosquito or tick
Inhalation of rodent excreta
Infected animal product exposure
Person-to-Person
Blood/body fluid exposure
Airborne potential for some arenaviridae, filoviridae
Arenaviridae
• Junin virus• Machupo virus• Guanarito virus• Lassa virus• Sabia virus
Arenaviridae History First isolated in 1933
1958: Junin virus - Argentina
First to cause hemorrhagic fever
Argentine hemorrhagic fever
1963: Machupo virus – Bolivia
Bolivian hemorrhagic fever
Guanarito (Venezuela)
Sabia (Brazil)
1969: Lassa virus – Nigeria
Lassa fever
Arenavirus Structure
Single-stranded, bi-segmented RNA genome
Large segment (7200nt), small one (3500nt)
Lipid envelope with
8-10nm club-shaped
projections
Arenaviridae Transmission
Virus transmission and amplification occurs in rodents
Shed virus through urine, feces, and other excreta
Human infection Contact with excreta
Contaminated materials
Aerosol transmission
Person-to-person transmission
Arenaviridae in Humans
Incubation period 10–14 days
Fever and malaise 2–4 days
Hemorrhagic stage
Hemorrhage, leukopenia, thrombocytopenia
Neurologic signs
Arenaviridae: Lassa Fever
First seen in Lassa, Nigeria in 1969.
Now in all countries of West Africa
5-14% of all hospitalized febrile illness
Rodent-borne (Mastomys natalensis)
Interpersonal transmission
Direct Contact
Sex
Breast Feeding
Lassa Fever Virus
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
Lassa Fever
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
Bunyaviridae• Rift Valley Fever virus
• Crimean-Congo Hemorrhagic Fever virus
• Hantavirus
L-segment codes for an L-protein (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 N-protein (nucleocapsid protein).
Bunyaviridae
Rift Valley Fever (RVF)
Crimean-Congo Hemorrhagic Fever (CCHF)
Hantavirus
Old World: Hemorrhagic fever with renal syndrome (HFRS)
New World: Hantavirus pulmonary syndrome (HPS)
5 genera with over 350 viruses
Bunyaviridae Transmission
Arthropod vector
Exception – Hantaviruses
RVF – Aedes mosquito
CCHF – Ixodid tick
Hantavirus – Rodents
Less common
Aerosol
Exposure to infected animal tissue
Bunyaviridae
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
Predominantly a disease of sheep and cattle
1930: First identified in an infected newborn lamb in Egypt
In livestock:
~100% abortion
90% mortality in young
5-60% mortality in adults
Rift Valley Fever
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
Distinguishing features
Abrupt onset
Most humans infected will develop hemorrhagic fever
Profuse hemorrhage
Mortality 15-40%
Therapy: Ribavirin
Bunyaviridae: Crimean-Congo
HF
Transmission to humans: Ixodid, Hyalomma spp. ticks
Contact with animal blood/products
Person-to-person
Laboratory aerosols
Extensive geographical distribution
Bunyaviridae: Hantaviruses
Transmission to humans:
Exposure to rodent saliva and excreta Inhalation
Bites
Ingestion in contaminated food/water (?)
Person-to-person (Andes virus in Argentina)
Hemorrhagic Fever with
Renal Syndrome (HFRS)
Distinguishing Features
Insidious onset
Intense headaches,
Blurred vision
kidney failure
(causing severe fluid overload)
Mortality: 1-15%
Bunyaviridae Humans
RVF
Incubation period – 2-5 days
0.5% - Hemorrhagic Fever
CCHF
Incubation period – 3-7 days
Hemorrhagic Fever - 3–6 days following clinical signs
Hantavirus
Incubation period – 7–21 days
HPS and HFRS
Ebola
Marburg
Ebola
Ebola-Zaire
Ebola-Sudan
Ebola-Ivory Coast
Ebola-Bundibugyo
(Ebola-Reston)
Marburg
Filoviridae
Filoviridae History 1967: Marburg, Frankfurt, Belgrade
European laboratory workers
1976: Ebola virus Ebola Zaire
Ebola Sudan
1989 and 1992: Ebola Reston USA and Italy
Imported macaques from Philippines
1994: Ebola Côte d'Ivoire
Filoviridae Transmission
Reservoir is UNKNOWN Bats implicated with Marburg
Intimate contact
Nosicomial transmission Reuse of needles and syringes
Exposure to infectious tissues, excretions, and hospital wastes
Aerosol transmission Primates
Filoviridae: Ebola
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
Filoviridae: Marburg
Transmission:
Animal host unknown
Person-to-person
infected animal blood/fluid exposure
Indigenous to Africa
Uganda
Western Kenya
Zimbabwe
Democratic Republic of Congo
Angola
Filoviridae: Marburg
Distinguising features
Sudden onset
Chest pain
Maculopapular rash on trunk
Pancreatitis
Jaundice
21-90% mortality
Filoviridae Humans
Most severe hemorrhagic fever
Incubation period: 4–10 days
Abrupt onset
Fever, chills, malaise, and myalgia
Hemorrhage and DIC
Death around day 7–11
Painful recovery
Flaviviridae
• Dengue virus
• Yellow Fever virus
• Omsk Hemorrhagic Fever virus
• Kyassnur Forest Disease virus
Flaviviridae History
1648 : Yellow Fever described
17th–20th century
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
Arthropod vector
Yellow Fever and Dengue viruses Aedes aegypti
Sylvatic cycle
Urban cycle
Kasanur Forest Virus Ixodid tick
Omsk Hemorrhagic Fever virus Muskrat urine, feces, or blood
Flaviviridae Epidemiology Yellow Fever Virus – Africa and Americas
Case fatality rate – varies
Dengue Virus – Asia, Africa, Australia, and Americas
Case fatality rate – 1-10%
Kyasanur Forest virus – India
Case fatality rate – 3–5%
Omsk Hemorrhagic Fever virus – Europe
Case fatlity rate – 0.5–3%
Flaviviridae Humans
Yellow Fever Incubation period – 3–6 days Short remission
Dengue Hemorrhagic Fever 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
Dengue Fever (DF) /Fatality: <1%
Dengue Hemorrhagic Fever (DHF)/ Fatality: 5-6%
Dengue Shock Syndrome (DSS) /Fatality 12-44%
Four distinct serotypes DEN-1, DEN-2, DEN-3, DEN-4
Distinguishing Features Sudden onset
Eye pain
Rash
Complications/sequelae uncommon
Illness less severe in younger children
Omsk Hemorrhagic Fever
Distinguishing Features
Acute Onset
Biphasic infection
Complications
Hearing loss
Hair loss
Psycho-behavioral difficulties
Mortality: 0.5 – 3%
Flaviviridae: Kyanasur Forest
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
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
Multisystem Involvement
Hematopoietic
Neurologic
Pulmonary
Hepatic (Ebola, Marburg, RVF, CCHF, Yellow Fever)
Renal (Hantavirus)
Hemorrhagic complications
Hepatic damage
Consumptive coagulopathy
Primary marrow injury to megakaryocytes
Common Clinical Features:
Early/Prodromal Symptoms
Fever
Myalgia
Malaise
Fatigue/weakness
Headache
Dizziness
Arthralgia
Nausea
Non-bloody diarrhea
Common Clinical Features:
Progressive Signs
Conjunctivitis
Facial & thoracic flushing
Pharyngitis
Exanthems
Periorbital edema
Pulmonary edema
Hemorrhage
Subconjunctivalhemorrhage
Ecchymosis
Petechiae
But the hemorrhage itself is rarely life-threatening.
Symptoms
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:
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 Multisystem compromise
Profuse bleeding
Consumptive coagulopathy/DIC
Encephalopathy
Shock
Death
Clinical Symptoms
More severe
Bleeding under skin
Petechiae, echymoses, conjunctivitis
Bleeding in internal organs
Bleeding from orifices
Blood loss rarely cause of death
< 2 days after viral infection1. Cytolysis by perforin-granzyme2. IFN γ: protect uninfected cells
and activate macrophages3. Mediate ADCC
1. Phagocytosis of virus and virus-infected cells
2. Kill virus-infected cells
3. Produce antiviral molecules: TNFα, NO, IFNα
Plasmcytoid DC2
1.A major IFNα producer after viral infection
2. Toll-like receptor -3
IFNγ
Major antiviral cells in early phrase
Protection
Killing
Adaptive (specific) immune response to viral infection
Neighboring
uninfected
cells
IFNγ IFNα and IFNβ
1
2
34
5
6
7
8
9
Cambridge University Immunology Lectures (www)
Innate & Adaptive Immunity Timeline
Lab studies
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:
• 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
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
Decrease person-to-person transmission
Isolation of infected individuals
Prevention and Control 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
Insects
Use insect repellents
Proper clothing and bed nets
Window screens and other barriers to insects
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
Experimental vaccines under study Argentine HF, Rift Valley Fever, Hantavirus
and Dengue HF
VHF Personal Protective Equipment
Airborne and Contact isolation for patients with respiratory 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 respiratorysymptoms
• 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?
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