Viral Hemorrhagic Fevers
Or
The Viruses that you Desperately want to Avoid
Eric Gorgon Shaw, MD, FACEP, FAAEM, FAWM
Objectives
Describe the relevance of Viral Hemorrhagic Fevers (VHF) to
Wilderness Medicine
Describe geographical distribution of VHFs
Describe common clinical features of VHFs
Describe preventative measures for travel with potential
exposure
List therapeutic options for patients with VHF
List infection control precautions for healthcare providers caring
for patients with VHF
Lecture Overview
Pathophysiology & Common Clinical Findings
Virus-specific information
VHF from the perspective of the traveler
VHF from the perspective of the clinician
Case Presentation
Why Learn about Viral Hemorrhagic Fevers
at a WMS Conference?
Remote locations of outbreaks
Worldwide distribution
Relation to Travel Medicine
Fever in a traveler
Viral Hemorrhagic Fever
What is it?
An acute viral infection causing:
Diffuse vascular damage
Hemorrhage
Multisystem compromise
Relatively high mortality
Quick Overview: Who are they?
VHFs are:
Lipid-encapsulated
Single-strand RNA
Zoonotic (animal-borne)*
Geographically restricted by host
Persistent in nature (rodents, bats, mosquitoes, ticks,
livestock, monkeys, primates)
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
Not to be confused with…
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
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
Subconjunctival
hemorrhage
Ecchymosis
Petechiae
But the hemorrhage
itself is rarely lifethreatening.
Common Clinical Features:
Laboratory Findings
Leukopenia
Thrombocytopenia (not Lassa)
Proteinuria
Hepatic inflammation
Common Clinical Features:
Severe/End-stage
Multisystem compromise
Profuse bleeding
Consumptive coagulopathy/DIC
Encephalopathy
Shock
Death
BUT…
Symptoms/Signs vary with
the type of VHF
Quick Overview: Mortality
Case-Fatality
<10%: Dengue HF, Rift Valley Fever
53% (225/425): Ebola-Sudan in Uganda (2000).
81% (257/317): Ebola-Zaire in Kikwit, Zaire
(1995). (2/3 of patients were health care workers =
171 health care workers dead!)
90% (227/252): Marburg in Angola (2004-2005)
Arenaviridae
Spread to humans by rodent contact (virus found
in urine, feces, and other excreta)
Lassa Fever (West Africa)
New World HFs
Machupo (Bolivia)
Junin (Argentina)
Guanarito (Venezuela)
Sabia (Brazil)
Explosive Nosocomial outbreaks with Lassa &
Machupo
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
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
Arenaviridae: South American HFs
Rodent-borne
Potential for person-to-person transmission
Junin: uncommon
Machupo: probable
Guanarito: not-documented
Distinguishing characteristics:
Gradual onset
Hyporeflexia, hyperesthesia
High mortality (20-30%)
70% recovery in 7-8 days without sequelae
Therapy: Ribavirin (?)
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)
• Sin Nombre (1993 outbreak in SW US)
5 genera with over 350 viruses
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
Bunyaviridae: Rift Valley Fever
Transmission to humans
Aedes mosquito
Contact with blood/products of infected
livestock
Found throughout Africa, not just around the
Rift Valley
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?
Bunyaviridae: Crimean-Congo HF
Transmission to humans:
Ixodid, Hyalomma spp. ticks
Contact with animal blood/products
Person-to-person
Laboratory aerosols
Extensive geographical distribution
Crimean-Congo Hemorrhagic Fever
1940s: Crimean Peninsula
Hemorrhagic Fever in agricultural workers
• >200 cases
• 10% case-fatality
Maintained in livestock, but
unapparent/subclinical disease
Crimean-Congo Hemorrhagic Fever
Distinguishing features
Abrupt onset
Most humans infected will develop hemorrhagic
fever
Profuse hemorrhage
Mortality 15-40%
Therapy: Ribavirin
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)
Hantavirus
Worldwide distribution = Rodent distribution
Old World: Hemorrhagic Fever with Renal Syndrome
(HFRS)
•
•
•
•
Hantaan virus: eastern Asia (China, Russia, Korea)
Seoul virus: worldwide
Dobrova-Belgrade virus: Balkans
Puumala virus: Scandinavia, western Europe, Russia
New World: Hantavirus Pulmonary Syndrome (HPS)
(non-hemorrhagic)
•
•
•
•
•
Sin Nombre virus of US
New York virus of US
Black Creek Canal virus of US
Bayou virus of US
Andes virus of Argentina, Chile
Hantavirus: Hemorrhagic Fever
with Renal Syndrome (HFRS)
1951: Korea – Hemorrhagic Fever in UN
Troops
>3000 cases of acute febrile illness
• ~33% hemorrhagic manifestations
• 5-10% case-fatality
One of 7 HFs researched by US for
biological weapons
Hemorrhagic Fever with Renal Syndrome
(HFRS)
Distinguishing Features
Insidious onset
Intense headaches,
Blurred vision
kidney failure
• (causing severe fluid overload)
Mortality: 1-15%
Filoviridae
Ebola
Ebola-Zaire
Ebola-Sudan
Ebola-Ivory Coast
Ebola-Bundibugyo
(Ebola-Reston)
Marburg
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, EbolaBundibugyo, Ebola-Reston
Ebola-Reston imported to US, but only causes illness in nonhuman primates
Human-infectious subtypes found only in Africa
Filoviridae: Ebola
Sporadic Outbreaks (16 from 1976 – 2008)
First described in 1976 along the Ebola River in
Zaire (now Congo) and Sudan.
Ebola River, Zaire, 1976 (Ebola-Zaire)
• 318 cases, 88% mortality
Kikwit, Zaire, 1995 (Ebola-Zaire)
• 315 cases, 81% mortality
Uganda, 2000 (Ebola-Sudan)
• 425 cases, 53% mortality
Congo, 2007 (Ebola-Zaire)
• 264 cases, 71% mortality
Uganda, 2007-8 (Ebola-Bundibugyo)
• 149 cases, 25% mortality
Filoviridae: Ebola
Distinguishing features:
Acute onset
Weight loss/protration
25-89% 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
Sporadic outbreaks (8 from 1967 – 2008)
First seen in 1967, in simultaneous outbreaks of
laboratories in Marburg, Frankfurt, and Belgrade
Marburg, Frankfurt, Belgrade, 1967
• 32 cases, 21% mortality
Durba, DRC, 1998-2000
• 154 cases, 83% mortality
Angola, 2004-2005
• 252 cases, 90% mortality
Filoviridae: Marburg
Distinguising features
Sudden onset
Chest pain
Maculopapular rash on trunk
Pancreatitis
Jaundice
21-90% mortality
Flaviviridae
Yellow Fever
Dengue
Omsk Hemorrhagic Fever (OHF)
Kyanasur Forest
Yellow Fever
1649: First reported in Cuba
Enormous toll of soldiers during SpanishAmerican War (1898)
American
• 400 Combat deaths
• 2000 from Yellow Fever
Spanish
• 16,000 deaths from YF between 1895-1898 (out of an
original force of 230,000)
Flaviviridae: Yellow Fever
Transmission:
Aedes aegypti mosquito
Sylvatic Cycle
• Infected monkeys
Urban Cycle
• Human host
Yellow Fever
Distinguishing features
Biphasic infection
Common hepatic involvement & jaundice (thus,
its name)
Mortality: 15-50%
Flaviviridae: Dengue
Dengue Fever (DF)
Dengue Hemorrhagic Fever (DHF)
Dengue Shock Syndrome (DSS)
Four distinct serotypes
DEN-1, DEN-2, DEN-3, DEN-4
• Infection with one does NOT confer immunity to the others
 A person can become infected multiple times with Dengue
 Counterintuitively increases the risk for DHF with
subsequent infection
Transmission
Aedes aegypti, Aedes albopictus mosquito spp.
Sylvatic & Urban Cycles
Dengue Fever: History & Distribution
1779-1780: First reported epidemic of DF
Near simultaneous occurrence in Asia, Africa, North
America
After WWII: pandemic began in SE Asia
1950s: DHF emergence into the Pacific region &
Americas
Since discontinuation of Ae. aegypti eradication
program, DF/DHF range has expanded
Dengue
50-100 million cases of DF/year
~300,000 cases of CHF/year
Distinguishing Features
Sudden onset
Eye pain
Rash
Complications/sequelae uncommon
Illness less severe in younger children
2000 Bangladesh epidemic:
• no deaths in pts < 5y/o
• 82% of hospitalized patients were adults
Case-Fatality:
DF: <1%
DHF: 5-6%
DSS: 12-44%
Flaviviridae: Omsk Hemorrhagic Fever
Transmission
Tick bite: Dermacentor, Ixodes
• Host: rodents (water vole, muskrat)
Infected Animal Contact
Milk from infected goats, sheep.
1945-1947: First described in Omsk, Russia
Distribution: western Siberia regions of Omsk,
Novosibirsk, Kurgan and Tyumen
Omsk Hemorrhagic Fever
Distinguishing Features
Acute Onset
Biphasic infection
Complications
• Hearing loss
• Hair loss
• Psycho-behavioral difficulties
Mortality: 0.5 – 3%
Flaviviridae: Kyanasur Forest
Transmission:
Tick bite (Haemaphysalis
spinigera nymphs, Ixodes
petauristae)
Contact with infected
animal
Host: small rodents,
monkeys, shrews, bats,
porcupines
Distribution: limited to
Karnataka State, India
1957: First identified from
a sick monkey
Distinguishing
Features
Acute onset
Biphasic
Case-fatality: 3-5%
(400-500 cases
annually)
VHFs Prevention for the World-traveller
Vaccinations
Yellow Fever
Kyanasur Forest Disease?
Investigational/non-FDA-approved
Argentine HF
Rift Valley Fever
Hantavirus
Ongoing research
All the others
• Dengue Fever
• Filoviridae
VHFs Prevention for the World-traveller
Rodent Exposure Precautions
Don’t mess with live/dead rodents, or their burrows/nests
Don’t use rodent-infested cabins/shelters
Don’t pitch tents or sleep near rodent feces, burrows, or potential
rodent shelters (garbage dumps, woodpiles)
Avoid sleeping on the ground (cot >12 inches up, or tent w/ floor)
Keep food rodent-proof
Dispose of waste appropriately
VHF Prevention for the World-traveller
Mosquito Exposure Precautions
DEET (20-30%) on exposed skin
Permethrine on clothing, bednets
Headnets
Bednets
VHF Prevention for the World-traveller
Tick Exposure Precautions
DEET (20-30%) on exposed skin
Permethrine on clothing, bednets
Light-colored clothing
Routine tick-check
VHF Prevention for the World-traveller
Livestock & Animal Exposure Precautions
Know from where your food is coming
Avoid participation in birthing or butchering of
livestock or game
Wild monkeys don’t make good pets!
VHF for the Clinician:
Identification of Suspected Cases
Temperature > 101 F (38.3 C) for < 3 weeks
No predisposing factors for hemorrhagic
manifestations
2 or more of the following:
Hemorrhagic rash
Epistaxis
Hematemesis
Hemoptysis
Hematochezia/melena
Other hemorrhagic signs
No established alternative diagnosis
VHF for the Clinician
Exposure Precautions
Body Fluid Exposure
Gloves (double)
Face & Eye shields
Gowns (impermeable) w/ leg & shoe coverings
Masks (surgical v. N95)
Sharp Instrument Precautions
Hand-washing & disinfectants
Cadaver-exposure
Avoid
Prompt burial by trained teams
VHF for the Clinician:
Infection Control
CDC Publication: "Infection Control for Viral
Haemorrhagic Fevers in the African
Health Care Setting“
Dedicated medical equipment
Stethoscopes
BP cuffs
Etc.
Point-of-care analysis of routine labs, if available
VHF in the lab: BSL-4
High-level protection required for:
Laboratory manipulation
Mechanical generation of aerosols
Concentrated infectious material
Viral culture
VHF for the Clinician:
Differential Diagnosis
Meningococcemia
Acute Leukemia
Hepatitis
Rickettsial Infection
Leptospirosis
Thrombocytopenia Purpura (ITP or TTP)
Fever in a traveller
Malaria
Typhoid fever
VHF
Others
VHF for the Clinician:
Distinguishing Characteristics
Signs:
Eye pain: Dengue
Exudative Pharyngitis:
Lassa Fever
Jaundice: Yellow Fever
Anuria: RVF
Severe ecchymosis: CCHF
Marked wt. loss/prostration:
Filoviridae
Vision Loss: RVF
Hearing Loss: Omsk
Hair Loss: Omsk
Onset:
Insidious: Arenaviridae
Acute: Filoviridae,
Flaviviridae, RVF
Course
Incubation period: 2-21
days (varies by virus)
Biphasic: Flaviviridae
Laboratory
Absence of/minor
thrombocytopenia: Lassa
Convalescence
Deafness (20% Lassa)
VHF for the Clinician:
Diagnostics
Isolation of virus from tissue, cell culture
Serum antigen detection
ELISA
RT-PCR
Immunohistochemical staining of infected
tissue
VHF for the Clinician:
Treatment
Specific Therapy
Ribavirin (not FDA-licensed):
• Lassa Fever
• New World Arenaviruses
• Crimean-Congo Hemorrhagic Fever
Convalescent-phase plasma
• Argentine Hemorrhagic Fever (Junin)
Non-specific Therapy: Supportive Care
•
•
•
•
•
Fluid & electrolyte management
Oxygenation
Blood pressure support
Correct coagulopathies as needed
No antiplatelet/anticoagulant drugs, IM therapy
VHF for the Clinician:
Management of Exposures
Medical surveillance x 21
days
Potential exposures
Close contacts
High-risk exposures
(percutaneous/mucocutaneous
exposure)
Percutaneous/mucocutaneous
exposure to infected
individual
Percutaneous: wash thoroughly
with soap & water
Mucocutaneous: flush/irrigate
with saline or water
Prophylaxis
Ribavirin for close
contacts
• Lassa fever
• Crimean-Congo HF
Convalescent
abstinence from sex x
3 months (!)
Arenaviridae
Filoviridae
VHF for the Clinician:
Infection Control
Risk Category
Description
Casual Contacts
Remote contact with
index case (eg, stayed
in same hotel)
Close Contacts
More than casual (eg, Place under surveillance
living with contact,
once index case
caretaker, shook hands confirmed
with contact)
High-Risk Contacts Mucous membrane
Surveillance
VHF not spread by
casual contact, no
special surveillance
Place under surveillance
contact (egg, kissing, as soon as VHF
or penetrating injury
diagnosis considered in
involving contact with index case
index case’s blood
such as needlestick)
Case Presentation
38 y/o male complains of fever, chills, diarrhea,
back pain, sore throat
• (Easy! Viral syndrome. Who’s next!)
PE: Temp 103.6 F, BP 90/60
Skin w/ diffuse ecchymosis, maculopapular rash on
extremities
• (Aw…Crap!)
Travel History: just got back from a 4 month stay
on his farms in Liberia and Sierra Leone
• (Oh…Frick!)
Case Presentation:
Hospital Course
Day #4:
Patient developed ARDS
• Despite empiric antibiotics (incl. antimalarials)
Intubated
Day #5:
Local & State Health Depts. notified.
Investigational New Drug (IND) protocol to
administer ribavirin
Patient died before ribavirin administered
Case Presentation:
Post-mortem
Samples sent to CDC
Lassa Fever confirmed
•
•
•
•
Serum antigen detection
Virus isolation in cell culture
RT-PCR sequencing of virus
Immunohistochemical staining of liver samples
Case Presentation:
Exposure Management/Infection Control
5 High risk contacts
5 (wife, kids, visitor)
183 Low risk contacts
9 other family members
139 HCW at hospital: 42 labworkers, 32 RN, 11 MD
16 labworkers in Virginia and California
19 passengers on flight from London to Newark
No additional cases
Summary
You probably won’t be carrying Biohazard
Level 4 gear.
If you don’t have religion, this might be a
good time…
Don’t breathe rat poop!