Viral Hemorrhagic Fevers (VHF)
Amber M. Vasquez, MD
Assistant Professor, Division of Infectious Diseases
Associate Program Director, Infectious Diseases Fellowship
The Ohio State University Wexner Medical Center
* Please contact Jose A. Bazan, DO | jose.bazan@osumc.edu with questions about this module.
Learning Objectives
At the end of this module
you will learn to:
 Describe the structure and microbial physiology of
Hemorrhagic Fever viruses and integrate this information
with the human pathophysiologic correlates

Describe physical and chemical properties of Hemorrhagic Fever
viruses

Describe the replication of Hemorrhagic Fever viruses

Describe the underlying genetic mechanisms of Hemorrhagic Fever
viruses

Describe the physiology of Hemorrhagic Fever viruses
 Identify the normal human immune response to infection
with Hemorrhagic Fever viruses
Learning Objectives
 Recognize the epidemiology and ecology of infection
due to Hemorrhagic Fever viruses
 Describe and differentiate the principles of laboratory
diagnosis for Hemorrhagic Fever viral infections
 Describe the treatment, prevention and control of
Hemorrhagic Fever viral infections
Hemorrhagic Fever viruses
 Filoviridae


Marburg virus
Ebola virus
 Flavivirdae


Yellow Fever virus
Dengue virus
- Japanese Encephalitis
- St. Louis Encephalitis
- West Nile Virus
…and more
 Bunyaviridae


Rift Valley Fever virus
Hantavirus
 Arenaviridae

Lassa Fever virus
- Guanarito Virus: Venezuelan hemorrhagic fever
- Machupo Virus: Bolivian hemorrhagic fever
…and more
Marburg and Ebola
 Filoviruses


Filamentous, enveloped, negative-strand RNA viruses
Severe or fatal hemorrhagic fevers
Ebola virion
php.med.unsw.edu.au
www.utmb.edu
Structure and Replication
viralzone.expasy.org
Pathogenesis
Lancet 2011;377:849-62
Epidemiology
 Mostly Sub-Saharan Africa
 Endemic in fruit bats, wild monkeys
Contact with animal reservoir

Human-to-human spread via
contact with infected blood or
secretions
 Monkey Handlers
 Healthcare exposures



Accidental Injection
Contaminated Syringes
Healthcare workers in close contact
www.who.int/csr/disease/ebola/Global_EbolaOutbreakRisk_20090510
2014 Ebola Outbreak
 West Africa





Sierra Leone
Guinea
Liberia
Nigeria, Senegal
United States, Mali, Spain
 Contributing factors




Sheer volume of cases
Strained infrastructure
Personal Protective Equipment
Local burial customs
http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/previous-updates.html
Clinical Syndromes
 Most severe causes of VHFs
 Incubation period typically 5 – 10 days
(up to 21 days)
Case fatality rate
of up to 90%
 Flu-like illness (fever, malaise)
 Nausea, vomiting, diarrhea; possible cough, pharyngitis
 May have photophobia, CNS symptoms (somnolence, delirium)
 Day 5: Maculo-papular rash may develop on trunk
 Subsequent hemorrhage from multiple sites (esp. GI tract)
 Week 2: Clinical improvement vs. Death from shock with multiorgan failure
Laboratory Diagnosis
 Biosafety Level 4 Isolation
 Marburg virus – rapid tissue culture growth
 Ebola virus may require animal inoculation
jamanetwork.com
 Eosinophilic cytoplasmic inclusion bodies
 Viral antigen detection in tissue by direct
immunoflourescence and in fluids by ELISA
 RT-PCR amplification in secretions
Macrophage
 IgM/IgG to filoviruses; false (+)’s  confirm testing
Journal of Infectious Diseases 1999;179 (Suppl 1):S54-9
Treatment and Infection Control
 No definitive management and no vaccine
 Supportive care

Replacement of coagulation factors and platelets as needed
 Antibody-containing serum and interferon therapy
 Containment is key!




Standard precautions
Mask, gloves, gown, goggles
Appropriate cleaning of medical supplies
Proper burial techniques
microbewiki.kenyon.edu
Yellow Fever and Dengue
 Flaviviruses
Yellow Fever virions
hardinmd.lib.uiowa.edu
Dengue Fever virions
www.stanford.edu
Structure and Replication
“Flavivirus”
cross-section
www.niaid.nih.gov
Pathogenesis
 Arthropod-borne viruses
(arboviruses)
 Aedes aegypti mosquito
 Human and Nonhuman
primate reservoir


Smaller mammals maintain
viremia
Humans are dead-end hosts
Immunity
 Humoral and cellular immunity
 Viral replication  Interferon  Stimulates innate and
immune responses  Rapid onset flu-like illness
 IgM blocks viremic spread
 Inflammation from cell-mediated response
 Weakens vasculature; causes rupture/hemorrhage
 Non-neutralizing antibody can enhance viral uptake
 Worsens symptoms on repeat infection
Epidemiology – Yellow Fever
 Sub-Saharan Africa
 Tropical S. America
 Summer months
 Rainy season
 Standing water, drainage
ditches, open sewers
 Winter – vector not present;
virus dormant in arthropod
larvae/eggs; migrating birds
www.who.int
Epidemiology – Dengue
www.yalescientific.org
Clinical Syndrome
Yellow Fever
 Most benign, self-limiting
 Incubation 3-6 days
 Fever, chills, myalgia, back
pain, severe headache




Most resolve after this
~15% progress to severe disease
High fever, jaundice, hepatitis,
hyperbilirubinemia, hemorrhage
Shock, multi-organ failure
Clinical Syndrome
Dengue
 Most benign, self-limiting

50-80% are asymptomatic or have
undifferentiated fever
 4 – 7 day incubation period
 Classic Dengue Fever

“Breakbone Fever”
 Dengue Hemorrhagic Fever

Bruises, epistaxis, gum and GI bleed
 Dengue Shock Syndrome

Hypotension
Laboratory Diagnosis
 IgM/IgG ELISA

Primary method of diagnosis in acute illness from Dengue

IgM (+) after 5 days from symptom onset (follow seroconversion)

IgG titers for recent or past infection (4-fold increase)

False positive risk – crossreactivity with other flaviviruses or
vaccinations
 RT-PCR from serum, CSF, autopsy tissue in first 7 days

Serum PCR to detect viremia is test of choice for Yellow Fever
 Viral culture not routinely done
Treatment and Prevention
 Supportive care only
Biosafety Level 3 or 4
 Yellow Fever Vaccine

Live vaccine

Confers lifelong immunity

Fever, myalgias, headache,
nausea/emesis 2 – 5 days after
administration

Only for those going to an endemic
region
 Mosquito vector control
profiles.nlm.nih.gov
Rift Valley Fever and Hantavirus
 Bunyaviruses
 “Supergroup” of 200 enveloped, segmented, negativestrand RNA viruses
Rift Valley Fever
web.uct.ac.za/depts/mmi/stannard/emimages.html
Hantavirus particle
virology-online.com/viruses/Hantaviruses
Structure and Replication
 Nucleocapsid




L RNA – large
M RNA – medium
S RNA – small
RNA Polymerase
 Replicate similar to other
enveloped, negativestrand RNA viruses
Pathogenesis
 Rift Valley Fever – arbovirus



Reservoir: Livestock (cattle, buffalo, sheep, goats)
Vector: mosquito (Aedes genus)
Humans infected by bite of mosquito or exposure to infected
tissue of the animal (more common)
Deer mouse
 Hantavirus – NOT an arbovirus

Certain species of rodents




Deer mouse, cotton rat, rice rat, white-footed mouse
Other rodents worldwide
Hantaan, Sin Nombre, and many more!
Aerosolized urine
www.cdc.gov
Epidemiology
 Rift Valley Fever
 Sub-Saharan and
North Africa



Kenya
Somalia
Tanzania
 Saudi Arabia and
Yemen
cdc.gov
Epidemiology
 Hantavirus
 Worldwide


“Old World”

Hantaan, Dobrava

Europe, Asia, Africa

Hemorrhagic fever
with renal syndrome
“New World”

Sin Nombre

N. and S. America

Hantavirus pulmonary
syndrome
Curry Village tent cabins
www.cdc.gov
Clinical Syndromes
Mortality as high as
50% with hemorrhagic
disease
 Rift Valley Fever




Incubation period of 48 hours
Flu-like illness from viremia; fever lasts about 3 days
Can be mild or progress to severe illness with hemorrhage
Petechial hemorrhages, ecchymosis, epistaxis, GI and gum bleeding
 Hantavirus

Hemorrhagic Fever with Renal Syndrome


Similar to Rift Valley Fever but with acute renal failure
Hantavirus Pulmonary Syndrome


Flu-like illness (fever, headache, myalgias, nausea/vomiting, diarrhea)
Rapid progression to cough, short of breath, pulmonary edema, respiratory
failure, and death within days
Laboratory Diagnosis
 RT-PCR to detect viral RNA

Most common diagnostic tool
 IgM antibodies by ELISA in acute illness
 IgG with four-fold increase in titers – recent infection
 ELISA may be able to detect antigen in very viremic
patients, such as those infected early with Rift Valley
Fever
Treatment, Prevention, and Control
 Biosafety Level 3 or 4
 Supportive management
 Rift Valley vaccine not licensed or commercially available

Has been used for veterinary and laboratory personnel at high risk
of exposure
 Vector control!!
Lassa Fever
 Arenavirus
 Pleomorphic, enveloped viruses
 Greek word “arenosa” = “sandy”
Lassa fever virion
Structure and Replication
Two single-stranded RNA
- L segment: encodes polymerase
- S segment: nucleoprotein and
glycoproteins
Vhfc.org/lassa fever/virology
Epidemiology
 Endemic to West Africa
 African rodent population

Mastomys natalensis
 Rodent urine, droppings

Colonize human homes
Inhalation of aerosols

Contaminated food

Contact with open cuts, sores

 Person-to-person spread

Infected secretions, bodily fluids
www.travelapproved.nl
Clinical Syndrome
 Incubation: 1 – 3 weeks
 Fever, sore throat, retrosternal pain, abdominal pain,
vomiting, diarrhea
 Facial swelling, proteinuria, conjunctivitis
 Coagulopathy, petechiae, occasional visceral hemorrhage
 Hemorrhage and Shock
 Highest rates of death in 3rd trimester pregnancy
 Varying degrees of deafness in approximately 1/3
www.standford.edu; www.g-influencemagazine.com
Laboratory Diagnosis
 Biosafety Level 3 or 4 Precautions
 Throat and urine specimens for isolation

Takes 7-10 days to grow
 ELISA: IgM/IgG or Lassa antigen
 RT-PCR
Treatment, Prevention, and Control
 Supportive care

Fluids, electrolytes, oxygen and blood pressure support
 Limited Ribavirin activity


Has successfully decreased mortality in prior studies
Most effective if given in the first 6 days of treatment
 Prevention



Rodent control; trapping
Proper food storage
Contact precautions and equipment sterilization
N Engl J Med. 1986 Jan 2:314:20-6
Summary
 Marburg and Ebola – Filoviruses



Sub-Saharan Africa; fruit bats, wild monkeys
Human-to-human spread via infected blood/tissue
Severe hemorrhagic fever syndrome
 Yellow Fever and Dengue Fever – Flaviviruses





YF: Sub-Saharan Africa; Tropical S. America (less)
DF: Similar to YF, plus Asia, Caribbean, the Pacific
Mosquito vector transmission (arboviruses) – Aedes aegypti
YF: Flu-like; progress to jaundice, hemorrhage
DF: Breakbone fever, Hemorrhagic fever, Shock Syndrome
Summary
 Rift Valley Fever and Hantavirus – Bunyaviruses


Rift Valley: mosquito vector; livestock reservoir; sub-Saharan and
North Africa
Hanta: infected urine from rodents; U.S. (pulmonary syndrome);
worldwide (hemorrhagic fever + renal failure)
 Lassa Fever – Arenavirus





West Africa
Rodents; aerosolized urine, contaminated food
Person to person spread – infected blood/tissue
Fever, sore throat, retrosternal pain, proteinuria
Hemorrhage and Shock
Summary
 All require Biosafety Level 3 or 4
 Most common means of diagnosis:


ELISA antibody testing (IgM/IgG)
RT-PCR
 All are primarily managed by supportive care
 Prevention: vector control (insect or rodent); isolation
precautions; sterile medical equipment
 Vaccines available for:


Yellow Fever (commonly used)
Rift Valley Fever (not commonly used)
Contact Information
THANK YOU!
Jose.bazan@osumc.edu
References
 Medical Microbiology, 7th Ed. Murray, Rosenthal &
Pfaller; Chapter 58, pages 537 – 538; Chapter 60,
pages 549 – 556; Chapter 61, pages 561 – 566.
 Principles and Practice of Infectious Diseases, 7th Ed.
Mandell, Douglas, and Bennett; Chapters 153, 164,
166, 167.