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