1. Viral Hemorrhagic Fevers
The Viral Hemorrhagic Fevers are a group of illnesses which are a diverse group of RNA viruses that present with common clinical characteristics known as the viral hemorrhagic fever syndrome. These illnesses range from a mild flu-like illness to endothelial damage resulting in increased vascular permeability and bleeding complications. This picture is an Electron micrograph of the Filovirus, Ebola

2. Objectives
Describe the natural geographic distribution of VHF and scenarios suggestive of bioterrorism
Describe the clinical manifestations of VHF in general
List exposure classification of contact for cases of VHF
Describe infection control precautions for personnel caring for patients with VHF
List therapeutic options for patients with VHF

3. Case Presentation
38 yo business man returned from West Africa via London, ill for 3 days
new onset fever
chills
severe sore throat
diarrhea
back pain
PE: T103.6 BP 90/60, alert
Skin with diffuse ecchymosis and a maculopapular rash on the extremities
Case presentation of an actual VHF presentation Sept in New Jersey in a businessman originally from Liberia who had resided in the US for 5 years. During the 4 months prior to his hospitalization, the patient had been in West Africa where he commuted between Liberia and Sierra Lione, where he owned some farms. In August, a month prior to presentation, he developed symptoms as described above. He traveled via London back to Newark, NJ where he took a train to Trenton, NJ and sought medical care.
MMWR 2004;53(38):

4. Differential Diagnosis
Fever in a traveler
Malaria
Typhoid fever
Other Differential Diagnoses
Meningococcemia
Rickettsial infection
Leptospirosis
Acute leukemia
Idiopathic or thrombotic thrombocytopenic purpura

5. Hospital Course Hospital Day #4
Despite empiric antibiotics including antimalarials, pt develops acute respiratory distress syndrome (ARDS)
Required intubation

6. Differential Diagnosis
Fever in a traveler
Malaria
Typhoid fever
Yellow fever
Lassa fever
Now you expand your DDx in a traveler to include the viral hemorrhagic fevers in Africa, particularly West Africa.

7. Hospital Course Hospital Day #4 Hospital Day #5
Despite empiric antibiotics including antimalarials, pt develops ARDS
Required intubation
Hospital Day #5
Local and state health departments notified
Investigational new drug (IND) protocol to administer IV ribavirin
Patient died before administration of any drug

8. Diagnosis Clinical and post-mortem specimens sent to CDC
Lassa virus confirmed
Serum antigen detection
Immunohistochemical staining liver tissue
Virus isolation in cell culture
RT-PCR sequencing of virus

9. FAMILY/GEOGRAPHY AGENT CASE-FATALITY
Filoviridae
Sub-saharan Africa
Ebola
Marburg
50-75%
25%
Arenaviridae
West Africa (Lassa)
South America, California (Whitewater)
Old World: Lassa
New World: Junin,
Machupo, Guanarito Sabia, Whitewater arroyo
Lassa:1-2% (up to 25% in hospitalized pts)
30% for New World
Bunyaviridae
Egypt, Yemen
SW US (Hantavirus)
Phlebovirus: Rift Valley
Nairovirus: Crimean Congo
Hantavirus: Sin Nombre
Rift Valley: <1% overall
50% in hemorrhagic
Flaviviridae
Central Asia
Yellow fever
Dengue
Omsk
Kyasanur
Yellow Fever: 5-7% overall
The Viral Hemorrhagic Fevers are comprised of a number of different diseases. All are single-stranded RNA viruses and enter the bloodstream through various routes (i.e. tick, mosquito, rodent bite vectors, mucous membrane exposure. Endothelial infection occurs which leads to thrombocytopenia and endothelial dysfunction which may result in disseminated intravascular coagulation (Ebola, Marburg, Rift Valley Fever, Crimean Congo Fever) and cytokine storm (Ebola and Marburg). Vascular permeability and disregulation can occur, leading to periorbital edema, hemoconcentration and flushing, respectively. Animal models of Ebola pathogenesis suggest that the virus leads to immunosuppression and apoptosis (self-destruction) of T-lymphocytes and natural killer cells. In this table the major families of VHF are listed along with the endemic region, the specific agents and average case fatality rates for the diseases listed. For more information see the Center for Infectious Disease Reasearch and Policy and Infectious Disease Society of America (CIDRAP/IDSA) summary document on VHF which can be found on the websites: or
accessed 2/4/05

10. Epidemiology Incubation period Endemic regions
2 days to 3 weeks for most VHF
Lassa fever: 21 days
Endemic regions
Sub-saharan Africa
Lassa fever causes ,000 infections and 5,000 deaths each year
20 imported cases reported worldwide
Human to human transmission has occured
South America
Pictured is the Mastomys rodent, the natural host of Lassa fever virus.

11. 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

12. Clinical Presentation
Initial:
High grade fever, headache, myalgias, fatigue, abdominal pain
Advanced disease:
Bleeding
Maculopapular rash
Exudative Pharyngitis (Lassa)
Meningoencephalitis
Jaundice

13. Eccyhmosis encompassing left upper extremity one week after onset of Crimean-Congo Hemorrhagic Fever.
D. Pigott, Associate Professor Dept. of Emergency Medicine, University of Alabama, Birmingham

14. Patients with Korean Hemorrhagic Fever caused by the Hantaan virus with the typical “sunburn flush” of the cheeks, chin, and base of the neck. Photograph courtesy of John Huggins, PhD. in article on emedicine by David C. Pigott, MD.

15. Morbiliform exanthem of Dengue fever with islands of sparing characteristic. Photo from Duane Gubler, PhD.

16. Ecchymoses complicating a case of Dengue hemorrhagic fever
Ecchymoses complicating a case of Dengue hemorrhagic fever. Photo from Duane Gubler, PhD.

17. Transmission Direct contact with blood/body fluids/cadavers
Aerosol spray (droplet v. airborne)
Sexual transmission
Percutaneous
Bite of infected tick or mosquito
Person to person transmission is greatest in the late stages of the illness when the patient has vomiting, diarrhea, and severe hemorrhage. VHF infection has not been reported in people whose contact with an infected patient occurred only during the incubation period (i.e. before the patient became febrile; the incubation period ranges from 2 days to 3 weeks). MMWR 1995;44(25):

18. Infection Control Lassa Fever in New Jersey Investigation:
5 high risk contacts (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 occurred

19. Infection Control Risk Category Description Surveillance
Casual Contacts
Remote contact with index case (eg, stayed in same hotel)
VHF not spread by casual contact, no special surveillance
Close Contacts
More than casual (eg, living with contact, caretaker, shook hands with contact)
Place under surveillance once index case confirmed
High-Risk Contacts
Mucous membrane contact (eg, kissing, or penetrating injury involving contact with index case’s blood such as needlestick)
Place under surveillance as soon as consider diagnosis of VHF in index case
Surveillance should be continued for 3 weeks after the person’s last contact with the index case. If a fever > than 101°F and/or symptoms develop, the patient should be immediately placed in isolation and treated as a VHF patient.
CDC Update: management of patients with suspected VHF-United States MMWR 1995;44:475-79

20. 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 respiratory symptoms
Surgical mask
Environmental surfaces
Cleaned with hospital approved disinfectant
Linen incinerated, autoclaved, double-bagged for wash
Isolation precautions will depend on the degree of illness and volume and location of blood loss. If a patient has respiratory symptoms with cough or aerosol generating procedures such as med nebs, or bronchoscopy are planned then use of airborne in addition to contact precautions are warranted. However, if a patient is not coughing than droplet and contact precautions are sufficient. PAPR is powered air-purifying respirator.

21. Treatment Supportive care: Fluid and electrolyte management
Hemodynamic monitoring
Ventilation and/or dialysis support
Steroids for adrenal crisis
Anticoagulants, IM injections, ASA, NSAIDS are contraindicated
Treat secondary bacterial infections

22. 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

23. Vaccination Argentine and Bolivian HF Yellow Fever
PASSIVE IMMUNIZATION
Treat with convalescent serum containing neutralizing antibody or immune globulin
Yellow Fever
ACTIVE IMMUNIZATION
Travelers to Africa and South America
Several vaccines are under investigational new drugs including vaccine for Rift Valley Fever, Argentine HF, Dengue
P. Jahrling, Chapter 29, Medical Aspects of Clinical and Biological Warfare; p

24. This completes the current presentation.
End presentation and distribute activity survey.