The viral hemorrhagic fevers (VHF's) are a group of clinical febrile illnesses with a propensity to cause significant bleeding. These illnesses are caused by a group of RNA viruses which belong to four distinct viral families: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae. The two viruses considered to be the greatest bioterrorism threats are Ebola and Marburg, the two members of the filovirus family, which are categorized as category A bioweapon agents. These viruses characteristically cause high mortality and morbidity, are person to person spread, are highly infectious at a low dose by the aerosol route, are stable in the environment, and large-scale production is feasible. Other viruses which could conceivably be used as terrorist weapons, but not considered as great a threat as the filoviruses, include:

Arenaviruses: Lassa Fever (Africa) and the New World Hemorrhagic Fevers - Bolivian Hemorrhagic Fever (BHF, Machupo virus), Argentine Hemorrhagic Fever (AHF, Junin virus), Venezuelan Hemorrhagic Fever (Guanarito virus), and Brazilian Hemorrhagic Fever (Sabia virus)

Bunyaviruses: Crimean-Congo Hemorrhagic Fever (CCHF), Rift Valley Fever (RVF)

Flaviviruses: Dengue, Yellow Fever, Omsk Hemorrhagic Fever, and Kyasanur Forest disease

State biological weapons programs have shown interest in hemorrhagic fever viruses (HFV's) as weapons; the former Soviet Union weaponized significant quantities of Marburg, Ebola, Lassa, Junin, and Machupo. The Aum Shinrikyo cult in Japan attempted to gain access to Ebola during the Kikwit, Zaire Ebola outbreak in the mid-90's.

Natural outbreaks of disease from these viruses have demonstrated their potential as deadly weapons and their ability to spread from person to person in some cases. The reservoir of several of the HFV's is either rodents or insects (ticks or mosquitoes); the reservoir(s) of Ebola and Marburg are unknown. In natural outbreaks of Ebola and Marburg, contact precautions have been sufficient to interrupt person-to-person spread. Airborne precautions have not been necessary, although some animal studies have raised concern about spread via small-particle aerosols.

Clinical Features

Clinical manifestations of VHF's vary according to the specific etiologic virus and may overlap, making specific clinical diagnosis unlikely. The incubation period varies from 2 to 21 days, and may be inoculum dependent. Prodromal symptoms are typical, with several days of fever, myalgias, headache, malaise, arthralgias, nausea, diarrhea, and abdominal pain. With some VHF's, such as CCHF, abdominal pain may be pronounced, mimicking an acute abdomen. All VHF's are characterized by an abrupt onset of symptoms, with the exception of the arenaviruses, where onset is more insidious.

After the prodrome, patients may develop conjunctivitis and pharyngitis, and most VHF patients have a rash, with the dermal manifestations varying by etiology. As these diseases progress, patients may exhibit a progressively worsening bleeding diathesis, with petechiae, conjunctival and mucosal hemorrhage, hematuria, hematemesis, and melena, followed by DIC and hypotension. As the patient worsens, CNS signs ensue, including delirium, seizures, and coma. Shock and multiple organ system failure presage death.
Case fatality rates vary according to the viral etiology, ranging from less than 5 percent to approximately 70 to 90 percent with Ebola Zaire subtype.

Evacuation for ICU care during the incubation period is acceptable; after onset of symptoms it is not advisable.

Epidemiologic Indicators: With natural cases, historical risk factors such as travel to Africa, Asia, or South America, or exposure to other patients may be present. In nature, most of these infections are spread by nosocomial or close personal contact with other victims, or by exposure to insect vectors. In a bioterrorism attack, patients may have common geographic factors, which may indicate simultaneous (aerosol) exposure. Presence of these viruses outside their normal range, and high attack and mortality rates may indicate non-natural exposure.

Diagnosis and Treatment

Presenting Symptoms (Clinical Diagnosis)

• Fever


• Malaise


• Erythematous Rash or Flushing (early)


• Conjunctivitis


• Pharyngitis


• Myalgias


• Abdominal Pain


• Nausea and/or Diarrhea


• Petechiae and Hemorrhagic Rash/Purpura (late)


• Hematemeis, Hemoptysis, Epistaxis, Hematochezia, or Melena


• Hypotension


• Signs of CNS Dysfunction: Seizures, Delirium, Coma

Laboratory Clinical Diagnostic Testing (Blood, Urine): WBC with Differential, Platelet Count, PT/PTT and Bleeding Time, LFT's, Fibrin Split Products, Fibrinogen, UA and BUN/Creatinine, Electrolytes, Glucose, and pH and bicarbonate levels (acid/base status).

Specific Diagnostic Testing (only available at specialized laboratories): Antigen-Capture ELISA, RT-PCR (most useful clinically), IgM by Antibody-Capture ELISA, Viral isolation (requires BSL-4 laboratory - CDC or USAMRIID), acute and convalescent IgG serologies in survivors (only helpful retrospectively)

Differential Diagnosis: Viral Hepatitis, Gram-negative sepsis, Toxic Shock Syndrome, Meningococcemia, other bacterial sepsis, Rocky Mountain Spotted Fever or other rickettsial disease, leptospirosis, borreliosis, Dengue Hemorrhagic Fever (DHF), malaria, septicemic plague, hemorrhagic smallpox.

Isolation: Strict VHF-specific barrier precautions initiated on suspicion of VHF disease. See guidelines in JAMA 2002, May 8: 287; 2391-2405, or at the CDC bioterrorism web site:

http://www.bt.cdc.gov/agent/vhf/index.asp

Also airborne precautions and a negative-pressure isolation room are recommended, if such a room is available. Close medical surveillance for all those with close or high-risk contact or blood exposure within 21 days of a patient's onset of symptoms. Convalescent patients should refrain from sexual activity for 3 months (filoviral or arenaviral infections).

Decontamination: Environmental surfaces and contaminated equipment - 1:10 to 1:100 dilution of household bleach (hypochlorite) or other EPA-registered disinfectant. Linens should be handled per CDC guidelines.

Treatment:

Intensive Supportive Care

Intravenous IND Ribavirin therapy (available from CDC or USAMRIID) - recommended for VHF of unknown etiology while diagnostic confirmation is pending VHF known to be due to Arenaviruses or Bunyaviruses (Ribavirin has efficacy against Lassa Fever, some new world Arenaviruses such as AHF, CCHF, RVF, and HFRS). See guidelines for dosing in JAMA 2002 May 8; 287:2391-2405 or at web link: http://jama.ama-assn.org/issues/v287n18/ffull/jst20006.html The main side effect is a reversible hemolytic anemia. Ribavirin has no efficacy against Filoviruses or Flaviviruses, and is contraindicated in pregnancy.