A. Definition

1. Disease process associated with infection by certain RNA viruses
2. Acute febrile illness with:
   1. Malaise and Prostration
   2. Signs of vascular permeability
   3. Abnormalities of clotting
3. Contact usually through animals or arthropods
4. Highly infectious via aerosol

B. Viruses Causing VHF [1]

1. All are enveloped, single stranded RNA viruses
2. Biological weapons potential denoted by asterisk (*)
3. Arenaviridea (all carried by rodents)
   1. Lassa Fever Virus*
   2. Junin Virus (Argentina)*
   3. Machupo VIrus (Bolivia)*
   4. Guanarito Virus (Venezuala)*
   5. Sabia Virus (Brazil)*
4. Bunyaviridae
   1. Rift Valley Fever Virus (Phlebovirus)* - mosquito
   2. Congo-Crimean Hemorrhagic Fever Virus (Nairovirus) - arthropod (tick) vectors
   3. Hantavirus - hemorrhagic fever with renal syndrome, rodent vectors
5. Filoviridae (unknown vectors) [6]
   1. Ebola Virus*
   2. Marburg Virus* [7,8]
6. Flavivurs [2]
   1. Dengue (1-4) - Dengue hemorrhagic fever and shock syndrome; mosquito vector
   2. Yellow Fever Virus* - mosquito
   3. Omsk hemorrhagic fever - tick
   4. Kyasanur Forest disease - tick

C. Clinical Presentation

1. Acute fevers, myalgias
2. Endothelial cell damage
   1. Leads to increased vascular permeability
   2. Marked peripheral and pulmonary edema
3. Early Disease
   1. Conjunctival infusion
   2. Mild Hypotension
   3. Flushing
   4. Petecchia
4. Disease Progression
   1. Marked hypotension
   2. Mucous Membrane Hemorrhage
   3. Cerebral Signs / Possible Hemorrhage
   4. Pulmonary Edema and/or Hemorrhage
   5. Hepatitis - jaundice only with Yellow Fever
   6. Renal Failure - tubular necrosis, proportional to cardiovascular collapse
   7. Hemorrhages generally due to frank disseminated intravascular coagulopathy (DIC)
5. Filiviridae Infection [6]
   1. Primarily affect adults, particularly hospital works in endemic areas
   2. Children rarely affected even when infected adult patient cared for at home
   3. Infection control precautions must be strictly followed to prevent spread
6. Asymptomatic Ebola Infection [2]
   1. Up to 20% of persons exposed to Ebola may be asymptomatic or have mild symptoms
   2. Infection documented by presence of IgM and/or IgG antibodies to Ebola proteins
   3. Strong inflammatory response (IL1ß, TNFa, IL6, MIP-1) to Ebola associated with reduced symptoms and clearance of infection
   4. Likely that host response to infection (rather than viral mutation) determines outcomes
7. Marburg case fatality rate 80-95% including outbreak in Congo in 1998-9 [7,8]

D. Diagnosis

1. High suspicion is required as timely intervention is essential
2. Viremia is common, detectable by ELISA or reverse transcription PCR
3. Viral isolation is not recommended unless a P3 or higher facility is available
4. ELISA for detection of IgM and IgG to Ebola antigens has been developed [3]

E. Management

1. Supportive intensive care is generally helpful
2. Invasive monitoring is generally not helpful and increases bleeding and infection risk
3. Heparin has been recommended for treatment of frank DIC
4. Aggressive high oncotic fluid resuscitation for shock
5. Mechanical ventillation is nearly always required for severe cases
6. Ribavirin [4]
   1. Definite benefit for Lassa Fever and other VHF agents
   2. Activity against Argentine hemorrhagic fever
   3. Probably not effective for Filaviruses
7. Plasma containing antiviral activities may be effective in some cases
8. Yellow Fever vaccine is available
9. Ebola Treatment [5]
   1. Ebola induces major changes in coagulation system leading to consumptive coagulopathy
   2. Recombinant inhibitor of coagulation factor VIIa and tissue factor evaluated in monkeys
   3. The protein inhibitor, NAPc2, is derived from nematodes
   4. Ebola infection of monkeys killed 100%; 33% survival in monkeys treated with NAPc2
10. Vaccine Against Marburg Virus [9]
    1. Attentuated recombinant vesicular stomatitis virus
    2. Tested in rhesus monkey model 20-30 minutes after high dose Marburg exposure
    3. All control and none of the five vaccinated rhesus macaques died by day 12
    4. None of the vaccinated animals developed symptoms of Marburg hemorrhagic fever

References

1. Borio L, Inglesby T, Peters CJ, et al. 2002. JAMA. 287(18):2391
2. Gould EA and Solomon T. 2008. Lancet. 371(9611):500
3. Leroy EM, Baize S, Vochkov VE, et al. 2000. Lancet. 355(9222):2210
4. Drugs and Vaccines Against Biological Weapons. 2001. Med Let. 43(1115):87
5. Geisbert TW, Hensley LE, Jahrling PB, et al. 2003. Lancet. 362(9400):1953
6. Peters CJ. 2005. NEJM. 352(25):2571
7. Ndayimirije N and Kindhauser MK. 2005. NEJM. 352(21):2155
8. Bausch DG, Nichol ST, Myembe-Tamfum JJ, et al. 2006. NEJM. 355(9):909
9. Daddario-DiCpario KM, Geisbert TW, Stroher U, et al. 2006. Lancet. 367(9520):1399