Eileen C. Farnon, Pierre E. Rollin

Infectious Agent

Viral hemorrhagic fevers (VHFs) are caused by several families of enveloped RNA viruses: filoviruses (Ebola and Marburg viruses), arenaviruses (including Lassa fever and Guanarito, Machupo, Junin, and Sabia viruses), bunyaviruses (Rift Valley fever [RVF], Crimean-Congo hemorrhagic fever [CCHF], and hantaviruses), and flaviviruses (dengue, yellow fever, Omsk hemorrhagic fever, and Kyasanur Forest disease [KFD] viruses) (see the Yellow Fever section in Chapter 2 and the Dengue Fever section in Chapter 5).

Mode of Transmission

• VHFs are spread person-to-person through direct contact with symptomatic patients, body fluids, cadavers, or inadequate infection control (filoviruses, arenaviruses, CCHF virus).
• Zoonotic spread includes—
  • Livestock via slaughter, or consumption of raw milk or meat from infected animals (CCHF, RVF viruses)
  • Bushmeat, likely via slaughter or consumption of infected animals (Ebola, Marburg viruses)
  • Rodent-borne (arenaviruses, Hantaan, Omsk, and KFD viruses) via inhalation of or contact with materials contaminated with rodent excreta
  • Other reservoir species, such as bats (Ebola, Marburg viruses)
• Vector-borne transmission also occurs via mosquitoes (RVF virus) or ticks (CCHF, Omsk, and KFD viruses).

Occurrence

The viruses that cause VHF are distributed over much of the globe. Each virus is associated with one or more nonhuman host or vector species, restricting the virus and the disease it causes to the areas inhabited by these species. These viruses are initially transmitted to humans when the habitats of infected reservoir hosts or vectors and humans overlap. Humans are incidental hosts for these enzootic diseases; however, person-to-person transmission of some viruses can result in large human outbreaks. Specific viruses are addressed below.

Ebola and Marburg: Filoviral Diseases

• Ebola and Marburg viruses cause hemorrhagic fever in humans and nonhuman primates.
• Five species of Ebola virus have been identified: Côte d’Ivoire, Sudan, Zaire, Bundibugyo, and Reston. Ebola-Reston has not been shown to cause human disease.
• Occurrence: tropical regions in Africa. Countries with confirmed human cases of Ebola hemorrhagic fever: Republic of Congo, Côte d’Ivoire, Democratic Republic of Congo, Gabon, Sudan, and Uganda; Marburg hemorrhagic fever: Uganda, Kenya, Democratic Republic of Congo, Angola, and possibly Zimbabwe.
• Reservoir host species: Growing evidence indicates that fruit bats are the natural reservoir for filoviruses. Outbreaks occur when an index case-patient becomes infected after exposure to the reservoir species or an infected nonhuman primate and transmits the virus to other people in the community.

Lassa Fever and Other Arenaviral Diseases

• Arenaviruses are transmitted from rodents to humans, except Tacaribe virus, which is found in bats. Most infections are mild, but some result in hemorrhagic fever with high fatality rates.
• Occurrence: Old and New World viruses, causing the following diseases:
  • Old World viruses: Lassa virus (Lassa fever) and lymphocytic choriomeningitis (LCM) virus (meningitis, encephalitis, and congenital fetal infection in normal hosts, hemorrhagic fever in organ transplant recipients). Lassa fever occurs in rural West Africa, with hyperendemic areas in Sierra Leone, Guinea, Liberia, and Nigeria.
  • New World viruses: Junin (Argentine hemorrhagic fever), Machupo (Bolivian hemorrhagic fever), Guanarito (Venezuelan hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), and recently discovered viruses (Chapare, Flexal).
• Reservoir host species: New World rats and mice (family Muridae, subfamily Sigmodontinae); Old World rats and mice (family Muridae, subfamily Murinae). These rodent types are found worldwide, including Europe, Asia, Africa, and the Americas.
• Transmission: inhalation of aerosols from rodent urine, ingestion of rodent-contaminated food, or direct contact of broken skin with rodent excreta. Risk of Lassa infection is associated with peridomestic rodent exposure. Inappropriate food storage increases the risk for exposure. Nosocomial transmission of Lassa and Machupo viruses has occurred through droplet and contact. One anecdotal report of possible airborne transmission exists.

Rift Valley Fever and Other Bunyaviral Diseases

• RVF causes fever, hemorrhage, encephalitis, and retinitis in humans, but primarily affects livestock. RVF is endemic to sub-Saharan Africa. Sporadic outbreaks have occurred in humans in Egypt, Madagascar, and Mauritania. Large epidemics occurred in Kenya, Somalia, and Tanzania in 1997–1998 and 2006–2007 and in Saudi Arabia and Yemen in 2000. RVF virus is transmitted by mosquito, percutaneous inoculation, and slaughter or consumption of infected animals.
• CCHF is endemic where ticks of the genus Hyalomma are found in Africa and Eurasia, including South Africa, the Balkans, the Middle East, Russia, and western China, and is highly endemic in Afghanistan, Iran, Pakistan, and Turkey. CCHF virus is transmitted to humans by infected ticks or direct handling and preparation of fresh carcasses of infected animals, usually domestic livestock. Nosocomial transmission often occurs.
• Hantaviruses cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). The viruses that cause HPS are present in the New World; those that cause HFRS occur worldwide. Both HPS and HFRS are transmitted to humans through contact with urine, feces, or saliva of infected rodents.

Risk for Travelers

• The risk of acquiring VHF is generally very low for international travelers.
• Viruses with rodent reservoirs are transmitted when humans have contact with excreta from infected rodents. Several cases of Lassa fever have been confirmed in international travelers living in traditional dwellings in the countryside. Travelers staying in rodent-infested dwellings are at risk for HPS and HFRS.
• Viruses associated with arthropod vectors are transmitted through mosquito or tick bites or by crushing infected ticks. Some vectors also infect animals, including livestock, and humans can be infected through care, slaughter, or consumption of infected animals.
• Travelers at increased risk for exposure include those engaging in animal research, health-care workers, and others providing care for patients in the community, particularly where outbreaks of VHF are occurring.
• Three cases of Marburg hemorrhagic fever have occurred in travelers to caves harboring bats, including Kitum cave in Kenya and Python cave in Maramagambo Forest, Uganda. Miners have also acquired Marburg infection from working in underground mines harboring bats in the Democratic Republic of Congo and Uganda.

Clinical Presentation

• Signs and symptoms vary by disease, but in general, patients with VHF present with abrupt onset of fever, myalgias, and prostration, followed by coagulopathy with a petechial rash or ecchymoses, and sometimes overt bleeding. Vascular endothelial damage leads to shock and pulmonary edema, and liver injury is common.
• Signs seen with specific viruses include renal failure (HFRS), ecchymoses (CCHF), hearing loss, anasarca and shock in newborns (Lassa fever), and spontaneous abortion (Lassa and LCM viruses).
• Because the incubation period may be as long as 21 days, patients may not develop illness until returning from travel, and a thorough travel and exposure history is critical.

Diagnosis

• U.S.-based clinicians should notify CDC’s Special Pathogens Branch immediately of any suspected cases of viral hemorrhagic fever occurring in patients residing in or requiring evacuation to the United States: 404-639-1115 or 404-639-2888 after hours. CDC also provides consultation for international clinicians and health ministries.
• Whole blood or serum may be tested for virologic (RT-PCR, antigen detection, virus isolation) and immunologic (IgM, IgG) evidence of infection. Tissue may be tested by immunohistochemistry, RT-PCR, and virus isolation. Postmortem skin biopsies fixed in formalin and blood collected within a few hours after death by cardiac puncture can be used for diagnosis. Samples should be sent for testing to a reference laboratory with Biosafety level 3 and 4 capability.

Treatment

• Supportive care. Ribavirin is effective for treating Lassa fever, New World arenaviruses, and likely for CCHF, but is not approved by FDA for these indications. Convalescent-phase plasma is effective in treating Argentine hemorrhagic fever.
• Intravenous ribavirin can be obtained for compassionate use through FDA, from Valeant Pharmaceuticals (Aliso Viejo, California), via 1) single-patient emergency Investigational New Drug (IND) or 2) protocol (for multiple uses). Requests should be provider-initiated through FDA, with simultaneous notification to Valeant: 800-548-5100, extension 5 (domestic telephone) or 949-461-6456 (international telephone). The IND process is explained on FDA’s website: www.fda.gov/cder/regulatory/applications/ind_page_1.htm#emergency.

Preventive Measures for Travelers

• Prevention should focus on avoiding contact with host or vector species. Travelers should not visit locations where an outbreak is occurring. Contact with rodents should be avoided. Travelers should avoid contact with livestock in RVF and CCHF-endemic areas, and they should use insecticide-treated bed nets and insect repellent to prevent vector-borne disease.
• Standard precautions and contact and droplet precautions for suspected VHF case-patients are recommended to avoid health care-associated transmission.
• Direct contact should be avoided with corpses of patients suspected of having died of Ebola, Marburg, or Old World arenavirus infection.
• Contact with or consumption of primates, bats, and other bushmeat should be avoided.
• Investigational vaccines exist for Argentine hemorrhagic fever and RVF; however, neither is FDA-approved nor commonly available in the United States.

References

1. Geisbert TW, Jahrling PB. Exotic emerging viral diseases: progress and challenges. Nature Med. 2004;10(Suppl 12):S110–21.
2. Marty AM, Jahrling PB, Geisbert TW. Viral hemorrhagic fevers. Clin Lab Med. 2006;26:345–86, viii.
3. Bausch DG, Ksiazek TG. Viral hemorrhagic fevers including hantavirus pulmonary syndrome in the Americas. Clin Lab Med. 2002;22:981–1020.
4. Peters CJ, Zaki SR. Overview of viral hemorrhagic fevers. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical infectious diseases: principles, pathogens and practice. 2nd ed. Philadelphia: Churchill Livingstone; 2006. p. 726–33.
5. Watts DM, Flick R, Peters CJ, et al. Bunyaviral fevers: Rift valley fever and Crimean–Congo hemorrhagic fever. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical infectious diseases: principles, pathogens and practice. Philadelphia: Churchill Livingstone; 2006. p. 756–61.
6. Wahl-Jensen V, Feldmann H, Sanchez A, et al. Filovirus infections. In: Guerrant RL, Walker DH, Weller P, editors. Tropical infectious diseases: principles, pathogens and practice. 2nd ed. Philadelphia: Churchill Livingstone; 2006. p. 784–96.
7. Bausch DG, Borchert M, Grein T, et al. Risk factors for Marburg hemorrhagic fever, Democratic Republic of the Congo. Emerg Infect Dis. 2003;9:1531–7.
8. Günther S, Lenz O. Lassa virus. Crit Rev Clin Lab Sci. 2004;41:339–90.
9. De Manzione N, Salas RA, Paredes H, et al. Venezuelan hemorrhagic fever: clinical and epidemiological studies of 165 cases. Clin Infect Dis. 1998;26:308–13.
10. Madani TA, Al-Mazrou YY, Al-Jeffri MH, et al. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical, and laboratory characteristics. Clin Infect Dis. 2003;37:1084–92.
11. Vapalahti O, Mustonen J, Lundkvist A, et al. Hantavirus infections in Europe. Lancet Infect Dis. 2003;3:653–61.
12. Rouquet P, Froment JM, Bermejo M, et al. Wild animal mortality monitoring and human Ebola outbreaks, Gabon and Republic of Congo, 2001–2003. Emerg Infect Dis. 2005;11:283–90.
13. Peters CJ, Jahrling PB, Khan AS. Patients infected with high-hazard viruses: scientific basis for infection control. Arch Virol Suppl. 1996;11:141–68.
14. Feldmann H, Jones SM, Schnittler HJ, Geisbert T. Therapy and prophylaxis of Ebola virus infections. Curr Opin Investig Drugs. 2005;6:823–30.
15. Ozkurt Z, Kiki I, Erol S, et al. Crimean–Congo hemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy. J Infect. 2006;52:207–15.