Description

Viral hemorrhagic fevers are a group of febrile illnesses caused by several distinct families of viruses, all of which are enveloped and have RNA genomes. These groups include Ebola and Marburg viruses, Lassa fever virus, the New World arenaviruses (Guanarito, Machupo, Junin, and Sabia), and Rift Valley fever and Crimean Congo hemorrhagic fever viruses (1-3). Although some types cause relatively mild illnesses, many of these viruses can cause severe, life-threatening disease. Severe illness is characterized by vascular damage and increased permeability, multiorgan failure, and shock. (See also the Dengue and Yellow Fever sections of this chapter.)

EBOLA AND MARBURG: FILOVIRAL DISEASES

Ebola and Marburg are filoviruses that belong to the family Filoviridae and can cause severe hemorrhagic fever in humans and nonhuman primates. Four species of Ebola virus have been identified: Côte d’Ivoire, Sudan, Zaire, and Reston (3). Ebola-Reston infection is fatal in monkeys, but no disease has been reported in humans. Confirmed cases of Ebola hemorrhagic fever have been reported in the Congo, Côte d’Ivoire, Democratic Republic of Congo, Gabon, Sudan, and Uganda. Occupational infection of laboratory workers resulting from needle-stick injury has been documented in England and Russia. Marburg virus also is indigenous to Africa. Although the precise geographic range for Marburg virus is unknown, it includes at least parts of Uganda, western Kenya, Democratic Republic of Congo, Angola, and possibly Zimbabwe. The reservoir hosts for Ebola and Marburg viruses have not yet been identified. Outbreaks can occur when an index case-patient who has been exposed to that unknown reservoir species or an infected nonhuman primate transmits the virus to others in a community (4,5). Within that community, the outbreak often becomes amplified in the health-care setting.

LASSA FEVER: ARENAVIRAL DISEASES

Lassa fever is caused by a virus transmitted from asymptomatically infected rodents to humans (6). Most infections are mild, but some are severe, causing a hemorrhagic fever that is often fatal. The virus, a member of the virus family Arenaviridae, is a single-stranded RNA virus. Arenaviruses are transmitted by rodent hosts (with the exception of Tacaribe virus, which has been isolated from bats) and can be divided into two groups: the New World or Tacaribe complex and the Old World or lymphocytic choriomeningitis virus (LCMV)/Lassa complex. Viruses causing human illness are Lassa virus (Lassa fever), Junin virus (Argentine hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Guanarito virus (Venezuelan hemorrhagic fever) (7), Sabia virus (Brazilian hemorrhagic fever), LCMV (meningitis, encephalitis, meningo-encephalitis, congenital fetal infection with neurological sequelae, fever, coagulopathy, and multi-organ failure and death in immunosuppressed organ recipients), and Flexal virus (an influenza-like illness that has caused deaths among laboratory personnel handling infected rodents in Brazil) (1).

Each virus is associated with one or more closely related rodent species that constitute its natural reservoir. Tacaribe complex viruses are generally associated with the New World rats and mice (family Muridae, subfamily Sigmodontinae). The LCM/Lassa complex viruses are associated with the Old World rats and mice (family Muridae, subfamily Murinae). Taken together, these types of rodents are located across most of the earth’s land mass, including Europe, Asia, Africa, and the Americas, although the individual viruses (with the exception of LCMV) are restricted to limited geographic areas.

Lassa fever is limited to rural areas of West Africa, with areas of hyperendemicity in eastern Sierra Leone, Guinea, Liberia, and Nigeria (6). Peridomestic exposure to infected rodents is the most likely source of human infection. Transmission of arenaviruses to humans can occur via inhalation of primary aerosols from rodent urine, by ingestion of rodent-contaminated food, or by direct contact of broken skin with rodent excreta (1,6). Rodent infestation facilitated by inappropriate food storage increases the risk of human infection. Person-to-person spread of Lassa and Machupo viruses has also been described, most notably by large droplet and contact transmission in the hospital setting. Despite one anecdotal report of possible airborne transmission, this mode is not believed to be an important route of infection from person to person. Laboratory handling of infectious specimens and contact with contaminated medical equipment are also associated with transmission.

RIFT VALLEY FEVER AND RELATED BUNYAVIRAL DISEASES

Rift Valley fever (RVF) is caused by a member of the Bunyaviridae family; it affects primarily livestock and may also infect humans. It is transmitted by several means, including the bites of mosquitoes, percutaneous inoculation, or exposure to aerosols from contaminated blood or fluids of infected animals (2,8). Other diseases caused by viruses of the family Bunyaviridae include Hantavirus pulmonary syndrome (HPS), hemorrhagic fever with renal syndrome (HFRS), and Crimean-Congo hemorrhagic fever. Both HPS and HFRS are transmitted to humans through contact with urine, feces, or saliva of infected rodents (9,10). Crimean-Congo virus is transmitted to humans by infected ticks or direct handling and preparation of fresh carcasses of infected animals, usually domestic livestock (2). Nosocomial transmission of Crimean-Congo virus has frequently been reported.

RVF virus is endemic to sub-Saharan Africa, where sporadic outbreaks occur in humans, for example, in the Nile Delta, Egypt (1978 and 1993), Madagascar (1991), and the lower Senegal River basin of Mauritania (1987) (2). A large epidemic also occurred in Kenya and Tanzania during 1997-1998. A recent outbreak (2000) of RVF occurred in southwestern Saudi Arabia and Yemen with a strain of RVF closely related to that of the 1997-1998 East African strain (8). This outbreak represented the first spread of the virus outside Africa, demonstrating its potential for spread to unaffected regions elsewhere in the tropics. Crimean-Congo hemorrhagic fever (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 (2). Recent cases of CCHF have been confirmed in Oman (1995), United Arab Emirates (1979 and 1994), and Saudi Arabia (1990). The disease is highly endemic in Pakistan, Iran, and Turkey . The viruses that cause HPS are present in the New World (9); those that cause HFRS occur worldwide (10).

Occurrence

Taken together, 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 (1). Viruses causing hemorrhagic fever are initially transmitted to humans when the habitats of infected reservoir hosts or vectors and humans overlap (11). Risk of VHF is associated with human incursion into such areas. In general, humans are incidental, “dead-end” hosts for these enzootic diseases.

Risk for Travelers

The risk for international travelers is generally considered to be low. The viruses carried in rodent reservoirs are transmitted when humans have contact with urine, fecal matter, saliva, or other excreta of infected rodents (6). The viruses associated with arthropod vectors are usually spread when the vector mosquito or tick bites a human or when a human crushes an infected tick. Some of these vectors may spread the virus to animals, including livestock. Humans may become infected through contact with infected animals (e.g., during birthing, veterinary care, or slaughter) (2). Travelers engaging in animal research, including ecologists, mammalogists, and primatologists, may be at increased risk for exposure to these zoonoses.

During recorded outbreaks of hemorrhagic fever caused by filovirus infections (e.g., Ebola), persons who cared for (fed, washed, or prepared for burial ceremonies) or worked very closely with infected persons were at highest risk for infection. Health care-associated transmission through contact with infectious body fluids has been an important factor in the spread of this disease (4,5).

Several cases of Lassa fever have been confirmed in international travelers who were staying or living in traditional dwellings in the countryside or in small villages; no risk has been associated with travelers who stay in hotels (6). Travel involving patient contact or rodent exposure is associated with increased risk. Medical personnel, researchers, and relief workers involved in the management of patients or working in disease-endemic areas should be aware of their risk and should minimize rodent exposure and use personal protective equipment appropriately to prevent health care-associated exposure (12).

Travelers exposed to the blood or tissues of sick animals or to infected mosquitoes in RVF-endemic areas are at risk for infection (8). Among travelers to Bunyavirus-endemic regions, those staying in rodent- infested dwellings may be at increased risk for HPS and HFRS.

Prevention

Prevention efforts should concentrate on avoiding contact with host or vector species. Travelers should not visit locations where an outbreak is occurring. Contact with rodents should be avoided, particularly in Lassa or Bunyavirus-endemic areas. Where RVF is endemic, travelers should avoid direct contact with livestock and minimize their exposure to arthropod bites by using permethrin-impregnated bed nets and insect repellents.

Strict compliance with infection control precautions (i.e., use of disposable gloves, face shields, and disposable gowns to prevent direct contact with body fluids and splashes to mucous membranes when caring for patients or handling clinical specimens; appropriate use and disposal of sharp instruments; hand washing and use of disinfectants) is recommended to avoid health care-associated infections (12).

Direct contact should be avoided with the remains of anyone suspected of having died of Ebola or Marburg infection. Remains should be buried promptly by trained, specially organized teams using appropriate safety equipment. Contact with or consumption of dead primates should be avoided.

Investigational vaccines have been developed for Argentine hemorrhagic fever, used extensively for community vaccination in the endemic region, and for Rift Valley fever; however, neither has been approved by the FDA and neither is commonly available. For the other viruses that cause VHF, no vaccines are available. If prevention methods fail and a traveler becomes ill with VHF, efforts should focus on supportive care and preventing further transmission from person to person, e.g., through occupational injury among health-care personnel, by re-use of injection needles or syringes, or splashes of infectious body fluids reaching unprotected mucous membranes (12).

Treatment

Patients should receive supportive care, including balancing fluids and electrolytes, maintaining oxygenation status and blood pressure, and preventing or providing treatment for any secondary infections (12). In general, no specific treatments or established cures have proven benefit for patients with VHF (13). Ribavirin, an antiviral drug, has been effective in treating some patients with Lassa fever (6), New World arenaviruses, and Crimean-Congo hemorrhagic fever (14); however, it is not FDA licensed for these indications. Treatment with convalescent-phase plasma has been used with success in some patients with Argentine hemorrhagic fever.

References

1. Peters CJ, Zaki SR. Overview of viral hemorrhagic fevers. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens and practice. 2nd ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2006; pp. 726-33.
2. Watts DM, Flick R, Peters CJ, Shope RE. Bunyaviral fevers: Rift valley fever and Crimean-Congo hemorrhagic fever. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens and practice. Philadelphia, PA, Elsevier Churchill Livingstone. 2006; pp. 756-61.
3. Wahl-Jensen V, Feldmann H, Sanchez A, et al. Filovirus infections. In: Guerrant RL, Walker DH, Weller P, eds. Tropical infectious diseases: principles, pathogens and practice. 2nd ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2006; pp. 784-96.  
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7. De Manzione N, Salas RA, Paredes H, Godoy O, Rojas L, Araoz F, et al. Venezuelan hemorrhagic fever: clinical and epidemiological studies of 165 cases. Clin Infect Dis. 1998;26:308-13.
8. Madani TA, Al-Mazrou YY, Al-Jeffri MH, Mishkhas AA, Al-Rabeah AM, Turkistani AM, et al. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical, and laboratory characteristics. Clin Infect Dis. 2003;37:1084-92.
9. Graziano KL, Tempest B. Hantavirus pulmonary syndrome: a zebra worth knowing. Am Fam Phys. 2002;66:1015-20.
10. Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavirus infections in Europe. Lancet Infect Dis. 2003;3:653-61.
11. Rouquet P, Froment JM, Bermejo M, Yaba P, Delicat A, Rollin PE, et al. Wild animal mortality monitoring and human Ebola outbreaks, Gabon and Republic of Congo, 2001–2003. Emerg Infect Dis. 2005;11:283-90.
12. Peters CJ, Jahrling PB, Khan AS. Patients infected with high-hazard viruses: scientific basis for infection control. Arch Virol Suppl. 1996;11:141-68.
13. Feldmann H, Jones SM, Schnittler H-J, Geisbert T. Therapy and Prophylaxis of Ebola virus infections. Curr Opinion Investig Drugs. 2005;6:823-30.
14. Ozkurt Z, Kiki I, Erol S, Erdem F, Yilmaz N, Parlak M, et al. Crimean-Congo hemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy. J Infect. 2006;52:207-15.

PIERRE E. ROLLIN, THOMAS G. KSIAZEK