Viral hemorrhagic fevers (VHFs) are caused by several families of enveloped RNA viruses: filoviruses (Ebola and Marburg hemorrhagic fever, also see the Ebola Virus Disease and Marburg Virus Disease section in this chapter), arenaviruses (Lassa fever, lymphocytic choriomeningitis virus [LCMV], Lujo, Guanarito, Machupo, Junin, Sabia, and Chapare viruses), bunyaviruses (Rift Valley fever [RVF], Crimean-Congo hemorrhagic fever [CCHF], and hantaviruses), and flaviviruses (dengue, yellow fever, Omsk hemorrhagic fever, Kyasanur Forest disease, and Alkhurma viruses) (also see the Dengue and Yellow Fever sections in this chapter).
Some VHFs are spread person-to-person through direct contact with symptomatic patients, body fluids, or cadavers, or through inadequate infection control in a hospital setting (filoviruses, arenaviruses, CCHF virus). Zoonotic spread may occur from contact with the following:
The viruses that cause VHF are distributed over much of the globe. Each virus is associated with 1 or more nonhuman host or vector species, restricting the virus and the initial contamination to the areas inhabited by these species. The diseases caused by these viruses are seen in people living in or having visited these areas. Humans are incidental hosts for these enzootic diseases; however, person-to-person transmission of some viruses can occur. Specific viruses are addressed below.
Arenaviruses are transmitted from rodents to humans, except Tacaribe virus, which was found in bats but has not been reported to cause disease in humans. Most infections are mild, but some result in hemorrhagic fever with high death rates. Old World (eastern hemisphere) and New World (western hemisphere) viruses cause the following diseases:
Reservoir host species are Old World rats and mice (family Muridae, subfamily Murinae) and New World rats and mice (family Muridae, subfamily Sigmodontinae). These rodent types are found worldwide, including Europe, Asia, Africa, and the Americas. Virus is transmitted through inhalation of aerosols from rodent urine, ingestion of rodent-contaminated food, or direct contact of broken skin or mucosa with rodent excreta. Risk of Lassa virus infection is associated with peridomestic rodent exposure, where inappropriate food storage increases the risk for exposure. Several cases of Lassa fever have been confirmed in international travelers staying in traditional dwellings in the countryside. Health care–associated transmission of Lassa, Lujo, and Machupo viruses has occurred through droplet and direct contact exposures.
RVF primarily affects livestock, causing stillbirths and high mortality in neonatal cattle, sheep, and goats. In humans, RVF virus infection causes fever, hemorrhage, encephalitis, and retinitis. RVF virus is endemic in 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; Saudi Arabia and Yemen in 2000; Madagascar in 1990 and 2008; and South Africa, Botswana, Namibia, and Mauritania in 2010. RVF virus is transmitted to livestock by mosquitoes, while people become infected more frequently through direct contact with clinically affected animals or their body fluids, including 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 Turkey, Afghanistan, Iran, and Pakistan. The first human cases were reported in Spain in 2016. The Hyalomma ticks are primarily associated with livestock but will also bite humans. Livestock and other tick hosts may develop CCHF viremia from tick bites but do not develop clinical disease. CCHF virus is transmitted to humans by infected ticks or direct handling and preparation of fresh carcasses of infected animals, usually domestic livestock. Nosocomial human-to-human transmission can occur through droplet or direct contact.
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. The viruses that cause both HPS and HFRS are transmitted to humans through contact with urine, feces, or saliva of infected rodents. Travelers staying in rodent-infested dwellings are at risk for HPS and HFRS. Human-to-human transmission of hantavirus has been reported only with Andes virus in Chile and Argentina.
Signs and symptoms vary by disease, but in general, patients with VHF present with abrupt onset of fever, myalgias, and prostration, followed in severe forms by coagulopathy with a petechial rash or ecchymoses and sometimes overt bleeding. Gastrointestinal symptoms (diarrhea, vomiting, abdominal pain) are commonly observed. Vascular endothelial damage leads to shock and pulmonary edema, and liver injury is common. Signs seen with specific viruses include renal failure (HFRS), ecchymoses and bruises (CCHF), pharyngitis, retrosternal pain, hearing loss in adults and anasarca in newborns (Lassa fever), and spontaneous abortion and birth defects (Lassa virus and LCMV). Laboratory abnormalities include elevations in liver enzymes, initial drop in leukocyte count, and thrombocytopenia. Because the incubation period may be as long as 21 days, patients may not develop illness until returning from travel; therefore, a thorough travel and exposure history is critical.
US-based clinicians should notify local health authorities immediately of any suspected cases of VHF occurring in patients residing in the United States, or notify the CDC directly regarding any patients requiring evacuation to the United States (contact the CDC Emergency Operations Center at 770-488-7100). Appropriate personal protective equipment is indicated for any patients where Lassa, Lujo, South American arenaviruses, or CCHFV infection is suspected and includes droplet and contact precautions. 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. Blood collected within a few hours after death by cardiac puncture can be used for diagnosis.
Ribavirin is effective if given early in course of disease for treating Lassa fever and other Old World arenaviruses, New World arenaviruses, and potentially CCHF, but it is not approved by the Food and Drug Administration (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). Requests should be initiated by the provider through FDA (301-796-1500 or after hours 866-300-4374), with simultaneous notification to Valeant Pharmaceuticals: 800-548-5100, extension 5 (domestic telephone). The process is explained on FDA’s website (www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approval Applications/InvestigationalNewDrugIND Application/ucm090039.htm).
The risk of acquiring VHF is very low for international travelers. Travelers at increased risk for exposure include those engaging in animal research, health care workers, and others providing care for patients in the community without adequate personal protection, particularly where outbreaks of VHF are occurring.
Prevention should focus on avoiding unprotected contact with people suspected of having VHF or host or vector species in endemic countries. Travelers should not visit locations where an outbreak is occurring, avoid contact with rodents, and avoid blood or body fluids of livestock in RVF- and CCHF-endemic areas. To prevent vectorborne disease, travelers should use insecticide-treated bed nets and wear insect repellent.
Standard precautions and contact and droplet precautions for suspected VHF patients are recommended to avoid transmission. Direct contact should be avoided with corpses of patients suspected of having died of CCHF or arenavirus infection. Investigational vaccines exist for Argentine hemorrhagic fever and RVF; however, neither is approved by FDA, nor are they commonly available in the United States.
Barbara Knust, Mary Choi