Several families of enveloped RNA viruses cause viral hemorrhagic fevers (VHFs).
Filoviruses include the Ebola viruses, which cause Ebola virus disease (EVD), and Marburg virus, which causes Marburg virus disease (MVD). Arenaviruses include Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Lujo, Guanarito, Machupo, Junin, Sabia, and Chapare viruses. Bunyaviruses include Rift Valley fever (RVF) virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and hantavirus. The flaviviruses include dengue virus, yellow fever virus, Omsk hemorrhagic fever virus, Kyasanur Forest disease virus, and Alkhurma hemorrhagic fever virus (also see the Dengue and Yellow Fever sections in this chapter).
Some of the VHF viruses (filoviruses, arenaviruses, CCHF virus) spread by direct contact with symptomatic patients, body fluids, or cadavers, or through inadequate infection control in health care settings. In community settings, disease transmission occurs when a person (without proper skin and mucous membrane protection) comes into direct physical contact with the blood or other infectious body fluids of patients in the acute phase of disease or who have died.
Zoonotic sources of VHF virus exposure include:
After recovery from acute EVD or MVD, the virus or its RNA persists in some specific body fluids of convalescent patients. Ebola virus RNA has been detected in breast milk up to 21 days after the onset of the disease and in vaginal secretions up to 33 days after onset. Ebola virus and Marburg virus have been cultured from ocular aqueous humor at 2 and 3 months after disease onset, respectively. Evidence suggests that Ebola and Marburg viruses can be sexually transmitted from a male survivor to his partner months after onset of disease. In pregnant women with EVD, there can be in utero transmission of Ebola virus to the fetus.
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 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.
People at greatest risk of EVD or MVD include family members, health care workers, or others who, without protective equipment, come into direct contact with infected patients or corpses; people who have come into contact or close proximity to bats (visiting bat caves); and people who have handled infected primates or carcasses. Additionally, sex partners of recent male EVD or MVD survivors may be at risk if they have had contact with virus-infected semen.
Countries where domestically acquired EVD cases have been reported and that should be considered areas where future epidemics could occur include Côte d’Ivoire, Democratic Republic of the Congo, Gabon, Guinea, Liberia, Republic of the Congo, Sierra Leone, South Sudan, and Uganda.
Typically, previous Ebola outbreaks had been limited in scope and geographic extent. However, in March of 2014, an outbreak of Ebola virus was detected in a rural area of Guinea near the border with Liberia and Sierra Leone. By June of 2014, cases were reported in all 3 countries and across many districts. The outbreak was the largest and most complex Ebola epidemic ever reported. Additional cases occurred in Nigeria, Senegal, Mali, Spain, the United Kingdom, Italy, and the United States, after infected people traveled from West Africa.
Countries with confirmed human cases of MVD include Angola, Democratic Republic of the Congo, Kenya, Uganda, and possibly Zimbabwe. Four cases of MVD have occurred in travelers visiting caves harboring bats, including Kitum Cave in Kenya and Python Cave in Maramagambo Forest, Uganda. Miners in the Democratic Republic of the Congo and Uganda have also acquired Marburg virus infection from working in underground mines harboring bats.
Reston virus is believed to be endemic to the Philippines but has not been shown to cause human disease.
Arenaviruses are maintained in rodents and transmitted 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. Arenaviruses may be divided into 2 categories, Old World (eastern hemisphere) and New World (western hemisphere).
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 rodent urine aerosols, ingestion of rodent-contaminated food, or by 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 and close family member infection with Lassa, Lujo, and Machupo viruses occurs through droplet spread and direct contact.
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 to sub-Saharan Africa. Sporadic outbreaks have occurred in humans in Comoros, Egypt, Madagascar, Mali, Mauritania, Senegal, South Sudan, Sudan, and Uganda. 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; Botswana, Mauritania, Namibia, and South Africa in 2010; and Niger in 2016–2017. 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 to areas of Africa and Eurasia where ticks of the genus Hyalomma are found, including South Africa, the Balkans, the Middle East, Russia, and western China, and particularly to Turkey, Afghanistan, Iran, and Pakistan. The first human cases were reported in Spain in 2016. Primarily associated with livestock, Hyalomma ticks will also bite humans. Livestock and other hosts may develop CCHF viremia from tick bites but do not develop clinical disease. CCHF virus is transmitted to humans by infected ticks or by direct handling and preparation of fresh carcasses of infected animals, usually domestic livestock. 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. The first reported case of imported Andes virus in the United States occurred in 2018 in a traveler returning from Chile and Argentina.
Signs and symptoms vary by disease, but in general, patients with VHF present with abrupt onset of fever, myalgias, headache, and prostration, followed by coagulopathy with a petechial rash or ecchymoses and sometimes overt bleeding in severe forms. Gastrointestinal symptoms (diarrhea, vomiting, abdominal pain) are commonly observed. Vascular endothelial damage leads to shock and pulmonary edema, and liver injury is common.
Findings associated with specific viruses include renal failure (hantavirus); ecchymoses and bruises (CCHF virus); pharyngitis, retrosternal pain, hearing loss in adults and anasarca in newborns (Lassa virus); retinitis and partial blindness (RVF virus); 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. For laboratory testing requests, notify the local or state health department. To 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 CCHF virus 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. Postmortem skin biopsies fixed in formalin and blood collected by cardiac puncture within a few hours after death can be used for diagnosis. Consider collection of an oral swab from deceased cases when an alternative sample cannot be collected.
Special handling procedures are required when submitting blood and other body fluid specimens for diagnostic testing. Please contact the CDC Emergency Operations Center at 770-488-7100 for more information.
The mainstay of treatment for VHFs is early, aggressive, supportive care directed at maintaining effective intravascular volume and correcting electrolyte imbalances. Ribavirin is effective if given early in the 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. 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/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm090039.htm).
There is no proven specific therapy for EVD. Several experimental immune therapy and antivirals treatments are under investigation. EVD patients may also have concomitant malaria infection. As such, empiric use of antimalarial therapy should be considered when rapid diagnostic testing is not immediately available. In general, NSAIDs such as ibuprofen and diclofenac are not recommended because of their antiplatelet activity.
There is no FDA-approved vaccine for any of the VHFs. Experimental Ebola vaccines are under development, including a recombinant vesicular stomatitis virus-based vaccine and a chimpanzee adenovirus-based vaccine. However, these investigational products are in the early stages of product development and are not yet available. Investigational vaccines exist for Argentine hemorrhagic fever and RVF; neither vaccine is approved by FDA or commercially available in the United States.
The risk of acquiring VHF is very low for international travelers. Travelers at increased risk for exposure include those engaging in animal research, and health care workers and others who, without adequate personal protection, provide care for patients in the community, particularly where outbreaks of VHF are occurring.
Prevention should focus on avoiding unprotected contact with sources of infection: people suspected of having VHF and hosts/vector species in endemic countries. Travelers should not visit locations where outbreaks are occurring, avoid contact with rodents and bats, and avoid blood or body fluids of livestock in RVF- and CCHF-endemic areas. To prevent vectorborne diseases, travelers should use insecticide-treated bed nets and wear insect repellent (see Chapter 3, Mosquitoes, Ticks & Other Arthropods).
For VHFs that can be transmitted person to person (EVD, MVD, Lassa Fever, CCHF), early identification and isolation of ill travelers, consistent implementation of basic infection control measures, and prompt notification of public health authorities are the keys to prevent secondary transmission. Early identification strategies include eliciting a travel history from all patients who present for care and posting signs and placards asking patients with recent international travel to self-identify. Those patients with recent international travel who have symptoms consistent with any VHF should be promptly isolated by placing them in a private room or a separate enclosed area with a private bathroom or covered bedside commode. To minimize disease transmission risk, only essential health care providers wearing personal protective equipment should evaluate a patient and provide care. Prompt notification of the facility’s infection control program as well as state and local health departments is also key.
CDC website: www.cdc.gov/vhf.
Trevor Shoemaker, Mary Choi