Author(s): Trevor Shoemaker, Mary Joung Choi

ARENAVIRUSES

BUNYAVIRUSES

FILOVIRUSES

FLAVIVIRUSES

Infectious Agent

Viral hemorrhagic fever (VHF) diseases are caused by 3 families (Arenaviridae, Filoviridae, Flaviviridae) and 1 order (Bunyavirales) of enveloped RNA viruses. Arenaviridae (arenaviruses) include Chapare, Guanarito, Junin, Lassa, and Lujo viruses; lymphocytic choriomeningitis virus (LCMV); and Machupo and Sabia viruses. Viruses in the order Bunyavirales include the Arenaviridae family viruses, Crimean-Congo hemorrhagic fever (CCHF) virus (family Nairoviridae), hantaviruses (family Hantaviridae), and Rift Valley fever (RVF) virus (family Phenuiviridae). Filoviridae (filoviruses) include Ebola, Marburg, and Reston viruses. Flaviviridae (flaviviruses) include Alkhurma, Kyasanur Forest disease, Omsk hemorrhagic fever, dengue, and yellow fever viruses. For details on dengue and yellow fever, see the respective chapters in this section.

Transmission

Human-to-Human

Some VHF viruses (arenaviruses, CCHF virus, filoviruses) spread from person to person by direct contact with symptomatic patients, body fluids, or cadavers, or through inadequate infection control in a hospital setting. In the community, VHF viruses are generally transmitted through direct physical contact of unprotected skin or mucous membranes and the blood or other infectious body fluids of patients in the acute phase of disease or from patients who have died.

After recovery from acute Ebola virus disease (EVD) or Marburg virus disease (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 recovery. In pregnant people with EVD, in utero transmission of Ebola virus to the fetus can occur.

Zoonotic

Arthropod Vectors

Some bunyaviruses (RVF virus) and flaviviruses (dengue and yellow fever) can be transmitted by the bites of infected mosquitoes. Other bunyaviruses (CCHF virus) and flaviviruses (Alkhurma, Kyasanur Forest disease, and Omsk viruses) can be transmitted by the bites of infected ticks or by crushing infected ticks.

Bats

Bats are suspected reservoir species for filoviruses (Ebola and Marburg viruses) in the genus Ebolavirus; the natural reservoir for Marburg virus is the Egyptian fruit bat (Rousettus aegyptiacus).

Livestock

Some bunyaviruses (CCHF and RVF viruses) and flaviviruses (Alkhurma virus) can be transmitted during the slaughter of infected animals or from the consumption of raw meat or unpasteurized milk of an infected animal.

Rodents & Insectivores

Arenaviruses and some bunyaviruses (hantaviruses) can be transmitted by direct contact with infected animals or from inhalation of, or contact with, materials contaminated with rodent excreta.

Epidemiology

The viruses that cause VHF are distributed over much of the globe. Each virus is associated with ≥1 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 who live in or visit these areas. Humans are incidental hosts for these enzootic diseases; person-to-person transmission of some viruses can occur, however.

Arenaviral Diseases

Except Tacaribe virus—which was found in bats but has not been reported to cause disease in humans—arenaviruses are maintained in rodents and transmitted to humans. Most infections are mild, but some result in hemorrhagic fever with high death rates. Arenaviruses are categorized as Old World (Eastern Hemisphere) and New World (Western Hemisphere).

Old World Arenaviruses

Old World arenaviruses (and the diseases they cause) include Lassa virus (Lassa fever), Lujo virus, and LCMV. In otherwise healthy people, LCMV infection can cause meningitis, encephalitis, and congenital fetal infection; in organ transplant recipients, it is reported to cause severe disease with multiple organ failure. Lassa fever occurs across rural West Africa, with hyperendemic areas in parts of Guinea, Liberia, Nigeria, and Sierra Leone. Lujo virus infection has been described in the Republic of South Africa during a health care–associated outbreak, and in Zambia.

New World Arenaviruses

New World arenaviruses (and the diseases they cause) include Chapare virus, Guanarito (Venezuelan hemorrhagic fever), Junin (Argentine hemorrhagic fever), Machupo (Bolivian hemorrhagic fever), and Sabia (Brazilian hemorrhagic fever).

Reservoir Host Species

Reservoir host species of arenaviruses include 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 Africa, the Americas, Asia, and Europe. 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 for 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 countryside dwellings. Health care–associated transmission and close family member infection with Lassa, Lujo, and Machupo viruses occurs through droplet spread and direct contact.

Bunyaviral Diseases

Crimean-Congo Hemorrhagic Fever

CCHF is endemic to areas where ticks of the genus Hyalomma are found in Africa (including South Africa) and Eurasia (including the Balkans, the Middle East, Russia, and western China). CCHF is highly endemic to Afghanistan, Iran, Pakistan, and Turkey. In 2016, Spain reported its first identified human cases. Hyalomma ticks are primarily associated with livestock but will also bite humans.

Livestock and other tick hosts might 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 droplets or direct contact.

Hantavirus Pulmonary Syndrome & Hemorrhagic Fever With Renal Syndrome

Hantaviruses can cause hantavirus pulmonary syndrome (HPS) or hemorrhagic fever with renal syndrome (HFRS). Viruses that cause HPS are found in the Western Hemisphere (North, Central, and South America); 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. A reported case of imported Andes virus in the United States occurred in 2018 in a traveler returning from Chile and Argentina.

Rift Valley Fever

RVF primarily affects livestock, causing stillbirths and high mortality in neonatal cattle, goats, and sheep. 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, Mayotte, Senegal, South Sudan, Sudan, and Uganda. Large epidemics occurred in Madagascar in 1990, and again in 2008; in Kenya, Somalia, and Tanzania during 1997–1998 and 2006–2007; in Saudi Arabia and Yemen in 2000; in Botswana, Mauritania, Namibia, and South Africa in 2010; and in Niger during 2016–2017. RVF virus is transmitted to livestock by mosquitoes; people more frequently become infected through direct contact with clinically affected animals or their body fluids, including through slaughter or consumption of infected animals.

Filoviral Diseases

People at greatest risk of EVD or MVD include family members, health care workers, or others who, without personal protective equipment (PPE), come into direct contact with infected patients or corpses. People who come into close contact or proximity to bats (e.g., those who visit caves or mines with bats) and people who handle infected primates or carcasses are also at risk. A postulated route of infection to humans (as well as to ground-dwelling animals) involves consumption of fallen or dropped fruit contaminated by the saliva or urine of infected, fruit-foraging bats. Additionally, the sexual partners of males who recently survived EVD or MVD might be at risk if they have had contact with virus-infected semen.

Ebola Virus Disease

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.

Prior to 2014, Ebola outbreaks typically had been limited in scope and geographic extent. In March of 2014, however, an outbreak of Ebola virus was detected in a rural area of Guinea near the borders with Liberia and Sierra Leone. By June 2014, cases were reported in all 3 countries and across many districts. Additional cases occurred in Italy, Mali, Nigeria, Senegal, Spain, the United Kingdom, and the United States, after infected people traveled from West Africa. The outbreak was the largest and most complex Ebola epidemic ever reported.

Since the 2014, Ebola outbreaks have been reported in the Democratic Republic of the Congo in 2017, 2018, 2020, and 2021, and in Guinea in 2021. Cases were also reported in Uganda in 2018–2019, and in 2022. Reston virus (in the genus Ebolavirus) is believed to be endemic to the Philippines but has not been shown to cause human disease.

Marburg Virus Disease

Countries with confirmed human cases of MVD include Angola, Democratic Republic of the Congo, Guinea, Kenya, Uganda, and possibly Zimbabwe. Four cases 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.

Clinical Presentation

Signs and symptoms vary by disease, but in general, patients with VHF present with abrupt onset of fever, headache, myalgias, and prostration, followed by coagulopathy with a petechial rash or ecchymoses and sometimes overt bleeding in severe forms. Gastrointestinal symptoms (abdominal pain, diarrhea, vomiting) are commonly observed. Vascular endothelial damage leads to shock and pulmonary edema; liver injury is common.

Syndromic findings associated with specific Arenaviridae infections include pharyngitis, retrosternal pain, hearing loss in adults, and anasarca in newborns (Lassa); and spontaneous abortion and birth defects (Lassa fever, LCMV). Syndromic findings associated with specific Bunyavirales infections include ecchymoses and bruising (CCHF virus); renal failure (hantavirus, HFRS); and retinitis and partial blindness (RVF). Laboratory abnormalities include elevated liver enzymes, initial drop in leukocyte count, and thrombocytopenia. Because the incubation period can extend up to 21 days, patients might not develop illness until they return from travel; a thorough travel and exposure history is critical.

Diagnosis

Immediately notify local health authorities of any suspected cases of VHF occurring in patients residing in the United States. For laboratory testing requests, notify your local or state health department. To notify the Centers for Disease Control and Prevention (CDC) directly about any patients requiring evacuation to the United States, contact the CDC Emergency Operations Center at 770-488-7100.

Appropriate PPE, including implementation of droplet and contact precautions, is indicated for any patients in whom a VHF is suspected. Airborne transmission of VHF viruses has not been documented in hospitals or households during any of the human outbreaks investigated to date. Certain procedures (e.g., bronchoscopy, endotracheal intubation) might, however, create mechanically generated aerosols that could be infectious. As such, airborne precautions are recommended for aerosol-generating procedures.

Postmortem samples of blood (collected by cardiac puncture) or skin collected within a few hours after death can be used for diagnosis. Whole blood or serum can be used for virologic testing by reverse transcription PCR (RT-PCR), antigen detection, or virus isolation, and to test for immunologic (IgM, IgG) evidence of infection. Skin biopsies fixed in formalin can be tested by immunohistochemistry, RT-PCR, and virus isolation. Consider collecting an oral swab from deceased patients 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.

Treatment

The mainstay treatment for VHFs is early and aggressive supportive care directed at maintaining effective intravascular volume and correcting electrolyte imbalances. Convalescent-phase plasma is effective in treating Argentine hemorrhagic fever but is available only in Argentina. 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 for use by the US Food and Drug Administration (FDA) for these indications. Compassionate use intravenous ribavirin can be obtained from Bausch Health; initiate requests by contacting CDC’s Viral Special Pathogens Branch (770-488-7100).

Two FDA-approved treatments are available for Ebola virus (species Zaire ebolavirus). Ebanga (single monoclonal antibody) and Inmazeb (triple monoclonal antibody cocktail) are both approved to treat acute EVD in adult and pediatric patients. In a randomized clinical control trial, Ebanga reduced mortality rates to 35%, and Inmazeb reduced rates to 33%. Both drugs particularly reduced deaths in patients with low viral loads; mortality rates in patients treated with Ebanga were 9.9% and were 11.2% in patients treated with Inmazeb.

Patients with EVD also might have concomitant malaria infection; consider empiric use of antimalarial therapy when rapid diagnostic testing is not immediately available. In general, avoid administering NSAIDs (e.g., diclofenac, ibuprofen) because of their antiplatelet activity.

Prevention

The risk of acquiring a VHF is very low for most international travelers. Travelers at increased risk for exposure include people who engage in animal research, and health care workers and others who do not have adequate PPE when caring for patients in communities where outbreaks are occurring. Prevention should focus on avoiding unprotected contact with sources of infection, including anyone suspected of having VHF, and host or vector species in endemic countries. Travelers should not visit locations where outbreaks are occurring. In addition, travelers should avoid contact with bats and rodents, and avoid blood or body fluids of livestock in RVF- or CCHF-endemic areas. To prevent vectorborne diseases, travelers should use insecticide-treated mosquito nets and use insect repellent (see Sec. 4, Ch. 6, 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 preventing 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. Promptly isolate any patients with recent international travel who have symptoms consistent with a VHF 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 appropriate PPE should evaluate a patient and provide care. Prompt notification of the facility’s infection-control program and state and local health departments is also key.

Vaccines

In February 2020, the Advisory Committee on Immunization Practices (ACIP) recommended ERVEBO for preexposure vaccination of adults aged ≥18 years in the United States at risk for Ebola exposure; groups meeting this definition include those responding to outbreaks of EVD due to Ebola virus (species Zaire ebolavirus). In November 2021, ACIP expanded its preexposure vaccination recommendations to include health care personnel at federally designated Ebola treatment centers in the United States, and laboratory workers or other staff at Biosafety Level 4 facilities in the United States that handle replication-competent Ebola virus (species Zaire ebolavirus).

Investigational vaccines exist for Argentine hemorrhagic fever and RVF, but neither is approved by FDA or commercially available in the United States.

CDC website: Viral hemorrhagic fever (VHFs)