CBRNE - Viral Hemorrhagic Fevers

Updated: Mar 31, 2021
Author: David C Pigott, MD, RDMS, FACEP; Chief Editor: Zygmunt F Dembek, PhD, MS, MPH, LHD 


Practice Essentials

Viral hemorrhagic fevers (VHFs) are a group of febrile illnesses caused by RNA viruses from several viral families. These highly infectious viruses lead to a potentially lethal disease syndrome characterized by fever, malaise, vomiting, mucosal and gastrointestinal (GI) bleeding, edema, and hypotension. The image below depicts palatal petechiae and hemorrhage in a patient with Ebola virus disease (EVD).

Filovirus disease - Ebola fever. Patient with Ebol Filovirus disease - Ebola fever. Patient with Ebola hemorrhagic fever during 1976 outbreak in Zaire demonstrating palatal petechiae and hemorrhage. Photo courtesy of Joel Breman.

Four viral families are known to cause VHFs in humans: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. General characteristics of these viral families can be found in the table below.

Table. Viral Families Causing Viral Hemorrhagic Fever (Open Table in a new window)

Virus Family

Disease (Virus)

Natural Distribution

Usual Source of Human Infection

Incubation (Days)







Lassa fever





Argentine HF (Junin)

South America




Bolivian HF (Machupo)

South America




Brazilian HF (Sabia)

South America




Venezuelan HF (Guanarito)

South America









Rift Valley fever





Crimean-Congo HF

Europe, Asia, Africa




Hemorrhagic fever with renal syndrome, Hantavirus pulmonary syndrome

Asia, Europe, worldwide









Marburg and Ebola


Fruit bat








Yellow fever

Tropical Africa, South America




Dengue HF

Asia, Americas, Africa


Unknown for dengue HF, 5-7 for dengue

See Ebola: Care, Recommendations, and Protecting Practitioners, a Critical Images slideshow, to review treatment, recommendations, and safeguards for healthcare personnel.

Also, see the 11 Travel Diseases to Consider Before and After the Trip slideshow to help identify and manage infectious travel diseases.

For patient education resources, see the First Aid and Injuries Center, as well as Biological Warfare and Personal Protective Equipment.



The primary defect in patients with viral hemorrhagic fever (VHF) is that of increased vascular permeability. Hemorrhagic fever viruses have an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias. Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse. The relative severity of the clinical presentation may vary depending on the virus in question, amount, and route of exposure.

In acute disease, patients are extremely viremic, and messenger ribonucleic acid (mRNA) evidence of multiple cytokine activation exists. In vitro studies reveal these cytokines lead to shock and increased vascular permeability, the basic pathophysiologic processes most often seen in viral hemorrhagic fever infection.

Another prominent pathologic feature is pronounced macrophage involvement. Inadequate or delayed immune response to these novel viral antigens may lead to rapid development of overwhelming viremia. Extensive infection and necrosis of affected organs also are described.

Hemorrhagic complications are multifactorial and are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes. 

Multisystem organ failure affecting the hematopoietic, neurologic, and pulmonary systems often accompanies the vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, Crimean-Congo hemorrhagic fever (CCHF), and yellow fever. Acute kidney injury with oliguria is a prominent feature of hemorrhagic fever with renal syndrome (HFRS) seen in Hantavirus infection and may be seen in other VHFs as intravascular volume depletion becomes more pronounced. Bleeding complications are particularly prominent with Ebola, Marburg, CCHF, and the South American arenaviruses.

Although the pathophysiology of dengue infection is complex and incompletely understood, severe dengue infection can be differentiated from milder forms by the presence of increased vascular permeability. The greatest risk factor for severe dengue infection is secondary infection with a dengue serotype different from the initial dengue infection. This increased vascular permeability is thought to be secondary to widespread T-cell activation and apoptosis and is also thought to be related to a process known as antibody-dependent enhancement, best described as the balance between neutralizing versus enhancing antibodies after an initial dengue infection, which can contribute to the severity of secondary dengue infection.



Arenaviridae are spread to humans by rodent contact and include Lassa virus in Africa and several rare South American hemorrhagic fevers such as Machupo, Junin, Guanarito, and Sabia. Lassa virus is the most clinically significant of the Arenaviridae, accounting for serious morbidity and mortality in West Africa.

Lassa fever first appeared in Lassa, Nigeria, in 1969. It has been found in all countries of West Africa and is a significant public health problem in endemic areas. In populations studied, Lassa fever accounts for 5-14% of hospitalized febrile illnesses. Its natural reservoir is a small rodent whose virus-containing excreta is the source of transmission. (See the image below.)

Mastomys natalensis, natural host of Lassa virus. Mastomys natalensis, natural host of Lassa virus. Photo courtesy of BioMed Central, originally published in Kelly JD, Barrie MB, Ross RA, Temple BA, Moses LM, Bausch DG. Housing equityfor health equity: a rights-based approach to the control of Lassa fever inpost-war Sierra Leone. BMC Int Health Hum Rights. 2013 Jan 2;13:2.


This group includes Rift Valley fever (RVF) virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and several hantaviruses. The RVF and CCHF viruses are both arthropod-borne viruses. RVF virus, an important African pathogen, is transmitted to humans and livestock by mosquitos and by the slaughter of infected livestock.

CCHF virus is carried by ticks and causes a fulminant, highly pathogenic form of VHF notable for aerosol transmission of infective particles (see the image below). CCHF virus has a wide geographic range that includes Africa, Asia, the Middle East, and Europe with sequence variation approaching 20% across the three negative-sense RNA genome segments. While phylogenetic clustering generally aligns with geographic origin of individual strains, distribution can be wide due to tick/CCHF virus dispersion via migrating birds.[1]

Many hantaviruses are spread worldwide, causing 2 major syndromes: hemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome (HPS). They are divided into Old World hantaviruses (such as the prototypical Hantaan virus of Korea), which generally cause HFRS, and New World hantaviruses, causing HPS. Rodents carry both types. A previously undiscovered Hantavirus, Sin Nombre virus, was the cause of an outbreak of highly lethal HPS in the southwestern United States in 1993. More than 450 cases have been identified in the US since 1993, with a 35% mortality rate.[2]


The most notorious of the VHF viruses, Ebola and Marburg viruses, belong to the Filoviridae family. Both viruses originated in sub-Saharan Africa.

Ebola virus

Ebola virus (see the image below) was first described in 1976 after outbreaks of a febrile, rapidly fatal hemorrhagic illness were reported along the Ebola River in Zaire (now the Democratic Republic of the Congo) and Sudan. Sporadic outbreaks have continued since that time, usually in isolated areas of central Africa. An outbreak in Kikwit, Zaire, in 1995 led to 317 confirmed cases, with an 81% mortality rate. Two thirds of the cases were in health care workers caring for infected individuals. An outbreak in Uganda in late 2000 resulted in 425 cases and claimed 225 lives.

Ebola virus. Electron micrograph courtesy of the C Ebola virus. Electron micrograph courtesy of the Centers for Disease Control and Prevention.

The largest Ebola outbreak to date occurred in West Africa from 2014 to 2016. This outbreak primarily occurred in Guinea, Sierra Leone, and Liberia, with >28,000 cases and >13,000 deaths. As a result of this outbreak, several sporadic cases of imported Ebola virus disease also occurred in industrialized nations, including the United States, the United Kingdom, Spain, and Italy.

From 2018 to 2020, the Democratic Republic of Congo (DRC) reported the emergence of another Ebola virus outbreak. As of June 2020, there were more than 3400 cases and 2200 deaths, making this the world’s second-largest Ebola outbreak to date.[3]

Ebola has 6 distinct subtypes:

  • Zaire ebolavirus
  • Sudan ebolavirus
  • Reston ebolavirus
  • Taï Forest ebolavirus
  • Bundibugyo ebolavirus
  • Bombali ebolavirus

The newest member of this genus is Bombali ebolavirus, discovered in 2018 and named after the Bombali area in Sierra Leone.[4]  Reston ebolavirus causes illness in nonhuman primates and pigs but not in humans.[5]

Fruit bats have been identified as a reservoir for Ebola virus.[6]

Marburg virus

Marburg virus (see the image below), named after the German town where it first was reported in 1967, is another highly pathogenic member of the Filoviridae family that is traced to central Africa. As with Ebola virus, the natural host for the virus is likely the fruit bat. Marburg virus was contracted by a traveler to central Africa in 1987 and has been endemic since 1998 in Durba, Democratic Republic of the Congo, and in persons exposed in caves or mines.

Marburg virus. Negative stain image courtesy of th Marburg virus. Negative stain image courtesy of the Centers for Disease Control and Prevention.

Marburg virus was determined to be the causative agent in a 2004-2005 outbreak of hemorrhagic fever in Angola that led to 252 confirmed cases and 227 deaths (90% case-fatality rate). In late 2012, an outbreak in Uganda resulted in 26 confirmed and probable cases of Marburg virus infection, including 15 deaths.[7]


Yellow fever and dengue fever are the most well-known diseases caused by flaviviruses. Both are mosquito-borne; yellow fever is found in tropical Africa and South America, and dengue fever is found in Asia, Africa, and the Americas. They are notable for their significant effect on prior military campaigns and their continued presence throughout endemic areas.

Due to a resurgence in the last 3 decades, dengue fever is now considered second only to malaria in terms of importance as a tropical disease. Multiple large outbreaks have occurred throughout the tropics recently, with the most severe outbreaks occurring in Southeast Asia and the western Pacific regions. Transmission is via the bite of the infected female Aedes mosquito, although dengue can also be transmitted via transfusion.[8]



United States

Cases of viral hemorrhagic fever (VHF) in the United States are extremely rare and usually are found in patients who recently have visited endemic areas or among those with potential occupational exposure to hemorrhagic fever viruses. Lassa fever has been reported in the United States in travelers from West Africa and was most recently reported in the United States in 2010.[9] In 1994, a virologist working with Sabia, a Brazilian HF virus, accidentally contracted the disease. Sporadic cases of Hantavirus pulmonary syndrome (HPS) continue to be reported throughout the western United States.[10]

During the 2014-2016 Ebola outbreak in West Africa, 2 imported cases were reported in the United States, including one death, as well as two locally acquired cases in healthcare workers.[11]  In 1989, an outbreak of hemorrhagic fever among imported macaque monkeys in Reston, Virginia, led to the discovery of Reston ebolavirus, a variant of Ebola virus that originated in the Philippines and does not cause disease in humans.

An estimated 100-200 cases of imported dengue fever are reported in the United States each year. Occasional dengue outbreaks have occurred in the United States, and well-documented local transmission of dengue continues to occur in south Florida, specifically in Key West.[12]


Lassa fever is responsible for an estimated 100,000-300,000 infections per year, with 5,000 deaths. Cases have been reported throughout West Africa, particularly in Nigeria, Sierra Leone, Guinea, and Liberia. Other arenaviruses are responsible for sporadic VHF outbreaks throughout South America.

Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) are responsible for intermittent epidemics in Africa (for RVF) and in areas of Africa, Asia, and Europe (for CCHF). Hemorrhagic fever with renal syndrome (HFRS) due to Hantavirus infection continues to be an ongoing health concern, particularly in Asia, affecting up to 200,000 patients annually.

Ebola virus appears sporadically in endemic areas of the former Zaire and Sudan. Ebola virus also has been reported in Gabon, the Ivory Coast, and Uganda. Outbreaks appear to propagate in hospital settings, often involving health care providers. In the 2014-2016 outbreak centered in Guinea, Sierra Leone, and Liberia, over 28,652 confirmed cases and 11,325 deaths were reported.[13]

Yellow fever continues to be a serious problem in tropical areas of South America and Africa, where vaccination is not widespread. World Health Organization 2013 estimates suggest that 84,000 to 170,000 cases per year occur in Africa, with 29,000 to 60,000 deaths.[14] A yellow fever outbreak in Brazil from 2016-2019 involved more than 2200 cases and resulted in nearly 800 deaths.[15]

Dengue is endemic in Southeast Asia, Africa, Central America, and South America. Statistical models suggest that as many as 390 million cases may occur annually, of which 96 million manifest clinically.[16]  According to the Pan American Health Organization, in 2018, a total of 560,586 cases of dengue were reported (incidence rate of 57.3 cases per 100,000 population) in the Americas, including 336 deaths. Rates of severe dengue and dengue with warning signs were higher than the previous 2 years but lower than in the preceding 10 years, and have remained below 1% of dengue cases overall since 2015.[17]  



Case-fatality rates of patients with viral hemorrhagic fever (VHF) vary from less than 10% (eg, in dengue) to as high as 90%, as has been reported in some filovirus outbreaks. The case-fatality rate for the 2014-2016 West Africa Ebola outbreak was ~40%.

Complications from VHF include the following:

  • Retinitis
  • Orchitis
  • Encephalitis
  • Hepatitis
  • Transverse myelitis
  • Uveitis

Following the recent West Africa Ebola outbreak, a post-Ebola syndrome has been reported that consists of myalgias, arthralgias, visual problems including blindness and uveitis, and neurologic findings including memory problems, lethargy, and fatigue.[18]  Persistence of Ebola virus RNA has been noted in semen samples even 13 months after infection, although a statistical analysis suggests that semen will be Ebola-free at 4 months in 50% of survivors.[19]

In patients who recover from Lassa fever infection, deafness is the most common complication. Spontaneous abortion also is common.

Recovery from hemorrhagic fever with renal syndrome may be complicated by chronic kidney disease. 




Obtain a detailed travel history, paying particular attention to recent travel to tropical or rural areas, such as Central or South America (yellow fever, arenaviruses), West Africa (Lassa fever), or to endemic portions of Central Africa (Ebola, Marburg, Rift Valley fever [RVF], Crimean-Congo hemorrhagic fever [CCHF]). Ask about contact with potential arthropod or rodent reservoirs.

Although several species of fruit bat have been implicated as the natural reservoir for Ebola and Marburg virus, contact with infected animals or humans is not a prerequisite for transmission of infection. Direct contact with rodents infected with hemorrhagic fever viruses (eg, arenaviruses, hantaviruses) is not necessary for transmission of infection, since aerosolized excreta may transmit infection. Aerosol transmission of some viral hemorrhagic fever infections is reported among nonhuman primates and likely is a mode of transmission in patients with severe infection.

Contacts of patients with known viral hemorrhagic fever (VHF), especially family members or health care workers caring for infected patients, are at risk for infection if appropriate barrier precautions are not used. Transmission of VHF has occurred from the reuse of unsterile needles and syringes used for treatment of infected patients. Transmission of VHF also has occurred to individuals handling the deceased in preparation for burial or to individuals involved in the slaughter of infected livestock (as in RVF or CCHF).

Because of their extreme pathogenicity and potential for transmission by fine-particle aerosol, VHF viruses are considered potential biological warfare agents. In addition, Dr Ken Alibek, the former Deputy Director of the once massive Soviet bioweapons program, Biopreparat, claims Soviet scientists successfully had produced a stable Marburg virus biological weapon that could be delivered as an aerosol. Large numbers of military personnel with VHF symptoms would suggest such an attack. An outbreak of VHF in a nonendemic area would also suggest a biological warfare attack.

Incubation periods for VHF vary from 2-21 days. The initial symptoms correspond to development of viremia and include the following:

  • High fever
  • Headache
  • Fatigue
  • Abdominal pain
  • Myalgias
  • Prostration

In more advanced disease, signs and symptoms include the following:

  • Hematemesis and bloody diarrhea
  • Generalized mucous membrane hemorrhage
  • Rash
  • Altered mental status and cardiovascular collapse (preterminal events)

Physical Examination

Depending on the progress of the disease, patients with viral hemorrhagic fever (VHF) initially may present with minimal signs, suggesting a more benign viral syndrome. Maintain a high index of suspicion.

As the disease progresses, more classic findings are present as follows:

  • Fever
  • Pharyngitis
  • Conjunctival injection
  • Nondependent edema
  • Petechial or ecchymotic rash
  • GI bleeding
  • Hypotension and/or shock

Most hemorrhagic fevers, except Rift Valley fever, can produce a variety of cutaneous findings that are principally caused by vascular instability and bleeding abnormalities. Such findings include flushing, petechiae, purpura, ecchymoses, and edema.

The Old World arenavirus causing Lassa fever results in the greatest amount of edema of any of the hemorrhagic fever viruses. Additionally, no bleeding abnormalities are present.

The New World arenaviruses (Junin, Machupo, Sabia, and Guanarito) cause less edema and variable amounts of petechiae, purpura, ecchymoses, palatal hyperemia, and mucosal hemorrhage.

The most severe hemorrhage from a hemorrhagic fever virus follows infection with the Congo Crimean hemorrhagic fever (CCHF) virus (see the image below).

Bunyavirus infection. Ecchymoses encompassing left Bunyavirus infection. Ecchymoses encompassing left upper extremity one week after onset of CCHF. Ecchymoses often are accompanied by hemorrhage in other locations: epistaxis, puncture sites, hematemesis, melena, and hematuria. Image provided by Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.

Hantaviruses can cause a relatively distinctive eruption with a petechial eruption around the neck and on the anterior and posterior axillary folds, arms, and trunk. A sunburn-like flush is seen on the head, neck, and upper chest and back and may be accompanied by facial edema (see the image below). Sometimes, a morbilliform eruption occurs. Oral and conjunctival surfaces may develop severe hemorrhages.

Bunyavirus infection - Hantaan virus. Patient with Bunyavirus infection - Hantaan virus. Patient with Korean hemorrhagic fever caused by Hantaan virus demonstrating typical 'sunburn flush' of cheeks, chin, and base of neck. Photo courtesy of John Huggins, PhD.

The filoviruses (Marburg and Ebola) exhibit characteristic exanthems that are best seen in fair-skinned patients. Soft palatal hyperemia accompanies the flu-like prodrome and is followed between days 5 and 7 by a nonpruritic, centripetal, pinhead-sized papular, erythematous exanthem. Within 24 hours, this can develop into large and coalescent, well-demarcated, sometimes hemorrhagic macules and papules. In severe cases, hemorrhage exudes from mucous membranes, venipuncture sites, and body orifices.

Dengue virus causes a characteristic erythematous exanthem with striking islands of sparing (see the image below).

Patient with morbilliform exanthem of dengue fever Patient with morbilliform exanthem of dengue fever. Note islands of sparing, which is characteristic for dengue. Photo courtesy Duane Gubler, PhD.


Diagnostic Considerations

Because of overlapping clinical and laboratory features, it may be difficult to distinguish between dengue and COVID-19 disease in endemic areas.[20] Diagnosis with one does not rule out a concomitant infection with the other, as co-infections have been reported.[21, 22, 23]

Other problems to be considered in the differential diagnosis include the following:

  • Typhoid fever
  • Shigellosis
  • Meningococcemia
  • Rickettsial infections
  • Acute leukemia
  • Idiopathic or thrombotic thrombocytopenic purpura

Differential Diagnoses



Approach Considerations

Most patients with viral hemorrhagic fever (VHF) are viremic at the time of presentation (Hantavirus is an exception). Specific viral diagnosis can be made using serologic tests, including enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). Difficult cases may require viral isolation in tissue culture.

Following the 2014 West Africa Ebola outbreak, reverse transcriptase PCR (RT-PCR) emerged as the most common method for detecting Ebola virus in patient serum, plasma, and whole blood. Novel antigen-capture ELISA techniques have also been developed in response to this outbreak.

Real-time reverse-transcription polymerase chain reaction (RT-PCR) remains the gold standard for quantitative, sensitive, and specific detection of Crimean-Congo hemorrhagic fever (CCHF) virus; however, these assays have sensitivity issues due to the genetic diversity of different CCHF viral strains.[1]

Because of the need for specialized microbiologic containment and handling of these viruses, initiate contact with the Centers for Disease Control and Prevention (CDC; Atlanta, GA) as soon as possible and prior to transport of specimens for virus-specific diagnosis. Specific state and federal statutes govern the shipment of highly infectious disease agents.

The CDC and the US Army Medical Research Institute for Infectious Diseases (USAMRIID; Frederick, MD) are among the 10 Biosafety Level 4 (BSL-4) laboratory facilities in the US with such diagnostic facilities.

Report all suspected cases of VHF immediately to local and state public health departments and to the CDC.

Laboratory Studies

Because of risks associated with handling infectious materials, perform the minimum necessary laboratory testing for diagnostic evaluation and patient care.

A complete blood count often indicates leukopenia and thrombocytopenia (these findings may not be present in Lassa fever). Significant electrolyte and metabolic disturbances have been reported in the recent Ebola virus disease outbreak, including hypokalemia, hypocalcemia, hyponatremia, elevated creatinine and elevated anion gap acidosis.[24]  

Elevated hepatic transaminases are observed in viral hemorrhagic fever (VHF) and are predictive of high mortality in Lassa fever infection.

Prothrombin time, activated partial thromboplastin time, international normalized ratio, and clotting times are prolonged. A disseminated intravascular coagulation profile including fibrinogen level, fibrin degradation products, and platelet count may be useful.



Approach Considerations

Notification of local and state public health departments and the Centers for Disease Control and Prevention (CDC) may provide resources for further epidemiologic investigation into the source of the infection.

Appropriate barrier precautions should remain in place throughout the hospital course because of the highly pathogenic nature of viral hemorrhagic fever infection and because various causes of viral hemorrhagic fever often are clinically indistinguishable.

Prehospital Care

Supportive care is based on the patient's physiologic condition. Because most patients requiring prehospital evaluation and transport are in the early stages of the disease, universal precautions should be adequate. In patients with respiratory symptoms (eg, cough, rhinitis), use face shields and high-efficiency particulate air (HEPA) filter masks.

Emergency Department Care

Fluid resuscitation and supportive care are the mainstays of emergency department therapy. Intravenous crystalloids, oxygen, and cardiac monitoring are the most appropriate initial steps in the treatment of patients in whom viral hemorrhagic fever (VHF) is suggested. Other measures include the following:

  • Administer blood and blood products as clinically indicated
  • Avoid intramuscular injections and the use of aspirin or other anticoagulants
  • Minimize invasive procedures because of the risk associated with viral transmission from sharp objects
  • Minimize aerosol-generating procedures such as bilevel positive airway pressure (biPAP), intubation, bronchoscopy and sputum induction.

Infection control measures include the following:

  • Place patients in a single-patient room with a private bathroom
  • Avoid entry of nonessential staff and visitors; facilities should maintain a log of all people entering the patient’s room
  • All staff entering the room should wear appropriate personal protective equipment (PPE); see below

PPE should include the following:

  • Impermeable garment
  • Respiratory protection (N95 mask with single-use surgical hood or single-use full face shield) or powered-air purifying respirator (PAPR) with full face shield or hood
  • Single-use examination gloves with extended cuffs
  • Single-use boot covers
  • Single-use apron (if patients have vomiting or diarrhea)

For donning of PPE, a trained observer should read aloud to the healthcare worker each step in the procedure checklist and visually confirm and document that the step has been performed correctly.

A separate area should be designated for donning and doffing of PPE. The space and layout must allow for clear separation between clean and contaminated areas

Note that these infection control recommendations were developed for use with patients with suspected or confirmed Ebola virus disease, but may also be used for any patient with suspected VHF infection. For more details, see the US Centers for Disease Control and Prevention's Ebola infection control recommendations.


Because fruit bats have been shown to be natural reservoirs for Ebola and Marburg,[25]  specific prevention measures should include avoidance of bats, their excreta, and areas with concentrated bat populations within endemic areas. Studies have suggested that contact with fruit bats may be responsible for some cases of filovirus infection.[26, 27]

An experimental Ebola vaccine, rVSV-ZEBOV, appears to offer substantial protection against Ebola virus disease.[28]  An open-label, cluster-randomised trial evaluated vaccine effectiveness in case contacts, where clusters of contacts of Ebola cases were randomised for immediate or delayed vaccination.The authors estimated the vaccine efficacy to be 100% (95% CI 68·9–100, P=0.0045) in individuals vaccinated in the immediate group compared with those eligible and randomized to the delayed group.[29]  However, the extent of this efficacy has been debated.[30]

Efforts are under way in West Africa to educate people in high-risk areas about ways to decrease rodent populations, thereby reducing transmission of Lassa fever.

Strict barrier precautions in the treatment of patients with known or suspected viral hemorrhagic fever infection reduce nosocomial transmission.

Proposed guidelines for the use of ribavirin for Lassa fever postexposure prophylaxis recommend the use of oral ribavirin exclusively for definitive, high-risk exposures, such as the following[31] :

  • Contaminated needlestick injury
  • Mucous membrane or nonintact skin exposure with contaminated blood or body fluids
  • Participation in emergency resuscitative procedures (eg, intubation, suctioning)
  • Prolonged close contact in an enclosed space with infected patients without appropriate personal protective equipment


Medication Summary

Supportive therapy should be the primary focus for clinicians treating patients with suspected or confirmed filovirus infection, including treatment for hypovolemia; electrolyte, metabolic, and hematologic abnormalities; shock; multiorgan failure; and disseminated intravascular coagulation.

Large-volume intravenous (IV) fluids have been used in resuscitation of patients with Ebola virus disease (EVD) evacuated from West Africa. Broad-spectrum antimicrobials have also been used in patients with evidence of septic shock.

Several experimental therapeutics and vaccines are in development for the treatment of EVD. ZMapp, a biopharmaceutical agent comprising three monoclonal antibodies against Ebola virus surface glycoproteins, was developed in a joint Canadian-US effort in 2014, and has shown efficacy in nonhuman primate trials.[32] Although it was used experimentally in 7 patients in 2014 (two of whom died), the utility of ZMapp in these patients was unclear. A multicenter randomized study of ZMapp versus standard therapy did not show clear efficacy, although there was a trend suggesting benefit in patients who received ZMapp.[33]  

During the Ebola virus disease outbreak in the Democratic Republic of Congo, Mulangu et al conducted a trial comparing ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, and the triple monoclonal antibody REGN-EB3. On interim analysis, MAb114 and REGN-EB3 showed superiority to ZMapp and remdesivir in reducing mortality.[34]  

In 2020, the US Food and Drug Administration (FDA) approved the first therapeutic for Zaire ebolavirus disease in adult and pediatric patients, a mixture of three monoclonal antibodies.[35]

Lassa fever and hemorrhagic fever with renal syndrome (HFRS) due to Hantavirus infection have been treated effectively with IV and oral ribavirin. Because of this, ribavirin has been recommended as a potential treatment for other arenaviruses and bunyaviruses. Treatment is most effective when given early in the clinical course. Ribavirin also is recommended for postexposure prophylaxis. Other potential antiviral therapies against Lassa fever include novel benzimidazole compounds such as ST-193 and other related heterocyclic compounds.[36]

Research into the development of antiarenaviral drugs has focused on broad screening of small molecules with potential antiviral activity. This high-throughput screening (HTS) strategy has previously identified antiviral drugs and may potentially provide novel inhibitors of viral cell entry in the future.[37, 38]

Development of a Lassa virus vaccine is continuing at the US Centers for Disease Control and Prevention (CDC). Yellow fever vaccine is readily available and is both safe and effective. A bivalent vaccine is being developed from the preexisting 17D yellow fever vaccine that would express not only yellow fever glycoproteins but also Lassa glycoproteins, theoretically stimulating a protective immune response against both viruses.[39] A  study evaluating the safety and efficacy of a tetravalent dengue vaccine demonstrated full seroconversion against all World Health Organization (WHO) dengue serotypes in flavivirus-naive adults.[40]

Argentine hemorrhagic fever (HF) vaccine (Junin virus vaccine) is also effective and may protect against Bolivian HF as well. Rift Valley fever and Hantaan (HFRS) vaccines are also available.

Although there is no approved vaccine for either Ebola or Marburg virus, significant progress has been made in developing effective experimental Ebola vaccines using multiple viral vector strategies, including vesicular-stomatitis virus (VSV-EBOV) and chimpanzee adenovirus (cAd3-EBO-Z). Human trials in Africa and Europe have yielded safe, immunogenic vaccines against both Ebola and Marburg, based on post-vaccine testing of antibody and T-cell response of trial participants.[41, 42]



Class Summary

The goals in the use of antivirals are to shorten the clinical course, prevent complications, prevent the development of latency and/or subsequent recurrences, decrease transmission, and eliminate established latency.

Ribavirin (Virazole)

Nucleoside analog with antiviral activity; may significantly reduce mortality in Lassa fever and Hantavirus infection if treatment begun within 6 d of onset.

Monoclonal Antibodies

Atoltivimab/maftivimab/odesivimab (Inmazeb, Ebola monoclonal antibodies, REGN-EB3)

Inmazeb is a combination of 3 monoclonal recombinant human IgG1-kappa monoclonal antibodies: atoltivimab, maftivimab, and odesivimab-ebgn. These antibodies simultaneously bind to the glycoprotein on the Ebola virus surface and block attachment and entry of the virus on host cell membranes.