Continuing Education Activity

Viral hemorrhagic fevers (VHFs) represent a group of severe systemic febrile illnesses caused by four families of viruses - Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. These enveloped viruses are characterized by a myriad of symptoms that range from coagulopathies, hemodynamic instability, altered mental status, and, if severe enough, death. This activity outlines the evaluation and management of viral hemorrhagic fevers and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of viral hemorrhagic fevers.
• Review the appropriate evaluation of patients with viral hemorrhagic fevers.
• Describe the management of viral hemorrhagic fevers.
• Summarize interprofessional team strategies for improving care coordination and communication to improve outcomes in patients with viral hemorrhagic fevers.

Introduction

Viral hemorrhagic fevers (VHFs) represent a group of severe systemic febrile illnesses caused by four families of viruses - Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae.[1] These enveloped viruses are characterized by a myriad of symptoms that range from coagulopathies, hemodynamic instability, altered mental status, and, if severe enough, death. The degree of clinical illness can vary widely with some viruses causing mild illness, while others can be life-threatening.

Most of the viruses implicated in these diseases require vectors for transmission to humans, with the majority being arthropod-borne or rodent-borne infections. Given their zoonotic nature, these diseases are generally confined to the endemic areas where their hosts live. However, given increased human migration and further globalization, these diseases are no longer limited to their geographic origins.[2] This article will provide a general overview of viral hemorrhagic fevers and focus on those diseases which have the highest overall mortality rates.

Etiology

Viruses implicated in viral hemorrhagic fevers and the diseases they cause are grouped by the family of viruses:

Arenaviridae family:

• Chapare virus (CHPV) - Chapare hemorrhagic fever
• Guanarito virus (GTOV) - Venezuelan hemorrhagic fever
• Junin virus (JUNV) - Argentine hemorrhagic fever
• Lassa virus (LASV) - Lassa fever
• Lujo virus (LUJV) - Lujo hemorrhagic fever
• Lymphocytic choriomeningitis virus (LCMV) - Lymphocytic choriomeningitis
• Machupo virus (MACV) - Bolivian hemorrhagic fever
• Sabia virus (SABV) - Brazilian hemorrhagic fever

Bunyaviridae family:

• Crimean-Congo hemorrhagic virus (CCHFV) - Crimean-Congo hemorrhagic fever
• Dobrava-Belgrade virus (DOBV) - Hemorrhagic fever with renal syndrome
• Hantaan virus (HTNV) - Hemorrhagic fever with renal syndrome
• Puumalavirus (PUUV) - Hemorrhagic fever with renal syndrome
• Rift Valley fever virus (RVFV) - Rift Valley fever
• Saaremaa virus (SAAV) - Hemorrhagic fever with renal syndrome
• Seoul virus (SEOV) - Hemorrhagic fever with renal syndrome
• Sin Nombre virus (SNV)- Hantavirus pulmonary syndrome
• Severe fever and thrombocytopenia syndrome virus (SFTSV) - Severe fever and thrombocytopenia syndrome
• Tula virus (TULV) - Hemorrhagic fever with renal syndrome

Filoviridae family:

• Bundibugyo ebolavirus (BDBV) - Ebola virus disease
• Marburg marburgvirus (MARV) - Marburg hemorrhagic fever
• Sudan ebolavirus (SUDV) - Ebola virus disease
• Taï Forest ebolavirus (TAFV) - Ebola virus disease
• Zaire ebolavirus (EBOV) - Ebola virus disease

Flaviviridae family:

• Dengue virus (DENV-1-4) - Dengue fever
• Kyasanur forest disease virus (KFDV) - Kyasanur forest disease
• Omsk hemorrhagic fever virus (OHFV) - Omsk hemorrhagic fever
• Yellow fever virus (YFV) - Yellow fever

Epidemiology

Viruses belonging to the family Arenaviridae are associated with rodent-borne diseases. These viruses are divided into two groups, New World and Old World. Each virus is affiliated with rodents that can be found across Africa, America, Asia, and Europe. Infection occurs via contact with rodent urine or droppings and can also occur via aerosol transmission when rodent excrement is stirred up, causing viral particles to get into the air. Some viruses can also cause human-to-human and nosocomial infections. Lassa virus, an arenavirus, has caused outbreaks in West Africa with case fatality rates as high as 50%.[3] This virus spreads efficiently, mostly through direct contact with multimammate rats, but infection can also occur when rodents are captured for consumption.[3]

Bunyaviruses are transmitted via arthropods and rodents and can cause mild to severe illness. These viruses can cause Crimean-Congo hemorrhagic fever, hantavirus infections, and Rift Valley fever. Crimean-Congo hemorrhagic fever is an important disease entity to be aware of as it is the most widespread tick-borne illness in humans.[4] This disease is caused by a Nairovirus that can be transmitted by Ixodid ticks and is endemic in Africa and Asia. Transmission also occurs via exposure to blood or other bodily fluids and can lead to a severe infection with high mortality risk.[5] 

Filoviruses are the culprits implicated in Ebola virus disease and Marburg hemorrhagic fever and have been detected in bats in Africa. Once humans are infected, there is a risk of person-to-person spread, especially in those caring for infected patients. There have been several Ebola outbreaks in the Democratic Republic of the Congo, with case fatality rates as high as 80% to 90%.[6] Fatality rates for Marburg hemorrhagic fever are also as high as 82% in low-income countries.[7]

Flaviviruses can cause a range of different diseases and can be transmitted via arthropods. Dengue virus, a flavivirus, is transmitted by Aedes aegypti or Aedes albopictus mosquitoes. Clinically, this virus can cause disease, which can be classified into three categories: dengue without warning signs, dengue with warning signs, and severe dengue. This disease is endemic in over 100 countries and can be found in Africa, the Americas, Asia, Australia, Europe, and the Pacific Islands.[8] Dengue fever has a mortality rate of 0.8% to 2.5% with more severe morbidity and mortality associated with dengue hemorrhagic fever and dengue shock syndrome.[8]

Pathophysiology

Pathogens implicated in viral hemorrhagic fevers are able to replicate within macrophages and dendritic cells, allowing for rapid dissemination within the host. Macrophages are triggered to release cytokines and chemokines, which cause increased vascular permeability and a procoagulant state.[9] These viruses can also trigger mechanisms resulting in disseminated intravascular coagulation. Infected dendritic cells are impaired, and the loss of its appropriate function can lead to lymphocytic apoptosis.[9]

History and Physical

Patients can present with nonspecific symptoms, including fevers, headaches, and malaise. Clinical features that are considered common for VHFs include retro-orbital pain, joint pains, eye redness, abdominal pain, vomiting, and diarrhea. Patients may also complain of bleeding gums or epistaxis. In these cases, a physical examination may be notable for petechiae.

Evaluation

The clinical evaluation for viral hemorrhagic fevers includes complete blood count with differential, comprehensive metabolic panel, type and cross, coagulation studies, liver function tests, as well as evaluation for bacterial infections with urinalysis, urine culture, chest x-ray, and blood cultures. Serological testing for virus-specific IgM and IgG can be helpful but is not as sensitive or specific as molecular-based testing. Reverse transcriptase-polymerase chain reaction and virus isolation via cell culture are methods that can be used for diagnostic testing.

Treatment / Management

Appropriate management of individuals suspected to have viral hemorrhagic fever includes early diagnosis to both increase chances of survival and prevent nosocomial infections. Patients with symptoms or travel history suggestive of these diseases should be isolated, and all staff caring for persons under investigation should wear appropriate personal protective equipment (referred to as viral hemorrhagic fever isolation precautions). Research regarding treatment is ongoing; however, the cornerstone of current treatment is supportive care. See specific management guidelines below for those diseases which have the highest overall mortality rates.

Lassa virus - Ribavirin has been shown to improve treatment outcomes when given early in the disease course; however, studies have been limited.[3] Newer agents such as favipiravir and LASV-specific monoclonal antibodies are currently being evaluated. There are currently no effective vaccines for Lassa fever. 

Crimean-Congo hemorrhagic fever - Treatment largely remains supportive. Ribavarin has demonstrated an antiviral effect against this virus in vitro.[7] There is currently no effective vaccine for humans. Agricultural workers and those working with animals are encouraged to use insect repellant and avoid contact with blood and other bodily fluids from animals or humans that may be infected. 

Ebola virus disease and Marburg hemorrhagic fever - Treatment involves supportive care. There are currently no vaccines available against the Marburg virus.[6][7] There is currently one Food and Drug Administration approved Ebola vaccine against the Zaire ebolavirus.[10]

Dengue fever - There are currently no effective antiviral regimens available for treatment, thus management involves supportive care.[8] One vaccine is currently available in Latin America and Southeast Asia. However, the World Health Organization has recommended that it only be given to individuals who have a previous history of dengue infection.[11]

Differential Diagnosis

• Acute human immunodeficiency virus (HIV) infection
• Chikungunya virus
• Leptospirosis
• Malaria
• Malignancy
• Systemic lupus erythematosus 
• Typhoid fever

Prognosis

As viral hemorrhagic fevers encompass a wide variety of diseases, the prognosis varies. Many of these diseases are capable of causing outbreaks and are associated with high morbidity and mortality, as there are currently no specific therapies available. Case fatality rates can be as high as 80%-90% in developing countries.[6]

Complications

The most severe complications of viral hemorrhagic fevers involve multi-organ system failure and death. Management is largely supportive. Given the risk for nosocomial infections and further outbreaks, viral hemorrhagic fever isolation precautions should be instituted immediately if this entity is suspected.

Deterrence and Patient Education

Patients should be educated regarding the geographical distribution of these viruses and practice infection prevention measures when traveling to areas where these diseases are endemic. The Centers for Disease Control, the World Health Organization, and the United States Department of State provide a list of resources regarding current areas with ongoing epidemics as well as travel notices and restrictions.

Pearls and Other Issues

These infectious diseases are classified as category A bioweapons agents as they are stable when aerosolized and are associated with severe morbidity and mortality in infected individuals.[12][13]

Enhancing Healthcare Team Outcomes

Health care outcomes can be improved with an interprofessional team approach whenever viral hemorrhagic fevers are suspected. Effective communication between clinicians, nurses, epidemiologists, virologists, and ecologists is necessary to help prevent any further spread of disease.[7]

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Racsa LD, Kraft CS, Olinger GG, Hensley LE. Viral Hemorrhagic Fever Diagnostics. Clin Infect Dis. 2016 Jan 15;62(2):214-9. [PMC free article: PMC4723665] [PubMed: 26354968]

2.

Montoya-Ruiz C, Rodas JD. Epidemiological Surveillance of Viral Hemorrhagic Fevers With Emphasis on Clinical Virology. Methods Mol Biol. 2018;1604:55-78. [PubMed: 28986825]

3.

Asogun DA, Günther S, Akpede GO, Ihekweazu C, Zumla A. Lassa Fever: Epidemiology, Clinical Features, Diagnosis, Management and Prevention. Infect Dis Clin North Am. 2019 Dec;33(4):933-951. [PubMed: 31668199]

4.

Bente DA, Forrester NL, Watts DM, McAuley AJ, Whitehouse CA, Bray M. Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Antiviral Res. 2013 Oct;100(1):159-89. [PubMed: 23906741]

5.

Hidalgo J, Richards GA, Jiménez JIS, Baker T, Amin P. Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. J Crit Care. 2017 Dec;42:366-372. [PubMed: 29128377]

6.

Rougeron V, Feldmann H, Grard G, Becker S, Leroy EM. Ebola and Marburg haemorrhagic fever. J Clin Virol. 2015 Mar;64:111-9. [PMC free article: PMC11080958] [PubMed: 25660265]

7.

Iannetta M, Di Caro A, Nicastri E, Vairo F, Masanja H, Kobinger G, Mirazimi A, Ntoumi F, Zumla A, Ippolito G. Viral Hemorrhagic Fevers Other than Ebola and Lassa. Infect Dis Clin North Am. 2019 Dec;33(4):977-1002. [PubMed: 31668201]

8.

Kularatne SA. Dengue fever. BMJ. 2015 Sep 15;351:h4661. [PubMed: 26374064]

9.

Bray M. Pathogenesis of viral hemorrhagic fever. Curr Opin Immunol. 2005 Aug;17(4):399-403. [PubMed: 15955687]

10.

Ollmann Saphire E. A Vaccine against Ebola Virus. Cell. 2020 Apr 02;181(1):6. [PubMed: 32243796]

11.

Gubler DJ, Halstead SB. Is Dengvaxia a useful vaccine for dengue endemic areas? BMJ. 2019 Oct 03;367:l5710. [PubMed: 31582375]

12.

Polesky A, Bhatia G. Ebola hemorrhagic fever in the era of bioterrorism. Semin Respir Infect. 2003 Sep;18(3):206-15. [PubMed: 14505282]

13.

Robenshtok E, Laster M, Katz L, Brenner B, Sagi R. [Viral hemorrhagic fever as a biological weapon]. Harefuah. 2002 May;141 Spec No:96-9, 119. [PubMed: 12170564]

Disclosure: Rupinder Mangat declares no relevant financial relationships with ineligible companies.

Disclosure: Ted Louie declares no relevant financial relationships with ineligible companies.