eMedicine Specialties > Dermatology > Viral Infections

Viral Hemorrhagic Fevers

Author: Arash Michael Saemi, MD, Department of Internal Medicine, Naval Medical Center San Diego
Coauthor(s): Nili N Alai, MD, FAAD, Assistant Clinical Professor, Department of Dermatology, Clinical Faculty and Preceptor, Department of Family Practice, University of California, Irvine; Clinical Faculty and Preceptor, Department of Family Practice Residency Training, Downey Medical Center; Medical Director, The Skin Center at Laguna; Expert Medical Reviewer, Medical Board of California
Contributor Information and Disclosures

Updated: Oct 1, 2008

Introduction

Background

Viral hemorrhagic fevers (VHFs) are a group of etiologically diverse viral diseases unified by common underlying pathophysiology. These febrile diseases result from infection by viruses from 4 viral families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae.

The viruses in the 4 families are all RNA viruses. All share the feature of having a lipid envelope. Survival and perpetuation of the viruses is dependent on an animal host known as a natural reservoir; humans are not the natural reservoir. With the exception of a vaccine for yellow fever and ribavirin, which is used as a drug treatment for some arenaviral infections, no cures or drug treatments for viral hemorrhagic fever exist. Only supportive treatment is possible.

Not all viruses in these families cause viral hemorrhagic fever. Viral hemorrhagic fevers share certain clinical manifestations, regardless of the virus that causes the disease. However, different viruses can cause a range of various clinical problems in addition to viral hemorrhagic fever. Common clinical manifestations of viral hemorrhagic fever are increased capillary permeability, leukopenia, and thrombocytopenia. Viral hemorrhagic fever is manifested by sudden onset, fever, headache, generalized myalgia, backache, petechiae, conjunctivitis, and severe prostration. Various hemorrhagic symptoms follow, ultimately resulting in focal inflammatory reaction and necrosis with leukocytosis.

Although the viruses are distributed all over the world, they have a higher occurrence in tropical areas, such as South America, Africa, and the Pacific Islands. They have a higher likelihood of importation because of increased travel and scientific research involving the use of imported tropical animals, which often serve as intermediate hosts. The viruses are transmitted by 2 main categories of natural reservoirs: arthropods and rodents. Arenaviruses and Hantavirus (a Bunyavirus) are primarily rodent-borne, whereas flaviviruses, as well as nairoviruses and phleboviruses (both bunyaviruses), are arthropod-borne.

Transmission occurs mainly by means of contact with the following: natural reservoirs (eg, mosquito bites, rodent bites); reservoir excretions, secretions, or blood; aerosolized particles contaminated by reservoir secretions, excretions, or blood; or intermediate hosts (eg, monkeys, livestock) or their excretions, secretions, or blood. Person-to-person transmission and nosocomial transmission also occur. Nosocomial outbreaks are not uncommon in developing countries, where safe infectious disease practices have not been implemented and supplies are in shortage.

Related resources include the following:

Pathophysiology

The main common underlying pathophysiologic feature of viral hemorrhagic fevers is that the vascular bed is attacked, with resultant microvascular damage and changes in vascular permeability. However, specific pathophysiologic findings can vary depending on the virus family and the species involved.

In general, an initial febrile illness is followed by hemorrhaging into the skin and the mucous membranes; hemorrhagic rashes; and hemorrhages from body orifices, especially gastrointestinal and genitourinary bleeding. Lassa fever, although fatal, is not characterized by significant bleeding. Other clinical findings include thrombocytopenia and leukocytopenia.

Frequency

United States

Most of the natural reservoirs of these viruses live in tropical areas. Hence, the virus does not typically infect persons in the United States. Random cases of infection occur as a result of the importation of viruses by travelers or the importation of scientific research animal subjects. Several cases of infection resulting in Hantavirus pulmonary syndrome (HPS), however, have been reported across the United States.1

International

Table 1. Geographic Distribution of Viral Hemorrhagic Fevers

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Table
Virus Family and GenusType of Hemorrhagic FeverGeographic Distribution
Arenaviridae
    Guanarito
    Junin
    Machupo
    Lassa
    Sabia

Venezuelan
Argentinian
Bolivian
Lassa (West Africa)
Brazilian or Sao Paulo

Venezuela
Argentina
Bolivia
West Africa
Brazil
Bunyaviridae
    Nairovirus
    Phlebovirus
    Hantaan virus

Crimean-Congo
Rift Valley
Korean

HPS


Crimea, Central Africa, South Africa, Iraq, Pakistan
Africa, Egypt
Korea, Eastern Europe, Russia, Scandinavia

North, Central, and South America

Flaviviridae
    Flavivirus
    Flavivirus
    Flavivirus
    Flavivirus

Yellow
Dengue
Chikungunya
Omsk

Tropical Africa, South America
Entire tropical zone
India, Southeast Asia
Siberia
Filoviridae
    Marburg
    Ebola

Marburg
Ebola

Africa
Africa
Virus Family and GenusType of Hemorrhagic FeverGeographic Distribution
Arenaviridae
    Guanarito
    Junin
    Machupo
    Lassa
    Sabia

Venezuelan
Argentinian
Bolivian
Lassa (West Africa)
Brazilian or Sao Paulo

Venezuela
Argentina
Bolivia
West Africa
Brazil
Bunyaviridae
    Nairovirus
    Phlebovirus
    Hantaan virus

Crimean-Congo
Rift Valley
Korean

HPS


Crimea, Central Africa, South Africa, Iraq, Pakistan
Africa, Egypt
Korea, Eastern Europe, Russia, Scandinavia

North, Central, and South America

Flaviviridae
    Flavivirus
    Flavivirus
    Flavivirus
    Flavivirus

Yellow
Dengue
Chikungunya
Omsk

Tropical Africa, South America
Entire tropical zone
India, Southeast Asia
Siberia
Filoviridae
    Marburg
    Ebola

Marburg
Ebola

Africa
Africa

Mortality/Morbidity

Children can develop dengue hemorrhagic shock syndrome (DHSS), a complication with a mortality rate of 4-12%.

Table 2. Viral Hemorrhagic Fever – related Mortality Rates

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Table
Virus Family and Type of VHFMortality Rate, %
Arenaviridae
    Argentinian and Bolivian
    Lassa (West African)
    Venezuelan and Sao Paulo

10-30
30-40
33
Bunyaviridae
    Korean and Seoul
    Rift Valley
    Congo-Crimean
    HPS

5-15
1
10-50
15-50
Flaviviridae
    Yellow
    Dengue

<1
5
Filoviridae
    Marburg
    Ebola

23-25
25-100
Virus Family and Type of VHFMortality Rate, %
Arenaviridae
    Argentinian and Bolivian
    Lassa (West African)
    Venezuelan and Sao Paulo

10-30
30-40
33
Bunyaviridae
    Korean and Seoul
    Rift Valley
    Congo-Crimean
    HPS

5-15
1
10-50
15-50
Flaviviridae
    Yellow
    Dengue

<1
5
Filoviridae
    Marburg
    Ebola

23-25
25-100

Race

No race is known to be more vulnerable than another to RNA viral infection. Geography is a determining factor.

Sex

Neither sex is known to be more or less vulnerable to RNA viral infection.

Age

Age plays a role in increasing the vulnerability to infection in only 2 circumstances, as follows:

  • First, young and elderly persons are more susceptible because of their weaker immune systems.
  • Second, adults are more susceptible if they work in settings in which the exposure risk is increased (eg, clinics or hospitals, agrarian settings).

Clinical

History

Not all individuals who are infected have viral hemorrhagic fever. The target organ is the vascular bed. As a result, the dominant clinical manifestations are due to microvascular damage and changes in vascular permeability.

Viral hemorrhagic fever should be suspected in patients who live in or who have returned from locations of viral occurrence if they have severe fever and evidence of vascular involvement (eg, subnormal blood pressure, postural hypotension, petechiae, easy bleeding, flushing, nondependent edema).

  • The severity of symptoms varies. Common symptoms include the following:
    • Myalgia
    • Fever
    • Prostration
    • Vomiting
    • Headache
    • Petechial hemorrhages
    • Hypotension
    • Flushing of the head and the chest
    • Edema
    • Malaise
    • Diarrhea
  • Severe viral hemorrhagic fever evolves to shock and generalized mucous membrane hemorrhage.
    • Viral hemorrhagic fever is often accompanied by neurologic, hematopoietic, or pulmonary involvement.
    • Hepatic damage is also common among viral hemorrhagic fevers, but hepatic failure, as indicated by jaundice and other evidence, is seen in some cases of Rift Valley fever (RVF), Congo-Crimean hemorrhagic fever (CCHF), Marburg fever, Ebola fever, and yellow fever.
    • Neurologic symptoms and thrombocytopenia are common in Argentinian and Bolivian hemorrhagic fevers.
    • Kyasanur Forest disease and Omsk fever are known for their pulmonary involvement and a biphasic illness with central nervous system (CNS) manifestations.
    • Hantavirus pulmonary syndrome (HPS) is known for its pulmonary involvement leading to noncardiogenic pulmonary edema.1

Physical

  • Arenaviruses2
    • Lassa, Argentinian, and Bolivian viral hemorrhagic fevers
      • The first signs are nonspecific and include fever, headache, and sore throat.
      • The second stage is characterized by an exacerbation of symptoms and rashes on the face or the neck.
      • Gastrointestinal and urogenital tract bleeding and shock may follow during the second week.
      • Neurologic sequelae are a main feature, especially in Lassa hemorrhagic fever.
    • Argentinian viral hemorrhagic fever
      • Early symptoms include high fever, malaise, headache, retro-orbital pain, anorexia, and nausea.
      • Signs are erythematous rash of the face, the neck, and the thorax, and hemorrhages into the skin and the mucous membranes.
      • CNS involvement appears around day 7 in fatal cases. It is an important indicator of severity and is a better indicator than hemorrhage.
    • Bolivian viral hemorrhagic fever
      • Bolivian hemorrhagic fever has an insidious onset, leading to high temperature, severe myalgia, headache, vomiting, retrobulbar pain, conjunctival hyperemia, leukopenia, and mild thrombocytopenia.
      • Petechiae of the skin and the oral mucous membranes usually appear around day 4.
      • Epistaxis, gingival bleeding, hematemesis, melena, and metrorrhagia may follow.
      • Hypotension and/or neurologic abnormalities, including tremors, delirium, and seizures, develop between days 6 and 10.
      • Circulatory collapse eventually results in death.
    • Lassa fever
      • Lassa fever can vary from a long-lasting acute fever to a fatal disease.
      • Its clinical manifestations include headache, fever, weakness, myalgia, ulcerative pharyngitis, dysphagia, anorexia, nausea, vomiting, cough, and constipation.
      • The aforementioned findings can be followed by diarrhea, melena, dysuria, cutaneous petechiae and ecchymoses, erythema of the face and the thorax, facial and cervical edema, rales, rhonchi, stridor, wheezing, hypotension, hepatic tenderness, pleural effusions, cloudy sensorium, and seizures.
  • Bunyaviruses
    • Rift Valley fever3
      • RVF is an influenzalike disease.
      • Its onset involves chills, fever, headache, retro-orbital pain, myalgia, anorexia, vomiting, and diarrhea.
      • Physical signs include fever, facial erythema, and conjunctival suffusion.
      • A small percentage of patients present with retinal lesions, which may result in permanent blindness, hemorrhagic diathesis, and encephalitis.
      • RVF may progress to a hemorrhagic fever stage. Clinical manifestations of this stage may include hematemesis, melena, petechial and ecchymotic cutaneous lesions, gingival bleeding, hematuria, epistaxis, and jaundice.
    • Congo-Crimean hemorrhagic fever
      • Early symptoms of CCHF include those previously mentioned for RVF.
      • Patients may present with erythema of the pharynx, the conjunctivae, the face, and the neck; a petechial rash on the trunk and the limbs; and hemorrhages of the uvula and the soft palate.
      • CCHF is a severe disease. On days 3-7, patients may have hematemesis; melena; cutaneous purpura; epistaxis; hematuria; hemoptysis; and bleeding from gingival, oral, uterine, and venipuncture sites.
    • Korean hemorrhagic fever4
      • This infection is a subgroup of hemorrhagic fever with renal syndrome (HFRS).
      • Disease progression is severe and is characterized by fever, hemorrhage, and renal failure.
    • Hantavirus pulmonary syndrome
      • The illness has 5 distinct phases and is marked by deterioration of breathing during the cardiopulmonary phase.
      • Capillary leakage results in noncardiogenic pulmonary edema and may progress to shock.
      • As in HFRS, disease progression is rapid with a high rate of mortality.
  • Filoviruses
    • Ebola and Marburg viruses are pantropic, that is, they infect and cause lesions in many organs, especially the liver and the spleen.
      • Both organs become enlarged and dark while undergoing severe degeneration.
      • Disseminated intravascular coagulation may be a feature of late disease.
      • Damage to endothelial cells increases vascular permeability, followed by hemorrhage and shock; these are central features of the infections, which have high mortality rates.
    • Ebola fever
      • Early symptoms of Ebola-induced viral hemorrhagic fever are high temperature, headache, myalgia, stomach pain, rashes, sore throat, and red and itchy eyes.
      • Within 1 week of disease onset, chest pain, hemorrhaging from body orifices, blindness, and death occur.
    • Marburg fever5
      • Disease onset is marked by fever, chills, headache, and myalgia.
      • Approximately 5 days after disease onset, a maculopapular rash may appear, with greatest prominence on the trunk.
      • Patients present with jaundice, inflammation of the pancreas, weight loss, delirium, shock, liver failure, and multiorgan dysfunction.
  • Flaviviruses
    • Omsk hemorrhagic fever
      • Physical findings include congested conjunctivae, papulovesicular eruptions on the soft palate (an important diagnostic sign), severe pain in the back and the limbs, fever, headache, diarrhea, and vomiting.
      • The illness is biphasic, with meningismus or meningoencephalitis occurring in the second phase.
      • The disease is also characterized by hyperemia of the face and the upper body.
      • Bleeding gums, epistaxis, hemoptysis, uterine hemorrhage, hematemesis, melena, and other hemorrhaging may occur.
    • Yellow fever
      • Yellow fever is characterized by jaundice, a result of midzone necrosis of the liver (by about the third day), flushing of the face, congested conjunctivae, and reddening edges of the tongue.
      • The heart and the kidney are damaged.
      • Hemorrhagic symptoms may appear early, with swelling and bleeding of the gums and epistaxis. Hemorrhaging from the gastrointestinal mucosa may cause black vomit and melena.
    • Dengue fever6,7
      • Patients present with maculopapular rashes and fever, severe joint and muscle pains, lymphadenopathy, and altered or diminishing gustation.
      • Dengue fever, like yellow fever, may progress from a febrile illness to a hemorrhagic one.
      • Minor hemorrhagic symptoms, such as epistaxis, petechiae, or bleeding gums, may accompany other febrile symptoms early in the disease.
      • An enlarged liver can be palpated during the later stages of the disease.
      • Children may develop DHSS, a complication with a mortality rate of 4-12%.

Causes

Causes of viral hemorrhagic fevers are the specific RNA viruses mentioned above.

  • Infection by different viruses results in hemorrhagic fever with different complications, symptoms, and severity, as previously discussed.
  • Viruses are usually transmitted by mosquitoes, ticks, or rodents. Some species of bats may also prove to be virus carriers.8
  • The strong immunologic response to the viruses may be central to the pathophysiology of plasma leakage associated with these diseases.9

More on Viral Hemorrhagic Fevers

Overview: Viral Hemorrhagic Fevers
Differential Diagnoses & Workup: Viral Hemorrhagic Fevers
Treatment & Medication: Viral Hemorrhagic Fevers
Follow-up: Viral Hemorrhagic Fevers
References

References

  1. Jonsson CB, Hooper J, Mertz G. Treatment of hantavirus pulmonary syndrome. Antiviral Res. Apr 2008;78(1):162-9. [Medline].

  2. Southern PJ. Arenaviridae: the viruses and their replication. In: Fields BN, Knipe DN, Howley PM, et al, eds. Fields Virology. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1996:1505-19.

  3. Peters CJ, Linthicum KJ. Rift valley fever. In: Handbook of Zoonoses. Boca Raton, Fla: CRC Press; 1994:129-43.

  4. Seo JH, Park KH, Lim JY, Youn HS. Hemorrhagic fever with renal syndrome (HFRS, Korean hemorrhagic fever). Pediatr Nephrol. Jan 2007;22(1):156-7. [Medline].

  5. Feldmann H. Marburg hemorrhagic fever--the forgotten cousin strikes. N Engl J Med. Aug 31 2006;355(9):866-9. [Medline].

  6. Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis. Oct 2006;19(5):429-36. [Medline].

  7. No Authors Listed. Dengue haemorrhagic fever: early recognition, diagnosis and hospital management--an audiovisual guide for health-care workers responding to outbreaks. Wkly Epidemiol Rec. Sep 22 2006;81(38):362-3. [Medline].

  8. Bausch DG, Sprecher AG, Jeffs B, Boumandouki P. Treatment of Marburg and Ebola hemorrhagic fevers: a strategy for testing new drugs and vaccines under outbreak conditions. Antiviral Res. Apr 2008;78(1):150-61. [Medline].

  9. Noisakran S, Perng GC. Alternate hypothesis on the pathogenesis of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in dengue virus infection. Exp Biol Med (Maywood). Apr 2008;233(4):401-8. [Medline].

  10. Ergonul O. Treatment of Crimean-Congo hemorrhagic fever. Antiviral Res. Apr 2008;78(1):125-31. [Medline].

  11. Ghosh D, Basu A. Present perspectives on flaviviral chemotherapy. Drug Discov Today. Jul 2008;13(13-14):619-24. [Medline].

  12. Daddario-DiCaprio KM, Geisbert TW, Geisbert JB, Ströher U, Hensley LE, Grolla A, et al. Cross-protection against Marburg virus strains by using a live, attenuated recombinant vaccine. J Virol. Oct 2006;80(19):9659-66. [Medline].

  13. Martin JE, Sullivan NJ, Enama ME, Gordon IJ, Roederer M, Koup RA, et al. A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol. Nov 2006;13(11):1267-77. [Medline].

  14. Kothari VM, Karnad DR, Bichile LS. Tropical infections in the ICU. J Assoc Physicians India. Apr 2006;54:291-8. [Medline].

  15. Collier L, Oxford J. Human Virology. 2nd ed. Oxford, England: Oxford University Press; 2000:171-97.

  16. Craighead JE, John E. Pathology and Pathogenesis of Human Viral Disease. San Diego, Calif: Academic Press; 2000:277-93.

  17. Fields BN, Knipe DM. Fundamental Virology. 2nd ed. New York, NY: Raven Press; 1991:19-24.

  18. Gear JH. Clinical aspects of African viral hemorrhagic fevers. Rev Infect Dis. May-Jun 1989;11 Suppl 4:S777-82. [Medline].

  19. Gear JH. Handbook of Viral and Rickettsial Hemorrhagic Fevers. Boca Raton, Fla: CRC Press; 1988:5-240.

  20. Medical Economics Staff. Physicians' Desk Reference. 55th ed. Montvale, NJ: Medical Economics; 2001:1547, 2932.

  21. Special Pathogens Branch. Marburg hemorrhagic fever, imported case – Netherlands ex Uganda, July 2008. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/dvrd/spb.

  22. Zuckerman AJ, Banatvala JE, Pattison JR. Principles and Practice of Clinical Virology. 4th ed. New York, NY: John Wiley & Sons; 2000:485-581.

Further Reading

Keywords

viral hemorrhagic fever, Ebola virus, dengue fever, Marburg virus, yellow fever, VHFs, Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae, Guanarito, Junin, Machupo, Lassa, Sabia, Nairovirus, Phlebovirus, Hantavirus, Flavivirus, Marburg, Ebola, Venezuelan fever, Argentinian fever, Bolivian fever, West African fever, Brazilian fever, Sao Paulo fever, Crimean-Congo fever, Congo-Crimean hemorrhagic fever, CCHF, Rift Valley fever, RVF, Korean fever, Seoul fever, Chikungunya fever, Omsk fever, dengue hemorrhagic shock syndrome, DHSS, Kyanasur Forest disease, Kyasanur Forest disease, arthropods, rodents

Contributor Information and Disclosures

Author

Arash Michael Saemi, MD, Department of Internal Medicine, Naval Medical Center San Diego
Arash Michael Saemi, MD is a member of the following medical societies: American College of Physicians, Radiological Society of North America, Sigma Xi, and Society of Interventional Radiology
Disclosure: Nothing to disclose.

Coauthor(s)

Nili N Alai, MD, FAAD, Assistant Clinical Professor, Department of Dermatology, Clinical Faculty and Preceptor, Department of Family Practice, University of California, Irvine; Clinical Faculty and Preceptor, Department of Family Practice Residency Training, Downey Medical Center; Medical Director, The Skin Center at Laguna; Expert Medical Reviewer, Medical Board of California
Nili N Alai, MD, FAAD is a member of the following medical societies: American Academy of Dermatology and American Society for MOHS Surgery
Disclosure: Nothing to disclose.

Medical Editor

James Fulton Jr, MD, PhD, Center for Cosmetic Dermatology; Consultant, Vivant Pharmaceuticals, LLC
James Fulton Jr, MD, PhD is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Dermatology, American Society for Laser Medicine and Surgery, Dermatology Foundation, International Society of Cosmetic and Laser Surgeons, and Skin Cancer Foundation
Disclosure: vivant pharmaceuticals Ownership interest Consulting

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Genetech Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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