AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 VHF exist. Only supportive treatment is possible.

Not all viruses in these families cause VHF. VHFs 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 VHF. Common clinical manifestations of VHF are increased capillary permeability, leukopenia, and thrombocytopenia. VHF 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.

Pathophysiology

The main common underlying pathophysiologic feature of VHFs 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

The natural reservoirs of these viruses live in tropical areas. Hence, the virus does not typically infect persons in the United States. Rare, random cases of infection occur as a result of the importation of viruses by travelers or the importation of scientific research animal subjects.

International

See Table 1.

Table 1. Geographic Distribution of VHFs

Mortality/Morbidity

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

Mortality rates for various types of VHFs are shown in Table 2.

Table 2. VHF-related Mortality Rates

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

VHF 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 VHF evolves to shock and generalized mucous membrane hemorrhage.
• • It is often accompanied by neurologic, hematopoietic, or pulmonary involvement.
  • Hepatic damage is also common among VHFs, 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.

Physical

• Arenaviruses
• • Lassa, Argentinian, and Bolivian VHFs
  • • 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 VHF
  • • 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 VHF
  • • 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 fever
  • • 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.
• 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 VHF 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 fever
  • • 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 fever
  • • 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 have DHSS, a complication with a mortality rate of 4-12%.

Causes

Causes of VHFs 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Rickettsial infections - Tick bite fever, epidemic typhus, and Q fever
Bacterial infections
Various septicemias - Meningococcal, staphylococcal, and streptococcal infections; typhoid; and plague
Leptospirosis, relapsing fever
Protozoal infection - Falciparum malaria and trypanosomiasis
Other viral infections - Hepatitis, Chikungunya, Sindbis, herpes, and influenza
Infectious mononucleosis
Other hemorrhagic fevers
Acute anemia
Acute leukemias, especially promyelocytic leukemia
Disseminated intravascular coagulation
Encephalitis
Hemolytic uremic syndrome
Thrombotic thrombocytopenic purpura
Meningitis
Pleural effusion
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Although the clinical findings can suggest a hemorrhagic fever, laboratory studies are required to identify disease, to distinguish it from other conditions, and to confirm its etiology.
• As a rule, clinical blood and/or urine tests reveal leukopenia (except in Lassa fever, Hantaan viral fever, and some severe cases of CCHF), thrombocytopenia (except in Lassa fever), and proteinuria and/or hematuria (in Argentinian VHF, Bolivian VHF, and hemorrhagic fever with renal syndrome [HFRS]; common in other VHFs). Such tests include the following:
• • Full blood count determination
  • Red cell and sedimentation rate analysis
  • White cell differential count determination
  • Platelet count
  • Tests for parasites, malaria, trypanosomiasis, or relapsing fever
  • Coagulation studies
  • Liver and kidney function tests
  • Bacterial culture and virus isolation from feces and urine samples
  • Electron microscopic examination of blood and urine samples
  • Positive tourniquet test in dengue fever (This test may also be helpful in other VHFs).
• The specific diagnosis is based on viral isolation or the demonstration of seroconversion, that is, the presence of specific immunoglobulin M (IgM) antibody or a 4-fold increase in the antibody titer.
• Specialized infectious disease containment is required for the safe handling of these viruses. Biochemical tests are available for the rapid detection of viral antigen during viremia or in postmortem specimens. Such tests include the following:
• • Immunofluorescence antibody (IFA) tests can be performed.
  • Reversed (or indirect) passive hemagglutination (RPHA) tests may be helpful.
  • Acute serum samples can be tested by using a polymerase chain reaction (PCR).
  • Enzyme-linked immunosorbent assays (ELISA) can be used to detect specific IgM or immunoglobulin G (IgG) antibodies or viral antigens in acute serum samples from patients with Lassa fever, Argentinian fever, RVF, CCHF, or yellow fever. Lassa- and Hantavirus-specific IgM antibodies are often detectable during acute illness.
  • Tests for viral genetic material are favored in diagnoses of acute arenaviral infections.
  • Virus cultivation and identification techniques require 3-10 days or longer for definitive identification. Viral isolation is a lengthy process, especially in Hantaan, Ebola, Marburg, and Congo-Crimean fevers.
  • Postmortem immunocytochemical analyses can be used to identify the viral phenotype.

Imaging Studies

• Electron microscopy of the infected tissue may be helpful.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Intensive supportive care is necessary for most cases of VHF. General supportive care principles apply to the treatment of hemodynamic, hematologic, pulmonary, and neurologic manifestations of VHF. Supportive care entails maintaining the patient's oxygen status and blood pressure and balancing fluid and electrolyte levels.

• Blood, platelet, and plasma replacement and management can be crucial, depending on the case. Convalescent plasma infusions may be effective in Argentinian hemorrhagic fever, if they are administered within the first 8 days of onset.
• The judicious use of sedative, pain-relieving, and amnesic medications can be helpful in managing malaise, confusion, myalgia, and hyperesthesia. Intramuscular injections and the use of aspirin and other anticoagulant drugs should be avoided.
• Antiviral therapy with ribavirin may be useful in several VHFs, especially those caused by Arenaviruses. Although ribavirin inhibits viral DNA and RNA synthesis, it is not sensitive to the replication mechanisms of all RNA viruses. Ribavirin is proven to be effective in the treatment of Lassa fever. It is somewhat effective in the treatment of other arenavirus and Hantavirus infections, in which it decreases mortality rates when used early in the course of the disease.
• Vaccination may be considered. The only approved vaccine is for yellow fever. Nonapproved vaccines include that developed for Argentinian VHF. This vaccine is a live-attenuated, investigational vaccine. It also seems to offer protection against Bolivian VHF. Both inactivated and live-attenuated vaccines for RVF are under investigation. No vaccines are currently available for filovirus infection or dengue. Preliminary results suggest potential for successful vaccination against Ebola and Marburg viruses.
• Persons percutaneously or mucocutaneously exposed to blood, excretions, or secretions of individuals who are infected should wash the affected areas with soap and water. Affected mucous membranes should be irrigated with water or sodium chloride solution.

Consultations

• Infectious disease specialist
• Hematologist
• Pathologist
• Internal medicine specialist
• Other specialists as necessary

Diet

Fluid and electrolyte balance should be maintained.

Activity

Malaise and myalgia, among other symptoms, dictate bed rest restrictions.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.

Drug Category: Antiviral agents

Antiviral agents inhibit the replication of RNA and DNA viruses.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients may require treatment for secondary infections that may arise.
• Intensive care management may be required.

Transfer

• If hospitals or clinics are not equipped to deal with such infectious diseases, patients should be transferred to facilities with the following:
• • Specialized and skilled staff
  • Appropriate isolation space
  • Sufficient laboratory and testing facilities
• Patient transfer in infectious disease cases may increase the chances of nosocomial transmission if proper precautions are not taken.

Deterrence/Prevention

• Prevention involves the following:
• • Avoiding areas with known rodent and arthropod populations, for example, avoiding rodent or insect bites and exposure to an environment contaminated with reservoir excretions or secretions
  • Avoiding contact with potential intermediate hosts, such as livestock or primates
  • Taking safety precautions when coming in contact with potential intermediate hosts, for example, when handling slaughtered livestock or primates for scientific experimentation
  • Preventing nosocomial transmissions by sterilizing equipment, such as needles; decontaminating and disinfecting facilities; isolating patients who are infected; practicing barrier nursing; and implementing safety infectious disease precautions and procedures
  • Avoiding travel to areas known to have VHF outbreaks
  • Administering mandatory vaccinations in susceptible populations (including travelers) against all VHFs for which a vaccine is available (eg, yellow fever, Argentinian fever) (see Medical Care)
  • Administering postexposure prophylaxis with virus-specific IgG in an attempt to suppress tick-borne flavivirus infections
• Deterrence involves the eradication of rodent and arthropod vectors.

Complications

• Rift Valley hemorrhagic fever may lead to blindness in some cases.
• Individuals who are infected can occasionally have encephalitis due to bunyavirus or flavivirus infections. By the time the patient presents with encephalitis, serum antibody levels are usually detectable.
• Lassa and Machupo viruses can cause nerve deafness.
• Multisystem shock leading to death is possible.

Prognosis

• Survival may be possible with appropriate support care, depending on the virus.

Patient Education

• Educate travelers and geographically vulnerable groups, especially health care workers, agrarian workers, and rural populations, about the following risks:
• • Transmission via rodent or arthropod bites
  • Potential contamination of food and/or water reservoirs with excretions or secretions
  • Contact with animals that may be intermediate hosts
• Educate health care workers and others about the detrimental effects of nosocomial transmission and about how such spread can be prevented by implementing infectious disease safety and contact precautions, such as the following:
• • Equipment sterilization
  • Isolation of individuals who are infected
  • Barrier nursing
• Educate health care workers and others about decontamination procedures, such as the use of hypochlorite or phenolic disinfectants.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. In addition, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Although lawsuits are the least of the concerns of hospitals in developing countries, in the United States, nosocomial infections due to lack of safety precautions for the protection of both hospital staff and others are definite invitations for lawsuits.
• A physician's failure to properly diagnose or refer a traveler who may have contracted one of the various VHFs while abroad could result in legal liability.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Centers for Disease Control and Prevention. Special Pathogens Branch. 2005;Available at: http://www.cdc.gov/ncidod/dvrd/spb. [Full Text].
• Collier L, Oxford J. Human Virology. 2nd ed. Oxford, England:. Oxford University Press;2000:171-97.
• Craighead JE, John E. Pathology and Pathogenesis of Human Viral Disease. San Diego, Calif:. Academic Press;2000:277-93.
• Daddario-DiCaprio KM, Geisbert TW, Geisbert JB, et al. Cross-protection against Marburg virus strains by using a live, attenuated recombinant vaccine. J Virol. Oct 2006;80(19):9659-66. [Medline].
• Feldmann H. Marburg hemorrhagic fever--the forgotten cousin strikes. N Engl J Med. Aug 31 2006;355(9):866-9. [Medline].
• Fields BN, Knipe DM. Fundamental Virology. 2nd ed. New York, NY:. Raven Press;1991:19-24.
• Gear JH. Handbook of Viral and Rickettsial Hemorrhagic Fevers. Boca Raton, Fla:. CRC Press;1988:5-240.
• Gear JH. Clinical aspects of African viral hemorrhagic fevers. Rev Infect Dis. May-Jun 1989;11 Suppl 4:S777-82. [Medline].
• Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis. Oct 2006;19(5):429-36. [Medline].
• Kothari VM, Karnad DR, Bichile LS. Tropical infections in the ICU. J Assoc Physicians India. Apr 2006;54:291-8. [Medline].
• Martin JE, Sullivan NJ, Enama ME, 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].
• Medical Economics Staff. Physicians Desk Reference. 55th ed. Montvale, NJ:. Medical Economics;2001:1547, 2932.
• 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].
• Peters CJ, Linthicum KJ. Rift valley fever. In: Handbook of Zoonoses. Boca Raton, Fla: CRC Press; 1994:. 129-43.
• Seo JH, Park KH, Lim JY, Youn HS. Hemorrhagic fever with renal syndrome (HFRS, Korean hemorrhagic fever). Pediatr Nephrol. Sep 16 2006;[Medline].
• 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.
• Zuckerman AJ, Banatvala JE, Pattison JR. Principles and Practice of Clinical Virology. 4th ed. New York, NY: John Wiley & Sons; 2000:. 485-581.

Article Last Updated: Feb 1, 2007