eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Viral Hemorrhagic Fevers

Author: Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Coauthor(s): Michelle L Whitner, PA-C, Physician Assistant, pediatrics, Parker Pediatrics and Adolescents
Contributor Information and Disclosures

Updated: Jan 27, 2009

Introduction

Background

The 12 distinct enveloped RNA viruses that cause most viral hemorrhagic fever (VHF) cases are members of 4 families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. Disease severity resulting from infection by these agents varies widely, but the most extreme manifestations include circulatory instability, increased vascular permeability, and diffuse hemorrhage. In May 1995, these diseases came to worldwide attention with an outbreak of Ebola virus near the city of Kikwik, Zaire.1 With increased international travel, these primarily tropical viruses may now be imported into nonendemic countries. Furthermore, several of these agents have been associated with nosocomial outbreaks involving health care workers and laboratory personnel.

Viral hemorrhagic fevers share many common features. Infectious agents that are arthropod-borne (usually mosquitoes) cause many viral hemorrhagic fevers. For several viral hemorrhagic fevers, person-to-person transmission may occur through direct contact with infected patients, their blood, or their secretions and excretions. Animal reservoirs are generally rats and mice, but domestic livestock, monkeys, and other primates may also serve as intermediate hosts.

Yellow fever (the prototype virus of the Flaviviridae family), dengue, Hantavirus pulmonary syndrome (HPS), and hemorrhagic fever with renal failure syndrome (HFRS) are discussed in separate chapters (see Differentials). The other flaviviral hemorrhagic fevers (HFs), Alkhurma HF virus, Kyasanur Forest disease, and Omsk HF, are described only in cursory detail because they have very limited geographic distribution and have virtually disappeared from the endemic zones in which they were previously found.

Pathophysiology

Although common themes occur, the different viruses display variable pathophysiology. Hemorrhage is typically present in many organs, and effusions are common in serous cavities (although they may be minimal or absent in some patients). Widespread necrosis generally occurs, may be present in any organ system, and varies from modest and focal to massive in extent. Liver and lymphoid systems are usually extensively involved, and the lung regularly demonstrates varying degrees of interstitial pneumonitis, diffuse alveolar damage, and hemorrhage. Acute tubular necrosis and microvascular thrombosis may also be observed. The inflammatory response is usually minimal.

Frequency

United States

Aside from the bunyaviral HPS (Bayou, Black Creek Canal, Four Corners, Muleshoe, Sin Nombre), which appears to be associated with rodent-contaminated, abandoned, and closed buildings, and rare cases of HFRS, the only viral hemorrhagic fever to occur in the United States are imported cases, most frequently Lassa fever. The first imported case of Lassa fever in more than 20 years occurred in New Jersey in 2004.2

International

Arenaviridae, including Guanarito (Venezuelan HF), Junin (Argentine HF), Machupo (Bolivian HF), Sabia (Brazilian HF), and Lassa viruses, are found throughout South America, particularly in the Argentine pampas, Bolivia, Venezuela, and rural Brazil near Sao Paulo. The most recent arenavirus, the Chapare virus, was recently identified in Bolivia.3 Arenaviridae are also found in West Africa (Lassa). Chronic infection of small field rodents makes rural residents and farmers the most frequently infected, with a strong seasonal predominance for the fall. In Argentina, agricultural workers are disproportionately infected. In Bolivia, rodents can invade towns and cause epidemics. In West Africa, Lassa fever is spread to humans when infected rodents are captured for consumption, as well as by person-to-person exposures. Currently, outbreaks of Lassa fever are occurring in West Africa.

Bunyaviridae (Crimean-Congo HF [CCHF], Rift Valley fever [RVF]) are seen throughout Africa, the Middle East, the Balkans, southern Russia, and western China.

Filoviridae (Ebola, Marburg viruses) are found in Africa and possibly in the Philippines. The vector is unknown, but infected primates sometimes provide a link for spread to humans. Later spread among humans or primates by close contact may also occur. Aerosol transmission is suspected in some monkey infections. It appears that outbreaks of Ebola disease often follow uncommonly dry periods, when rainfall resumes and reaches unusually high levels. Outbreaks of Marburg in Angola have been recently identified.

Flaviviridae include Alkhurma HF virus, Kyasanur Forest disease, and Omsk HF. Alkhurma HF virus is a variant of Kyasanur Forest disease virus found in Saudi Arabia and reported in 24 patients since the 1990s.4 Kyasanur Forest disease follows a tick bite in rural areas of the endemic zone, Karnataka, India. Monkey die-offs may accompany increased virus activity. Omsk HF was observed in western Siberia and has a poorly understood vector and reservoir cycle that involves ticks, voles, muskrats, and, possibly, water-borne and mosquito transmission. Very few cases have been reported in recent years.

Mortality/Morbidity

Ebola and Marburg are considered the most severe viral hemorrhagic fevers, with 25-100% mortality rates. The infection rate is high, particularly for the Zaire subtype of Ebola virus. During pregnancy, Ebola infection has been universally fatal. The South American HF has a case-infection ratio of more than 50% of those exposed. The mortality rate is 15-30%. Lassa fever is a milder infection, with a fatality rate of 2-15%, and is probably much more common than is recognized. Approximately 1% of individuals exposed to RVF virus become infected, but the mortality rate of persons infected is 50%. CCHF has an infection rate of 20-100% and a fatality rate of 15-30%.

Race

No racial predilection has been reported.

Sex

No known sex predilection for viral hemorrhagic fever has been noted, except as occupational exposures dictate.

Age

Persons affected are frequently those who have the most occupational exposure, although susceptibility in endemic regions is often highest for young children.

Clinical

History

Initial symptoms of viral hemorrhagic fevers (VHFs) are nonspecific and follow an incubation period of 2-14 days. Patients experience an insidious or sudden onset of progressive fever (that may be biphasic), chills, malaise, generalized myalgias and arthralgias, headache, anorexia, and cough. Most patients have a severe sore throat and may have epigastric pain, vomiting, and diarrhea.

Physical

Typical findings are not distinctive, including nonspecific conjunctival injection, facial and truncal flushing, petechiae, purpura, ecchymoses, icterus, epistaxis, gastrointestinal and genitourinary bleeding, and lymphadenopathy. Severe illness is associated with hypotension and shock, relative bradycardia, pneumonitis, pleural and pericardial effusions, hemorrhage, encephalopathy, seizures, coma, and death.

  • Arenaviridae
    • Patients with one of the South American HFs may present with conjunctivitis, pharyngeal enanthema with petechiae but without exudate, sore throat, or cough. Retrosternal pain is also a major symptom.
    • The South American HFs may be marked by encephalopathic changes, including intention tremor, cerebellar signs, convulsions, and coma.
    • Lassa fever often manifests with classic signs of meningitis.
    • Swollen baby syndrome describes severe Lassa fever in infants and toddlers with anasarca, abdominal distention, and spontaneous bleeding but pediatric disease is otherwise not distinctive from that observed in older patients.
  • Bunyaviridae
    • Patients with Rift Valley Fever (RVF) develop retinal vasculitis that may cause permanent blindness.
    • Cotton wool spots are visible on the macula.
    • Severe disease is associated with bleeding, shock, anuria, and icterus.
    • Encephalitis may also occur without overlapping hemorrhagic fever.
    • The most severe bleeding and ecchymoses among the viral hemorrhagic fevers characterize Crimean-Congo hemorrhagic fever (CCHF).
  • Filoviridae
    • Ebola virus causes clinically similar but more severe disease than the Marburg agent.
    • On about the fifth day of illness with Ebola or Marburg virus, a distinct morbilliform rash develops on the trunk and an expressionless ghostlike facies has been described during this stage of illness.
    • Patients with progressive disease hemorrhage from mucous membranes, venipuncture sites, and body orifices.
    • Disseminated intravascular coagulation may be a feature of late disease.
  • Flaviviridae: Kyasanur Forest disease and Omsk HF are typical biphasic diseases with a febrile or hemorrhagic period that is often followed by CNS involvement, similar to tick-borne encephalitis (Central European encephalitis, Russian spring-summer encephalitis) except that hemorrhagic manifestations are not characteristic of the first phase of the tick-borne encephalitides. Alkhurma HFV typically produces fever, headache, retroorbital pain, joint pain, myalgias, anorexia, vomiting, leukopenia, thrombocytopenia, and elevated serum hepatic transaminases. Hemorrhagic or encephalitic manifestations occur in some patients.

Causes

  • South American HF and Lassa fever arise from inhalation of aerosolized fecal matter or urine of infected rodents and from rodent bites, usually during harvest, with work on small farms, or in newly developed areas. Interhuman transmission usually does not occur but is possible.
  • RVF is acquired from mosquito bites or contact with the blood of infected domestic livestock. No interhuman transmission has been observed.
  • CCHF results from tick bites, squashing ticks, or exposure to aerosols or fomites from slaughtered sheep and cattle. Nosocomial epidemics have been observed a number of times.
  • Ebola and Marburg infections occur from unknown sources, but links to primates and contact with other infected humans are observed.

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
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Further Reading

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Keywords

viral hemorrhagic fever, VHF, Alkhurma, Arenaviridae, Argentine hemorrhagic fever, AHF, Bayou virus, Black Creek Canal virus, Bolivian hemorrhagic fever, Brazilian hemorrhagic fever, Bunyaviridae, Chapare virus, Crimean-Congo hemorrhagic fever, CCHF, dengue, dengue fever, dengue hemorrhagic fever, dengue shock syndrome, Dobrava/Belgrade virus, Ebola, Ebola hemorrhagic fever, Filoviridae, Flaviviridae, Four Corners virus, Guanarito virus, Hantaan virus, Hantavirus, Hantavirus pulmonary syndrome, HPS, hemorrhagic fever with renal syndrome, HFRS, Junin virus, Kyasanur Forest disease, Lassa fever, Machupo virus, Marburg virus disease, Muleshoe virus, New York virus, Omsk hemorrhagic fever, Puumala virus, Rift Valley fever, RVF, Sabia virus, Seoul virus, Sin Nombre virus, tropical viral infection, Venezuelan hemorrhagic fever, yellow fever

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Contributor Information and Disclosures

Author

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Consulting; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching; sanofi pasteur Grant/research funds Unrestricted research grant; sanofi pasteur  Consulting; sanofi pasteur Honoraria Speaking and teaching; Tap Honoraria Speaking and teaching; Baxter Healthcare Honoraria Speaking and teaching

Coauthor(s)

Michelle L Whitner, PA-C, Physician Assistant, pediatrics, Parker Pediatrics and Adolescents
Michelle L Whitner, PA-C is a member of the following medical societies: American Academy of Physician Assistants
Disclosure: Nothing to disclose.

Medical Editor

Glenn J Fennelly, MD, MPH, Director, Division of Pediatric Infectious Diseases, Jacobi Medical Center; Associate Professor, Department of Pediatrics, Albert Einstein College of Medicine
Glenn J Fennelly, MD, MPH is a member of the following medical societies: Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine
Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

 
 
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