eMedicine from WebMD
 

eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Viral Hemorrhagic Fevers

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
Michelle L Whitner, PA-C, Physician Assistant, pediatrics, Parker Pediatrics and Adolescents

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.

Differential Diagnoses

Acidosis, Metabolic
Malaria
Acute Tubular Necrosis
Meningitis, Aseptic
Amebic Meningoencephalitis
Meningitis, Bacterial
Anemia, Acute
Meningococcal Infections
Babesiosis
Naegleria
Bacteremia
Neonatal Sepsis
Candidiasis
Nephrotic Syndrome
Cholera
Neurocysticercosis
Chorioretinitis
Parvovirus B19 Infection
Coarctation of the Aorta
Pericarditis, Bacterial
Cytomegalovirus Infection
Pericarditis, Viral
Dengue
Pharyngitis
Diarrhea
Plague
Diphtheria
Pleural Effusion
Ehrlichiosis
Q Fever
Fever in the Toddler
Respiratory Distress Syndrome
Fever in the Young Infant
Rickettsial Infection
Fever Without a Focus
Rocky Mountain Spotted Fever
Food Poisoning
Salmonella Infection
Gastroenteritis
Scrub Typhus
Hantavirus Pulmonary Syndrome
Sepsis
Hematuria
Shock
Hemorrhagic Disease of Newborn
Shock and Hypotension in the Newborn
Hemorrhagic Fever With Renal Failure Syndrome
Streptococcal Infection, Group A
Herpes Simplex Virus Infection
Toxic Shock Syndrome
Hospital-Acquired Infections
Yellow Fever
Human Immunodeficiency Virus Infection
Influenza
Leptospirosis

Other Problems to Be Considered

Boutonneuse fever
Encephalitis
Tick-borne encephalitis
Epstein-Barr virus
Gastrointestinal bleeding

Workup

Laboratory Studies

  • Characteristic hematologic abnormalities in viral hemorrhagic fever (VHF)
    • Leukopenia
    • Leukocytosis
    • Thrombocytopenia
    • Hemoconcentration
    • Occasionally, disseminated intravascular coagulation
  • Elevated hepatocellular enzyme levels and hypoalbuminemia are typically present.
  • Proteinuria is a universal finding.
  • Enzyme-linked immunosorbent assays for virus-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) are the best serologic tests for etiologic diagnosis because of their sensitivity, although antibody may not be detected during the acute stages of Marburg and Ebola virus infections.
  • Direct examination of blood and tissues (eg, skin biopsies) for viral antigen by enzyme immunoassay and for virions by electron microscopy are specific and sensitive.
  • Polymerase chain reaction (PCR) on serum during the acute stages of infection has been successfully applied for viral hemorrhagic fever. It is usually more sensitive but also more subject to artifact and contamination than more established methodologies.
  • Viral cultures of blood and tissues have been performed at the Centers for Disease Control and Prevention.
  • Recently, MassTag PCR has been applied to the differential diagnosis of these illnesses.

Procedures

  • Skin biopsy may provide material for electron microscopy or immunoassay.

Treatment

Medical Care

  • Early diagnosis and supportive care can be lifesaving for most patients with viral hemorrhagic fever (VHF). The cornerstone of therapy for all these infections is judicious fluid and electrolyte management.
  • Blood, platelet, and plasma replacement may be useful for Crimean-Congo hemorrhagic fever (CCHF). Infusion of convalescent plasma during the first 8 days of illness with Argentine HF reduces the mortality rate from 15-30% to less that 1%.

Consultations

  • Infectious diseases specialist (urgent)
  • Hematologist
  • Others as dictated by the clinical circumstances

Medication

Ribavirin is effective for treating patients with Lassa fever and markedly reduces the mortality rate if used within the first week of illness. Its use is under investigation for the treatment of patients with South American hemorrhagic fever (HF) but it is recommended for infection with all arenaviruses until a more effective alternative treatment becomes available. Widespread clinical trials have not established the efficacy of ribavirin in Crimean-Congo hemorrhagic fever (CCHF). No evidence suggests any benefit of antiviral agents, passive antibodies, or interferon in the treatment for Ebola or Marburg virus infection.

Antiviral agents

Some evidence suggests that ribavirin may be effective in the viral hemorrhagic fevers (VHFs) (in addition to Lassa fever, for which it is effective), particularly among the other arenaviruses. Treatment must be initiated promptly at the onset of the infection to effectively inhibit the replicating virus.


Ribavirin (Virazole)

DOC for VHF caused by arenaviruses, until other more effective drugs are identified and made available. Inhibits viral replication by inhibiting DNA and RNA synthesis.

Dosing

Adult

Lassa fever and AST >150:
Loading dose: 32 mg/kg IV infused over 30 min
Postloading regimen: 64 mg/kg/d IV divided q6h for 4 d, followed by 24 mg/kg/d IV divided q8h for 6 d
Similar dosing for other indications is reasonable (in the absence of further information)

Pediatric

Few data exist, but likely administer as in adults

Interactions

Inhibits zidovudine phosphorylation, thus decreasing its effects

Contraindications

Although ribavirin should not be used when renal impairment is present, it may be necessary for severe disease in which the potential benefit may outweigh the risks

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Anemia (most commonly), insomnia, depression, irritability, and suicidal behavior have been reported with PO administration; with IV administration, reversible suppression of erythropoiesis, mild hemolysis, and mild direct hyperbilirubinemia are expected and generally manageable

Follow-up

Further Inpatient Care

  • Intensive care treatment, when available, is most likely required for viral hemorrhagic fevers (VHFs).

Transfer

  • Transfer to another facility is appropriate when the required level of care and specialists are not available locally.

Deterrence/Prevention

  • The most important measure for preventing viral hemorrhagic fever is avoidance of insect bites from the vectors and exposure to rodent sources of infection.
  • Immunization with live attenuated Junin virus in Argentina has reduced the incidence of disease to fewer than 100 cases in recent years.4
  • Elimination of specific reservoir rodents from towns is practical and effective for most South American HFs. Care should be taken before entering or cleaning closed buildings with potential rodent infestation.
  • Infection with one of the Bunyaviridae leads to full immunity.
  • Since 1994, live, attenuated, and inactivated Rift Valley fever (RVF) virus vaccines have been available for domestic livestock and an experimental inactivated RVF virus vaccine is available for human use.5
  • Avoidance of ticks and slaughtering of acutely infected animals may eliminate much of the risk of RVF and Crimean-Congo hemorrhagic fever (CCHF). Tick-borne flaviviruses may be suppressed by postexposure prophylaxis with virus-specific IgG.
  • Barrier nursing and needle sterilization in African hospitals are of particular importance to eliminate epidemics of Ebola and Marburg diseases, as is avoidance of close contact with infected patients. Promising vaccines against these viruses are in preliminary primate studies.
  • Careful evaluation of all sick primates should also be undertaken.

Complications

  • Hearing deficits have been reported in up to one third of patients with severe Lassa fever.
  • Uveitis, orchitis, transverse myelitis, and recurrent hepatitis are late complications of Ebola and Marburg infections.
  • Infection with RVF may lead to blindness in as many as 20% of patients.

Prognosis

  • Individuals who survive and do not experience specific sequelae typically return to their premorbid state.

Patient Education

  • Discussing protective measures with prospective travelers is of utmost importance for avoidance of VHFs and many other infections.
  • For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

Miscellaneous

Medicolegal Pitfalls

  • Failure to consider the diagnosis of viral hemorrhagic fever (VHF) in a traveler or resident from an endemic region
  • Failure to institute proper protective isolation for caretakers

References

  1. Gonzalez JP, Pourrut X, Leroy E. Ebolavirus and other filoviruses. Curr Top Microbiol Immunol. 2007;315:363-87. [Medline].

  2. CDC. Imported Lassa fever--New Jersey, 2004. MMWR Morb Mortal Wkly Rep. Oct 1 2004;53(38):894-7. [Medline].

  3. Charrel RN, Zaki AM, Fakeeh M, et al. Low diversity of Alkhurma hemorrhagic fever virus, Saudi Arabia, 1994-1999. Emerg Infect Dis. May 2005;11(5):683-8. [Medline].

  4. Ambrosio AM, Riera LM, Saavedra Mdel C, Sabattini MS. Immune response to vaccination against Argentine hemorrhagic Fever in an area where different arenaviruses coexist. Viral Immunol. 2006;19(2):196-201. [Medline].

  5. Baize S, Marianneau P, Georges-Courbot MC, Deubel V. Recent advances in vaccines against viral haemorrhagic fevers. Curr Opin Infect Dis. Oct 2001;14(5):513-8. [Medline].

  6. Ahmeti S, Raka L. Crimean-Congo haemorrhagic fever in Kosova: a fatal case report. Virol J. 2006;3:85. [Medline]. [Full Text].

  7. Aleksandrowicz P, Wolf K, Falzarano D, Feldmann H, Seebach J, Schnittler H. Viral haemorrhagic fever and vascular alterations. Hamostaseologie. Feb 2008;28(1-2):77-84. [Medline].

  8. Bausch DG, Borchert M, Grein T, et al. Risk factors for Marburg hemorrhagic fever, Democratic Republic of the Congo. Emerg Infect Dis. Dec 2003;9(12):1531-7. [Medline].

  9. Bausch DG, Nichol ST, Muyembe-Tamfum JJ, et al. Marburg hemorrhagic fever associated with multiple genetic lineages of virus. N Engl J Med. Aug 31 2006;355(9):909-19. [Medline].

  10. 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].

  11. Berger SA, Calisher CH, Keystone JS. Exotic Viral Diseases: A Global Guide. Ontario, Canada: BC Decker Inc; 2003.

  12. Borchert M, Mulangu S, Van der Stuyft P. Lessons from the outbreak of Marburg virus. N Engl J Med. Sep 15 2005;353(11):1185. [Medline].

  13. Bray M. Highly pathogenic RNA viral infections: challenges for antiviral research. Antiviral Res. Apr 2008;78(1):1-8. [Medline].

  14. Bray M, Mahanty S. Ebola hemorrhagic fever and septic shock. J Infect Dis. Dec 1 2003;188(11):1613-7. [Medline].

  15. Briese T, Palacios G, Kokoris M, Jabado O, Liu Z, Renwick N. Diagnostic system for rapid and sensitive differential detection of pathogens. Emerg Infect Dis. Feb 2005;11(2):310-3. [Medline].

  16. Celikbas A, Ergonul O, Dokuzoguz B, et al. Crimean Congo hemorrhagic fever infection simulating acute appendicitis. J Infect. May 2005;50(4):363-5. [Medline].

  17. Cevik MA, Erbay A, Bodur H, et al. Viral load as a predictor of outcome in Crimean-Congo hemorrhagic fever. Clin Infect Dis. Oct 1 2007;45(7):e96-100. [Medline].

  18. Charrel RN. Arenaviridae. In: Feigin RD, Cherry JD, Fletcher J, eds. Textbook of Pediatric Infectious Diseases. WB Saunders Co; 2004:2364-79.

  19. Charrel RN, Fagbo S, Moureau G, Alqahtani MH, Temmam S, de Lamballerie X. Alkhurma hemorrhagic fever virus in Ornithodoros savignyi ticks. Emerg Infect Dis. Jan 2007;13(1):153-5. [Medline].

  20. Chiodini J. Mosquito-borne viral infections and the traveller. Nurs Stand. May 7-13 2008;22(35):50-7; quiz 58. [Medline].

  21. de la Torre JC. Reverse genetics approaches to combat pathogenic arenaviruses. Antiviral Res. Dec 2008;80(3):239-50. [Medline].

  22. Delgado S, Erickson BR, Agudo R, Blair PJ, Vallejo E, Albarino CG. Chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in Bolivia. PLoS Pathog. Apr 2008;4(4):e1000047. [Medline].

  23. Djavani MM, Crasta OR, Zapata JC, et al. Early blood profiles of virus infection in a monkey model for Lassa fever. J Virol. Aug 2007;81(15):7960-73. [Medline].

  24. Doganci L. New insights on the bleeding disorders in CCHF. J Infect. Oct 2007;55(4):379-81. [Medline].

  25. Dong J, Olano JP, McBride JW, Walker DH. Emerging pathogens: challenges and successes of molecular diagnostics. J Mol Diagn. May 2008;10(3):185-97. [Medline].

  26. Doyle TJ, Bryan RT, Peters CJ. Viral hemorrhagic fevers and hantavirus infections in the Americas. Infect Dis Clin North Am. Mar 1998;12(1):95-110. [Medline].

  27. Enria DA, Briggiler AM, Sanchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. Apr 2008;78(1):132-9. [Medline].

  28. Ergonul O. Crimean-Congo haemorrhagic fever. Lancet Infect Dis. Apr 2006;6(4):203-14. [Medline].

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

  30. Ergonul O, Celikbas A, Dokuzoguz B, et al. Characteristics of patients with Crimean-Congo hemorrhagic fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis. Jul 15 2004;39(2):284-7. [Medline].

  31. Estrada-Pena A, Zatansever Z, Gargili A, et al. Modeling the spatial distribution of crimean-congo hemorrhagic Fever outbreaks in Turkey. Vector Borne Zoonotic Dis. 2007;7(4):667-78. [Medline].

  32. Fair J, Jentes E, Inapogui A, et al. Lassa virus-infected rodents in refugee camps in Guinea: a looming threat to public health in a politically unstable region. Vector Borne Zoonotic Dis. 2007;7(2):167-71. [Medline].

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

  34. Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting conflicts of interest, financial aspects of research, and role of sponsors in funded studies. JAMA. Jul 6 2005;294(1):110-1. [Medline].

  35. Garrison AR, Alakbarova S, Kulesh DA, et al. Development of a TaqMan minor groove binding protein assay for the detection and quantification of Crimean-Congo hemorrhagic fever virus. Am J Trop Med Hyg. Sep 2007;77(3):514-20. [Medline].

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

  37. Gould EA, Solomon T. Pathogenic flaviviruses. Lancet. Feb 9 2008;371(9611):500-9. [Medline].

  38. Gowen BB, Holbrook MR. Animal models of highly pathogenic RNA viral infections: hemorrhagic fever viruses. Antiviral Res. Apr 2008;78(1):79-90. [Medline].

  39. Gozalan A, Esen B, Fitzner J, et al. Crimean-Congo haemorrhagic fever cases in Turkey. Scand J Infect Dis. 2007;39(4):332-6. [Medline].

  40. Groseth A, Feldmann H, Strong JE. The ecology of Ebola virus. Trends Microbiol. Sep 2007;15(9):408-16. [Medline].

  41. Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens, and Practice. New York, NY: Churchill Livingstone; 1999.

  42. Gunther S, Weisner B, Roth A, et al. Lassa fever encephalopathy: Lassa virus in cerebrospinal fluid but not in serum. J Infect Dis. Aug 1 2001;184(3):345-9. [Medline].

  43. Haas WH, Breuer T, Pfaff G, et al. Imported Lassa fever in Germany: surveillance and management of contact persons. Clin Infect Dis. May 15 2003;36(10):1254-8. [Medline].

  44. Hall RC, Hall RC. The 1995 Kikwit Ebola outbreak--model of virus properties on system capacity and function: a lesson for future viral epidemics. Am J Disaster Med. Sep-Oct 2007;2(5):270-6. [Medline].

  45. Hampton T. Vaccines against Ebola and Marburg viruses show promise in primate studies. JAMA. Jul 13 2005;294(2):163-4. [Medline].

  46. Howard CR. Viral Haemorrhagic Fevers: Perspectives in Medical Virology. Vol 11. Amsterdam: Elsevier; 2005.

  47. Isaacson M. Viral hemorrhagic fever hazards for travelers in Africa. Clin Infect Dis. Nov 15 2001;33(10):1707-12. [Medline].

  48. Jones SM, Feldmann H, Stroher U, et al. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med. Jul 2005;11(7):786-90. [Medline].

  49. Khabbaz RF. Emerging viral infections. Adv Pediatr Infect Dis. 1999;14:1-27. [Medline].

  50. Khan AS. Lymphocytic choriomeningitis virus, lassa fever, and new world arenaviruses. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone; 2003:1168-71.

  51. Khan AS. Ebola and Marburg viruses. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone; 2003:1166-8.

  52. Khan SH, Goba A, Chu M, et al. New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res. Apr 2008;78(1):103-15. [Medline].

  53. Kurosaki Y, Takada A, Ebihara H, et al. Rapid and simple detection of Ebola virus by reverse transcription-loop-mediated isothermal amplification. J Virol Methods. Apr 2007;141(1):78-83. [Medline].

  54. Lacy MD, Smego RA. Viral hemorrhagic fevers. Adv Pediatr Infect Dis. 1996;12:21-53. [Medline].

  55. Ligon BL. Outbreak of Marburg hemorrhagic fever in Angola: a review of the history of the disease and its biological aspects. Semin Pediatr Infect Dis. Jul 2005;16(3):219-24. [Medline].

  56. Lima EQ, Nogueira ML. Viral hemorrhagic fever-induced acute kidney injury. Semin Nephrol. Jul 2008;28(4):409-15. [Medline].

  57. Macher AM, Wolfe MS. Historical Lassa fever reports and 30-year clinical update. Emerg Infect Dis. May 2006;12(5):835-7. [Medline].

  58. Magill AJ. Fever in the returned traveler. Infect Dis Clin North Am. Jun 1998;12(2):445-69. [Medline].

  59. Mahanty S, Bray M. Pathogenesis of filoviral haemorrhagic fevers. Lancet Infect Dis. Aug 2004;4(8):487-98. [Medline].

  60. Mairuhu AT, Brandjes DP, van Gorp EC. Treating viral hemorrhagic fever. IDrugs. Nov 2003;6(11):1061-6. [Medline].

  61. Marburg haemorrhagic fever, Uganda--update. Wkly Epidemiol Rec. Sep 7 2007;82(36):317. [Medline].

  62. Mardani M, Jahromi MK, Naieni KH, Zeinali M. The efficacy of oral ribavirin in the treatment of crimean-congo hemorrhagic fever in Iran. Clin Infect Dis. Jun 15 2003;36(12):1613-8. [Medline].

  63. Morikawa S, Saijo M, Kurane I. Recent progress in molecular biology of Crimean-Congo hemorrhagic fever. Comp Immunol Microbiol Infect Dis. Sep 2007;30(5-6):375-89. [Medline].

  64. Moureau G, Temmam S, Gonzalez JP, et al. A real-time rt-PCR method for the universal detection and identification of flaviviruses. Vector Borne Zoonotic Dis. 2007;7(4):467-78. [Medline].

  65. Ogbu O, Ajuluchukwu E, Uneke CJ. Lassa fever in West African sub-region: an overview. J Vector Borne Dis. Mar 2007;44(1):1-11. [Medline].

  66. Outbreak news. Ebola virus haemorrhagic fever, Democratic Republic of the Congo--update. Wkly Epidemiol Rec. Oct 5 2007;82(40):345-6. [Medline].

  67. Outbreak news. Marburg haemorrhagic fever, Uganda. Wkly Epidemiol Rec. Aug 17 2007;82(33):297-8. [Medline].

  68. Outbreak of Marburg haemorrhagic fever: Uganda, June-August 2007. Wkly Epidemiol Rec. Oct 26 2007;82(43):381-4. [Medline].

  69. Palacios G, Briese T, Kapoor V, et al. MassTag polymerase chain reaction for differential diagnosis of viral hemorrhagic fever. Emerg Infect Dis. Apr 2006;12(4):692-5. [Medline].

  70. Papa A, Christova I, Papadimitriou E, Antoniadis A. Crimean-Congo hemorrhagic fever in Bulgaria. Emerg Infect Dis. Aug 2004;10(8):1465-7. [Medline].

  71. Peters CJ. Marburg and Ebola--arming ourselves against the deadly filoviruses. N Engl J Med. Jun 23 2005;352(25):2571-3. [Medline].

  72. Peters CJ, LeDuc JW. An introduction to Ebola: the virus and the disease. J Infect Dis. Feb 1999;179 Suppl 1:ix-xvi. [Medline].

  73. Peterson AT, Bauer JT, Mills JN. Ecologic and geographic distribution of filovirus disease. Emerg Infect Dis. Jan 2004;10(1):40-7. [Medline].

  74. Pigott DC. Hemorrhagic fever viruses. Crit Care Clin. Oct 2005;21(4):765-83, vii. [Medline].

  75. Pugachev KV, Guirakhoo F, Monath TP. New developments in flavivirus vaccines with special attention to yellow fever. Curr Opin Infect Dis. Oct 2005;18(5):387-94. [Medline].

  76. Robertson J, Shilkofski N. Drug doses. In: The Harriet Lane Handbook: A Manual for Pediatric House Officers. Philadelphia, Pa: Mosby; 2005:679-1009.

  77. Schuster FL, Honarmand S, Visvesvara GS, Glaser CA. Detection of antibodies against free-living amoebae Balamuthia mandrillaris and Acanthamoeba species in a population of patients with encephalitis. Clin Infect Dis. May 1 2006;42(9):1260-5. [Medline].

  78. Sharifi-Mood B, Mardani M, Keshtkar-Jahromi M, Rahnavardi M, Hatami H, Metanat M. Clinical and Epidemiologic Features of Crimean-Congo Hemorrhagic Fever Among Children and Adolescents From Southeastern Iran. Pediatr Infect Dis J. Apr 23 2008;27(6):561-3. [Medline].

  79. Sheikh AS, Sheikh AA, Sheikh NS, et al. Bi-annual surge of Crimean-Congo haemorrhagic fever (CCHF): a five-year experience. Int J Infect Dis. Jan 2005;9(1):37-42. [Medline].

  80. Smego RA, Sarwari AR, Siddiqui AR. Crimean-Congo hemorrhagic fever: prevention and control limitations in a resource-poor country. Clin Infect Dis. Jun 15 2004;38(12):1731-5. [Medline].

  81. Stein DA, Shi PY. Nucleic acid-based inhibition of flavivirus infections. Front Biosci. Jan 1 2008;13:1385-95. [Medline].

  82. Tarantola A, Nabeth P, Tattevin P, et al. Lookback exercise with imported Crimean-Congo hemorrhagic fever, Senegal and France. Emerg Infect Dis. Sep 2006;12(9):1424-6. [Medline].

  83. Tsai TF, Halstead SB. Tropical viral infections. Curr Opin Infect Dis. Oct 1998;11(5):547-53. [Medline].

  84. Vorou R, Pierroutsakos IN, Maltezou HC. Crimean-Congo hemorrhagic fever. Curr Opin Infect Dis. Oct 2007;20(5):495-500. [Medline].

  85. Wang CC, Liu SF, Liao SC, et al. Acute respiratory failure in adult patients with dengue virus infection. Am J Trop Med Hyg. Jul 2007;77(1):151-8. [Medline].

  86. WHO. Marburg haemorrhagic fever, Angola. Wkly Epidemiol Rec. May 6 2005;80(18):158-9. [Medline].

  87. WHO. Update on Lassa fever in West Africa. Wkly Epidemiol Rec. Mar 11 2005;80(10):86-8. [Medline].

  88. Wolfel R, Paweska JT, Petersen N, Grobbelaar AA, Leman PA, Hewson R. Virus detection and monitoring of viral load in Crimean-Congo hemorrhagic fever virus patients. Emerg Infect Dis. Jul 2007;13(7):1097-100. [Medline].

  89. Woodrow CJ, Eziefula AC, Agranoff D, et al. Early risk assessment for viral haemorrhagic fever: experience at the Hospital for tropical diseases, London, UK. J Infection. 2007;54:6-11. [Medline].

  90. Yang C, Ye L, Compans RW. Protection against filovirus infection: virus-like particle vaccines. Expert Rev Vaccines. Apr 2008;7(3):333-44. [Medline].

  91. Zampieri CA, Sullivan NJ, Nabel GJ. Immunopathology of highly virulent pathogens: insights from Ebola virus. Nat Immunol. Nov 2007;8(11):1159-64. [Medline].

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

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

Further Reading

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)