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Review Article| Volume 26, ISSUE 2, P345-386, June 2006

Viral Hemorrhagic Fevers

      Members of Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae that cause acute viral hemorrhagic fever (VHF) have in common the presence of a single-stranded RNA genome and a lipid envelope but vary considerably in morphology, from small isometric or moderately sized spherical virions to highly atypical pleomorphic or filamentous particles. Their lipid envelopes render them relatively vulnerable to detergents, low-pH environments, and household bleach but makes them very stable at neutral pH, especially when protein is present. Thus, these viruses are stable in blood for long periods, and can be isolated from a patient's blood specimen after weeks of storage at refrigerator or even at ambient temperatures. Most of these viruses replicate in cell culture to concentrations sufficiently high to produce a small terrorist weapon suitable for introducing lethal doses of virus into the air intake of an airplane or office building. Some replicate to even greater concentrations, with obvious ramifications. Except for dengue viruses, all of these viruses are typically stable and highly infectious as fine-particle aerosols and produce disease with high morbidity and mortality, and are classified as either biosafety level three (BSL-3), or biosafety level four (BSL-4) agents. The requirement for conducting research under biosafety levels 3 and 4 has slowed progress in understanding the pathophysiology of VHF.
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      References

        • McKay D.G.
        • Margaretten W.
        Disseminated intravascular coagulation in virus diseases.
        Arch Intern Med. 1967; 120: 129-152
        • Lee H.W.
        Hemorrhagic fever with renal syndrome in Korea.
        Rev Infect Dis. 1989; 11: S864-S876
        • Canonico P.G.
        • Kende M.
        • Luscri B.J.
        • et al.
        In-vivo activity of antivirals against exotic RNA viral infections.
        J Antimicrob Chemother. 1984; 14: 27-41
        • McCormick J.B.
        • King I.J.
        • Webb P.A.
        • et al.
        Lassa fever. Effective therapy with ribavirin.
        N Engl J Med. 1986; 314: 20-26
        • Huggins J.W.
        • Hsiang C.M.
        • Cosgriff T.M.
        • et al.
        Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
        J Infect Dis. 1991; 164: 1119-1127
        • Barry M.
        • Russi M.
        • Armstrong L.
        • et al.
        Brief report: treatment of a laboratory-acquired Sabia virus infection.
        N Engl J Med. 1995; 333: 294-296
        • Enria D.A.
        • Briggiler A.M.
        • Levis S.
        • et al.
        Tolerance and antiviral effect of ribavirin in patients with Argentine hemorrhagic fever.
        Antiviral Res. 1987; 7: 353-359
        • Huggins J.W.
        Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug.
        Rev Infect Dis. 1989; 11: S750-S761
        • Kilgore P.E.
        • Ksiazek T.G.
        • Rollin P.E.
        • et al.
        Treatment of Bolivian hemorrhagic fever with intravenous ribavirin.
        Clin Infect Dis. 1997; 24: 718-722
        • Fisher-Hoch S.P.
        • Khan J.A.
        • Rehman S.
        • et al.
        Crimean Congo-haemorrhagic fever treated with oral ribavirin.
        Lancet. 1995; 346: 472-475
        • Mardani M.
        • Jahromi M.K.
        • Naieni K.H.
        • et al.
        The efficacy of oral ribavirin in the treatment of crimean-congo hemorrhagic fever in Iran.
        Clin Infect Dis. 2003; 36: 1613-1618
        • 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. 2004; 39: 284-287
        • Sbrana E.
        • Xiao S.Y.
        • Guzman H.
        • et al.
        Efficacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease.
        Am J Trop Med Hyg. 2004; 71: 306-312
        • Ignat'ev G.M.
        • Strel'tsova M.A.
        • Agafonov A.P.
        • et al.
        Experimental study of possible treatment of Marburg hemorrhagic fever with desferal, ribavirin, and homologous interferon.
        Vopr Virusol. 1996; 41: 206-209
        • Jahrling P.B.
        • Geisbert T.W.
        • Geisbert J.B.
        • et al.
        Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections.
        J Infect Dis. 1999; 179: S224-S234
        • Kolokol'tsov A.A.
        • Davidovich I.A.
        • Strel'tsova M.A.
        • et al.
        The use of interferon for emergency prophylaxis of Marburg hemorrhagic fever in monkeys.
        Bull Exp Biol Med. 2001; 132: 686-688
        • Morrill J.C.
        • Jennings G.B.
        • Cosgriff T.M.
        • et al.
        Prevention of Rift Valley fever in rhesus monkeys with interferon-α.
        Rev Infect Dis. 1989; 11: S815-S825
        • Morrill J.C.
        • Czarniecki C.W.
        • Peters C.J.
        Recombinant human interferon-gamma modulates Rift Valley fever virus infection in the rhesus monkey.
        J Interferon Res. 1991; 11: 297-304
        • Stille W.
        • Bohle E.
        • Helm E.
        • et al.
        Uber eine durch Cercopithecus aethiops ubertragene Infektionskrankheit. (“Grune-Meerkatzen-Krankheit”, “Green Monkey Disease”) (German).
        Dtsch Med Wochenschr. 1968; 93 ([On an infectious disease transmitted by Cercopithecus aethiops (“Green monkey disease”)]): 572-582
        • Leifer E.
        • Gocke D.J.
        • Bourne H.
        Lassa fever, a new virus disease in man from West Africa, II: report of a laboratory-acquired infection treated with plasma from a person recently recovered from the disease.
        Am J Trop Med Hyg. 1970; 19: 677-679
        • White H.A.
        Lassa fever: a study of 23 hospital cases.
        Trans R Soc Trop Med Hyg. 1972; 66: 390-401
        • Monath T.P.
        • Maher M.
        • Casals J.
        • et al.
        Lassa fever in the Eastern Province of Sierra Leone, 1970–1972, II: clinical observations and virological studies on selected hospital cases.
        Am J Trop Med Hyg. 1974; 23: 1140-1149
        • Clayton A.J.
        Lassa immune serum.
        Bull World Health Organ. 1977; 55: 435-439
        • Emond R.T.
        • Evans B.
        • Bowen E.T.
        • et al.
        A case of Ebola virus infection.
        BMJ. 1977; 2: 541-544
        • Maiztegui J.I.
        • Fernandez N.J.
        • de Damilano A.J.
        Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome.
        Lancet. 1979; 2: 1216-1217
        • Enria D.A.
        • Fernandez N.J.
        • Briggiler A.M.
        • et al.
        Importance of neutralizing antibodies in treatment of Argentine hemorrhagic fever with immune plasma.
        Lancet. 1984; 4: 255-256
        • Frame J.D.
        • Verbrugge G.P.
        • Gill R.G.
        • et al.
        The use of Lassa fever convalescent plasma in Nigeria.
        Trans R Soc Trop Med Hyg. 1984; 78: 319-324
        • Mupapa K.
        • Massamba M.
        • Kibadi K.
        • et al.
        Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients.
        J Infect Dis. 1999; 179: S18-S23
        • Sadek R.F.
        • Khan A.S.
        • Stevens G.
        • et al.
        Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995: determinants of survival.
        J Infect Dis. 1999; 179: S24-S27
        • Alibek K.
        • Handelman S.
        Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World. Told From the Inside by the Man Who Ran It.
        Random House, New York1999
      1. Center for Nonproliferation Studies. Chemical and biological weapons: possession and programs past and present. November 2000. Available at: http://cns.miis.edu/research/cbw/possess.htm Accessed June 4, 2006.

        • Miller J.
        • Engelberg S.
        • Broad W.J.
        Germs: Biological Weapons and America's Secret War.
        Simon & Schuster, Waterville, ME2001
        • Monath T.P.
        Yellow fever vaccine.
        Expert Rev Vaccines. 2005; 4: 553-574
        • McKee Jr., K.T.
        • Oro J.G.
        • Kuehne A.I.
        • et al.
        Candid No. 1 Argentine hemorrhagic fever vaccine protects against lethal Junin virus challenge in rhesus macaques.
        Intervirology. 1992; 34: 154-163
        • Maiztegui J.I.
        • McKee Jr., K.T.
        • Barrera Oro J.G.
        • et al.
        Protective efficacy of a live attenuated vaccine against Argentine hemorrhagic fever.
        J Infect Dis. 1998; 177: 277-283
        • Pittman P.R.
        • Liu C.T.
        • Cannon T.L.
        • et al.
        Immunogenicity of an inactivated Rift Valley fever vaccine in humans.
        Vaccine. 1999; 18: 181-189
        • Hooper J.W.
        • Li D.
        Vaccines against hantaviruses.
        Curr Top Microbiol Immunol. 2001; 256: 171-191
        • Sullivan N.J.
        • Sanchez A.
        • Rollin P.E.
        • et al.
        Development of a preventive vaccine for Ebola virus infection in primates.
        Nature. 2000; 408: 605-609
        • Sullivan N.J.
        • Geisbert T.W.
        • Geisbert J.B.
        • et al.
        Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates.
        Nature. 2003; 424: 681-684
        • Sullivan N.J.
        • Geisbert T.W.
        • Geisbert J.B.
        • et al.
        Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified GPs.
        PLoS Med. 2006; 3: e177
        • Jones S.M.
        • Feldmann H.
        • Stroher U.
        • et al.
        Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses.
        Nat Med. 2005; (5 [Epub ahead of print])
        • Geisbert T.W.
        • Jones S.
        • Fritz E.A.
        • et al.
        Development of a new vaccine for the prevention of Lassa fever.
        PLoS Med. 2005; (Jun;2(6):e183. Epub 2005 Jun 28)
        • Daddario-DiCaprio K.M.
        • Geisbert T.W.
        • Stroher U.
        • et al.
        Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment.
        Lancet. 2006; 367: 1399-1404
        • Warfield K.L.
        • Bosio C.M.
        • Welcher B.C.
        • et al.
        Ebola virus-like particles protect from lethal Ebola virus infection.
        Proc Natl Acad Sci USA. 2003; 100: 15889-15894
        • Hevey M.
        • Negley D.
        • Pushko P.
        • et al.
        Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates.
        Virology. 1998; 251: 28-37
        • Geisbert T.W.
        • Pushko P.
        • Anderson K.
        • et al.
        Evaluation in nonhuman primates of vaccines against Ebola virus.
        Emerg Infect Dis. 2002; 8: 503-507
        • Bowen M.D.
        • Peters C.J.
        • Nichol S.T.
        The phylogeny of New World (Tacaribe complex) arenaviruses.
        Virology. 1996; 219: 285-290
        • McCormick J.B.
        • Webb P.A.
        • Krebbs J.W.
        • et al.
        A prospective study of epidemiology and ecology of Lassa fever.
        J Infect Dis. 1987; 155: 437-444
        • Birmingham K.
        • Kenyon G.
        Lassa fever is unheralded problem in West Africa.
        Nat Med. 2001; 7: 878
        • Freedman D.O.
        • Woodall J.
        Emerging infectious diseases and risk to the traveler.
        Med Clin North Am. 1999; 83: 865-883
        • Schmitz H.
        • Kohler B.
        • Laue T.
        • et al.
        Monitoring of clinical and laboratory data in two cases of imported Lassa fever.
        Microbes Infect. 2002; 4: 43-50
        • Centers for Disease Control and Prevention (CDC)
        Imported Lassa fever – New Jersey, 2004.
        MMWR Morb Mortal Wkly Rep. 2004; 53: 894-897
        • Maiztegui J.
        • Feuillade M.
        • Briggiler A.
        Progessive extension of the endemic area and changing incidence of Argentine hemorrhagic fever.
        Med Microbiol Immunol (Berl). 1986; 175: 149-152
        • Johnson K.M.
        • Wiebenga N.H.
        • Mackenzie R.B.
        • et al.
        Virus isolations from human cases of hemorrhagic fever in Bolivia.
        Proc Soc Exp Biol Med. 1965; 118: 113-118
        • Salas R.
        • de Manzione N.
        • Tesh R.B.
        • et al.
        Venezuelan haemorrhagic fever.
        Lancet. 1991; 338: 1033-1036
        • Lisieux T.
        • Coimbra M.
        • Nassar E.S.
        • et al.
        New arenavirus isolated in Brazil.
        Lancet. 1994; 343: 391-392
        • Centers for Disease Control and Prevention
        Fatal illness associated with a new world arenavirus-California.
        MMWR Morb Mortal Wkly Rep. 2000; 49: 709-711
        • Buchmeier M.J.
        • Bowen M.D.
        • Peters C.J.
        Arenaviridae: the viruses and their replication.
        in: Fields B.N. Knipe D.M. Howley P.M. Fields Virology. Lippincott Williams & Wilkins, Philadelphia2001: 1635-1668
        • Bowen M.D.
        • Peters C.J.
        • Nichol S.T.
        The phylogeny of New World (Tacaribe complex) arenaviruses.
        Virology. 1996; 219: 285-290
        • Strecker T.
        • Eichler R.
        • Meulen J.
        • et al.
        Lassa virus Z protein is a matrix protein and sufficient for the release of virus-like particles.
        J Virol. 2003; 77: 10700-10705
        • Buchmeier M.J.
        • Southern P.J.
        • Parekh B.S.
        • et al.
        Site-specific antibodies define a cleavage site conserved among arenavirus GP-C glycoproteins.
        J Virol. 1987; 61: 982-985
        • Buchmeier M.J.
        • Lewicki H.A.
        • Tomori O.
        • et al.
        Monoclonal antibodies to lymphocytic choriomeningitis and pichinde viruses: generation, characterization, and cross-reactivity with other arenaviruses.
        Virology. 1981; 113: 73-85
        • Bruns M.
        • Cihak J.
        • Muller G.
        • et al.
        Lymphocytic choriomeningitis virus. VI. Isolation of a glycoprotein mediating neutralization.
        Virology. 1983; 130: 247-251
        • Glushakova S.E.
        • Lukashevich I.S.
        • Baratova L.A.
        Prediction of arenavirus fusion peptides on the basis of computer analysis of envelope protein sequences.
        FEBS Lett. 1990; 269: 145-147
        • Di Simone C.
        • Zandonatti M.A.
        • Buchmeier M.J.
        Acidic pH triggers the LCMV membrane fusion activity and conformational change in the glycoprotein spike.
        Virology. 1994; 198: 455-465
        • Daubney R.
        • Hudson J.R.
        • Garnham P.C.
        Enzootic hepatitis or Rift valley fever. An undescribed virus disease of sheep, cattle and man from East Africa.
        J Pathol Bacteriol. 1931; 34: 545-579
        • Easterday B.C.
        Rift Valley fever.
        Adv Vet Sci. 1965; 10: 65-127
        • Shawky S.
        Rift Valley fever.
        Saudi Med J. 2000; 21: 1109-1115
      2. Collaborating WHO. Centre for Research and Training in Veterinary Epidemiology and Management. Report of the WHO/IZSTE Consultation on Recent Developments in Rift Valley Fever (RVF) (With the Participation of FAO and OIE).1993;128:1–23. Civitella del Tronto, Italy; 14–15 September 1993. WHO/CDS/VPH/93.123.

        • van Eeden P.J.
        • van Eeden S.F.
        • Joubert J.R.
        • et al.
        A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital, II: Management of patients.
        S Afr Med J. 1985; 68: 718-721
        • Nuzum E.O.
        • Rossi C.A.
        • Stephenson E.H.
        • et al.
        Aerosol transmission of Hantaan and related viruses to laboratory rats.
        Am J Trop Med Hyg. 1988; 38: 636-640
        • Lee H.W.
        Hemorrhagic fever with renal syndrome in Korea.
        Rev Infect Dis. 1989; 11: S864-S876
        • Butler J.C.
        • Peters C.J.
        Hantaviruses and Hantavirus Pulmonary Syndrome.
        Clin Infect Dis. 1994; 19: 387-395
        • Peters C.J.
        • Khan A.S.
        Hantavirus pulmonary syndrome: the new American hemorrhagic fever.
        Clin Infect Dis. 2002; 34: 1224-1231
        • Elliott R.M.
        Molecular biology of the Bunyaviridae.
        J Gen Virol. 1990; 71: 501-522
        • Bouloy M.
        Bunyaviridae: genome organization and replication strategies.
        Adv Virus Res. 1991; 40: 235-275
        • Schmaljohn C.S.
        • Hooper J.W.
        Bunyaviridae: The Viruses and Their Replication.
        in: Fields B.N. Knipe D.M. Howley P.M. Fields Virology. Lippincott Williams & Wilkins, Philadelphia2001: 1581-1602
        • Weber F.
        • Bridgen A.
        • Fazakerley J.K.
        • et al.
        Bunyamwera bunyavirus nonstructural protein NSs counteracts the induction of alpha/beta interferon.
        J Virol. 2002; 76: 7949-7955
        • Martini G.A.
        Marburg virus disease. Clinical syndrome.
        in: Martini G.A. Siegert R. Marburg Virus Disease. Springer-Verlag, New York1971: 1-9
        • Zeller H.
        Les leçons de l'épidémie a virus Marburg a Durba, République Démocratique du Congo (1998–2000).
        Med Trop (Mars). 2000; 60 ([French]. [Lessons from the Marburg virus epidemic in Durba, Democratic Republic of the Congo (1998–2000)]): 23-26
        • Centers for Disease Control and Prevention (CDC)
        Outbreak of Marburg virus hemorrhagic fever–Angola, October 1, 2004-March 29, 2005.
        MMWR Morb Mortal Wkly Rep. 2005; 54: 308-309
        • World Health Organization International Study Team
        Ebola haemorrhagic fever in Zaire, 1976.
        Bull World Health Organ. 1978; 56: 271-293
        • World Health Organization International Study Team
        Ebola haemorrhagic fever in Sudan, 1976.
        Bull World Health Organ. 1978; 56: 247-270
        • Khan A.S.
        • Tshioko F.K.
        • Heymann D.L.
        • et al.
        The reemergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995.
        J Infect Dis. 1995; 179: S76-S86
        • Georges-Courbot M.C.
        • Sanchez A.
        • Lu C.Y.
        • et al.
        Isolation and phylogenetic characterization of Ebola viruses causing different outbreaks in Gabon.
        Emerg Infect Dis. 1997; 3: 59-62
        • Centers for Disease Control and Prevention
        Outbreak of Ebola hemorrhagic fever Uganda, August 2000-January 2001.
        MMWR Morb Mortal Wkly Rep. 2001; 50: 73-77
        • Walsh P.D.
        • Abernethy K.A.
        • Bermejo M.
        • et al.
        Catastrophic ape decline in western equatorial Africa.
        Nature. 2003; 422: 611-614
        • Rouquet P.
        • Froment J.M.
        • Bermejo M.
        • et al.
        Wild animal mortality monitoring and human Ebola outbreaks, Gabon and Republic of Congo, 2001–2003.
        Emerg Infect Dis. 2005; 11: 283-290
        • Jahrling P.B.
        • Geisbert T.W.
        • Dalgard D.W.
        • et al.
        Preliminary report: isolation of Ebola virus from monkeys imported to the USA.
        Lancet. 1990; 335: 502-505
        • Le Guenno B.
        • Formentry P.
        • Wyers M.
        • et al.
        Isolation and partial characterisation of a new strain of Ebola virus.
        Lancet. 1995; 345: 1271-1274
        • Swanepoel R.
        • Leman P.A.
        • Burt F.J.
        • et al.
        Experimental inoculation of plants and animals with Ebola virus.
        Emerg Infect Dis. 1996; 2: 321-325
        • Leroy E.M.
        • Kumulungui B.
        • Pourrut X.
        • et al.
        Fruit bats as reservoirs of Ebola virus.
        Nature. 2005; 438: 575-576
        • Sanchez A.
        • Kiley M.P.
        • Holloway B.P.
        • et al.
        Sequence analysis of the Ebola virus genome: organization, genetic elements, and comparison with the genome of Marburg virus.
        Virus Res. 1993; 29: 215-240
        • Sanchez A.
        • Khan A.S.
        • Zaki S.R.
        • et al.
        Filoviridae: Marburg and Ebola viruses.
        in: Fields B.N. Knipe D.M. Howley P.M. Fields Virology. Lippincott Williams & Wilkins, Philadelphia2001
        • Takada A.
        • Robison C.
        • Goto H.
        • et al.
        A system for functional analysis of Ebola virus glycoprotein.
        Proc Natl Acad Sci USA. 1997; 94: 14764-14769
        • Ito H.
        • Watanabe S.
        • Sanchez A.
        • et al.
        Mutational analysis of the putative fusion domain of the Ebola virus glycoprotein.
        J Virol. 1999; 73: 8907-8912
        • Sanchez A.
        • Yang Z.Y.
        • Xu L.
        • et al.
        Biochemical analysis of the secreted and virion glycoproteins of Ebola virus.
        J Virol. 1998; 72: 6442-6447
        • Volchkov V.E.
        • Feldmann H.
        • Volchkova V.A.
        • et al.
        Processing of the Ebola virus glycoprotein by the proprotein convertase furin.
        Proc Natl Acad Sci USA. 1998; 95: 5762-5767
        • Volchkov V.E.
        • Becker S.
        • Volchkova V.A.
        • et al.
        GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases.
        Virology. 1995; 214: 421-430
        • Sanchez A.
        • Trappier S.G.
        • Mahy B.W.
        • et al.
        The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.
        Proc Natl Acad Sci USA. 1996; 93: 3602-3607
        • Noda T.
        • Sagara H.
        • Suzuki E.
        • et al.
        Ebola virus VP40 drives the formation of virus-like filamentous particles along with GP.
        J Virol. 2002; 76: 4855-4865
        • Han Z.
        • Boshra H.
        • Sunyer J.O.
        • et al.
        Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding.
        J Virol. 2003; 77: 1793-1800
        • Monath T.P.
        Yellow fever: Victor Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future.
        Am J Trop Med Hyg. 1991; 45: 1-43
        • Halstead S.B.
        Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade.
        Rev Infect Dis. 1989; 11: S830-S839
        • Rosen L.
        Disease exacerbation caused by sequential dengue infections: myth or reality?.
        Rev Infect Dis. 1989; 11: S840-S842
        • Kurane I.
        • Takasaki T.
        Dengue fever and dengue haemorrhagic fever: challenges of controlling an enemy still at large.
        Rev Med Virol. 2001; 11: 301-311
        • Lei H.Y.
        • Yeh T.M.
        • Liu H.S.
        • et al.
        Immunopathogenesis of dengue virus infection.
        J Biomed Sci. 2001; 8: 377-388
        • Guzman M.G.
        • Kouri G.
        Dengue: an update.
        Lancet Infect Dis. 2002; 2: 33-42
        • Pavri K.
        Clinical, clinicopathological, and hematologic features of Kyasanur Forest disease.
        Rev Infect Dis. 1989; 11: S854-S859
        • Chumakov M.P.
        (1959) Studies of virus hemorrhagic fevers.
        J Hyg Epidemiol Microbiol Immunol. 1959; 7: 125-135
        • Charrel R.N.
        • Zaki A.M.
        • Attoui H.
        • et al.
        Complete coding sequence of the Alkhurma virus, a tick-borne flavivirus causing severe hemorrhagic fever in humans in Saudi Arabia.
        Biochem Biophys Res Commun. 2001; 287: 455-461
        • Chambers T.J.
        • Hahn C.S.
        • Galler R.
        • et al.
        Flavivirus genome organization, expression, and replication.
        Annu Rev Microbiol. 1990; 44: 649-688
        • Lindenbach B.D.
        • Rice C.M.
        Flaviviridae: The viruses and their replication.
        in: Fields B.N. Knipe D.M. Howley P.M. Fields Virology. Lippincott Williams & Wilkins, Philadelphia2001: 991-1041
        • Mackenzie J.M.
        • Jones M.K.
        • Young P.R.
        Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication.
        Virology. 1996; 220: 232-240
        • Mackenzie J.M.
        • Khromykh A.A.
        • Jones M.K.
        • et al.
        Subcellular localization and some biochemical properties of the flavivirus Kunjin nonstructural proteins NS2A and NS4A.
        Virology. 1998; 245: 203-215
        • Liu W.J.
        • Chen H.B.
        • Wang X.J.
        • et al.
        Analysis of adaptive mutations in Kunjin virus replicon RNA reveals a novel role for the flavivirus nonstructural protein NS2A in inhibition of beta interferon promoter-driven transcription.
        J Virol. 2004; 78: 12225-12235
        • Clum S.
        • Ebner K.E.
        • Padmanabhan R.
        Cotranslational membrane insertion of the serine proteinase precursor NS2B–NS3(Pro) of dengue virus type 2 is required for efficient in vitro processing and is mediated through the hydrophobic regions of NS2B.
        J Biol Chem. 1997; 272: 30715-30723
        • Gorbalenya A.E.
        • Donchenko A.P.
        • Koonin E.V.
        • et al.
        N-terminal domains of putative helicases of flavi- and pestiviruses may be serine proteases.
        Nucleic Acids Res. 1989; 17: 3889-3897
        • Preugschat F.
        • Yao C.W.
        • Strauss J.H.
        In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3.
        J Virol. 1990; 64: 4364-4374
        • Arias C.F.
        • Preugschat F.
        • Strauss J.H.
        Dengue 2 virus NS2B and NS3 form a stable complex that can cleave NS3 within the helicase domain.
        Virology. 1993; 193: 888-899
        • Failla C.
        • Tomei L.
        • De Francesco R.
        Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins.
        J Virol. 1994; 68: 3753-3760
        • Lin C.
        • Wu J.W.
        • Hsiao K.
        • et al.
        The hepatitis C virus NS4A protein: interactions with the NS4B and NS5A proteins.
        J Virol. 1997; 71: 6465-6471
        • Munoz-Jordan J.L.
        • Sanchez-Burgos G.G.
        • Laurent-Rolle M.
        • et al.
        Inhibition of interferon signaling by dengue virus.
        Proc Natl Acad Sci USA. 2003; 100: 14333-14338
        • Koonin E.V.
        Computer-assisted identification of a putative methyltransferase domain in NS5 protein of flaviviruses and lambda 2 protein of reovirus.
        J Gen Virol. 1993; 74: 733-740
        • Tan B.H.
        • Fu J.
        • Sugrue R.J.
        • et al.
        Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity.
        Virology. 1996; 216: 317-325
      3. Centers for Disease Control and Prevention. Category A agents. Available at: http://www.bt.cdc.gov/Agent/agentlist.asp. Accessed June 4, 2006.

        • Williams P.
        • Wallace D.
        Unit 731, Japan's Secret Biological Warfare in World War II.
        The Free Press, New York1989 (38–40)
        • P'yankov O.V.
        • Sergeev A.N.
        • P'yankova O.G.
        • et al.
        Experimental Ebola fever in macaca rhesus.
        Vopr Virusol. 1995; 40 ([Russian]): 113-115
        • Johnson E.
        • Jaax N.
        • White J.
        • et al.
        Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus.
        Int J Exp Pathol. 1995; 76: 227-236
        • Bazhutin N.B.
        • Belanov E.F.
        • Spiridonov V.A.
        • et al.
        The effect of the methods for producing an experimental Marburg virus infection on the characteristics of the course of the disease in green monkeys.
        Vopr Virusol. 1992; 37 ([Russian]): 153-156
      4. Lub M. Iu, Sergeev AN, P'iankov OV, et al. Certain pathogenetic characteristics of a disease in monkeys infected with the Marburg virus by an airborne route [Russian]. Vopr Virusol 1995;40:158–61.

        • Stephenson E.H.
        • Larsen E.W.
        • Dominik J.W.
        Effect of environmental factors on aerosol-induced Lassa virus infection.
        J Med Virol. 1984; 14: 295-303
        • Kenyon R.H.
        • McKee Jr., K.T.
        • Zack P.M.
        • et al.
        Aerosol infection of rhesus macaques with Junin virus.
        Intervirology. 1992; 33: 23-31
      5. Global Proliferation of Weapons of Mass Destruction. Hearings Before the Permanent Subcommittee on Investigations of the Committee on Governmental Affairs, United States Senate, 104th Congress, 1st-2nd Session (1996). Available at: http://www.fas.org/irp/congress/1995_rpt/aum/part05.htm. Accessed on June 4, 2006.

      6. Federation of American Scientists. Chemical and Biological Arms Control Program. Weapons of Mass Destruction Around the World. Report on North Korea. Biological Systems. Available at: http://www.fas.org/nuke/guide/dprk/bw/index.html. Accessed June 4, 2006.

        • World Health Organization Group of Consultants
        Health aspects of chemical and biologic weapons.
        World Health Organization, Geneva1970 (98–109)
        • Borio L.
        • Inglesby T.
        • Peters C.J.
        • et al.
        Hemorrhagic fever viruses as biological weapons.
        JAMA. 2002; 287: 2391-2405
        • Peters C.J.
        • Jahrling P.B.
        • Khan A.S.
        Patients infected with high-hazard viruses.
        Arch Virol. 1996; 11: 141-168
        • Maiztegui J.I.
        • Laguens R.P.
        • Cossio P.M.
        • et al.
        Ultrastructural and immunohistochemical studies in five cases of Argentine hemorrhagic fever.
        J Infect Dis. 1975; 132: 35-53
        • Gonzalez P.H.
        • Cossio P.M.
        • Arana R.
        • et al.
        Lymphatic tissue in Argentine hemorrhagic fever. Pathologic features.
        Arch Pathol Lab Med. 1980; 104: 250-254
        • Jahrling P.B.
        • Hesse R.A.
        • Eddy G.A.
        • et al.
        Lassa virus infection of rhesus monkeys: pathogenesis and treatment with ribavirin.
        J Infect Dis. 1980; 141: 580-589
        • De Brito T.
        • Siqueira S.A.
        • Santos R.T.
        • et al.
        Human fatal yellow fever. Immunohistochemical detection of viral antigens in the liver, kidney and heart.
        Pathol Res Pract. 1992; 188: 177-181
        • Geisbert T.W.
        • Jahrling P.B.
        • Hanes M.A.
        • et al.
        Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States.
        J Comp Pathol. 1992; 106: 137-152
        • Zaki S.R.
        • Greer P.W.
        • Coffield L.M.
        • et al.
        Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease.
        Am J Pathol. 1995; 46: 552-579
        • Jaax N.K.
        • Davis K.J.
        • Geisbert T.W.
        • et al.
        Lethal experimental infection of rhesus monkeys with Ebola-Zaire (Mayinga) virus by the oral and conjunctival route of exposure.
        Arch Pathol Lab Med. 1996; 120: 140-155
        • Burt F.J.
        • Swanepoel R.
        • Shieh W.J.
        • et al.
        Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis.
        Arch Pathol Lab Med. 1997; 121: 839-846
        • Geisbert T.W.
        • Jaax N.K.
        Marburg hemorrhagic fever: report of a case studied by immunohistochemistry and electron microscopy.
        Ultrastr Pathol. 1998; 22: 3-17
        • Zaki S.R.
        • Goldsmith C.S.
        Pathologic features of filovirus infections in humans.
        Curr Top Microbiol Immunol. 1999; 235: 97-116
        • de Filippis A.M.
        • Nogueira R.M.
        • Schatzmayr H.G.
        • et al.
        Outbreak of jaundice and hemorrhagic fever in the Southeast of Brazil in 2001: detection and molecular characterization of yellow fever virus.
        J Med Virol. 2002; 68: 620-627
        • Geisbert T.W.
        • Hensley L.E.
        • Larsen T.
        • et al.
        Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection.
        Am J Pathol. 2003; 163: 2347-2370
        • Geisbert T.W.
        • Young H.A.
        • Jahrling P.B.
        • et al.
        Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells.
        Am J Pathol. 2003; 163: 2371-2382
        • Monath T.P.
        • Barrett A.D.
        Pathogenesis and pathophysiology of yellow fever.
        Adv Virus Res. 2003; 60: 343-395
        • Pensiero M.N.
        • Sharefkin J.B.
        • Dieffenbach C.W.
        • et al.
        Hantaan virus infection of human endothelial cells.
        J Virol. 1992; 66: 5929-5936
        • Khaiboullina S.F.
        • St Jeor S.C.
        Hantavirus immunology.
        Viral Immunol. 2002; 15: 609-625
        • Gallaher W.R.
        • DiSimone C.
        • Buchmeier M.J.
        The viral transmembrane superfamily: possible divergence of Arenavirus and Filovirus glycoproteins from a common RNA virus ancestor.
        BMC Microbiol. 2001; 1
        • Takada A.
        • Watanabe S.
        • Ito H.
        • et al.
        Downregulation of beta1 integrins by Ebola virus glycoprotein: implication for virus entry.
        Virology. 2000; 278: 20-26
        • Takada A.
        • Fujioka K.
        • Tsuiji M.
        • et al.
        Human macrophage C-type lectin specific for galactose and N-acetylgalactosamine promotes filovirus entry.
        J Virol. 2004; 78: 2943-2947
        • Becker S.
        • Spiess M.
        • Klenk H.D.
        The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus.
        J Gen Virol. 1995; 76: 393-399
        • Chan S.Y.
        • Empig C.J.
        • Welte F.J.
        • et al.
        Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses.
        Cell. 2001; 106: 117-126
        • Alvarez C.P.
        • Lasala F.
        • Carrillo J.
        • et al.
        C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans.
        J Virol. 2002; 76: 6841-6844
        • Simmons G.
        • Reeves J.D.
        • Grogan C.C.
        • et al.
        DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells.
        Virology. 2003; 305: 115-123
        • Marzi A.
        • Gramberg T.
        • Simmons G.
        • et al.
        DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus.
        J Virol. 2004; 78: 12090-12095
        • Gavrilovskaya I.N.
        • Shepley M.
        • Shaw R.
        • et al.
        β3 integrins mediate the cellular entry of hantaviruses that cause respiratory failure.
        Proc Natl Acad Sci USA. 1998; 95: 7074-7079
        • Cao W.
        • Henry M.D.
        • Borrow P.
        • et al.
        Identification of α-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus.
        Science. 1998; 282: 2079-2081
        • Spiropoulou C.F.
        • Kunz S.
        • Rollin P.E.
        • et al.
        New World arenavirus clade C, but not clade A and B viruses, utilizes alpha-dystroglycan as its major receptor.
        J Virol. 2002; 76: 5140-5146
        • Yang Z.
        • Duckers H.J.
        • Sullivan N.J.
        • et al.
        Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury.
        Nat Med. 2000; 6: 886-889
        • Lukashevich I.S.
        • Maryankova R.
        • Vladyko A.S.
        • et al.
        Lassa and Mopeia virus replication in human monocytes/macrophages and in endothelial cells: different effects on IL-8 and TNF-alpha gene expression.
        J Med Virol. 1999; 59: 552-560
        • Elsner B.
        • Schwarz E.
        • Mando O.G.
        • et al.
        Pathology of 12 fatal cases of Argentine hemorrhagic fever.
        Am J Trop Med Hyg. 1973; 22: 229-236
        • Terrell T.G.
        • Stookey J.L.
        • Eddy G.A.
        • Kastello M.D.
        Pathology of Bolivian hemorrhagic fever in the rhesus monkey.
        Am J Pathol. 1973; 73: 477-494
        • Walker D.H.
        • Murphy F.A.
        Pathology and pathogenesis of arenavirus infections.
        Curr Top Microbiol Immunol. 1987; 133: 89-113
        • Gear J.S.
        • Cassel G.A.
        • Gear A.J.
        • et al.
        Outbreak of Marburg virus disease in Johannesburg.
        BMJ. 1975; 4: 489-493
        • Murphy F.A.
        Pathology of Ebola virus infection.
        in: Pattyn S.R. Ebola Virus Haemorrhagic Fever. Elsevier/North-Holland Biomedical Press, New York1978: 43-59
        • Feldmann H.
        • Bugany H.
        • Mahner F.
        • et al.
        Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages.
        J Virol. 1996; 70: 2208-2214
        • Child P.L.
        • MacKenzie R.B.
        • Valverde L.R.
        • Johnson K.M.
        Bolivian hemorrhagic fever: a pathological description.
        Arch Path. 1967; 83: 434-445
        • Gedigk P.
        • Bechtelsheimer H.
        • Korb G.
        Pathologic anatomy of the Marburg virus disease.
        in: Martini G.A. Siegert R. Marburg Virus Disease. Springer-Verlag, New York1971: 50-53
        • Winn Jr., W.C.
        • Walker D.H.
        The pathology of human Lassa fever.
        Bull World Health Organ. 1975; 52: 535-545
        • Walker D.H.
        • McCormick J.B.
        • Johnson K.M.
        • et al.
        Pathologic and virologic study of fatal Lassa fever in man.
        Am J Pathol. 1982; 107: 349-356
        • Green D.E.
        • Mahlandt B.G.
        • McKee Jr., K.T.
        Experimental Argentine hemorrhagic fever in rhesus macaques: virus-specific variations in pathology.
        J Med Virol. 1987; 22: 113-133
        • Elton N.W.
        • Romero A.
        • Trejos A.
        Clinical pathology of yellow fever.
        Am J Clin Pathol. 1955; 25: 135-146
        • Joubert J.R.
        • King J.B.
        • Rossouw D.J.
        • et al.
        A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part III. Clinical pathology and pathogenesis.
        S Afr Med J. 1985; 68: 722-728
        • Peters C.J.
        • Jahrling P.B.
        • Liu C.T.
        • et al.
        Experimental studies of arenaviral hemorrhagic fevers.
        Curr Top Microbiol Immunol. 1987; 134: 5-68
        • Fisher-Hoch S.P.
        • McCormick J.B.
        • Sasso D.
        • et al.
        Hematologic dysfunction in Lassa fever.
        J Med Virol. 1988; 26: 127-135
        • Peters C.J.
        • Jones D.
        • Trotter R.
        • et al.
        Experimental Rift Valley fever in rhesus macaques.
        Arch Virol. 1988; 99: 31-44
        • Swanepoel R.
        • Gill D.E.
        • Shepherd A.J.
        • et al.
        The clinical pathology of Crimean-Congo hemorrhagic fever.
        Rev Infect Dis. 1989; 11: S794-S800
        • Morrill J.C.
        • Jennings G.B.
        • Johnson A.J.
        • et al.
        Pathogenesis of Rift Valley fever in rhesus monkeys: role of the interferon response.
        Arch Virol. 1990; 110: 195-212
        • Fisher-Hoch S.P.
        • Brammer T.L.
        • Trappier S.G.
        • et al.
        Pathogenic potential of filoviruses: role of geographic origin of primate host and virus strain.
        J Infect Dis. 1992; 166: 753-763
        • McCormick J.B.
        • Mitchell S.W.
        • Kiley M.P.
        • et al.
        Inactivated Lassa virus elicits a non protective immune response in rhesus monkeys.
        J Med Virol. 1992; 37: 1-7
        • Elisaf M.
        • Stefanaki S.
        • Repanti M.
        • et al.
        Liver involvement in hemorrhagic fever with renal syndrome.
        J Clin Gastroenterol. 1993; 17: 33-37
        • Callis R.T.
        • Jahrling P.B.
        • DePaoli A.
        Pathology of Lassa virus infection in the rhesus monkey.
        Am J Trop Med Hyg. 1982; 31: 1038-1045
        • Frame J.D.
        Clinical features of Lassa fever in Liberia.
        Rev Infect Dis. 1989; 11: S783-S789
        • McLeod Jr., C.G.
        • Stookey J.L.
        • White J.D.
        • et al.
        Pathology of Bolivian Hemorrhagic fever in the African green monkey.
        Am J Trop Med Hyg. 1978; 27: 822-826
        • Cosgriff T.M.
        Mechanisms of disease in Hantavirus infection: pathophysiology of hemorrhagic fever with renal syndrome.
        Rev Infect Dis. 1991; 13: 97-107
        • Duchin J.S.
        • Koster F.T.
        • Peters C.J.
        • et al.
        Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group.
        N Engl J Med. 1994; 330: 949-955
        • Peters C.J.
        Arenaviruses.
        in: Richman D.D. Whitley R.J. Hayden F.G. Clincal Virology. Churchill Livingstone, New York1997: 973-996
        • Fisher-Hoch S.P.
        • Mitchell S.W.
        • Sasso D.R.
        • et al.
        Physiological and immunologic disturbances associated with shock in a primate model of Lassa fever.
        J Infect Dis. 1987; 155: 465-474
        • Hudson N.
        The pathology of experimental yellow fever in the Macaca rhesus. III. Comparison with the pathology of yellow fever in man.
        Am J Pathol. 1928; 4: 419-439
        • Klotz O.
        • Belt T.H.
        Pathology in spleen in yellow fever.
        Am J Pathol. 1930; 6: 655-662
        • Zlotnik I.
        Marburg agent disease: Pathology.
        Trans R Soc Trop Med Hyg. 1969; 63: 310-323
        • Murphy F.A.
        • Simpson D.I.H.
        • Whitfield S.G.
        • et al.
        Marburg virus infection in monkeys.
        Lab Invest. 1971; 24: 279-291
        • Edington G.M.
        • White H.A.
        The pathology of Lassa fever.
        Trans R Soc Trop Med Hyg. 1972; 66: 381-389
        • Monath T.P.
        • Brinker K.R.
        • Chandler F.W.
        • et al.
        Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues.
        Am J Trop Med Hyg. 1981; 30: 431-443
        • Baskerville A.
        • Satti A.
        • Murphy F.A.
        • et al.
        Congo-Crimean haemorrhagic fever in Dubai: histopathological studies.
        J Clin Pathol. 1981; 34: 871-874
        • Fisher-Hoch S.P.
        • Platt G.S.
        • Lloyd G.
        • et al.
        Haematological and biochemical monitoring of Ebola infection in rhesus monkeys: implications for patient management.
        Lancet. 1983; 2: 1055-1058
        • Fisher-Hoch S.P.
        • Platt G.S.
        • Neild G.H.
        • et al.
        Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola).
        J Infect Dis. 1985; 152: 887-894
        • McKee Jr., K.T.
        • Mahlandt B.G.
        • Maiztegui J.I.
        • et al.
        Virus-specific factors in Argentine hemorrhagic fever in rhesus macaques.
        J Med Virol. 1987; 22: 99-111
        • Simpson D.I.H.
        Marburg agent disease: in monkeys.
        Trans R Soc Trop Med Hyg. 1969; 63: 303-309
        • Havemann K.
        • Schmidt H.A.
        Haematological findings in Marburg virus disease: evidence for involvement of the immunological system.
        in: Martini G.A. Siegert R. Marburg Virus Disease. Springer-Verlag, New York1971: 34-40
        • Kastello M.D.
        • Eddy G.A.
        • Kuehne R.W.
        A rhesus monkey model for the study of Bolivian hemorrhagic fever.
        J Infect Dis. 1976; 133: 57-62
        • Wagner F.S.
        • Eddy G.A.
        • Brand O.M.
        The African green monkey as an alternate primate host for studying Machupo virus infection.
        Am J Trop Med Hyg. 1977; 26: 159-162
        • Fisher-Hoch S.P.
        • McCormick J.B.
        • Auperin D.
        • et al.
        Protection of rhesus monkeys from fatal Lassa fever by vaccination with a recombinant vaccinia virus containing the Lassa virus glycoprotein gene.
        Proc Natl Acad Sci USA. 1989; 86: 317-321
        • Vallejos D.A.
        • Ambrosio A.M.
        • Feuillade M.R.
        • et al.
        Lymphocyte subsets alteration in patients with Argentine hemorrhagic fever.
        J Med Virol. 1989; 27: 160-163
        • Sanchez A.
        • Lukwiya M.
        • Bausch D.
        • et al.
        Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels.
        J Virol. 2004; 78: 10370-10377
        • Baize S.
        • Leroy E.M.
        • Georges-Courbot M.C.
        • et al.
        Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients.
        Nat Med. 1999; 5: 423-426
        • Geisbert T.W.
        • Hensley L.E.
        • Gibb T.R.
        • et al.
        Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses.
        Lab Invest. 2000; 80: 171-186
        • Reed D.S.
        • Hensley L.E.
        • Geisbert J.B.
        • et al.
        Depletion of peripheral blood T lymphocytes and NK cells during the course of Ebola hemorrhagic fever in cynomolgus macaques.
        Viral Immunol. 2004; 17: 390-400
        • Hensley L.E.
        • Young H.A.
        • Jahrling P.B.
        • et al.
        Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily.
        Immunol Lett. 2002; 80: 169-179
        • Mahanty S.
        • Hutchinson K.
        • Agarwal S.
        • et al.
        Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.
        J Immunol. 2003; 170: 2797-2801
        • Baize S.
        • Kaplon J.
        • Faure C.
        • et al.
        Lassa virus infection of human dendritic cells and macrophages is productive but fails to activate cells.
        J Immunol. 2004; 172: 2861-2869
        • Baize S.
        • Leroy E.M.
        • Georges A.J.
        • et al.
        Inflammatory responses in Ebola virus-infected patients.
        Clin Exp Immunol. 2002; 128: 163-168
        • Calandra T.
        • Gerain J.
        • Heumann D.
        • et al.
        High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.
        Am J Med. 1991; 91: 23-29
        • Damas P.
        • Ledoux D.
        • Nys M.
        • et al.
        Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.
        Ann Surg. 1992; 215: 356-362
        • Marty C.
        • Misset B.
        • Tamion F.
        • et al.
        Circulating interleukin-8 concentrations in patients with multiple organ failure of septic and nonseptic origin.
        Crit Care Med. 1994; 22: 673-679
        • Levis S.C.
        • Saavedra M.C.
        • Ceccoli C.
        • et al.
        Endogenous interferon in Argentine hemorrhagic fever.
        J Infect Dis. 1984; 149: 428-433
        • Levis S.C.
        • Saavedra M.C.
        • Ceccoli C.
        • et al.
        Correlation between endogenous interferon and the clinical evolution of patients with Argentine hemorrhagic fever.
        J Interferon Res. 1985; 5: 383-389
        • Heller M.V.
        • Saavedra M.C.
        • Falcoff R.
        • et al.
        Increased tumor necrosis factor-alpha levels in Argentine hemorrhagic fever.
        J Infect Dis. 1992; 166: 1203-1204
        • Groeneveld P.H.
        • Colson P.
        • Kwappenberg K.M.
        • et al.
        Increased production of nitric oxide in patients infected with the European variant of hantavirus.
        Scand J Infect Dis. 1995; 27: 453-456
        • Krakauer T.
        • Leduc J.W.
        • Krakauer H.
        Serum levels of tumor necrosis factor-alpha, interleukin-1, and interleukin-6 in hemorrhagic fever with renal syndrome.
        Viral Immunol. 1995; 8: 75-99
        • Marta R.F.
        • Montero V.S.
        • Hack C.E.
        • et al.
        Proinflammatory cytokines and elastase-α-1-antitrypsin in Argentine hemorrhagic fever.
        Am J Trop Med Hyg. 1999; 60: 85-89
        • Mori M.
        • Rothman A.L.
        • Kurane I.
        • et al.
        High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome.
        J Infect Dis. 1999; 179: 295-302
        • Villinger F.
        • Rollin P.E.
        • Brar S.S.
        • et al.
        Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection.
        J Infect Dis. 1999; 179: S188-S191
        • Ignatiev G.M.
        • Dadaeva A.A.
        • Luchko S.V.
        • et al.
        Immune and pathophysiological processes in baboons experimentally infected with Ebola virus adapted to guinea pigs.
        Immunol Lett. 2000; 71: 131-140
        • Mahanty S.
        • Bausch D.G.
        • Thomas R.L.
        • et al.
        Low levels of interleukin-8 and interferon-inducible protein-10 in serum are associated with fatal infections in acute Lassa fever.
        J Infect Dis. 2001; 183: 1713-1721
        • Davis I.C.
        • Zajac A.J.
        • Nolte K.B.
        • et al.
        Elevated generation of reactive oxygen/nitrogen species in hantavirus cardiopulmonary syndrome.
        J Virol. 2002; 76: 8347-8359
        • ter Meulen J.
        • Sakho M.
        • Koulemou K.
        • et al.
        Activation of the cytokine network and unfavorable outcome in patients with yellow fever.
        J Infect Dis. 2004; 190: 1821-1827
        • Ergonul O.
        • Tuncbilek S.
        • Baykam N.
        • et al.
        Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever.
        J Infect Dis. 2006; 193: 941-944
        • Stroher U.
        • West E.
        • Bugany H.
        • et al.
        Infection and activation of monocytes by Marburg and Ebola viruses.
        J Virol. 2001; 75: 11025-11033
        • Sundstrom J.B.
        • McMullan L.K.
        • Spiropoulou C.F.
        • et al.
        Hantavirus infection induces the expression of RANTES and IP-10 without causing increased permeability in human lung microvascular endothelial cells.
        J Virol. 2001; 75: 6070-6085
        • Gomez R.M.
        • Pozner R.G.
        • Lazzari M.A.
        • et al.
        Endothelial cell function alteration after Junin virus infection.
        Thromb Haemost. 2003; 90: 326-333
        • Leroy E.M.
        • Baize S.
        • Volchkov V.E.
        • et al.
        Human asymptomatic Ebola infection and strong inflammatory response.
        Lancet. 2000; 355: 2210-2215
        • Li H.
        • Forstermann U.
        Nitric oxide in the pathogenesis of vascular disease.
        J Pathol. 2000; 190: 244-254
        • Peters C.J.
        • Liu C.T.
        • Anderson Jr., G.W.
        • et al.
        Pathogenesis of viral hemorrhagic fevers: Rift Valley fever and Lassa fever contrasted.
        Rev Infect Dis. 1989; 11: S743-S749
        • Asper M.
        • Sternsdorf T.
        • Hass M.
        • et al.
        Inhibition of different Lassa virus strains by alpha and gamma interferons and comparison with a less pathogenic arenavirus.
        J Virol. 2004; 78: 3162-3169
        • Foster G.R.
        • Finter N.B.
        Are all type I human interferons equivalent?.
        J Viral Hepat. 1998; 5: 143-152
        • Basler C.F.
        • Wang X.
        • Muhlberger E.
        • et al.
        The Ebola virus VP35 protein functions as a type I IFN antagonist.
        Proc Natl Acad Sci USA. 2000; 97: 12289-12294
        • Basler C.F.
        • Mikulasova A.
        • Martinez-Sobrido L.
        • et al.
        The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3.
        J Virol. 2003; 77: 7945-7956
        • Basler C.F.
        • Palese P.
        Modulation of innate immunity by filoviruses.
        in: Klenk H.D. Feldmann H. Ebola and Marburg viruses: molecular and cellular biology. Horizon Bioscience, Norfolk, UK2004: 305-349
        • Bouloy M.
        • Janzen C.
        • Vialat P.
        • et al.
        Genetic evidence for an interferon-antagonist function of rift valley fever virus nonstructural protein NSs.
        J Virol. 2001; 75: 1371-1377
        • Martini G.A.
        • Knauff H.G.
        • Schmidt H.A.
        • et al.
        A hitherto unknown infectious disease contracted from monkeys. “Marburg-virus” disease.
        Ger Med Mon. 1968; 13: 457-470
        • Bwaka M.A.
        • Bonnet M.J.
        • Calain P.
        • et al.
        Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients.
        J Infect Dis. 1999; 179: S1-S7
        • Bowen E.T.
        • Platt G.S.
        • Simpson D.I.
        • et al.
        Ebola haemorrhagic fever: experimental infection of monkeys.
        Trans R Soc Trop Med Hyg. 1978; 72: 188-191
        • Geisbert T.W.
        • Hensley L.E.
        • Jahrling P.B.
        • et al.
        Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys.
        Lancet. 2003; 362: 1953-1958
        • Mackenzie R.B.
        • Beye H.K.
        • Valverde L.
        • et al.
        Epidemic hemorrhagic fever in Bolivia. I. A preliminary report of the epidemiological and clinical findings in a new epidemic area in South America.
        Am J Trop Med Hyg. 1964; 13: 620-625
        • Peters C.J.
        • Zaki S.R.
        • Rollin P.E.
        Viral hemorrhagic fevers.
        in: Feteky R. Atlas of Infectious Diseases. Churchill Livingstone, Philadelphia1997: 10.1-10.26
        • Molinas F.C.
        • de Bracco M.M.
        • Maiztegui J.I.
        Coagulation studies in Argentine hemorrhagic fever.
        J Infect Dis. 1981; 143: 1-6
        • Dennis L.H.
        • Reisberg B.E.
        • Crosbie J.
        • et al.
        The original haemorrhagic fever: yellow fever.
        Br J Haematol. 1969; 17: 455-462
        • Scott S.K.
        • Hickman R.L.
        • Lang C.M.
        • et al.
        Studies of the coagulation system and blood pressure during experimental Bolivian hemorrhagic fever in rhesus monkeys.
        Am J Trop Med Hyg. 1978; 27: 1232-1239
        • Molinas F.C.
        • Giavedoni E.
        • Frigerio M.J.
        • et al.
        Alteration of blood coagulation and complement system in neotropical primates infected with Junin virus.
        J Med Virol. 1983; 12: 281-292
        • Heller M.V.
        • Marta R.F.
        • Sturk A.
        • et al.
        Early markers of blood coagulation and fibrinolysis activation in Argentine hemorrhagic fever.
        Thromb Haemost. 1995; 73: 368-373
        • Courouble P.
        • Vanpee D.
        • Delgrange E.
        • et al.
        Hantavirus infections: clinical presentation in the emergency room.
        Eur J Emerg Med. 2001; 8: 17-20
        • Geisbert T.W.
        • Young H.A.
        • Jahrling P.B.
        • et al.
        Mechanisms underlying coagulation abnormalities in Ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event.
        J Infect Dis. 2003; 188: 1618-1629
        • Knobloch J.
        • McCormick J.B.
        • Webb P.A.
        • et al.
        Clinical obersvations in 42 patients with Lassa fever.
        Tropenmed Parasitol. 1980; 31: 389-398
        • Lange J.V.
        • Mitchell S.W.
        • McCormick J.B.
        • et al.
        Kinetic study of platelets and fibrinogen in Lassa virus-infected monkeys and early pathologic events in Mopeia virus-infected monkeys.
        Am J Trop Med Hyg. 1985; 34: 999-1007
        • Mammen E.F.
        Disseminated intravascular coagulation (DIC).
        Clin Lab Sci. 2000; 13: 239-245
        • Levi M.
        Current understanding of disseminated intravascular coagulation.
        Br J Haematol. 2004; 124: 567-576
        • Rippey J.J.
        • Schepers N.J.
        • Gear J.H.
        The pathology of Marburg virus disease.
        S Afr Med J. 1984; 66: 50-54
        • Isaacson M.
        • Sureua P.
        • Courtielle G.
        • et al.
        Clinical aspects of Ebola virus disease at the Ngaliema hospital, Kinshasa, Zaire, 1976.
        in: Pattyn S.R. Ebola Virus Haemorrhagic Fever. Elsevier/North-Holland Biomedical Press, New York1978: 15-20
        • Lee M.
        • Lee J.S.
        • Kim B.K.
        Disseminated intravascular coagulation in Korean hemorrhagic fever.
        Bibl Haematol. 1983; 49: 181-199
        • Nolte K.B.
        • Feddersen R.M.
        • Foucar K.
        • et al.
        Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent.
        Hum Pathol. 1995; 26: 110-120
        • Santos F.
        • Pereira L.C.
        • Paiva M.
        • et al.
        Coagulacao intravascular diseminada aguda na febre amarela: dosagem dos factores da coagulacao.
        Brasilia Med. 1973; 9: 9-16
        • Grignani G.
        • Maiolo A.
        Cytokines and hemostasis.
        Haematologica. 2000; 85: 967-972
        • Neumann F.-J.
        • Ott I.
        • Marx N.
        • et al.
        Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.
        Arterioscler Thromb Vasc Biol. 1997; 17: 3399-3405
        • Centers for Disease Control and Prevention
        • National Institutes of Health
        Biosafety in Microbiology and Biomedical Laboratories.
        Government Printing Office, Washington, DC1999 (Available at:) (also at) (. Accessed June 4, 2006)
        • van der Groen G.
        • Elliot L.H.
        Use of betapropiolactone inactivated Ebola, Marburg and Lassa intracellular antigens in immunofluorescent antibody assay.
        Ann Soc Belg Med Trop. 1982; 62: 49-54
        • Trappier S.G.
        • Contay A.L.
        • Farrar B.B.
        • et al.
        Evaluation for the polymerase chain reaction for diagnosis of Lassa virus infection.
        Am J Trop Med Hyg. 1993; 49: 214-221
        • Leroy E.M.
        • Baize S.
        • Lu C.Y.
        • et al.
        Diagnosis of Ebola hemorrhagic fever by RT-PCR in an epidemic setting.
        J Med Virol. 2000; 60: 463-467
        • Drosten C.
        • Gottig S.
        • Schilling S.
        • et al.
        Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR.
        J Clin Microbiol. 2002; 40: 2323-2330
        • Towner J.S.
        • Rollin P.E.
        • Bausch D.G.
        • et al.
        Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome.
        J Virol. 2004; 78: 4330-4341
        • Geisbert T.W.
        • Rhoderick J.B.
        • Jahrling P.B.
        Rapid identification of Ebola and related filoviruses in fluid specimens by indirect immunoelectron microscopy.
        J Clin Pathol. 1991; 44: 521-522
        • Geisbert T.W.
        • Jahrling P.B.
        Differentiation of filoviruses by electron microscopy.
        Virus Res. 1995; 39: 129-150
        • Zaki S.R.
        • Shieh W.J.
        • Greer P.W.
        • et al.
        A novel immunohistochemical assay for the detection of Ebola virus in skin: implications for diagnosis, spread, and surveillance of Ebola hemorrhagic fever. Commission de Lutte contre les Epidemies a Kikwit.
        J Infect Dis. 1999; 179: S36-S47
        • Schnittler H.J.
        • Feldmann H.
        Viral hemorrhagic fever–a vascular disease?.
        Thromb Haemost. 2003; 89: 967-972
        • Geisbert T.W.
        • Marty A.M.
        • Jahrling P.B.
        Viral Hemorrhagic Fevers.
        in: Roy M.J. Physician's Guide to Terrorist Attack. Humana Press, Totowa, NJ2004: 221-242
        • Geisbert T.W.
        • Jahrling P.B.
        Exotic emerging viral diseases: progress and challenges.
        Nat Med. 2004; 10: S110-S121

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        • Bausch D.G.
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        Viral hemorrhagic fevers including hantavirus pulmonary syndrome in the Americas.
        Clin Lab Med. 2002; 22: 981-1020
        • Bolken T.C.
        • Laquerre S.
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        • et al.
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        • Endy T.P.
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        • Enria D.A.
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        • Ergonul O.
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        • Feldmann H.
        • Jones S.
        • Klenk H.D.
        • Schnittler H.J.
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        Nat Rev Immunol. 2003; 3: 677-685
        • Feldmann H.
        • Wahl-Jensen V.
        • Jones S.M.
        • Stroher U.
        Ebola virus ecology: a continuing mystery.
        Trends Microbiol. 2004; 12: 433-437
        • Feldmann H.
        • Jones S.M.
        • Schnittler H.J.
        • Geisbert T.
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        Curr Opin Investig Drugs. 2005; 6: 823-830
        • Fisher-Hoch S.P.
        • McCormick J.B.
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        Expert Rev Vaccines. 2004; 3: 189-197
        • Flick R.
        • Bouloy M.
        Rift Valley fever virus.
        Curr Mol Med. 2005; 5: 827-834
        • Flick R.
        • Whitehouse C.A.
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        Curr Mol Med. 2005; 5: 753-760
        • Geisbert T.W.
        • Hensley L.E.
        Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions.
        Expert Rev Mol Med. 2004; 6: 1-24
        • Geisbert T.W.
        • Jahrling P.B.
        Towards a vaccine against Ebola virus.
        Expert Rev Vaccines. 2003; 2: 777-789
        • Grolla A.
        • Lucht A.
        • Dick D.
        • Strong J.E.
        • Feldmann H.
        Laboratory diagnosis of Ebola and Marburg hemorrhagic fever.
        Bull Soc Pathol Exot. 2005; 98: 205-209
        • Gunther S.
        • Lenz O.
        Lassa virus.
        Crit Rev Clin Lab Sci. 2004; 41: 339-390
        • Hartlieb B.
        • Weissenhorn W.
        Filovirus assembly and budding.
        Virology. 2006; 344: 64-70
        • Hensley L.E.
        • Jones S.M.
        • Feldmann H.
        • Jahrling P.B.
        • Geisbert T.W.
        Ebola and Marburg viruses: pathogenesis and development of countermeasures.
        Curr Mol Med. 2005; 5: 761-772
        • Hjelle B.
        Vaccines against hantaviruses.
        Expert Rev Vaccines. 2002; 1: 373-384
        • Hoenen T.
        • Groseth A.
        • Falzarano D.
        • Feldmann H.
        Ebola virus: unravelling pathogenesis to combat a deadly disease.
        Trends Mol Med. 2006; 12: 206-215
        • Jasenosky L.D.
        • Kawaoka Y.
        Filovirus budding.
        Virus Res. 2004; 106: 181-188
        • Khaiboullina S.F.
        • Morzunov S.P.
        • St Jeor S.C.
        Hantaviruses: molecular biology, evolution and pathogenesis.
        Curr Mol Med. 2005; 5: 773-790
        • Kunz S.
        • de la Torre J.C.
        Novel antiviral strategies to combat human Arenavirus infections.
        Curr Mol Med. 2005; 5: 735-751
        • Levi M.
        Disseminated intravascular coagulation: What's new?.
        Crit Care Clin. 2005; 21: 449-467
        • Maes P.
        • Clement J.
        • Gavrilovskaya I.
        • Van Ranst M.
        Hantaviruses: immunology, treatment, and prevention.
        Viral Immunol. 2004; 17: 481-497
        • Mahanty S.
        • Bray M.
        Pathogenesis of filoviral haemorrhagic fevers.
        Lancet Infect Dis. 2004; 4: 487-498
        • McCormick J.B.
        • Fisher-Hoch S.P.
        Lassa fever.
        Curr Top Microbiol Immunol. 2002; 262: 75-109
        • Palacios G.
        • Briese T.
        • Kapoor V.
        • et al.
        MassTag polymerase chain reaction for differential diagnosis of viral hemorrhagic fever.
        Emerg Infect Dis. 2006; 12: 692-695
        • Rothman A.L.
        Immunology and immunopathogenesis of dengue disease.
        Adv Virus Res. 2003; 60: 397-419
        • Ruf W.
        Emerging roles of tissue factor in viral hemorrhagic fever.
        Trends Immunol. 2004; 25: 461-464
        • Tomori O.
        Yellow fever: the recurring plague.
        Crit Rev Clin Lab Sci. 2004; 41: 391-427
        • Vieth S.
        • Drosten C.
        • Charrel R.
        • Feldmann H.
        • Gunther S.
        Establishment of conventional and fluorescence resonance energy transfer-based real-time PCR assays for detection of pathogenic New World arenaviruses.
        J Clin Virol. 2005; 32: 229-235
        • Warfield K.L.
        • Panchal R.G.
        • Aman M.J.
        • Bavari S.
        Antisense treatments for biothreat agents.
        Curr Opin Mol Ther. 2006; 8: 93-103