Viral Hemorrhagic Fever (VHF): Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis

Last updated March 25, 2009

Agents and Pathogenesis
Epidemiology
Hemorrhagic Fever Viruses as Biological Weapons
Clinical Characteristics and Differential Diagnosis
Laboratory Diagnosis
Treatment, Postexposure Prophylaxis, and Vaccines
Infection Control (Including Autopsies and Burial)
Public Health Reporting
References

Agents and Pathogenesis

Agents

Several different viruses can cause a hemorrhagic fever syndrome and hence are designated as hemorrhagic fever viruses.

• All possess single-stranded RNA (which requires reverse transcriptase for multiplication or amplification by polymerase chain reaction [PCR])
• All possess a lipid envelope

Hemorrhagic fever viruses belong to four taxonomic families:

• Filoviridae
• Arenaviridae
• Bunyaviridae
• Flaviviridae

Specific hemorrhagic fever viruses in each of the four families and key characteristics are included in the table below.

Characteristics of Hemorrhagic Fever Viruses
Familya	Agents	Characteristics
Filoviridaeb	—Ebola virus     ~Traditionally four species (Zaire, Sudan, Cote d'Ivoire, Reston) with varying degrees of antigenic cross-reactivity     ~A new species, most closely related to the Cote d'Ivoire species has been identifiedc     ~Subspecies further differentiated into named strains —Marburg virus     ~Two lineages, with less genetic diversity than Ebola virus     ~No serologic cross-reactivity with Ebola virus, which is classified in a separate genus	—Origin of family and genus names from Latin "filo" for "thread" —Filamentous virions, 80 nm in diameter with variable length (although basic length of replicative form for Ebola is 970 nm and for Marburg 790 nm) —Genome contains single-stranded nonsegmented RNA (negative sense) —Size: 19 kbp —Pleomorphic morphology may occur: branched, circular, "6" or "U"-shaped —50-nm nucleocapsid surrounded by spike-studded membrane —Transmembrane spike glycoprotein antigenically distinct for each species —In infected patients, Ebola virus produces large amounts of a secreted nonstructural glycoprotein with unknown function, encoded in 2 reading frames and joined during transcriptional editing as homodimerd —Reston species causes disease in monkeys, but only asymptomatic infection recognized in humans to date
Arenaviridaee	—Old World arenaviruses:     ~Lassa virus —New World arenaviruses that cause disease in humans:     ~Junin virus (Argentine hemorrhagic fever)     ~Machupo virus (Bolivian hemorrhagic fever)     ~Guanarito virus (Venezuelan hemorrhagic fever)     ~Sabia virus (Brazilian hemorrhagic fever)     ~Whitewater Arroyo virus (3 suspected cases in California, 1999-2000)	—Origin of family and genus names from Latin "arenosos" for "sandy" —Spherical or pleomorphic virions, generally 110-130 nm in diameter (may range from 50-300 nm) —Genome contains single-stranded RNA with 2 segments (both ambisense) —Size: 11 kbp —Viral particles contain host ribosomes, which appear as dense granules 20–25 nm in diameter and give viruses "sandy" appearance —Distinct club-shaped or spike projections on viral envelope composed of glycoproteins —Epitopes mediating antibody-complement cell lysis and neutralization localized on envelope glycoproteins —Lassa fever viruses exhibit 4 genetic lineages (3 in Nigeria and 1 in Guinea, Liberia, and Sierra Leone)f
Bunyaviridaeg	—Phlebovirus (includes Rift Valley fever virus) —Nairovirus (includes Crimean-Congo hemorrhagic fever virus) —Hantavirus (includes Sin Nombre virus [SNV] and agents that cause hemorrhagic fever with renal syndrome)	—Spherical to slightly pleomorphic virions, 80-120 nm in diameter —Genome contains single-stranded RNA with 3 segments (S, M, and L; all negative-sense) that code for no more than 6 proteins (including a nucleoprotein, 2 glycosylated proteins [G1 and G2], and a viral polymerase) —Size: 11-19 kpb —Genetic reassortment is facilitated by segmented genome and has been demonstrated to occur between genera —G1 and G2 proteins are hemagglutinins and targets for virus neutralization —Filamentous nucleocapsid, helical symmetry
Flaviviridaeh	—Yellow fever virus —Kyasanur Forest disease virus —Omsk hemorrhagic fever virus —Dengue virus (primary infection only rarely causes hemorrhagic fever) —Alkhumra virus (identified in Saudi Arabia in 1995 and 2001; similar to Kyasanur Forest disease virus)	—Origin of family name from Latin "flavus" for "yellow" (yellow fever virus) —Isometric virions, 40-50 nm in diameter —Single-stranded nonsegmented RNA (positive-sense) —Size: 10-12 kbp —Virions covered with surface projections composed of M (membrane) and E (envelope) glycoproteins —E glycoproteins involved in cell attachment, endosomal membrane fusion; serve as target for neutralizing antibody and hemagglutination
aSome of these viral families include pathogenic viruses that cause illnesses other than hemorrhagic fever; those agents are not included here. bSee References: Feldmann 1999; Jahrling 1999; NIH; Peters 2005: Marburg and Ebola virus hemorrhagic fevers; Marty 2006. cSee References: Towner 2008 dSee References: Sanchez 1996, Sanchez 1998, Sanchez 1999. eSee References: Jahrling 1999; NIH; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Marty 2006. fSee References: Bowen 2000. gSee References: NIH; Peters 2005: California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers; Gerrard 2004; Tsai 1999; Marty 2006. hSee References: Madani 2005, Tsai 2000, NIH, Marty 2006.

Pathogenesis

The pathogenesis of hemorrhagic fever viruses is not completely understood; however, key points include the following (see References: Peters 2002).

• Hemorrhagic fever viruses enter the bloodstream through various mechanisms (eg, the bite of a mosquito or tick, inhalation, mucous membrane exposure, parenteral exposure), and all (except hantaviruses) cause disease during the period of viremia.
• The infectious dose for hemorrhagic fever viruses appears to be low (1 to 10 organisms) (see References: Franz 1997).
• Endothelial infection occurs with most VHF viruses and may be limited or widespread, depending on the virus.
• Hemorrhagic manifestations occur as a result of thrombocytopenia or severe platelet dysfunction along with endothelial dysfunction.
• Increased vascular permeability is common and may result in periorbital edema and hemoconcentration. Vascular dysregulation also often occurs, manifested by flushing of the face and chest.
• Hemorrhagic fever viruses can cause necrosis and hemorrhage in most organs; however, hepatic involvement often is particularly prominent.
• Hantaviruses, New World arenaviruses, and Ebola, Marburg, and Lassa viruses cause cytokine activation. The relative lack of histologic lesions in fatal cases and the lack of immunopathology suggest that cytokines are the primary mediators of hemorrhagic fever in arenavirus infections and that they play a major role in the clinical features of filovirus infections as well (see References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Peters 2005: Marburg and Ebola virus hemorrhagic fevers).
• Ebola, Marburg, yellow fever, and Rift Valley fever viruses have a marked cytopathic effect (ie, are highly destructive to the cells they infect).
• Ebola and Lassa viruses also appear to infect monocyte-derived dendritic cells; dendritic cells exposed to these viruses do not up-regulate, fail to secrete pro-inflammatory or immunoregulatory cytokines, and do not effectively stimulate T cells (see References: Bosio 2003, Mahanty 2003). These changes delay an effective early host response.
• Ebola, Marburg, Rift Valley fever, and Crimean-Congo hemorrhagic fever viruses can cause disseminated intravascular coagulation (DIC); the other hemorrhagic fever viruses generally do not.
• Coagulation abnormalities noted with Ebola virus infection appear to be triggered by immune-mediated mechanisms rather than occurring as the result of direct cytolysis of endothelial cells (see References: Geisbert 2003).
• Suppression of the host antiviral response appears to play a critical role in pathogenesis of Ebola virus infection (see References: Ebihara 2006).

A model of the pathogenesis of Ebola virus based on observations of infection in cynomolgus monkeys is as follows (see References: Geisbert 2003):

• Ebola virus spreads from the initial site of infection via monocytes and dendritic cells to lymph nodes (likely via the lymphatics) and to the liver and spleen (via blood). At these sites, the virus infects tissue macrophages, dendritic cells, and fibroblastic reticular cells.
• A series of events then occur that lead to virus-induced immunosuppression and apoptosis of T lymphocytes. As the disease progresses, apoptosis of natural killer cells also occurs, which limits the innate immune response.
• Unchecked viral replication then leads to increased levels of additional proinflammatory cytokines, which trigger the coagulation cascade, ultimately leading to DIC.
• DIC then can result in hemorrhagic shock, multiple organ failure, and death.

Characteristic pathologic features of selected hemorrhagic fever viruses are shown in the table below.

Pathologic Features of Selected Hemorrhagic Fever Virusesa
Agent	Major Pathologic Features
Ebola virusb	—Extensive hepatocellular necrosis with intracytoplasmic viral inclusions —Necrosis involving parenchymal cells, macrophages, and endothelial cells in major organs —Follicular necrosis and necrotic debris in spleen and lymph nodes —Myocardial edema —Microvascular infection and injury
Marburg virusc	—Extensive hepatocellular necrosis with intracytoplasmic viral inclusions —Necrosis and hemorrhage in major organs —Follicular necrosis and necrotic debris in spleen and lymph nodes —Microvascular infection and injury
Lassa virusd	—Extensive reticuloendothelial involvement —Multifocal hepatocellular necrosis with Councilman-like bodies, cytoplasmic degeneration of hepatocytes, and minimal inflammatory response —Focal adrenal necrosis and adrenal cytoplasmic inclusions —Interstitial pneumonia
New World arenaviruses (Junin, Machupo, Guanarito, Sabia)e	—Multifocal hepatocellular necrosis with Councilman body formation, nuclear pyknosis, cytoplasmic eosinophilia, cytolysis, and mild inflammatory cell infiltrates composed of neutrophils and mononuclear cells —Small focal hemorrhages with minimal inflammatory response may occur in any organ —Extensive infection of mesothelial cells and macrophages lining serosal surfaces (may lead to serous effusions) —Interstitial or bronchial pneumonia with pulmonary edema and hemorrhage
Rift Valley fever virusf	—Widespread hepatocellular necrosis and hemorrhage with focal cytoplasmic degradation and formation of eosinophilic or dark bodies —Extensive infection of vascular endothelium —Encephalitis —Vasculitis —Retinitis with macular and perimacular hemorrhagic lesions —Generalized lymphoid depletion
Yellow fever virusg	—Midzonal hepatocellular necrosis —Lymphocytic necrosis in germinal centers of spleen and lymph nodes —Fatty degeneration of myocardial fibers —Widespread hemorrhages on mucosal surfaces and within major organs
Kyasanur Forest disease virush	—Focal hepatocellular degeneration, fatty infiltration, and necrosis —Hemorrhagic pneumonia —Myocarditis —Encephalitis
Omsk hemorrhagic fever virusi	—Scattered focal hemorrhages —Perivascular infiltration with thrombi in small vessels —Interstitial pneumonia
aOnly those agents considered to be potential biological weapons are included. bSee References: CDC: Filovirus infections among persons with occupational exposure to nonhuman primates or their tissues; Gubler 1998; Peters 1999; WHO 1985: Viral haemorrhagic fevers; Zaki 1997. cSee References: Gubler 1998; WHO 1985: Viral haemorrhagic fevers; Zaki 1997. dSee References: Gubler 1998; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. eSee References: Gubler 1998; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Salas 1991; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. fSee References: Al-Hazmi 2003; Gubler 1998; Peters 2002; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. gSee References: Gubler 1998; Tsai 2000; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. hSee References: Gubler 1998; Pavri 1989. iSee References: Gubler 1998.

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Epidemiology

Global Disease Occurrence

Overview

Most hemorrhagic fever viruses that cause disease in humans occur in relatively localized areas of the world (notably sub-Sarahan Africa and focal areas of South America). The major geographic location and general pattern of occurrence for each virus are included in the table below.

General Epidemiologic Features of Hemorrhagic Fever Viruses
Virus	Major Geographic Location for Human Disease	General Pattern of Disease Occurrence
Ebola virus	Sub-Saharan Africa	—First identified in 1976 —Outbreaks recognized with increasing frequency since mid-1990s —Relatively rare, despite recent increase in outbreak occurrence
Marburg virus	Sub-Saharan Africa	—First identified in 1967 —Only a few small outbreaks recognized until 1998, when large outbreak (lasting until 2000) occurred in DRC, and 2004-05, when largest outbreak to date occurred in Angola —Rare
Lassa virus	West Africa	—First identified in 1969 —Endemic in many West African countries —Relatively common
New World arenaviruses	South America (except Whitewater Arroyo virus, which has only been associated with illnesses in California)	—Five different viruses known to cause human disease —Only Junin virus has endemic focus (in rural areas of northeastern Argentina); others occur infrequently
Rift Valley fever virus	—Sub-Saharan Africa —Egypt —Saudi Arabia, Yemen	—First identified in animals in 1930 and in humans in 1975 —Relatively common in sub-Saharan Africa and Egypt (particularly in livestock)
Yellow fever virus	—Sub-Saharan Africa —Tropical regions of South America	—Has been recognized for centuries —Urban, sylvatic, and intermediate forms occur —Endemic in areas of Africa and South America —Relatively common
Kyasanur Forest disease virus	Karnataka State, India (west-central area of country)	—First identified in 1957 —Relatively uncommon
Omsk hemorrhagic fever virus	Central Asia	—First identified in 1940s —Several outbreaks reported in 1950s —Few cases in recent years
Abbreviation: DRC, Democratic Republic of the Congo.

Ebola hemorrhagic fever

Ebola hemorrhagic fever is an important emerging infection in central Africa and has received much attention in recent years owing to the documented high case-fatality rates (50% to 90%) associated with past outbreaks. Much is still unknown about Ebola virus transmission, natural reservoirs, disease pathogenesis, and treatment. A large outbreak occurred in 1995 and since then, outbreaks have been recognized with increasing frequency in central Africa.

Ebola virus was first recognized in 1976 when two outbreaks of VHF occurred in Africa during that year (one in southern Sudan and one in northwest Zaire [now the Democratic Republic of the Congo]) (see References: Peters 1999, Pourrut 2005, WHO 1978: Ebola hemorrhagic fever in Zaire). Recognized outbreaks related to African strains are outlined in the following table (see References: CDC 2008: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order).

Recognized Outbreaks of Ebola Hemorrhagic Fever Related to African Strainsa
Location	Year(s)	Strain	Cases, Deaths, CFR (%)
Sudan	1976	Ebola Sudan	284 cases, 153 deaths, CFR 53%
Zaire	1976	Ebola Zaire	318, 280, 88%
England	1976	Ebola Sudan	1 case (survived); laboratory infection
Zaire	1977	Ebola Zaire	1 case (died)
Sudan	1979	Ebola Sudan	34, 22, 65%
Cote d'Ivoire	1994	Ebola Ivory Coast	1 human case (survived) and an epidemic in wild chimpanzees
Gabon	1994-1995	Ebola Zaire	52, 31, 60%
Democratic Republic of the Congo (DRC)	1995	Ebola Zaire	315, 250, 81%
Gabon	1996	Ebola Zaire	37, 21 deaths, 57%
Gabon	1996-1997	Ebola Zaire	60, 45, 74%
South Africa	1990	Ebola Zaire	2, 1, 50%
Uganda	2000-2001	Ebola Sudan	425, 224, 53%
Gabon	2001-2002	Ebola Zaire	65, 53, 82%
Republic of Congo	2001-2002	Ebola Zaire	57, 43, 75%
Republic of Congo	2002-2003	Ebola Zaire	143, 128, 89%
Republic of Congo	2003	Ebola Zaire	35, 29, 83%
Southern Sudan	2004	Ebola Sudan	17, 7, 41%
Democratic Republic of the Congo	2007	Ebola Zaire	264, 187, 71%
Uganda	2007-2008	New Ebola strain (proposed name Bundibugyo ebolavirus) that is distantly related to the Cote d'Ivoire speciesb	149, 37, 25%
Kasai Occidental Province, DRCc	2008		32, 15, 47%
Abbreviation: CFR, case-fatality rate. aReferences: CDC 2008: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order. bReferences: Towner 2008. cReferences: WHO: End of Ebola outbreak in the Democratic Republic of the Congo.

Since the discovery of Ebola virus in 1976, a geographic pattern has emerged in which the Zaire strain affects predominantly central Africa, the Sudan strain affects east Africa, and the Ivory Coast strain affects west Africa (see References: Pourrut 2005). In some situations, human Ebola outbreaks have occurred in conjunction with deaths in animals species (including gorillas, chimpanzees, mandrills, and bush pigs) (see References: Lahm 2007; Vogel 2007). Characterization of Zaire isolates from wild ape carcasses implicated recombinant viruses from the apes as the cause of outbreaks among humans in 2003-2005 (see References: Wittmann 2007).

In addition to animal and human disease in Africa, several outbreaks of Ebola virus infection have been recognized in cynomolgus monkeys imported from the Philippines into the United States; the identified strain is referred to as Ebola Reston (see References: CDC 1990: Filovirus infections among persons with occupational exposure to nonhuman primates or their tissues; CDC 1990: Filovirus infection associated with contact with nonhuman primates or their tissues; CDC 1996: Ebola-Reston virus infection among quarantined nonhuman primates; Miranda 1999).

• The first outbreak occurred at a primate facility in Reston, Virginia; therefore, the strain associated with these outbreaks is called the Reston strain (see References: Peters 1991).
• Several persons working with infected primates have had serologic evidence of recent filovirus infection; however, no clinical illnesses associated with this strain have been reported in humans.
• More recently, the Ebola Reston strain has been isolated from pigs in the Phillipines, although the clinical significance of this finding is not yet well understood (see References: WHO: Ebola Reston found in domestic pigs in the Philippines). Several people in contact with infected pigs have tested positive for antibodies to the virus (see References: WHO 2009: Ebola Reston in pigs and humans in the Philippines).

Marburg hemorrhagic fever

Marburg hemorrhagic fever, like Ebola, is an emerging disease in sub-Saharan Africa, although Marburg appears to be less common and case-fatality rates may be somewhat lower than those for Ebola virus infection.

Marburg virus was first recognized in 1967 when outbreaks occurred simultaneously in laboratory workers in Marburg, Germany; Frankfort, Germany; and Belgrade, Yugoslavia (now Serbia) (see References: Martini 1971).

Since the initial outbreaks, several additional cases and outbreaks have been reported; all have occurred among persons living or traveling in rural southern and eastern Africa; recognized outbreaks are shown in the table below (see References: CDC 2007: Known cases and outbreaks of Marburg hemorrhagic fever, in chronological order).

Recognized Outbreaks of Marburg Hemorrhagic Fevera
Location	Year(s)	Cases	Comments
Frankfort, Germany, and Belgrade, Yugoslavia	1967	31	—Cases occurred in laboratory workers who had been exposed to African green monkeys or their tissues; the monkeys originally were from Uganda —Several family members and healthcare workers who were exposed to primary cases also became ill —7 deaths occurred (CFR 21%)
South Africa	1975	3	1 index case and 2 secondary cases occurred; the index patient had been traveling extensively in Zimbabwe before illness onset. 1 death (CFR 33%)
Western Kenya	1980	2	1 index case and a secondary infection in a healthcare worker; 1 death occurred (CFR 50%)
Kenya	1987	1	A single case occurred in a man who had been traveling extensively in Kenya (he died)
Democratic Republic of the Congo	1998-2000	154	—Most cases occurred in young male miners who worked in an underground mine —128 cases died (CFR 83%) —Studies of bats from the mine revealed that 1 species of fruit bat and 2 species of insectivorous bats harbored antibodies to Marburg virus (although viral presence was not found); these findings suggest that bats in the mine may have served as reservoir hosts for the outbreak (see References: Swanepoel 2007)
Angola (predominantly in the northern Uige Province)	2004-2005	252	227 of the cases died (CFR 90%)
Uganda	2007	2	Both cases were young males who worked in a mine; both died (CFR 100%)
Abbreviation: CFR, case-fatality rate. aCDC 2007: Known cases and outbreaks of Marburg Hemorrhagic Fever, in chronolgocial order

Lassa fever

Lassa fever is a disease that has become endemic in West Africa over the past 30 years. Rodents are the primary reservoir for Lassa virus, and the disease has a seasonal pattern. Case-fatality rates are somewhat lower for Lassa fever than for Ebola and Marburg infections, although they can be as high as 15% to 25% among hospitalized patients. Ribavirin therapy has been shown to be efficacious in treating some cases.

• Lassa fever was first recognized in 1969 in northern Nigeria, when a small outbreak occurred among several nurses working in a rural missionary hospital.

• Subsequent outbreaks have been recognized in Nigeria, Sierra Leone, and Liberia, and the disease is endemic in areas of West Africa.
• Although infections can occur year-round, the incidence of disease is highest during the dry season (see References: LeDuc 1989). This finding may be related to aggregation of rodents inside houses during the dry season because of limited food supplies outdoors (see References Fichet-Calvet 2007).

• An estimated 100,000 to 300,000 Lassa fever virus infections occur annually in West Africa (see References: McCormick 1987: A prospective study of the epidemiology and ecology of Lassa fever).

• Occasionally, cases are imported from Africa into other countries (see References: Isaacson 2001, Macher 2006). As of 2004, 24 patients with imported Lassa fever had been identified worldwide, with cases occurring in Europe, the United States, Canada, Israel, and Japan.
• An investigation into a case of imported Lassa fever in Germany demonstrated that the risk of transmission following exposure to the index case was low. Thirty persons were identified who had high-risk contact with the index case and serologic evidence of infection developed in only one of them. This secondary case was a physician who cared for the patient on day 9 of her illness; the physician received ribavirin and remained asymptomatic (see References: Haas 2003). Similarly, investigation of a case of imported Lassa fever in New Jersey did not identify transmission of the virus to five high-risk contacts (all family members) (see References: CDC 2004: Imported Lassa fever—New Jersey).

New World hemorrhagic fever

New World hemorrhagic fever is caused by several different arenaviruses. Most cases have occurred in regional areas of South America, although Whitewater Arroyo virus was identified in recent years as a cause of VHF in California. These viruses appear to be transmitted via contact with rodents or rodent excreta. New World hemorrhagic fever is relatively uncommon and for some viruses (eg, Sabia and Whitewater Arroyo virus); only a handful of cases have been recognized to date.

New World arenaviruses that cause disease in humans include the following (see References: Charrel 2003):

• Junin virus (Argentine hemorrhagic fever)
• It was first recognized in 1955.
• The disease was initially localized to rural populations in the northwestern region of Buenos Aires province.
• In the 1980s, infection became endemic in several provinces of Argentina (eg, Buenos Aires, Santa Fe, Cordoba, La Pampa) (see References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984). These provinces are all located in the northeastern part of the country and are contiguous to each other.
• Between 100 and 4,000 cases are reported annually; however, in 1993, 24,000 cases were reported (see References: Lacy 1996).
• Disease occurrence is seasonal and peaks during the months March through June (corresponding to the corn harvest season).
• Machupo virus (Bolivian hemorrhagic fever)
• The disease was first described in 1959 and the etiologic agent was identified in 1965.
• Between 1959 and 1962, 470 cases resulting in 142 deaths were reported (see References: CDC 1994: Bolivian hemorrhagic fever—El Beni Department, Bolivia).
• No outbreaks were recognized between 1971 and 1994. In the summer of 1994 an outbreak involving 10 people occurred in northeastern Bolivia (see References: CDC 1994: Bolivian hemorrhagic fever—El Beni Department, Bolivia).
• Guanarito virus (Venezuelan hemorrhagic fever)
• It was first recognized in 1989 when an outbreak involving more than 100 cases occurred in the Portuguesa state of central Venezuela (see References: Salas 1991).
• Sabia virus (Brazilian hemorrhagic fever)
• The disease was first recognized in Brazil in 1990 when a single fatal case occurred (see References: Lisieux 1994).
• Two additional infections have been identified; both were laboratory-acquired (one in Brazil and one in the United States) (see References: Armstrong 1999, Barry 1995, Lisieux 1994).
• Chapare virus
• A newly discovered arenavirus, Chapare, is responsible for some cases of viral hemorrhagic fever in Bolivia that have occurred outside the epidemic area for Machupo virus.
• Genomic analysis of viruses from patients revealed that Chapare virus is most closely related to Sabia virus. The virus should be considered as an etiologic agent for VHF cases in Bolivia (see References: Delgado 2008).
• Whitewater Arroyo virus
• Three cases were reported from California between June 1999 and May 2000 (see References: CDC 2000: Fatal illnesses associated with a New World arenavirus); two patients lived in southern California and one lived in the San Francisco Bay area.
• All three cases were fatal.
• These case reports suggest that Whitewater Arroyo virus can cause VHF in humans; however, documentation of additional cases would support these initial findings.

Rift Valley fever

Rift Valley fever is a mosquitoborne disease primarily found in sub-Saharan and North Africa. The disease, which affects livestock (eg, cattle, sheep) and humans, was first recognized in animals in 1930 in Kenya (see References: Daubney 1931). Epizootics in animals characteristically involve high rates of prenatal mortality and spontaneous abortions. Human illnesses generally are mild, although severe forms of disease (eg, VHF, meningoencephalitis) occur in about 1% of cases, and retinitis can occur in up to 10% of cases.

• Outbreaks of Rift Valley fever most often occur after heavy rainfalls flood natural depressions; the flooding allows extensive hatching of the primary mosquito vector (see References: LeDuc 1989; Anyamba 2006).

• Infections in ruminants can amplify the viral burden in an area, and seasonal movement of ruminants may enhance spread of Rift Valley Fever virus to previously uninfected areas (see References: Chevalier 2005).
• Analysis of an outbreak in 2003 revealed that east-central African strains were present in West Africa and may have flourished because of increased rainfall (see References: Faye 2007).

• A major epidemic involving thousands of livestock cases and 18,000 human cases with approximately 600 deaths occurred in Egypt in 1977 (see References: Meegan 1979). Additional outbreaks in Egypt have been reported (probably representing repeated introductions of the virus).
• Another large outbreak involving thousands of cases occurred in Somalia and Kenya in 1997 and 1998 (see References: Woods 2002). More recently, an outbreak occurred in Kenya, beginning in November 2006 and involving nearly 700 reported cases, including more than 150 deaths. The outbreak peaked in late December 2006, with cases tapering from January to mid-March 2007. Analysis of specimens from animals indicated that multiple viral lineages were responsible for the outbreak (see References: Bird 2008).
• Smaller outbreaks involving a few cases occurred in 2006 and 2007 in Somalia and Tanzania (see References: CDC 2007: Rift Valley fever outbreak—Kenya, November 2006–January 2007; WHO 2007: Outbreaks of Rift Valley fever).
• Until 2000, the disease had been identified only in sub-Saharan and North Africa. However, in the fall of 2000, outbreaks occurred simultaneously in Yemen and Saudi Arabia, thought to have been introduced from Africa through the sheep trade (see References: CDC 2000: Outbreak of Rift Valley fever—Yemen; CDC 2000: Outbreak of Rift Valley fever—Saudi Arabia; Shoemaker 2002). More than 1,000 cases occurred in Yemen, and 886 cases were identified in Saudi Arabia (see References: Madani 2003).
• The Rift Valley Fever Working Group in the United States has developed a research agenda and response plan to address possible introduction of the virus into the United States, as was seen with West Nile virus in 1999 (see References: Britch 2007). Pathway analyses have identified ways in which Rift Valley fever might be introduced into the United States. Such information can help in developing an effective targeted surveillance plan for rapid detection and response. Possible mechanisms of introduction include importation of infected animals, entry of Rift Valley fever–infected people, mechanical transport of insect vectors, and smuggling of live virus (see References: Kasari 2008).

Yellow fever

Outbreaks of yellow fever were first recognized in the 1600s, and the disease is now endemic in sub-Saharan Africa (between 15°N and 10°S latitude) and in tropical regions of South America. The vectors for yellow fever virus include several mosquito species. Illness can range from mild to severe, with an overall case-fatality rate of 5% to 7%. A vaccine against yellow fever is available.

• Three cycles have been recognized (see References: WHO 2001: Yellow fever):
• A sylvatic or jungle cycle that primarily involves transmission between mosquitoes and nonhuman primates, with humans as incidental hosts.
• An urban cycle that involves transmission between mosquitoes and humans in urban areas. The most important mosquito vector is Aedes aegypti. Urban outbreaks can involve hundreds (or even thousands) of people and pose a substantial public health threat.
• An intermediate cycle that is found in villages in humid and semi-humid savannahs of Africa, where small epidemics occur. This form involves semi-domestic mosquitoes that can infect both humans and nonhuman primates.
• In South America, most sylvatic yellow fever cases involve workers who spend time in the forested areas of Bolivia, Brazil, Ecuador, Colombia, and Peru.
• No outbreaks of urban yellow fever have been documented in the Americas since 1942 owing to public health programs aimed at eliminating the mosquito vector; however, reinfestation of urban areas with A aegypti mosquitoes has raised concern about the re-emergence of urban yellow fever.
• In Africa, sylvatic and occasional urban outbreaks occur. Outbreaks occur in West, Central, and East Africa, with the largest number of outbreaks reported in West Africa. A relatively large outbreak occurred in southern Sudan in 2003 (see References: Onyango 2004).
• Yellow fever is occasionally exported to Europe or North America (most often because of failure to vaccinate travelers to endemic areas).
• The WHO estimates that 200,000 cases and 30,000 deaths occur each year, although most cases are not reported (see References: WHO 2001: Yellow fever).
• Since 2005, outbreaks of yellow fever have been reported in several African countries as well as South America.
• Paraguay vaccinated more than 1.27 million people in 2008 in response to a yellow fever outbreak (see References: WHO: Yellow fever in Paraguay—update 2).
• Urban cases provoked additional vaccination campaigns in African countries in late 2008. Two laboratory-confirmed cases in Burkina Faso prompted a vaccination campaign targeting more than 350,000 in the Ouahigouya health district (see References: WHO 2008: Yellow fever in Burkina Faso), and a laboratory-confirmed case and four other patients who had fever or jaundice prompted a decision to vaccinate more than 180,000 people in the Central African Republic (see References: WHO 2008: Yellow fever in the Central African Republic).

Kyasanur forest disease

Kyasanur forest disease (KFD), which is a tick-borne infection, is relatively rare and found only in one region in the southwestern part of India (see References: Gritsun 2003, Pattnaik 2006). The major clinical manifestations are VHF or meningoencephalitis and the case-fatality rate is 3% to 5%. Key features of the virus or the disease are: (see References: CDC: Kyasanur forest disease: fact sheet)

• KFD virus was first recognized in 1957 when it was isolated from a sick monkey from the Kyasanur forest in Karnataka State, India.
• Rodents, monkeys, bats, and other small mammals are the natural reservoirs. Larger animals (such as goats, cows, and sheep) may become infected, but they don’t have a role in transmission of the disease.
• Natural infections have been identified only in several districts of Karnataka State, India (located in the southwestern region of the country).
• Outbreaks occur periodically and are usually signaled by epizootics in the local monkey population.
• A seasonal pattern has been noted, with most of the cases occurring in the spring months.

Omsk hemorrhagic fever virus

Omsk hemorrhagic fever (OHF) also is a rare form of tick-borne VHF and is limited to regions of Central Asia (see References: Gritsun 2003). Few cases have been recognized in recent years, and limited information is available about the current epidemiology. Key features of the virus or the disease are: (see References: CDC: Omsk hemorrhagic fever: fact sheet)

• The disease was first recognized in the early 1940s in Omsk, Russia.
• Most reported illnesses occurred in the 1940s and 1950s, although a series of outbreaks also occurred between 1988 and 1997.
• OHF occurs in the western Siberia regions of Omsk, Novosibirsk, Kurgan, and Tyumen.
• Muskrats and water voles appear to be the main animal reservoirs.
• Although illness is acquired predominantly through the bite of an infected tick, exposure to muskrats (eg, through skinning or contact with blood, feces, or urine of an infected animal) also has been shown to be a mode of transmission.
• OHF virus can be transmitted through the milk of infected goats or sheep and has been isolated from aquatic animals and water, suggesting that the virus is relatively stable in the environment.
• Two relatively large outbreaks have been identified: one in 1945 (involving at least 200 cases) and one in 1946 (involving about 600 cases) (see References: WHO 1985: Viral hemorrhagic fevers: report of a WHO expert committee).

Reservoirs/Vectors/Modes of Transmission

The modes of transmission and reservoirs vary somewhat by agent; these features are outlined in the following table.

For those viruses that are transmitted person-to-person, the period of communicability apparently begins after onset of symptoms. Transmission during the incubation period has not been demonstrated. In one instance, transmission may have occurred from an infected patient several hours before actual onset of symptoms (see References: WHO 1978: Ebola haemorrhagic fever in Zaire), but later systematic studies of the same disease demonstrated that the greatest risk for transmission is late in the clinical course (see References: Dowell 1999).

Risk of transmission from fomites in an isolation ward and from convalescent patients is low when healthcare workers follow recommended infection control guidelines for viral hemorrhagic fevers (see References: Bausch 2007: Assessment of risk).

For both filoviral and arenaviral infections, virus may persist in urine and seminal fluids for several months; therefore, patients infected with these agents should refrain from sexual activity for 3 months after clinical recovery (see References: Borio 2002).

Reservoirs and Modes of Transmission for Selected Hemorrhagic Fever Virusesa
Agent	Reservoir	Arthropod Vector	Modes of Transmission
Ebola virusb,c	Unknown (although asymptomatic infection has been  found in several species of fruit bats)	Unknown	—Person-to-person (most likely through contact with blood or body fluids) —Percutaneous through reuse of needles or accidental needlesticks —Contact with cadavers during preparation for burial —Direct contact with infected nonhuman primates (eg, chimpanzees, gorillas) —Possibly airborne through virus-containing aerosols (experimentally induced in monkeys) —Contact with oral mucosa or conjunctivae through infectious droplets or direct contact (experimentally induced in monkeys; one healthcare worker may have become infected by touching eyes with contaminated glove) —Sexual transmission (virus has been found in semen)
Marburg virusb,d	Unknown	Unknown	—Contact with blood, tissues, or tissue cultures from infected monkeys —Person-to-person (most likely through contact with blood or body fluids) —Percutaneous through accidental needlesticks —Sexual transmission (virus has been found in semen) —Contact with oral mucosa through infectious droplets, infectious aerosols, or direct contact (experimentally induced in monkeys)
Lassa virusb,e	Mastomys species (multimammate mice)	None	—Predominantly airborne through virus-containing aerosols of rodent excreta —Person-to-person (eg, contact with blood or body fluids) —Percutaneous through accidental needlesticks or reuse of injection equipment —Possibly person-to-person airborne (in at least one instance, transmission may have occurred in hospital setting from patient with extensive pulmonary involvement) —Sexual transmission (virus has been found in semen)
New World arenaviruses
Juninb	Calomys musculinus (drylands vesper mouse)	None	Predominantly airborne through virus-containing aerosols of rodent excreta
Machupof	Calomys callosus (large vesper mouse)	None	—Predominantly airborne through virus-containing aerosols of rodent excreta —Person-to-person transmission (as demonstrated in a limited number of nosocomial outbreaks)
Guanaritog	Zygodontomys brevicauda (cane mouse)	None	Unknown, but presumably through aerosolized rodent excreta
Sabiah	Not known; presumably a rodent	None	Unknown, although laboratory-acquired cases appear to have been contracted through aerosols
Chapare	Not known, presumably a rodent	Unknown	Unknown
Whitewater     Arroyo  virusi	Neotoma species (woodrats)	None	Unknown, but presumably airborne through aerosolized rodent excreta
Rift Valley fever virusb	Ruminants (eg, cattle, sheep), rats in some areas (eg, Egypt)	Aedes mosquitoes	—Bite of infected mosquito —Contact with blood or amniotic fluid of infected animals (through fomites, droplets, or aerosols) —Airborne through virus-containing aerosols in the laboratory setting
Yellow fever virusb	Primates	Predominantly Aedes and Haemagogus mosquito species; Aedes aegypti is most important vector for urban yellow fever	—Bite of infected mosquito —Laboratory infections through parenteral exposure or unexplained routes (presumably aerosols)
Kyasanur Forest disease virusb,j	Rodents, bats, and other small mammals; monkeys (eg, black-faced langur, South Indian bonnet macaque) appear to be amplifying hosts	Ticks (Haemaphysalis spinigera)	—Bite of infected tick —Airborne through virus-containing aerosols in laboratory setting
Omsk hemorrhagic fever virusb	Rodents (including muskrats and voles)	Ticks (Dermacentor pictus, Dermacentor reticulatus)	—Bite of infected tick —Possibly through direct contact with carcasses of infected animals (eg, muskrats) —Waterborne and airborne transmission may occur, but direct evidence lacking
aOnly agents that are considered to be potential biological weapons are considered here. bSee References: Borio 2002; LeDuc 1989; Leroy 2005; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee; Youssef 2002. cSee References: Dowell 1999; Formenty 1999; Guimard 1999; Jaax 1995; Jaax 1996; Johnson 1995; WHO 1978: Ebola hemorrhagic fever in Zaire. dSee References: Martini 1971. eSee References: Carey 1972; Fisher-Hoch 1995; McCormick 1987; WHO 2001: Lassa hemorrhagic fever. fSee References: CDC 1974: Bolivian hemorrhagic feve; Peters 1974. gSee References: Salas 1991. hSee References: Armstrong 1999. iSee References: CDC 2000: Fatal illnesses associated with a New World arenavirus. jSee References: Banerjee 1979.

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Hemorrhagic Fever Viruses as Biological Weapons

Animal studies using nonhuman primates have demonstrated that clinical infection can be caused by aerosolized preparations of some hemorrhagic fever viruses, including Ebola, Marburg, Lassa, and yellow fever viruses as well as New World arenaviruses (see References: Johnson 1995, Kenyon 1992, Stephenson 1984). Additional viruses (Rift Valley fever virus and flaviviruses) have been shown to cause aerosol infections in the laboratory setting (see References: Banerjee 1979, Smithburn 1949). These viruses are considered potentially suitable as biological weapons (see References: Borio 2002, Bray 2003) because:

• They can be disseminated through aerosols.
• They have a low infectious dose.
• They cause high morbidity and mortality.
• They cause fear and panic in the general public.
• Effective vaccines are not available or supplies are limited.
• These pathogens are available and most can be readily produced in large quantities.
• Research on weaponizing various hemorrhagic fever viruses has been conducted in the past despite the lack of treatment options or protective vaccines.

Examples of countries that have either weaponized hemorrhagic fever viruses or conducted biological weapons research on these viruses include the following (see References: MIIS):

• The Soviet Union produced weaponized Marburg virus and conducted research on Ebola, Lassa, Rift Valley fever, and yellow fever viruses and New World arenaviruses.
• The United States conducted biological weapons research on Lassa, Rift Valley fever, and yellow fever viruses and New World arenaviruses.
• North Korea may have weaponized yellow fever virus.

In 2000, CDC published a list of Category A agents (ie, those that are most likely to cause mass casualties if deliberately disseminated, can be released as small aerosols, and require broad-based public health preparedness). The list included New World arenaviruses and Ebola, Marburg, and Lassa viruses (see References: CDC 2000: Biological and chemical terrorism).

According to the Working Group on Civilian Biodefense, hemorrhagic fever viruses that pose serious threats as potential biological weapons include the following (see References: Borio 2002):

• Ebola virus
• Marburg virus
• Lassa virus
• New World arenaviruses
• Machupo (Bolivian hemorrhagic fever)
• Junin (Argentine hemorrhagic fever)
• Guanarito (Venezuelan hemorrhagic fever)
• Sabia (Brazilian hemorrhagic fever)
• Rift Valley fever virus
• Yellow fever virus
• Kyasanur Forest disease virus
• Omsk hemorrhagic fever virus

The Working Group determined that several important hemorrhagic fever viruses are less likely than those mentioned above to be used as biological weapons. These agents are not discussed further in this document; they include:

• Dengue virus (is not transmissible by small-particle aerosol, requires mosquito-vector transmission, and primary dengue infection only rarely causes hemorrhagic fever)
• Crimean-Congo hemorrhagic fever virus (does not replicate to high concentrations in currently available systems [a barrier to mass production])
• Hantaviruses (do not replicate to high concentrations in currently available systems)

In addition to the three agents mentioned above, a new flavivirus has been described in Saudi Arabia, referred to as Alkhumra virus (see References: Madani 2005).This virus, which was isolated initially in 1995 and again in 2001, appears to be similar to Kyasanur Forest disease virus. Because Alkhumra virus is not considered a potential bioterrorism agent at this time, it is not addressed further in this document.

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Clinical Characteristics and Differential Diagnosis

Clinical Characteristics

Although clinical features vary somewhat for the various hemorrhagic fever viruses, the clinical presentations overlap substantially. All of the agents cause a febrile prodrome associated with varying degrees of prostration; other notable features include the following.

• Bleeding manifestations occur in variable proportions of patients (eg, in about 30% of patients with Ebola or Marburg hemorrhagic fever and in only about 1% of patients with Rift Valley fever).
• A maculopapular rash may be noted early in the clinical course in some forms of VHF (notably in Ebola and Marburg hemorrhagic fevers).
• Severe exudative pharyngitis is a characteristic early feature of Lassa fever.
• Several agents cause meningoencephalitis in addition to VHF (eg, Rift Valley fever, Kyasanur Forest disease, Omsk hemorrhagic fever).
• Jaundice may be a prominent feature in some infections (eg, Ebola and Marburg hemorrhagic fevers, Lassa fever, Rift Valley fever, yellow fever).

Major clinical features for each of the agents are included in the tables below.

Clinical Features of Ebola Hemorrhagic Fever
Characteristic	Features
Incubation period	2-21 days
Prodromea	—Abrupt onset of fever, severe prostration, headache, myalgias is typical —Other features may include abdominal pain, nausea/vomiting, diarrhea, chest pain, cough, pharyngitis, lymphadenopathy, photophobia, and conjunctival injection
Clinical signs/symptomsb	—Maculopapular rash (predominantly on trunk) occurs about 5 days after illness onset —Jaundice and pancreatitis often occur —As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses, oozing of blood at puncture sites) —In 1995 DRC outbreak, some form of bleeding was reported in 37% of 219 patients —CNS findings include psychosis, delirium, coma, seizures —Shock (with DIC and end-organ failure) often ensues during second week of illness —Signs and symptoms recorded for 219 patients in 1995 DRC outbreak (recorded at time of admission or during clinical course) included:     ~Asthenia (78%)     ~Diarrhea (74%)     ~Headache (73%)     ~Anorexia (73%)     ~Nausea/vomiting (70%)     ~Abdominal pain (56%)     ~Myalgias/arthralgias (51%)     ~Dysphagia (41%)     ~Conjunctival inflammation/hemorrhage (34%)     ~Dyspnea (25%)     ~Gingival hemorrhage (21%)     ~Petechiae (15%)     ~Melena (14%)     ~Hiccups (14%)     ~Hematemesis (13%) —Asymptomatic infections can occur —Recovery may take up to several weeks
Laboratory featuresc	—Leukopenia early in clinical course; leukocytosis (may occur later) —Thrombocytopenia early in clinical course —Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses —Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen
Complicationsd (generally occur at least 2 wk after illness onset)	—Migratory arthralgias —Ocular disease (unilateral vision loss, uveitis) —Suppurative parotitis —Orchitis —Hearing loss —Pericarditis —Illness-induced abortion among pregnant women
Case-fatality ratee	—Varies by virus subtype:     ~Zaire, 57%-90%     ~Sudan, about 50%     ~Cote d'Ivoire, not established     ~Reston, 0% (not known to cause clinical disease in humans) —In 1995 DRC outbreak: mean number of days from symptom onset to death, 9.6 days (range, 0-34 days)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; DIC, disseminated intravascular coagulation; DRC, Democratic Republic of the Congo. aSee References: Borio 2002; Peters 2005: Marburg and Ebola Virus Hemorrhagic Fevers. bSee References: Borio 2002; Bwaka 1999; Khan 1999; Leroy 2000: Human asymptomatic Ebola infection; Peters 2005: Marburg and Ebola virus hemorrhagic fevers. cSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. dSee References: Bwaka 1999, Kibadi 1999. eSee References: Kahn 1999; WHO 2007: Ebola hemorrhagic fever; Zaki 1997.

Clinical Features of Marburg Hemorrhagic Fever
Characteristic	Features
Incubation period	2-14 days
Prodromea	—Abrupt onset of fever, severe prostration, headache, myalgias is typical. —Other features may include abdominal pain, nausea/vomiting, diarrhea, chest pain, cough, pharyngitis, lymphadenopathy, photophobia, and conjunctival injection. —The following may also occur: enanthem on soft palate, hyperesthesias, and "clouded consciousness."
Clinical signs/symptomsa	—Maculopapular rash occurs on the 5th to 7th day (trunk, face, neck, proximal regions of extremities) and is nonpruritic. —Jaundice and pancreatitis usually occur. —As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, melena, bleeding from gums, petechiae, ecchymoses, hematuria). —In one report of 23 patients, bleeding manifestations occurred in 7 (30%). —CNS findings include restlessness, confusion, apathy, somnolence, meningismus. —Shock (with DIC and end-organ failure) may ensue during 2nd week of illness —Recovery may take up to several weeks.
Laboratory featuresb	—Leukopenia early in clinical course (1,000-2,000/mm3); leukocytosis (may occur later) —Atypical lymphocytes (may be present) —Marked thrombocytopenia early in clinical course (may be as low as 10,000/mm3) —Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses —Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen
Complicationsa (generally occur at least 2 wk after illness onset)	—Orchitis —Alopecia —Uveitis —Recurrent hepatitis
Case-fatality rateb	Varies by outbreak (23%-93%)
Abbreviations: ALT, alanine aminotransferase; CNS, central nervous system; AST, aspartate aminotransferase; DIC, disseminated intravascular coagulation. aSee References: Gear 1975; Martini 1971; Peters 2005: Marburg and Ebola virus hemorrhagic fevers. bSee References: Martini 1971; WHO: Marburg haemorrhagic fever: situation updates.

Clinical Features of Lassa Fever
Characteristic	Features
Incubation period	5-16 days
Prodromea	—Illness begins gradually with fever, weakness, generalized malaise. —Arthralgias, back pain, nonproductive cough, retrosternal pain often appear by 3rd to 4th day.
Clinical signs/symptomsa	—Severe exudative pharyngitis may occur (40% in one series of 306 patients).b —Macolopapular rash may be noted on some fair-skinned patients. —Severe prostration may occur by 6th to 8th day. —As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses). —In one outbreak in Sierra Leone, bleeding manifestations occurred in 17% of 306 patients.b —Other findings that may occur include:     ~Edema of head and neck     ~Pleural, pericardial effusions     ~Neurologic involvement (encephalopathy, coma, meningeal signs, cerebellar syndromes, tremors, seizures, eighth cranial nerve involvement)     ~Capillary leak syndrome     ~Shock with end-organ failure —For those with less severe disease, recovery begins at about 10 days, although weakness and fatigue may persist for several weeks. —Most infections are thought to be mild or subclinical; severe disease occurs in 5%-10% of cases.
Laboratory featuresb	—Leukocyte counts: occasionally decreased but most often normal or moderately increased —Hemoconcentration, proteinuria, and elevated hepatic enzymes( may occur) —Thrombocytopenia mild or does not occur (although marked loss of platelet function has been demonstrated in vitro) —Mean laboratory values at time of admission (and highest recorded) for 441 patients with Lassa fever in Sierra Leone:     ~ALT: 96.5 U/L (147.1 U/L)     ~Amylase: 259.1 U/L (381.6 U/L)     ~AST: 408.2 U/L (602 U/L)     ~BUN: 27.8 mg/dL (34.5 mg/dL)     ~CPK: 515.7 U/L (893 U/L)     ~Hematocrit: 50.6% (50.6%)     ~Hemoglobin: 10.7 g/dL (14.9 g/dL)     ~WBC count: 5,976/mm3 (4,603/mm3)
Complicationsc (generally occur in 2nd and 3rd wk of illness)	—8th cranial nerve damage with hearing loss (may improve or may result in permanent hearing loss) —Pericarditis (about 2% of patients in one series, all male, all recovered)b —Transient alopecia during convalescence —Illness-induced abortion among pregnant women —Uveitis and orchitis (uncommon)
Case-fatality rate	—Overall mortality (including nonhospitalized patients), 1%-2%.d —Hospitalized patients, 15%-25%e —Series of 150 hospitalized patients, 9%f —Series of 441 hospitalized patients, 16.5%b
Abbreviations: ALT, alanine aminotransferase; AST: aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase; WBC, white blood cell. aSee References: Borio 2002; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. bSee References: McCormick 1987: A case-control study. cSee References: McCormick 1987: A case-control study; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. dSee References: McCormick 1987: A prospective study. eSee References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. fSee References: Frame 1989.

Clinical Features of New World Hemorrhagic Fever
Characteristic	Features
Incubation period	7-16 days
Prodrome	Gradual onset of fever, sore throat, myalgias, low back pain, abdominal pain
Clinical signs/symptomsa	—Common early findings include:     ~Conjunctival injection     ~Flushing of face, upper body     ~Enanthem (petechiae and/or small vesicles)     ~Skin petechiae     ~Generalized lymphadenopathy —As disease progresses, vascular or neurologic manifestations may occur (5-7 days after illness onset). —Vascular manifestations include:     ~Capillary leak syndrome     ~Proteinuria     ~Bleeding manifestations (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses)     ~In one series of 14 patients with Venezuelan hemorrhagic fever, bleeding manifestations in 13 (92%)     ~Vasoconstriction, shock —Neurologic manifestations include:     ~Tremors     ~Myoclonic movements     ~Seizures     ~Dysarthria     ~Coma —Clinical findings on admission for 14 patients with Venezuelan hemorrhagic fever includedb:     ~Dehydration (71%)     ~Pharyngitis (71%)     ~Somnolence (64%)     ~Conjunctivitis (50%)     ~Crackles (43%)     ~Petechiae (29%)     ~Cervical adenopathy (21%)     ~Facial edema (14%)     ~Tonsillar exudates (14%)     ~Hand tremors (7%)     ~Rash (7%) —Recovery occurs over 2-3 wk.
Laboratory featuresc	—Leukopenia (1,000-2,500/mm3) —Thrombocytopenia (40,000-80,000/mm3) —Proteinuria (may be >10 g/day; occurs occasionally) —Hemoconcentration
Complicationsd	—Transient alopecia and nail furrows may occur. —Most patients who survive recover without sequelae, although convalescence may require several weeks.
Case-fatality ratee	—Junin (Argentine hemorrhagic fever), 15%-30% —Machupo (Bolivian hemorrhagic fever), 30% —Guanarito (Venezuelan hemorrhagic fever),: 25% —Sabia (Brazilian hemorrhagic fever), 33% (only 3 cases identified, 1 fatal) —Whitewater Arroyo, 100% only 3 cases identified; all fatal)
aSee References: Borio 2002; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. bSee References: Salas 1991. cSee References: WHO1985: Viral haemorrhagic fevers: report of a WHO expert committee. dSee References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. eSee References: CDC 2000: Fatal illnesses associated with a New World arenavirus; CDC 1994: Bolivian hemorrhagic fever; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Salas 1991.

Clinical Features of Rift Valley Fever
Characteristic	Features
Incubation period	2-6 days
Prodromea	Fever, headache, photophobia, retro-orbital pain
Clinical signs/symptomsb	—Subclinical infection is common. —Four clinical patterns occur:     ~Undifferentiated fever lasting 2-7 days (>90% of cases; often associated with nausea, vomiting, and abdominal pain)     ~Hemorrhagic fever with marked hepatitis and bleeding manifestations (<1% of cases; occurs 2-4 days after onset of fever)     ~Encephalitis (<1% of cases; occurs 1-4 wk after onset of fever)     ~Retinitis (up to 10% of cases; occurs 1-4 wk after onset of fever; often bilateral; hemorrhages, exudates, and cotton wool spots may be visible on macula; retinal detachment may occur) —Common bleeding manifestations include gastrointestinal bleeding and epistaxis. —Neurologic symptoms include confusion, lethargy, tremors, ataxia, coma, seizures, meningismus, vertigo, and choreiform movements. —Hepatitis, hepatic failure, and renal failure may occur. —A report of the 2001 outbreak in Saudi Arabia identiied the following clinical features for 683 laboratory-confirmed cases:     ~Fever: 92.6%     ~Nausea: 59.4%     ~Vomiting: 52.6%     ~Abdominal pain: 38.0%     ~Diarrhea: 22.1%     ~Jaundice: 18.1%     ~Neurologic manifestations: 17.1%     ~Hemorrhagic manifestations: 7.1%
Laboratory featuresc	—Initial leukocytosis (may occur, followed by leukopenia) —Thrombocytopenia in severe cases —Laboratory features of DIC in severe cases (prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen) —Elevated hepatic enzymes (eg, ALT, AST) and bilirubin
Complicationsd	—Blindness following retinitis —Neurologic sequelae following encephalitis
Case-fatality ratee	—Overall, <1% —For hemorrhagic disease, about 50% —In 2000 outbreak in Saudi Arabia, 17% among symptomatic patients and 33.3% among hospitalized patients admitted to RVF unit at local referral hospital —Death usually due to hepatic necrosis and DIC
Abbreviations: ALT, alanine aminotransferase; AST: aspartate aminotransferase; DIC, disseminated intravascular coagulation; RVF, Rift Valley fever. aSee References: Borio 2002. bSee References: Al-Hazmi 2003; Borio 2002; CDC 2000: Outbreak of Rift Valley fever--Yemen; CDC: Rift Valley fever fact sheet; Madani 2003; WHO 1984: Viral hemorrhagic fevers: report of a WHO expert committee. cSee References: Lacy 1996. dSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee. eSee References: Al-Hazmi 2003, Borio 2002, Madani 2003, Morrill 1996.

Clinical Features of Yellow Fever
Characteristic	Features
Incubation period	3-6 days
Prodromea	—Fever, headache, myalgias, facial flushing, conjunctival injection, relative bradycardia (Faget's sign) —Resembles two of the disease categories below, very mild and mild
Clinical signs/symptomsb	—Subclinical infection is common (5%-50%). —Five clinical patterns occur:     ~Very mild (transient fever, mild headache; illness lasting about 1 day)     ~Mild (more pronounced fever and headache; nausea, vomiting, epigastric pain, myalgias, epistaxis, photophobia, asthenia [may be present]; illness lasting 2-3 days).     ~Moderately severe (high fever; severe headache/backache; biphasic course with jaundice, albuminuria, oliguria, protracted vomiting, and bleeding manifestations in second phase; illness lasting about 1 wk)     ~Malignant (fulminant infection with severe hepatic involvement, bleeding manifestations, renal failure, shock, and death [usually 7-10 days after illness onset])     ~Fever accompanied by only meningeal signs and symptoms —Bleeding manifestations include hematemesis, bloody diarrhea, epistaxis, gum bleeding, petechial and purpuric hemorrhages. —Severe disease develops in about 15% of patients; of these, about 50% go on to the malignant form and die.
Laboratory featuresc	—Leukopenia early in clinical course; leukocytosis (may occur later) —Thrombocytopenia —Albuminuria —Elevated hepatic enzymes (eg, ALT, AST) —Elevated bilirubin (5-10 mg/dL)
Complicationsc	—Myocarditis
Case-fatality rated	—Overall, 5%-7% —Hospitalized patients or in some epidemics, about 20% —Patients in whom severe disease develops (jaundice, bleeding manifestations), about 50%
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aSee References: Tsai 2000. bSee References: Lacy 1996; Tsai 2000; WHO 2001: Yellow fever; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984. cSee References: Lacy 1996. dSee References: Borio 2002; Lacy 1996; WHO 2001: Yellow fever.

Clinical Features of Kyasanur Forest Disease
Characteristic	Features
Incubation period	2-9 days (usually 3-8 days)
Prodrome	Sudden onset of fever, myalgias, headache
Clinical signs/symptomsa	—Diarrhea and vomiting occur by the 3rd or 4th day. —Enanthem with papulovesicular lesions occurs on soft palate. —Ocular findings include conjunctival congestion, subconjunctival hemorrhage, superficial punctate keratitis, mild iritis, and retinal and vitreous hemorrhage.b —Cervical and axillary lymphadenopathy are usually present. —Bleeding manifestations are seen as early as third day (bleeding from nose, gums, gastrointestinal tract). —In one series of 152 patients, bleeding occurred in 26 patients (17%).b —The initial illness phase lasts 6 days to 2 wk. —Illness may be biphasic for up to 50% of cases; after initial illness, afebrile period of 9-21 days occurs, followed by meningoencephalitis. —Findings associated with meningoencephalitis include tremors, headache, mental status changes, and abnormal reflexes. —Hemorrhagic pulmonary edema and renal failure occur in severe cases. —Recovery takes up to 4 wk.
Laboratory featuresc	—Leukopenia (average: 2,000/mm3) —Lymphopenia or lymphocytosis, atypical lymphocytes (may occur) —Thrombocytopenia (average: 86,000/mm3) —Abnormal liver function tests may occur
Complications	Not prominent feature of disease
Case-fatality rate*	3%-10%
aSee References: Borio 2002, Pavri 1989, Pattnaik 2006. bSee References: Nayak 1983. cSee References: Pavri 1989.

Clinical Features of Omsk Hemorrhagic Fever
Characteristic	Features
Incubation period	2-9 days (usually 3-8 days)
Prodromea	Fever, headache, vomiting, enanthem on palate, hyperemia of skin on upper body and mucous membranes
Clinical signs/symptomsa,b	—Initial febrile illness lasting 5-12 days occurs, followed by second phase several days later in 30%-50% of patients that is often more severe. —Generalized lymphadenopathy and splenomegaly commonly occur. —During second phase, pneumonia occurs in about 30% of patients and meningeal symptoms are common. —Diffuse encephalitis may occur. —Recovery may take several weeks.
Laboratory featuresb	—Leukopenia —Thrombocytopenia —Monocytosis
Complicationsb	Transient alopecia may occur
Case-fatality ratea,b	0.5%-10%
aSee References: Borio 2002. bSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.

Pediatric Considerations

In general, the clinical manifestations of VHF are similar in children and adults. One review of 33 pediatric cases of Lassa fever identified the following clinical presentations on the basis of age (see References: Monson 1987):

• Fetal infection (18 pregnancies):
• Spontaneous abortion following onset of infection occurred in 16 cases (one mother later died).
• Fetal death in utero occurred in 2 cases; just prior to death, spontaneous abortion appeared likely in both.
• All pregnancies terminated between the 3rd and 9th months.
• Congenital infection (1 case):
• One child died of Lassa fever 4 days after birth; the mother denied any recent febrile illness at the time of the child's death, but she was lost to follow-up and could not be reached when the positive culture was reported.
• Nursing infants (7 cases):
• Presenting symptoms included fever, vomiting, seizures, pneumonia, edema, anorexia, cough, diarrhea, irritability, stomatitis, obtundation, bleeding, lethargy, and abdominal tenderness and distention.
• Leukocyte counts ranged from 3,600/mm³ to 20,000/mm³.
• The case-fatality rate was 29%.
• Children over 2 years of age (7 cases):
• Presenting symptoms included fever, cough, edema, bleeding, abdominal pain, vomiting, seizures, sore throat, conjunctivitis, and obtundation.
• Leukocyte counts ranged from 3,000/mm³ to 42,000/mm³.

• The case-fatality rate was 14%.

• "Swollen baby syndrome" (4 cases):
• Four children (aged 4 days, 6 weeks, 7 months, and 9 years) presented with the triad of edema, abdominal distention, and bleeding, which investigators referred to as "swollen baby syndrome."
• Three of the four children died.

A review of 15 pregnant women with Ebola hemorrhagic fever demonstrated high rates of fetal loss (similar to those just noted for Lassa fever) and also demonstrated a high case-fatality rate for pregnant women (see References: Mupapa 1999):

• Spontaneous abortion occurred in 10 women
• All the mothers presented with severe bleeding; all except 1 subsequently died.

• One woman delivered a stillborn infant and subsequently died.
• One woman delivered a full-term baby; the infant died 3 days after birth and the mother died from severe postpartum hemorrhage.
• Three additional women died in their 3rd trimester of pregnancy.

Vertical transmission also has been reported for Rift Valley fever (see References: Adam 2008, Arishi 2006).

Differential Diagnosis

A wide range of conditions (bacterial, viral, and parasitic infections as well as noninfectious causes) should be considered in the differential diagnosis of VHF. However, most of these conditions do not cause bleeding manifestations as a primary feature and most are not likely to occur epidemiologically as a point-source epidemic with simultaneous presentation of many cases. Primary agents to consider in the differential diagnosis are outlined in the table below.

Differential Diagnosis for Viral Hemorrhagic Fevers That Pose a Bioterrorist Threata,b,c
Condition	Agent(s)	Distinguishing Features
Bacterial and Rickettsial Infections
Septicemia caused by gram-negative bacteria	Various	Underlying illness is usually present.
Staphylococcal or streptococcal toxic shock syndrome	—Staphylococcus aureus —Streptococcus pyogenes	—Streptococcal TSS may be associated with necrotizing fasciitis. —Staphylococcal TSS is often associated with characteristic epidemiologic features (eg, tampon use in menstruating women, antecedent trauma).
Meningococcemia	Neisseria meningitidis	Rapid progression to shock and often death may occur.
Secondary syphilis	Treponema pallidum	—Maculopapular rash that begins on the trunk (palms and soles often involved) is characteristic. —Constitutional symptoms often occur but are not as severe as would be expected with VHF.
Septicemic plague	Yersinia pestis	Often occurs secondary to bubonic plague (characteristic bubo present in groin, axilla, or cervical region).
Typhoid fever	Salmonella typhi	—Symptoms of enterocolitis and abdominal pain may be more prominent with typhoid fever than with VHF. —Hemorrhagic manifestations are generally less common than with VHF.
Rocky Mountain spotted fever	Rickettsia rickettsii	—A history of tick exposure may be obtained. —The disease occurs in April through May. —Most US cases occur in southeastern and south-central states.
Ehrlichiosis	—Ehrlichia chaffeensis —Erhlichia phagocytophilia	—A history of tick exposure history may be obtained. —Petechial rash is uncommon. —Peripheral blood smear may show morulae in neutrophils of patients with human granulocytic ehrlichiosis.
Leptospirosis	Leptospira interrogans	—This is most often self-limited but may be severe in about 10% of patients. —The disease is often associated with aseptic meningitis (characteristic of the immune phase of illness).
Viral Infections
Influenza	Influenza virus	—Respiratory symptoms are prominent. —It is not associated with bleeding diathesis or rash. —It is usually seasonal (October to March in United States) or associated with a history of recent cruise ship travel or travel to tropics.
Hemorrhagic smallpox	Smallpox virus	—In late-onset form, a pustular rash usually is present before hemorrhagic manifestations. —In early-onset form, hemorrhagic manifestations occur soon after illness onset without usual prodrome (ie, bleeding generally will occur sooner than would be expected with VHF).
Measles	Rubeola virus	—Presenting features usually include cough, coryza, conjunctivitis. —Hemorrhagic features are rare.
Rubella	Rubella virus	—Occurs in persons without history of rubella vaccination (such as migrant workers). —Hemorrhagic features are extremely rare.
Hemorrhagic varicella	Varicella-zoster virus	—Usually occurs in immunocompromised children.
Viral hepatitis	Usually hepatitis A, B, C viruses (hepatitis E and G virus and other viruses also may cause)	—Hepatic findings predominate. —Hemorrhagic manifestations are associated with fulminant hepatic failure. —It is most likely to mimic yellow fever or Rift Valley fever (both characterized by icteric disease).
Parasitic Infections
Malaria	Plasmodium species	—Fever is cyclic (every 48 hr for P vivax or P ovale; every 72 hr for P malariae) or continuous with intermittent spikes (most common pattern for P falciparum). —Hemolysis commonly occurs; hemorrhagic manifestations are less common. —Parasites may be seen on microscopic examination of thick or thin smears.
African trypanosomiasis	Trypanosoma brucei complex	—Painful chancre may occur at site of tsetse fly bite. —Disease is associated with travel to Africa. —Characteristic features are fever and neurologic manifestations.
Acute Conditions That May Be Associated With a Bleeding Diathesis
Hemolytic uremic syndrome	Usually occurs as complication of infection with Escherichia coli O157:H7 or other Shiga toxin–producing E coli	—Disease involves a triad of renal involvement, thrombocytopenia, and hemolytic anemia. —It is more common in young children. —Antecedent diarrheal illness occurs. —Hemorrhagic manifestations are uncommon, although bloody diarrhea often occurs.
Thrombotic thrombocytopenic purpura	May occur as complication of infection with E coli O157:H7 or other Shiga toxin–producing E coli, although may be noninfectious	—Disease includes renal involvement, thrombocytopenia, hemolytic anemia, neurologic involvement. —Hemorrhagic manifestations are uncommon.
Idiopathic thrombocytopenic purpura	Noninfectious	—Low platelet count is predominant feature. —Disease is generally not accompanied by severe systemic toxicity.
Acute leukemia	Noninfectious	Peripheral blood smear shows characteristic features of leukemia.
Collagen vascular disease	Noninfectious	Acute onset of febrile illness not likely.
Abbreviations:; TSS, toxic shock syndrome. aConditions included: Ebola hemorrhagic fever, Marburg hemorrhagic fever, Lassa fever, New World hemorrhagic fever, Rift Valley fever, yellow fever, Kyasanur Forest disease, and Omsk hemorrhagic fever. bSeveral diseases caused by hemorrhagic fever viruses are not considered to pose a bioterrorist threat; these conditions also should be considered in the differential diagnosis and include dengue fever or dengue hemorrhagic fever, hantavirus pulmonary syndrome, hantavirus hemorrhagic fever with renal syndrome, and Crimean-Congo hemorrhagic fever. cMany of the conditions considered in this differential diagnosis would not occur as epidemic diseases; the purpose of this list is to help sort out individual cases that may herald an epidemic of VHF.

When to Consider the Diagnosis of VHF

Most clinicians in the United States have little or no clinical experience with the syndromes that characterize VHF; therefore, a high index of suspicion is needed to make an accurate diagnosis.

The diagnosis of VHF should be considered for any patient who presents with:

• Acute onset of fever (less than 3 weeks' duration)
• Severe prostrating or life-threatening illness
• Bleeding manifestations (ie, at least two of the following: hemorrhagic or purpuric rash, petechiae [particularly in nondependent areas], epistaxis, hematemesis, hemoptysis, blood in stool, or other evidence of bleeding)
• No predisposing factors for a bleeding diathesis

In naturally occurring cases, an appropriate travel or exposure history will usually be present. In the setting of a bioterrorist event, such a history will not be present and multiple patients will likely present simultaneously.

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Laboratory Diagnosis

Specimen Collection and Transport

A local public health laboratory that participates in the Laboratory Response Network (LRN) should be consulted regarding collection of clinical specimens from patients with suspected VHF.

In an outbreak setting, it may not be necessary to collect multiple types of specimens from each patient once the etiologic agent is known. In such situations, public health authorities will provide specific recommendations for confirmation of outbreak-associated cases.

Collection and Transport of Clinical Laboratory Specimens for the Diagnosis of Viral Hemorrhagic Fever
Agent	Specimen	Collectiona.b and Transport
		Note: samples should be transported double-bagged and hand-carried to the laboratory
Filoviruses, arenavirusesc	Blood/serum	—Use Vacutainer or other sealed, sterile, dry tube for blood collection. —For virus culture: During acute febrile illness, collect serum, heparinized plasma, or whole blood in tubes and store at 4oC or frozen on dry ice or liquid nitrogen. —For serologic tests: Avoid collection tubes with citrate, oxalate, or EDTA. If blood is collected for serologic testing only, freeze at –20oC or colder. —For PCR tests: Add EDTA tube —Specimens should be centrifuged at low speed (to reduce risk of accidental infection). —Collect acute-phase specimen within 7 days after illness onset. —Collect convalescent-phase specimen at least 14 days after illness onset (although antibody may be detectable earlier, as patient begins to recover); paired serum specimens should be collected 7-20 days apart).
	Other clinical specimens	—Marburg and Ebola viruses may be recovered from soft tissue effusates, semen, and anterior eye fluid, especially in the late stages of illness. —One report demonstrated that Ebola virus antigen can be detected in oral fluid specimens using RT-PCR.d —Lassa virus often can be recovered from throat swabs, pleural effusions, placental tissue, or urine and has been demonstrated in CSF of patients with fever and neurologic signs. —Mix throat wash specimens or urine specimens with equal volume of viral transport medium and freeze at –40°C or colder.
	Autopsy specimens	—Specimens should be collected only by very experienced pathologists with advice from appropriate experts. —Perform skin biopsy for Ebola immunohistochemistry; use CDC skin biopsy kit, instructions, and safety precautions:     ~Cut small piece of skin from nape of neck.     ~Use forceps to lift skin sample.     ~Place sample in vial of formalin and tighten cap.     ~Dip closed vial in disinfectant for 1 min, then set aside to dry —Collect other appropriate specimens (eg, spleen, lymph node, liver, kidney) for culture. —Place tissues in sterile containers with 1-2 drops sterile normal saline to keep moist. —In parallel, tissues should be formaldehyde-fixed or paraffin-embedded for immunohistochemistry. —Fix impression smears of tissues by immersion in cold acetone and freeze. —Finely divide aliquot for electron microscopy and place in glutaraldehyde. —Transport tissues at room temperature to laboratory for immediate processing. —Swabs of tissue are not recommended.
Rift Valley fever virus, flavivirusese	Blood/serum	—Collect acute and convalescent sera 2-3 wk apart (although antibody may be detectable earlier, as patient begins to recover). —Single serum specimen (collected later in clinical course) may be evaluated for IgM antibody response if acute/convalescent pair unavailable. —Collect CSF for patients with evidence of CNS infection. —Store specimens at 4oC or frozen at –70oC.
	Autopsy specimens	—Collect tissue from infected organs (eg, liver). —Collect brain tissue from patients with evidence of CNS infection; obtain samples from multiple areas (eg, cortex, brain nuclei, cerebellum, brain stem). —Store aliquots frozen at –70oC. —Finely divide aliquots for electron microscopy and place in glutaraldehyde. —Fix aliquots for immunohistochemistry in buffered formalin or embed in freeze medium and freeze. —Freeze aliquots for RT-PCR or immunologic assays at –70o C or place on dry ice.
Abbreviations: CDC, Centers for Disease Control and Prevention; CNS, central nervous system; CSF, cerebrospinal fluid; EDTA, ethylenediaminetetraacetic acid; IFA, indirect fluorescent antibody; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase PCR. aFor general specimen collection procedures, see References: WHO: Guidelines for the collection of clinical specimens. bSee References: Borio 2002. cSee References: Drosten 2003; Jahrling 1999; Peters 2005: Marburg and Ebola virus hemorrhagic fevers; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; WHO: WHO recommended guidelines for epidemic preparedness and response). dSee References: Formenty 2006. eSee References: Drosten 2003; Peters 2005: California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers; Tsai 2000.

Guidelines have been published for packing and shipping infectious substances, diagnostic specimens, and biological agents from suspected bioterrorist attacks (see References: ASM 2008). VHF viruses are classified under WHO risk group 4. Specimens and isolates that are reasonably suspected to contain a VHF virus must be transported as "infectious substances." International Air Transport Association (IATA) rules require training of all individuals involved in the transport of dangerous goods, including infectious substances. Isolates of Ebola, Marburg, Lassa fever, Rift Valley fever, Junin, Machupo, Sabia, Guanarito, and Crimean-Congo hemorrhagic fever viruses and specimens known to contain these viruses are regulated as select agents (see below) and are subject to additional transport requirements. Chain-of-custody should be documented for material that may constitute evidence of criminal activity.

Laboratory Biosafety and Biosecurity Information

• Laboratory personnel are at high risk for infection with hemorrhagic fever viruses, and laboratory-acquired infections have been documented following exposure to a number of different agents (eg, some New World arenaviruses, and Ebola, Marburg, Lassa, Kyasanur Forest disease, and Rift Valley fever viruses) (see References: Armstrong 1999; Banerjee 1979; Borio 2002; CDC: Biosafety in microbiological and biomedical laboratories; CDC: Bolivian hemorrhagic fever—El Beni Department, Bolivia; Martini 1971; ITAR_TASS News Agency 2004; Smithburn 1949). This is of particular concern for arenaviruses, since all of them are infectious as aerosols (see References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers).
• Hazards in the laboratory setting include (see References: CDC: Biosafety in microbiological and biomedical laboratories):
• Respiratory exposure to infectious aerosols (such as those generated through centrifugation)
• Mucous membrane exposure to infectious droplets
• Accidental parenteral inoculation
• A report from the US Army Medical Research Institute of Infectious Diseases (USAMRIID) described a situation whereby a research scientist was potentially exposed to Ebola virus via a needlestick injury in 2004 (see References: Kortepeter 2008). The report discusses approaches for confining a potentially exposed patient in a medical containment suite. USAMRIID has suggested a stepwise approach for handling such incidents that includes contacting appropriate experts, determining sufficient infection control measures, and addressing isolation logistics.
• To minimize risk to laboratory personnel, all laboratory staff should be alerted, if possible, to the potential diagnosis of VHF and designated laboratory workers should receive training in handling specimens from such patients in advance.
• The further minimize risk, all specimens, regardless of test requested or suspected diagnosis, should be processed using at a minimum biosafety level (BSL)–2 containment and protocols (see References: ASM 2003; CDC: Biosafety in microbiological and biomedical laboratories).
• Specimens from patients with suspected VHF should be referred to an LRN national laboratory (eg, CDC) for diagnostic testing under appropriate BSL conditions.
• Point-of-care analyzers should be used, if available, for bedside analysis of blood gases and critical values such as electrolytes to minimize risks to laboratory workers (see References: Borio 2002, Chance 2000, Lindemans 1999).
• If point-of-care analyzers are not available, then efforts should be made to limit potential exposures of laboratory personnel in the hospital clinical laboratory (see References: Armstrong 1999, Borio 2002):
• Laboratory testing should be limited to critical diagnostic tests only.
• Laboratory specimens should be clearly identified, double-bagged, and hand-carried to the laboratory at prescheduled times.
• Specimens should not be transported in pneumatic tube systems.
• The number of laboratory technicians handling specimens from patients with VHF should be limited to dedicated trained personnel.
• Serum samples should be pretreated with Triton X-100 (10 mcL of 10% Triton X-100 per 1 mL of serum for 1 hour) to reduce the risk of accidental exposure, although the efficacy of this procedure has not been demonstrated (see References: Borio 2002).
• Heating of samples at 60°C for 1 hour will virtually inactivate infectivity but will still allow measurement of electrolytes, creatinine, and other heat-stable markers (see References: Jahrling 1999). Routine procedures with automated analyzers may be conducted, but analyzers should be disinfected with a 1:100 bleach solution or as recommended by the manufacturer (see References: CDC 1995: Management of patients with suspected viral hemorrhagic fever—United States).
• Blood smears for malaria are considered noninfectious for VHF viruses after solvent fixation (see References: CDC 1995: Management of patients with suspected viral hemorrhagic fever).
• Laboratory workers in hospital clinical laboratories should wear appropriate personal protective equipment (PPE) (see Infection Control: Isolation Precautions) when handling specimens from patients suspected of having VHF. All specimens should be handled at a minimum in a class 2 biological safety cabinet following BSL-3 practices (see References: Borio 2002).

• The hemorrhagic fever viruses included in this report (except for yellow fever virus) are classified as select agents and therefore are regulated under 42 CFR part 73 (Possession, Use, and Transfer of Select Agents and Toxins), which was published as an Interim Final Rule in the Federal Register on Dec 13, 2002 (see References: HHS 2002). As specified in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, 42 CFR part 73 provides requirements for laboratories that handle select agents (including registration, security risk assessments, safety plans, security plans, emergency response plans, training, transfers, record keeping, inspections, and notifications). These new requirements went into effect on Feb 7, 2003, and override earlier government requirements regarding possession and transfer of select agents. The Final Rule went into effect on Apr 18, 2005, and incorporated changes made in the Interim Rule (see References: HHS 2005). For more information about CDC's program, see References: CDC: Select Agent Program. In addition, CDC has published additional guidelines for enhancing laboratory security for laboratories working with select agents (see References: CDC 2002: Laboratory security and emergency response guidance).
• Sentinel laboratories should not accept environmental or animal specimens if VHF is suspected (see References: ASM 2003).

The Laboratory Response Network

The Laboratory Response Network (LRN) is a national network of approximately 150 laboratories. It includes the following types of labs: federal, state and local public health, military, food testing, environmental, veterinary, and international (located in Canada, the United Kingdom, and Australia) (see References: CDC: Facts about the Laboratory Response Network).

The LRN structure for bioterrorism designates laboratories as either national, reference, or sentinel. Designation depends on the types of tests a laboratory can perform and how it handles infectious agents to protect workers and the public.

• National laboratories have unique resources to handle highly infectious agents and the ability to identify specific agent strains.
• Reference laboratories, sometimes referred to as "confirmatory reference," can perform tests to detect and confirm the presence of a threat agent. These laboratories ensure a timely local response in the event of a terrorist incident. Rather than having to rely on confirmation from laboratories at the CDC, reference laboratories are capable of producing conclusive results; this allows local authorities to respond quickly to emergencies. These are mostly state or local public health laboratories with BSL-3 containment facilities that have been given access to nonpublic testing protocols and reagents.
• Sentinel laboratories represent the thousands of hospital-based labs that are on the front lines and have direct contact with patients. In an unannounced or covert terrorist attack, patients provide specimens during routine patient care. Sentinel laboratories could be the first facilities to spot a suspicious specimen. A sentinel laboratory's responsibility is to refer a suspicious sample to the right reference laboratory. These laboratories generally have at least BSL-2 containment.

The following factors are important in terms of LRN testing for VHF:

• Most of the hemorrhagic fever viruses currently require testing under BSL-4 conditions (see References: Borio 2002).
• BSL-4 agents are considered dangerous/exotic agents which pose high risk of life-threatening disease, aerosol-transmitted lab infections, or related agents with unknown risk of transmission.
• Yellow fever and Rift Valley fever viruses can be tested under BSL-3 conditions, which are available at many laboratories in the LRN. Laboratory personnel should be vaccinated and additional lab engineering controls, such as high-efficiency particulate air (HEPA)–filtered exhaust air, should be in place. In general, specialized tests for these viruses generally are only available at BSL-4 (LRN national) laboratories.
• Although testing for hemorrhagic fever viruses is limited to LRN national laboratories, the LRN has an established communication network that allows for rapid response and transportation of clinical specimens in the event of a bioemergency. US physicians are advised to contact their state health department before sending samples to the CDC.

Tests for Detection of Hemorrhagic Fever Virus Infection (available only at specialized laboratories)

• Antigen detection by antigen-capture enzyme-linked immunosorbent assay (ELISA), performed on serum or other samples, can be used to detect most hemorrhagic fever viruses (see References: Saijo 2006, Saijo 2007, Towner 2004, Bausch 2000).
• Serology (either testing an acute-phase specimen for IgM antibody or testing paired sera) also can be used to diagnose most VHF infections.
• Reverse transcriptase (RT)-PCR methods have been developed for a number of hemorrhagic fever viruses (see References: Drosten 2002; Drosten 2003; Leroy 2000: Diagnosis of Ebola haemorrhagic fever; Towner 2004; Gibb 2001: Development and evaluation of a fluorogenic 5'-nuclease assay to identify Marburg virus; Gibb 2001: Development and evaluation of a fluorogenic 5' nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan; Sall 2002; Sall 2001; Vieth 2007; Weidmann 2004). As with other rare diseases, the positive predictive value of PCR in the absence of other corroborating medical or epidemiologic evidence is exceedingly low.
• Immunohistochemistry methods are rapid, work directly on patient samples, are relatively sensitive and specific, and can be used on formalin-fixed samples. These methods have been described for Ebola virus (see References: Zaki 1999), Marburg virus (see References: Geisbert 1998), and Rift Valley fever virus (demonstrated in lambs; see References: Van der Lugt 1996) and would presumably be equally effective with the other hemorrhagic fever viruses.
• Electron microscopy has been used for rapid diagnosis of VHF (particularly filovirus infections) using serum, buffy coat, and tissue (see References: Peters 2005: Marburg and Ebola virus hemorrhagic fevers).
• Cell culture: Although this is the "gold standard" of virus detection and identification, performance of cell culture with these viruses is time consuming and extremely dangerous, and should be performed on suspect cases only at BSL-4 laboratories.
• Generally, hemorrhagic fever viruses can be recovered from serum or virtually any infected tissue.
• Most hemorrhagic fever viruses will grow in Vero and other mammalian cell lines. Passage in laboratory animals may increase cell culture sensitivity (see References: Drosten 2003).

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Treatment, Postexposure Prophylaxis, and Vaccines

Treatment

Supportive care is essential for patients with all types of VHF and includes the following:

• Maintenance of fluid and electrolyte balance, with hemodynamic monitoring as needed
• Mechanical ventilation, as indicated
• Dialysis, as indicated
• Steroids have not been shown to be of value; however, because adrenal involvement may occur in VHF cases, steroids could be considered in certain situations (see References: Abraham 2002, Annane 2002)
• Anticoagulant therapies, aspirin, nonsteroidal anti-inflammatory medications, and intramuscular injections are contraindicated
• Appropriate therapy for secondary infections

Management of severe bleeding complications is controversial. Potential therapies include (see References: Jahrling 1997):

• Clotting factor concentrates
• Platelets
• Fresh frozen plasma
• Heparin for DIC

Convalescent human plasma has been shown to be effective in the treatment of Argentine hemorrhagic fever and has been suggested for treatment of other New World arenavirus infections (see References: Enria 2008; Peters 2005: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).

Ribavirin has some in vivo and in vitro activity against:

• Arenaviruses (Lassa fever and New World hemorrhagic fevers) (see References: Enria 1994; Enria 2008; Huggins 1989; Kilgore 1997; McCormick 1986)
• Bunyaviruses (Rift Valley fever and others) (see References: Borio 2002); ribavirin appears to be effective in animals (see References: Peters 1986) and could potentially be used cautiously in humans

Antiviral agents have not been shown to be effective, and are not recommended, for infections caused by:

• Filoviruses (Ebola and Marburg hemorrhagic fever)
• Flaviviruses (yellow fever, Kyasanur Forest disease, and Omsk hemorrhagic fever)

The recommended regimens for use of ribavirin are shown in the table below.

Ribavirin Therapy Recommendations for Patients With Viral Hemorrhagic Fever of Unknown Cause or Known to Be Caused by an Arenavirus or Bunyavirusa
Patient Group	Contained-Casualty Setting	Mass-Casualty Settingb
Adults (including pregnant women)c	—Loading dose of 30 mg/kg (maximum dose, 2 gm) IV once —Then 16 mg/kg (maximum dose, 1 gm) IV every 6 hr for 4 days —Then 8 mg/kg (maximum dose, 500 mg) IV every 8 hr for 6 days	Loading dose of 2,000 mg PO once, then:     ~Weight >75 kg: 1,200 mg/day PO in 2 divided doses for 10 daysd     ~Weight <75 kg: 1,000 mg/day PO in divided doses (400 mg in am and 600 mg in pm) for 10 daysd
Children	—Loading dose of 30 mg/kg (maximum dose, 2 gm) IV once —Then 16 mg/kg (maximum dose, 1 gm) IV every 6 hr for 4 days —Then 8 mg/kg (maximum dose, 500 mg IV) every 8 hr for 6 days	—Loading dose of 30 mg/kg PO once —Then 15 mg/kg/d PO in 2 divided doses for 10 days
Abbreviations: IV, intravenously; PO, orally. aThese are the recommendations of the Working Group on Civilian Biodefense; ribavirin is not approved by the US Food and Drug Administration for treatment of viral hemorrhagic fever and must be used under an Investigational New Drug (IND) protocol, although in a mass-casualty setting, this requirement may need to be modified. bThe decision to use oral rather than parenteral medication will depend on available resources. cGenerally, ribavirin is contraindicated in pregnant women; however, the Working Group believes that the benefits appear to outweigh the fetal risk of ribavirin therapy. Also, the mortality of viral hemorrhagic fever appears to be higher in pregnancy. dA 1,000-mg dosage per day given in 3 divided doses has been used to treat patients with Lassa fever; however, this regimen cannot be used in the United States, because the current available formulation of ribavirin is 200-mg capsules, which cannot be broken open. Adapted from Borio 2002 (see References).

Postexposure Prophylaxis

The Working Group on Civilian Biodefense does not recommend prophylactic antiviral therapy for persons exposed to any hemorrhagic fever viruses (including Lassa virus) in the absence of clinical illness (see References: Borio 2002). Instead, the working group recommends that exposed persons be placed under medical surveillance. Specific recommendations include:

• Exposed persons are defined as those with exposure to the initial bioterrorist release and those who are close contacts of, or have high-risk exposure to, a patient with VHF.
• High-risk exposures and close contacts are defined in the section on Infection Control: Isolation Precautions below.
• Exposed patients should monitor their temperatures daily and report any temperature of 101°F (38.3°C) or higher.
• Exposed persons should also report any other symptoms suggestive of VHF (see the section on Clinical Characteristics).
• If symptoms suggestive of VHF occur or if a temperature of at least 101°F (38.3°C) is documented by medical staff, ribavirin therapy should be initiated unless another diagnosis is confirmed (or the etiologic agent is known to be a filovirus [Ebola, Marburg] or flavivirus [yellow fever, Kyasanur Forest disease, Omsk hemorrhagic fever]).
• Surveillance should be continued for 21 days after the last exposure.

The CDC has not published recent recommendations on antiviral prophylaxis for persons exposed to hemorrhagic fever viruses. The most recent recommendations from the CDC on this issue were published in 1988 and differ from the current recommendations of the Working Group on Civilian Biodefense. The 1988 CDC recommendations state that prophylactic therapy with ribavirin should be given to persons exposed to Lassa virus (500 mg orally every 6 hours for 7 days) (see References: CDC 1988: Management of patients with suspected viral hemorrhagic fever). However, the efficacy of ribavirin in this context has not been documented, and the CDC did not recommend postexposure prophylaxis for persons exposed to an imported cases of Lassa fever in 2004 (see References: CDC 2004: Imported Lassa fever—New Jersey).

Vaccination

Yellow Fever Vaccine

The only vaccine available for hemorrhagic fever viruses is yellow fever vaccine, which is a 17D-derived live-virus vaccine (see References: CDC 2002: Yellow fever vaccine recommendations of the ACIP).

• Yellow fever vaccine is in limited supply and, in the United States, is recommended only for:
• Travelers to tropical areas of South America and Africa that are endemic for yellow fever
• Laboratory personnel who might be exposed to virulent yellow fever virus by direct or indirect contact or by aerosols
• Over the past several years, severe adverse events associated with yellow fever vaccination have been recognized (see References: CDC 2001: Fever, jaundice, and multiple organ system failure; CDC: Adverse events associated with 17D-derived yellow fever vaccination; Belsher 2007; Hayes 2007). Cases of both vaccine-associated viscerotropic disease (YEL-AVD) and vaccine-associated neurotropic disease (YEL-AND) have been recognized.
• In the event of a bioterrorist attack, yellow fever vaccine would not be useful for postexposure prophylaxis because the incubation period for yellow fever is short  (3 to 6 days) and immunity post vaccination does not develop for 10 days (see References: Borio 2002, Monath 2001).

Yellow fever vaccine is given as a single primary dose with a booster dose every 10 years, according to the schedule outlined in the table below.

Yellow Fever Vaccinea for Persons Older Than 9 Months of Ageb,c
Dose	Dosage and Route	Comments
Primary	0.5 mL subcutaneously	10 days before traveld
Booster	0.5 mL subcutaneously	1 dose every 10 yre
aYellow fever vaccine is administered only at designated yellow fever centers. bYellow fever vaccine is contraindicated for infants <6 mo of age because of the risk of postvaccinal encephalitis. Vaccination of children <9 mo of age should be avoided whenever possible. cThe risk of adverse events appears to be greater in persons who are age 65 and older; therefore, travelers of this age should discuss with their physician the risk and benefits of vaccination in the context of the destination-specific risk for exposure to yellow fever virus. dImmunity develops by the 10th day. eWHO requires revaccination every 10 yr to maintain travelers' vaccination certificates.

Vaccines for Other Hemorrhagic Fever Viruses

• Vaccines against Argentine hemorrhagic fever (ie, Junin virus) and Rift Valley fever are available as investigational new drugs (see References: Maiztegui 1998, Pittman 1999). The Argentine hemorrhagic fever vaccine is a live-attenuated vaccine, which has shown greater than 95% efficacy and no side effects (see References: Maiztegui 1998).
• A formalin inactivated vaccine against Kyasanur forest disease virus, produced in chick embryo fibroblasts, was shown to be efficacious in field trials in the early 1990s (see References: Dandawate 1994). The vaccine has been licensed and is currently being used routinely in endemic areas (see References: Pattnaik 2006).
• Efforts to develop a vaccine against Lassa fever virus are ongoing (see References: Cleri 2006, Fisher-Hoch 2004).
• A number of studies on vaccines for Marburg and Ebola viruses have been published over the last few years.
• Most involve use of viral vectors that express either the Ebola or Marburg glycoproteins (see References: Jones 2005; Daddario-DiCaprio 2006; Bausch 2007: Development of vaccines for Marburg; Kobinger 2006; Sullivan 2006; Swenson 2008; Geisbert 2008: Vesicular stomatitis virus-based vaccines protect).
• Using vaccine or monoclonal antibodies for postexposure prophylaxis against Ebola infection has been suggested in several recent reports (see References: Feldmann 2007, Sullivan 2003, Geisbert 2008: Recombinant vesicular stomatitis virus vector mediates postexposure). If postexposure vaccination is shown to be effective, a ring vaccination containment strategy could potentially be recommended for control of Ebola hemorrhagic fever outbreaks.
• One report found that a DNA vaccine for Ebola virus was safe and immunogenic in a phase I clinical trial (see References: Martin 2006). The National Institutes of Health and Vical, Inc. are working on an intramuscular needle-free delivery system for such a DNA vaccine (see References: Dery 2008).
• Monoclonal antibodies and peptide antigens may provide the basis for future vaccines against Ebola virus.

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Infection Control (Including Autopsies and Burial)

Nosocomial Transmission

Transmission within healthcare settings has been noted for a number of hemorrhagic fever viruses, including Ebola, Marburg, Lassa, Machupo, and Crimean-Congo viruses (see References: Weber 2001).

• Nosocomial and household transmission most often has been associated with contact with infected blood or body fluids (see References: Dowell 1999, Monath 1975).
• In some instances, transmission has resulted from reuse of needles or accidental needlesticks (see References: Fisher-Hoch 1995, Guimard 1999).
• In one situation, investigators postulated that a healthcare worker became infected with Ebola virus after touching her eyes with a contaminated glove (see References: Guimard 1999).
• Person-to-person airborne transmission appears to be rare; one patient with Lassa fever who had extensive pulmonary involvement may have transmitted the virus by this route (see References: Carey 1972).
• Airborne transmission of Machupo virus presumably occurred in one situation where a nursing student became infected after watching an instructor change the bed linens of an infected patient; the student had no direct or close contact with the patient or with any associated fomites (see References: Peters 1974).
• Although person-to-person airborne transmission appears unlikely, the potential for airborne transmission of hemorrhagic fever viruses in the healthcare setting cannot be excluded (see References: Borio 2002).
• In some Third World countries inconsistent use of protective gear can contribute to infection of healthcare workers. Reasons for poor usage include unavailability of the gear, adherence to traditional explanatory models of disease origin, and bonding with sick colleagues (see References: Borchert 2007).
• Contact with cadavers has also been shown to be a source of exposure during outbreaks of Ebola hemorrhagic fever (see References: CDC 2001: Outbreak of Ebola hemorrhagic fever—Uganda; Roels 1999).

Isolation Precautions

Appropriate isolation precautions for patients with suspected or confirmed VHF include a combination of Airborne and Contact Precautions (see References: Weber 2001). Although airborne transmission of these agents appears to be rare, airborne transmission theoretically may occur; therefore, airborne precautions should be instituted for all patients with suspected VHF. According to the Working Group on Civilian Biodefense, the following precautions should be implemented for such patients (see References: Borio 2002):

• Provide the following PPE for healthcare providers:
• N-95 respirator or powered air-purifying respirator (PAPR)
• Double (leak-proof) gloves
• Impermeable gowns
• Face shields
• Goggles for eye protection
• Leg and shoe coverings
• Place the patient in a private room with:
• Negative air pressure
• 6 to 12 air changes per hour
• Restricted access of nonessential staff and visitors
• Dedicate medical equipment (eg, stethoscopes, glucose monitors, point-of-care analyzers [if available]).
• Assure that healthcare providers adhere strictly to hand hygiene:
• Clean hands prior to donning PPE for patient contact
• After patient care, remove gloves, gown, and leg and shoe coverings and immediately clean hands
• Clean hands prior to the removal of facial protective equipment to minimize exposure of mucous membranes to potentially contaminated hands
• Clean hands again after all PPE is removed
• Place all persons (including medical and laboratory personnel) who have had a close or high-risk contact with a patient suspected of having VHF during the 21 days following onset of symptoms (and before onset of appropriate barrier precautions) under medical surveillance (see References: Borio 2002).
• High risk is defined as having mucous membrane contact or having percutaneous injury involving contact with secretions, excretions, or blood from a patient with VHF
• Close contact is defined as those who live with, shake hands with, hug, process laboratory specimens from, or care for a patient with VHF
• If a filovirus or arenavirus infection is confirmed for the index patient, then medical surveillance should be continued until 21 days after the last exposure
• If the index patient has Rift Valley fever or a flavivirus infection, then medical surveillance needs to be continued until 21 days after the last exposure only for those who processed laboratory specimens from the infected patient prior to initiation of appropriate precautions (since these conditions are transmitted in the laboratory setting but not via person-to-person transmission)
• If multiple patients with suspected VHF are admitted to one healthcare facility, cohort them in the same part of the hospital to minimize exposure to other patients and healthcare workers.

Environmental Decontamination

Hemorrhagic fever viruses have lipid envelopes and are not environmentally stable; therefore, these viruses would not be expected to persist in the environment following a bioterrorist attack. According to the Working Group on Civilian Biodefense, decisions about decontamination of the environment following an intentional release would depend upon the specific events surrounding the attack and should be made by experts who are familiar with the situation (see References: Borio 2002).

The Working Group on Civilian Biodefense and CDC make the following recommendations for environmental decontamination in the hospital setting (see References: Borio 2002; CDC: Update: Management of patients with suspected viral hemorrhagic fever—United States).

• Environmental surfaces, inanimate contaminated objects, or contaminated equipment should be disinfected with an Environmental Protection Agency–registered hospital disinfectant or a 1:100 dilution of household bleach using standard procedures.
• Contaminated linens should be incinerated, autoclaved, or placed in double (ie, leak-proof) bags at the site of use and washed without sorting in a normal hot water cycle with bleach.
• Hospital housekeeping staff and linen handlers should wear appropriate PPE (as outlined in the section on isolation practices above) when handling or cleaning potentially contaminated material or surfaces.

The 1995 CDC guidelines for management of patients with VHF indicate that efforts should be made to decontaminate stool, fluids, and secretions before disposal. According to CDC, such fluids should be autoclaved, processed in a chemical toilet, or treated with several ounces of household bleach for 5 or more minutes before flushing or disposal (see References: CDC: Update: Management of patients with suspected viral hemorrhagic fever—United States). However, the Working Group on Civilian Biodefense has stated that since hemorrhagic fever viruses are not likely to survive standard US sewage treatment, such practices are unnecessary (see References: Borio 2002).

Issues Related to Autopsies and Burial

Autopsy Practices

• Guidelines from the CDC indicate that Standard Precautions should be used for postmortem care. These include using a surgical scrub suit, surgical cap, impervious gown or apron with full sleeve coverage, a form of eye protection (eg, goggles or face shield), shoe covers, and double surgical gloves with an interposed layer of cut-proof synthetic mesh (see References: CDC: Medical examiners, coroners, and biologic terrorism: a guidebook for surveillance and case management).
• In addition, autopsy personnel should wear N-95 respirators during all autopsies, regardless of suspected or known pathogens. Powered air-purifying respirators (PAPRs) equipped with N-95 or high-efficiency particulate air (HEPA) filters should be considered.
• Other experts have recommended that aerosol-generating procedures (such as bone sawing) should be avoided during autopsies if possible. If such procedures are necessary, then HEPA-filtered masks and negative-pressure rooms should be used (see References: Inglesby 2000: Plague as a biological weapon; Weber 2001).

Burial

• Contact with corpses should be limited to trained personnel, and routine precautions should be implemented when transporting corpses.
• According to CDC guidelines, "Bodies contaminated with hemorrhagic fever viruses should be cremated without embalming. If cremation is not an option, the body should be properly secured in a sealed container (eg, a Zigler case or other hermetically sealed casket) to reduce the potential risk of pathogen transmission" (see References: CDC 2004: Medical examiners, coroners, and biologic terrorism).
• The Working Group on Civilian Biodefense has made the following recommendations for postmortem care of patients with VHF (see References: Borio 2002).
• Trained personnel should perform autopsies using appropriate barrier precautions and HEPA-filtered respirators (N-95 masks or PAPRs).
• Autopsies should be performed in negative-pressure rooms.
• Postmortem examinations should be performed only if absolutely indicated.

An example of the type of system that can be used to seal remains prior to placing them in a casket for burial is the BioSeal Facility System, produced by Barrier Products (see References). This system utilizes a poly-aluminum foil–extruded laminate material that when used with a heat sealer will provide Level 1 containment for all gases, fluids, vapors, and odors associated with the transport and storage of human and animal remains.

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Public Health Reporting

Cases of suspected viral hemorrhagic fever should be reported immediately to state or local public health officials, according to disease reporting requirements.

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References

Abraham E, Evans T. Corticosteroids and septic shock. (Editorial) JAMA 2002 Aug 21;288(7):886-7

Adam I, Karsany MS. Case report: Rift Valley fever with vertical transmission in a pregnant Sudanese woman. J Med Virol 2008 May;80(5):929 [Abstract]

Al-Hazmi M, Ayoola EA, Abdurahman M, et al. Epidemic Rift Valley fever in Saudi Arabia: a clinical study of severe illness in humans. Clin Infect Dis 2003 Feb 1;36(3);245-52 [Abstract]

Alsop Z. Ebola outbreak in Uganda "atypical," say experts. Lancet 2007 Dec 22/29;370(9605):2085 [Full text]

Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002 Aug 21;288(7):862-71 [Abstract]

Anyamba A, Chretien J-P, Formenty PBH, et al. Rift Valley fever potential, Arabian Peninsula. (Letter) Emerg Infect Dis 2006 Mar;12(3):518-20 [Full text]

Arishi HM, Ageel AY, Al Hazmi MM. Vertical transmission of fatal Rift Valley fever in a newborn. Ann Trop Paediatr 2006 Sep;26(3):251-3 [Abstract]

Armstrong LR, Dembray LM, Rainey PM, et al. Management of a Sabia virus-infected patient in a US hospital. Infect Control Hosp Epidemiol 1999 Mar;20:176-82 [Abstract]

ASM. Sentinel laboratory guidelines for suspected agents of bioterrorismand emerging infectious diseases: packing and shipping infectious substances. Revised Jan 1, 2008 [Full text]

ASM. Sentinel laboratory guidelines for suspected agents of bioterrorism: unknown viruses. 2003 Oct 10 [Full text]

Banerjee K, Gupta NP, Goverdhan MK. Viral infections in laboratory personnel. Indian J Med Res 1979;69:363-73

Barrier Products, LLC. BioSeal Facility System [Home page]

Barry M, Russi M, Armstrong L, et al. Brief report: treatment of a laboratory acquired Sabia virus infection. N Engl J Med 1995 Aug 3;333(5):294-6 [Abstract]

Bausch DG, Geisbert TW. Development of vaccines for Marburg hemorrhagic fever. Expert Rev Vaccines 2007 Feb;6(1):57-74 [Abstract]

Bausch DG, Rollin PE, Demby AH, et al. Diagnosis and clinical virology of Lassa fever as evaluated by enzyme-linked immunosorbent assay, indirect fluorescent-antibody test, and virus isolation. J Clin Microbiol 2000 Jul;38(7):2670-7 [Full text]

Bausch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007 Nov 15;196(suppl 2):S142-7 [Abstract]

Belsher JL, Gay P, Brinton M, et al. Fatal multiorgan failure due to yellow fever vaccine-associated viscerotropic disease. Vaccine 2007 Dec 5;25(30):8480-5 [Abstract]

Bergthaler A, Gerber NU, Merkler D, et al. Envelope exchange for the generation of live-attenuatated arenavirus vaccines. PLoS Pathog 2006 Jun;2(6):e51 [Abstract]

Bird BH, Githinji JWK, Macharia JM, et al. Multiple virus lineages sharing recent common ancestry were associated with a large Rift Valley fever outbreak among livestock in Kenya during 2005-2007. J Virol 2008 Nov;82(22):11152-66 [Abstract]

Bosio CM, Aman MJ, Grogan C, et al. Ebola and Marburg viruses replicate in monocyte-derived dentritic cells without inducing the production of cytokines and full maturation. J Infect Dis 2003 Dec 1;188(11):1630-8 [Abstract]

Borchert M, Mulangu S, Lefevre P, et al. Use of protective gear and the occurrence of occupational Marburg hemorrhagic fever in health workers from Watsa health zone, Democratic Republic of Congo. J Infect Dis 2007 Nov 15;196(suppl 2):S168-75 [Abstract]

Borio L, Inglesby T, Peters CJ, et al. Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA 2002 May 8;287(18):2391-405 [Full text]

Bowen MD, Rollin PE, Ksiazek TG, et al. Genetic diversity among Lassa virus strains. J Virol 2000 Aug;74(15):6992-7004 [Full text]

Bray M. Defense against filoviruses used as biological weapons. Antiviral Res 2003 Jan;57(1-2):53-60 [Abstract]

Bredenbeek PJ, Molenkamp R, Spaan WJ, et al. A recombinant Yellow fever 17D vaccine expressing Lassa virus glycoproteins. Virology 2006 Feb 20;345(2):299-304 [Full text]

Britch SC, Linthicum KJ, and the Rift Valley Fever Working Group. Developing a research agenda and a comprehensive national prevention and response plan for Rift Valley fever in the United States. Emerg Infect Dis 2007 Aug;13(8):e1 [Full text]

Bukreyev A, Rollin PE, Tate MK, et al. Successful topical respiratory tract immunization of primates against Ebola virus. J Virol 2007 Jun;81(12):6379-88 [Abstract]

Bukreyev A, Yang L, Zaki SR, et al. A single intranasal inoculation with a paramyxovirus-vectored vaccine protects guinea pigs against a lethal-dose Ebola virus challenge. J Virol 2006 Mar;80(5):2267-79 [Abstract]

Bwaka MA, Bonnet MJ, Calain P, et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J Infect Dis 1999 Feb;179(suppl 1):S1-7 [Abstract]

Carey DE, Kemp GE, White HA, et al. Lassa fever: epidemiologic aspects of the 1970 epidemic, Jos, Nigeria. Trans R Soc Trop Med Hyg 1972;66(3):402-8

CDC. Adverse events associated with 17D-derived yellow fever vaccination—United States, 2001-2002. MMWR 2002 Nov 8;51(44):989-93 [Full text]

CDC. Biological and chemical terrorism: strategic plan for preparation and response. MMWR 2000 Apr 21;49(RR04);1-14 [Full text]

CDC. Biosafety in microbiological and biomedical laboratories (BMBL). Ed 4, April 1999 [Full text]

CDC. Bolivian hemorrhagic fever—El Beni Department, Bolivia, 1994. MMWR 1994 Dec 23;43(50):943-6 [Full text]

CDC. Ebola-Reston virus infection among quarantined nonhuman primates—Texas, 1996. MMWR 1996 Apr 19;45(15):314-6 [Full text]

CDC. Facts about the Laboratory Response Network [Web page]

CDC. Fatal illnesses associated with a New World arenavirus—California, 1999-2000. MMWR 2000 Aug 11;49(31):709-11 [Full text]

CDC. Fever, jaundice, and multiple organ system failure associated with 17D-derived yellow fever vaccination, 1996-2001. MMWR 2001 Aug 3;50(30):643-5 [Full text]

CDC. Filovirus infections among persons with occupational exposure to nonhuman primates or their tissues. MMWR 1990 Apr 27;39(16):266,273 [Full text]

CDC. Filovirus infection associated with contact with nonhuman primates or their tissues. MMWR 1990 Jun 22;39(24):404-5 [Full text]

CDC. Imported Lassa fever—New Jersey 2004. MMWR 2004 Oct 1;53(38):894-7 [Full text]

CDC. Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order. 2008 Jan 14 [Full text]

CDC. Known cases and outbreaks of Marburg hemorrhagic fever, in chronolgocial order. 2007 Aug 19 [Full text]

CDC. Kyasanur forest disease: fact sheet [Full text]

CDC. Laboratory security and emergency response guidance for laboratories working with select agents. MMWR 2002 Dec 6;51(RR-19):1-6 [Full text]

CDC. Management of patients with suspected viral hemorrhagic fever. MMWR 1988 Feb 26;37(S-3):1-16 [Full text]

CDC. Management of patients with suspected viral hemorrhagic fever—United States. MMWR 1995 Jun 30;44(25):475-9 [Full text]

CDC. Questions and answers about Marburg hemorrhagic fever [Full text]

CDC. Medical examiners, coroners, and biologic terrorism: a guidebook for surveillance and case management. MMWR 2004 Jun 11;53(RR08):1-36 [Full text]

CDC. Omsk hemorrhagic fever: fact sheet [Full text]

CDC. Outbreak of Ebola hemorrhagic fever—Uganda, August 2000-January 2001. MMWR 2001 Feb 9;50(5):73-7 [Full text]

CDC. Outbreak of Rift Valley fever—Saudi Arabia, August-November 2000. MMWR 2000 Nov 3;49(43):982-5 [Full text]

CDC. Outbreak of Rift Valley fever—Yemen, August-October 2000. MMWR 2000 Dec 1;49(47):1065-6 [Full text]

CDC. Rift Valley fever fact sheet [Full text]

CDC. Rift Valley fever outbreak—Kenya, November 2006-January 2007. MMWR 2007 Feb 2;56(04):73-6 [Full text]

CDC. Select Agent Program [Web page]

CDC. Yellow fever vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002. MMWR 2002 Nov 8;51(RR17):1-10 [Full text]

Chance JJ, Li DJ, Sokoll LJ, et al. Multiple site analytical evaluation of a portable blood gas/electrolyte analyzer for point of care testing. Crit Care Med 2000 Jun;28(6):2081-5 [Abstract]

Charrel RN, de Lamballerie X. Arenaviruses other than Lassa virus. Antiviral Res 2003 Jan:57(1-2):89-100 [Abstract]

Chevalier V, Lancelot R, Thiongane Y, et al. Rift Valley fever in small ruminants, Senegal, 2003. Emerg Infect Dis 2005 Nov;11(11):1693-700 [Full text]

Cleri DJ, Ricketti AJ, Porwancher RB, et al. Viral hemorrhagic fevers: current status of endemic disease and strategies for control. Infect Dis Clin North Am 2006 Jun;20(2):359-93

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

Dandawate CN, Desai GB, Achar TR, et al. Field evaluation of formalin inactivated Kyasanur forest disease virus tissue culture vaccine in 3 districts of Karnataka state. Indian J Med Res 1994 Apr;99:152-8 [Abstract]

Daubney R, Hudson JR, Garnham PC. Enzootic hepatitis or Rift Valley fever: an undescribed virus disease of sheep, cattle, and man from East Africa. J Pathol Bacteriol 1931;34:545-79

Delgado S, Erickson BR, Agudo R, et al. Chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in Bolivia. PLoS Pathog 2008 Apr 18;4(4):e1000047 [Full text]

Dery M, Bausch DG. A DNA vaccine for the prevention of Ebola virus infection. Curr Opin Mol Ther 2008 Jun;10(3):285-93 [Abstract]

Dowell SF, Mukundu R, Ksiazek TG, et al. Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis 1999 Feb:179(suppl 1): S87-91 [Abstract]

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 Jul;40(7):2323-30 [Abstract]

Drosten C, Kummerer BM, Schmitz H, et al. Molecular diagnostics of viral hemorrhagic fevers. Antiviral Res 2003 Jan;57(1-2):61-87 [Abstract]

Ebihara H, Takada A, Kobasa D, et al. Molecular determinants of Ebola virus virulence in mice. PLoS Pathog 2006 Jul;2(7):e73 [Full text]

Enria DA, Maiztegui JI. Antiviral treatment of Argentine hemorrhagic fever. Antiviral Res 1994 Jan;23(1):23-31 [Abstract]

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

Faye O, Diallo M, Diop D, et al. Rift Valley fever outbreak with east-central African virus lineage in Mauritania, 2003. Emerg Infect Dis 2007 Jul;13(7):1016-23 [Full text]

Feldmann H, Volchkov VE, Volchcova VA, et al. The glycoproteins of Marburg and Ebola virus and their potential roles in pathogenesis. Arch Virol 1999;159(suppl):159-69

Feldmann H, Jones SM, Daddario-Dicaprio KM, et al. Effective post-exposure treatment of Ebola infection. PLoS Pathog 2007 Jan 19;3(1):e2 [Full text]

Fichet-Calvet E, Lecompte E, Koivoqui L, et al. Fluctuation of abundance and Lassa virus prevalence in Mastomya natalensis in Guinea, West Africa. Vector Borne Zoonotic Dis 2007 Summer;7(2):119-28 [Abstract]

Fisher-Hoch SP, Hutwagner L, Brown B, et al. Effective vaccine for Lassa fever. J Virol 2000 Aug;74(15):6777-83 [Full text]

Fisher-Hoch SP, McCormick JB. Lassa fever vaccine. Expert Rev Vaccines 2004 Apr;3(2):189-97 [Abstract]

Fisher-Hoch SP, Tomori O, et al. Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice. BMJ 1995 Sep 30;311(7009):857-9 [Full text]

Formenty P, Hatz C, Le Guenno B, et al. Human infection due to Ebola virus, subtype Cote d'Ivoire: Clinical and biologic presentation. J Infect Dis 1999 Feb;179(suppl 1):S48-53 [Abstract]

Formenty P, Leroy EM, Epelboin A, et al. Detection of Ebola virus in oral fluid specimens during outbreaks of Ebola virus hemorrhagic fever in the Republic of Congo. Clin Infect Dis 2006 Jun 1;42(11):1521-6 [Abstract]

Frame JD. Clinical features of Lassa fever in Liberia. Rev Infect Dis 1989 May-Jun;11(suppl 4):S783-9 [Abstract]

Franz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997 Aug 6;278(5):399-411 [Abstract]

Geisbert TW, Daddario-DiCaprio KM, Geisbert JB, et al. Vesicular stomatitis virus-based vaccines protect nonhman primates against aerosol challenge with Ebola and Marburg viruses. Vaccine 2008 Dec 9;26(52):6894-900 [Abstract]

Geisbert TW, Daddario-DiCaprio KM, Williams KJN, et al. Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates. J Virol 2008 Jun;82(11):5664-8 [Abstract]

Geisbert TW, Jaax NK. Marburg hemorrhagic fever: report of a case studied by immunohistochemistry and electron microscopy. Ultrastruct Pathol 1998 Jan-Feb;22(1):3-17 [Abstract]

Geisbert TW, Jones S, Fritz EA, et al. Development of a new vaccine for the prevention of Lassa fever. PLoS Med 2005 Jun;2(6):e183 [Full text]

Geisbert TW, Young HA, Jahrling PB, 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 Dec;163(6):2371-82 [Abstract]

Geisbert TW, Young HA, Jahrling PB, 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 Dec;163(6):2347-70 [Abstract]

Georges AJ, Leroy, EM, Renaut AA, et al. Ebola hemorrhagic fever outbreaks in Gabon, 1994-1997: epidemiologic and health control issues. J Infect Dis 1999 Feb:179(suppl 1):S65-75 [Abstract]

Gerrard SR, Li L, Barrett AD, et al. Ngari virus is a Bunyamwera virus reassortant that can be associated with large outbreaks of hemorrhagic fever in Africa. J Virol 2004 Aug;78(16):8922-6 [Abstract]

Gibb TR, Norwood DA Jr, Woollen N, et al. Development and evaluation of a fluorogenic 5' nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan. J Clin Microbiol 2001 Nov;39(11):4125-30 [Full text]

Gibb TR, Norwood DA Jr, Woollen N, et al. Development and evaluation of a fluorogenic 5'-nuclease assay to identify Marburg virus. Mol Cell Probes 2001 Oct;15(5):259-66 [Abstract]

Gritsun TS, Lashkevich VA, Gould EA. Tick-borne encephalitis. Antiviral Res 2003 Jan;57(102):129-46 [Abstract]

Gubler DJ, Zaki SR. Dengue and other viral hemorrhagic fevers. In: Nelson AM, Horsburgh CR Eds. Pathology of Emerging Infections 2. Washington, DC: American Society of Microbiology Press, 1998:43-71

Guimard Y, Bwaka MA, Colebunders R, et al. Organization of patient care during the Ebola hemorrhagic fever epidemic in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis 1999 Feb:179(suppl 1):S268-73 [Abstract]

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

Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop Med Hyg 2007 Oct;101(10):967-71 [Abstract]

Heymann DL, Weisfeld JS, Webb PA, et al. Ebola hemorrhagic fever: Tandala, Zaire, 1977-1978. J Infect Dis 1980 Sep;142(3):372-6 [Abstract]

HHS. 42 CFR Part 73: Possession, use, and transfer of select agents and toxins. Interim Final Rule. Fed Reg 2002 Dec 13;240(67):76885-905 [Full text]

HHS. 42 CFR Parts 72 and 73, Part 1003: Possession, use, and transfer of select agents and toxins. Final Rule. Fed Reg 2005 Mar 18;70(52):13294-325 [Full text]

Huggins JW. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis 1989 May-Jun;11(suppl 4):S750-61 [Abstract]

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

ITAR-TASS News Agency. Ebola, lab accident death—Russia (Siberia). ProMED-mail 2004 May;20040522.1377 [Web page]

Jaax N, Jahrling P, Geisbert T, et al. Transmission of Ebola virus (Zaire strain) to uninfected control monkeys in a biocontainment laboratory. Lancet 1995 Dec 23-30;346(8991-2):1669-71 [Abstract]

Jaax NK, Davis KH, Geisber TJ, 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;120:140-55

Jahrling P. Viral hemorrhagic fevers. Chap 29. In: Zajtchuk R, Bellamy RF, eds. Textbook of military medicine: medical aspects of chemical and biological warfare. Washington, DC: Office of the Surgeon General, Borden Institute, Walter Reed Army Medical Center, 1997, pp 591 ff [Full text]

Jahrling PB. Filoviruses and arenaviruses. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of clinical microbiology. Ed 7. Washington DC: American Society for Microbiology Press, 1999:1125-36

Johnson E, Jaax N, White J, et al. Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus. Int J Exp Pathol 1995 Aug;76(4):227-36 [Abstract]

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

Kasari TR, Carr DA, Lynn TV, et al. Evaluation of pathways for release of Rift Valley fever virus into domestic ruminant livestock, ruminant wildlife, and human populations in the continental United States. J Am Vet Med Assn 2008 Feb 15;232(4):514-29 [Abstract]

Kenyon RH, McKee KT Jr, Sack PM, et al. Aerosol infection of rhesus macaques with Junin virus. Intervirology 1992;33(1):23-31 [Abstract]

Khan AS, Tshioko FK, Heymann DL, et al. The re-emergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995. J Infect Dis 1999 Feb;179(suppl 1):S76-86 [Abstract]

Kibadi K, Mupapa K, Kuvula K, et al. Late ophthalmologic manifestations in survivers of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis 1999 Feb;179(suppl 1):S13-4 [Abstract]

Kilgore PE, Ksiazek TB, Rollin PE, et al. Treatment of Bolivian hemorrhagic fever with intravenous ribavirin. Clin Infect Dis 1997 Apr;24(4):718-22 [Abstract]

Kobinger GP, Feldmann H, Zhi Y, et al. Chimpanzee adenovirus vaccine protects against Zaire Ebola virus. Virology 2006 Mar 15;346(2):394-401 [Abstract]

Kortepeter MG, Martin JW, Rusnak JM, et al. Managing potential laboratory exposure to Ebola virus by using a patient biocontainment care unit. Emerg Infect Dis 2008 Jun;14(6):881-7 [Full text]

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

Lahm SA, Kombila M, Swanepoel R, et al. Morbidity and mortality of wild animals in relation to outbreaks of Ebola haemorrhagic fever in Gabon, 1994-2003. Trans R Soc Trop Med Hyg 2007 Jan;101(1):64-78 [Abstract]

LeDuc JW. Epidemiology of hemorrhagic fever viruses. Rev Infect Dis 1989 May-Jun;11(suppl 4):S730-5 [Abstract]

Leroy EM, Baize S, Lu CY, et al. Diagnosis of Ebola haemorrhagic fever by RT-PCR in an epidemic setting. J Med Virol 2000 Apr;60(4):463-7 [Full text]

Leroy EM, Baize S, Volchkov VE, et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet 2000 Jun 24;355(9222):2210-5 [Abstract]

Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature 2005 Dec 1:438(7068):575-6) [Abstract]

Lindemans JP, Hoefkens AL, van Kessel M, et al. Portable blood gas and electrolyte analyzer evaluated in a multiinstitutional study. Clin Chem 1999;45(1):111-7 [Abstract]

Lisieux T, Coimbra M, Nassar ES, et al. New arenavirus isolated in Brazil. Lancet 1994 Feb 12;343(8894):391-2 [Abstract]

Lucht A, Grunow R, Moller P, et al. Development, characterization and use of monoclonal VP40-antibodies for the detection of Ebola virus. J Virol Methods 2003 Jul;111(1):21-8 [Abstract]

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

Madani TA. Alkhumra virus infection, a new viral hemorrhagic fever in Saudi Arabia. J Infect 2005 Aug;51(2):91-7 [Abstract]

Madani TA, Al-Mazrou YY, Al-Jeffri MH, et al. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical, and laboratory characteristics. Clin Infect Dis 2003 Oct 15;37(8):1084-92 [Abstract]

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 Mar 15;170(6):2797-802 [Abstract]

Maiztegui JI, McKee KT, Barrera Oro JG, et al. Protective efficacy for a live attenuated vaccine against Argentine hemorrhagic fever. J Infect Dis 1998 Feb;177(2):277-83 [Abstract]

Martin JE, Sullivan NJ, Enama ME, et al. A DNA Vaccine for Ebola Virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 2006 Nov;13(11):1267-77 [Abstract]

Martini GA, Sieger R, eds. Marburg virus disease. Berlin: Springer-Verlag, 1971

Marty AM, Jahrling PB, Geisbert TW. Viral hemorrhagic fevers. Clin Lab Med 2006 Jun;26(2):345-86 [Abstract]

McCormick JB, King IJ, Webb PA, et al. A case-control study of the clinical diagnosis and course of Lassa fever. J Infect Dis 1987 Mar;155(3):445-55 [Abstract]

McCormick JB, King IJ, Webb PA, et al. Lassa fever: effective therapy with ribavirin. N Engl J Med 1986 Jan 2;314(1):20-6 [Abstract]

McCormick JB, King IJ, Webb PA, et al. A case-control study of the clinical diagnosis and course of Lassa fever. J Infect Dis 1987 Mar;155(3):445-55 [Abstract]

McCormick JB, Webb PA, Krebs JW, et al. A prospective study of the epidemiology and ecology of Lassa fever. J Infect Dis 1987 Mar;155(3):437-44 [Abstract]

Meegan JM. Rift Valley fever epizootic in Egypt: description of the epizootic and virological studies. Trans R Soc Trop Med Hyg 1979;73(6):618-23 [Abstract]

MIIS (Monterey Institute of International Studies): Center for Nonproliferation Studies. Chemical and biological weapons possession and programs past and present. Nov 2000 [Full text]

Miranda ME, Ksiazek TG, Retuya TJ, et al. Epidemiology of Ebola (subtype Reston) in the Phillipines, 1996. J Infect Dis 1999 Feb;179(suppl 1):S115-9 [Full text]

Monath TP. Lassa fever: review of epidemiology and epizootiology. Bull World Health Organ 1975;52:577-92

Monath TP. Yellow fever: an update. Lancet Infect Dis 2001 Aug;1(1):11-20 [Abstract]

Monson MH, Cole AK, Frame JD, Serwint JR, et al. Pediatric Lassa fever: a review of 33 Liberian cases. Am J Trop Med Hyg 1987 Mar;36(2):408-15 [Abstract]

Morrill JC, McClain DJ. Epidemiology and pathogenesis of Rift Valley fever and other phleboviruses. In: The Bunyaviridae. New York: Plenum Press, 1996:281-93

Morse SA, Kellogg RB, Perry S, et al. Detecting biothreat agents: the Laboratory Response Network. ASM News 2003 Sep;69(9):433-7

Mupapa K, Mudundu W, Bwaka MA, et al. Ebola hemorrhagic fever and pregnancy. J Infect Dis 1999 Feb;179(suppl 1):S11-2 [Abstract]

Nayak AJ, Srinivasa Rao PN. Ocular changes in Kyasanur Forest disease. J Indian Med Assoc 1983;81(9-10):158-60

Niedrig M, Schmitz H, Becker S, et al. First international quality assurance study on the rapid detection of viral agents of bioterrorism. J Clin Microbiol 2004 Apr;42(4):1753-5 [Full text]

NIH (National Institutes of Health). ICTVdB: Universal virus database [Web page]

Onyango CO, Grobbelaar AA, Gibson VF, et al. Yellow fever outbreak, Southern Sudan, 2003. Emerg Infect Dis 2004 Sep:10(9):1668-70 [Full text]

Pattnaik P. Kyasanur forest disease: an epidemiological view in India. Rev Med Virol 2006 May-Jun;16(3):151-65 [Abstract]

Pattyn SR, ed. Proceedings of an international colloquium on Ebola virus infection and other haemorrhagic fevers. Antwerp, Belgium, Dec 6-8, 1977 [Full text]

Pavri K. Clinical, clinicopathologic, and hematologic features of Kyasanur Forest disease. Rev Infect Dis 1989;11(suppl 4):S854-9

Paweska JT, Burt FJ, Swanepoel R. Validation of IgG-sandwich and IgM-capture ELISA for the detection of antibody to Rift Valley fever virus in humans. J Virol Methods 2005 Mar;124(1-2):173-81 [Abstract]

Peters CJ. California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. Ed 6. New York: Churchill Livingstone, 2005:2086-90

Peters CJ. Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. Ed 6. New York: Churchill Livingstone, 2005:2090-8

Peters CJ. Marburg and Ebola virus hemorrhagic fevers. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. Ed 6. New York: Churchill Livingstone, 2005:2057-60

Peters CJ, Johnson ED, Jarhling PB, et al. Filoviruses. In: Emerging viruses. Morse S, ed. New York, NY: Oxford University Press, 1991:159-75

Peters CJ, Kuehne RW, Mercado RR, et al. Hemorrhagic fever in Cochabamba, Bolivia, 1971. Am J Epidemiol 1974 Jun;99(6):425-33

Peters CJ, LeDuc JW. An introduction to Ebola: the virus and the disease. J Infect Dis 1999 Feb;179(suppl 1):ix-xvi [Full text]

Peters CJ, Reynolds JA, Slone TW, et al. Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator. Antiviral Res 1986;6:285-97 [Abstract]

Peters CJ, Zaki SR. Role of the endothelium in viral hemorrhagic fevers. Crit Care Med 2002 May;30(5 suppl):S268-73 [Full text]

Pittman PR, Liu CT, Cannon TL, et al. Immunogenicity of an inactivated Rift Valley fever vaccine in humans. Vaccine 1999 Aug 20;18(1-2):181-9 [Abstract]

Pourrut X, Kumulungui B, Wittman T, et al. The natural history of Ebola virus in Africa. Microbes and Infection 2005 Jun;7(7-8):1005-14 [Abstract]

Rodriguez-Carreno MP, Nelson MS, Botten J, et al. Evaluating the immunogenicity and protective efficacy of a DNA vaccine encoding Lassa virus nucleoprotein. Virology 2005 Apr 25;335(1):87-98 [Abstract]

Roels TH, Bloom AS, Buffington J, et al. Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo: risk factors for patients without a reported exposure. J Infect Dis 1999 Feb;179(suppl 1):S92-7 [Abstract]

Saijo M, Georges-Courbot MC, Marianneau P, et al. Development of recombinant nucleoprotein-based diagnostic systems for Lassa fever. Clin Vaccine Immunol 2007 Sep;14(9):1182-9 [Abstract]

Saijo M, Niikura M, Ikegami T, et al. Laboratory diagnostic systems for Ebola and Marburg hemorrhagic fevers developed with recombinant proteins. Clin Vaccine Immunol 2006 Apr;13(4):444-51 [Full text]

Salas R, de Manzione N, Tesh RB et al. Venezuelan haemorrhagic fever. Lancet 1991 Oct 26;338(8774):1033-6 [Abstract]

Sall AA, Macondo EA, Sene OK, et al. Use of reverse transcriptase PCR in early diagnosis of Rift Valley fever. Clin Diagn Lab Immunol 2002 May;9(3):713-5 [Abstract]

Sall AA, Thonnon J, Sene OK, et al. Single-tube and nested reverse transcriptase-polymerase chain reaction for detection of Rift Valley fever virus in human and animal sera 1. J Virol Methods 2001 Jan;91(1):85-92 [Abstract]

Sanchez A, Ksiazek TG, Rollin PE, et al. Detection and molecular characterization of Ebola viruses causing disease in human and nonhuman primates. J Infect Dis 1999 Feb;179(suppl 1):S164-S169 [Abstract]

Sanchez A, Trappier SG, Mahy BW, 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 Apr;93(8):3602-7 [Full text]

Sanchez A, Yang ZY, Xu L, et al. Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. J Virol 1998 Aug;72(8):6442-7 [Full text]

Shoemaker J, Boulianne C, Vincent MJ, et al. Genetic analysis of viruses associated with emergence of Rift Valley fever in Saudi Arabia and Yemen, 2000-01. Emerg Infect Dis 2002 Dec;8(12):1415-20 [Full text]

Smithburn KC, Mahaffy AF, Haddow AJ, et al. Rift Valley fever: accidental infections among laboratory workers. J Immunol 1949;62:213-27

Stephenson EH, Larson EW, Dominik JW. Effect of environmental factors on aerosol-induced Lassa virus infection. J Med Virol 1984;14:295-303

Sullivan NJ, Geisbert TW, Geisbert JB, et al. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 2003 Aug 7;424(6949):681-3 [Abstract]

Sullivan NJ, Geisbert TW, Geisbert JB, et al. Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified GPs. PLoS Med 2006 Jun;3(6):e177 [Full text]

Swanepoel R, Smits SB, Rollin PE, et al. Studies of reservoir hosts for Marburg virus. Emerg Infect Dis 2007 Dec;13(12):1847-51[Full text]

Swenson DL, Wang D, Luo M, et al. Vaccine to confer to nonhuman primates complete protection against multistrain Ebola and Marburg virus infections. Clin Vaccine Immunol 2008 Mar;15(3):460-7 [Abstract]

Towner JS, Rollin PE, Bausch DG, 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 Apr;78(8):4330-41 [Full text]

Towner JS, Sealy TK, Khristova ML, et al. Newly discovered Ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog 2008 Nov 21;4(11):e1000212 [Full text]

Tsai TF. Arboviruses. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of clinical microbiology. Ed 7. Washington, DC: American Society for Microbiology Press, 1999:1107-24

Tsai TF. Flaviviruses (yellow fever, Dengue, Dengue hemorrhagic fever, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis). In: Mandell GL, Bennett JE, Dolin R. Principles and practice of infectious diseases. Ed 5. New York: Churchill Livingstone, 2000:1855-73

Van der Lugt JJ, Coetzer JA, Smit MM. Distribution of viral antigen in tissues of new-born lambs infected with Rift Valley fever virus. Onderstepoort J Vet Res 1996 Dec;63(4):341-7

Vela EM, Bowick GC, Herzog NK, et al. Genistein treatment of cells inhibits arenavirus infection. Antiviral Res 2008 Feb;77(2):153-6 [Abstract]

Vieth S, Drosten C, Lenz O, et al. RT-PCR assay for detection of Lassa virus and related Old World arenaviruses targeting the L gene. Trans R Soc Trop Med Hyg 2007 Dec;101(12):1253-64 [Abstract]

Vogel G. Scientists say Ebola has pushed Western gorillas to the brink. Science 2007 Sep 14;317(5844):1484 [Abstract]

Weber DJ, Rutala WA. Risks and prevention of nosocomial transmission of rare zoonotic diseases. Clin Infect Dis 2001 Feb 1;32(3):446-56 [Full text]

Weidmann M, Muhlberger E, Hufert FT. Rapid detection protocol for filoviruses. J Clin Virol 2004 May;30(1):94-9 [Abstract]

WHO. Ebola haemorrhagic fever in Zaire, 1976. Report of an International Commission. Bull World Health Org 1978;56(2);271-93

WHO. Ebola Reston found in domestic pigs in the Philippines (frequently asked questions). [Full text]

WHO. Ebola Reston in pigs and humans in the Philippines. 2009 Feb 3 [Full text]

WHO. End of Ebola outbreak in the Democratic Republic of the Congo. 2009 Feb 17 [Full text]

WHO. Guidelines for the collection of clinical specimens during field investigation of outbreaks [Full text]

WHO. Lassa hemorrhagic fever. Dec 2001 [Full text]

WHO. Outbreaks of Rift Valley fever in Kenya, Somalia and United Republic of Tanzania, December 2006-April 2007. Wkly Epidemiol Rec 2007 May 18;82(20):169-80 [Full text]

WHO. Viral hemorrhagic fevers: report of a WHO expert committee, 1984 WHO technical report series 721. 1985 [Full text]

WHO. WHO recommended guidelines for epidemic preparedness and response: Ebola haemorrhagic fever (EHF). WHO/EMC/DIS/97.7 [Full text]

WHO. Yellow fever. Dec 2001 [Full text]

WHO. Yellow fever in Burkina Faso. 2008 Nov 3 [Full text]

WHO. Yellow fever in Paraguay—update 2. 2008 Mar 7 [Full text]

WHO. Yellow fever: situation updates [Web page]

WHO. Yellow fever in the Central African Republic. 2008 Oct 30 [Full text]

Wittmann TJ, Biek R, Hassanin A, et al. Isolates of Zaire ebolavirus from wild apes reveal genetic lineage and recombinants. Proc Natl Acad Sci 2007 Oct 23;104(43):17123-7 [Abstract]

Woods CW, Karpati AM, Grein T, et al. An outbreak of Rift Valley fever in northeastern Kenya, 1997-98. Emerg Infect Dis 2002 Feb;8(2):138-44 [Full text]

Youssef BZ, Donia HA. The potential role of Rattus rattus in enzootic cycle of Rift Valley fever in Egypt 2-application of reverse transcriptase polymerase chain reaction (RT-PCR) in blood samples of Rattus rattus. J Egypt Public Health Assoc 2002;77(1-2):133-41 [Abstract]

Zaki SR, Kilmarx PH. Ebola virus hemorrhagic fever. In: Nelson AM, Horsburgh CR, eds. Pathology of emerging infections. Washington, DC: American Society of Microbiology Press, 1997:299-312

Zaki SR, Shieh WJ, Greer PW, 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 Feb;179(suppl 1):S36-47 [Abstract]

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