VHF

Viral hemorrhagic fever

Overview

Last updated Jun 21, 2012

Agents and Pathogenesis

Agents
Pathogenesis

Agents

A wide range of viruses can cause viral hemorrhagic fever (VHF) 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, only one of which, Filoviridae, has been assigned to an order (Mononegavirales):

  • Filoviridae
  • Arenaviridae
  • Bunyaviridae
  • Flaviviridae

Specific hemorrhagic fever viruses in each of the four families and key characteristics are included in the table below. The table includes the predominant hemorrhagic fever viruses but is not a comprehensive list. For example, a new arenavirus (Lujo virus) was identified in 2008 as a cause of illness in humans in Africa (Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers). 

Characteristics of Hemorrhagic Fever Viruses
Familya
Agents
Characteristics

Filoviridaeb

—Ebola virus
    ~Five species (Zaire, Sudan, Cote d'Ivoire, Reston, and Bundibugyo) with varying degrees of antigenic cross-reactivityc
—Marburg virus
    ~Virus strains primarily fall into one major clade, 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

Arenaviridaee

—Old World arenaviruses:
    ~Lassa virus
—New World arenaviruses that cause disease in humans:
    ~Junin virus (Argentine hemorrhagic fever)
    ~Machupo virus (Bolivian hemorrhagic fever)

    ~Chapare virus (also found in Bolivia)
    ~Guanarito virus (Venezuelan hemorrhagic fever)
    ~Sabia virus (Brazilian hemorrhagic fever)
    ~Whitewater Arroyo virus (found in North America)

—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
    ~Alkhumra virus (identified in Saudi Arabia in 1995; considered a variant of Kyasanur Forest disease virus)
    ~Nanjianyin virus (identified in China; considered a variant of Kyasanur Forest disease virus)
—Omsk hemorrhagic fever virus
—Dengue virus (primary infection rarely causes hemorrhagic fever)

—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.
bFeldmann 1999; Jahrling 1999; Marty 2006; NIH; Peters 2010: Marburg and Ebola virus hemorrhagic fevers.
cTowner 2008.
dSanchez 1996, Sanchez 1998, Sanchez 1999.
eJahrling 1999; Marty 2006; NIH; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
fBowen 2000.
gNIH; Peters 2010: California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers; Gerrard 2004; Tsai 1999; Marty 2006.
hMadani 2005, Marty 2006, NIH, Ruzek 2010, Vaughn 2010, Wang 2009.

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Pathogenesis

The pathogenesis of hemorrhagic fever viruses is not completely understood; however, key points include the following (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) (Franz 1997).
  • Endothelial infection occurs with most hemorrhagic fever 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 (Gomez 2011; Feldmann 2011; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Peters 2010: Marburg and Ebola virus hemorrhagic fevers).
    • 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
    • Studies in primates demonstrate that Ebola and Marburg viruses lead to a dysregulation of the immune response, with elevated circulating levels of cytokines and chemokines (Geisbert 2003: Pathogenesis of Ebola hemorrhagic fever in primate models; Hensley 2011).
  • 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 (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 (Geisbert 2003: Pathogenesis of Ebola hemorrhagic fever in primate models). Findings from a study in rhesus macaques suggest that a mixed anti-inflammatory response syndrome (MARS) occurs following Ebola virus infection, similar to what is seen in severe sepsis and septic shock (Ebihara 2011).
  • Suppression of the host antiviral response appears to play a critical role in the pathogenesis of Ebola virus infection (Peters 2010: Marburg and Ebola virus hemorrhagic fevers; Ebihara 2006). Failure to mount an effective immune response may be related to an immunosuppressive amino acid sequence in the filovirus glycoprotein or the secretion of a soluble glycoprotein by infected cells (Peters 2010: Marburg and Ebola virus hemorrhagic fevers). In addition, extensive lymphoid necrosis (in the spleen, thymus, and lymph nodes) and lymphocyte depletion through apoptosis also may play a role in suppression of the immune response (Feldmann 2011); however, one report suggests that lymphocyte apoptosis may be not be essential for disease progression (Bradfute 2010).

A model of the pathogenesis of Ebola virus based on observations of infection in cynomolgus monkeys is as follows (Geisbert 2003: Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques):

  • 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, chemokines, and possibly other mediators, which cause vascular impairment and trigger the coagulation cascade, ultimately leading to DIC.
  • DIC then results in hemorrhagic shock, failure of multiple organs, 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

—Apoptosis of lymphocytes and lymphoid depletion
—Myocardial edema
—Microvascular infection and injury

Marburg virusc

—Extensive hepatocellular necrosis with intracytoplasmic viral inclusions
—Necrosis and hemorrhage in major organs

—Apoptosis of lymphocytes and lymphoid depletion
—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 (including 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; pathologic changes are most pronounced in the liver and kidneys

Kyasanur Forest disease virush

—Focal hepatocellular degeneration, fatty infiltration, and necrosis
—Hemorrhagic pneumonia
—Myocarditis
—Encephalitis

Omsk hemorrhagic fever virusi

—Scattered focal hemorrhages (particularly in the brain)
—Perivascular infiltration with thrombi in small vessels
—Interstitial pneumonia
—Hemosiderin deposits in hepatic Kupffer cells
—Brain edema

aOnly those agents considered to be potential biological weapons are included.
bEbihara 2011, Feldmann 2011, Gubler 1998; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
cGubler 1998; Hensley 2011; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
dGubler 1998; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
eGubler 1998; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Salas 1991; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
fAl-Hazmi 2003; Gubler 1998; Ikegami 2011; Peters 2002; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
gGubler 1998; Vaughn 2010; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
hGubler 1998; Pavri 1989.
iGubler 1998; Ruzek 2010

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Epidemiology

Global Disease Occurrence
    Ebola
    Marburg
    Lassa
    New World
    Rift Valley
    Yellow Fever
    Kyasanur Forest
    Omsk
Reservoirs/Vectors/Modes of Transmission 

Global Disease Occurrence 

Overview 

Most hemorrhagic fever viruses that cause disease in humans occur in relatively localized areas of the world (primarily sub-Saharan 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 Animal or Human Disease
General Pattern of Disease Occurrence

Ebola virus

—Sub-Saharan Africa (all except Ebola-Reston)
—Philippines (Ebola-Reston)

—First identified in 1976
—Outbreaks recognized primarily in sub-Saharan Africa
—Ebola-Reston first recognized in 1996 in the United States in monkeys imported from the Philippines

Marburg virus

Sub-Saharan Africa

—First identified in 1967
—Only 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
—Relatively 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 been associated with several illnesses in the western United States)

—At least six different New World arenaviruses 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)
—Expanded into the Arabian peninsula in 2000

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
—Several variant viruses have been discovered in recent years

Omsk hemorrhagic fever virus

Central Asia (Western Siberia)

—First identified in 1940s
—Several outbreaks reported in 1950s
—Few cases in recent years
—Relatively uncommon

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 outbreaks. 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]) (Peters 1999;Pourrut 2005; WHO 1978: Ebola hemorrhagic fever in Zaire).
  • Since 1976, nearly 20 outbreaks have been recognized in Equatorial Africa (CDC 2011: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order). Furthermore, a geographic pattern has emerged in which the Ebola-Zaire strain affects predominantly central Africa and the Ebola-Sudan strain affects Southern Sudan and East Africa. The only strain identified in West Africa is the Ivory Coast strain, although as of mid-2012, this virus had been detected only on one occasion (Pourrut 2005). The Ebola-Bundibugyo strain has been found in East Africa (in Uganda) (McNeil 2010, Wamala 2010).
  • The incidence of filovirus infections (with Ebola virus or Marburg virus) continues to be relatively low. As of 2008, these viruses combined have caused approximately 2,317 clinical cases and 1,671 confirmed deaths (Leroy 2011).
  • In some situations, human Ebola outbreaks have occurred in conjunction with deaths in animals species (including gorillas, chimpanzees, mandrills, and bush pigs) (Lahm 2007; Vogel 2007). Characterization of Ebola-Zaire isolates from wild ape carcasses implicated recombinant viruses from the apes as the cause of outbreaks among humans from 2003 through 2005 (Wittmann 2007). During outbreaks in rural settings, multiple introductions of the virus into the human population through wildlife likely occur; whereas, during outbreaks in urban settings, a single introduction of the virus in the community appears to be more common (Allaranga 2010).

A recent large serological survey of rural populations in Gabon, using a sensitive and specific enzyme-linked immunosorbent assay (ELISA), found an overall Immunoglobulin G (IgG) seroprevalence of 15.3% to the Ebola-Zaire strain (Becquart 2010, Nkoghe 2011). The survey lasted 3 years and included 4,349 adults and 362 children from 220 randomly selected villages, representing 10.7% of all villages in Gabon. These results suggest that a large portion of the population may have been exposed to low levels of the virus through a common source, such as bat saliva on contaminated fruits. The findings also indicate that mild illness or asymptomatic infection may occur with greater frequency than previously suggested and support the perspective that the Ebola-Zaire strain is endemic in Gabon. 

In addition to disease occurrence in Africa, several outbreaks of Ebola virus infection have been recognized in cynomolgus macaques in the Philippines or in monkeys imported from the Philippines into the United States or Italy; these situations have all involved the Ebola-Reston strain (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 in 1989 at a primate facility in Reston, Virginia, which is why the strain associated with these outbreaks is referred to as the Ebola-Reston strain. At that time, animal cases also occurred in primate facilities in Pennsylvania and Texas. All three locations had received monkeys from the same export facility in the Philippines.

  • Subsequently, outbreaks also occurred at the primate facility in the Philippines that exported the infected animals.
  • Several persons working with infected primates had serologic evidence of recent filovirus infection; however, as of mid-2012, no clinical illnesses associated with this strain have been reported in humans. 

In 2008, the Ebola-Reston strain was isolated from pigs in the Philippines. At the time, an increase in mortality was occurring on swine farms and samples from pigs that had died demonstrated evidence of infection with porcine reproductive and respiratory syndrome (PRRS) virus. In additions, some pigs had evidence of co-infection with the Reston-Ebola strain (Miranda 2011). 

  • Several people in contact with infected pigs had serologic evidence of infection, and all were asymptomatic; these results suggest that pigs can transmit the Ebola-Reston strain to humans. The most likely routes of transmission from pigs to humans include direct contact with the blood, secretions, organs, or other bodily fluids of infected animals and possibly respiratory transmission (WHO 2009: WHO expert consultation on Ebola Reston pathogenicity in humans).
  • Ongoing circulation of the Ebola-Reston strain in the pig population provides an unusual opportunity for continued genetic evolution to occur as a result of passage, adaptation, and possible natural selection of this virus (WHO 2009: WHO expert consultation on Ebola Reston pathogenicity in humans). Monitoring the virus in pig populations, therefore, is appropriate.

Experimental challenge studies have demonstrated that the Ebola-Reston strain can cause asymptomatic infection in pigs and that viral shedding can occur from the nasopharynx following infection. These findings suggest that infected pigs can pose a transmission risk to farm, veterinary, and abattoir workers (Marsh 2011). In response to the isolation of the Ebola-Reston strain from pigs, another group of investigators challenged domesticated pigs with the Ebola-Zaire strain. They found that pigs also can be infected with the Ebola-Zaire strain and that infected pigs develop severe respiratory disease (Kobinger 2011). Furthermore, infected pigs shed virus from the nasopharynx for approximately 14 days after infection and can transmit the virus to uninfected pigs.

Ebola hemorrhagic fever cases and outbreaks identified between 1976 and mid-2012 are outlined in the table below, which can be found on the Centers for Disease Control and Prevention (CDC) Web site (CDC 2011: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order).  

Recognized Cases and Outbreaks of Ebola Hemorrhagic Fever, In Chronological Ordera
Year(s)
Location
Strain
Cases, Deaths, CFR (%)

1976

Zaire (now DRC)

Ebola-Zaire

318 cases, 280 deaths, CFR 88%

1976

Sudan

Ebola-Sudan

284, 151, 53%

1976

England

Ebola-Sudan

1 case (survived); laboratory infection

1977

Zaire

Ebola-Zaire

1 case (died)

1979

Sudan

Ebola-Sudan

34, 22, 65%

1989

United States

Ebola-Reston

Cases in macaques only; no human cases

1990

United States

Ebola-Reston

Cases in macaques only; 4 asymptomatic human cases identified by serology

1989-1990

Philippines

Ebola-Reston

Cases in macaques only; 3 asymptomatic human cases identified by serology

1992

Italy

Ebola-Reston

Cases in macaques only; no human cases

1994

Gabon

Ebola-Zaire

52, 31, 60%

1994

Cote d'Ivoire

Ebola-Ivory Coast

Epidemic in wild chimpanzees; 1 human case (survived)

1995

DRC (formerly Zaire)

Ebola-Zaire

315, 250, 81%

1996

Gabon

Ebola-Zaire

37, 21, 57%

1996-1997

Gabon

Ebola-Zaire

60, 45, 74%

1996

South Africa

Ebola-Zaire

2, 1, 50%

1996

United States

Ebola-Reston

Cases in macaques only; no human cases

1996

Philippines

Ebola-Reston

Cases in macaques only; 1 asymptomatic human case identified by serology

2000-2001

Uganda

Ebola-Sudan

425, 224, 53%

2001-2002

Gabon

Ebola-Zaire

65, 53, 82%

2001-2002

Republic of Congo

Ebola-Zaire

57, 43, 75%

2002-2003

Republic of Congo

Ebola-Zaire

143, 129, 89%

2003

Republic of Congo

Ebola-Zaire

35, 29, 83%

2004

Southern Sudan

Ebola-Sudan

17, 7, 41%

2007

DRC

Ebola-Zaire

264, 187, 71%

2007-2008

Uganda

Ebola-Bundibugyo

131, 42, 32%

2008

Philippines

Ebola-Reston

Pigs shown to be infected; 6 asymptomatic human cases identified by serology

2008-2009

DRC

Ebola-Zaire

32, 15, 47%

2011

Uganda

Ebola-Sudan

1 (died)

 

 

 

 

Abbreviation: CFR, case-fatality rate; DRC: Democratic Republic of the Congo.

aCDC 2011: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order.

Marburg Hemorrhagic Fever 

Marburg hemorrhagic fever, like Ebola hemorrhagic fever, is an emerging disease in sub-Saharan Africa, although Marburg virus infection 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). These outbreaks were related to contact with African green monkeys that were imported from Uganda. 

The incidence of filovirus infections (with Ebola virus or Marburg virus) continues to be relatively low. As of 2008, these viruses combined have caused approximately 2,317 clinical cases and 1,671 confirmed deaths (Leroy 2011). 

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 cases and outbreaks are shown in the table below (CDC 2009: Known cases and outbreaks of Marburg hemorrhagic fever, in chronological order).  

Recognized Outbreaks of Marburg Hemorrhagic Fever, in Chronological Ordera
Location
Year(s)
Cases
Comments

1967

Frankfort, Germany, and Belgrade, Yugoslavia

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 23%).

1975

South Africa

3

1 index case and 2 secondary cases occurred; the index patient had been traveling extensively in Zimbabwe before illness onset; 1 death occurred (CFR 33%).

1980

Western Kenya

2

1 index case and a secondary infection in a healthcare worker; 1 death occurred (CFR 50%).

1987

Kenya

1

A single case occurred in a man who had been traveling extensively in Kenya (he died).

1998-2000b

DRC

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 suggested that bats in the mine may have served as reservoir hosts for the outbreak.

2004-2005

Angola (predominantly in the northern Uige Province)

252

227 of the cases died (CFR 90%).

2007

Uganda

4

All cases were young males who worked in a mine; 2 workers died (CFR 50%).

2008c

United States (exposure in Uganda)

1

The case occurred in a traveler returning from Uganda. He had visited a cave in Maramagambo forest at the southern edge of Queen Elizabeth National Park. The likely source of exposure was bats in the cave. The case survived.

2008d

Netherlands (exposure in Uganda)

1

This case also had visited the same cave in Maramagambo forest during a trip to Uganda; she died.

Abbreviation: CFR, case-fatality rate.

aCDC 2009: Known cases and outbreaks of Marburg hemorrhagic fever, in chronological order.
bSwanepoel 2007.
cCDC 2009.
dTimen 2009.

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 virus 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 (LeDuc 1989). This finding may be related to aggregation of rodents inside houses during the dry season because of limited food supplies outdoors (Fichet-Calvet 2007).
  • An estimated 100,000 to 300,000 Lassa fever virus infections occur annually in West Africa (McCormick 1987: A prospective study of the epidemiology and ecology of Lassa fever).
  • In a cross-sectional seroprevalence study conducted in the tropical forest area of Guinea, West Africa, the prevalence of Lassa virus antibodies was estimated at 12.9% and 10.0% in rural and urban areas, respectively (Kerneis 2009).
  • Occasionally, cases are imported from Africa into other countries (Isaacson 2001, Macher 2006). One report documented 24 cases of imported Lassa fever through 2004, with cases occurring in Europe, the United States, Canada, Israel, and Japan. A Lassa fever case occurred in 2010 in a US traveler who had visited rural Liberia and had become ill while in that country (Amorosa 2010). He sought medical care in Pennsylvania upon returning to the United States, where his illness was confirmed as Lassa fever. The patient recovered with supportive therapy, and no secondary cases were identified.
  • 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 (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) (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 (Charrel 2003): 

  • Junin virus (Argentine hemorrhagic fever)
    • This virus 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) (WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee). These provinces are all located in the northeastern part of the country and are contiguous to each other.
    • Traditionally, between 200 and 2,000 cases were reported annually; however, in 1993, 24,000 cases were reported (Lacy 1996). Vaccination of the local population has dramatically decreased the incidence of disease (Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).
    • 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.
    • Bolivian hemorrhagic fever is restricted to the El Beni district in northeastern Bolivia.
    • Between 1959 and 1962, 470 cases resulting in 142 deaths were reported (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 (CDC 1994: Bolivian hemorrhagic fever—El Beni department, Bolivia).
    • More than 200 cases occurred in 2008 (Aguilar 2009).
    • Small outbreaks tend to occur, with several years of quiescence between outbreaks.
  • Guanarito virus (Venezuelan hemorrhagic fever)
    • This virus was first recognized in 1989 when an outbreak involving more than 100 cases occurred in the Portuguesa state of central Venezuela (Salas 1991).
  • Sabia virus (Brazilian hemorrhagic fever)
    • This virus was first recognized in Brazil in 1990 when a single fatal case occurred (Lisieux 1994).
    • Two additional infections have been identified; both were laboratory-acquired (one in Brazil and one in the United States) (Armstrong 1999, Barry 1995, Lisieux 1994).
  • Chapare virus
    • A new arenavirus was discovered in 2004. The virus, referred to as Chapare virus, is responsible for some cases of VHF in Bolivia that have occurred outside the epidemic area for Machupo virus.
    • Genomic analysis of viruses from clinically ill patients revealed that Chapare virus is most closely related to Sabia virus (Delgado 2008).
  • Whitewater Arroyo virus
    • Three cases were reported from California from June 1999 to May 2000 (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.
    • Serum samples from patients with acute central nervous system disease or undifferentiated febrile illnesses that were submitted to the Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, CDC, from 1989 to 2000 demonstrated that two of 1,185 specimens had a fourfold rise in IgG antibody titers to Whitewater Arroyo virus, suggesting that this virus was the cause of illness (Milazzo 2011). 

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 (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 (LeDuc 1989; Anyamba 2006).

  • Mosquito eggs infected with Rift Valley fever virus can remain dormant but viable in soil for years while awaiting heavy rains for hatching.
  • 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 (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 (Faye 2007).
  • A major epidemic involving thousands of livestock cases and 18,000 human cases with approximately 600 deaths occurred in Egypt in 1977 (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 (Woods 2002).
  • More recently, a series of outbreaks occurred in 2006 and 2007 in several countries in East Africa (Kenya, Somalia, and Tanzania) (CDC 2007: Rift Valley fever outbreak—Kenya, November 2006–January 2007; Hassan 2011; Jost 2010; Mohamed 2010; Nderitu 2011). Analysis of specimens from animals in Kenya indicated that multiple viral lineages were responsible for the outbreak in that country (Bird 2008).
  • Recent outbreaks also have occurred in Madagascar (2008 and 2009), Mauritania (2010), and South Africa (2010) (Andriamandimby 2010; El Mamy 2011; WHO 2010: Rift Valley fever, South Africa).
  • 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 (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 (Madani 2003).
  • In 2007 and 2009, experts met to address possible introduction of the virus into the United States, as was seen with West Nile virus in 1999 (Britch 2007; Hartley 2011). 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 (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%. Vaccines against yellow fever are available.

The WHO estimates that 200,000 cases of yellow fever, causing 30,000 deaths, occur worldwide each year (WHO 2011: Yellow fever). According to the WHO, the incidence of yellow fever has increased over the past two decades owing to declining population immunity to infection, deforestation, urbanization, population movements, and climate change.

  • Three cycles have been recognized (WHO 2011: 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.
  • Outbreaks of urban yellow fever have occurred only rarely in the Americas since the mid-1900s 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. This concern was heightened following the occurrence of an outbreak of urban yellow fever in Paraguay in 2008 (Vaughn 2010).
  • In South America, most sylvatic yellow fever cases involve workers who spend time in the forested areas of Bolivia, Brazil, Ecuador, Colombia, and Peru.
  • In Africa, sylvatic and occasional urban outbreaks occur (WHO: Yellow fever: situation updates). Outbreaks primarily 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 (Onyango 2004).
  • Yellow fever is occasionally exported to Europe or North America (most often because of failure to vaccinate travelers to endemic areas).

The geographical risk assessment for yellow fever was updated in 2010 by the Informal WHO Working Group on Geographic Risk for Yellow Fever (Jentes 2011; WHO 2011: Revised recommendations for yellow fever vaccination for international travellers, 2011). This revised assessment takes into account recent trends in yellow fever occurrence, such as re-emergence of the disease in 2007 and 2008 in Paraguay and Argentina after more than 30 years and increased incidence of yellow fever in a number of countries in Central Africa. 

Kyasanur Forest Disease

Kyasanur forest disease, which is a tick-borne infection, is relatively rare and found only in one region in the southwestern part of India (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 and the disease are: (CDC: Kyasanur forest disease: fact sheet)

Kyasanur forest disease 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.
  • A variant of Kyasanur forest disease virus (referred to as the Alkhumra virus) was identified in Saudi Arabia in 1995 (Madani 2005). Since 1995, additional outbreaks and cases have been recognized in Saudi Arabia (Madini 2011).
  • Another variant of Kyasanur forest disease virus (referred to as the Nanjianyin virus) was isolated in 1989 from the serum of a patient in Yunnan province, China. Results of a serosurvey conducted in Yunnan between 1987 and 1990 demonstrated that 169 (19.5%) of 867 healthy residents of western Yunnan province and 6 (3.7%) of 161 healthy residents of northwestern Yunnan province carried antibodies against this virus (Wang 2009).

Omsk Hemorrhagic Fever Virus

Omsk hemorrhagic fever also is a rare form of tick-borne VHF and is limited to regions of Central Asia (CDC: Omsk hemorrhagic fever: fact sheet; Gritsun 2003; Ruzek 2010). Key epidemiologic features of the virus and the disease are: 

  • The disease was first recognized in the early 1940s in Omsk, Russia.
  • Two relatively large outbreaks occurred in the 1940s: one in 1945 (involving at least 200 cases) and one in 1946 (involving about 600 cases) (WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee).
  • From 1946 to 1958, 972 cases of Omsk hemorrhagic fever were officially recorded. After 1960, the incidence decreased substantially, and since that time Omsk hemorrhagic fever has been recognized infrequently. From 1988 to 1997, 165 cases were reported; 10 were associated with tick bites and 155 were in muskrat hunters and poachers. Small outbreaks were recognized in 1990 (29 cases) and 1991 (38 cases).Omsk hemorrhagic fever 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.
  • Omsk hemorrhagic fever 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.

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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, Ebola virus transmission may have occurred from an infected patient several hours before actual onset of symptoms (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 (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 VHF (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 (Borio 2002).  

Reservoirs and Modes of Transmission for Selected Hemorrhagic Fever Virusesa
Agent
Reservoir
Arthropod Vector
Modes of Transmission

Ebola virusb,c

Fruit bats (various species); possibly other reservoirs

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)

—Direct contact with infected pigs (Ebola-Reston strain only)
—Direct contact with infected bats (probable mode of transmission)—Possibly airborne through virus-containing droplets and aerosols (experimentally induced in monkeys and a probable mode of transmission for monkey-to-monkey spread)
—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

Rousettus aegyptiacus

(fruit bat species); possibly other reservoirs 

Unknown

—Contact with blood, tissues, or tissue cultures from infected monkeys

—Contact with infected bats or bat secretions (noted in confined spaces such as caves or mines in Africa)
—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,j

Ruminants (eg, cattle, sheep, and possibly wild ruminants), 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

—Possible consumption of raw milk from infected animals

Yellow fever virusb,k

Primates

Predominantly Aedes and Haemagogus mosquito species; A aegypti is most important vector for urban yellow fever

—Bite of infected mosquito
—Laboratory infections through parenteral exposure or unexplained routes (presumably aerosols)

—Vertical transmission from mother to infant
—Transmission through breastfeeding (yellow fever vaccine virus only)
 —Transfusion-associated transmission (yellow fever vaccine virus only)

Kyasanur forest disease virusb,k

Rodents, bats, and other small mammals (eg, striped forest squirrel, house shrew); 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,k

Rodents (including muskrats and voles)

Ticks (Dermacentor pictus, D 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.
bBorio 2002; LeDuc 1989; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee. cDowell 1999; Feldmann 2011; Formenty 1999Guimard 1999; Jaax 1995; Jaax 1996; Johnson 1995; Leroy 2005; Leroy 2009; Pourrut 2009; Taniguchi 2011; WHO 1978: Ebola hemorrhagic fever in Zaire.
d Adjemian 2011, Kuzmin 2010, Maganga 2011, Pourrut 2009, Towner 2009.
eCarey 1972; Fisher-Hoch 1995; McCormick 1987; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; WHO: Lassa fever: fact sheet.
fCDC 1994: Bolivian hemorrhagic fever; Peters 1974; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
gSalas 1991; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
hArmstrong 1999; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
iCDC 2000: Fatal illnesses associated with a New World arenavirus.
jLaBeaud 2011; Olive 2012; Peters 2010: California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers; Youssef 2002.
kBentlin 2011; CDC 2010: Transmission of yellow fever vaccine virus through breastfeeding; CDC 2010: Transfusion related transmission of yellow fever vaccine virus; Dobler 2010; Ruzek 2010; Vaughn 2010.

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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, New World arenaviruses, and yellow fever viruses (Alves 2010, Johnson 1995, Kenyon 1992, Reed 2011, Stephenson 1984). Additional viruses (Rift Valley fever virus and flaviviruses) have been shown to cause aerosol infections in the laboratory setting (Banerjee 1979, Smithburn 1949). These viruses are considered potentially suitable as biological weapons (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 (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, the 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 (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 (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

Several other hemorrhagic fever viruses have been identified as human pathogens; examples include Chapare virus (a New World arenavirus found in Bolivia), Whitewater Arroyo virus (a New World arenavirus found in the western United States), Alkhumra virus (a variant of Kyasanur forest disease virus found in Saudi Arabia), and Nanjianyin virus (a variant of Kyasanur forest disease virus found in Yunnan province, China). The role of these viruses as potential bioterrorism agents is unknown.

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 overview; 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)

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Clinical Characteristics and Differential Diagnosis

Clinical Characteristics
Pediatric Considerations
Differential Diagnosis
When to Consider the Diagnosis of VHF

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 viruses).
  • 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 disease are included in the tables below.

Clinical Features of Ebola Hemorrhagic Fever
Characteristic
Features

Incubation period

The most reliable information suggests 3-13 days, although some reports indicate a range of 2-21 days.

Prodrome

—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/symptoms

—Maculopapular rash (predominantly on trunk) about 5 days after illness onset occurs in about 50% of patients.
—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); massive bleeding is relatively uncommon and occurs late in the clinical course in fatal cases.
—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 features

—Leukopenia occurs early in clinical course; leukocytosis may occur later.
—Thrombocytopenia occurs early in clinical course.
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) may be seen as disease progresses.
—Laboratory features of DIC may occur as disease progresses, including prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen.

Complications (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 rate

—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)
    ~Bundibugyo, 32% in one recognized outbreak
—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.

References: Borio 2002; Bwaka 1999; Feldmann 2011; Khan 1999; Kibadi 1999; Kortepeter 2011; Leroy 2000: Human asymptomatic Ebola infection; Peters 2010: Marburg and Ebola Virus Hemorrhagic Fevers; WHO 2011: Ebola hemorrhagic fever; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.

Clinical Features of Marburg Hemorrhagic Fever
Characteristic
Features

Incubation period

2-21 days (average 5-9 days)

Prodrome

—Abrupt onset of fever, severe prostration, headache, myalgias is typical, but the patient may present with an influenza-like illness.
—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/symptoms

—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 features

—Leukopenia occurs early in clinical course (1,000-2,000/mm3); leukocytosis may occur later.
—Atypical lymphocytes may be present.
—Marked thrombocytopenia can occur early in clinical course and may be as low as 10,000/mm3.
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) are seen as disease progresses.
—Laboratory features of DIC may occur as disease progresses, including prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen.

Complications (generally occur at least 2 wk after illness onset)

—Orchitis
—Alopecia
—Uveitis
—Recurrent hepatitis

Case-fatality rate

Varies by outbreak (23%-93%)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; DIC, disseminated intravascular coagulation.

References: Gear 1975; Mehedi 2011; Peters 2010: Marburg and Ebola virus hemorrhagic fevers; WHO: Marburg haemorrhagic fever situation updates.

Clinical Features of Lassa Fever
Characteristic
Features

Incubation period

5-16 days

Prodrome

—Illness begins gradually with fever, weakness, generalized malaise.
—Arthralgias, back pain, nonproductive cough, retrosternal pain often appear by 3rd to 4th day.

Clinical signs/symptoms

—Most Lassa virus infections in Africa are mild or subclinical; severe multisystem disease occurs in only 5%-10% of infections.
—Severe exudative pharyngitis may occur (40% in one series of 306 patients).b
—Maculopapular 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.
—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.

Laboratory features

—Leukocyte counts occasionally are decreased but most often are normal or moderately increased.
—Hemoconcentration, proteinuria, and elevated hepatic enzymes may occur.
—Thrombocytopenia is mild or does not occur, although marked loss of platelet function has been demonstrated in vitro.
—Mean laboratory values noted 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)

Complications (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)
—Transient alopecia during convalescence
—Illness-induced abortion among pregnant women
—Uveitis and orchitis (uncommon)

Case-fatality rate

—Overall mortality (including nonhospitalized patients), 1%-2%
—Hospitalized patients, 15%-25%
—Series of 150 hospitalized patients, 9%
—Series of 441 hospitalized patients, 16.5%

Abbreviations: ALT, alanine aminotransferase; AST: aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase; WBC, white blood cell.

References: Borio 2002; Frame 1989; McCormick 1987: A case-control study; McCormick 1987: A prospective study; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.

Clinical Features of New World Hemorrhagic Fever
Characteristic
Features

Incubation period

7-12 days (range 5-19 days) following natural exposure

Prodrome

Gradual onset of fever, sore throat, myalgias, low back pain, abdominal pain

Clinical signs/symptoms

—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 included:
    ~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 features

—Leukopenia (1,000-2,500/mm3)
—Thrombocytopenia (40,000-80,000/mm3)
—Proteinuria (may be >10 g/day; occurs occasionally)
—Hemoconcentration

Complications

—Transient alopecia and nail furrows may occur.
—Most patients who survive recover without sequelae, although convalescence may require several weeks.

Case-fatality rate

—Junin (Argentine hemorrhagic fever), 15%-30%
—Machupo (Bolivian hemorrhagic fever), 15%-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)

References: Borio 2002; CDC 2000: Fatal illnesses associated with a New World arenavirus; CDC 1994: Bolivian hemorrhagic fever; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Salas 1991; WHO1985: Viral haemorrhagic fevers: report of a WHO expert committee.

Clinical Features of Rift Valley Fever
Characteristic
Features

Incubation period

2-6 days

Prodrome

Fever, headache, photophobia, retro-orbital pain

Clinical signs/symptoms

—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 identified 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 features

—Initial leukocytosis may occur, followed by leukopenia.
—Thrombocytopenia may be seen in severe cases.
—Laboratory features of DIC may occur in severe cases, including prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen.
—Elevated hepatic enzymes (eg, ALT, AST) and bilirubin

Complications

—Blindness following retinitis
—Neurologic sequelae following encephalitis

Case-fatality rate

—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.

References: Al-Hazmi 2003; Borio 2002; CDC 2000: Outbreak of Rift Valley fever--Yemen; CDC: Rift Valley fever fact sheet; Ikegami 2011; Lacy 1996; Madani 2003; Morrill 1996; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.

Clinical Features of Yellow Fever
Characteristic
Features

Incubation period

3-6 days (median, 4.3 days)

Prodrome

—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/symptoms

—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 features

—Leukopenia occurs early in clinical course; leukocytosis may occur later.
—Thrombocytopenia
—Albuminuria
—Elevated hepatic enzymes (eg, ALT, AST)
—Elevated bilirubin (5-10 mg/dL)

Complications

—Myocarditis

Case-fatality rate

—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.

References: Borio 2002; Johansson 2010; Lacy 1996; Vaughn 2010; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee; WHO 2011: 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/symptoms

—Diarrhea and vomiting occur by 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.
—Cervical and axillary lymphadenopathy are usually present.
—Bleeding manifestations are seen as early as 3rd day (bleeding from nose, gums, gastrointestinal tract).
—In one series of 152 patients, bleeding occurred in 26 patients (17%).
—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 features

—Leukopenia (average: 2,000/mm3)
—Lymphopenia or lymphocytosis, atypical lymphocytes (may occur)
—Thrombocytopenia (average: 86,000/mm3)
—Abnormal liver function tests may occur

Complications

Iridokeratitis has been reported in survivors.

Case-fatality rate

3%-10%

References:Borio 2002, Nayak 1983, Pavri 1989, Pattnaik 2006, Vaughn 2010.

Clinical Features of Omsk Hemorrhagic Fever
Characteristic
Features

Incubation period

2-9 days (usually 3-8 days)

Prodrome

Fever, headache, vomiting, enanthem on palate, hyperemia of skin on upper body and mucous membranes

Clinical signs/symptoms

—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 features

—Leukopenia
—Thrombocytopenia
—Monocytosis

Complications

Transient alopecia may occur

Case-fatality rate

0.5%-10%

References: Borio 2002; Ruzek 2010; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.

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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 (Monson 1987):

  • Fetal infection (18 pregnancies):
    • Spontaneous abortion following onset of infection occurred in 16 cases (one mother later died).
    • Fetal death occurred in 2 cases; 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 noted above for Lassa fever) and also demonstrated a high case-fatality rate for pregnant women (Mupapa 1999):

  • Spontaneous abortion occurred in 10 women
  • All the mothers presented with severe bleeding; all but 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 third trimester of pregnancy.

Vertical transmission also has been reported for Rift Valley fever (Adam 2008, Arishi 2006) and for yellow fever (Bentlin 2011).

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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 primarily April through May.
—Most US cases occur in southeastern and south-central states.

Ehrlichiosis

Ehrlichia chaffeensis
Erhlichia phagocytophilia

—A history of tick exposure 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 travel to the 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 the usual prodrome (ie, bleeding generally will occur sooner than would be expected with VHF).

Measles

Rubeola virus

—Presenting features usually include cough, coryza, and 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 viruses and other viruses less commonly)

—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 is 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.

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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
Laboratory Biosafety and Biosecurity Information
The Laboratory Response Network
Tests for Detection of Hemorrhagic Fever Virus Infection

Specimen Collection and Transport

The American Society for Microbiology (ASM), in collaboration with the CDC and the Association of Public Health Laboratories (APHL), has developed sentinel laboratory guidelines to provide information regarding the diagnosis of microorganisms that could be agents of bioterrorism (ASM: Sentinel level clinical microbiology laboratory guidelines).

According to the sentinel laboratory guidelines for unknown viruses, clinical laboratories should consult public health authorities before collection of specimens for diagnostic testing (ASM 2003).

The CDC recommends that patients with suspected VHF have paired acute blood specimens (ideally collected during days 0 to 4 and days 4 to 9 of the acute illness) tested at a World Reference Laboratory (eg, the CDC) with biosafety level 4 capability using multiple methods as appropriate for the timing of the sample, including virus isolation, reverse transcription PCR (RT-PCR), and IgM and IgG ELISA (CDC 2009: Imported case of Marburg hemorrhagic fever).

Guidelines have been published for packing and shipping of infectious substances, diagnostic specimens, and biological agents from suspected acts of bioterrorism (ASM 2011).

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Laboratory Biosafety and Biosecurity Information

Biosafety

  • 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) (Armstrong 1999; Banerjee 1979; Borio 2002; CDC: Biosafety in microbiological and biomedical laboratories; CDC 1994: Bolivian hemorrhagic fever—El Beni department, Bolivia; Smithburn 1949). This is of particular concern for arenaviruses, since all of them are infectious as aerosols (Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers).
  • Hazards in the laboratory setting include (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 (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.
  • Specimens from patients with suspected VHF should be referred to an LRN national laboratory (eg, the 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 (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 (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.
    • 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 (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 (CDC 1995: Update: Management of patients with suspected viral hemorrhagic fever—United States).
    • Blood smears for malaria are considered noninfectious for hemorrhagic fever viruses after solvent fixation (CDC 1995: Update: 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 (Borio 2002).

Biosecurity

  • 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 in final form in the Federal Register in March 2005 (HHS 2005). 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). Select agents are biological agents designated by the US government to be major threats to public health and safety. A current list of select agents is published on the CDC Web site under information about the Select Agent Program (CDC/APHIS 2011). In addition, the CDC has published additional guidelines for enhancing laboratory security for laboratories working with select agents (CDC 2002: Laboratory security and emergency response guidance for laboratories working with select agents).
  • Most hemorrhagic fever viruses are classified as WHO risk group 4. Specimens and isolates that are reasonably suspected to contain a hemorrhagic fever virus must be transported as "infectious substances." The US Department of Transportation (DOT) regulations and International Air Transport Association (IATA) rules require training of all individuals involved in the transport of dangerous goods, including infectious substances (DOT and IATA 2012).

Chain-of-custody should be documented for material that may constitute evidence of criminal activity.

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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, Australia, Mexico, and South Korea) (CDC: Facts about the Laboratory Response Network).

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

  • Sentinel laboratories, formally called "level A laboratories,"represent an estimated 25,000 hospital-based laboratories that have direct contact with patients. In an unannounced or covert terrorist attack, sentinel laboratories could be the first facilities to encounter suspicious specimens. These laboratories generally have at least BSL-2 containment capabilities. A sentinel laboratory's responsibility is to rule out conditions of interest or refer suspicious samples to the nearest LRN reference laboratory. Sentinel laboratories use the ASM Sentinel Level Clinical Microbiology Laboratory Guidelines to rule out microorganisms that might be suspected as agents of bioterrorism (ASM).
  • 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 but also include military, international, veterinary, agriculture, and food- and water-testing laboratories. Reference laboratories operate with BSL-3 containment facilities that have been given access to nonpublic testing protocols and reagents. One of the roles of the LRN reference laboratories is to provide guidance, training, outreach, and communications to the sentinel laboratories in their jurisdictions.
  • National laboratories have unique resources to handle highly infectious agents and the ability to identify specific agent strains through molecular characterization methods. These laboratories also are responsible for methods development, bioforensics, and select-agent activity.

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 (CDC: Biosafety in microbiological and biomedical laboratories).
  • 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 of the reference laboratories in the LRN. Laboratory personnel should be vaccinated as appropriate 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.

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

Laboratory Testing for Most Viral Hemorrhagic Fever Viruses
Agent
Diagnostic Tests
Comments

Ebola and Marburg Virusesa

—RT-PCR, including quantitative real-time RT-PCR
—Antigen detection by antigen-capture ELISA
—Viral isolation (virus can be cultured from clinical specimens during the acute stages of illness)
—IgM antibodies detected in capture ELISA (are useful in early convalescence)
—Serology (seroconversion occurs 8-12 days after illness onset)

IgG serologic testing has not been reliable; use of the IgG ELISA may address this issue.

Lassa Fever Virus and New World Arenavirusesb

—RT-PCR (can be used to diagnose all arenavirus infections)
—Viral isolation (viruses can be recovered from blood during acute illness; viremic phase range is 3-20 days)
—Viral isolation from biopsy or autopsy specimens of lymphoid tissues, bone marrow, and liver
—Throat swabs (for Lassa fever; late shedding can occur as late as 67 days after illness onset)
—IgM antibodies detected by IFA or ELISA (for Lassa fever)

—Machupo virus can be difficult to isolate.
—One report found that IgM can persist for months in patients with Lassa fever, suggesting that IgM status alone cannot necessarily be considered a diagnostic marker of acute infection in suspected cases living in endemic areas of West Africa.c

Rift Valley Fever Virusd

—PCR—Antigen-detection ELISA
—Viral culture (virus is readily recovered from blood during acute illness)
—Serology (seroconversion usually occurs 5-14 days after illness onset and coincides with clinical improvement)
—IgM-capture ELISA for antibody detection

The virus can be easily aerosolized, so attempts to isolate it should be limited to facilities with maximal containment.

Yellow Fever Viruse

—RT-PCR
—Viral isolation from blood (early in the clinical course)
—Viral identification from biopsy or autopsy specimens
—IgM detection by antibody-capture ELISA
—Serology (fourfold change in serum antibody titer)

—For virus isolation, tissue samples should be divided into aliquots that are frozen at −70°C.
—For light and electron microscopy, tissue samples should be fixed in buffered formalin and glutaraldehyde.

Abbreviations: ELISA, enzyme-linked immunosorbent assay; IFA, indirect fluorescent antibody; IgG, immunoglobulin G; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase PCR.

aDrosten 2002; Drosten 2003; Leroy 2000; Nakayama 2010; Ogawa 2011; Peters 2010: Marburg and Ebola virus hemorrhagic fevers; Saijo 2006; Towner 2004; Trombley 2010.
bDrosten 2003; Panning 2010; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Saijo 2007; Trombley 2010; Vieth 2007.
cBranco 2011.
dPaweska 2005; Peters 2010: California encephalitis, hantavirus pulmonary syndrome, and Bunyavirid hemorrhagic fevers; Sall 2001; Sall 2002.
eVaughn 2010.

Additional points:

  • The common clinical material used for VHF PCR is serum or plasma. Collection of blood in ethylenediaminetriacetic acid tubes ensures the highest PCR efficiency compared with serum, heparin, or citrate tubes (Drosten 2003).
  • Serology (either testing an acute-phase specimen for IgM antibody or testing paired sera) can be used to diagnose most VHF infections.
  • 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 (Zaki 1999), Marburg virus (Geisbert 1998), and Rift Valley fever virus (demonstrated in lambs; see Van der Lugt 1996) and would presumably be equally effective with the other hemorrhagic fever viruses.
  • Although cell culture 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 (Drosten 2003).

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Treatment, Postexposure Prophylaxis, and Vaccines

Treatment
Postexposure Prophylaxis
Vaccination

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, which have not been shown to be of value, may be considered in certain situations because adrenal involvement may occur with VHF (Abraham 2002, Annane 2002)
  • Anticoagulant therapies, aspirin, nonsteroidal anti-inflammatory medications, and intramuscular injections are contraindicated
  • Appropriate therapy for secondary infections

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 (Enria 2008; Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).

Ribavirin has some in vivo and in vitro activity against:

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)

Examples of experimental modalities under consideration for treatment of filovirus infections include the following (Kondratowicz 2012, Roddy 2011):

  • Recombinant nematode anticoagulant protein c2 (a known inhibitor of tissue factor [TF]–initiated blood coagulation)
  • Recombinant human-activated protein C (currently licensed treatment of sepsis)
  • Therapies that target the mRNA of different viral genes directly through steric hindrance or degradation of the target sequence
  • Small molecules that directly target Ebola virus glycoprotein  

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 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.

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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 (Borio 2002) and others have echoed this approach (Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers). 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) (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 case of Lassa fever in 2004 (CDC 2004: Imported Lassa fever—New Jersey).

One group of researchers has suggested that ribavirin be used for postexposure prophylaxis against Lassa fever only following exposure to an acutely ill patient and when high-risk contact has occurred, such as in the following situations (Bausch 2010):

  • Penetration of skin by a contaminated sharp instrument (eg, needlestick injury)
  • Contamination of mucous membranes or broken skin with blood or bodily secretions (eg, blood splashing in the eyes or mouth)
  • Participation in emergency procedures (eg, resuscitation after cardiac arrest, intubation, or suctioning) without use of appropriate PPE
  • Prolonged (ie, for hours) and continuous contact in an enclosed space without use of appropriate PPE (eg, a healthcare worker accompanying a patient during medical evacuation)

Several studies have examined the use of postexposure prophylaxis for protection against filovirus infection. This issue is further addressed in the section on vaccines below.

  • A recombinant vesicular stomatitis virus–based vaccine was used in Germany to protect a laboratory worker following accidental needlestick exposure to Ebola virus. The worker did not develop illness and apparently was protected by the vaccine (Gunther 2011).
  • Another study found that postexposure prophylaxis using concentrated polyclonal IgG antibodies can protect nonhuman primates from infection with Marburg and Ebola viruses (Dye 2012).

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Vaccination

Yellow Fever Vaccine

Two yellow fever vaccines are manufactured: the 17DD and 17D-204 yellow fever vaccines. Both are attenuated live-virus vaccines. The yellow fever virus strains in these two vaccines share 99.9% sequence homology (CDC 2010: Yellow fever vaccine).

  • The 17DD vaccine is manufactured in Brazil and is used in Brazil and other South American countries.
  • The 17D-204 vaccine is manufactured and used outside of Brazil, including in the United States. Currently, yellow fever vaccination is carried out for three primary reasons: to protect populations living in areas subject to endemic and epidemic spread of yellow fever, to protect travelers visiting these areas, and to prevent international spread by minimizing the risk of importation and translocation of the virus by viremic travelers (WHO 2011: Revised recommendations for yellow fever vaccination for international travellers, 2011).
  • For US citizens, yellow fever vaccine is recommended only for:
    • Travelers (9 months of age and older) to tropical areas of South America and Africa that are endemic for yellow fever (Certain countries require evidence of vaccination from all entering travelers, which includes direct travel from the United States.) Laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of yellow fever vaccine virus strains by direct or indirect contact or by aerosols
  • 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 following vaccination does not develop for approximately 10 days (Borio 2002, Monath 2001).

The CDC recommends a single subcutaneous injection of 0.5 mL of reconstituted vaccine for primary vaccination. Booster doses are recommended every 10 years.

Details about the vaccine, including contraindications, precautions, and adverse reactions, can be found in the 2010 statement from the Advisory Committee on Immunization Practices (CDC 2010: Yellow fever vaccine).

Current yellow fever vaccines have potentially serious and life-threatening adverse reactions, so researchers are exploring potentially safer candidates. One, referred to as XRX-001, is a whole-virus inactivated vaccine. In a 2011 study, a two-dose regimen of XRX-001 induced neutralizing antibodies in a high percentage of subjects (Monath 2011).

Vaccines for Other Hemorrhagic Fever Viruses

  • A live-attenuated vaccine against Argentine hemorrhagic fever virus (ie, Junin virus) has shown greater than 95% efficacy and no side effects (Maiztegui 1998). This vaccine has been used in Argentina and has contributed to a decrease in VHF cases in that country (Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).
  • A number of Rift Valley fever vaccines have been developed, and additional work in this area is ongoing (Ikegami 2009). An inactivated Rift Valley fever vaccine has been used by the US Army (Pittman 1999).
  • 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 (Dandawate 1994). The vaccine has been licensed and is currently being used routinely in endemic areas (Pattnaik 2006).
  • Efforts to develop a vaccine against Lassa fever virus are ongoing (Cleri 2006, Fisher-Hoch 2004, Geisbert 2005, Grant-Klein 2011).
  • A number of studies on vaccines for Marburg and Ebola viruses have been published over the last few years.
    • Currently, multiple vaccine platforms have provided protection against filovirus infections in nonhuman primates, including DNA, recombinant adenovirus serotype 5, recombinant human parainfluenza virus 3, recombinant vesicular stomatitis virus, and virus-like particles (Falzarano 2011).
    • A recombinant vesicular stomatitis virus (rVSV) vaccine that expresses a filovirus glycoprotein has been shown to completely protect nonhuman primates against Marburg virus and three different species of Ebola virus (Geisbert 2011).
    • Postexposure vaccination may be useful in accidental exposure situations and could also be used to control secondary transmission during naturally occurring outbreaks or deliberate releases (Feldmann 2007). rVSV-based vaccines have shown utility when administered as a postexposure treatment against filovirus infections. Studies have shown that virus-like particle vaccines can confer complete homologous protection against Ebola virus and Marburg virus in a prophylactic setting in macaques (Warfield 2011).

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Infection Control (Including Autopsies and Burial)

Nosocomial Transmission
Isolation Precautions
Environmental Decontamination
Issues Related to 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 (Weber 2001).

  • Nosocomial and household transmission most often has been associated with contact with infected blood or body fluids (Dowell 1999, Monath 1975).
  • In some instances, transmission has resulted from reuse of needles or accidental needlesticks (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 (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 (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 (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 (Borio 2002).
  • In some developing countries, inconsistent use of protective gear can contribute to infection of healthcare workers (Borchert 2011). Reasons for poor usage include unavailability of the gear, adherence to traditional explanatory models of disease origin, and bonding with sick colleagues (Borchert 2007).
  • Contact with cadavers has also been shown to be a source of exposure during outbreaks of Ebola hemorrhagic fever (CDC 2001: Outbreak of Ebola hemorrhagic fever—Uganda; Roels 1999).

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Isolation Precautions

Appropriate isolation precautions for patients with suspected or confirmed VHF include a combination of Airborne and Contact Precautions (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 (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 (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, they can be cohorted in the same part of the hospital to minimize exposure to other patients and healthcare workers.

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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. However, such viruses can persistent on inanimate surfaces for up to several weeks (Percy 2010).

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 (Borio 2002).

The Working Group on Civilian Biodefense and the CDC make the following recommendations for environmental decontamination in the hospital setting (Borio 2002; CDC 1995: 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 the 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 (CDC 1995: 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 (Borio 2002).

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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 (CDC 2004: Medical examiners, coroners, and biologic terrorism).
  • In addition, autopsy personnel should wear N-95 respirators during all autopsies, regardless of suspected or known pathogens. PAPRs equipped with N-95 or 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 (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" (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 (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. 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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Recent News

Apr 11, 2014

News Scan for Apr 11, 2014

MSF Ebola site resumes
Ionizing radiation for seafood
Apr 10, 2014

WHO steps up West Africa Ebola response, reports new cases

Five more suspected cases have been detected in Guinea and Liberia.

Apr 07, 2014

Guinea, Liberia investigate more Ebola cases

Each country has confirmed 6 new cases, bringing the outbreak total to 143.

Apr 04, 2014

Minnesota Lassa fever case is first in US since 2010

Minnesota health officials diagnosed Lassa fever in a man who had traveled to West Africa.

Apr 02, 2014

Five more Ebola cases, 3 more dead in Guinea

The new Ebola cases push the outbreak total to 127 cases, including 83 fatal ones.

Apr 01, 2014

More deaths reported in Guinea Ebola outbreak

Two more patients have died in Guinea's Ebola outbreak, pushing the number of fatal cases to 80.

Mar 31, 2014

Tests confirm Ebola infections in Liberia

Lab tests have confirmed Ebola in two patients from a district that borders Guinea.

Mar 27, 2014

Four Ebola cases confirmed in Guinea's capital

The number of suspected and confirmed cases in the nation climbed from 86 to 103.

Mar 24, 2014

Ebola outbreak kills 59 in Guinea

The WHO today said Guinea has 86 suspected Ebola cases—13 of them lab-confirmed—and 59 deaths.

Mar 21, 2014

News Scan for Mar 21, 2014

MERS-CoV in man and his camel
UK panel recommends Bexsero
PAHO cholera update
New antiviral center
Grant for Ebola therapeutics

Resources & Literature

Recent Literature

Akinci E, Bodur H, Leblebiciouglu H. Pathogenesis of Crimean-Congo hemorrhagic fever. Vector Borne Zoonotic Dis 2013 Jul 2;13(7):429-37

Albarino CF, Shoemaker T, Khristova ML, et al. Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012. Virology 2013 Aug 1;442(2):97-100

Antonis AFG, Kortekaas J, Kant J, et al. Vertical transmission of Rift Valley fever virus without detectable maternal viremia. Vector Borne Zoonotic Dis 2013 May 19;13(8):601-6

Boone I, Wagner-Wiening C, Reil D, et al. Rise in the number of notified human hantavirus infections since October 2011 in Baden-Wurttemberg, Germany. Euro Surveill 2012 May 24;17(21):pii=20180

Breed AC, Meers J, Sendow I, et al. The distribution of henipaviruses in southeast Asia and Australasia: is Wallace's Line a barrier to nipah virus? PLoS One 2013 Apr 24;8(4):e61316

CDC. Notes from the field: hantavirus pulmonary syndrome in visitors to a national park--Yosemite Valley, California, 2012. MMWR 2012 Nov 23;61(46):952

CDC. Ongoing dengue epidemic--Angola, June 2013. MMWR 2013 Jun 21;62(24):504-7

Celikbas AK, Dokuzoguz B, Baykam N, et al. Crimean-Congo hemorrhagic fever among health care workers, Turkey. Emerg Infect Dis 2014 (published online Jan 27)

Ceylan B, Calica A, Ak O, et al. Ribavirin is not effective against Crimean-Congo hemorrhagic fever: observations from the Turkish experience. Int J Infect Dis 2013 (published online Jun 17)

Dokuzoguz B, Celikbas AK, Gok ES, et al. Severity scoring index for Crimean-Congo hemorrhagic fever and the impact of ribavirin and corticosteriods on fatality. Clin Infect Dis 2013 Aug 14;57(9):1270-4

Du Hong, Wang PZ, Li J, et al. Clinical characteristics and outcomes in critical patients with hemorrhagic fever with renal syndrome. BMC Infect Dis 2014 Apr 8;14(191)

Faye O, Ba H, Ba Y, et al. Reemergence of Rift Valley fever, Mauritania, 2010. Emerg Infect Dis 2014 (published online Jan 8)

Gozel MG, Dokmetas I, Oztop AY, et al. Recommended precaution procedures protect healthcare workers from Crimean-Congo hemorrhagic fever virus. Int J Infect Dis 2013 (published online Jun 29)

Hernandez-Avila JE, Rodriguez MH, Santos-Luna R, et al. Nation-wide, web-based, geographic information system for the integrated surveillance and control of dengue fever in Mexico. PLoS One 2013 Aug 6;8(8):e70231

Knust B, Rollin PE. Twenty-year summary of surveillance for human hantavirus infections, United States. Emerg Infect Dis 2013 (published online Nov 14)

Koksal I, Yilmax G, Aksoy F, et al. The seroprevalance of Crimean-Congo haemorrhagic fever in people living in the same environment with Crimean-Congo haemorrhagic fever patients in an endemic region in Turkey. Epidemiol Infect 2013 (published online May 21)

Lagerqvist N, Moiane B, Mapaco L, et al. Antibodies against Rift Valley fever virus in cattle, Mozambique. (Letter) Emerg Infect Dis 2013 Jul;19(7):1177-9

Li W, He YW. Infection with a novel virus causes hemorrhagic fever in China. Int J Infect Dis 2013 Jul;17(7):e556-61

Metras R, Baguelin M, Edmunds WJ, et al. Transmission potential of Rift Valley fever virus over the course of the 2010 epidemic in South Africa. Emerg Infect Dis 2013 Jun;19(6):916-24

Monaco F, Pinoni C, Cosseddu GM, et al. Rift Valley fever in Namibia, 2010. Emerg Infect Dis 2013 (published online Nov 8)

Oflaz B, Kucukdurmaz Z, Guven AS, et al. Bradycardia seen in children with Crimean-Congo hemorrhagic fever. Vector Borne Zoonotic Dis 2013 (published online Oct 9)

Papa A, Sidira P, Larichev V, et al. Crimean-Congo hemorrhagic fever virus, Greece. Emerg Infect Dis 2014 (published online Jan 9)

Safronetz D, Falzarano D, Scott DP, et al. Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Antimicrob Agents Chemother 2013 (published online Jul 15)

Sam SS, Omar SFS, Teoh BT, et al. Review of dengue hemorrhagic fever fatal cases seen among adults: a retrospective study. PLoS Negl Trop Dis 2013 May 2;7(5):e2194

Sindato C, Karimuribo ED, Pfeiffer DU, et al. Spatial and temporal pattern of Rift Valley fever outbreaks in Tanzania; 1930 to 2007. PLoS One 2014 Feb 25;9(2):e88897

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