| |
 |
|
|
|
|
|
|
|
|
Viral Hemorrhagic Fever (VHF): Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis
Last updated May 22, 2008
Agents
Pathogenesis
Epidemiology
—Hemorrhagic Fever Viruses as Biological Weapons
—Global Disease Occurrence
—Reservoirs/Vectors/Modes of Transmission
Clinical Characteristics
—Ebola Hemorrhagic Fever
—Marburg Hemorrhagic Fever
—Lassa Fever
—New World Hemorrhagic Fever
—Rift Valley Fever
—Yellow Fever
—Kyasanur Forest Disease
—Omsk Hemorrhagic Fever
Pediatric Considerations
Differential Diagnosis
When to Consider the Diagnosis of VHF
Laboratory Diagnosis
—Specimen Collection and Transport
—Laboratory Biosafety and Biosecurity Information
—Laboratory Response Network
—Tests for Detection of Hemorrhagic Fever Viruses
Treatment
Postexposure Prophylaxis
Vaccination
Infection Control
Issues Related to Autopsies and Burial
Public Health Reporting
References
Agents
Several different viruses can cause a hemorrhagic fever syndrome and hence are designated as hemorrhagic fever viruses.
-
All possess single-stranded RNA (which requires reverse transcriptase for multiplication or amplification by polymerase chain reaction [PCR])
-
All possess a lipid envelope
Hemorrhagic fever viruses belong to four taxonomic families:
-
Filoviridae
-
Arenaviridae
-
Bunyaviridae
-
Flaviviridae
Specific hemorrhagic fever viruses in each of the four families and key characteristics are included in the table below.
|
Family*
|
Agents
|
Characteristics
|
|
Filoviridae†
|
—Ebola virus
~Four species (Zaire, Sudan, Cote d'Ivoire, Reston) with varying degrees of antigenic cross-reactivity
~Subspecies further differentiated into named strains
—Marburg virus
~Two lineages, with less genetic diversity than Ebola virus
~No serologic cross-reactivity with Ebola virus, which is classified in a separate genus
|
—Origin of family and genus names from Latin "filo" for "thread"
—Filamentous virions, 80 nm in diameter with variable length (although basic length of replicative form for Ebola is 970 nm and for Marburg 790 nm)
—Genome contains single-stranded nonsegmented RNA (negative sense)
—Size: 19 kbp
—Pleomorphic morphology may occur: branched, circular, "6" or "U"-shaped
—50-nm nucleocapsid surrounded by spike-studded membrane
—Transmembrane spike glycoprotein antigenically distinct for each species
—In infected patients, Ebola virus produces large amounts of a secreted nonstructural glycoprotein with unknown function, encoded in 2 reading frames and joined during transcriptional editing as homodimer‡
—Reston species causes disease in monkeys, but only asymptomatic infection recognized in humans to date
|
|
Arenaviridae§
|
—Old World arenaviruses:
~Lassa virus
—New World arenaviruses that cause disease in humans:
~Junin virus (Argentine hemorrhagic fever)
~Machupo virus (Bolivian hemorrhagic fever)
~Guanarito virus (Venezuelan hemorrhagic fever)
~Sabia virus (Brazilian hemorrhagic fever)
~Whitewater Arroyo virus (3 suspected cases in California, 1999-2000)
|
—Origin of family and genus names from Latin "arenosos" for "sandy"
—Spherical or pleomorphic virions, generally 110-130 nm in diameter (may range from 50-300 nm)
—Genome contains single-stranded RNA with 2 segments (both ambisense)
—Size: 11 kbp
—Viral particles contain host ribosomes, which appear as dense granules 20–25 nm in diameter and give viruses "sandy" appearance
—Distinct club-shaped or spike projections on viral envelope composed of glycoproteins
—Epitopes mediating antibody-complement cell lysis and neutralization localized on envelope glycoproteins
—Lassa fever viruses exhibit 4 genetic lineages (3 in Nigeria and 1 in Guinea, Liberia, and Sierra Leone)**
|
|
Bunyaviridae††
|
—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
|
|
Flaviviridae‡‡
|
—Yellow fever virus
—Kyasanur Forest disease virus
—Omsk hemorrhagic fever virus
—Dengue virus (primary infection only rarely causes hemorrhagic fever)
—Alkhumra virus (identified in Saudi Arabia in 1995 and 2001; similar to Kyasanur Forest disease virus)
|
—Origin of family name from Latin "flavus" for "yellow" (yellow fever virus)
—Isometric virions, 40-50 nm in diameter
—Single-stranded nonsegmented RNA (positive-sense)
—Size: 10-12 kbp
—Virions covered with surface projections composed of M (membrane) and E (envelope) glycoproteins
—E glycoproteins involved in cell attachment, endosomal membrane fusion; serve as target for neutralizing antibody and hemagglutination
|
Back to top
Pathogenesis
The pathogenesis of hemorrhagic fever viruses is not completely understood; however, key points include the following (see References: Peters 2002).
-
Hemorrhagic fever viruses enter the bloodstream through various mechanisms (eg, the bite of a mosquito or tick, inhalation, mucous membrane exposure, parenteral exposure), and all (except hantaviruses) cause disease during the period of viremia.
-
The infectious dose for hemorrhagic fever viruses appears to be low (1 to 10 organisms) (see References: Franz 1997).
-
Endothelial infection occurs with most VHF viruses and may be limited or widespread, depending on the virus.
-
Hemorrhagic manifestations occur as a result of thrombocytopenia or severe platelet dysfunction along with endothelial dysfunction.
-
Increased vascular permeability is common and may result in periorbital edema and hemoconcentration. Vascular dysregulation also often occurs, manifested by flushing of the face and chest.
-
Hemorrhagic fever viruses can cause necrosis and hemorrhage in most organs; however, hepatic involvement often is particularly prominent.
-
Hantaviruses, New World arenaviruses, and Ebola, Marburg, and Lassa viruses cause cytokine activation. It is unknown whether or not the other hemorrhagic fever viruses cause cytokine activation. Filovirus infection appears to cause an uncontrolled release of cytokines (ie, cytokine storm) that is similar to that seen with sepsis caused by gram-negative bacteria (see References: Schnittler 2003). The relative lack of histologic lesions in fatal cases and the lack of immunopathology suggest that cytokines are the primary mediators of hemorrhagic fever in arenavirus infections and that they play a major role in the clinical features of filovirus infections as well (see References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Peters 2005: Marburg and Ebola virus hemorrhagic fevers).
-
Ebola, Marburg, yellow fever, and Rift Valley fever viruses have a marked cytopathic effect (ie, are highly destructive to the cells they infect).
-
The release of cellular proteases into the extracellular milieu (caused by protease/inhibitor imbalance) may enhance Ebola virus-induced cell damage. Progressive metabolic acidosis associated with infection appears to worsen this effect (see References: Barrientos 2007).
-
Ebola and Lassa viruses also appear to infect monocyte-derived dendritic cells; dendritic cells exposed to these viruses do not up-regulate, fail to secrete pro-inflammatory or immunoregulatory cytokines, and do not effectively stimulate T cells (see References: Bosio 2003, Mahanty 2003). These changes delay an effective early host response. Experiments in marmosets infected with Lassa virus demonstrate that viral replication in tissues is associated with immunophenotypic alterations that would likely impair adaptive immunity (see References: Carrion 2007: Lassa virus infection).
-
Ebola, Marburg, Rift Valley fever, and Crimean-Congo hemorrhagic fever viruses can cause disseminated intravascular coagulation (DIC); the other hemorrhagic fever viruses generally do not.
-
Coagulation abnormalities noted with Ebola virus infection appear to be triggered by immune-mediated mechanisms rather than occurring as the result of direct cytolysis of endothelial cells (see References: Geisbert 2003: Pathogenesis of Ebola hemorrhagic fever in primate models). Overexpression of tissue factor (TF) by monocytes/macrophages may be a key factor in causing observed coagulation abnormalities (see References: Geisbert 2003: Mechanisms underlying coagulation abnormalities in Ebola hemorrhagic fever).
-
In a cell-culture model, convalescent sera and complement component C1q enhanced the infectivity of Ebola Zaire virus, suggesting a role for antibody and complement in viral pathogenesis (see References: Takada 2003).
-
Ebola and Marburg viruses appear to require viral glycoprotein interaction with cellular receptors for effective cell entry (see References: Brindley 2007, Manicassamy 2007). Cell infection with Ebola virus also appears to require the activity of endosomal cysteine proteases (cathepsin B and cathepsin L), and cathepsin inhibitors may block replication of the virus in humans (see References: Chandran 2005, Kawaoka 2005).
-
Arenaviruses appear to cause a loss of cellular function without any obvious signs of cellular damage (ie, these viruses are not cytopathic or cytotoxic).
-
Suppression of the host antiviral response appears to play a critical role in pathogenesis of Ebola virus infection (see References: Ebihara 2006).
A model of the pathogenesis of Ebola virus based on observations of infection in cynomolgus monkeys is as follows (see References: Geisbert 2003: 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, which trigger the coagulation cascade, ultimately leading to DIC.
-
DIC then can result in hemorrhagic shock, multiple organ failure, and death.
Characteristic pathologic features of selected hemorrhagic fever viruses are shown in the table below.
|
Agent
|
Major Pathologic Features
|
|
Ebola virus†
|
—Extensive hepatocellular necrosis with intracytoplasmic viral inclusions
—Necrosis involving parenchymal cells, macrophages, and endothelial cells in major organs
—Follicular necrosis and necrotic debris in spleen and lymph nodes
—Myocardial edema
—Microvascular infection and injury
|
|
Marburg virus‡
|
—Extensive hepatocellular necrosis with intracytoplasmic viral inclusions
—Necrosis and hemorrhage in major organs
—Follicular necrosis and necrotic debris in spleen and lymph nodes
—Microvascular infection and injury
|
|
Lassa virus§
|
—Extensive reticuloendothelial involvement
—Multifocal hepatocellular necrosis with Councilman-like bodies, cytoplasmic degeneration of hepatocytes, and minimal inflammatory response
—Focal adrenal necrosis and adrenal cytoplasmic inclusions
—Interstitial pneumonia
|
|
New World arenaviruses (Junin, Machupo, Guanarito, Sabia)**
|
—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 virus††
|
—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 virus‡‡
|
—Midzonal hepatocellular necrosis
—Lymphocytic necrosis in germinal centers of spleen and lymph nodes
—Fatty degeneration of myocardial fibers
—Widespread hemorrhages on mucosal surfaces and within major organs
|
|
Kyasanur Forest disease virus§§
|
—Focal hepatocellular degeneration, fatty infiltration, and necrosis
—Hemorrhagic pneumonia
—Myocarditis
—Encephalitis
|
|
Omsk hemorrhagic fever virus***
|
—Scattered focal hemorrhages
—Perivascular infiltration with thrombi in small vessels
—Interstitial pneumonia
|
Back to top
Epidemiology
Hemorrhagic Fever Viruses as Biological Weapons
Animal studies using nonhuman primates have demonstrated that clinical infection can be caused by aerosolized preparations of some hemorrhagic fever viruses, including Ebola, Marburg, Lassa, and yellow fever viruses as well as New World arenaviruses (see References: Johnson 1995, Kenyon 1992, Stephenson 1984). Additional viruses (Rift Valley fever virus and flaviviruses) have been shown to cause aerosol infections in the laboratory setting (see References: Banerjee 1979, Smithburn 1949). These viruses are considered potentially suitable as biological weapons (see References: Borio 2002, Bray 2003) because:
-
They can be disseminated through aerosols.
-
They have a low infectious dose.
-
They cause high morbidity and mortality.
-
They cause fear and panic in the general public.
-
Effective vaccines are not available or supplies are limited.
-
These pathogens are available and most can be readily produced in large quantities.
-
Research on weaponizing various hemorrhagic fever viruses has been conducted in the past despite the lack of treatment options or protective vaccines.
Examples of countries that have either weaponized hemorrhagic fever viruses or conducted biological weapons research on these viruses include the following (see References: MIIS):
-
The Soviet Union produced weaponized Marburg virus and conducted research on Ebola, Lassa, Rift Valley fever, and yellow fever viruses and New World arenaviruses.
-
The United States conducted biological weapons research on Lassa, Rift Valley fever, and yellow fever viruses and New World arenaviruses.
-
North Korea may have weaponized yellow fever virus.
In 2000, CDC published a list of Category A agents (ie, those that are most likely to cause mass casualties if deliberately disseminated, can be released as small aerosols, and require broad-based public health preparedness). The list included New World arenaviruses and Ebola, Marburg, and Lassa viruses (see References: CDC 2000: Biological and chemical terrorism).
According to the Working Group on Civilian Biodefense, hemorrhagic fever viruses that pose serious threats as potential biological weapons include the following (see References: Borio 2002):
-
Ebola virus
-
Marburg virus
-
Lassa virus
-
New World arenaviruses
-
Machupo (Bolivian hemorrhagic fever)
-
Junin (Argentine hemorrhagic fever)
-
Guanarito (Venezuelan hemorrhagic fever)
-
Sabia (Brazilian hemorrhagic fever)
-
Rift Valley fever virus
-
Yellow fever virus
-
Kyasanur Forest disease virus
-
Omsk hemorrhagic fever virus
The Working Group determined that several important hemorrhagic fever viruses are less likely than those mentioned above to be used as biological weapons. These agents are not discussed further in this document; they include:
-
Dengue virus (is not transmissible by small-particle aerosol, requires mosquito-vector transmission, and primary dengue infection only rarely causes hemorrhagic fever)
-
Crimean-Congo hemorrhagic fever virus (does not replicate to high concentrations in currently available systems [a barrier to mass production])
-
Hantaviruses (do not replicate to high concentrations in currently available systems)
In addition to the three agents mentioned above, a new flavivirus was recently described in Saudi Arabia, referred to as Alkhumra virus (see References: Madani 2005).This virus, which was isolated initially in 1995 and again in 2001, appears to be similar to Kyasanur Forest disease virus. Because Alkhumra virus is not considered a potential bioterrorism agent at this time, it is not addressed further in this document.
Back to top
Global Disease Occurrence
Overview
Most hemorrhagic fever viruses that cause disease in humans occur in relatively localized areas of the world (notably sub-Sarahan Africa and focal areas of South America). The major geographic location and general pattern of occurrence for each virus are included in the table below.
|
Virus
|
Major Geographic Location for Human Disease
|
General Pattern of Disease Occurrence
|
|
Ebola virus
|
Sub-Saharan Africa
|
—First identified in 1976
—Outbreaks recognized with increasing frequency since mid-1990s
—Relatively rare, despite recent increase in outbreak occurrence
|
|
Marburg virus
|
Sub-Saharan Africa
|
—First identified in 1967
—Only a few small outbreaks recognized until 1998, when large outbreak (lasting until 2000) occurred in DRC, and 2004-05, when largest outbreak to date occurred in Angola
—Rare
|
|
Lassa virus
|
West Africa
|
—First identified in 1969
—Endemic in many West African countries
—Relatively common
|
|
New World arenaviruses
|
South America (except Whitewater Arroyo virus, which has only been associated with illnesses in California)
|
—Five different viruses known to cause human disease
—Only Junin virus has endemic focus (in rural areas of northeastern Argentina); others occur infrequently
|
|
Rift Valley fever virus
|
—Sub-Saharan Africa
—Egypt
—Saudi Arabia, Yemen
|
—First identified in animals in 1930 and in humans in 1975
—Relatively common in sub-Saharan Africa and Egypt (particularly in livestock)
|
|
Yellow fever virus
|
—Sub-Saharan Africa
—Tropical regions of South America
|
—Has been recognized for centuries
—Urban, sylvatic, and intermediate forms occur
—Endemic in areas of Africa and South America
—Relatively common
|
|
Kyasanur Forest disease virus
|
Karnataka State, India (west-central area of country)
|
—First identified in 1957
—Relatively uncommon
|
|
Omsk hemorrhagic fever virus
|
Central Asia
|
—First identified in 1940s
—Several outbreaks reported in 1950s
—Few cases in recent years
|
Ebola hemorrhagic fever
Ebola hemorrhagic fever is an important emerging infection in central Africa and has received much attention in recent years owing to the documented high case-fatality rates (50% to 90%) associated with past outbreaks. Much is still unknown about Ebola virus transmission, natural reservoirs, disease pathogenesis, and treatment. A large outbreak occurred in 1995 and since then, outbreaks have been recognized with increasing frequency in central Africa.
Ebola virus was first recognized in 1976 when two outbreaks of VHF occurred in Africa during that year (one in southern Sudan and one in northwest Zaire [now the Democratic Republic of the Congo]) (see References: Peters 1999, Pourrut 2005, WHO 1978: Ebola hemorrhagic fever in Zaire).
-
The outbreak in Sudan occurred between June and November 1976; 284 cases were identified and 150 (53%) deaths occurred.
-
The outbreak in Zaire occurred during September and October 1976; 318 cases were identified and 284 (89%) deaths occurred.
-
One subsequent case was recognized in Zaire in 1977, and a small outbreak occurred in Sudan in 1979 (affecting 34 people and killing 22 [65%]).
-
These outbreaks were caused by the Zaire strain.
Examples of additional outbreaks include the following (see References: CDC: Outbreak of Ebola hemorrhagic fever—Uganda; Georges 1999; Heymann 1980; Khan 1999; Peters 1999; Pourrut 2005; WHO: Ebola haemorrhagic fever: situation updates).
-
Cote d'Ivoire (1994; one human case and an epidemic in wild chimpanzees; discovery of the Cote d'Ivoire, or Ivory Coast, strain)
-
Gabon (one outbreak in 1994-1995 with 49 cases, and two outbreaks in 1996 with 31 and 60 cases; overall case-fatality rate was 68%; caused by the Zaire strain)
-
Democratic Republic of the Congo (DRC) (1995; 315 cases with 256 deaths [81%]; caused by the Zaire strain)
-
Uganda (2000-2001; 425 presumptive cases with 173 deaths [41%]; caused by the Sudan strain)
-
Gabon (2001-2002; ended in May 2002; 65 cases with 53 deaths [82%]; caused by the Zaire strain)
-
DRC (2002; ended in May 2002; 57 cases with 43 deaths [75%] in two regions geographically close to Gabon; caused by the Zaire strain)
-
An outbreak in southern Sudan occurred in May 2004. Seventeen cases with 7 deaths were reported, and WHO declared the outbreak over in August 2004; caused by the Sudan strain (see References: WHO: WHO announces end of Ebola outbreak in southern Sudan).
-
Between Apr 25 and Jun 16, 2005, 12 cases with 9 deaths occurred in the Republic of Congo (see References: WHO 2005: Ebola haemorrhagic fever in the Republic of the Congo).
-
In the fall of 2007, an outbreak occurred in the Kasai Occidentale province in the Democratic Republic of Congo. The most recent information can be found on the WHO Web site (see References: WHO: Ebola haemorrhagic fever: situation updates).
-
An Ebola outbreak in the Bundibugyo district of western Uganda began in late fall 2007 and continued into January 2008. (see References: WHO Ebola haemorrhagic fever: situation updates). The Ministry of Health reported that 149 cases occurred, and 37 of these patients died (see References: CDC 2008: Known cases and outbreaks of Ebola). Laboratory analysis confirmed a new species of the virus in 9 cases (see References: Alsop 2007; WHO: Ebola haemorrhagic fever: situation updates).
Since the discovery of Ebola virus in 1976, a geographic pattern has emerged in which the Zaire strain affects predominantly central Africa, the Sudan strain affects east Africa, and the Ivory Coast strain affects west Africa (see References: Pourrut 2005). In some situations, human Ebola outbreaks have occurred in conjunction with deaths in animals species (including gorillas, chimpanzees, mandrills, and bush pigs) (see References: Lahm 2007; Vogel 2007). Characterization of Zaire isolates from wild ape carcasses implicated recombinant viruses from the apes as the cause of outbreaks among humans in 2003-2005 (see References: Wittmann 2007).
Some human leukocyte antigen–B (HLA-B) alleles have been associated with fatal or nonfatal outcomes in humans and may contribute to death rates among those infected. Among 77 cases from an outbreak in northern Uganda in 2000-2001 involving the Sudan strain, HLA B-67 and B-15 alleles were associated with fatal outcomes, while B-07 and B-14 were associated with nonfatal outcomes. Several epitopes in viral proteins predict strong binding to HLA B-07 molecules; additional studies may help characterize host responses (see References: Sanchez 2007).
In addition to animal and human disease in Africa, several outbreaks of Ebola virus infection have been recognized in cynomolgus monkeys imported from the Philippines into the United States (see References: CDC 1990: Filovirus infections among persons with occupational exposure to nonhuman primates or their tissues; CDC 1990: Filovirus infection associated with contact with nonhuman primates or their tissues; CDC 1996: Ebola-Reston virus infection among quarantined nonhuman primates; Miranda 1999).
-
The first outbreak occurred at a primate facility in Reston, Virginia; therefore, the strain associated with these outbreaks is called the Reston strain (see References: Peters 1991).
-
Several persons working with infected primates have had serologic evidence of recent filovirus infection; however, no clinical illnesses associated with this strain have been reported in humans.
Marburg hemorrhagic fever
Marburg hemorrhagic fever, like Ebola, is an emerging disease in sub-Saharan Africa, although Marburg appears to be less common and case-fatality rates may be somewhat lower than those for Ebola virus infection.
Marburg virus was first recognized in 1967 when outbreaks occurred simultaneously in laboratory workers in Marburg, Germany; Frankfort, Germany; and Belgrade, Yugoslavia (now Serbia) (see References: Martini 1971).
-
The workers 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.
-
The case-fatality rate was 23%.
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 (see References: CDC: Questions and answers about Marburg hemorrhagic fever; Conrad 1975; Gear 1975).
-
In 1975, a small outbreak involving three cases (one index case and two secondary cases) occurred in South Africa in 1975; the index patient had been traveling extensively in Zimbabwe before illness onset.
-
In 1980, two cases occurred in Western Kenya (one index case and a secondary infection in a healthcare worker).
-
In 1987, a single case occurred in a man who had been traveling extensively in Kenya.
-
In 1998-2000, an outbreak occurred in the northeastern part of the Democratic Republic of the Congo; 154 confirmed or suspected cases were identified. Approximately half of the cases were young male miners who worked in an underground mine. The case-fatality rate was 83% (125 deaths among 150 patients for whom information was available) (see References: Bausch 2006).
-
The secondary infection rate among case contacts was 21% (see References: Borchert 2006).
-
A serosurvey of household contacts of Marburg patients found no serologic evidence of asymptomatic or mild infection (see References: Borchert 2006).
-
A seasonal pattern of cases was noted during the two years of the outbreak, with an upsurge in cases in the fall months and a peak in January or February (see References: Bausch 2006).
-
Multiple genetic variants of the virus were identified among the cases, suggesting ongoing introductions of virus into the human population. Furthermore, only 27% of the miners who became ill had contact with another case, suggesting that they acquired infection through other exposures, such as reservoir hosts that inhabited the mine (see References: Bausch 2006). The end of the outbreak coincided with flooding of the mine.
-
Studies of bats from the mine revealed that one species of fruit bat and two species of insectivorous bats harbored antibodies to Marburg virus (although viral presence was not found); these findings suggest that bats in the mine may have served as reservoir hosts for the outbreak (see References: Swanepoel 2007). Another recent study found Marburg virus in a common species of fruit bat in Gabon (as shown by finding virus-specific RNA and IgG antibody in individual bats), which corroborates bats as a natural reservoir for the virus (see References: Towner 2007).
-
In 2004-2005, a large outbreak of Marburg hemorrhagic fever occurred in Angola, predominantly in the northern Ulge Province. The final report issued by the International Federation of Red Cross and Red Crescent Societies (IFRC) noted that 374 cases occurred, including 329 fatalities, for a case-fatality rate of 88% (see References: IFRC 2006). A very high percentage of cases occurred in children under the age of 5 years (see References: WHO: Marburg haemorrhagic fever: situation updates). Genomic sequencing data suggest that a single introduction of the virus from a reservoir host into the human population occurred with subsequent person-to-person transmission (see References: Towner 2006).
-
A small outbreak of Marburg hemorrhagic fever occurred among miners in Uganda in the summer of 2007 (see References: WHO Oct 26: Outbreak of Marburg haemorrhagic fever, Uganda, June-August 2007). According to the WHO report, “the risk of infection for miners is likely related to their regular exposure to bats in the confined space of the mine.”
Lassa fever
Lassa fever is a disease that has become endemic in West Africa over the past 30 years. Rodents are the primary reservoir for Lassa virus, and the disease has a seasonal pattern. Case-fatality rates are somewhat lower for Lassa fever than for Ebola and Marburg infections, although they can be as high as 15% to 25% among hospitalized patients. Ribavirin therapy has been shown to be efficacious in treating some cases.
-
Lassa fever was first recognized in 1969 in northern Nigeria, when a small outbreak occurred among several nurses working in a rural missionary hospital.
-
Subsequent outbreaks have been recognized in Nigeria, Sierra Leone, and Liberia, and the disease is endemic in areas of West Africa.
-
Although infections can occur year-round, the incidence of disease is highest during the dry season (see References: LeDuc 1989). This finding may be related to aggregation of rodents inside houses during the dry season because of limited food supplies outdoors (see References Fichet-Calvet 2007).
-
An estimated 100,000 to 300,000 Lassa fever virus infections occur annually in West Africa (see References: McCormick 1987: A prospective study of the epidemiology and ecology of Lassa fever).
-
Occasionally, cases are imported from Africa into other countries (see References: Isaacson 2001, Macher 2006). As of 2004, 24 patients with imported Lassa fever had been identified worldwide, with cases occurring in Europe, the United States, Canada, Israel, and Japan.
-
An investigation into a case of imported Lassa fever in Germany demonstrated that the risk of transmission following exposure to the index case was low. Thirty persons were identified who had high-risk contact with the index case and serologic evidence of infection developed in only one of them. This secondary case was a physician who cared for the patient on day 9 of her illness; the physician received ribavirin and remained asymptomatic (see References: Haas 2003). Similarly, investigation of a case of imported Lassa fever in New Jersey did not identify transmission of the virus to five high-risk contacts (all family members) (see References: CDC 2004: Imported Lassa fever).
-
Investigators have found that poor housing quality in refugee camps may contribute to rodent infestation and transmission of the virus to humans in such settings (see References: Bonner 2007, Fair 2007).
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 recently identified as a cause of VHF in California. These viruses appear to be transmitted via contact with rodents or rodent excreta. New World hemorrhagic fever is relatively uncommon and for some viruses (eg, Sabia and Whitewater Arroyo virus), only a handful of cases have been recognized to date.
New World arenaviruses that cause disease in humans include the following (see References: Charrel 2003):
-
Junin virus (Argentine hemorrhagic fever)
-
It was first recognized in 1955.
-
The disease was initially localized to rural populations in the northwestern region of Buenos Aires province.
-
In the 1980s, infection became endemic in several provinces of Argentina (eg, Buenos Aires, Santa Fe, Cordoba, La Pampa) (see References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984). These provinces are all located in the northeastern part of the country and are contiguous to each other.
-
Between 100 and 4,000 cases are reported annually; however, in 1993, 24,000 cases were reported (see References: Lacy 1996).
-
Disease occurrence is seasonal and peaks during the months March through June (corresponding to the corn harvest season).
-
Machupo virus (Bolivian hemorrhagic fever)
-
The disease was first described in 1959 and the etiologic agent was identified in 1965.
-
Between 1959 and 1962, 470 cases resulting in 142 deaths were reported (see References: CDC 1994: Bolivian hemorrhagic fever—El Beni Department, Bolivia).
-
No outbreaks were recognized between 1971 and 1994. In the summer of 1994 an outbreak involving 10 people occurred in northeastern Bolivia (see References: CDC 1994: Bolivian hemorrhagic fever—El Beni Department, Bolivia).
-
Guanarito virus (Venezuelan hemorrhagic fever)
-
It was first recognized in 1989 when an outbreak involving more than 100 cases occurred in the Portuguesa state of central Venezuela (see References: Salas 1991).
-
Sabia virus (Brazilian hemorrhagic fever)
-
The disease was first recognized in Brazil in 1990 when a single fatal case occurred (see References: Lisieux 1994).
-
Two additional infections have been identified; both were laboratory-acquired (one in Brazil and one in the United States) (see References: Armstrong 1999, Barry 1995, Lisieux 1994).
-
Whitewater Arroyo virus
-
Three cases were reported from California between June 1999 and May 2000 (see References: CDC: Fatal illnesses associated with a New World arenavirus); two patients lived in southern California and one lived in the San Francisco Bay area.
-
All three cases were fatal.
-
These case reports suggest that Whitewater Arroyo virus can cause VHF in humans; however, documentation of additional cases would support these initial findings.
Rift Valley fever
Rift Valley fever is a mosquitoborne disease primarily found in sub-Saharan and North Africa. The disease, which affects livestock (eg, cattle, sheep) and humans, was first recognized in animals in 1930 in Kenya (see References: Daubney 1931). Epizootics in animals characteristically involve high rates of prenatal mortality and spontaneous abortions. Human illnesses generally are mild, although severe forms of disease (ie, VHF, meningoencephalitis) occur in about 1% of cases and retinitis can occur in up to 10% of cases.
-
Outbreaks of Rift Valley fever most often occur after heavy rainfalls flood natural depressions; the flooding allows extensive hatching of the primary mosquito vector (see References: LeDuc 1989; Anyamba 2006).
-
Infections in ruminants can amplify the viral burden in an area, and seasonal movement of ruminants may enhance spread of Rift Valley Fever virus to previously uninfected areas (see References: Chevalier 2005).
-
Analysis of an outbreak in 2003 revealed that east-central African strains were present in West Africa and may have flourished because of increased rainfall (see References: Faye 2007).
-
A major epidemic involving thousands of livestock cases and 18,000 human cases with approximately 600 deaths occurred in Egypt in 1977 (see References: Meegan 1979). Additional outbreaks in Egypt have been reported (probably representing repeated introductions of the virus).
-
Another large outbreak involving thousands of cases occurred in Somalia and Kenya in 1997-1998 (see References: Woods 2002). More recently, an outbreak occurred in Kenya, beginning in November 2006 and involving nearly 700 reported cases, including more than 150 deaths. The outbreak peaked in late December 2006, with cases tapering from January to mid-March 2007.
-
Smaller outbreaks involving a few cases occurred in 2006 and 2007 in Somalia and Tanzania (see References: CDC 2007: Rift Valley fever outbreak—Kenya, November 2006–January 2007; WHO 2007: Outbreaks of Rift Valley fever).
-
Analysis of archived sera from human populations in Kenya indicates that an undetected epidemic may have occurred in that country before 1980 (see References: LaBeaud 2007).
-
Until 2000, the disease had been identified only in sub-Saharan and North Africa. However, in the fall of 2000, outbreaks occurred simultaneously in Yemen and Saudi Arabia, thought to have been introduced from Africa through the sheep trade (see References: CDC 2000: Outbreak of Rift Valley fever—Yemen; CDC 2000: Outbreak of Rift Valley fever—Saudi Arabia; Shoemaker 2002). More than 1,000 cases occurred in Yemen, and 886 cases were identified in Saudi Arabia (see References: Madani 2003).
-
The Rift Valley Fever Working Group in the United States has developed a research agenda and response plan to address possible introduction of the virus into the United States, as was seen with West Nile virus in 1999 (see References: Britch 2007).
Yellow fever
Outbreaks of yellow fever were first recognized in the 1600s, and the disease is endemic in sub-Saharan Africa (between 15°N and 10°S latitude) and in tropical regions of South America. The vectors for yellow fever virus include several mosquito species. Illness can range from mild to severe, with an overall case-fatality rate of 5% to 7%. A vaccine against yellow fever is available.
-
Three cycles have been recognized (see References: WHO 2001: Yellow fever):
-
A sylvatic or jungle cycle that primarily involves transmission between mosquitoes and nonhuman primates, with humans as incidental hosts.
-
An urban cycle that involves transmission between mosquitoes and humans in urban areas. The most important mosquito vector is Aedes aegypti. Urban outbreaks can involve hundreds (or even thousands) of people and pose a substantial public health threat.
-
An intermediate cycle that is found in villages in humid and semi-humid savannahs of Africa, where small epidemics occur. This form involves semi-domestic mosquitoes that can infect both humans and nonhuman primates.
-
In South America, most sylvatic yellow fever cases involve workers who spend time in the forested areas of Bolivia, Brazil, Ecuador, Colombia, and Peru.
-
No outbreaks of urban yellow fever have been documented in the Americas since 1942 owing to public health programs aimed at eliminating the mosquito vector; however, reinfestation of urban areas with A aegypti mosquitoes has raised concern about the re-emergence of urban yellow fever.
-
In Africa, sylvatic and occasional urban outbreaks occur. Outbreaks occur in West, Central, and East Africa, with the largest number of outbreaks reported in West Africa. A relatively large outbreak occurred in southern Sudan in 2003 (see References: Onyango 2004).
-
Yellow fever is occasionally exported to Europe or North America (most often because of failure to vaccinate travelers to endemic areas).
-
The World Health Organization (WHO) estimates that 200,000 cases and 30,000 deaths occur each year, although most cases are not reported (see References: WHO 2001: Yellow fever).
-
Since 2005, outbreaks of yellow fever have been reported in several African countries as well as South America. Paraguay has vaccinated more than 1.27 million people in response to a recent yellow fever outbreak (see References: WHO: Yellow fever in Paraguay—update 2).
Kyasanur forest disease
Kyasanur forest disease (KFD), which is a tick-borne infection, is relatively rare and found only in one region in the southwestern part of India (see References: Gritsun 2003, Pattnaik 2006). The major clinical manifestations are VHF or meningoencephalitis and the case-fatality rate is 3% to 5%. Key features of the virus or the disease are: (see References: CDC: Kyasanur forest disease: fact sheet)
-
KFD virus was first recognized in 1957 when it was isolated from a sick monkey from the Kyasanur forest in Karnataka State, India.
-
Rodents, monkeys, bats, and other small mammals are the natural reservoirs. Larger animals (such as goats, cows, and sheep) may become infected, but they don’t have a role in transmission of the disease.
-
Natural infections have been identified only in several districts of Karnataka State, India (located in the southwestern region of the country).
-
Outbreaks occur periodically and are usually signaled by epizootics in the local monkey population.
-
A seasonal pattern has been noted, with most of the cases occurring in the spring months.
Omsk hemorrhagic fever virus
Omsk hemorrhagic fever (OHF) also is a rare form of tick-borne VHF and is limited to regions of Central Asia (see References: Gritsun 2003). Few cases have been recognized in recent years, and limited information is available about the current epidemiology. Key features of the virus or the disease are: (see References: CDC: Omsk hemorrhagic fever: fact sheet)
-
The disease was first recognized in the early 1940s in Omsk, Russia.
-
Most reported illnesses occurred in the 1940s and 1950s, although a series of outbreaks also occurred between 1988 and 1997.
-
OHF occurs in the western Siberia regions of Omsk, Novosibirsk, Kurgan, and Tyumen.
-
Muskrats and water voles appear to be the main animal reservoirs.
-
Although illness is acquired predominantly through the bite of an infected tick, exposure to muskrats (eg, through skinning or contact with blood, feces, or urine of an infected animal) also has been shown to be a mode of transmission.
-
OHF virus can be transmitted through the milk of infected goats or sheep and has been isolated from aquatic animals and water, suggesting that the virus is relatively stable in the environment.
-
Two relatively large outbreaks have been identified: one in 1945 (involving at least 200 cases) and one in 1946 (involving about 600 cases) (see References: WHO 1985: Viral hemorrhagic fevers: report of a WHO expert committee).
Back to top
Reservoirs/Vectors/Modes of Transmission
The modes of transmission and reservoirs vary somewhat by agent; these features are outlined in the following table.
For those viruses that are transmitted person-to-person, the period of communicability apparently begins after onset of symptoms. Transmission during the incubation period has not been demonstrated. In one instance, transmission may have occurred from an infected patient several hours before actual onset of symptoms (see References: WHO 1978: Ebola haemorrhagic fever in Zaire), but later systematic studies of the same disease demonstrated that the greatest risk for transmission is late in the clinical course (see References: Dowell 1999). Risk of transmission from fomites in an isolation ward and from convalescent patients is low when healthcare workers follow recommended infection control guidelines for viral hemorrhagic fevers (see References: Bausch 2007: Assessment of risk).
For both filoviral and arenaviral infections, virus may persist in urine and seminal fluids for several months; therefore, patients infected with these agents should refrain from sexual activity for 3 months after clinical recovery (see References: Borio 2002).
|
Agent
|
Reservoir
|
Arthropod Vector
|
Modes of Transmission
|
|
Ebola virus†‡
|
Unknown (although asymptomatic infection has been found in several species of fruit bats)
|
Unknown
|
—Person-to-person (most likely through contact with blood or body fluids)
—Percutaneous through reuse of needles or accidental needlesticks
—Contact with cadavers during preparation for burial
—Direct contact with infected nonhuman primates (eg, chimpanzees, gorillas)
—Possibly airborne through virus-containing aerosols (experimentally induced in monkeys)
—Contact with oral mucosa or conjunctivae through infectious droplets or direct contact (experimentally induced in monkeys; one healthcare worker may have become infected by touching eyes with contaminated glove)
—Sexual transmission (virus has been found in semen)
|
|
Marburg virus†§
|
Unknown
|
Unknown
|
—Contact with blood, tissues, or tissue cultures from infected monkeys
—Person-to-person (most likely through contact with blood or body fluids)
—Percutaneous through accidental needlesticks
—Sexual transmission (virus has been found in semen)
—Contact with oral mucosa through infectious droplets, infectious aerosols, or direct contact (experimentally induced in monkeys)
|
|
Lassa virus†**
|
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
|
|
Junin†
|
Calomys musculinus (drylands vesper mouse)
|
None
|
—Predominantly airborne through virus-containing aerosols of rodent excreta
|
|
Machupo††
|
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)
|
|
Guanarito‡‡
|
Zygodontomys brevicauda (cane mouse)
|
None
|
—Unknown, but presumably through aerosolized rodent excreta
|
|
Sabia§§
|
Not known; presumably a rodent
|
None
|
—Unknown, although laboratory-acquired cases appear to have been contracted through aerosols
|
|
Whitewater
Arroyo
virus***
|
Neotoma species (woodrats)
|
None
|
—Unknown, but presumably airborne through aerosolized rodent excreta
|
|
Rift Valley fever virus†
|
Ruminants (eg, cattle, sheep), rats in some areas (eg, Egypt)
|
Aedes mosquitoes
|
—Bite of infected mosquito
—Contact with blood or amniotic fluid of infected animals (through fomites, droplets, or aerosols)
—Airborne through virus-containing aerosols in the laboratory setting
|
|
Yellow fever virus†
|
Primates
|
Predominantly Aedes and Haemagogus mosquito species; Aedes aegypti is most important vector for urban yellow fever
|
—Bite of infected mosquito
—Laboratory infections through parenteral exposure or unexplained routes (presumably aerosols)
|
|
Kyasanur Forest disease virus†,†††
|
Rodents, bats, and other small mammals; monkeys (eg, black-faced langur, South Indian bonnet macaque) appear to be amplifying hosts
|
Ticks (Haemaphysalis spinigera)
|
—Bite of infected tick
—Airborne through virus-containing aerosols in laboratory setting
|
|
Omsk hemorrhagic fever virus†
|
Rodents (including muskrats and voles)
|
Ticks (Dermacentor pictus, Dermacentor reticulatus)
|
—Bite of infected tick
—Possibly through direct contact with carcasses of infected animals (eg, muskrats)
—Waterborne and airborne transmission may occur, but direct evidence lacking
|
Back to top
Clinical Characteristics
Although clinical features vary somewhat for the various hemorrhagic fever viruses, the clinical presentations overlap substantially. All of the agents cause a febrile prodrome associated with varying degrees of prostration; other notable features include the following.
-
Bleeding manifestations occur in variable proportions of patients (eg, in about 30% of patients with Ebola or Marburg hemorrhagic fever and in only about 1% of patients with Rift Valley fever).
-
A maculopapular rash may be noted early in the clinical course in some forms of VHF (notably in Ebola and Marburg hemorrhagic fevers).
-
Severe exudative pharyngitis is a characteristic early feature of Lassa fever.
-
Several agents cause meningoencephalitis in addition to VHF (eg, Rift Valley fever, Kyasanur Forest disease, Omsk hemorrhagic fever).
-
Jaundice may be a prominent feature in some infections (eg, Ebola and Marburg hemorrhagic fevers, Lassa fever, Rift Valley fever, yellow fever).
Major clinical features for each of the agents are included in the tables below.
Back to top
|
Characteristic
|
Features
|
|
Incubation period
|
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) occurs about 5 days after illness onset.
—Jaundice and pancreatitis often occur.
—As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses, oozing of blood at puncture sites).
—In 1995 DRC outbreak, some form of bleeding was reported in 37% of 219 patients.
—CNS findings include psychosis, delirium, coma, seizures.
—Shock (with DIC and end-organ failure) often ensues during second week of illness.
—Signs and symptoms recorded for 219 patients in 1995 DRC outbreak (recorded at time of admission or during clinical course) included:
~Asthenia (78%)
~Diarrhea (74%)
~Headache (73%)
~Anorexia (73%)
~Nausea/vomiting (70%)
~Abdominal pain (56%)
~Myalgias/arthralgias (51%)
~Dysphagia (41%)
~Conjunctival inflammation/hemorrhage (34%)
~Dyspnea (25%)
~Gingival hemorrhage (21%)
~Petechiae (15%)
~Melena (14%)
~Hiccups (14%)
~Hematemesis (13%)
—Asymptomatic infections can occur.
—Recovery may take up to several weeks.
|
|
Laboratory features‡
|
—Leukopenia early in clinical course; leukocytosis (may occur later)
—Thrombocytopenia early in clinical course
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses
—Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen
|
|
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)
—In 1995 DRC outbreak: mean number of days from symptom onset to death, 9.6 days (range, 0-34 days)
|
Back to top
|
Characteristic
|
Features
|
|
Incubation period
|
2-14 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.
—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 early in clinical course (1,000-2,000/mm3); leukocytosis (may occur later)
—Atypical lymphocytes (may be present)
—Marked thrombocytopenia early in clinical course (may be as low as 10,000/mm3)
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses
—Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen
|
|
Complications* (generally occur at least 2 wk after illness onset)
|
—Orchitis
—Alopecia
—Uveitis
—Recurrent hepatitis
|
|
Case-fatality rate†
|
Varies by outbreak (23%-93%)
|
Back to top
|
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*
|
—Severe exudative pharyngitis may occur (40% in one series of 306 patients).†
—Macolopapular rash may be noted on some fair-skinned patients.
—Severe prostration may occur by 6th to 8th day.
—As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses).
—In one outbreak in Sierra Leone, bleeding manifestations occurred in 17% of 306 patients.†
—Other findings that may occur include:
~Edema of head and neck
~Pleural, pericardial effusions
~Neurologic involvement (encephalopathy, coma, meningeal signs, cerebellar syndromes, tremors, seizures, eighth cranial nerve involvement)
~Capillary leak syndrome
~Shock with end-organ failure
—For those with less severe disease, recovery begins at about 10 days, although weakness and fatigue may persist for
several weeks.
—Most infections are thought to be mild or subclinical; severe disease occurs in 5%-10% of cases.
|
|
Laboratory features†
|
—Leukocyte counts: occasionally decreased but most often normal or moderately increased
—Hemoconcentration, proteinuria, and elevated hepatic enzymes( may occur)
—Thrombocytopenia mild or does not occur (although marked loss of platelet function has been demonstrated in vitro)
—Mean laboratory values at time of admission (and highest recorded) for 441 patients with Lassa fever in Sierra Leone:
~ALT: 96.5 U/L (147.1 U/L)
~Amylase: 259.1 U/L (381.6 U/L)
~AST: 408.2 U/L (602 U/L)
~BUN: 27.8 mg/dL (34.5 mg/dL)
~CPK: 515.7 U/L (893 U/L)
~Hematocrit: 50.6% (50.6%)
~Hemoglobin: 10.7 g/dL (14.9 g/dL)
~WBC count: 5,976/mm3 (4,603/mm3)
|
|
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%†
|
Back to top
|
Characteristic
|
Features
|
|
Incubation period
|
7-16 days
|
|
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), 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)
|
Back to top
|
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
identiied the following clinical features for 683 laboratory-confirmed cases:
~Fever: 92.6%
~Nausea: 59.4%
~Vomiting: 52.6%
~Abdominal pain: 38.0%
~Diarrhea: 22.1%
~Jaundice: 18.1%
~Neurologic manifestations: 17.1%
~Hemorrhagic manifestations: 7.1%
|
|
Laboratory features‡
|
—Initial leukocytosis (may occur, followed by leukopenia)
—Thrombocytopenia in severe cases
—Laboratory features of DIC in severe cases (prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen)
—Elevated hepatic enzymes (eg, ALT, AST) and bilirubin
|
|
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
|
Back to top
|
Characteristic
|
Features
|
|
Incubation period
|
3-6 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 7-1 | | | |
