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Hemorrhagic Fever Viruses as Biological Weapons
Medical and Public Health Management
Luciana Borio, MD;
Thomas Inglesby, MD;
C. J. Peters, MD;
Alan L. Schmaljohn, PhD;
James M. Hughes, MD;
Peter B. Jahrling, PhD;
Thomas Ksiazek, DVM, PhD;
Karl M. Johnson, MD;
Andrea Meyerhoff, MD;
Tara O'Toole, MD, MPH;
Michael S. Ascher, MD;
John Bartlett, MD;
Joel G. Breman, MD, DTPH;
Edward M. Eitzen, Jr, MD, MPH;
Margaret Hamburg, MD;
Jerry Hauer, MPH;
D. A. Henderson, MD, MPH;
Richard T. Johnson, MD;
Gigi Kwik, PhD;
Marci Layton, MD;
Scott Lillibridge, MD;
Gary J. Nabel, MD, PhD;
Michael T. Osterholm, PhD, MPH;
Trish M. Perl, MD, MSc;
Philip Russell, MD;
Kevin Tonat, DrPH, MPH;
for the Working Group on Civilian Biodefense
JAMA. 2002;287:2391-2405.
ABSTRACT
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Objective To develop consensus-based recommendations for measures to be taken by medical and public health professionals if hemorrhagic fever viruses (HFVs) are used as biological weapons against a civilian population.
Participants The Working Group on Civilian Biodefense included 26 representatives from academic medical centers, public health, military services, governmental agencies, and other emergency management institutions.
Evidence MEDLINE was searched from January 1966 to January 2002. Retrieved references, relevant material published prior to 1966, and additional sources identified by participants were reviewed.
Consensus Process Three formal drafts of the statement that synthesized information obtained in the evidence-gathering process were reviewed by the working group. Each draft incorporated comments and judgments of the members. All members approved the final draft.
Conclusions Weapons disseminating a number of HFVs could cause an outbreak of an undifferentiated febrile illness 2 to 21 days later, associated with clinical manifestations that could include rash, hemorrhagic diathesis, and shock. The mode of transmission and clinical course would vary depending on the specific pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these diseases, heterogeneous clinical presentation within an infected cohort, and lack of widely available diagnostic tests. Initiation of ribavirin therapy in the early phases of illness may be useful in treatment of some of these viruses, although extensive experience is lacking. There are no licensed vaccines to treat the diseases caused by HFVs.
INTRODUCTION
Hemorrhagic fever viruses (HFVs) are the subject of the sixth article in a series on medical and public health management of civilian populations following use of biological weapons.1-5 Historically, the term viral hemorrhagic fever (VHF) has referred to a clinical illness associated with fever and a bleeding diathesis caused by a virus belonging to 1 of 4 distinct families: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae (Table 1).
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Table 1.Hemorrhagic Fever Viruses*
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The HFVs are transmitted to humans via contact with infected animal reservoirs or arthropod vectors (the natural reservoirs and vectors of the Ebola and Marburg viruses are unknown). The mode of transmission, clinical course, and mortality of these illnesses vary with the specific virus, but each is capable of causing a hemorrhagic fever syndrome. Clinical and epidemiological data are limited; outbreaks are sporadic and unanticipated, and there are few case series or clinical trials involving human subjects.
The Working Group on Civilian Biodefense previously established a list of key features that characterize biological agents that pose particularly serious risks if used as biological weapons against civilian populations: (1) high morbidity and mortality; (2) potential for person-to-person transmission; (3) low infective dose and highly infectious by aerosol dissemination, with a commensurate ability to cause large outbreaks; (4) effective vaccine unavailable or available only in limited supply; (5) potential to cause public and health care worker anxiety; (6) availability of pathogen or toxin; (7) feasibility of large-scale production; (8) environmental stability; and (9) prior research and development as a biological weapon. Some HFVs exhibit a significant number of these key characteristics and pose serious risk as biological weapons, including Ebola and Marburg viruses (Filoviridae), Lassa fever and New World arenaviruses (Arenaviridae), Rift Valley fever (Bunyaviridae), and yellow fever, Omsk hemorrhagic fever, and Kyasanur Forest disease (Flaviviridae).
Several viruses that can cause VHF will not be considered further in this analysis. Dengue is excluded because it is not transmissible by small-particle aerosol,7 and primary dengue causes VHF only rarely. Crimean-Congo hemorrhagic fever (CCHF) and the agents of hemorrhagic fever with renal syndrome (HFRS) also have been excluded after much deliberation. Although these pathogens can cause VHF and may be transmissible by small-particle aerosol, the working group noted that technical difficulties (ie, barriers to large-scale production) currently preclude their development as mass casualty weapons. Crimean-Congo hemorrhagic fever and the agents of HFRS do not readily replicate to high concentrations in cell cultures, a prerequisite for weaponization of an infectious organism. However, CCHF, the agents of HFRS, and dengue may carry great morbidity and mortality in naturally occurring outbreaks. In particular, CCHF may be transmitted from person to person, has a high case-fatality rate, and is endemic in central Asia and southern Africa. We acknowledge that technical difficulties may be overcome with advances in technology and science, and these excluded viruses may become a greater threat in the future. Other sources provide information on the viruses not addressed herein.8-12
The consequences of an unannounced aerosol attack with an HFV are the primary focus of this analysis. A variety of attack scenarios with these agents are possible. This analysis does not attempt to forecast the most likely but focuses on perhaps the most serious scenario. Understanding and planning for a covert aerosol attack with HFVs will improve preparedness for other scenarios as well.
CONSENSUS METHODS
The working group for this article was composed of 26 professionals from academic medical centers, public health, military services, governmental agencies, and emergency management institutions. MEDLINE databases were searched from January 1966 to January 2002 for the Medical Subject Headings viral hemorrhagic fever, Ebola, Marburg, Lassa, arenavirus, Junin, Guanarito, Machupo, Sabia, CCHF, Rift Valley fever, hantavirus, dengue, yellow fever, Omsk hemorrhagic fever, Kyasanur Forest disease, biological weapons, biological terrorism, biological warfare, and biowarfare. The references were reviewed and relevant materials published prior to 1966 were identified. The working group also identified other published and unpublished references for review.
A first draft resulted from the synthesis of information obtained during the evidence-gathering process. Members of the working group were convened to discuss the first draft of the formulated guidelines on January 10, 2002. Subsequently, a second draft was produced incorporating comments and judgments of the working group. They reviewed the second draft and submitted comments, which were incorporated into a third and final draft of the document.
HISTORY AND POTENTIAL AS BIOLOGICAL WEAPONS
Hemorrhagic fever viruses have been weaponized by the former Soviet Union, Russia, and the United States.13-15 There are reports that yellow fever may have been weaponized by North Korea.14 The former Soviet Union and Russia produced large quantities of Marburg, Ebola, Lassa, and New World arenaviruses (specifically, Junin and Machupo) until 1992.13, 15 Soviet Union researchers quantified the aerosol infectivity of Marburg virus for monkeys, determining that no more than a few virions are required to cause infection.16 Yellow fever and Rift Valley fever viruses were developed as weapons by the US offensive biological weapons program prior to its termination in 1969.14 The Japanese terrorist cult Aum Shinrikyo unsuccessfully attempted to obtain Ebola virus as part of an effort to create biological weapons.17
Several studies have demonstrated successful infection of nonhuman primates by aerosol preparations of Ebola,18 Marburg,19 Lassa,20 and New World arenaviruses.21 Arguments asserting that the absence of effective antiviral therapy and vaccines would make these viruses too dangerous to develop as weapons are not supported by the historical record.
In 1999, the Centers for Disease Control and Prevention (CDC) classified the HFVs as category A bioweapon agents, based on the potential to cause widespread illness and death, ease of dissemination or person-to-person transmission, potential for major public health impact, and requirement of special action for public health preparedness.22
EPIDEMIOLOGY OF DISEASE TRANSMISSION
In nature, HFVs reside in animal hosts or arthropod vectors. The natural reservoir of filoviruses is unknown. Humans are infected incidentally, acquiring the disease by the bite of an infected arthropod, via aerosol generated from infected rodent excreta, or by direct contact with infected animal carcasses.23 With the exception of Rift Valley fever and the diseases caused by flaviviruses (yellow fever, Omsk hemorrhagic fever, and Kyasanur Forest disease), which are not transmissible from person to person, infected humans can spread the disease to close contacts, which may result in community outbreaks and nosocomial infections. Limited knowledge exists about transmission because outbreaks of these diseases are sporadic and unpredicted and often occur in areas without adequate medical and public health infrastructure. Outbreaks are usually well under way or have subsided by the time data gathering begins. The risks associated with various modes of transmission are not well defined because most persons who acquire these infections have a history of multiple contacts by multiple modes. Infections acquired percutaneously are associated with the shortest incubation period and highest mortality. Person-to-person airborne transmission appears to be rare but cannot be ruled out.
Filoviridae: Ebola and Marburg
Since 1967, when the first outbreak of VHF caused by Marburg virus occurred in Germany and Yugoslavia, there have been 18 reports of human outbreaks of VHF secondary to Ebola or Marburg viruses, resulting in approximately 1500 cases to date.24 Most have occurred in Africa. Epidemiological investigation indicates that most cases occurred after direct contact with blood, secretions, or tissues of infected patients or nonhuman primates.
Several cases have followed needlestick injuries. During the 1976 Ebola epidemic in Zaire (now Democratic Republic of the Congo), 85 (26.7%) of 318 cases occurred in individuals who had received an injection, and every case of disease acquired by contaminated syringes resulted in death.25 Mortality was substantially higher when the disease was acquired percutaneously. Evidence suggests that percutaneous exposure to very low inocula can result in infection.26
Filoviruses can also be transmitted by mucosal exposure. Experiments in nonhuman primates have documented transmission of infection after direct administration of Marburg virus into the mouths and noses of experimental animals27 and after direct administration of Ebola virus into the mouths or conjunctiva28 of experimental animals. Human infections might occur through contact of contaminated fingers with oral mucosa or conjunctiva,29 but direct evidence is lacking.
Copious numbers of Ebola viral particles found in human skin and lumina of sweat glands have raised concern that disease transmission may occur from touching an infected patient or corpse.30 In the 1995 Ebola outbreak in Kikwit, Democratic Republic of the Congo, several persons preparing bodies for burial acquired the infection.31-33 According to local custom, burial practices may involve washing the body and cutting the hair and nails of the corpse.34 However, a study using guinea pigs was unable to document Marburg virus transmission through intact skin, while infection through skin lesions did occur.35
A few cases of disease transmission by uncertain mechanisms described in 2 recent Ebola outbreaks,36-37 and findings from animal studies16, 18, 38 and 1 outbreak of Ebola in nonhuman primates,39 raise concern about the potential for person-to-person transmission by way of small-droplet airborne nuclei. However, to date, Ebola epidemics in Africa were ultimately controlled and ended without use of specific airborne precautions. (HICPAC's definitions of standard, contact, droplet, and airborne precautions are at http://www.cdc.gov/ncidod/hip/isolat/isopart2.htm.)
Airborne transmission of Marburg virus was not observed in the 1967 outbreak in Germany and Yugoslavia following the importation of infected African green monkeys from eastern Africa.40 In 1975, only 1 of 35 health care workers who cared for 2 patients with Marburg disease in South Africa without any barrier precautions became ill.41 In 1979, an outbreak of Ebola in southern Sudan infected 34 people. Although direct physical contact could not be established in 2 instances, 29 cases resulted from direct physical contact with an infected person and there were no cases of illness among 103 persons who were exposed to cases in confined spaces without any physical contact.42 In 1994, only 1 of 70 contacts of a patient with Ebola acquired the disease despite lack of airborne precautions.43 In 1996, none of the 300 contacts of 2 patients with Ebola acquired the disease44 despite involvement in numerous hazardous procedures prior to the patients' diagnosis, protected only by standard blood and bodily fluid precautions.
In 1995, 316 people became ill with Ebola in the Democratic Republic of the Congo; 25% of the cases involved health care workers. When barrier precautions were instituted, only 3 health care workers became infected. One was nonadherent to barrier precautions, the second had a needlestick injury, and it is speculated that the third, who always used protective equipment, became infected after touching her eyes with a contaminated glove.45 None of the 78 household members who did not have direct physical contact with an infected person developed disease.31 However, in this outbreak, the only risk factor identified for 5 patients was visiting an infected patient in the absence of physical contact. These few cases led researchers to conclude that airborne transmission could not be ruled out37 but seemed to be, at most, a minor mode of transmission.
In 2000, 224 people died in Uganda during an Ebola outbreak.37 Fourteen (64%) of 22 medical personnel were infected after institution of isolation wards and infection control measures37 including donning gowns, gloves, and shoe covers, standard surgical masks, and either goggles or eye glasses.46 It is not clear whether lack of adherence to guidelines contributed to nosocomial cases in this outbreak, but airborne transmission could not be ruled out.
Although Marburg virus has been isolated from healthy-appearing infected monkeys several days before clinical signs appear,27 no transmission has been observed in this stage.40 In humans, transmission of Ebola during the incubation period does not appear to be common.31 Transmissibility of Ebola increases with the duration of disease, and direct physical contact with an ill person during the late phase of clinical illness confers an additional risk.31 There has been only 1 reported case, during the outbreak in Zaire in 1976, in which the only possible source of infection was contact with an unconfirmed case hours before the patient developed symptoms.25 The preponderance of evidence suggests that transmission of Ebola and Marburg virus rarely, if ever, occurs before the onset of signs and symptoms.
In several studies after the 1995 Kikwit outbreak, Ebola was detected in the seminal fluid of convalescing patients by reverse transcriptase polymerase chain reaction (RT-PCR) up to 101 days after disease onset,47-48 and virus was isolated 82 days after disease onset in the seminal fluid of 1 patient.48 Marburg has been isolated 83 days after disease onset from the seminal fluid of a patient who may have sexually transmitted the disease to his spouse.40
Arenaviridae: Lassa Fever and New World Arenaviruses
In nature, arenaviruses are transmitted to humans via inhalation of aerosols present in rodent urine and feces,49 by ingestion of food contaminated with rodent excreta, or by direct contact of rodent excreta with abraded skin and mucous membranes.50 Like filoviruses, person-to-person transmission of the arenaviruses occurs predominantly by direct contact with infectious blood and bodily fluids. A number of nosocomial outbreaks of Lassa fever51-53 and of New World arenaviruses54 have occurred via this mechanism. As with filoviruses, person-to-person airborne transmission has been suspected in a few instances.
In 1969, during a nosocomial outbreak in Nigeria, an index patient with severe pulmonary involvement caused 16 secondary cases in persons who shared the same hospital ward with her. Airborne transmission was believed to have contributed to this outbreak, as there were no tertiary cases of Lassa fever in the hospital, despite the admission of Lassa fever–infected patients to other hospital wards.51 However, there is no definitive evidence of airborne transmission and the exact mechanisms of disease transmission during that outbreak remain unknown. Conversely, in the case of 1 Lassa fever–infected individual who traveled from Sierra Leone to the United States, no cases were detected in 522 contacts, even prior to initiating additional barrier precautions beyond standard precautions.55 In another instance, in which an infected individual originated in Nigeria and traveled to St Thomas in the US Virgin Islands, none of the 159 people who had direct contact with the patient developed clinical or serological evidence of infection, even though they attended to the patient, without barrier precautions, during a 5-day period before the diagnosis.56
Airborne transmission of Bolivian hemorrhagic fever has been implicated after a student became infected after watching a nursing instructor demonstrate the changing of bed linens of an infected patient, although the student did not touch the patient or any objects in the room and kept a distance of greater than 6 ft from the patient.54 Conversely, approximately 80 involved health care workers who did not use airborne precautions remained healthy. Definitive evidence of person-to-person airborne transmission is lacking but, in these rare instances, there have been no plausible alternative explanations.
There have been no reports documenting transmission of arenaviruses by infected persons during the incubation period.54, 57 However, Lassa fever virus can be detected in semen up to 3 months after acute infection58 and in urine 32 days after disease onset,59 and Argentine hemorrhagic fever has been transmitted to spouses of convalescent patients 7 to 22 days after onset of illness.60
Bunyaviridae: Rift Valley Fever
Humans acquire Rift Valley fever from the bite of an infected mosquito, direct contact with infected animal tissues, or aerosolization of virus from infected animal carcasses.61 Ingestion of contaminated raw animal milk has been implicated epidemiologically.62 Despite high levels of viremia and isolation of low titers of virus from throat washings, there are no reported cases of person-to-person transmission of Rift Valley fever.62 However, laboratory technicians are at risk of acquiring the disease by inhalation of infectious aerosols generated from specimens.61, 63
If Rift Valley fever were used as a biological weapon, susceptible domestic livestock (sheep, cattle, buffalo, and goats) could also be infected. Infected livestock develop high levels of viremia, sufficient to infect susceptible mosquito vectors and lead to establishment of the disease in the environment61 and large epizootic epidemics, as occurred in Egypt in 197764 and the Arabian peninsula in 2000.65 Several genera of mosquitoes (eg, Aedes, Anopheles, and Culex) in the United States have the capacity to act as vectors of Rift Valley fever.66-67
Flaviviridae: Yellow Fever, Omsk Hemorrhagic Fever, and Kyasanur Forest Disease
Humans acquire yellow fever virus from the bite of an infected mosquito68 and acquire Omsk hemorrhagic fever and Kyasanur Forest disease viruses from the bite of an infected tick.69 There are no reported cases of person-to-person transmission or nosocomial spread of flaviviruses. Infection of laboratory personnel via inhalation of aerosols during cultivation of these viruses has been reported.69-70 As with Rift Valley fever, there is a theoretical risk of flaviviruses becoming established in an environment following infection of susceptible arthropod vectors.
MICROBIOLOGY AND PATHOGENESIS
All of the HFVs are small RNA viruses with lipid envelopes. Specific microbiological characteristics of these viruses are listed in Table 2.
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Table 2. Microbiology of Hemorrhagic Fever Viruses71
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Information regarding the pathogenesis of these agents following infection in humans is incomplete. Most data have been derived from clinical observations and experimentally induced disease in nonhuman primates. Interpretation of data derived from animal studies may be confounded by a series of factors, such as the species of the animal, the route of inoculation, and the virus dose.40
All of the viruses of concern may lead to thrombocytopenia, and data suggest that platelet dysfunction is present in Ebola, Lassa fever, and Argentine hemorrhagic fever.72 Reduced levels of coagulation factors may be secondary to hepatic dysfunction and/or disseminated intravascular coagulation and are most prominent in Rift Valley fever and yellow fever.72 In addition, Ebola and Marburg viruses may lead to a hemorrhagic diathesis through direct damage of cells involved in hemostasis (such as platelets and endothelial cells) and/or indirectly through immunological and inflammatory pathways.72
Filoviruses are extremely virulent in nonhuman primates and humans.73 Necrosis of visceral organs (such as liver, spleen, and kidneys) has been associated with both direct viral-induced cellular damage and impairment of the microcirculation. Filoviruses are cytotoxic to cells. In general, inflammatory infiltration is absent in the affected visceral organs.74 Even when viral titers in the lungs of monkeys are elevated, the virus is not apparent in the alveoli or airways, occurring primarily in the vascular structures.28 All experimentally infected monkeys develop disseminated intravascular coagulation. Ebola, but not Marburg virus, makes a secreted form of its glycoprotein that has been suggested to have a role in virulence.73 Endothelial cells support Marburg virus replication, and their destruction may contribute to the associated hemorrhagic diathesis and shock.75
Infection with arenaviruses is initiated in nasopharyngeal mucosa.76 Arenaviruses produce carrier states in rodents, their natural hosts, and viral multiplication is not associated with extensive cell damage. In vitro infections with Arenaviridae show that virus spreads throughout a variety of different cellular monolayers, with little or absent cytopathic effects77; hence, it is believed that these viruses may exert their effects (at least in part) by inducing the secretion of inflammatory mediators from macrophages. Following experimental infection of nonhuman primates with arenaviruses, virtually all tissues become infected, with little histologic evidence of damage.78 Hemorrhage following arenavirus infection appears to be associated with the presence of a circulating inhibitor of platelet aggregation and thrombocytopenia. However, disseminated intravascular coagulation does not appear to be a central pathogenic mechanism.79 Lassa fever appears to be terminated by a cellular, not humoral, immune response,77 whereas in New World arenaviruses, recovery is preceded by cellular and humoral immune responses.80
In contrast with arenaviruses, Rift Valley fever virus leads to destruction of infected cells.77 The hemostatic derangements in Rift Valley fever are poorly understood, and a combination of vasculitis and hepatic necrosis has been postulated.81-82 Interferon alfa given shortly before or after experimental infection with Rift Valley fever virus has been shown to protect rhesus monkeys from viremia and hepatocellular damage.83 Clinical recovery is associated with appearance of neutralizing antibodies, and passive immunization prevented development of viremia in nonhuman primates inoculated with the virus.83
Like Rift Valley fever, yellow fever virus leads to destruction of infected cells. Hepatocyte infection and degeneration is a late event in the course of infection,84 associated with virtually no inflammation.68 Neutralizing antibodies correlate with clearance of viremia, and paradoxically, with the second phase of illness, when patients may develop hemorrhage and shock.68
Little is known about the pathogenesis of Omsk hemorrhagic fever and Kyasanur Forest disease viruses. Findings from postmortem examinations of 3 individuals who died of Kyasanur Forest disease showed degeneration of the larger visceral organs (especially liver and spleen) and hemorrhagic pneumonia.85
CLINICAL MANIFESTATIONS
Information on the clinical manifestations of these diseases is derived from naturally occurring outbreaks. Although data derived from experimentally infected animals do not support marked differences in the clinical presentation according to route of exposure (parenteral vs aerosol),18, 21 it is not possible to be certain that the same manifestations would follow bioweapons attacks on humans.
There are a variety of potential clinical manifestations following infection with these viruses, and not all patients develop the classic VHF syndrome. Clinical manifestations are nonspecific and may include fever, myalgias, rash, and encephalitis. The propensity to cause the classic VHF syndrome also differs among agents. Therefore, in the event of a bioterrorist attack with one of these agents, infected patients may have a variety of clinical presentations, complicating early detection and management. It may not be possible to differentiate among these diseases on clinical grounds alone, although a number of specific clinical features may be useful clues to diagnosis (Table 3).
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Table 3. Clinical Characteristics of Hemorrhagic Fever Viruses Noted in Past Case Series or Outbreaks
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The overall incubation period for HFVs ranges from 2 to 21 days. Patients initially exhibit a nonspecific prodrome, which typically lasts less than 1 week. Symptoms typically include high fever, headache, malaise, arthralgias, myalgias, nausea, abdominal pain, and nonbloody diarrhea. Filoviruses, Rift Valley fever, and flaviviruses are characterized by an abrupt onset, while arenaviruses have a more insidious onset.40, 54, 61, 68-69,99-100
Early signs typically include fever, hypotension, relative bradycardia, tachypnea, conjunctivitis, and pharyngitis. Most diseases are associated with cutaneous flushing or a skin rash (Figure 1 and Figure 2), but the specific characteristics of the rash vary with each disease (Table 3). Later, patients may show signs of progressive hemorrhagic diathesis, such as petechiae, mucous membrane and conjunctival hemorrhage (Figure 3); hematuria; hematemesis; and melena. Disseminated intravascular coagulation and circulatory shock may ensue. Central nervous system dysfunction may be present and manifested by delirium, convulsions, cerebellar signs, or coma and imparts a poor prognosis.
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Figure 1. Maculopapular Rash in Marburg Disease
A nonpruritic maculopapular rash (resembling the rash of measles) may occur in up to 50% of patients infected with the Ebola or Marburg viruses within the first week of illness. The rash is more common in light-colored skin and desquamates on resolution. Reprinted with permission from Thieme (Martini GA, Knauff HG, Schmidt HA, et al. A hitherto unknown infectious disease contracted from monkeys. Ger Med Mon. 1968;13:457-470).
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Figure 2. Erythematous Rash in Bolivian Hemorrhagic Fever
This macular, flushed, erythematous rash that blanches with pressure may be associated with infections caused by arenaviruses. The rash most commonly involves the face and thorax and may desquamate on convalescence. Reprinted with permission from Current Science/Current Medicine (Peters CJ, Zaki SR, Rollin PE. Viral hemorrhagic fevers. In: Fekety R, vol ed. Atlas of Infectious Diseases, Volume VIII. Philadelphia, Pa: Churchill Livingstone; 1997:10.1-10.26).
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Figure 3. Ocular Manifestations in Bolivian Hemorrhagic Fever
Ocular manifestations associated with hemorrhagic fever viruses range from conjunctival injection to subconjunctival hemorrhage, as seen in this patient. Reprinted with permission from Current Science/Current Medicine (Peters CJ, Zaki SR, Rollin PE. Viral hemorrhagic fevers. In: Fekety R, vol ed. Atlas of Infectious Diseases, Volume VIII. Philadelphia, Pa: Churchill, Livingstone; 1997:10.1-10.26).
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The differential diagnosis includes a variety of viral and bacterial diseases: influenza, viral hepatitis, staphylococcal or gram-negative sepsis, toxic shock syndrome, meningococcemia, salmonellosis and shigellosis, rickettsial diseases (such as Rocky Mountain spotted fever), leptospirosis, borreliosis, psittacosis, dengue, hantavirus pulmonary syndrome, malaria, trypanosomiasis, septicemic plague, rubella, measles, and hemorrhagic smallpox. Noninfectious processes associated with bleeding diathesis that should be included in the differential diagnosis include idiopathic or thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute leukemia, and collagen-vascular diseases.
Laboratory abnormalities include leukopenia (except in some cases of Lassa fever, in which leukocytosis occurs), anemia or hemoconcentration, thrombocytopenia, and elevated liver enzymes. Jaundice is typical in Rift Valley fever and yellow fever.61, 68 In addition, coagulation abnormalities may include prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen. Urinalysis may reveal proteinuria and hematuria, and patients may develop oliguria and azotemia.26, 40, 54, 61, 68, 100-101
Convalescence may be prolonged and complicated by weakness, fatigue, anorexia, cachexia, alopecia, and arthralgias.43, 45 Reported clinical sequelae include hearing or vision loss, impaired motor coordination, transverse myelitis, uveitis, pericarditis, orchitis, parotitis, and pancreatitis.36, 40, 52, 54, 61, 102
The case-fatality rate varies markedly among these agents, ranging from as low as 0.5% for Omsk hemorrhagic fever69 to as high as 90% for Ebola (subtype Zaire).33 Death is typically preceded by hemorrhagic diathesis, shock, and multiorgan system failure 1 to 2 weeks following onset of symptoms.
DIAGNOSIS
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