Viral Hemorrhagic Fevers
Erik J. Won
Anthony Carbone
NAME AND DESCRIPTION OF AGENTS
Viral hemorrhagic fever (VHF) has a variety of clinical manifestations and causative agents but is best characterized as an acute febrile illness with abnormalities of circulatory regulation and generalized signs of increased vascular permeability. Bleeding manifestations with fever in the presence of a bioterrorist threat should raise suspicions of VHF.
The etiology of VHF syndrome is represented by a diverse group of RNA viruses in four distinct families: (a) Arenaviridae, (b) Bunyaviridae, (c) Filoviridae, and (d) Flaviviridae. All of these viruses are enveloped with animal or insect reservoirs, although the natural host of the filoviruses (Ebola and Marburg) remains unknown. Viruses causing VHF are initially transmitted to humans via contact with the reservoir host or vector. Viruses carried by rodent reservoirs are transmitted to humans through contact with urine, feces, or carcasses of infected rodents. Arthropod vectors spread the virus by mosquito or tick bite. Humans are not the natural reservoir for any strains; however, some of these viruses can be spread from person to person by either direct contact or aerosolized particles.
THEORETICAL AND SCIENTIFIC BACKGROUND:
A consensus statement from an expert panel of 26 professionals (1) determined the VHF agents posing the most serious risk as biological weapons were 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). These agents met several criteria set forth by The Working Group on Civilian Biodefense for agents that pose particularly serious health risks as bioweapons. These criteria include: (a) high morbidity and mortality; (b) potential for person-to-person transmission; (c) low infective dose and highly infectious by aerosol dissemination, with a commensurate ability to cause large outbreaks; (d) effective vaccine unavailable or available only in limited supply; (e) potential to cause public and health care worker anxiety; (f) availability of pathogen or toxin; (g) feasibility of large-scale production; (h) environmental stability; and (i) prior research and development as a biological weapon. The viruses excluded from this list had limitations in their potential use as weapons of mass destruction (some were difficult to produce in large amounts; others did not replicate to high enough concentrations in cell cultures to be weaponized).
FILOVIRIDAE (EBOLA AND MARBURG)
The filoviruses include Ebola and Marburg viruses. Both viruses are recognized as Category A, or high priority, by the National Institute for Allergy and Infectious Diseases (NIAID) (2) and Category A (Biosafety Level 4) agents by the Center for Disease Control and Prevention (CDC) (3,4).
The first recorded outbreak of Marburg occurred in Europe (Germany and Yugoslavia) in 1967 and remains the only outbreak to have occurred outside of Africa. This outbreak resulted from the unwitting importation of infected monkeys from Uganda. A total of 18 human outbreaks of Ebola and Marburg VHF have been reported with 10 outbreaks involving 30 or more victims.
The reservoir for Ebola and Marburg viruses is currently unknown. Isolating the wild reservoir has proven to be an arduous and daunting task. During the 1995 outbreak in Kikwit, Zaire, 3,000 vertebrates of multiple species and 30,000 arthropods were sampled without any trace of Ebola detected (5). As such, there have been no confirmatory studies to evaluate how virus is transmitted from host to human. The primary mode of person-to-person transmission is through direct contact with blood, secretions, and infected tissue. Experiments in nonhuman primates have documented transmission of infection after direct administration of Marburg virus into the mouths and noses of experimental animals (6). Several human infections have also occurred through contact of contaminated fingers with oral mucosa and conjunctiva (7). Percutaneous needle-stick injuries are thought to be a particularly lethal mode of transmission. Eighty-five of 318 cases (26.7%) in a 1976 Ebola epidemic in Zaire occurred from individuals injected with contaminated syringes, and all cases acquired by injection resulted in death (8). Evidence suggests that percutaneous exposure to very low concentrations of virus can result in infection (9).
It is unclear whether disease transmission can occur from touching an infected patient or corpse through intact skin. A review of the Ebola outbreak in 1995 (Kikwit, Democratic Republic of the Congo) revealed infection in several subjects who prepared bodies for burial (10,11). Local customs and burial practices involve washing the body and trimming hair and nails, both of which pose a significant contact exposure to the subjects (12). Animal studies using guinea pigs were unable to demonstrate Marburg virus transmission through intact skin; however, infection through open skin lesions did occur (4).
Some animal studies have raised concerns about person-to-person transmission through aerosolized particles (5,13). Epidemiologic data suggests this is an unlikely route of human transmission, but it cannot be completely ruled out. In 1995 in the Democratic Republic of the Congo, 316 subjects were infected with Ebola. Only three health care workers became infected: one had a needlestick injury, one was nonadherent to barrier precautions, and one who always used barrier precautions is believed to have accidentally rubbed her eyes with a contaminated glove (14). Seventy-eight household members, without direct physical contact, were disease-free. However, in this outbreak, the only risk factor identified for five patients was visiting an infected patient in the absence of physical contact. These cases led researchers to conclude that airborne transmission could not be ruled out (15) but seemed, at most, a secondary mode of transmission. In 2000 in Uganda, 224 people died in an outbreak of Ebola. Of the medical personnel who became ill, 64% were infected after isolation wards and infection control measures (gloves, gowns, shoe covers, surgical masks, and eye protection) were employed (16). Airborne transmission could not be ruled out in this case.
Nevertheless, studies of other outbreaks argue strongly against a respiratory route of transmission. Most Ebola epidemics in Africa were ultimately controlled and ended without the use of specific airborne precautions. Airborne transmission of Marburg virus was not observed in the 1967 outbreak in Germany and Yugoslavia following the importation of infected African green monkeys (17). In 1975, only 1 in 35 health care workers exposed to Marburg disease without any barrier precautions became ill (18). In 1979, an outbreak of Ebola in Sudan infected 34 people. Twenty-nine cases of infection were reported among subjects who made direct physical contact, while no cases among 103 persons exposed in confined spaces without physical contact were reported (19). In 1994, only 1 of 70 contacts of an Ebola-infected patient acquired the disease despite no airborne precautions (20). In 1996, 300 contacts of Ebola-infected patients did not contract disease. These contacts were involved in numerous procedures prior to the patient’s diagnosis with only standard blood and bodily fluid precautions. Again, no airborne precautions were taken (21).
ARENAVIRIDAE: LASSA FEVER AND NEW WORLD ARENAVIRUSES
Lassa fever and the New World arenaviruses (Lymphocytic Choriomeningitis virus, Junin virus, Machupo virus, Sabia virus, and Guanarito virus) are considered to have bioterrorism potential and are classified as Category A, or high priority, agents by the NIAID (2) and Category A (Biosafety Level 4) viruses by the CDC (3,4).
Rodents represent the natural reservoir for arenaviruses. Most Lassa virus infections can be traced to contact with the rodent, Mastomys natilensis (22). Argentine hemorrhagic fever, caused by Junin virus, is carried by the field mouse Calomys colossus. They can be transmitted to humans via inhalation of aerosolized particles from rodent urine/feces, direct contact with open wounds and mucous membranes, and ingestion of food contaminated with rodent excrement (23,24).
The primary route of person-to-person transmission is through direct contact with infectious blood or bodily fluids. There have been no documented cases of respiratory transmission of VHF arenaviruses; however, the possibility cannot be ruled out.
In 1970, a nosocomial outbreak of Lassa fever occurred in Nigeria. A single patient with pulmonary involvement caused 16 secondary cases of infection in subjects who shared the same hospital ward. Airborne transmission was believed to be the most likely cause of infection, but no definitive evidence of respiratory transmission was found, and the exact mechanism of disease transmission in this outbreak remains unknown (25). In 1971, a student became infected with Bolivian hemorrhagic fever watching a nursing instructor demonstrate the changing of bed linens of an infected patient. The student did not touch the bed linens nor any object in the room and kept a distance of approximately 6 feet from the patient. Approximately 80 other health care workers working with the patient, without respiratory precautions, did not become infected. Definitive evidence of person-to-person airborne transmission is lacking, but no alternative explanation to respiratory transmission was found for the single case of infection involving the student (26).
Findings that suggest a respiratory route of transmission is unlikely include the case of a single infected patient traveling from Sierra Leone to the United States. No secondary cases developed among 522 contacts (27). Another case involving a single infected patient traveling from Nigeria to St. Thomas (U.S. Virgin Islands) saw no secondary infections in 159 people who had direct contact with the patient (28).
Incubation periods vary between 5 and 17 days. There have been no documented cases of arenavirus transmission by infected persons during the incubation period (23,29). Disease transmission occurs primarily during the active phase of infection, but there have been reports of disease transmission from convalescing patients to spouses. Infectivity has been documented at 7 to 22 days after onset of illness (30) and Lassa fever virus has been detected in semen samples up to 3 months after acute infection (31). Mortality for Lassa fever ranges from 15% to 20%, while New World arenaviruses range from 15% to 30% (27,27,29).
BUNYAVIRIDAE: RIFT VALLEY FEVER, CRIMEAN CONGO HEMORRHAGIC FEVER, HANTAVIRUS
Rift Valley fever (RVF) and hantaviruses have been recognized as Category A, or high priority, agents by the NIAID, while Crimean Congo Hemorrhagic Fever (CCHF) has been classified as Category C by the same agency (2). The CDC places a lower priority on these agents with RVF and CCHF fitting the general definition of Category B agents and hantavirus listed among emerging pathogens in Category C (3,4,32).
The bunyaviruses are transmitted by both rodent and arthropod vectors. RVF is carried by mosquito vector,
CCHF is transmitted by a tick vector, and the hantaviruses have rodent vectors. All of these can be transmitted by bites, direct contact with infected animal tissues, or aerosolization of virus from infected animal carcasses.
CCHF is transmitted by a tick vector, and the hantaviruses have rodent vectors. All of these can be transmitted by bites, direct contact with infected animal tissues, or aerosolization of virus from infected animal carcasses.
RVF disease frequently resembles human influenza with fevers, fatigue, loss of appetite, and associated constitutional symptoms lasting for 2 to 5 days. In epidemic areas, human infection rates can be as high as 35% (33). Severe cases can cause significant morbidity from liver necrosis, hemorrhagic phenomena, retinitis with visual impairment, and meningoencephalitis (34,35), but fatality rates tend to stay relatively low < 1% (36,37). There are no reported cases of person-to-person transmission of RVF (38). A group of World Health Organization (WHO) consultants have estimated that if 50 kg of RVF virus were released from an aircraft on a population of 500,000 persons, 400 would die and 35,000 would be incapacitated (39). Susceptible livestock could also become infected resulting in the potential establishment of disease in the environment (1).
CCHF fatality rates can be quite high with rates of 13% to 50% being reported in the literature (40). Humans may acquire the infection through tick bite, contact with blood or tissues from infected livestock, and infections of medical personnel treating or performing surgery on CCHF patients (41). There are reports that Iraq studied CCHF virus as a potential biological weapon and concluded that it was unsuitable as a biological weapon because it required vectors for dispersal (42). More recent reports, however, suggest that advances in viral replication technology may allow CCHF to be a viable aerosolized bioweapon (43).
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