Jeffrey Lewis. Encyclopedia of Pestilence, Pandemics, and Plagues. Editor: Joseph P Byrne. Volume 1. Westport, CT: Greenwood Press, 2008.
The term hemorrhagic fevers describes a broad group of human illnesses caused by viruses from four families: Arenaviridae (including Lassa and New World Arenaviruses), Bunyaviridae (including Hantavirus), Filoviridae (including Ebola and Marburg viruses), and Flaviviridae (including the viruses responsible for Yellow Fever and Dengue fever). All hemorrhagic fever viruses (HFVs) have RNA for their genetic material, and all are enveloped in a fatty (lipid) covering. Although there is significant variation from virus to virus, in general they can cause a severe, potentially fatal illness affecting several different organ systems. The severity of the illness depends on several factors, including the type of virus, the size of the dose, and the route of infection.
After exposure, the virus incubates for 2 to 21 days and then attacks cells in the bloodstream, typically white blood cells (macrophages) and their predecessor cells (monocytes), leading to general fever and aches in the early stages of illness. From the blood, the infection can spread to a number of different organs including the kidneys, liver, and lungs. In many cases, as the disease progresses it damages the smallest blood vessels, the capillaries, causing fluid leakage into the surrounding tissues. It may also cause significant internal and external bleeding (hemorrhage), from which viral hemorrhagic fevers take their collective name. In severe cases, patients may bleed from the skin and eyes and may excrete copious amounts of blood through vomiting and diarrhea. Death can result from several causes, including heart or kidney failure, blood loss, pulmonary distress, seizure, or shock.
All viral hemorrhagic fevers are of animal origin (zoonotic). Ordinarily the virus replicates in a host species, typically a rodent or arthropod, which suffers few if any ill effects from the infection. Hemorrhagic fever viruses are therefore geographically restricted to the areas inhabited by their host species. Infection of the human body results from close contact with the host species. HFVs can be spread to humans via bites, as is commonly the case when arthropods such as ticks or mosquitoes are the host species. When rodents are the host, the virus is usually secreted in saliva, droppings, or urine, which can then dry and become airborne as dust particles. In some cases, the primary host may spread the virus to other animals such as livestock, which then pass the virus on to the humans who care for or slaughter them. Because HFVs exist normally in an animal reservoir, human outbreaks are sporadic and very difficult to predict.
The jump from host species to human is called primary transmission. Many hemorrhagic fever viruses are incapable of spreading from person to person, and their outbreaks are caused entirely by primary transmission. However, some HFVs can be spread from person to person in a process called secondary transmission. Secondary transmission occurs via direct contact with infected blood or other bodily fluids. There is little evidence that HFVs are normally transmitted via coughing or sneezing, although such a means of spread cannot be ruled out entirely. Secondary transmission can occur through the skin if infected fluid contacts a cut or other break in the surface. Puncturing the skin via a needle stick allows the virus direct access to the bloodstream and is therefore a particularly dangerous mode of transmission. In numerous documented cases, the repeated use of syringes under conditions of poor hygiene has served to amplify naturally occurring outbreaks of HFVs, contributing to both the spread and the lethality of the illness. HFVs are probably not transmissible from person to person before major symptoms have manifested themselves.
Because poor public health practices have contributed so significantly to the emergence of viral hemorrhagic fevers, it follows that good public health has been the most effective way to halt outbreaks. In cases of secondary transmission, quick identification, followed by quarantine of suspects and isolation of infected individuals has been successful. For some such outbreaks, the introduction of basics for personal hygiene such as clean water, soap, gloves, and appropriate clothing has been sufficient to halt secondary transmission of the illness via contact with infected fluids. Proper use and disposal of equipment such as needles and thermometers is essential. In cases of primary transmission via rodents, controlling the host population through trapping or poisoning has been effective, as have efforts to eliminate rodents from human dwellings and food sources where their urine and feces readily come into contact with people. When arthropods serve as the host, measures such as fumigation, wearing of proper clothing, and use of nets, screens, and other barriers are effective.
There has been little opportunity to observe most hemorrhagic fevers in a clinical setting, so evidence regarding individual treatment is sketchy at best. For all hemorrhagic fevers, treatment consists of supportive therapy—the administering of fluids and electrolytes to ensure that blood pressure and circulatory volume remain high enough to allow the body’s defenses to deal with the infection. Careful observation must accompany fluid treatment, as damage to blood vessels can permit the leakage of added fluids from the circulatory system into surrounding tissues causing complications such as pulmonary edema, the swelling of lung tissue leading to suffocation. In the case of Lassa fever, the use of antiserum derived from the blood of previously infected patients has been effective in early stages of the disease, but this necessitates prompt and accurate diagnosis, which often is not available in early stages of hemorrhagic fever outbreaks. Trials have shown that treatment with the drug ribavirin after infection may reduce the mortality rates of several hemorrhagic fever viruses. There are no known treatments for illnesses caused by the Filoviridae and Flaviviridae families. With the exception of yellow fever, there are no licensed vaccines for any hemorrhagic fever viruses.
HFVs as Biological Weapons
Since the 1990s hemorrhagic fever viruses have received considerable public attention as potential weapons in biological warfare or bioterrorism. There is some justification for this concern. Outbreaks of the Ebola virus in 1976 killed between 53 percent and 88 percent of infected persons, and in Angola, an outbreak of the closely related Marburg virus killed 235 of 257 infected individuals in 2005 (a 91.4 percent mortality rate). In addition, both the Soviet Union and the United States worked on weaponizing various HFVs during the Cold War, and the Soviet Union is known to have worked with Ebola and Marburg. Studies carried out in former Soviet bioweapons facilities have demonstrated that high concentrations of these agents in aerosolized form can cause illness in guinea pigs and nonhuman primates. In addition, a nonvirulent strain of the Ebola virus, dubbed Ebola Reston, may be somewhat transmissible in aerosol form. This evidence suggests that although HFVs such as Ebola and Marburg are not ordinarily very infectious, they are a short evolutionary leap away from high infectivity. The lethality of these viruses coupled with the lack of any effective therapy would make such a modified form a devastating weapon. Accordingly, in 1999 the Centers for Disease Control and Prevention (CDC) in Atlanta classified hemorrhagic fever viruses as Category A bioweapon agents.
Families of Hemorrhagic Fever Viruses
Arenaviruses are spherical and have a grainy appearance under the electron microscope. The host species for arenaviruses are rodents. There are four strains of arenavirus in the Western Hemisphere, which cause Argentine, Bolivian, Venezuelan, and Brazilian hemorrhagic fevers. All four of these hemorrhagic fevers tend to occur in limited, sporadic outbreaks. The best-known arenavirus causes Lassa fever, which is endemic in several countries of western Africa. In approximately 80 percent of patients, Lassa fever shows few if any observable symptoms. In the remaining 20 percent, the virus causes a severe disease that may affect the liver, spleen, and kidneys. For approximately 1 percent of all infected individuals, death occurs within 14 days of infection. Approximately 300,000 to 500,000 cases of Lassa fever occur each year in West Africa, with about 5,000 fatalities. Lassa may be spread from person to person via direct contact with infected fluids, but there is no definitive evidence to support direct airborne transmission of the virus. The animal reservoir for the Lassa virus consists of several closely related species of rat; because these rats have a wide geographic distribution, the Lassa virus may have a wider range than is currently believed. Treatment with ribavirin in the early stages of infection may reduce the mortality rate in Lassa fever outbreaks.
Bunyaviridae is a large family of viruses including five genera, each with many different serotypes. Bunyavirus diseases have been documented throughout much of the world, including Africa, Asia, and most recently North America. In Africa, the primary Bunyavirus diseases are Rift Valley Fever (RVF; genus Phlebovirus) and Crimean-Congo Hemorrhagic Fever (CCHF; genus Nairovirus). In both cases the animal host of the virus is an arthropod—mosquitoes in the case of RVF and ticks for CCHF. RVF is confined to Sub-Saharan Africa. Mosquitoes transmit the virus to both people and livestock, which then pass it on to humans. In most people RVF causes a mild illness with few if any symptoms, but in some patients the disease can progress to hemorrhagic fever accompanied by encephalitis and eye damage, including conjunctivitis. Approximately 1 percent of infected humans die of the disease. In late 2006 and early 2007, the World Health Organization (WHO) reported outbreaks of Rift Valley Fever in the United Republic of Tanzania, Kenya, and Somalia, all of which had extremely high mortality rates ranging between 23 percent and 45 percent, but this is at least partially attributable to the fact that surveillance was only able to detect severe cases of the disease. In contrast, CCHF is endemic throughout Africa, Asia, the Middle East, and Eastern Europe. Ticks transmit the virus for CCHF to humans and many other species of mammal. CCHF often causes death from liver, kidney, or lung failure, with a mortality rate of approximately 30 percent. The use of ribavirin in the early stages of infection may reduce the mortality of both illnesses.
The third genus of Bunyaviruses that cause hemorrhagic fever in humans are the Hantaviruses. In Asia, Hantavirus infections often lead to kidney failure and are thus referred to as hemorrhagic fevers with renal syndrome. These illnesses have been known in China and Russia for centuries; they received international attention during the Korean War, when thousands of UN troops became ill with Hantavirus infections. The virus was not identified until 1976, followed by identification of the main host species, the striped field mouse, several years later. Recently a new form of Hantavirus endemic to the southwestern United States has been discovered, one that causes an immune reaction producing very fine damage in the capillaries, which allows fluid but not cells to leak out. Consequently the lungs of victims fill with liquid while the blood congeals, leading to rapid death from pulmonary edema. By 1995, 115 cases of this new Hantavirus disease had been confirmed, most in the four corners region of the southwestern United States; the mortality was a very high 51.3 percent. The host animals for this virus are also mice. There is evidence that Asian Hantaviruses respond to treatment with ribavirin, but there seems to be no treatment other than supportive therapy with careful observation for the American Hantavirus.
Filoviruses are the most recently discovered family of hemorrhagic fever viruses, having first been observed in 1967. The name means threadlike or filamentous, describing the threadlike structure of the viral particles. There are two genera of filoviruses, Marburg and Ebola, and Ebola has four sub-types, three of which cause severe hemorrhagic fevers in humans. Marburg virus was discovered in 1967 when workers in Marburg, Germany, were exposed to the virus via a shipment of green monkeys from Uganda. In this initial outbreak, there were 31 confirmed cases in Germany and Yugoslavia, of which 7 (23 percent) were fatal. Ebola first became known through two unrelated but simultaneous outbreaks in Zaire (now Democratic Republic of Congo) and Sudan in 1976. Each outbreak resulted in approximately 300 confirmed illnesses. The mortality rate for the Sudan epidemic was 53 percent; that of Zaire was 88 percent. There was another major Ebola epidemic in Congo in 1995, leading to 316 illnesses and a 77 percent mortality rate. The most recent epidemic, as noted above, was an outbreak of Marburg in Angola in early 2005, which killed a staggering 235 of 257 known cases (91.4 percent mortality).
The courses of all filovirus infections are similar. After an incubation period of 2 to 21 days, in which the virus infects the macrophages and monocytes, the illness spreads to other tissues such as the kidneys and spleen. Victims suffer high fevers and excruciating pain. In later stages the viruses cause capillary damage resulting in massive internal and external hemorrhaging. The cause of death is typically described as terminal shock. Filoviruses are spread via direct contact with infected fluids. Airborne spread has not been observed among people, but laboratory research suggests it might be possible. Poor public health has been a significant factor contributing to the secondary transmission of filovirus infections. In all three major Ebola outbreaks, hospitals have served to amplify rather than reduce the incidence of the disease by reusing syringes, needles, and other medical equipment without sterilization. There is no known treatment for filovirus infections other than supportive therapy. The natural range for most filovirus strains appears to be Africa, but some strains (such as the Reston strain) occur naturally in Asia and the Philippines. The animal host of filoviruses is currently unknown, but evidence is increasingly pointing toward bats as the host species. The mode of primary transmission from host to human remains unknown.
Viruses of the Flaviviridae family cause four hemorrhagic fevers in human beings: yellow fever, Omsk Hemorrhagic Fever, Kyasanur Forest Disease, and Dengue fever. Omsk Hemorrhagic Fever and Kyasanur Forest Disease have ticks as their host species and have a limited impact on human health. Of the four, Dengue fever poses the greatest public health threat. Dengue may be caused by one of four closely related types of flavivirus. In most cases it causes a severe flu-like illness, but in a minority of cases the fever leads to symptoms consistent with other HFVs—high fever, liver damage, internal and external bleeding, and death as a result of general shock. Dengue is a very widespread disease, endemic in more than 100 countries, particularly in Southeast Asia and the western Pacific. The incidence of Dengue has increased dramatically in the past two decades. Currently, WHO estimates that there may be 50 million cases of Dengue infection worldwide every year, with approximately 500,000 cases requiring hospitalization. Dengue is most prevalent in urban and semi-urban environments, affects children under the age of 15 preferentially, and is the leading cause of hospitalization and death among children in several countries. Dengue viruses are transmitted via the bites of infected female mosquitoes. There is no treatment for Dengue fever, but proper supportive therapy can reduce mortality to 1 percent or lower. There is no vaccine, and the only current method for controlling the spread of Dengue is to combat the mosquitoes that transmit the virus.