Viral hemorrhagic fever (VHF) is a severe, often fatal, illness caused by four distinct families of viruses: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. These viruses are all RNA viruses; are dependent upon a rodent, tick, or mosquito host for survival; have no drug treatment or cure, with few exceptions; and are restricted geographically to the areas where the host lives. The viruses that cause VHF are found all over the world but each virus is associated with one or more host species. Some VHF infections are rare while others affect millions of people each year.
VHF is spread to humans by contact with urine, saliva, or feces from infected rodents or a bite from an insect, such as a mosquito or tick. Each virus is usually associated with a specific insect or rodent host or closely related species. These animals maintain the virus and are not known to exhibit any symptoms of viral illness.
Some VHF organisms can enter the body by inhaled airborne particles or by direct contact with broken or chafed skin. Some arenaviruses, such as Machupo and Lassa viruses, can be spread by person-to-person contact. For example, hospital workers caring for infected individuals can acquire the infection.
Most VHF organisms are totally dependent on their host organism for replication and survival. The cotton rat, multimammate rat, house mouse, deer mouse, and other field rodents are examples of rodent hosts. The hosts of some VHF organisms, such as Marburg and Ebola, are currently unknown.
Arenavirus, Argentine hemorrhagic, Bolivian hemorrhagic fever, Brazilian hemorrhagic fever, bunyavirus, filovirus, flavivirus, GTOV, guanarito virus, junin virus, JUNV, lassa virus, LASV, LMCV, lymphocytic choriomeningitis virus, machupo virus, MACV, mosquitoes, rats, sabia virus, SABV, ticks, Venezuelan hemorrhagic fever, VHF.
types of the disease
Arenaviruses: In some parts of the world, arenavirus infections are fairly common in humans. Arenavirus infections range from inconsequential (i.e., a mild flu-like illness that resolves without treatment) to fatal. Arenaviruses are divided into two groups: the New World or Tacaribe complex and the Old World or Lassa complex. In Africa (Old World), the virus that causes VHF is the Lassa virus (LASV; Lassa fever). In South America (New World), arenavirus infections are caused by the Machupo virus (MACV), which causes Bolivian hemorrhagic fever; the Guanarito virus (GTOV), which causes Venezuelan hemorrhagic fever; the Junin virus (JUNV), which causes Argentine hemorrhagic fever; and the Sabia virus (SABV), which causes Brazilian hemorrhagic fever.
One type of arenavirus, the lymphocytic choriomeningitis virus (LMCV), causes lymphocytic choriomeningitis (LCM). LCM infections have been reported in Europe, the Americas, Japan, and Australia. Bunyavirus, filovirus, and flavivirus infections all begin as arenavirus infections and can progress to internal bleeding.
Bunyaviruses: With one notable exception, bunyaviruses are transmitted by mosquitoes, ticks, or sand flies. These insects are known as bunyavirus vectors. A vector is an organism that can transmit a virus or bacterium from one organism to another without developing the illness itself. Hantaviruses are transmitted by infected rodents through exposure to their urine, feces, or saliva. Rarely, humans are infected through a rodent bite. Hantavirus pulmonary syndrome (PS) is a deadly disease that can cause dangerously low blood pressure (hypotension) and respiratory failure.
Filoviruses: The first genus (type) of filovirus was discovered in 1967 when 31 people in Marburg, Germany, were infected with a virus that was subsequently named the Marburg virus. These individuals were working with tissue from monkeys imported from Uganda. Seven of the infected individuals died. Since that time, all outbreaks have occurred in sub-Saharan Africa. Ebola virus, the second filovirus genus, was discovered in 1976 when outbreaks occurred in southern Sudan and northern Zaire. The Ebola virus is extremely deadly, having a mortality rate of 20% to 90%. The mechanisms by which filoviruses are transmitted are unknown. Bats have been suspected as the vector.
Flaviviruses: Flaviviruses are a family of viruses transmitted by mosquitoes and ticks. These viruses cause yellow fever, Kyasanur forest disease, Omsk hemorrhagic fever, and dengue fever. Dengue fever is one of the most common and widespread types of VHF. Fifty to 100 million cases occur worldwide each year.
Current research is focused on the control of the organisms that carry the disease and the development of antiviral medications and vaccines. Organisms that carry the disease are called vectors, and these include rodents and mosquitoes.
Researchers are currently seeking appropriate animal models in which to test vaccines. Nonhuman primate (i.e., monkeys) models usually mimic human disease. However, less costly and more readily available rodent models are also being studied.
A few antiviral medicines, including carboxamide, ribavirin, tiazofurin, and pyrazoline compounds, have been evaluated for the treatment of viral hemorrhagic fever (VHF). Ribavirin has successfully treated hamsters when a high dose of the drug is given within two days of infection. However, the drug has not produced similar results in nonhuman primate models. Potent inhibitors of both Old World and New World arenaviruses responsible for VHF are being identified in genetics laboratories.
Research is currently being done on virus-like particle (VLP)-based vaccines. These particles, which are produced from the live virus in a laboratory, have a similar form to the live virus from which they are produced. They also produce a similar immune response. To date, VLP-based vaccines have been tested on animal models such as the guinea pig. In these studies, the vaccines have been completely effective in preventing infection.
Researchers are currently studying the antiviral activity of the natural human hormones, dehydroepiandrosterone (DHEA) and epiandrosterone (EA), and 16 synthetic derivatives of these hormones. These hormones slow the replication of these viruses.
Early diagnosis is essential for the successful treatment of infected individuals, so researchers are developing and evaluating accurate and uncomplicated diagnostic tests. Antiviral medications, such as interferon, are highly effective when administered shortly after infection. However, they are ineffective when given after the infection is established.
Future research will focus on the development of new antiviral medications and vaccines as well as the control of rodents and mosquitoes that carry viral hemorrhagic fever (VHF). In addition, future work should focus on evaluating higher doses of ribavirin alone or in combination with other antiviral drugs, such as interferon, to increase the effectiveness of ribavirin. These combination drugs are known as synergistic drugs.
Because all the VHF viruses in a specific family (e.g., flaviviruses) have very similar structures, a drug that is effective against one type of VHF will likely be effective against other viruses in that family.
A better understanding of the ecology of VHF and the host organisms will help researchers to develop preventive public health measures that can reduce the chance of infection. Ecology refers to the relationships between an organism, in this case VHF, and its environment.
Other goals of future research include the development of molecular and immunologic tools for earlier diagnosis and better understanding of the transmission and progression of the viruses.
Recently, "reverse genetics systems" have been developed for several VHF organisms. These systems create infectious viruses from cloned complementary DNA (cDNA), or DNA synthetically produced from VHF RNA. This cDNA can generate mutated viruses, which can be used to develop antiviral medications and vaccines.
Several VHF viruses have gone through reverse genetics systems. This process has led to the generation of infectious viruses from cloned (copied) cDNA. The cloned cDNA is produced in a laboratory using VHF as a template. These reverse genetics systems will allow researchers to further understand how the virus replicates and how it produces an infection. The process will also lead to the development of antiviral medications and vaccines.
T cells are a specific type of infection-fighting white blood cell (lymphocyte) that can recognize invading viruses or bacteria that were present in a past infection. T cell memory is known to be the foundation of protective immunity. It is also the essential element of an effective VHF vaccine. Future research will be conducted in the area of T cell memory.
Further understanding of the molecular basis of VHF infections will increase the ability of physicians to treat these infections. The increased understanding of the molecular basis of VHF infections will include the identification of factors that determine the virulence of the virus, or how aggressive it is, and an understanding of how the host responds to the infection.