Bunyaviruses
Robert E. Shope
General Concepts
Clinical Manifestations
Bunyaviruses cause fevers sometimes with rash. In addition, Crimean-Congo hemorrhagic fever virus may cause hemorrhage; Rift Valley fever virus may cause hemorrhagic hepatitis, encephalitis, or blindness; La Crosse virus and related viruses may cause encephalitis; and Hantaan virus and related viruses may cause hemorrhage and renal failure or the hantavirus pulmonary syndrome.
Structure
Bunyaviruses are spherical, enveloped particles 90 to 100 nm in diameter. They contain three segments of antisense (and sometimes ambisense) single-stranded RNA combined with nucleoprotein. Two external glycoproteins form surface projections. A virus-encoded transcriptase is present in the virion.
Classification and Antigenic Types
There are four genera Bunyaviruses, Phlebovirus, Nairovirus, and Hantavirus which include 35 serogroups with at least 304 types and subtypes.
Multiplication
Bunyaviruses replicate in the cytoplasm. Their RNA genome is transcribed to mRNA. The host RNA sequence in some representative viruses primes viral mRNA synthesis. Bunyaviruses mature by budding into vesicles at or near the Golgi apparatus. Reassortment of RNA segments occurs between closely related members.
Pathogenesis
Fever accompanies viremia, which seeds the liver in Rift Valley fever and Crimean-Congo hemorrhagic fever. Encephalitis, retinitis, and renal involvement usually appear later in infection (after antibody formation). More specific mechanisms of pathogenesis are not known.
Host Defenses
Interferon is an early defense mechanism. Viremia ceases with the appearance of humoral antibody, which does not alter established encephalitis, retinitis, or renal lesions.
Epidemiology
The distribution of each disease is determined by the distributions of the vector and vertebrate host. Except for hantaviruses, biologic transmission is by a tick, mosquito, midge, or sand fly vector. Arthropods are infected for life. Transovarial transmission is common in arthropods. Wild or domestic vertebrates usually are needed to maintain the cycle. Humans are usually dead-end hosts for all these viruses except phleboviruses. There is a secondary nosocomial spread of Crimean-Congo hemorrhagic fever. Hantaan virus cycles among rodents, probably by aerosol or fomite transmission from infected rodent urine. Human infection is incidental.
Diagnosis
Knowledge of the geographic site of exposure, season, and presence of arthropods leads to presumptive diagnosis in febrile cases. Diagnosis is confirmed by virus isolation, presence of specific IgM, an antibody titer rise in paired sera, or detection of RNA by reverse transcriptase-polymerase chain reaction (RT-PCR).
Control
Control is often achieved by control of vector arthropods or vaccination (of humans for Crimean-Congo hemorrhagic fever and of hantavirus hemorrhagic fever with renal syndrome, and of sheep and cattle for Rift Valley fever). Control of the rodent host is important for hemorrhagic fever with renal syndrome.
INTRODUCTION
Bunyaviridae is a family of arthropod-borne or rodent-borne, spherical, enveloped RNA viruses. Bunyaviruses are responsible for a number of febrile diseases in humans and other vertebrates. They have either a rodent host or an arthropod vector and a vertebrate host.
Clinical Manifestations
The Bunyaviridae are divided into arthropod-borne viruses (arboviruses) and rodent-borne viruses (roboviruses). Bunyaviruses cause several diseases of human and domestic animals, including fever, hemorrhagic fever, renal failure, encephalitis, meningitis, blindness, and, in domestic animals, congenital defects. Most illnesses are self-limited fevers that last 1 to 4 days and are accompanied by headache, muscle aches, nausea, conjunctival injection, and generalized weakness. A few are more serious illnesses: La Crosse encephalitis is characterized by fever, convulsions, drowsiness, and focal neurologic signs; Crimean-Congo hemorrhagic fever is characterized by headache, pain in limbs, and, in severe cases, bleeding from multiple orifices; hemorrhagic fever with renal syndrome (Korean hemorrhagic fever, nephropathia epidemica) is characterized by fever, hemorrhage, and acute renal failure; and hantavirus pulmonary syndrome is characterized by fever and acute respiratory distress. Rift Valley fever may mimic the febrile, encephalitic, or hemorrhagic illness of other bunyavirus infections, and the patient may also go blind as a result of retinal vasculitis. These illnesses are significant, currently uncontrolled human diseases. La Crosse virus causes most of the arbovirus encephalitis in North America. Also, more than 100,000 cases of hemorrhagic fever with renal syndrome occur annually in Asia and Europe. Rift Valley fever has explosive potential, as shown in Egypt in 1977, when an estimated 200,000 cases, with 598 deaths, were recorded. Hantavirus pulmonary syndrome is uncommon, but is associated with a 50% case fatality rate.
Structure
Bunyaviruses are spherical, enveloped particles 90 to 100 nm in diameter. They contain single-stranded RNA, which, with the nucleoprotein, forms three nucleocapsid segments. The segments are large, medium, and small helical, circular structures. The RNA has a total molecular weight of 5 X 106. The nucleocapsid is surrounded by a lipid-containing envelope. Surface spikes are composed of two glycoproteins that confer properties of neutralization of infectivity and hemagglutination of red blood cells.
Classification and Antigenic Types
The family Bunyaviridae includes four genera containing 35 serogroups with at least 304 viruses, of which 51 in the four genera are known to cause human disease (Table 56-1).
Multiplication
Replication occurs in the cytoplasm. In most bunyaviruses the genome is antisense. In some phleboviruses, the small RNA segment is ambisense (i.e., one portion is viral complementary in sense and the other portion is viral in sense). Genetic reassortment can occur during infection because the RNA is segmented (Fig. 56-1). Virus particles bud into the Golgi cisternae and are liberated from the cell by plasma membrane disruption and by fusion of intracellular vacuoles with the plasma membrane.
FIGURE 56-1 Genetic reassortment in bunyaviruses. Reassortment occurs when a cell is infected simultaneously with two different but closely related bunyaviruses. Each of the three RNA segments is a gene. Parent viruses A and B each donate three genes. These replicate in the cytoplasm, are packaged in different combinations, and are released as eight kinds of progeny viruses, two of which are identical to the parent strains and six have reassorted genes.
Pathogenesis
Except for members of the genus Hantavirus, bunyaviruses replicate in arthropods. The gut of the vector is infected initially, and after a few days or weeks the virus appears in the saliva; the arthropod then remains infective for life but is not ill. When the vector takes a blood meal, the infective saliva enters the small capillaries or lymphatics of the human or other vertebrate host (Fig. 56-2). The primary site of replication in humans is not known; it may be the vascular endothelium, the skin, or the regional lymph nodes. An incubation period of a few days ensues, after which the vertebrate host develops viremia. The infection is usually inapparent. Less often, the host becomes febrile, manifesting the more serious signs and symptoms that are characteristic of the infecting virus. Viremia subsides with the appearance of humoral antibody, and the host recovers unless a specific target organ is affected. This target organthe liver in Rift Valley fever, the brain in La Crosse encephalitis, the liver and vascular endothelium in Crimean-Congo hemorrhagic fever and hemorrhagic fever with renal syndrome, and the lung in hantavirus pulmonary syndromeis damaged, and a specific disease occurs. Although the damage in most infections is believed to result from direct invasion by the virus and not from a host-mediated antigen-antibody or antigen-lymphocyte reaction, the pathogenesis of bunyaviruses in
FIGURE 56-2 Pathogenesis of bunyavirus infections. Humans are dead-end hosts of most bunyaviruses; however, the blood of Crimean-Congo hemorrhagic fever patients may be highly infectious.
the vertebrate host has not been extensively studied. The damage to the kidneys in hemorrhagic fever with renal syndrome and to the brain and retina in Rift Valley fever occurs after humoral antibody is formed. These complications have been postulated to result from a host reaction.
Host Defenses
The initial response to bunyavirus infection is the production of interferon. Bunyaviruses are sensitive to the action of interferon, so this response may play a protective role. Humoral antibody is also protective. The appearance of antibody, either natural or passively administered, is associated with the disappearance of virus from the blood. The role of cell-mediated immunity has not been fully evaluated.
Epidemiology
Except for hantaviruses the life cycle of the bunyaviruses involves replication alternately in an arthropod (mosquito, tick, Culicoides midge, or phlebotomine sand fly) and in a vertebrate host, usually a small mammal. Humans may become ill when infected, but human blood rarely infects biting arthropods in the natural cycle; therefore, humans are usually dead-end hosts. In addition to the arthropod-vertebrate-arthropod cycle, some bunyaviruses, such as those in the California and phlebotomus fever groups, are transmitted transovarially in the arthropod and can therefore overwinter in the egg and be transmitted to humans in the late spring or early summer, when the adult arthropod emerges. Bunyaviruses are found throughout the world, but each serotype has a limited geographic distribution because it relies on one or, at best, a few arthropod species to maintain its natural cycle. Hantaviruses are maintained in rodent reservoirs and are not arthropod borne. Transmission to humans is believed to occur by inhalation of virus excreted in rodent urine and other body fluids (Fig. 56-3).
FIGURE 56-3 Hantavirus transmission. Hantaviruses are maintained in a rodent reservoir. The rodents are asymptomatic and transmit virus to other rodents and humans by way of infected urine and perhaps other body secretions. Humans are dead-end hosts. Hantaviruses cause hemorrhagic fever with renal syndrome in Europe and Asia.
La Crosse Virus
The most serious disease of bunyavirus origin in the United States is La Crosse encephalitis. First recognized when there was a fatal case in La Crosse, Wisconsin, in 1960, it is now diagnosed not only in the north central United States, but also in much of the eastern portion of the country and in Canada. The closely related California encephalitis, snowshoe hare, and Jamestown Canyon viruses are also occasionally implicated as agents of encephalitis. At least 1,000 cases have been reported since 1960, with a case fatality ratio of about 1:200. La Crosse encephalitis affects children; boys are infected more frequently than girls because boys are more often exposed. The vector of La Crosse virus is the woodland mosquito Aedes triseriatus, which breeds in tree holes. Consequently, the infection usually occurs after exposure in the woods when camping, or among children living in rural areas. Chipmunks and tree squirrels are amplifying hosts. Virus may also be transmitted from male to female mosquitoes venereally (Fig. 56-4).
FIGURE 56-4 La Crosse encephalitis transmission cycle. La Crosse virus is maintained in the hardwood forest habitat and in discarded tires in the suburban habitat by transovarial transmission in Aedes triseriatus mosquitoes. An adult female mosquito is able to transmit virus to humans and to squirrels and chipmunks with her first blood meal. Squirrels and chipmunks become viremic and amplify the cycle when fed upon by infected Aedes mosquitoes. Uninfected female mosquitoes can also be infected by venereal transmission from male mosquitoes. Humans, mostly children, develop encephalitis and do not transmit the virus (dead-end hosts).
Group C and Guama Viruses
The group C and Guama viruses cause self-limited febrile disease in humans in Central and South America. The disease lasts 2 to 4 days and may be severe enough to incapacitate even the most robust forest worker. Infection is usually transmitted by forest Culex (Melanoconion) mosquitoes. Forest rodents and marsupials are the vertebrate hosts, and infection in humans is dead end. Bunyamwera group virus illnesses occur in Africa and South America. These are transmitted by mosquitoes and are also self-limited febrile diseases.
Phlebotomus Fever Viruses
Naples and Sicilian phlebotomus fevers are endemic in North Africa and southern Europe and from the Middle East to Pakistan. Humans and sand flies are believed to be the reservoirs. During World War II, severe epidemics of these diseases were recognized as febrile illnesses in troops in the Mediterranean theater. The sand fly Phlebotomus papatasii proved to be the vector. Subsequently, related viruses such as Candiru, Chagres, and Punta Toro viruses were discovered in the New World tropics, where a cycle of phlebotomine sand flies and forest rodents was responsible for maintaining the infection.
Oropouche Virus
Oropouche virus causes a major nonfatal febrile disease in Brazil, Trinidad, Peru, and Panama. Tens of thousands of cases have been recorded in epidemics. The vertebrate host is not yet known; Culicoides midges are implicated as vectors.
Crimean-Congo Hemorrhagic Fever Virus
Crimean-Congo hemorrhagic fever is a tick-transmitted viral disease found in Bulgaria, Yugoslavia, the former Soviet Union, China, Iraq, United Arab Emirates, Pakistan, and sub-Saharan Africa. The vector tick is usually of the Hyalomma genus. Domestic and wild mammals may be amplifying and reservoir hosts. Human infection also occurs directly from contaminated blood of hospitalized patients; therefore, patients hospitalized with this disease should be isolated.
Rift Valley Fever Virus
Rift Valley fever appears as epizootics in sheep, cattle, camels, and goats in Africa. Massive outbreaks have been recognized in South Africa, Kenya, Uganda, Sudan, Egypt, and Mauritania. Human cases usually are restricted to veterinarians, butchers, and others in close contact with blood of domestic livestock. However, in Egypt in l977 and again in Mauritania in l987, widespread human epidemic disease was recognized. Transmission is via aerosolized infected blood and mosquitoes. Epizootics in the Rift Valley arise periodically after heavy rains. There is evidence that the virus is maintained in nature in the dried eggs of Aedes mosquitoes that hatch only in very moist years.
Diagnosis
Illnesses caused by bunyaviruses are diagnosed by isolating the virus, detecting RNA by RT-PCR, or by showing a fourfold or greater rise in antibody titer between acute- and convalescent-phase sera. The virus can be isolated from blood (or from brain, liver, and other organs postmortem) during the viremic phase, but not usually after the third day of fever. It is propagated in baby mice or mosquitoes or in vertebrate or invertebrate tissue cultures. The RNA has been detected in lung tissue from cases of hantavirus pulmonary syndrome postmortem. Serologic tests used to diagnose bunyavirus infections include the enzyme-linked immunosorbent assay and complement fixation, fluorescent antibody, neutralization, and hemagglutination inhibition tests. The complement fixation and fluorescent antibody tests and the enzyme-linked immunosorbent assay (ELISA) are often group reactive; the neutralization and hemagglutination inhibition tests are type specific. Assessments of IgM may be especially useful in establishing an early diagnosis. Once isolated, virus is identified by the same tests with a reference immune serum.
Bunyavirus diseases usually are restricted to focal geographic areas because of the limited distribution of their vectors and vertebrate hosts. Awareness of their geographic distribution, seasonality, and clinical syndrome may help in establishing a diagnosis. For instance, hemorrhagic fever with renal syndrome should be strongly suspected in a person in Europe or Asia who has fever, proteinuria, thrombocytopenia, and elevated blood urea nitrogen, especially if the patient has been exposed to rodents. Definitive diagnosis, however, can be made only by laboratory tests.
Control
Bunyavirus transmission is controlled by restricting the arthropod vector or vertebrate reservoir. Personal measures, such as the use of proper protective clothing, repellents, bed nets, and house screens, are effective but are often forgotten. Pesticides are used on a community-wide basis, as well as at the breeding sites of arthropods. Proper disposal of tires (a breeding site of the mosquito transmitting La Crosse encephalitis virus) is effective. Rodenticides are used in outbreaks of hemorrhagic fever with renal syndrome.
Rift Valley fever vaccines are used in Africa to immunize sheep and cattle and hence to stop the transmission cycle to humans. A human vaccine for Crimean-Congo hemorrhagic fever is used in the former Soviet Union and Bulgaria. Human vaccine is also used in Asia to prevent hemorrhagic fever with renal syndrome. Treatment of cases of hemorrhagic fever with renal syndrome during the first week of illness with ribavirin has proved efficacious.
Patients in the viremic phase of illness should be protected from arthropod bites by the use of pesticides, bed nets, and screening. Medical personnel who care for viremic patients should be careful in handling needles and surgical instruments to prevent accidental transmission by blood. When hemorrhage occurs, as in Crimean-Congo hemorrhagic fever, hospital personnel should wear a gown and mask to prevent aerosol infection. For other bunyavirus infections, no quarantine, isolation, or concurrent disinfection is needed other than the precautions noted above.
REFERENCES
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Gear JHS (ed): Handbook of Viral and Rickettsial Hemorrhagic Fevers. CRC Press, Boca Raton, FL, 1988
Monath TP (ed): The Arboviruses: Epidemiology and Ecology. CRC Press, Boca Raton, FL, 1988
Shope RE: Arbovirus. In Balows A, Hausler WJ Jr, Herrmann KL, Isenberg HD, Shadomy HJ (eds): Manual of Clinical Microbiology. 5th Ed. American Society for Microbiology, Washington, DC, 1991