Bunyaviridae

Article about Bunyaviridae.

Topics covered

  • Essentials
  • Viral taxonomy and vectors
  • Genus Orthobunyavirus
  • Genus Hantavirus
  • Genus Nairovirus
  • Genus Phlebovirus
  • Unassigned viruses and viruses causing only minor disease in humans
  • Further reading

Essentials

Viruses of the family Bunyaviridae contain a 3-segmented, single-stranded, negative-sense RNA genome. They are divided into five genera, of which four are known to include human pathogens—Orthobunyavirus, Phlebovirus, Hantavirus, and Nairovirus. These viruses are found throughout the world and are transmitted between vertebrate hosts and to humans through the bite of infected arthropod vectors (mosquitoes, ticks, others), or from infectious excreta of rodents and other small mammals, and rarely person to person. Many of viruses are transmitted from infected arthropod vector females to the next generation by transovarial transmission, thereby surviving adverse environmental conditions and leading to marked seasonal distribution of disease. There are few vaccines available to protect against infection. Prevention is by avoidance of exposure to potentially infected arthropod and small-mammal vectors.

Clinical features

Bunyaviridae cause a wide range of clinical illnesses, ranging from self-limited febrile disease to severe, life-threatening haemorrhagic fever, acute respiratory distress, or encephalitis. The most important human diseases include those caused by:

La Crosse virus—the commonest cause of ‘California encephalitis’, most cases of which are relatively mild and with good prognosis; treatment is supportive.

Oropouche fever—causes epidemics of febrile illness, sometimes with meningitis, throughout the Amazon basin; prognosis is good; treatment is supportive.

Haemorrhagic fever with renal syndrome—caused by four distinct viruses (Hantaan, Dobrava, Puumala, Seoul); Hantaan and Dobrava cause the most severe disease, characterized sequentially by (1) febrile phase with features including headache, myalgias, petechiae and conjunctival haemorrhage, (2) hypotensive phase with shock, (3) oliguric phase, when one-third of cases have severe haemorrhage, (4) diuretic phase, (5) convalescent phase, which may be prolonged; ribavirin is effective if started early in disease. Inactivated vaccines against Hantaviruses are available for use in Asia.

Hantavirus pulmonary syndrome – most commonly reported from the western United States, Canada, Central and South America; symptoms are primarily those of acute unexplained adult respiratory distress syndrome; treatment is supportive; mortality is 20-40%.

Other diseases caused by Bunyaviridae—these include sandfly fever, Rift Valley fever and Crimean-Congo haemorrhagic fever. Some viruses of the family, e.g. Rift Valley fever virus and Nairobi sheep disease virus, are important pathogens of domestic animals.

Viral taxonomy and vectors

The family Bunyaviridae currently contains around 300 viruses, and is divided into five genera (Table 1). The family name, and that of the genus Orthobunyavirus, is derived from the type species Bunyamwera virus, which was isolated in Uganda from Aedes mosquitoes. The other genera are Hantavirus named after Hantaan virus (the cause of Korean haemorrhagic fever), Nairovirus after Nairobi sheep disease virus, Phlebovirus after phlebotomus or sandfly fever virus, and Tospovirus after tomato spotted wilt virus. All members of the family share structural, biochemical, and genetic properties, such as a spherical enveloped virion 80 to 120 nm in diameter and a genome of single-stranded negative-sense RNA divided into three segments (L, M, S). Members of different genera vary substantially in their biological and biochemical properties and in their mechanisms of replication. Orthobunyaviruses, nairoviruses, and phleboviruses, which together make up most of the family, are all arthropod-borne animal viruses (arboviruses). These circulate in a wide variety of different vertebrate hosts and are transmitted between vertebrates, including humans, by the bites of blood-sucking arthropods, principally mosquitoes for orthobunyaviruses, sandflies for phleboviruses, and ticks for nairoviruses. Hantaviruses are zoonotic agents infecting rodents and other small mammals. They may spread to humans who are in close contact with infected excreta. Tospoviruses are arthropod-transmitted plant viruses of no known medical importance.

Viruses within the larger genera are further subdivided into serogroups; orthobunyaviruses have at least 18 serogroups and nairoviruses have 7 (Table 1). Of over 60 Bunyaviridae that are known to infect humans, the type species and those causing major human diseases are shown in bold type in Table 1 and are described in more detail. Table 2 lists the distribution of the remaining viruses that cause minor human infections with their principal arthropod vectors. The habitats of the different viruses and their vectors range from arctic to tropical. The enzootic cycles of arboviruses are poorly understood. Most viruses undergo alternate cycles of replication in vertebrate and invertebrate hosts, but transovarial and trans-stadial transmission within some mosquitoes, ticks, and phlebotomine flies, and venereal transmission from vertically infected male mosquitoes to uninfected females is also known to occur. Most arboviruses have a narrow host range, occur within a limited area, and are transmitted by specific vectors to a limited number of vertebrate hosts, but some viruses infect a wider host range, are transmitted by more than one type of vector, and may occur in more than a single continent. Tick transmission predominates in Asia, but is unknown in South or Central America, and although some Bunyaviridae have been isolated in Australia, none is known to infect humans in that continent. Viruses of this family are among the most common apparently emerging diseases. Following viral entry, whether through the skin after the bite of an infected arthropod or by another route, there is replication in draining lymph nodes, which may be enlarged, and then viraemia. Symptoms develop when virus is deposited and replicates in other sites. The viruses are killed by bleach, phenolic disinfectants and detergents, autoclaving, boiling, and γ-irradiation. Enzymes such as nucleases also inactivate these viruses. Biosafety level 3 is recommended for handling most human pathogens with the ability to spread by aerosol (e.g. hantaviruses and Oropouche virus), but level 4 is required for Crimean–Congo haemorrhagic fever virus. Added precautions are necessary when handling hantavirus-infected animals and virus concentrates.

Genus Orthobunyavirus 

Studies with Bunyamwera and similar viruses show reassortment within the three-segmented genome when two closely related viruses infect the same cell, either in nature or in the laboratory. Such studies have been used to analyse the molecular basis of virulence for vertebrate and invertebrate hosts. Two orthobunyaviruses, Akabane and Aino viruses in the Simbu serogroup, produce congenital deformities in sheep, goats, and cattle in Japan, Australia, Africa, and the Middle East. However, there is no evidence that any member of the genus or family produces teratogenic effects in humans, but there is concern that Oropouche virus, a Simbu serogroup pathogen of Central and South America, may be a threat to pregnant women.

Bunyamwera virus

Symptoms

A mild febrile illness, usually with headache, joint and back pains, sometimes with a rash, and occasionally with mild involvement of the central nervous system. Serological surveys indicate widespread human infection in sub-Saharan Africa but it is rarely recognized. Laboratory infections have been recorded. Garissa virus, isolated from haemorrhagic fever patients during outbreak investigations in Kenya and Somalia, has genome segments virtually identical to both Bunyamwera and Cache Valley viruses, but neither of these is known to cause haemorrhagic disease in humans.

Treatment and prognosis

No treatment is necessary and the prognosis is excellent.

California encephalitis, Inkoo, Jamestown Canyon, La Crosse, Tahyna, and snowshoe hare viruses

The viruses named above, and perhaps others currently unrecognized, are responsible for the clinical condition known as California encephalitis. The viruses are widely distributed throughout many parts of North America, Europe, and Eurasia. In the United States of America most reported human infections are due to La Crosse virus in Ohio, Wisconsin, West Virginia, and Minnesota. From 1995 to 2005, 70 to 167 cases were reported annually. Most occurred in children, usually in boys, although Jamestown Canyon virus is found more often in adults. There is nearly always a history of outdoor exposure during warmer months in areas where woodland mosquitoes are prevalent. The incubation period is 5 to 10 days. Most cases of La Crosse encephalitis are relatively mild with headache, fever, and vomiting, progressing to lethargy, behavioural changes, and occasional brief seizures, followed by improvement. Severe cases (10–20%) develop sudden fever and headache, disorientation, and seizures during the first 24 h of illness, sometimes progressing to coma and requiring intensive supportive care. Overall, about 50% of symptomatic children have seizures with status epilepticus in 10 to 15%. The case fatality rate approaches 1%. Residual seizures occur in 6 to 13%, persistent hemiparesis in about 1%, and cognitive dysfunction in a few. In appropriate epidemiological settings, the disease should be considered in children presenting with aseptic meningitis or encephalitis.

Table 1 The family Bunyaviridae: its genera, serogroups, vectors, and viruses infecting humans
Genus Serogroup Vector Viruses infecting humans
Orthobunyavirus (over 150) Anopheles A (12) Mosquito Tacaiuma
Anopheles B (2) Mosquito  
Bakau (5) Mosquito  
Bunyamwera (33) Mosquito Bunyamwera, Calovo, Garissa, Germiston, Ilesha, Maguari, Shokwe, Tensaw, Wyeomyia
Bwamba (2) Mosquito Bwamba, Pongola
C group (14) Mosquito Apeu, Caraparu, Itaqui, Madrid, Marituba, Murutucu, Nepuyo, Oriboca, Ossa, Restan
California (14) Mosquito California encephalitis, Guaroa, Inkoo, Jamestown Canyon, Keystone La Crosse, snowshoe hare, Tahyna, trivittatus
Capim (10) Mosquito  
Gamboa (8) Mosquito  
Guama (12) Mosquito Catu, Guama
Koongol (2) Mosquito  
Minatitlan (2) Mosquito  
Nyando (2) Mosquito Nyando
Olifantsvlei (5) Mosquito  
Patois (7) Mosquito  
Simbu (24) Mosquito Oropouche, Shuni
Tete (5) Mosquito  
Turlock (5) Mosquito  
Unassigned (3) Mosquito  
Hantavirus (8) Hantaan (26) None Andes, Bayou, Black Creek Canal, Dobrava, Hantaan, Juquitiba, Laguna Negra, Lechiguanas, Monongahela, Oran, Prospect Hill, Puumala, Seoul, Sin Nombre
Nairovirus (32) Crimean–Congo (3) Tick Crimean–Congo haemorrhagic fever, Hazara
Dera Ghazi Khan (6) Tick  
Hughes (10) Tick Soldado
Nairobi sheep disease (3) Tick Dugbe, Ganjam, Nairobi sheep disease
Qalyub (3) Tick  
Sakhalin (7) Tick Avalon
Thiafora (2) Tick  
Phlebovirus (57) Phlebotomus (44) Sandflya Alenquer, Candiru, Chagres, Corfou, Punta Toro, Rift Valley fever a , Naples, sandfly fever, Sicilian, Toscana
Uukuniemi (13) Tick Uukuniemi, Zaliv-Terpeniya
Tospovirus (1)   Thrips  
Unassigned (53)   Mosquito Bangui, Kasokero, Tataguine
  Tick Bhanja, Issyk-kul Keterah, Tamdy, Wanowrie

Numbers in parentheses indicate the approximate number of viruses in the genus or serogroup.

Bold type indicates the type species and viruses causing major disease in humans.

a Mosquito vector for Rift Valley fever virus.

In Europe, Tahyna virus is widely distributed in Austria, former Czechoslovakia, France, Germany, Italy, Norway, Romania, former Yugoslavia, and the former Soviet Union. Seroprevalence exceeds 95% in parts of former Czechoslovakia, and is about 50% in the Rhone valley in France and the Danube basin near Vienna, but overt disease is seldom recognized. Inkoo virus is prevalent in Finland and also in neighbouring regions of Russia. Most adult Lapps have antibodies. Small children may have signs of central nervous system involvement during acute infection. Antibodies reactive with California serogroup viruses have also been found in human sera collected in Sri Lanka, China, and in the far northern latitudes of Eurasia where several California serogroup viruses have been isolated from mosquitoes, some related to Inkoo and Tahyna viruses, but others to snowshoe hare virus. In another Russian study of c.50 people, mainly 14 to 30 years old, with infections caused by California serogroup viruses, about two-thirds had influenza-like illnesses without central nervous system involvement, while the remaining one-third had aseptic meningitis.

Control, treatment, and prognosis

Measures to limit mosquito breeding, particularly of Aedes triseriatus, are useful in endemic regions. No vaccines are available, and there is no specific treatment. Fluid and electrolyte balance must be maintained, and anticonvulsive drugs may be required to control seizures. Intravenous ribavirin has been used to treat severe La Crosse encephalitis.

Oropouche virus

Symptoms

Before 1961, Oropouche virus was known to have caused only a mild fever in a single forest worker in Trinidad, but that year it was responsible for a substantial epidemic in the Belém area of northern Brazil, where c.7000 people were affected. Over the ensuing 50 years, massive epidemics of febrile illness have been recorded throughout the Amazon Basin and beyond, with many thousands infected. Symptoms include headache, generalized pain including back pain, prostration, and fever (40°C). Rash, meningitis, or meningism occasionally accompany infection. Illness lasts from 2 to 5 days, occasionally with protracted convalescence. No fatalities have been reported.

Control, treatment, and prognosis

No vaccine is available. Transmission is probably by the biting midge Culicoides paraensis and outbreaks appear to be a consequence of agricultural development of the Amazon Basin. Accumulated organic waste from cacao and banana production provides ideal breeding sites for Culicoides, leading to massive populations and subsequent epidemic Oropouche disease. Measures to reduce Culicoides breeding may be beneficial. Treatment is supportive and the prognosis is good, although convalescence may be protracted.

Genus Hantavirus

Haemorrhagic fever with renal syndrome Hantaan virus of the genus Hantavirus is the cause of Korean haemorrhagic fever in Korea. The Hantaan River is near the demilitarized zone between North and South Korea where the virus was first recovered in 1976 from its rodent host Apodemus agrarius. The clinical diseases caused by Hantaan and related viruses in the Eurasian continent have long been known by different synonyms: epidemic haemorrhagic fever, Korean haemorrhagic fever, or nephropathia epidemica, but haemorrhagic fever with renal syndrome (HFRS) is preferred. Four distinct viruses are responsible for most recognized cases of HFRS: Hantaan virus, found primarily in Asia; Dobrava virus in an enclave of disease in the Balkan region and sparsely elsewhere in Europe; Puumala virus in Scandinavia, western Russia, and much of Europe; and Seoul virus is probably global wherever uncontrolled populations of Rattus norvegicus exist. Hantaan and Dobrava viruses cause severe life-threatening disease with mortality of about 5%, reaching up to 30% in select populations. Puumala virus infections are less severe, although patients still require admission to hospital, but fewer than 1% of admitted patients die. Seoul virus is thought to be the least severe of the pathogenic strains of Old World hantaviruses, although it has been associated with human deaths.

Table 2 Bunyaviridae causing only mild or trivial infections in humans, arranged on a geographical basis
Africa North America Central America South America Europe Asia
Bangui (M) Avalon (T) Fort Sherman Alenquer (P) Bhanja (T) Batai (M)
Bhanja (T) Keystone (M) Madrid (M) Apeu (M) Calovo (M) Bhanja (T)
Dugbe (T) Prospect Hill Nepuyo Candiru (P) Corfou (P) Issyk-Kul (T)
Germiston (M) Tensaw (M) Ossa (M) Caraparu (M) Tamdy (T) Ganjam (T)
Ilesha (M) Trivittatus (M) Restan (M) Catu (M) Uukuniemi (T) Hazara (T)
Kasokero (M)   Soldado Guama (M, P)   Keterah (T)
Nairobi sheep disease   Trivittatus (M) Guaroa (M)   Wanowrie (T)
Nyando (M)     Itaqui   Zaliv-Terpeniya (M, T)
Pongola (M)     Maguari (M)    
Shokwe (M)     Marituba (M)    
Shuni (M)     Murutucu (M)    
Tataguine (M)     Oriboca    
Thiafora     Restan (M)    
Wanowrie (T)     Tacaiuma (M)    
      Wyeomyia (M)    

M, virus transmitted by mosquitoes; P, virus transmitted by phlebotomine flies; T, virus transmitted by ticks.

Each hantavirus is associated with a particular rodent host: Hantaan virus with the striped field mouse Apodemus agrarius; Dobrava virus with the yellow-necked mouse Apodemus flavicollis; Puumala virus with the bank vole Myodes; and Seoul virus with the Norway rat Rattus norvegicus. Humans are infected by aerosols of rodent excreta, or rarely by rodent bites. It is seen among adult men in rural environments and may be an occupational disease. Those at greatest risk include farmers, woodcutters, shepherds, and, especially, soldiers in the field. Most hantavirus disease is seasonal, with a peak incidence in late autumn and early winter, although the Balkan form is found most often during summer months in Greece and adjacent countries.

Symptoms The incubation period for hantaviruses is variable; it is usually 12 to 16 days but it can be up to 2 months. Severe disease, typically associated with Hantaan or Dobrava virus infections in Asia or the Balkans, is characterized by five phases:

  1. Febrile: 3- to 7-day duration
  2. Hypotensive: lasting from a few hours to 3 days
  3. Oliguric: from 3 to 7 days
  4. Diuretic: from a few days to weeks
  5. Convalescent: prolonged

Signs and symptoms of the febrile phase include fever, malaise, headache, myalgia, back pain, abdominal pain, nausea and vomiting, facial flushing, petechiae, and conjunctival haemorrhage. In the hypotensive phase, patients have nausea, vomiting, tachycardia, hypotension, blurred vision, haemorrhagic signs, and shock. About one-third of fatalities occur during this phase. In the oliguric phase, nausea and vomiting may persist and blood pressure may rise. Renal failure develops with anuria, and about one-third of cases have severe haemorrhage (epistaxis, gastrointestinal, cutaneous, or bleeding at other sites). Nearly one-half of the deaths occur during the oliguric phase. In the diuretic phase, urine output increases to several litres per day. Convalescence is protracted and it maybe months before full strength and function are regained.

Not all the phases are seen in the less severe forms of the disease. The milder forms of HFRS, such as nephropathia epidemica due to Puumala virus, follow a similar but less severe course, with abrupt onset of fever of 38 to 40°C, headache, malaise, backache, and generalized abdominal pain. Back or loin pain is especially common. Signs of renal failure are usually not as pronounced, and the need for renal dialysis varies. Transient blurred vision occurs in about 10% of cases. Infection due to Seoul virus follows a similar course, but may present with more evidence of liver involvement. There is no evidence of person-to-person transmission.

Treatment and prognosis

Admission to hospital, avoidance of trauma and unnecessary movement, close observation, and careful supportive care are essential for patient survival. Treatment is phase specific, with special attention to fluid balance and volume, and control of hypotension and shock. Renal dialysis may be required. Antiviral therapy using ribavirin has been shown to be effective if started early in disease. Recovery is protracted but complete, with the exception of Seoul virus infection which carries the risk of chronic renal disease, hypertension, or stroke.

Hantavirus pulmonary syndrome

Hantavirus pulmonary syndrome, first reported from the United States of America in 1993, also occurs in Canada, Central and South America. The initial cases had a mortality of more than 50%, but rates have declined to 20 to 40% as clinical experience has increased. Most disease was reported from the western United States of America and Canada, and more recently from Argentina, Chile, Brazil, and other Central and South American countries. Sin Nombre virus was first associated with HPS, but many additional hantaviruses have now been recognized as likely causes of this syndrome (Table 1). As Old World hantaviruses are generally associated with specific microtine rodents (Microtinae: voles, lemmings, muskrats, and their allies, distributed worldwide), so each American hantavirus appears to be associated with a specific sigmodontine host (Sigmodontinae: cotton rats and their allies found in the western hemisphere). Apparent human-to-human transmission of Andes virus occurred during an outbreak in southern Argentina, including transmission to medical staff. Protective precautions are recommended when treating suspected cases of HPS.

Symptoms

Symptoms are primarily those of acute unexplained adult respiratory distress syndrome, rather than the expected renal disease. Nonspecific prodromal features of fever, myalgia, and malaise may last 4 to 6 days, with nausea, vomiting, and abdominal pain, often accompanied by dizziness. On admission, physical examination of patients with confirmed infection reveals fever (more than 38°C), tachycardia (more than 100 beats/min), tachypnoea (more than 20 breaths/min), and often hypotension (systolic pressure less than 100 mmHg), with audible rales in the chest. Laboratory findings include hypoxia, leukocytosis, haemoconcentration, thrombocytopenia, atypical lymphocytosis, elevated transaminases, and prolonged prothrombin time. Chest radiography shows progression from subtle interstitial findings to bilateral frank pulmonary oedema; pleural effusions are usually present. Thrombocytopenia and haemoconcentration are independent statistical predictors of HPS, although not infallible. In a patient with rapidly progressive pulmonary oedema, a blood smear showing four of the following five characteristics is a highly sensitive and specific means of establishing the diagnosis of HPS:

  1. thrombocytopenia,
  2. haemoconcentration,
  3. lack of toxic granulation in neutrophils,
  4. more than 10% immunoblasts, and
  5. myelocytosis.

Disease progresses rapidly once the lungs begin to fill, and death is commonly seen 24 to 48 h after admission, or sooner if there is hypoxia or circulatory failure. The severity of disease correlates with the degree of pulmonary oedema on chest radiography. Hypotension and shock may occur independently in patients whose hypoxaemia is medically controlled.

Treatment and prognosis

Treatment is supportive, ideally in a modern intensive care unit, with careful management of hypoxia, fluid balance, and shock. About two-thirds of patients require intubation and mechanical ventilation. Fluid loss into the lungs leads to haemoconcentration, but infusion of fluids exacerbates pulmonary oedema; therefore fluids should be administered cautiously with careful monitoring. Limited experience suggests that intravenous ribavirin has little effect on the course of HPS, perhaps because of the speed with which the disease progresses.

Control

Prevention involves avoidance of infected rodents either through efficient rodent control programmes in cities, for Seoul virus, or maintenance of clean campsites so that waste food is not allowed to accumulate and attract rodents. Nationally approved inactivated vaccines, reported to be safe and effective against hantaviruses, are available for use in Asia.

Genus Nairovirus 

The genus Nairovirus, named after Nairobi sheep disease, is an acute haemorrhagic gastroenteritis affecting sheep and goats in East Africa, with transmission by the sheep tick Rhipicephalus appendiculatus. It has caused laboratory infections, but the genus includes Crimean–Congo haemorrhagic fever virus and several other viruses known to infect humans, e.g. Ganjam virus, almost indistinguishable from Nairobi sheep disease virus but first isolated in India from Haemaphysalis intermedia ticks collected from healthy goats; Hazara virus, recovered from Ixodes redkorzevi ticks collected from the vole Alticola roylei in a subarctic habitat at an altitude of 3660 m in the Kaghan valley of Hazara district, Pakistan; Dugbe virus, isolated in Nigeria from Amblyomma variegatum ticks collected from healthy cattle; and Soldado virus, repeatedly isolated from a variety of bird ticks but recently linked to a mild illness in humans.

Crimean–Congo haemorrhagic fever virus

This was first recognized as a cause of an acute febrile haemorrhagic disease affecting humans in the Crimean region of the former Union of Soviet Socialist Republics, transmitted by ticks and carrying a mortality of 5 to 30%. In Africa, Congo virus was first isolated in the then Belgian Congo (now Democratic Republic of the Congo) from the blood of a local 13-year-old boy, and it caused a moderately severe laboratory infection. Related viruses were isolated in Uganda where more laboratory infections occurred, one of which ended fatally after a severe haematemesis. In Asia, a virus indistinguishable from Congo virus was isolated from pools of ticks collected from a variety of wild and domestic animals in western Pakistan. Crimean haemorrhagic fever virus was later proved to be serologically indistinguishable from Congo virus, hence the use of the term Crimean–Congo haemorrhagic fever virus. Different strains of this virus have been associated with outbreaks of severe and sometimes fatal disease in the Crimea, Rostov, and Astrakhan regions of Russia, in Albania, Bulgaria, and the Balkans, in East, West, and South Africa, in Iran, Iraq, and western Pakistan, and in China. From 2002 to 2008, ~2500 cases were reported in Turkey, although it was virtually unknown there previously. Most infections are seen among farmers or abattoir workers and acquired by tick bites or exposure to viraemic animal blood, but infections have occurred in both hospitals and laboratories.

Symptoms

The incubation period is 3 to 7 days. Fever usually starts suddenly and is normally continuous, although occasionally it is remittent or biphasic. Other clinical features are headache, nausea, vomiting, joint pains, backache, photophobia, circulatory disorders, thrombocytopenia, and leukopenia. Haemorrhagic manifestations are common. Patients show cutaneous petechiae and extensive ecchymoses, and bleed from nasal, gastric, intestinal, uterine, and urinary tract mucosae. Patients may present with acute abdominal pain, mimicking an acute surgical emergency, and operating-theatre staff have become infected and died through exposure to infected blood or secretions at operation. The mortality is about 5 to 30%, but may be up to 40% or higher in hospital or nosocomial outbreaks. Transient hair loss has been reported.

Control, treatment, and prognosis

No vaccine is available. Avoidance of tick bites may reduce the risk of infection. In hospital outbreaks, meticulous attention to the containment of infected secretions is essential and barrier nursing should be used. Overt disseminated intravascular coagulation usually indicates a poor prognosis, and haematemesis, melaena, and somnolence are significantly more common in fatal cases. Supportive therapy is essential, with monitoring of fluid and electrolyte balance. The antiviral ribavirin is recommended for severe cases based on observational studies. Limiting injections and avoidance of aspirin or other drugs affecting coagulation may reduce bleeding. Patients who recover may have residual polyneuritis persisting for months, but eventual recovery is to be expected. Laboratory investigations with live virus require biological safety level 4 containment.

Genus Phlebovirus 

At least nine different phleboviruses are known to infect humans (see Table 1). Pappataci fever, sandfly fever, or phlebotomus fever was recognized as a clinical entity in the Mediterranean area during the 19th century, and the association with Phlebotomus papatasi sandflies was demonstrated by showing that filtrates of human blood reproduced the disease in human volunteers. It was thought that humans were the only vertebrate host, but antibody studies indicate that gerbils, cattle, and sheep may also be infected. Naples virus was isolated from human serum collected during an outbreak of sandfly fever in Naples, and the Sicilian virus was isolated from American troops with a similar disease in Palermo, Sicily. The two viruses have many common properties, but are serologically quite distinct. Sandfly fever is widespread throughout the Mediterranean area, and also occurs in Egypt, Greece, Iran, Turkey, the former Yugoslavia, Bangladesh, India, Pakistan, and the southern states of Russia. Toscana virus, serologically related to the Naples virus, is found in countries bordering the Mediterranean; it is notable for its ability to infect the central nervous system, especially in central Italy where it is thought to be responsible for at least 80% of acute summertime infections of the central nervous system in children. The viruses that cause sandfly fever do not occur in the New World, but in South and Central America a similar clinical condition follows infection with Alenquer, Candiru, Chagres, and Punta Toro viruses.

Rift Valley fever has long been known as a disease of domestic animals, mainly sheep, in East Africa, which occasionally spreads to farm workers and others handling infected animals. The infection is endemic, but seldom recognized, in many wild game animals in Africa. Rift Valley fever virus differs from the sandfly fever viruses, Punta Toro virus, and most other members of the genus in being normally transmitted by mosquitoes rather than sandflies. Uukuniemi and Zaliv-Terpeniya viruses are tick-transmitted; the only evidence that Uukuniemi virus can infect humans is the finding of specific antibodies in some human sera collected in Estonia and in former Czechoslovakia. Zaliv-Terpeniya virus was isolated from bird ticks collected on an island in the Sea of Okhotsk, Sakhalin region, and there is some evidence that it may be pathogenic to humans.

Sandfly fever, Naples, and Sicilian viruses

Symptoms

After an incubation period of 2 to 6 days, fever starts abruptly with chills, nausea and vomiting, epigastric pain, and often severe generalized headache leading to incapacitating prostration. Fever of 38 to 40°C usually resolves after 2 to 3 days, but may be biphasic and persist for a week. There is no rash, but small haemorrhages into the skin and mucous membranes may be seen. Photophobia and eye pain occur, lymphadenopathy is often seen, and the liver may be tender although jaundice is rare. The disease is self-limiting, with complete recovery. No deaths have been attributed to either sandfly fever, Naples, or Sicilian viruses.

Rift Valley fever virus

Following its initial isolation in 1930 as the agent of enzootic hepatitis of domestic animals in Kenya, Rift Valley fever virus was recognized as the cause of sporadic human infections in East, Central, and West Africa, with a particular tendency to infect laboratory workers handling the virus. In East and Central Africa the virus has been isolated from a variety of mosquito species and it is capable of persisting in mosquito eggs during the dry season, emerging when larvae hatch in the rainy season. From 1951 to 1956 there were severe epizootics in lambs in southern Africa, and many human cases occurred. Further human cases with several deaths were seen in South Africa in 1975, and a major outbreak occurred in East Africa following El Niño flooding in 1997 to 1998, apparently seeding a ‘virgin soil’ outbreak in Saudi Arabia and Yemen in 2000. In 1997–8 and 2006–7 there were epizootics in Kenya, Tanzania, Burundi, and Somalia. In the recent epidemic, 684 cases with 155 deaths were reported in Kenya (case fatality 23%), 264 cases with 109 deaths in Tanzania (case fatality 41%), and 114 cases with 51 deaths in Somalia (case fatality 45%). Heavy rains in East Africa during 2006–7 triggered another outbreak with many human and animal cases.

In the Central African Republic in 1969, a virus isolated from Mansonia africana mosquitoes and named Zinga virus was associated with several cases of haemorrhagic fever; Zinga virus was later shown to be a strain of Rift Valley fever virus. In West Africa, Rift Valley fever virus was isolated from mosquitoes in Nigeria and from bats in Guinea, but despite the presence of antibodies in human sera collected in Nigeria and Senegal, human disease was unrecognized until 1987 when a substantial epidemic occurred in Mauritania, with further epidemics in following years. In 1977 the virus spread, apparently for the first time, into Egypt, producing a major epizootic in domestic animals, principally sheep and goats but also cattle, and causing about 600 human deaths within 3 months. The virus has been detected intermittently since then in Egypt. The principal known vector is the mosquito Culex pipiens. Both the Egyptian and the Mauritanian epidemics appeared to be linked to major ecological changes following the construction of the Aswan Dam on the Nile and dams on the Senegal River.

Symptoms

After an incubation period of 3 to 6 days, fever starts abruptly with shivering, nausea and vomiting, epigastric pain, arthralgia, and often severe generalized headache. The fever may be biphasic, with temperatures between 38 and 40°C, and may remain elevated for at least a week. There is no rash, but small haemorrhages appear on mucous membranes. Photophobia and eye pains occur. There may be conjunctival inflammation, and a central serous retinitis leading to central scotoma and sometimes to retinal detachment can occur late in disease. The fundus may show macular exudates that are slow to disappear. There is often a lymphadenopathy and although the liver is frequently involved and may be tender, jaundice is rare. Convalescence may be protracted but is usually uncomplicated.

A few patients develop severe disease with haemorrhage, encephalitis, or eye lesions. Haemorrhagic disease presents as above but progresses with cutaneous and mucous membrane petechiae, ecchymoses, gastrointestinal haemorrhage, and jaundice with severe liver and renal dysfunction often progressing to disseminated intravascular coagulation, hepatorenal syndrome, and death. Patients with encephalitis usually recover from acute febrile disease only to present within a few days to 2 weeks later with headache, meningism, confusion, and fever, often leading to residual defects or ending in death. Ocular complications are characterized by rapid onset of decreased visual acuity with scotomas due to retinal haemorrhage, exudates, and macular oedema. These are also seen after apparent recovery from the initial disease. About one-half of these patients have some degree of permanent visual loss. Death from Rift Valley fever was rarely recognized before the 1977 outbreak in Egypt, but the Mauritanian epidemics with mortality due to jaundice and haemorrhagic manifestations, and the recent East African and Arabian Peninsula outbreaks with several hundred suspect fatalities establish it as a life-threatening infection.

Control, treatment, and prognosis

Veterinary vaccines have been used for some years, and formalin-inactivated vaccines have also had limited use for the prevention of disease in laboratory workers and others exposed to high risk of infection. Improved vaccines based on molecular techniques are under development. Treatment is supportive. Although there are no reports of nosocomial transmission, barrier nursing would be a sensible precaution.

Unassigned viruses and viruses causing only minor disease in humans

The great majority of the viruses listed in Table 2 cause only a mild febrile illness, but the following show certain additional features.

Bhanja virus (unassigned)

This virus was first isolated from Haemaphysalis intermedia ticks collected from healthy goats in India, but has since been isolated in Sri Lanka, Africa, and Europe. Infection of goats is widespread in Italy and the Balkans where there have been several reported human cases, including some with severe neurological disease and at least two deaths. Laboratory infections have also occurred.

Bwamba virus (Orthobunyavirus)

This was first isolated in Uganda in 1941 and is very widespread throughout sub-Saharan Africa. More than 75% of adult human sera collected in Nigeria and over 95% of human sera collected in Uganda and Tanzania have antibodies against Bwamba virus. The original cases showed fever, headache, generalized pain, and conjunctivitis but no rash, although a rash has been described in the Central African Republic. No fatalities have been reported.

Nyando virus (Orthobunyavirus)

This virus was first isolated from mosquitoes in Kenya. It has since been isolated from humans in the Central African Republic where it caused fever, myalgia, and encephalitis.

Tataguine virus (unassigned)

This causes fever, rash, and joint pains in at least five African countries (Cameroon, Central African Republic, Ethiopia, Nigeria, and Senegal).

Wanowrie virus (unassigned)

This virus was first isolated in India from Hyalomma marginatum ticks collected from sheep. It has also been isolated in Egypt and Iran, and in Sri Lanka where it was recovered from the brain of a 17-year-old girl who died following a 2-day fever with abdominal pain and vomiting.

Further reading

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Bartelloni PJ, Tesh RB (1976). Clinical and serologic responses of volunteers infected with phlebotomus fever virus (Sicilian type). Am J Trop Med Hyg, 25, 456–62.

Calisher CH, Thompson WH (eds) (1983). California serogroup viruses. Progress in clinical and biological research, vol. 123. Liss, New York.

Ergonul O (2006). Crimean-Congo haemorrhagic fever. Lancet Infect Dis, 6, 203–14.[CrossRef] [Web of Science] [Medline]

Koster F, et al. (2001). Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review. Am J Clin Pathol, 116, 665–72.

LeDuc JW (1995). Hantavirus infections. In: Porterfield JS (ed)Exotic viral infections, pp. 261–84. Chapman & Hall, London.

LeDuc JW, Pinheiro FP (1989). Oropouche fever. In: Monath TP (ed) The arboviruses: epidemiology and ecology, vol. 4, pp. 1–14. CRC Press, Boca Raton.

Lee HW, Calisher C, Schmaljohn CS (1999). Manual of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. WHO Collaborating Center for Virus Reference and Research (Hantaviruses), Seoul.

Madani TA, et al. (2003). Rift Valley fever epidemic in Saudi Arabia: epidemiology, clinical and laboratory characteristics. Clin Infect Dis, 37, 1084–92.

Monath TP (ed) (1989). The arboviruses: epidemiology and ecology. CRC Press, Boca Raton.

Peters CJ (1997). Emergence of Rift Valley fever. In: Saluzzo JF, Dodet B (eds) Factors in the emergence of arbovirus diseases, pp. 253–64. Elsevier, Paris.

Peters CJ (1998). Hantavirus pulmonary syndrome in the Americas. Emerg Infections, 2, 17–64.

Peters CJ, LeDuc JW (1991). Bunyaviridae: bunyaviruses, phleboviruses, and related viruses. In: Belshe RB (ed) Textbook of human virology, 2nd edition, pp. 571–614. Mosby Year Book, St. Louis.

Peters CJ, Simpson GL, Levy H (1999). Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med, 50, 531–45.

Saluzzo JF, Dodet B (eds) (1999). Factors in the emergence and control of rodent-borne viral disease (hantaviral and arenal diseases). Elsevier, Paris.

Swanepoel R (1995). Nairovirus infections. In: Porterfield JS (ed) Exotic viral infections, pp. 285–93. Chapman & Hall, London.