Alphaviruses

Article about alphaviruses.

Topics covered:

  • Essentials
  • Introduction
  • Laboratory diagnosis
  • Alphaviruses associated with arthritis and rash
  • Alphaviruses associated with neuroinvasive disease
  • Further reading

Essentials

There are 29 registered alphaviruses belonging to the family Togaviridae, 16 of which are known to cause human infection. They are RNA viruses with global geographical distribution and complex transmission cycles between wild or domestic animals or birds and one or more mosquito species; humans are infected by mosquito bites. They cause a spectrum of clinical manifestations ranging from nonspecific febrile illness to acute encephalitis and death. Diagnosis of infection is made serologically by detection of IgM and IgG antibody responses, virus isolation, or by polymerase chain reaction and immunohistochemistry on tissue samples.

Old World alphaviruses, including Chikungunya, Ross River, Sindbis, Barmah Forest, Mayaro and O’nyong-nyong, generally have mammals as their natural vertebrate host and, cause acute febrile illness characterized by rash and arthritis. Management is symptomatic; prevention and control is by reducing vector mosquito populations and by avoiding mosquito bites.

New World alphaviruses, including Eastern, Western and Venezuelan Equine Encephalitides, generally have birds as their natural vertebrate hosts; about 2% of adults infected with Eastern Equine Encephalitis virus (less for other types) develop encephalitis, which can be fatal, with permanent neurological sequelae in many survivors; management is symptomatic; prevention and control is by reducing vector mosquito populations and by avoiding mosquito bites. Various vaccines have been used in laboratory workers and others at high risk of exposure. New generation vaccines are in clinical trials.

Introduction

The genus Alphavirus of the family Togaviridae comprises 29 registered viruses, 16 of which are known to cause human infection (Table 1 below). Alphaviruses are lipid-enveloped virions with a diameter of 60 to 70 nm whose genome is a molecule of single-stranded, positive-sense RNA approximately 12 000 nucleotides in length.

Most alphaviruses are maintained in nature in complex transmission cycles between wild or domestic animals and one or more mosquito species. Humans are infected when the infective mosquito takes a blood meal. Patients develop high viraemias with some alphaviruses and this may contribute to the transmission cycle by infecting mosquitoes. The epidemiology and geographical distribution of the alphaviruses depend on several factors including the presence of suitable amplifying hosts, the presence and feeding behaviour of a suitable arthropod vector, and the frequency of exposure of nonimmune reservoir hosts and humans to infected vectors. Alphavirus infections are not directly communicable between humans.

Most infections in humans are asymptomatic, but alphaviruses can cause a spectrum of clinical illness ranging from nonspecific febrile illness, often with rash, myalgia, or arthralgia, to frank encephalitis and death. They cause two main clinical syndromes: Old World alphaviruses generally cause illness characterized by rash and arthritis while New World alphaviruses are generally associated with neuroinvasive disease. No specific therapy is available. Vaccines for some alphaviruses are used in animals, although none have been licensed for humans.

Laboratory diagnosis

Alphavirus infections are diagnosed serologically by detection of IgM and IgG responses. All alphaviruses have common antigenic determinants that result in cross-reactions in immunodiagnostic tests. Neutralization tests may be necessary for serological confirmation in areas where multiple alphaviruses are endemic/enzootic. Isolation of virus from acute-phase serum is possible with some alphaviruses, but they are seldom recovered from the central nervous system, including cerebrospinal fluid, except from fatal cases. Virological diagnosis may also be made using polymerase chain reaction and immunohistochemistry on tissue samples.

Alphaviruses associated with arthritis and rash 

Chikungunya

Aetiology and epidemiology

Chikungunya virus is found in Africa and Asia and is transmitted primarily by day-biting aedes mosquitoes. Nonhuman primates such as monkeys and baboons may be the primary maintenance hosts in sylvatic environments in Africa. In urban surroundings in Africa and Asia, the virus is transmitted between humans by Aedes aegypti mosquitoes, although Ae albopictus mosquitoes have been implicated in some outbreaks. Explosive urban epidemics occur during the rainy season. Since 2004, a major epidemic has occurred in India (more than 1.3 million cases), adjacent Asian countries, Kenya, and Indian Ocean islands (Comoros, Mauritius, Seychelles, Madagascar, Mayotte, and Réunion where 34% of the population was infected), and in 2007 it reached Gabon in Central Africa and Italy. This epidemic was exacerbated by a new variant virus. A single mutation in the envelope protein increased infectivity to Ae albopictus, a mosquito that has spread throughout the tropics and subtropics and has a wider distribution in urban, semiurban, and rural habitats than Ae aegypti, which favours urban environments.

Serosurveys following outbreaks have shown antibody prevalences generally ranging from 30 to 70%. Infections in travellers returning to Europe and the United States of America from areas experiencing outbreaks have been frequently reported. More than 800 cases were imported into France and 100 into the United Kingdom from Réunion and the other islands popular with tourists. In August 2007, local transmission of chikungunya by Ae albopictus mosquitoes was confirmed around Ravenna in Italy, resulting in 205 cases and one death. Neonatal infection has occurred from mothers ill shortly before or at the time of delivery.

Clinical characteristics

‘Chikungunya’ means ‘that which bends up’ in Makonde, an East African language, and refers to the crippling arthralgia that characterizes the disease. After an incubation period of 2 to 3 days (range 1–12 days), there is sudden fever and severe arthralgia. In some patients, the fever may remit for 1 to 2 days and then recur (‘saddleback’ fever). Arthralgias are polyarticular, with the knees, ankles, elbows, and small joints of the hands and feet most commonly affected. They are often associated with low back pain.

A useful sign is pain on squeezing the wrists (tenosynovitis). Headache, injected pharynx, gastrointestinal symptoms, and myalgias are frequent during the acute illness. Rashes, typically on the trunk and limbs, occur in about one-half of the patients usually during the second to fifth day of illness. They are very variable in appearance: papular or maculopapular erythemas (blanching as in dengue), vesicular, bullous, dyshidrotic, keratolytic, purpuric and hyperpigmented associated with facial oedema, erythema nodosum, and aphthous ulcers. Arthralgia may last several months and is associated with effusions and bursitis; a few patients may have symptoms 5 years after infection.

Haemorrhage, meningoencephalitis, Guillain–Barré polyradiculopathy, myocarditis, and hepatic and renal complications are uncommon but may be fatal. Rheumatological manifestations are less frequent in children. Conjunctival suffusion and cervical or generalized lymphadenopathy are common. Serological surveys suggest that asymptomatic infections may occur.

Table 1 Known disease associations of alphaviruses a
Virus Geographical distribution Disease in humans Outbreaks Other features
Aura South America   No  
Barmah Forest Australia SFI, arthropathy Yes Clinically similar to Ross River virus infection
Bebaru Malaysia   No Laboratory infection only
Cabassou French Guiana   No  
Chikungunya Tropical Africa, India, Southeast Asia, Philippines SFI, arthropathy Yes Large outbreaks in urban settings
Eastern equine encephalitis North and South America on Atlantic and Gulf Coasts, Caribbean SFI, encephalitis Yes Isolated cases or small outbreaks occur mainly in North America
Everglades Florida SFI, encephalitis No Variant of Venezuelan equine encephalitis
Fort Morgan Colorado   No  
Getah Asia SFI No  
Highlands J North America   No  
Mayaro Trinidad, Brazil, Bolivia, Surinam, French Guiana, Peru, Venezuela SFI, arthropathy Yes  
Middleburg South, West, and Central Africa Not described No  
Mosso das Pedras Brazil   No Venezuelan equine encephalitis complex
Mucambo Trinidad, Brazil, Surinam, French Guiana, Colombia, Venezuela SFI No Proposed species in the Venezuelan equine encephalitis antigenic complex
Ndumu Africa   No  
O’nyong-nyong East and West Africa, Zimbabwe SFI, arthropathy Yes Igbo-ora virus is a subtype of o’nyong-nyong
Pixuna Brazil SFI No Laboratory infection only
Rio Negro Argentina   No  
Ross River Australia, South Pacific SFI, arthropathy Yes Periodic epidemics in South Pacific
Salmon Pancreas disease North Atlantic   No  
Semliki Forest Sub-Saharan Africa SFI, encephalitis No  
 Sindbis Africa, East Mediterranean, South and Southeast Asia, Borneo, Philippines, Australia, Sicily, Scandinavia SFI, arthropathy Yes  
 Babanki West and Central Africa SFI, arthropathy Yes Subtype of Sindbis
 Kyzylagach Azerbaijan SFI, arthropathy Yes Subtype of Sindbis
Southern elephant seal Antarctica   No  
Tonate French Guiana SFI, encephalitis No Venezuelan equine encephalitis complex
Trocara South America   No Proposed species in the Venezuelan equine encephalitis antigenic complex; fatal encephalitis in one infant
Una South America, Trinidad   No  
Venezuelan equine encephalitis Northern South America, Central America, Mexico SFI, encephalitis Yes  
Western equine encephalitis North and South America SFI, encephalitis Yes Human disease rare outside of North America and Brazil
Whataroa New Zealand, Australia   No  

SFI, systemic febrile illness.

Adapted from Griffin D (2007). Alphaviruses. In: Knipe DM, Howley PM (eds) Fields virology, 5th edition, vol. 1, pp. 1023–67. Lippincott Williams & Wilkins, Philadelphia.

Diagnosis

Leukopenia and elevation of liver and muscle enzymes are common early in infection. Detection of viral RNA by reverse transcription–polymerase chain reaction (RT-PCR) is useful for diagnosis during the first week of illness. Haemagglutinin inhibition and IgM antibodies will be present in nearly all patients by the seventh day of illness. IgM antibodies detectable in serum by IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) may persist for 6 months after infection. Virus isolation is confirmatory.

Prevention, control, and treatment

Prevention and control can only be achieved by reducing vector mosquito populations in the large urban centres of the tropics and by avoiding mosquito bites. The American military has an effective vaccine, but it is not licensed for general use. Several new vaccines are all in late stage development. There is no specific treatment. Anti-inflammatory drugs may relieve arthralgia. An uncontrolled study suggested that chloroquine phosphate may be helpful for refractory arthralgias.

Ross River virus

Aetiology and epidemiology

This virus causes ‘epidemic polyarthritis’ in Australia, south-western Pacific islands, and Fiji. Aedes vigilax is an important vector in Australia and Ae scutellaris complex mosquitoes in some south Pacific islands, although the virus has been isolated from more than 30 mosquito species. An epidemic in various Pacific islands in 1979 to 1980 affected more than 50 000 people. An average of 4800 cases is reported annually from Australia. Explosive outbreaks and viraemias in humans implicate virus transmission from human to human by certain mosquitoes. Outbreaks tend to be associated with periods of increased rainfall. Camping is a significant risk factor in tropical Australia.

Clinical characteristics

The incubation period ranges from 2 to 21 days (7–9 days on average). The illness begins suddenly with fever and arthralgias predominantly in the ankles, wrists, knees, fingers, and feet. A maculopapular rash occurs in about one-half of patients within 2 days of onset and is most prominent on the trunk and limbs, but can cover the entire body; the rash may progress to small vesicles. Myalgias, headache, anorexia, nausea, and tenosynovitis are common, but the temperature is only slightly elevated. Arthralgia generally resolves within 3 to 6 months. Symptomatic infection is rare in children.

Diagnosis

Isolation of virus from serum is possible for the first few days of illness. IgM antibodies will be detected by MAC-ELISA within 5 to 10 days of onset. Complement fixation, haemagglutinin inhibition, and neutralization tests may be useful, particularly when paired serum samples are available. Virus isolation and PCR are confirmatory.

Prevention, control, and treatment

Avoidance of mosquito bites and peridomestic mosquito control can effectively reduce the risk of infection. No specific treatment is available. Nonsteroidal anti-inflammatory drugs may relieve symptoms. One study suggested that corticosteroids might hasten recovery.

Sindbis

Aetiology and epidemiology

Sindbis virus is widely distributed in Africa, India, tropical Asia, Australia, and Europe. However, clinical disease is common only in geographically restricted areas. In Europe, the main vectors to humans are late summer, ornithophilic mosquitoes of the genera Culex and Culiseta. High antibody prevalences in Africa suggest that human exposure is common. Several outbreaks have been noted.

Clinical characteristics

In northern Europe, symptomatic disease is recognized from Sweden (Ockelbo disease), through Finland (Pogosta disease), to the former Karelian Soviet Socialist Republic (Karelian fever). The clinical features include mild fever, rash, arthralgia, myalgia, malaise, headache, and pruritus. The maculopapular rash progresses from trunk to extremities and vesicles can occur on the palms and soles. Ankle, finger, wrist, and knee joints are most commonly affected. Prominent rheumatic symptoms, sometimes persisting for several years, have been noted in Europe and South Africa.

Diagnosis

Haemagglutinin inhibition and IgM antibodies will be present in nearly all patients by the eighth day of illness. IgM antibodies detectable in serum by MAC-ELISA may persist for 6 months after infection. Virus can be infrequently detected by culture or RT-PCR from blood or skin lesions.

Prevention, control, and treatment

Avoidance of mosquito bites can reduce the risk of infection. No specific treatment is available.

Barmah Forest virus

Since its first recognition as a cause of human disease in 1988, the geographical distribution of Barmah Forest virus has expanded recently in Australia. It causes sporadic disease and epidemics, with up to 300 serologically confirmed cases. The disease resembles that of Ross River virus infection, although the rash tends to be more florid and true arthritis is less common. The illness is prolonged in some patients. Little is known about the ecology of Barmah Forest virus, although outbreaks have coincided with Ross River virus outbreaks and the virus has been identified in the same mosquito species.

Mayaro virus

Mayaro virus has been isolated from humans and various mosquito species (mostly Haemagogus ssp.) in Trinidad, Brazil, Bolivia, French Guiana, Surinam, Peru, and Venezuela. Serosurveys suggest the virus is widespread in South America. Several outbreaks have been identified, most recently in Venezuela in 2000. Following an incubation period of approximately 1 week, illness onset is abrupt with fever, chills, headache, retro-orbital pain, myalgia, gastrointestinal symptoms, and arthralgia mostly in the small joints of the extremities. A maculopapular rash may occur 2 to 5 days after defervescence. Arthralgia may persist for several months.

O’nyong-nyong virus

From 1959 to 1962, this virus caused epidemics in Uganda, Kenya, Tanzania, and Malawi involving approximately 2 million people. The virus was isolated in 1978 from Anopheles funestus mosquitoes in Kenya after a long period of no apparent o’nyong-nyong virus activity. In 1996 to 1997, an outbreak occurred in Uganda. In 2003, an outbreak occurred among refugees in the Côte d’Ivoire and a human infection was confirmed in Chad in 2004. O’nyong-nyong is closely related to chikungunya and produces a similar illness, although fever is less pronounced and lymphadenopathy is more common. An funestus and An gambiae transmit the virus.

Alphaviruses associated with neuroinvasive disease

Eastern equine encephalitis

Aetiology and epidemiology

The virus is widely distributed throughout North, Central, and South America and the Caribbean. However, little is known about the epidemiology of eastern equine encephalitis outside North America, where it is maintained in a bird–mosquito cycle in hardwood swamps in coastal areas from the Great Lakes to the Gulf Coast. In the United States of America human infections are usually sporadic, and small outbreaks occur each summer mostly along the Atlantic and Gulf Coasts. In recent years, 1 to 21 cases have been reported annually. In North America, wild birds and Culiseta melanura mosquitoes maintain the virus.

Clinical characteristics

Most infections are inapparent. The incubation period exceeds 1 week and the onset is abrupt with high fever. About 2% of infected adults and 6% of children develop encephalitis. Eastern equine encephalitis is the most severe of the arboviral encephalitides, with a mortality of 35 to 75%. Symptoms and signs include dizziness, decreasing level of consciousness, tremors, seizures, and focal neurological signs. Death can occur within 3 to 5 days of onset. Sequelae are common in nonfatal encephalitis and include convulsions, paralysis, and mental retardation. Illness due to eastern equine encephalitis in South America appears to be less severe.

Diagnosis

Cerebrospinal fluid pressure may be raised, with slightly increased protein, normal sugar, and up to 2000 cells/mm3. IgM antibodies are readily detected in serum or cerebrospinal fluid by ELISA. Paired serum samples can be tested by haemagglutinin inhibition, ELISA, or neutralization tests. Horse or pheasant deaths and the proximity to swamps provide clues to the diagnosis. Prevention, control, and treatment

Prevention

This depends on the avoidance of mosquito bites and mosquito control in suburban areas. Inactivated vaccines have been used successfully in horses, and an inactivated vaccine has been used experimentally in laboratory workers and others at high risk of exposure. No specific treatment is available.

Venezuelan equine encephalitis complex

Aetiology and epidemiology

Six subtypes (I–VI) within the Venezuelan equine encephalitis virus complex have been identified. Five antigenic variants exist within subtype I (IAB, IC, ID, IE, IF). These subtypes and variants are classified as epizootic or enzootic, based on their apparent virulence and epidemiology. Epizootic variants of subtype I (IAB and IC) cause equine epizootics and are associated with more severe human disease. Enzootic strains (ID–F, II (Everglades), III (Mucambo [A,B,D], Tonate [B]), IV (Pixuna), V (Cabassou), VI (Rio Negro)) do not cause epizootics in horses, but may produce sporadic disease in humans. Large epizootics (IAB and IC) have occurred in equines in northern countries of South America and Central America, sometimes reaching the United States of America. In 1969 to 1972, a massive epizootic extending from Ecuador to Texas killed more than 200 000 horses and caused several thousand human infections. In 1995, a large epizootic, which began in Venezuela and spread to Colombia, affected thousands of horses and caused approximately 90 000 human infections. Epizootic strains are carried by a wide variety of mosquitoes including Aedes, Mansonia, and Psorophora spp. Horses are the principal amplifying hosts during epizootics but are not amplifying hosts for enzootic transmission. Enzootic strains are maintained in a cycle involving Culex (Melanoconion) mosquitoes and rodents.

Clinical characteristics (epizootic virus infections)

After an incubation period of 1 to 6 days, there is a brief febrile illness of sudden onset characterized by malaise, nausea or vomiting, headache, and myalgia. Acute symptoms last 2 to 5 days, and generalized asthenia up to 3 weeks. Among those with clinical illness, less than 0.5% of adults and less than 4% of children develop encephalitis. Nausea and vomiting, nuchal rigidity, ataxia, convulsions, paralysis, and death may occur. Long-term sequelae following encephalitis are uncommon.

Diagnosis (epizootic virus infections)

A marked leukopenia is universal, often accompanied by neutropenia and thrombocytopenia, with moderate lymphocytosis in the cerebrospinal fluid. Virus can be detected by isolation or by PCR from serum or throat swab is possible within the first few days of illness. Paired sera can be tested by haemagglutinin inhibition and neutralizing tests. Specific IgM can be detected by MAC-ELISA in the second week of illness.

Prevention, control, and treatment

Equine immunization is effective in controlling epizootic disease. Venezuelan equine encephalitis is highly infectious by the aerosol route; many laboratory infections have occurred. Live attenuated and inactivated vaccines have been used in laboratory workers. People in affected areas should avoid mosquito bites. No specific treatment is available.

Western equine encephalitis

Aetiology and epidemiology

This is a complex of closely related viruses found in North and South America, but human disease is rare outside North America and Brazil. Summer outbreaks may be precipitated by flooding, which increases breeding of Culex mosquitoes (particularly Culex tarsalis in the western United States of America). Large outbreaks of western equine encephalitis in humans and horses occurred in the western United States of America in the 1950s and 1960s; however, a declining horse population, equine vaccination, and improved vector control have reduced the reported number of human cases to zero in most recent years.

Clinical characteristics

The ratio of apparent to inapparent infection in adults is less than 1 in 1000; however, this ratio increases to 1:1 in infants under 1 year of age. Following an incubation period of about 7 days, headache, vomiting, stiff neck, and backache are typical; restlessness and irritability are seen in children. Weakness and hyporeflexia are common. Convulsions occur in 90% of affected infants and 40% of affected children between 1 and 4 years, but are rare in adults. Recovery in 5 to 10 days is common, but convalescence may be protracted. Although rare in adults and older children, sequelae are common in infants, with one-half of those with encephalitis being left with convulsions and/or severe motor or intellectual deficits. The case fatality rate is 3 to 7%.

Diagnosis

Clinical laboratory findings in western equine encephalitis are often unremarkable. IgM antibodies are readily detected in serum by ELISA. Paired sera can be tested by haemagglutinin inhibition, IgG ELISA, or neutralization tests. Virus can occasionally be isolated from serum or cerebrospinal fluid.

Prevention, control, and treatment

Prevention of western equine encephalitis relies on mosquito control and the avoidance of mosquito bites. Vaccine is available for horses. An inactivated vaccine has been used for laboratory staff and others at high risk of exposure. No specific treatment is available.

Further reading

Top

Centers for Disease Control and Prevention (2006). Eastern equine encephalitis: New Hampshire and Massachusetts, August–September 2005 MMWR Morb Mortal Wkly Rep, 55, 697–700.  

Griffin D (2007). Alphaviruses. In: Knipe DM, Howley PM (eds) Fields virology, 5th edition, vol. 1, pp. 1023–67. Lippincott Williams & Wilkins, Philadelphia.

Harley D, et al. (2001). Ross River virus transmission, infection, and diseases: a cross-disciplinary review. Clin Microbiol Rev, 14, 909–32.

Kiwanuka N, et al. (1999). O’nyong-nyong fever in South-Central Uganda, 1996–1997: clinical features and validation of a clinical case definition for surveillance purposes. Clin Infect Dis, 29, 1243–50.

Laine M, et al. (2004). Sindbis virus and other alphaviruses as cause of human arthritic disease. J Int Med, 256, 457–71.

Pialoux G, et al. (2007). Chikungunya, an epidemic arbovirosis. Lancet Infect Dis, 7, 319–27.

Weaver SC, Frolov IV (2005). Togaviruses. In: Mahy BWJ, ter Meulen V (eds) Topley and Wilson’s microbiology and microbial infections, 10th edition, vol. 2, pp. 1010–24. Hodder Arnold, London.

Weaver SC, et al. (2004). Venezuelan equine encephalitis. Annu Rev Entomol, 49, 141–74.