Facts about Sindbis fever
Sindbis virus (SINV) is an enveloped RNA virus of the genus Alphavirus in the virus family Togaviridae. Sindbis virus is related to Chikungunya alphavirus.
Sindbis virus was first isolated from Culex mosquitoes in 1952 in the Nile river delta in Egypt. The first human cases were described in Uganda in 1961, South Africa in 1963, and Australia in 1967. The virus was subsequently acknowledged as the causative agent of a rash-arthritis syndrome.
The clinical disease caused by SINV infection is known as Pogosta disease (Finland), Ockelbo disease (Sweden), and Karelian fever (Russia).
The incubation period of SINV infection is often less than seven days, but has not been established. Maculopapular and often itchy exanthema over the trunk and limbs, mild fever, and joint symptoms, particularly in wrists, hips, knees, and ankles, are the hallmarks of acute SINV infection, sometimes accompanied by nausea, general malaise, headache, and muscle pain. Infectious and basic blood parameters are typically within normal range. In children, the clinical disease is usually mild, and can present without joint symptoms. Asymptomatic infections are not uncommon. Fatal infections have not been reported.
Extra-articular symptoms usually diminish within 1–2 weeks, but in a considerable proportion of patients SINV infection leads to persistent joint manifestations that can continue for months or years, and in rare cases can even result in chronic arthritis.
Sindbis virus is widely and continuously found in insects (the main vectors are Culex and Culiseta mosquitoes) and vertebrates in Eurasia, Africa, and Oceania. However, clinical SINV infection in humans has almost exclusively been reported in Northern Europe where it is endemic and where large outbreaks occur intermittently. Cases are occasionally reported in Australia, China, and South Africa.
Sindbis virus or antibodies to SINV have been identified in wildlife in the following countries: Austria, Belarus, Bulgaria, Czech Republic, Estonia, Finland, Germany, Hungary, Italy, Moldova, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Spain, Sweden, Ukraine, and also in the UK.
Outbreaks have been reported in Finland and Sweden. In Finland, cases are reported every year, but larger outbreaks have occurred every seven years; during the 2002 outbreak in the highly endemic region of North Karelia, the incidence rate (counting serodiagnosed infections) was 81 cases/100 000 population. The proportion of subclinical and mild cases is probably high, but the available evidence is too limited to be able to quantify it.
The hypothesis is that SINV cycles between ornithophilic mosquito species and birds. Birds might be involved in the natural cycle of SINV as important reservoirs, but spillover to other vertebrates may occur. Grouse and passerines are probable amplifying hosts for SINV. The close relationship of South African and Northern European SINV strains suggests that migratory birds may carry the virus over long distances.
Mosquitoes of genera Culex and Culiseta are considered the primary vectors to transmit SINV to humans, but the virus has been also isolated from Aedes and Anopheles mosquitoes. In Northern Europe, practically all human infections take place in August and September, when the primary vector species are prevalent. The current understanding is that SINV infection provides a lifelong immunity against repeat infections. There is no evidence of human-to-human transmission. No evidence is available regarding risk of blood donation, but it cannot be excluded. Nevertheless, the viraemic window in SINV infection is narrower and with lower titres than in Chikungunya virus infection, suggesting a probably low risk of transmission through blood donation. This is also highlighted by the considerable difficulty in detecting virus or viral nucleic acid from acutely ill patients.
All persons who are not immune to SINV and are exposed to vector mosquitoes may become infected. In endemic areas the incidence rates are highest in those aged 30–69 years. Symptomatic infection occurs equally in males and females.
No vaccine or prophylactic medication is available for SINV infection. Personal protective measures to reduce the risk of mosquito bites include the use of mosquito bed nets (preferably insecticide-treated nets), sleeping or resting in screened or air-conditioned rooms, the wearing of clothes that cover most of the body, and the use of mosquito repellent in accordance with the instructions indicated on the product label.
A clinically suspected SINV infection requires laboratory confirmation. The laboratory diagnosis of acute SINV infection is based on detection of SINV immunoglobulin M (IgM) antibodies or IgG seroconversion between paired samples taken two weeks apart, usually using enzyme-linked immunosorbent assay (ELISA) platform. Antibodies can also be detected with immunofluorescence and hemagglutination inhibition techniques. Diagnostic tests are performed only in specialised laboratories using in-house assays.
Immunoglobulin M antibodies become detectable within eight days, and IgG antibodies within 11 days from onset of symptoms. More than one-third of the patients show IgM antibodies even six months after infection, which may be related to persisting symptoms. Immunoglobulin G antibodies remain detectable for life. A positive IgG with a negative IgM test result is a sign of previous immunity. Molecular diagnostic techniques (e.g., RT-PCR) are not presently applicable for routine laboratory diagnostics of SINV infection. Parvovirus B19, rubellavirus, and measles can be considered in the differential diagnosis.
Management and treatment
No specific antiviral treatment is available for SINV infection. Treatment is symptomatic: antihistamins can be used for itching rash, and non-salicylate analgesics for joint pain. Intra-articular corticosteroids are sometimes used for persisting joint symptoms, but there is little evidence on their effectiveness.
Key areas of uncertainty
- Lack of vaccine or antiviral treatment
- Vastly unknown epidemiology
- Virus circulation in nature
- Range of possible viral hosts
- Range of possible vector mosquitoes
- Host response mechanisms in relation to susceptibility to symptomatic infection
- Brummer-Korvenkontio M, Vapalahti O, Kuusisto P, Saikku P, Manni T, Koskela P, et al. Epidemiology of Sindbis virus infections in Finland 1981-96: possible factors explaining a peculiar disease pattern. Epidemiol Infect 2002;129:335-45.
- Doherty RL, Bodey AS, Carew JS. Sindbis virus infection in Australia. Med J Aust 1969;2:1016–7.
- Espmark A, Niklasson B. Ockelbo disease in Sweden: epidemiological, clinical, and virological data from the 1982 outbreak. Am J Trop Med Hyg 1984;33:1203-11.
- Francy DB, Jaenson TG, Lundström JO, Schildt EB, Espmark A, Henriksson B, Niklasson B. Ecologic studies of mosquitoes and birds as hosts of Ockelbo virus in Sweden and isolation of Inkoo and Batai viruses from mosquitoes. Am J Trop Med Hyg 1989;41:355-63.
- Hubálek Z. Mosquito-borne viruses in Europe. Parasitol Res 2008;103 Suppl 1:S29-43.
- Kurkela S, Helve T, Vaheri A, Vapalahti O. Arthritis and arthralgia three years after Sindbis virus infection: clinical follow-up of a cohort of 49 patients. Scand J Infect Dis 2008;40:167-73.
- Kurkela S, Manni T, Myllynen J, Vaheri A, Vapalahti O. Clinical and laboratory manifestations of Sindbis virus infection: prospective study, Finland, 2002-2003. J Infect Dis 2005;191:1820-9.
- Kurkela S, Manni T, Vaheri A, Vapalahti O. Causative agent of Pogosta disease isolated from blood and skin lesions. Emerg Infect Dis 2004;10:889-94.
- Kurkela S, Rätti O, Huhtamo E, Uzcátegui NY, Nuorti JP, Laakkonen J, Manni T, Helle P, Vaheri A, Vapalahti O. Sindbis virus infection in resident birds, migratory birds, and humans, Finland. Emerg Infect Dis 2008;14:41-7.
- Laine M, Luukkainen R, Jalava J, Ilonen J, Kuusisto P, Toivanen A. Prolonged arthritis associated with Sindbis-related (Pogosta) virus infection. Rheumatology (Oxford) 2000;39:1272-4.
- Lundström JO. Mosquito-borne viruses in western Europe: a review. J Vector Ecol 1999;24:1-39.
- Lundström JO, Lindström KM, Olsen B, Dufva R, Krakower DS. Prevalence of sindbis virus neutralizing antibodies among Swedish passerines indicates that thrushes are the main amplifying hosts. J Med Entomol 2001;38:289-97.
- Lundström JO, Pfeffer M. Phylogeographic Structure and Evolutionary History of Sindbis Virus. Vector Borne Zoonotic Dis 2010. In press.
- Lundström JO, Turell MJ, Niklasson B. Antibodies to Ockelbo virus in three orders of birds (Anseriformes, Galliformes and Passeriformes) in Sweden. J Wildl Dis 1992;28:144-7.
- Luukkainen R, Laine M, Nirhamo J. Chronic arthritis after Sindbis-related (Pogosta) virus infection. Scand J Rheumatol 2000;29:399-400.
- L'vov DK, Skvortsova TM, Berezina LK, Gromashevsky VL, Yakovlev BI, Gushchin BV, Aristova VA, Sidorova GA, Gushchina EL, Klimenko SM. Isolation of Karelian fever agent from Aedes communis mosquitoes. Lancet 1984;2:399-400.
- Malherbe H, Strickland-Cholmley M, Jackson AL. Sindbis virus infection in man. Report of a case with recovery of virus from skin lesions. S Afr Med J 1963;37:547-52.
- Manni T, Kurkela S, Vaheri A, Vapalahti O. Diagnostics of Pogosta disease: antigenic properties and evaluation of Sindbis virus IgM and IgG enzyme immunoassays. Vector Borne Zoonotic Dis 2008;8:303-11.
- Niklasson B, Espmark A. Ockelbo disease: arthralgia 3-4 years after infection with a Sindbis virus related agent. Lancet 1986;1:1039-40.
- Niklasson B, Espmark A, LeDuc JW, Gargan TP, Ennis WA, Tesh RB, Main AJ,Jr. Association of a Sindbis-like virus with Ockelbo disease in Sweden. Am J Trop Med Hyg 1984;33:1212-7.
- Niklasson B, Espmark A, Lundström J. Occurrence of arthralgia and specific IgM antibodies three to four years after Ockelbo disease. J Infect Dis 1988;157:832-5.
- Norder H, Lundström JO, Kozuch O, Magnius LO. Genetic relatedness of Sindbis virus strains from Europe, Middle East, and Africa. Virology 1996;222:440-5.
- Sane J, Guedes S, Kurkela S, Lyytikäinen O, Vapalahti O. Epidemiological analysis of mosquito-borne Pogosta disease in Finland, 2009. Euro Surveill. 2010;15(2). pii: 19462
- Turunen M, Kuusisto P, Uggeldahl PE, Toivanen A. Pogosta disease: clinical observations during an outbreak in the province of North Karelia, Finland. Br J Rheumatol 1998;37:1177-80.
- Vene S, Franzen C, Niklasson B. Development of specific antibody patterns and clinical symptoms following Ockelbo virus infection. Arch Virol 1994;134:61-71.
- Woodall JP, Williams MC and Ellice JM. Sindbis infection in man. East Afr Virus Res Inst Rep 1962, 12:17.