Barmah Forest Virus

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Virology

Barmah Forest virus (BFV) is a member of the Alphavirus genus of the family Togaviridae. Alphaviruses are enveloped positive sense single stranded RNA viruses. The alpha virus genus contains 31 species including the type species Sindbis virus. Barmah Forest virus’ uniqueness amongst the Alphaviruses is based on genomic sequencing, structural and non-structural proteins and serological reactivity (16). The most closely related Alphaviruses are Ross River and Semliki viruses (16). Phenotypically there are at least 5 other Alphaviruses that are similar in that they cause mosquito transmitted predominantly arthritogenic diseases namely Ross River virus, Sindbis virus, O’nyong-nyong virus (also known as Igbo Ora), Mayaro virus and Chikungunya virus (19).

Epidemiology

Barmah Forest virus (BFV) was first isolated in 1974 from mosquitoes collected in the Barmah Forest near the Murray River in northern Victoria (17), and at approximately the same time from mosquitoes collected in southwest Queensland (8); however, human infection was not reported until 1986 (2, 26). Barmah Forest virus is found endemically in all states and territories of Australia (except Tasmania) with epidemics reported in Queensland, New South Wales, Victoria, Northern Territories and Western Australia. Approximately 1500 to 2000 cases are notified in Australia per year with a 5 year mean rate up to the 2010-11 season reported at 8.2 per 100 000 (15). Typically the greatest number of notifications occurs in Queensland (5 year mean of 915 cases), with the highest incidence occurring in the Northern Territory with a 5 year mean of 44 cases per 100 000 (15). The small number of cases reported in Tasmania (1 to 2 per year) suggests that BFV is not endemic on the island and only introduced periodically (9, 15). While currently endemic only in mainland Australia, the potential for spread of Barmah Forest virus to neighboring Tasmania, New Zealand and Papua New Guinea has been suggested based on the presence of both likely intermediate hosts and vectors (14, 24). The highest incidence of Barmah Forest virus infection typically occurs between February and April with a clear seasonal trend but this is of less concern than RRV infection (15). Incidence is affected by rainfall, humidity, temperature and flooding levels, and so increased disease activity has been predicted with global warming (18, 19, 25). Infection is acquired by humans from mosquitoes, particularly Ochlerotatus (Aedes) vigilax in coastal areas and to a lesser extent Culex annulirostris in inland areas (3, 23). A vertebrate reservoir of Barmah Forest virus is suspected but not definitively identified to date. Studies have demonstrated the highest seroprevalence of Barmah Forest virus in brush tail possums and horses suggesting a potential role (3, 4,13).

Clinical Manifestations

The incubation period is usually 8 days with a range of 3 to 11 (9). Infection can occur at any age although the majority of cases are reported among middle aged adults peaking in the 45 to 64 year old age groups with an equal male and female predisposition (15). Subclinical infection is thought to be common, especially in children, although the rate is unknown. Clinical illness is characterized by acute onset of arthralgia (in approximately 90%), myalgia (in approximately 75%), lethargy (in approximately 85%) and a maculopapular rash (in approximately 75%) (9, 27). Arthritic symptoms or signs (as distinct from arthralgia) are found in only approximately 30% of cases and are usually mild (9). Joint symptoms persisting for more than 6 months are found in approximately 10% of cases (9). Polyarthralgia is common with the joints most commonly involved the knees, wrists, ankles, metacarpophalangeals and interphalangeals. The main differential diagnosis is with Ross River virus infection which is generally considered more severe with a higher incidence of arthritis which can be more prolonged but rash is less likely than in Barmah Forest virus (9). Apart from a single case of glomerulonephritis (12) and a possible case of Guillain-Barre syndrome (21) no reports of involvement of tissues other than joints or muscles could be found.

Laboratory Diagnosis

Inflammatory markers such as erythrocyte sedimentation rate or C reactive protein are usually either normal or only mildly elevated and the peripheral blood white cell count is usually normal. Joint effusions are rare but if aspirated low grade inflammatory changes can be found predominantly composed of monocytes (9). Barmah Forest virus infection is notifiable in Australia based on laboratory definitive evidence which currently is defined as either; isolation of Barmah Forest virus, detection of Barmah Forest virus by nucleic acid testing, an IgG seroconversion or a significant increase in antibody level or a fourfold or greater rise in titre to Barmah Forest virus, Detection of Barmah Forest virus-specific IgM in the absence of Ross River virus IgM unless Barmah Forest virus IgG is also detected, or finally detection of Barmah Forest virus-specific IgM in the presence of Barmah Forest virus IgG. The most common method of diagnosis is by an enzyme linked immunoassay (EIA) which is available at the majority of diagnostic serology laboratories in Australia. However, a single positive IgM needs to be interpreted with caution and particularly in context with the clinical presentation given the high false positive rate demonstrated (5). More specific testing modalities are now reasonably readily available including a confirmatory neutralizing antibody assay and real time RT-PCR (5, 11).

Pathogenesis

Alphaviruses including Barmah Forest virus disseminate via the blood stream to the liver, spleen, muscle and lymph nodes which are the primary sites replication following inoculation from the bite of an infected mosquito (1). The majority of studies on pathogenesis have been in the closely related alphaviral infections of Ross River virus and Chikungunya virus, with the predominant mechanism of joint manifestations proposed to be due to the release of proinflammatory mediators predominantly IL-6, IL-1, chemokine ligand 2 (CCL2) and monocyte chemotactic protein-1 (MCP-1) (6, 7, 22). More recent studies in RRV indicate that alphaviral infection may infect osteoblasts and induce bone loss (7). The first animal model of Barmah Forest virus infection has recently been reported and demonstrated significantly increased levels of inflammatory mediators including TNFα and IL-6 in RRV infected mouse quadriceps but not in those infected with BFV and therefore future studies are planned (10).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There are no in vitro or in vivo drug susceptibility studies.

ANTIVIRAL THERAPY

There are no clinical reports on antiviral therapy and none have been used in clinical practice.

ADJUNCTIVE THERAPY

Non steroidal anti-inflammatory drugs and paracetamol (acetaminophen) are widely used for symptomatic relief.

ENDPOINTS FOR MONITORING THERAPY

No therapeutic endpoints have been established.

VACCINES

There are no available vaccines currently.

PREVENTION OR INFECTION CONTROL MEASURES

Prevention is based on mosquito avoidance measures, particularly the use of repellants at dusk and dawn.

REFERENCES

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