Miscellaneous Arboviruses • While the Geographic Distribution of KUNV and MVEV Overlap, the Latter Is More Widely Distributed

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Miscellaneous Arboviruses • While the geographic distribution of KUNV and MVEV overlap, the latter is more widely distributed. • The term “Australian encephalitis” (AE) has been used Disease Agents: to indicate encephalitis induced by infection with either • Murray Valley Encephalitis virus (MVEV) MVEV and/or KUNV. However, because these are different • Kunjin virus (KUNV) viruses, with slightly different clinical symptoms, it is more • Ross River virus (RRV) accurate to specify the diseases in terms of the causative virus. Disease Agent Characteristics: • The first reports of disease potentially attributed to MVEV • Family: Flaviviridae; Genus: Flavivirus (MVEV and KUNV) infection in humans in Australia occurred in southeastern Togaviridae; Genus: Alphavirus (RRV) Australia in 1917, 1918 and 1925 (114, 67 and 10 cases, • Virion morphology and size: All are enveloped, spherical respectively) and were described under the title of “Austra- particles, with icosahedral nucleocapsid symmetry; RRV lian ‘X’ disease”. The virus, designated as MVEV, was later diameter ~ 60-70 nm, MVEV and KUNV ~ 40-65 nm. isolated from fatal cases during an epidemic in 1951, when • Nucleic acid: Linear, positive-sense, single-stranded RNA there were 48 cases (19 fatalities); MVEV has been accepted (~11 kb in length) as the causal agent of the earlier Australian ‘X’ disease out- • Physicochemical properties: Alphaviruses and flaviviruses breaks or outbreaks previously referred to as “Australian are labile in the environment and rapidly inactivated by lipid encephalitis.” solvents, such as ether or chloroform, and by formaldehyde, • MVEV has a natural endemic cycle, which involves water heat and low pH as well as by common lab disinfectants fowl as the vertebrate host and Culex annulirostris (which (70% ethanol, 1% sodium hypochlorite, 2% glutaraldehyde breeds in freshwater environments) as the major vector in and quaternary ammonium compounds). northern regions of Australia. Epidemic activity in the south- • MVEV and KUNV each has a single genetic type and evolved east has been associated with excessive rainfall which slowly and uniformly in geographically separate areas of increases bird and mosquito populations and leads to a virus Australia. They are closely related antigenically and geneti- overflow infecting humans. cally to Japanese encephalitis virus; KUNV is a variant • KUNV was first isolated from C. annulirostris in Northern (member of lineage 1) of West Nile virus. Queensland in 1960. • RRV belongs to the same alphavirus antigenic group as Chi- • RRV was first isolated from Aedes vigilax in Northern kungunya and Barmah Forest viruses. Queensland in 1959. Prior to the introduction of serological blood testing, RRV was inseparable from Barmah Forest Disease Names: virus (the latter only known in Australia where it was first • Murray Valley Encephalitis (MVE) described in 1974). • KUNV disease • RRV infection is responsible for most arboviral disease in • RRV disease Australia. The largest epidemic on record occurred in the 1979-1980 when an RRV epidemic in Fiji spread to Samoa, Priority Level: the Cook Islands and New Caledonia. RRV cases continue to • Scientific/Epidemiologic evidence regarding blood safety: be reported from Fiji, and the virus remains endemic in Aus- Theoretical; other flaviviruses and alphviruses are known to tralia and Papua New Guinea. be transmitted via blood. • Public perception and/or regulatory concern regarding Common Human Exposure Routes: blood safety: Absent in nonendemic areas including the US • Vector-borne; transmission occurs through a mosquito- and Canada human or other vertebrate host -mosquito cycle. • Public concern regarding disease agent: Absent in  MVEV and KUNV can infect animals such as horses, nonendemic areas; high in endemic areas and during kangaroos and non-water birds; however, they are not epidemics thought to play a role in the transmission cycle. Background:  RRV infects Australian native mammals, particularly kangaroos and wallabies; humans can also act as ver- • MVEV occurs naturally throughout the northern half of tebrate reservoir hosts. Australia, Papua New Guinea and eastern Indonesia. MVE usually occurs in remote northwestern Australia. In south- Likelihood of Secondary Transmission: eastern Australia, MVE is seen when heavy rainfall, flooding and hot weather favor bird and mosquito breeding. In New • MVEV, KUNV and RRV are not transmitted person-to- South Wales, the pattern of disease over the last century has person. been outbreaks occurring decades apart, with no or very few • MVEV, KUNV and RRV infection results in long-lasting cases identified in between. immunity that is probably life-long.

October 2011 1 At-Risk Populations: • Using the data from the 2004 RRV outbreak in Cairns, Queensland, the risk of transfusion transmission (assuming • Many people who have lived for a long time in affected areas that RRV is transfusion transmissible) has been estimated at will be immune due to previous infections. Those at highest 1:13,500 (range of 1:4800-1:48,000). risk are individuals who have not had previous exposure, including: Cases/Frequency in Population:  Infants and young children • The last major epidemic of MVEV in Australia was in 1974  Those who visit or have recently moved to MVEV/RRV- (58 cases/13 fatalities). Sporadic cases occur in non- affected areas. epidemic years. • The aboriginal population in northern Australia has the • There is a lower incidence of KUNV infections, although highest exposure rate. Others at risk are those who bush- some cases were implicated during the MVEV epidemics. walk, camp, boat, fish and bird-watch in MVEV/RRV-affected • An estimated 4,800 cases of RRV are reported annually. areas. Incubation Period: Vectors and Reservoir Involved: • 5-28 days for MVEV and KUNV • Culex annulirostris is the major vector in Australia for all • 2-21 days for RRV (usually 7-9 days) three viruses and feeds on a variety of vertebrate species. C. tritaeniorhyncus and C. pipiens may also transmit. Aedes Likelihood of Clinical Disease: vigilax, A. camptorhynchus and A. notoscriptus are also • Most human MVEV infections are subclinical, but clinical common vectors for RRV. cases can be fatal. The ratio of clinical to subclinical cases • Water fowl are the major vertebrate hosts for MVEV and ranges from 1:500 to 1:5000 for MVEV and KUNV and 1:1.2 KUNV, especially ciconiiforms (herons and egrets). Antibod- to 1:3 for RRV. ies to MVEV have been detected in many vertebrate species, including ciconiiforms, pelecaniforms (pelicans and cormo- Primary Disease Symptoms: rants), and placental and marsupial mammals. • Most common symptoms of mild MVEV and KUNV diseases • RRV is enzootic in Australian native mammals (kangaroos, are nonspecific and include fever, headache, nausea, vomit- wallabies, and the dusky rat, Rattus colletti). There is evi- ing and loss of appetite, diarrhea, and muscle aches. dence that humans act as reservoir hosts in epidemic situa-  Severe symptoms include convulsions, brainstem tions and may also distribute the virus geographically. disease or respiratory failure in severe and fatal cases, Blood Phase: and involvement of the spinal cord, cranial nerves, or cerebellum in moderate cases. • The blood phase for MVEV and KUNV is not well character-  This can progress to trouble with coordination and ized. The viremic period is believed to be short and the virus speech, seizures, loss of consciousness, coma and is cleared from the blood by the time symptoms appear. In death. Some individuals who recover from MVE are left a single case report, MVEV RNA was detected in serum 3 with permanent neurological complications. days after the onset of illness and 4 days before the appear-  KUNV is similar clinically, but with usually milder ance of MVEV-specific IgM. disease than MVEV or closely-related WNV. KUNV • Skeletal muscle in humans is the primary site of RRV repli- infection can result in rare cases of non-fatal cation. The virus enters the blood where IgM can be encephalitis. detected in acute infection and may persist for months to • Common symptoms of RRV are fever, polyarthritis and rash; years. IgG can usually be detected within 10-14 days of IgM, other symptoms include lymphadenopathy, lethargy, head- peaks within 4 weeks and persists indefinitely. The duration ache, myalgias, photophobia and glomerulonephritis. The of viremia in humans is not well characterized but most length of time that symptoms persist varies, but usually likely has a short duration. In mice, the viremic period is several weeks. typically 5 days with low-level viremia extending up to 9 days. Severity of Clinical Disease: • Those with clinical MVE demonstrate 25-50% permanent Survival/Persistence in Blood Products: neurological sequelae. • Unknown • Generalized malaise and polyarthritis RRV infection may persist for a year or more. Transmission by Blood Transfusion: Mortality: • In Australia, there have been no documented cases of transfusion transmission for any of the three arboviruses. Given • There is 15-31% mortality for those with clinically significant the asymptomatic viremic period, the potential for transfu- MVEV disease. sion transmission exists. • RRV and KUNV infections are not known to be fatal.

2 Chronic Carriage: Pathogen Reduction Efficacy for Plasma Derivatives:

• Chronic carriage is not reported; however, for RRV, the virus • Expected to be effective. may persist in synovial cells and in cell lines of mouse mac- Other Prevention Measures: rophages for months. • No vaccines are available. Treatment Available/Efficacious: • RRV vaccine is in development.

• Supportive treatment only Other Comments:

Agent-Specific Screening Question(s): • A May 2011 report describes a fatal case of a 19-year old Canadian that returned to Canada from extended travel in • None the northern territory of Australia infected with MVEV. This Laboratory Test(s) available: is the first lab-confirmed Canadian case.

• No licensed tests are available. We would like to acknowledge the contributions from the Austra- • For MVEV and KUNV, infection is usually diagnosed from lian Red Cross Blood Services in sharing their “Infectious Disease measuring levels of antibody in samples of blood or cerebro- Agent Templates for MVEV and RRV, May 2011.” spinal fluid, or from detecting viral nucleic acids in these samples. It can sometimes be difficult to distinguish recent Suggested Reading: infections from prior infections by testing one specimen. 1. Broom AK, Lindsay MD, Wright AE, Smith DW, Mackenzie JS. Two samples of blood taken a week apart usually need to be Epizootic activity of Murray valley Encephalitis and Kunjin tested to see if there has been an increase in antibody levels. Viruses in an aboriginal community in the Southeast Kim- Testing includes: berly region of Western Australia: Results of mosquito fauna  Detection of antigens or antibody, including IgG sero- and virus isolation studies. AM J Trop Med Hyg 2003;69: conversion with exclusion of related viruses 277-83.  Detection of virus-specific IgM in serum or cerebrospi- 2. Carver S, Bestall A, Jardine A, Ostfeld RS. Influence of hosts nal fluid with exclusion of related viruses on the ecology of arboviral transmission: Potential mecha-  Culture of the virus from clinical samples nisms influencing Dengue, Murray Valley Encephalitis, and  Detection of viral RNA in clinical samples Ross River Virus in Australia. Vector Borne Zoonotic Dis • Neutralization or epitope blocking EIAs can be used to dis- 2009;9:51-64. tinguish MVEV from KUNV. 3. CBW Factsheets on Chemical and Biological Warfare Agents. • Both serological (IgG and IgM-specific immunoassays) and Murray valley Encephalitis: essential data. http://www. PCR are available for RRV. cbwinfo.com/Biological/Pathogens/MVEV.html. Currently Recommended Donor Deferral Period: 4. Department of Health, Government of Western Australia. Murray Valley Encephalitis. Environmental Health Guide • No FDA Guidance or AABB Standard exists. March 2010. • Australia: 2 weeks after RRV recovery, then plasma for frac- 5. Jacups SP, Whelan PI, Currie BJ. Ross River Virus and Barhmah tionation is the only component utilized for the next 12 Forest Virus Infections: A Review of History, Ecology, and months; N/A for MVEV or KUNV. Predictive Models, with Implications of Tropical Northern  The 12-month interval for fractionated plasma use is Australia. Vector-Borne Zoo Diseases 2008;8:283-97. based on operational considerations; the apparent 6. Johansen CA, Susai V, Hall RA, Mackenzie JS, Clark DC, short duration of viremia suggests that deferral periods May FJ, Hemmerter S, Smith DW, Broom AK. Genetic and substantially less than 12 months for other blood com- phenotypic differences between isolates of Murray Valley ponents would be adequate and would not compro- encephalitis virus in Western Australia, 1972-2003. Virus mise patient safety. Genes 2007;35:147-54. 7. Klapsing P, MacLean JD, Glaze S, McClean KL, Drebot MA, Impact on Blood Availability: Lanciotti RS, Campbell GL. Ross River virus disease reemer- • Agent-specific screening question(s): Not applicable gence, Fiji, 2003-2004. Emerg Infect Dis http://wwwnc.cdc. • Laboratory test(s) available: Not applicable gov/eid/article/11/4/04-1070.htm. 8. Mackenzie JS, Poidinger M, Lindsay MD, Hall RA, Sammels Impact on Blood Safety: LM. Molecular epidemiology and evolution of mosquito- • Agent-specific screening question(s); Not applicable borne flaviviruses and alphaviruses enzootic in Australia. • Laboratory test(s) available: Not applicable Virus Genes 1996;11(2/3):225-37. 9. McMinn PC, Carman PG, Smoth DW. Early diagnosis Leukoreduction Efficacy: of Murray Valley Encephalitis by reverse transcriptase- • No data available polymerase chain reaction. Pathol 2000;32:49-51.

3 10. Murray Valley Encephalitis Factsheet. NSW Health Depart- V, Lipkin WI, Briese T, Gould EA, Hall RA. The relationships ment http://www.health.nsw.gov.au/factsheets/infectious/ between West Nile and Kunjin viruses. Emerg Infect Dis murray_valley_enceph.html. 2001;7:697-705. 11. ProMed-mail. Murray valley encephalitis—Australia (07): 14. Shang G, Seed CR, Rolph MS, Mahalingam S. Duration of Canada ex Australia (Northern Territory); ProMed mail Ross River viraemia in a mouse model—implications for 2011; 25 May 2011. http://www.promedmail.org/pls/pm/ transfusion transmission. Vox Sang DOI:10.1111/j.1423- pm?an=20110526.1610. Accessed 08 October 2011. 0410.2011.01536.x. 12. Russell RC, Dwyer DE. Arboviruses associates with 15. Williams DT, Daniels PW, Lunt RA, Wang LF, Newberry KM, human disease in Australia. Microbes Infect 2000;2:1693- Mackenzie JS. Experimental infection of pigs with Japanese 704. encephalitis virus and closely related Australian flaviviruses. 13. Scherret JH, Poidinger M, Mackenzie JS, Broom AK, Deubel Am J Trop Med Hyg 2001;65:379-87.