Ross River Virus

Authors: Paul Griffin, MBBS FRACP FRCPA

Monograph
Tables
What's New
Reviews
History

Virology

Ross River virus (RRV) is a member of the Alphavirus genus of the family Togaviridae. Alphaviruses. They are enveloped positive sense single stranded RNA viruses. It is an icosahedral RNA virus whose structure and genomic sequence have been characterized; its closest relatives are Barmah Forest, Sagiyama and Semliki viruses (13, 33). The alpha virus genus contains 31 species including the type species Sindbis virus (55). Phenotypically there are at least 5 other Alphaviruses that are similar in that they cause mosquito transmitted predominantly arthritogenic diseases, namely Barmah Forest virus, Sindbis virus, O’nyong-nyong virus (also known as Igbo Ora), Mayaro virus and Chikungunya virus (49).

Epidemiology

A viral etiology for epidemic polyarthritis (subsequently known to be due to Ross River virus) was recognized as early as 1928 (48), although the virus and its association with the disease were not identified until the early 1960s when the prototype strain was isolated from mosquitoes collected near Ross River in Townsville in northeastern Australia in 1959 (14). Ross River Virus is the most common mosquito borne virus affecting humans in Australia typically causing an illness characterized by fever with polyarthritis, also referred to as epidemic polyarthritis (16, 17, 32, 44). Evidence of Ross River virus infection has been found throughout Australia, Papua New Guinea, the Solomon Islands and several Pacific Island nations including American Samoa, Cook Islands, Fiji, New Caledonia, Samoa and Wallis and Futuna (12, 31, 42, 40). Ross River virus is enzootic and endemic in all states and territories of Australia with approximately 5000 cases notified nationally per year with a 5 year mean rate up to the 2010-11 season reported at 23 per 100,000 (32, 59). Typically the greatest number of notifications occurs in Queensland (5 year mean of 2359.2 cases) with Queensland accounting for on average almost 50% of the total cases generally (16). The highest incidence typically occurs in the Northern Territory with a 5 year mean of 138.6 cases per 100,000 (58). Epidemics occur in different areas from year to year: an epidemic in 1979-80 was responsible for introduction of infection to a large proportion of the population in the Pacific Islands (40). There are a number of factors that impact on Ross River virus incidence with higher rates of infection occurring during times of high rainfall, humidity, temperature and tide levels resulting in peak activity typically between January and May (8, 24, 54, 59). Of these factors rainfall seems to be the single most important risk factor with over 90% of major outbreak locations receiving higher than average rainfall in the preceding months (29). Although difficult to project with any certainty due to the complex epidemiology involving the interaction between vectors, animal hosts and humans with unpredictable social and environmental variables (58), it seems likely that disease activity will increase with climate change but further work is required to predict the extent to which this may occur (5, 25, 35, 39, 53, 58). Ross River virus has been isolated from more than 30 species of mosquitoes (42, 43) although the comparative competency of all of them to transmit Ross River virus has not been formally reported. The most common mosquito species responsible for Ross River virus transmission areAedes vigilax,Culex annulirostris andAedes vittiger near the coastline andAedes vigilax, Culex annulirostris andAedes notoscriptus in inland areas (23, 26, 42). Macropods (kangaroos and wallabies) are thought to act as reservoirs but other species, including possums, horses, dogs, cats and bats can also be infected and may potentially act as amplifying hosts (6, 7, 27, 28, 42, 45). Although many species are capable of being infected few are known to exhibit disease although horses have been reported to show clinical signs similar to humans following infection (12, 15).

Clinical Manifestations

The incubation period is generally approximately 8 days with a range of 3 to 21 and infection can occur at any age; however, disease occurs most commonly in adults with symptoms being milder and of shorter duration in children (16, 21, 36, 40). Incidence of disease decreases with increasing age presumably due to increasing rates of prior exposure and therefore immunity (1). Subclinical infection is common, with an estimated ratio of clinical to subclinical infection between 1:2 and 1:65 (11, 21). Clinical illness is characterized by acute onset of arthralgia (in approximately 90%), arthritis (in approximately 70%), myalgia (in approximately 60%), lethargy (in approximately 75%) a maculopapular rash (in approximately 50%) and fever (in approximately 40%) (16, 20, 37). Although earlier studies suggested high rates of persisting or chronic arthritis 16, it has been subsequently shown that in the majority of patients resolution occurs within 3 months and that prolonged symptoms are usually associated with pre-existing chronic arthritic conditions or depression (19, 37). The joints most commonly involved are the knees, wrists, ankles, metacarpophalangeals and interphalangeals and the usual pattern is one of polyarthritis. The main differential diagnosis is with Barmah Forest virus infection which is typically milder and associated with polyarthralgia more so than polyarthritis, a lesser likelihood of persistence and a higher likelihood of rash 16. There has been one case of glomerulonephritis associated with Ross River virus infection (18) but no reports of involvement of tissues other than joints or muscles. Experimental demyelination has been induced in mice (46) but it is unclear if human neural tissue involvement can occur.

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 are found with predominance of mononuclear cells (50). Ross River virus infection is notifiable in Australia based on laboratory definitive evidence which currently is defined as either; isolation of Ross River virus, detection of Ross River virus by nucleic acid testing, an IgG seroconversion or a significant increase in antibody level or a fourfold or greater rise in titre to Ross River virus, detection of Ross River virus-specific IgM in the absence of Barmah Forrest virus IgM unless Ross River virus IgG is also detected, or finally detection of Ross River virus-specific IgM in the presence of Ross River virus IgG (51). While diagnosis is mostly based on the results as described above obtained by EIA performed at the majority of diagnostic laboratories in Australia, care needs to be taken in interpretation particularly of low titre IgM’s owing to the high rate of false positive and cross reacting antibodies particularly to other Alphaviruses (such as Barmah Forest). More specific tests are available, however rarely required including confirmatory neutralizing antibody tests and molecular methods which are available at multiple laboratories including Queensland Health Forensic and Scientific Services (Coopers Plains, Brisbane, Australia) and the Institute for Clinical Pathology and Medical Research (Westmead Hospital, Sydney, Australia).

Pathogenesis

Following the bite of an infected vector mosquito alphaviruses including Ross River virus disseminate via the blood stream to the liver, spleen, muscle and lymph nodes which are the primary sites replication (4). Ross River virus infection is facilitated by a process known as antibody-dependent enhancement whereby virus attaches to antibody or complement allowing entry into target cells (52). Macrophages can be infected with Ross River virus resulting in activation of Natural Killer cells and suppression of cytokines while immune complexes do not seem to play a role (34, 56). The predominant mechanism of joint manifestations in alpha viral infections (including Ross River Virus) has been proposed to be due to the release of proinflammatory mediators predominantly IL-6, IL-1, chemokine ligand 2 (CCL2), monocyte chemotactic protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) (5, 9, 10, 41). More recent studies indicate that Ross River virus may infect osteoblasts and induce bone loss (10).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There are no in vitro or in vivo susceptibility studies for conventional antiviral drugs. Some Australian Aboriginal herbal derivatives have been studied and antiviral effects have been observed for extracts from two plants (47) however, without sufficient success to become mainstream therapies.

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 beneficial in ameliorating symptoms. Steroid treatment has been shown to potentially improve outcomes in a small cohort of RRV infected patients however it is likely that the risks outweigh the benefits of this treatment modality and therefore it is not generally recommended (38).

ENDPOINTS FOR MONITORING THERAPY

No therapeutic endpoints have been established.

VACCINES

Given the lack of genetic variability and the long lasting immunity induced by infection, Ross River virus is an ideal candidate for the development of a vaccine. Thus far no vaccines are available for clinical use. A number of methodologies have been employed in an effort to develop a vaccine with most in more recent times focusing on inactivated vaccines (2, 22, 30, 57). A number of candidate vaccines have progressed through various stages of clinical trials with some human trials reported with promising early results (3).

PREVENTION OR INFECTION CONTROL MEASURES

Mosquito avoidance measures, particularly the use of repellants at dusk and dawn are the mainstay of prevention.

REFERENCES

1. Aaskov J, Doherty R. Arboviral zoonosis of Australasia. Handbook of zoonoses. 1994;289–304. [PubMed]

2. Aaskov J, Williams L, Yu S. A candidate Ross River virus vaccine: preclinical evaluation. Vaccine. Elsevier; 1997;15:1396–404. [PubMed]

3. Aichinger G, Ehrlich HJ, Aaskov JG, Fritsch S, Thomasser C, Draxler W, et al. Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: a randomized trial. Vaccine. Elsevier; 2011;29:9376–84. [PubMed]

4. Assunção-Miranda I, Cruz-Oliveira C, Da Poian AT. Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis. BioMed research international. Hindawi Publishing Corporation; 2013; 2013:973516. [PubMed]

5. Bambrick H, Woodruff R. P2-365 Climate change impacts on Ross river virus in Australia. Journal of Epidemiology and Community Health. BMJ Publishing Group Ltd; 2011;65(Suppl 1):A323–A323. [PubMed]

6. Boyd AM, Hall RA, Gemmell RT, Kay BH. Experimental infection of Australian brushtail possums, Trichosurus vulpecula (Phalangeridae: Marsupialia), with Ross River and Barmah Forest viruses by use of a natural mosquito vector system. Am J Troop Med Hyg. ASTMH; 2001;65:777–82. [PubMed]

7. Boyd A, Kay B. Assessment of the potential of dogs and cats as urban reservoirs of Ross River and Barmah Forest Viruses. Aust Vet J. Wiley Online Library; 2002;80:83–6. [PubMed]

8. Broom A, Whelan PI, acups SP, Melville L, Currie BJ, Krause VL, Brogan B, Smith F, Porigneaux P. Rainfall and vector mosquito numbers as risk indicators for mosquito-borne disease in Central Australia. Communicable Diseases Intelligence Quarterly Report. Department of Health and Ageing; 2003;27:110–6. [PubMed]

9. Chaaithanya IK, Muruganandam N, Sundaram SG, Kawalekar O, Sugunan AP, Manimunda SP, Ghosal SR, Muthumani K, Vijayachari P. Role of proinflammatory cytokines and chemokines in chronic arthropathy in CHIKV infection. Viral Immunol 2011;24:265–71. [PubMed]

10. Chen W, Foo S-S, Rulli NE, Taylor A, Sheng K-C, Herrero LJ, Herring BL, Lidbury BA, Li RW, Walsh NC, Sims NA, Smith PN, Mahalingam S. Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc Natl Acad Sci U S A. 2014;111:6040–5. [PubMed]

11. Choi Y, Comiskey C, Lindsay M, Cross J, Anderson M. Modelling the transmission dynamics of Ross River virus in Southwestern Australia. Mathematical Medicine and Biology. IMA; 2002;19:61–74. [PubMed]

12. Dhama K, Kapoor S, Pawaiya R, Chakraborty S, Tiwari R, Verma A. Ross River Virus (RRV) Infection in Horses and Humans: A Review. Pakistan Journal of Biological Sciences. 2014;17(6).

13. Dalgarno L, Rice CM, Strauss JH. Ross River virus 26 s RNA: complete nucleotide sequence and deduced sequence of the encoded structural proteins. Virology. 1983;129:170–87. [PubMed]

14. Doherty R, Whitehead R, Gorman B, O’gower A. The isolation of a third group A arbovirus in Australia, with preliminary observations on its relationship to epidemic polyarthritis. Aust J Sci. 1963;26:183–4

15. El-Hage C, McCluskey M, Azuolas J. Disease suspected to be caused by Ross River virus infection of horses. Australian veterinary journal. Wiley Online Library; 2008;86(9):367–70. [PubMed]

16. Flexman J, Smith D, Mackenzie J, Fraser J, Bass S, Hueston L, Lindsay MD, Cunningham AL. A comparison of the diseases caused by Ross River virus and Barmah Forest virus. The Medical Journal of Australia. 1998;169:159–63. [PubMed]

17. Fraser J. Epidemic polyarthritis and Ross River virus disease. Clin Rheum Dis<. 1986;12:369–88. [PubMed]

18. Fraser J, Cunningham A, Muller H, Sinclair R, Standish H. Glomerulonephritis in the acute phase of Ross River virus disease (epidemic polyarthritis). Clin Nephro. 1988;29:149–52. [PubMed]

19. Harley D, Bossingham D, Purdie DM, Pandeya N, Sleigh AC. Ross River virus disease in tropical Queensland: evolution of rheumatic manifestations in an inception cohort followed for six months. Med J Aust. 2002;177:352–5. [PubMed]

20. Harley D, Sleigh A, Ritchie S. Ross River virus transmission, infection, and disease: a cross-disciplinary review. Clinical microbiology reviews. Am Soc Microbiol; 2001;14:909–32. [PubMed]

21. Hawkes R, Boughton C, Naim H, Stallman N. A major outbreak of epidemic polyarthritis in New South Wales during the summer of 1983/1984. Med J Aust. 1985;143:330–3. [PubMed]

22. Holzer GW, Coulibaly S, Aichinger G, Savidis-Dacho H, Mayrhofer J, Brunner S, Schmid K, Kistner O, Aaskov JG, Falkner FG, Ehrlich H, Barrett PN, Kreil TR. Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection. Vaccine.2011;29(24):4132–41. [PubMed]

23. Hu W, Mengersen K, Dale P, Tong S. Difference in mosquito species (Diptera: Culicidae) and the transmission of Ross River virus between coastline and inland areas in Brisbane, Australia. Environmental entomology. BioOne; 2010;39:88–97. [PubMed]

24. Hu W, Tong S, Mengersen K, Oldenburg B. Exploratory spatial analysis of social and environmental factors associated with the incidence of Ross River virus in Brisbane, Australia. Am J Trop Med Hyg 2007;76:814–9. [PubMed]

25. Jacups SP, Whelan PI, Currie BJ. Ross River virus and Barmah Forest virus infections: a review of history, ecology, and predictive models, with implications for tropical northern Australia. Vector-Borne Zoonotic Diseases. 2008;8:283–98. [PubMed]

26. Jeffery JA, Kay BH, Ryan PA. Role of Verrallina funerea (Diptera: Culicidae) in transmission of Barmah Forest virus and Ross River virus in coastal areas of eastern Australia. J Med Entomol 2006;43:1239–47. [PubMed]

27. Kay BH, Boyd AM, Ryan PA, Hall RA. Mosquito feeding patterns and natural infection of vertebrates with Ross River and Barmah Forest viruses in Brisbane, Australia. Am J Trop Med Hyg. 2007;76:417–23. [PubMed]

28. Kay B, Pollitt C, Fanning I, Hall R. The experimental infection of horses with Murray Valley encephalitis and Ross River viruses. Aust Vet J 1987;64:52–5. [PubMed]

29. Kelly-Hope LA, Purdie DM, Kay BH. Ross River virus disease in Australia, 1886-1998, with analysis of risk factors associated with outbreaks. J Med Entomol. 2004;41:133–50. [PubMed]

30. Kistner O, Barrett N, Brühmann A, Reiter M, Mundt W, Savidis-Dacho H, Schober-Bendixen S, Dorner F, Aaskov J. The preclinical testing of a formaldehyde inactivated Ross River virus vaccine designed for use in humans. Vaccine. Elsevier; 2007;25:4845–52. [PubMed]

31. Klapsing P, MacLean JD, Glaze S, McClean KL, Drebot MA, Lanciotti RS, Campbell GL. Ross River virus disease reemergence, Fiji, 2003-2004. Emerg Infect Dis 2005;11:613. [PubMed]

32. Knope K, Whelan P, Smith D, Nicholson J, Moran R, Doggett S, Sly A, Hobby M, Wright P, Nicholson J; National Arbovirus and Malaria Advisory Committee. Arboviral diseases and malaria in Australia, 2010-11: annual report of the National Arbovirus and Malaria Advisory Committee. Commun Dis Intell Q Rep. 2013;37(1):E1-20. [PubMed]

33. Lee E, Stocks C, Lobigs P, Hislop A, Straub J, Marshall I, Weir R , Dalgarno L. Nucleotide sequence of the Barmah Forest virus genome. Virology. 1997;227:509–14. [PubMed]

34. Mahalingam S, Lidbury BA. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-κB) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc Natl Acad Sci USA . 2002;99:13819-24. [PubMed]

35. McMichael AJ. Global climate change: will it affect vector-borne infectious diseases? Internal medicine Journal 2003; 33: 554-5. [PubMed]

36. Mudge P, Aaskov J. Epidemic polyarthritis in Australia, 1980-1981. Med J Aust 1983;2:269–73. [PubMed]

37. Mylonas A, Brown AM, Carthew TL, McGrath B, Purdie DM, Pandeya N, Vecchio PC, Collins LG, Gardner ID, de Looze FJ, Reymond EJ, SuhrbierA. Natural history of Ross River virus-induced epidemic polyarthritis. Med J Aust 2002;177:356–60. [PubMed]

38. Mylonas AD, Harley D, Purdie DM, Pandeya N, Vecchio PC, Farmer JF, Suhrbier A. Corticosteroid therapy in an alphaviral arthritis. JCR: Journal of Clinical Rheumatology. LWW; 2004;10(6):326–30. [PubMed]

39. Nye ER. Global warming and possums: contributors in the future to new mosquito-borne human diseases in New Zealand. N Z Med J. 2007;120:U2839 [PubMed]

40. Rosen L, Gubler DJ, Bennett PH. Epidemic polyarthritis (Ross River) virus infection in the Cook Islands. Am J Trop Med Hyg 1981;30:1294–302. [PubMed]

41. Rulli NE, Melton J, Wilmes A, Ewart G, Mahalingam S. The molecular and cellular aspects of arthritis due to alphavirus infections. Ann N Y Acad Sci. 2007;1102:96–108. [PubMed]

42. Russell RC. Ross River virus: ecology and distribution. Annu Rev Entomol 2002;47:1–31. [PubMed]

43. Russell R. Arboviruses and their vectors in Australia: an update on the ecology and epidemiology of some mosquito-borne arboviruses. Review of Medical and Veterinary Entomology (United Kingdom). 1995. [PubMed]

44. Russell RC, Dwyer DE. Arboviruses associated with human disease in Australia. Microbes Infect. 2000 ;2:1693-704. [PubMed]

45. Ryan PA, Martin L, Mackenzie JS, Kay BH. Investigation of gray-headed flying foxes (Pteropus poliocephalus)(Megachiroptera: Pteropodidae) and mosquitoes in the ecology of Ross River virus in Australia. Am J Trop Med Hyg 1997;57:476–82. [PubMed]

46. Seay AR, Wolinsky JS. Ross river virus-induced demyelination: I. Pathogenesis and histopathology. Ann Neurol. 1982;12:380–9. [PubMed]

47. Semple SJ, Reynolds GD, O’leary M, Flower RL. Screening of Australian medicinal plants for antiviral activity. Ethnopharmacol 1998;60:163–72.[PubMed]

48. Shope R, Anderson S. The virus aetiology of epidemic exanthem and polyarthritis. MMed J Aust 1960;1:156–8. [PubMed]

49. Suhrbier A, Jaffar-Bandjee M-C, Gasque P. Arthritogenic alphaviruses—an overview. Nat Rev Rheumatol 2012;8:420–9. [PubMed]

50. Suhrbier A, La Linn M. Clinical and pathologic aspects of arthritis due to Ross River virus and other alphaviruses. Curr Opin Rheumatol. 2004;16:374–9. [PubMed]

51. Surveillance Case Definitions for the Australian National Notifiable Diseases Surveillance System [Internet]. 1 January 2004 to 1 January 2014. [cited 2014 Jun 14]. Available from: www.health.gov.au/casedefinitions

52. Takada A, Kawaoka Y. Antibody-depend5ent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 2003;13:387–98. [PubMed]

53. Tong S, Bi P, Donald K, McMichael AJ. Climate variability and Ross River virus transmission. Epidemiol Community Health. 2002;56:617-21. [PubMed]

54.Tong S, Hu W, Nicholls N, Dale P, MacKenzie J, Patz J, et al. Climatic, high tide and vector variables and the transmission of Ross River virus. Intern Med J 2005;35:677–80. [PubMed]

55. Virus Taxonomy: 2013 release. Available online: [Internet]. [cited 2014 Jun 13]. Available from: http://www.ictvonline.org/virusTaxonomy.asp

56. Way SJ, Lidbury BA, Banyer JL. Persistent Ross River Virus Infection of Murine Macrophages: An in Vitro Model for the Study of Viral Relapse and Immune Modulation during Long-Term Infection. Virology 2002; 301: 281-92. [PubMed]

57. Yu S, Aaskov JG. Development of a candidate vaccine against Ross River virus infection. Vaccine.1994;12:1118–24 [PubMed]

58. Yu W, Dale P, Turner L,Tong S. Projecting the impact of climate change on the transmission of Ross River virus: methodological challenges and research needs. Epidemiol Infect. 2014;1–11. [PubMed]

59. Yu W, Mengersen K, Dale P, Mackenzie JS, Toloo GS, Wang X, Tong S. Epidemiologic Patterns of Ross River Virus Disease in Queensland, Australia, 2001-2011. Am J Trop Med Hyg. 2014;13–0455. [PubMed]