1. Arboviruses of public health concern in NSW Dr Linda Hueston Arbovirus Emerging Diseases Unit CIDMLS – ICPMR PathologyWest

2. What are arboviruses? Viruses transmitted by the bite of an infected blood feeding invertebrate to a susceptible vertebrate host Must replicate in both hosts Replication cycle makes them unique among all viruses

3. How many arboviruses are there? Currently 534 viruses in International Catalogue of Arboviruses - 214 are known or probable arboviruses - 287 are known or possible arboviruses - 33 are probably or definitely not arboviruses

4. What makes them important to public health? 134 are known to cause disease in humans - many have been the cause of large outbreaks and significant morbidity and mortality 40 are known to cause disease in animals - several have been the cause of significant stock losses and subsequent economic hardship in many countries

5. What makes them important to public health? They are found on all continents - mosquito borne arboviruses are generally found in tropical climates - but ticks, midges, black flies, nest bugs and sea lice have expanded the geographic range of arboviruses to include Siberia in the north and Macquarie Island in the south They have caused significant morbidity and mortality worldwide They have had major impacts on economic life of countries and communities They are adaptable and have demonstrated potential for spread

6. Which arboviruses are important to public health? Depends on perspective - globally those with wide distribution, potential for spread, high prevalence, morbidity, disease severity and mortality have greater importance - locally those with high prevalence, mortality and disease severity will have a greater importance

7. Important Arboviral Diseases Globally - Dengue - Yellow fever - Tickborne encephalitis - Japanese encephalitis - St Louis encephalitis - West Nile virus - Californian encephalitis - Kyasanur Forest disease - Chikungunya - Ross River - Zika virus Locally - Ross River - Barmah Forest - Murray Valley Encephalitis - Kunjin - Dengue - Japanese encephalitis ?? - Chikungunya ?? - Zika??

8. Burden of Arboviral Disease Burden of arboviral disease is dependent on a multitude of factors - disease presentation & severity - symptomatic rate - incidence & prevalence - economic cost

9. Disease presentation & severity febrile illness with or without rash febrile illness with arthralgia, myalgia febrile illness with haemorrhagic symptoms encephalitis / meningitis

10. Symptomatic rate Majority of arboviral infections don’t result in disease RRV 1 in 9 cases will be symptomatic approx. 5000 cases reported each yr BFV difficult to estimate JE 1 in 300 is symptomatic MVE 1 in 150 to 1 in 1200 are symptomatic Kun not known (only 7 cases recorded in recent years) but WNV NY99 was 1 in 5 Dengue – variable symptomatic rate

11. Incidence & Prevalence RRV and BFV cases every year, RRV throughout the state; BFV largely coastal JE approx. 50,000 cases per yr & 15,000 deaths 50% survivors have severe neuropsychiatric disease Den approx 50 to 100 million cases/year; several hundred throusand cases DHF; fatality rate approx. 5% MVE case fatality 15 to 30%; 30-50% have long-term neurological deficits; 40% recover completely

12. Cost of Diagnosis & Treatment some estimates of $500 - $1000 to investigate and diagnose a case of RRV estimates of $5M/ yr for RRV testing across the country costs similar for BFV flavivirus diagnosis cost approx $100 - $200/ case depending on flavivirus involved but treatment costs of flavivirus infection much higher often involve hospital stays $1000/day in wards up to $3000/day for ICU ongoing cost of treatment and long term care for encephalitic cases have been estimated in the millions

13. Economic losses economic damage due to loss of manpower disruption of public services overload on health facilities indirect costs due to loss of tourism, school absenteeism cost of vector control, vaccines, surveillance and quarantine cost of stock losses associated crop losses

14. Diagnosis of Arboviral Diseases Isolation of virus from blood or CSF - the holy grail of diagnosis - allows detailed study of a virus Detection of viral antigens by PCR - sensitive and specific

15. Diagnosis of Arboviral Diseases Serology - can diagnose recent infection - can determine the success of vaccination programmes - used to determine prevalence of a virus in a community which can be used in predicting risk of virus introduction -can be used in various surveillance settings - relatively inexpensive - readily available and widely used in first world settings

16. Problems with Diagnosis Serology - significant problems with some commercially available test systems (false positive and false negatives common) - persistence of IgM in some infections can confuse recent with remote infections - in some test systems there is significant cross reactivity between closely related viruses - too great a reliance on IgM positivity - insufficient use of confirmation testing

17. What can be done to resolve these problems? undertake independent evaluations of commercial kits to determine their sensitivity, specificity and positive and negative predictive values develop test systems with greater specificity sequential testing of selected patients to determine the immune response over time follow-up cases to ensure onset date and travel history fits with the clinical picture discourage the use of single IgM positivity as a definite indicator of infection encourage the use of confirmation testing

18. Information required when following up cases of arboviral infection Clinical picture Onset date of symptoms Travel history (date left country, countries visited and dates, type of travel, date of return, how often do they travel) Vaccination history (yellow fever and JE vaccinations are common in Aust travellers but TBE and SLE vaccinations may be common in overseas visitors)

19. Information required when following up cases of arboviral infection Previous medical history – any documented history of previous arboviral infection. Country of birth Occupation Test results – who did the tests, what test system was used, what were the results, are serum samples still available Obtain follow-up serum collection and forward this sample along with any previous samples to the reference laboratory

20. Ross River & Barmah Forest viruses in NSW RRV is the most commonly diagnosed alphavirus infection BFV is the second most commonly diagnosed alphavirus infection RRV is endemic throughout the state BFV is endemic on the north coast and epidemic on the south coast. Rarely found west of the mountains

21. Ross River & Barmah Forest viruses in NSW Clinically the presentation are similar but there are notable differences - rash is more common and more obvious in BFV - arthralgia is more common in RRV - IgM has been shown to persist for long periods (18 to 48 months) post onset in RRV infections and 6 to 12 months for BFV - this can contribute to inaccurate reporting to health authorities and inaccurate diagnosis in patients.

22. Mysterious disease Summer 1917 epidemic of encephalitis with a high fatality rate 132 cases in NSW 71% fatality rate 9 cases in Qld78% fatality rate Summer 1918 cases appear again 31 cases Qld > 50% fatality rate 13 cases Vic Some investigators believed “Mysterious Disease” was aberrant polio

23. Mysterious disease Further epidemics in 1922 and 1925 1923 Aust Medical Congress accepted that “Mysterious Disease” was a new and distinct clinical disease. Disease renamed Australian X disease Curiously no further cases noted for 25 years Interestingly this lack of activity coincided with WW2 when > 1 million young servicemen were present in the endemic north for 4 yrs without incident

24. Mysterious disease 1951 first isolate by Eric French from fatality at Mooroopna, Vic Virus named – Murray Valley encephalitis virus 45 cases severe encephalitis 42% fatality rate Serologic testing became available Sporadic cases 1956 after which virus seemed to disappear

25. Mysterious disease 1960 Kunjin virus isolated 1971 sporadic human cases, antibody also detected in horses with “nervous disease” 1974 largest epidemic involving all mainland states 1984 an isolated case of severe encephalomyelitis in Vic due to Kunjin From 1951 to 1984 104 cases of encephalitis accepted as being caused by MVE or Kun

26. MVE & Kunjin Since 1951 birds were the most attractive hypothetical host Human infection confined to the flood plains of the river system where significant bird breeding Closely related to JEV and SLE viruses which use birds as a host Principal vector C. annulirostris was related to vectors of JEV and SLE

27. MVE & Kunjin By 1974 the only hypothesis explaining the periodic epidemics required movement of viraemic waterbirds from the northern endemic regions. Hypothesis that floods in NT or northern parts of SA drove the movement of viraemic birds south Hypothesis that flooding rains in southern or eastern Aust or both stimulates southerly movement of viraemic birds across southern Qld and northern NSW Causing outbreaks which would disappear with decreases in vector numbers and the increased no. of immune hosts

28. MVE & Kunjin Serosurveys implicated 15 species of birds as hosts Human serosurveys in 1952-53 suggested no evidence of virus since the summer of 1951-52 Human serosurveys suggested the antibody prevalence only west of the Great Dividing Range Believed the Great Dividing Range presented physical barrier to vertebrate and invertebrate hosts Cryptic foci theory was considered but as none had been found it was discounted These hypotheses held sway for 56 years

29. MVE & Kunjin 1974 outbreak accompanied extensive flooding which devastated agriculture in the region Disease caused significant morbidity and mortality Widespread fear prevented itinerant workers for coming to the area Tourism industry failed Establishment of sentinel chicken programmes in NSW, SA and Vic to monitor viral presence and provide early warning

30. MVE & Kunjin MVE was detected in the Darling in 2001, 2003, 2008 MVE detected at Paringa SA 2003 Kun was detected in the Murray in 1998, 2001, 2007, 2008 and 2012 MVE exploded in Vic in March 2008 with seroconversions in sentinel chickens Human cases MVE since 1974 NSW 2MVE fully recovered, 1 Kun mild illness Vic 1 suspected MVE SA 2 MVE one death, one recovered

31. Evidence for Cryptic foci in eastern Aust 1971 MVE in 2 young children, Charleville and Albury & surveys of chickens suggest virus active in absence of high rainfall 8% of Aust birds are true north-south migrants, with a max viraemia 7 days unlikely would still be viraemic by the time they make it south 2001 serosurvey in Macquarie Marshes demonstrates antibody in people born post 1974 & in young animals 2002 serosurvey in Vic shows approx 6% prevalence in those born after 1974. 2003 MVE detected in chickens in Menindee –Darling River stopped flowing

32. Protection of the Great Dividing Range Long held view birds and vectors can’t cross the range so the coast is safe Serosurveys suggest MVE and KUN absent from coast However significant colonies of potentially suitable bird hosts live on the coast No viral isolates from coastal region up to 2011 AND THEN............................

33. 2011 Kunjin appearance

34. What Happened to Kunjin in 2011? >1000 horses in SE Aust developed encephalitic illness with 10-15% fatality rate Kunjin isolated from brain Outbreak unprecedented size & severity Happened despite low mossie numbers Suggesting virus more virulent Transmitted more efficiently Two other curiosities – how did it cross the mountains & why no human cases

35. What are the arboviral threats to NSW? RRV & BFV will remain the most common cause of alphavirus infection within the state The absence of a suitable host makes the use of sentinel animals as an early warning system unlikely for RRV and BFV The use of sentinel chickens as an early warning of MVE and Kunjin activity appears to be successful and has provided some evidence that there may be cryptic foci of MVE within the state Dengue fever is most likely to be the most commonly diagnosed flavivirus infection in the state. The increase in infections will have an impact on the health budget as the cost of diagnosis and treatment increases The appearance of WNV (through imported horses & travellers) and CHIK, Zika and JE (through travellers) in the state are reminders that viral hitchhiking is possible As 47% to 49% of all tourist entries into Australia are through Sydney the potential for new incursions of arboviruses is an ever present danger.

36. Conclusions Need to consider the implications outbreaks of arboviral disease would have on: Health Potential outbreaks in large cities eg Sydney, Newcastle, Wollongong How would testing be handled What type of warnings should be issued Economy Major transport links between NSW, Vic, Qld and SA could be disrupted due to fear of disease