ESCMID Online Lecture by author TICK-BORNE ENCEPHALITIS CHANGES OF THE DISEASE INCIDENCE. atjana Avšič Županc

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1 TICK-BORNE ENCEPHALITIS CHANGES OF THE DISEASE INCIDENCE atjana Avšič Županc Institute of Microbiology and Immunology, Faculty of Medicine Ljubljana, SLOVENIA

2 Emerging vector-borne diseases Kilpatrick AM et al: Lancet 2012,380(9857):

3 Tick borne encephalitis virus - TBEV Genus Flavivirus, Flaviviridae family Spheric form Viral particles: nm Lipid membrane Positive strand ssrna virus

4 Tick borne encephalitis virus - TBEV 3 structural and 7 nonstructural proteins E protein host cell receptor binding protein; target for NT antibodies NS5 protein conserved region; RNA replication; blocks immune system; virulence factor

5 Tick borne encephalitis virus - TBEV TBEV consist of 3 subtypes: - European (TBEV-Eu) Central European Encephalitis (CEE) - Siberian (TBEV Sib) Russian Spring-Summer Encephalitis (RSSE) - Far Eastern (TBEV FE) - RSSE Lindquist L, Vapalahti O. Lancet 2008;371:

6 Tick borne encephalitis virus - TBEV Fajs L. et al. PLoS ONE 2012; 7(11): e48420

7 Natural cycle of TBEV VERTICAL TRANSMISSION Sexual transmission Transovarial (female adult eggs) - not efficient Transstadial (larvae nymph - adult tick) HORIZONTAL TRANSMISSON Ticks feed on infected rodent hosts Cofeeding transmission (uninfected larvae feeds in close proximity to infected nymphs on a rodent host) Infected tick stays infected throughout his life!

8 TBE virus transmission to humans Transmitted by Ixodes spp. ticks Transmission by infectious milk or dairy products

9 Tick borne encephalitis - TBE Viral infectious disease involving the central nervous system % asimptomatic infections 2-30 % simptomatic infections Biphasic course (3/4) Abortive TBE Meningitis, encephalitis, meningoencephalitis or encephalomyelitis

10 Tick borne encephalitis virus - TBEV European (TBEV-Eu) Ixodes ricinus - biphasic course; < 2% fatality rate; long lasting sequelae in older patients Siberian (TBEV Sib) Ixodes persulcatus - less severe; tendency of chronic or prolonged infections; 1 3% fatality rate Far Eastern (TBEV FE) Ixodes persulcatus - severe disease; frequent encephalitic symptoms with 5-35% fatality rate

11 Tick borne encephalitis - diagnostics

12 Tick borne encephalitis diagnostics SEROLOGY: Specific IgM and IgG antibodies from sera and CSF Standardized, automated method Sensitivity (IgM=98,8 %, IgG=99,5 %) Specificity (IgM=99,9 %???, IgG =96,8%) Pitfalls: Cross-reactivity exclusion of other viral exposure factors (vaccinations, exotic travel), neutralisation test, quantitative ELISA Post-vaccination TBE quantitative ELISA No antibodies in the first phase - PCR

13 Tick borne encephalitis diagnostics MOLECULAR Diagnostics: I. phase TBE viremia (no antibodies) EDTA blood, urin II. phase CSF (fresh or frozen), urin Quantitative real-time PCR with reverse transcription and internal controle Sensitivity (5 copies/reaction)

14 Tick borne encephalitis diagnostics VACCINATION BREAKTHROUGH Exclusion of other flavivirus infection Confirmation of CSF antibody formation Avidity testing for IgG antibodies TBE patients after vaccination have high avidity IgM antibodies are usually delayed! Subsequent sera samples for conformation of delayed IgM response, or an increase in specific IgG antibodies

15 TBE epidemiology- overview in Europe TBE notification TBE is a notifiable disease in 16 European countries, including 13 EU Member States (AT, CZ, EE, FI, D, GR, HU, LV, LT, PL, SK, SI, SE) and in three non-eu Member States (Norway, Russia, Switzerland) TBE is not notifiable in BE, FR, IT, PT, ES, DK, NL In 19 European countries TBE is endemic (outside Europe TBE is endemic in Mongolia, China, Kazakhstan, Japan, and South Korea) Survey on TBE in Europe Suss J: Eurosurveillance, Vol 13 (26) 2008 Donoso Mantke O et al: Eurosurveillance, Vol 13 (17) 2008

16 TBE case definition CLINICAL CRITERIA any person with symptoms of inflammation of the CNS (e.g. meningitis, meningoencephalitis, encephalomyelitis, encephaloradiculitis) LABORATORY CRITERIA At least one of the following five: TBE specific IgM AND IgG antibodies in blood TBE specific IgM antibodies in CSF Sero-conversion or four-fold increase of TBE-specific antibodies in paired serum samples Detection of TBE viral nucleic acid in a clinical specimen Isolation of TBE virus from clinical specimen Laboratory criteria for a probable case: Detection of TBE-specific IgM-antibodies in a unique serum sample EPIDEMIOLOGICAL CRITERIA Exposure to a common source (unpasteurised dairy products)

17 Recorded cases of tick-borne encephalitis, Europe TBE cases in Europe Data: S. Randolph; Amicizia, Human Vaccines & Immunotherapeutics, 2013, 9:5,

18 TBE cases reported in 16 EU countries, Number of cases Year ECDC: Epidemiological situation on TBE in EU and EFTA; 2012

19 TBE cases reported in 16 EU countries, seasonal distribution Number of cases Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Month of onset ECDC: Epidemiological situation on TBE in EU and EFTA; 2012

20 TBE cases in Europe Suss J: Eurosurveillance, Vol 13 (26)2008

21 Tick borne encephalitis - vaccination 3 dose vaccination Vaccination also for children (from 1 year on) In Austria a significant decrease due to massive vaccination Zenz W: Ped Inf Dis J, Vol 24 (10)2005

22 TBE annual incidence rate in EU/EFTA ( ) ECDC: Epidemiological situation on TBE in EU and EFTA; 2012

23 I. ricinus current distribution in EU

24 TBD incidence factors Human society Human behaviour & settlements Host & reservoir animals Climate Tick habitat Pathogen transmission Tick borne diseases incidence Ticks

25 TBE in Slovenia cases/year (14/ population) Average annual incidence of TBE in municipalities ( )

26 TBE in Slovenian ticks Prevalence of infected ticks affects the incidence of TBE Durmiši E et. al.:. VBZD 2011;11:

27 Drivers that have impact on tick biology Medlock JF et al.: Parasites&Vectors 2013; 6:1.

28 Ixodes ricinus dynamics in Slovenia Tick number Jan Feb Mar April May Jun Jul Aug Sep Oct Nov Dec Month Patients Nymphs No. of patients

29 Ixodes ricinus dynamics in Slovenia 0 Jan Jan Feb Feb Mar Mar April April May May Rakovnik Jun Jun Jul Črni kal Jul Aug Aug Sep Sep Oct Oct Nov Nov Dec Dec Bimodal seasonal dynamics Coastal region unimodal activity Influenced by temperature and humidity saturation deficit Knap N et al.: Vet Par 2009;164:

30 Biology of ticks influences epidemiology of TBEV Jan Feb Mar April Rakovnik May Jun Jul Aug Sep Oct Nov Dec χ TBE TBE Knap N et al.: Vet Par 2009;164:

31 TBE and tick hosts Small mammals are numerous in TBE endemic areas Important tick hosts Viremic transmisson Non-viremic transmission Yellow-necked mouse (Apodemus flavicollis) Bank vole (Myodes glareolus)

32 TBE and tick hosts Correlation between prevalence of infection in rodents and TBE incidence in humans Knap N et al.: VBZD 2012; 12(3):

33 TBE and tick hosts Long lasting viremia Importance as viral hosts Knap N et al.: VBZD 2012; 12(3):

34 TBE and tick hosts WILDLIFE Large mammals (important reproductive hosts for ticks) Abundance is increasing (red deer and roe deer) Knap N et al.: PLoS ONE 2013; 8(6): e66380

35 TBE and tick hosts LIVESTOCK Low viremia No sign of infection Excretion of the virus in milk!

36 TBE outbreak goat milk PATIENT CLINICAL PRESENTATION TREATMENT LABORATORY TESTING MICROBIAL CONFORMATION TBEV ELISA IgM IgG TBEV NT TBEV RT-PCR 1 Biphasic course outpatient 8. May x 2 Biphasic course hospitalization 8. May x 3 Abortive form No treatment 4 NO DISEASE 15. May June / 15. May June / RNA TBEV was detected in goat sera (1,50x10 3 copies RNA/ml) and goat milk (1,88x10 5 copies RNA/ml) TBEV antibodies in sera of 5/9 goats. Sheep samples (9) were negative. VACCIN ATION No long term recovery in any of the patients. Conformation of rare, abortive form of TBE. Short incubation period only two days!!! Important for medical history! Hudopisk N et al.: EID 2013; 19(5): x

37 Influence of anthropogenic factors Influence of weather on TBE incidence!

38 Influence of anthropogenic factors Farmlands No significant connection between decrease of farmlands and increase of TBE Forest increasing forest arreas significantlly influences TBE

39 Predictive maps Precipitation Elevation Vegetation Mean temp. of driest period Maxent

40 Factors that influence the transmission of vector borne diseases CLIMATE mean temperature, precipitation, humidity, extreme weather events TRANSMISSION BIOLOGY microbe replication/movement, vector reproduction/movement, microbe/vector evolution DISEASE OUTCOME risk, rate of transmission ECOLOGY vegetation, soil moisture, species competition SOCIAL FACTORS sanitation, vector control, travel/migration, behavior/economy, population/demographics

41 What can we do? In the present and future: Need to improve surveillance homogenous data Combined effort of clinicians and PH officials Uniform use of diagnostic methods for TBEV detection Use of data from tick and animal surveys Need to develop vaccination recommendations In the present and future: Understanding the pathogen Understanding the pathogenesis of the disease Developing (new) drugs and vaccines AWARNESS SURVEILLANCE RESEARCH