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Tick-borne encephalitis: Disease epidemiology and burden

of disease

Jochen Süss National Reference Laboratory for Tick-borne Diseases

Friedrich-Loeffler-Institute, Jena, Germany

WHO-Meeting of the Strategic Advisory Group of

Experts on Immunization (SAGE) 5-7 April 2011

CCV/CICG, Geneva

Tick-borne encephalitis (TBE)

- human TBE cases transmitted by tick bites, and – more rarely – by milk and milk products

- important viral zoonose

- the most important cause of viral infections of the central nervous system in Central and Eastern European countries and in Russia

- the most important and widespread of arbovirus diseases that can be transmitted by ticks in Europe (and Asia?)

TBEV - Host - Vector - Interactions

Pathogen

Vector

(i) (ii)

(iii) e.g. rodents, birds (humans)

e.g. Ixodes ricinus TBEV prevalence 1-3% Germany, Austria 1.7% Lithuania 14.3% special focus Switzerland 3-5% (25%) Latvia

I. persulcatus acc. to P. Nuttal, 1999, mod.

Vertebrate host

focal nature of the disease!

Ixodes ricinus and I. persulcatus in Europe and Far East

according to Lindgren, Jaenson, Sonenshine, Minar

Phylogenetic tree of flaviviruses (glycoprotein E)

Source: Heinz and Stiasny, 2010; Jääskeläinen et al., 2010; Chausov et al., 2010 (mod.)

Sofjin

Siberian/Siberian

Siberian/Baltic

Neudoerfl

Zausaev Vasilchenko

Ixodes ricinus

Ixodes persulcatus

TBEV subtype pattern in Europe and Asia

EU SI FE

EU

SI

FE SI EU

EU

FE FE SI

Alimentary transmission of TBEV (dairy products from livestock)

Raw milk: goat < sheep < dairy cow

Russia Czech Republic Hungary Austria Slovakia Lithuania Latvia Poland Lithuania Estonia Albania Bosnia Serbia

Recent alimentary outbreaks: 2007: Hungary/Lakhegy: 154 exposed individuals 25 confirmed cases (Balogh et al., 2009) 2008: Austria/Vorarlberg: 7 exposed individuals 4 confirmed cases (Holzmann et al., 2009)

XXXXX: from the 1990 more milk-borne cases and outbreaks!

Historical alimentary outbreak: 1954: Slovakia/Roznava: > 261 patients (Blaškovič, 1954)

TBE is a notifiable disease in 16 European countries (Austria, Czech Republic, Estonia, Finland, Germany, Greece, Hungary, Latvia, Lithuania, Norway, Poland, Russia, Slovak Republic, Slovenia, Sweden, Switzerland) . At present, TBE is not notifiable in Belgium, France, Italy, Portugal, Spain, Denmark, and the Netherlands. In 19 European countries TBE is endemic AND which report reliable data:

Between 1990 and 2009 169,937 TBE cases were reported, an average of 8,497 cases/year.

This is considered an underestimate due to insufficient routine diagnostics and surveillance!

In Belgium, Portugal, Spain, and the Netherlands no authochthonous TBE cases were reported; the reasons are largely unknown. (Süss, J., Eurosurveillance 2008; 13(26))

TBE: Reporting structures / surveillance activities Clinically and diagnostically confirmed AUTOCHTHONOUS TBE cases Detection (and characterization) of TBEV in unengorged ticks (selected points) Detection of TBEV in rodents (and specific antibodies) Surveillance in wildlife Surveillance in livestock sentinels (antibodies; goat and sheep flocks)

TBE risk areas have been monitored by TBE incidence since 2007 (Robert-Koch-Institute, 2007). Risk areas (districts) are defined as areas with a mean of 1 case per 100.000 inhabitants in the district (Landkreis) in the course of 5 years. Previously, TBE risk areas in Germany were determined by the number of confirmed human cases per district a year and not by incidence

Def. risk area (Germany) – Robert-Koch-Institute

TBE – case definition (Germany and other countries)

Clinical picture typical of TBE

Detection of TBEV-specific IgM and IgG antibodies in the serum

Place of exposure

Typically a biphasis course with flu-like symptoms during the first phase, signs of meningitis, encephalitis or radiculitis or mixed forms after an asymptomatic period without fever

Detection of TBEV-specific antibodies in the CSF – increased CSF serum index cross reactive antibodies against other flaviviruses (or vaccinations) – ELISA test versus neutralization test moderate pleocytosis

Further epidemiological circumstances: history, vaccination status, tick bite, exposure in known risk areas, raw milk in risk areas

However, case definitions vary in different countries

TBE – case definition (Germany and other countries)

Clinical picture typical of TBE

Detection of TBEV-specific IgM and IgG antibodies in the serum

Place of exposure

Typically a biphasis course with flu-like symptoms during the first phase, signs of meningitis, encephalitis or radiculitis or mixed forms after an asymptomatic period without fever

Detection of TBEV-specific antibodies in the CSF – increased CSF serum index cross reactive antibodies against other flaviviruses (or vaccinations) – ELISA test versus neutralization test moderate pleocytosis

Further epidemiological circumstances: history, vaccination status, tick bite, exposure in known risk areas, raw milk in risk areas

However, case definitions vary in different countries

Rhineland Palatinate

Baden- Wuerttemberg

Bavaria

Hesse Thuringia

1998 Definition risk area risk area

Development of TBE risk areas in Germany

1998

1998: 63 TBE risk districts 2010: 136 TBE risk districts

2010 (Germany:440 districts)

Recorded (!) TBE cases in Europe and Russia 1990 – 2009 (2010)

Europe without Russia

Russia

Europe including Russia

(Süss, 2011, TTBDIS)

2010 preliminary

0

1000

2000

3000

4000

5000

6000

7000

TBE in Europe 2000 – 2009

CZ 6542

LT 3848

D 2977 SLO 2620

LV 2608

PL 2362 EST 1740

S 1549 CH 1328

H A SK FIN

HR I

TBE cases

N F DK 25

without Russia

Number of TBE cases in 10 years

Czech Republic Lithuania Germany Slovenia Latvia Poland Estonia Sweden Switzerland Hungary Austria Slovakia Finland Croatia Italy Norway France Denmark

(Süss, unpublished)

0

2

4

6

8

10

12

14

RU

TBE in Europe 2000 – 2009 (incidence)

CZ

LT

D

SLO

LV

PL

EST

S CH H A SK

FIN

HR

I

TBE incidence

N

Mean value of incidence in the last 10 years

RU

Estonia 12.91 Slovenia 12.82 Latvia 11.31 Lithuania 11.15 Czech Rep. 6.19 Russia 3.02 Sweden 1.77 Switzerland 1.76 Slovakia 1.36 Austria 0.88 Hungary 0.72 Poland 0.62 Finland 0.42 Germany 0.36

(Süss, unpublished)

China: North east, Heilongjiang province, (Zhi Lu et al., Vector-borne and Zoonotic Diseases, 2008). Kazakhstan: East region and region Almaty (Pavel N. Deryabin, pers. commun., 2010)

Mongolia: North, (Walder et al., IJMM 296 S1, 69-75 (2006) (Khasnatinov et al., 2010: first fatal case, Far East subtype)

Japan: Hokkaido (Ikuo Takashima et al.)

Korea: (Su-Yeon Kim et al., Vector-borne and zoonotic diseases (2008), no cases

TBEV outside Europe

Kyrgyzstan: siberian subtype (Atkinson, 2010)

Korenberg, E., Advances in Virus Research 74 (2009) 124-144

TBE-incidence (per 100.000 inhabitants)

TBE cases (incidence) in Russia 1950 - 2009

Climate change? Anthropogenic influence? Vaccination coverage? Reporting? Diagnostics?

?

?

1990 - 2009

?

Age & Clinical Manifestation of TBE

acc. to Kaiser, 2005 (unpublished)

66 62 5441 33

14

34 38 4659 67

86

1-15 16-30 31-45 46-60 61-75 76-90Age (Years)

0%

20%

40%

60%

80%

100%

Meningitis Encephalitis/Myelitis

Long-term prognosis in TBE (encephalomyelitis)

Patients 57

n

Death due to TBE 17 (30%)

Persisting dysfunctions 29 (51%)

Recovered 11 (19%)

(R. Kaiser, submitted to TTBDIS)

Case fatality rates, TBEV subtypes and regions, a contradiction

European subtype: 1-2% Siberian subtype: 6-8% (some patients develop chronic TBE?) Far Eastern subtype: 20-40% (?)

Gritsun et al. (2003) Platonov et al. unpubl.

Siberia (south): 1.2% Far Eastern (south): 12.1% Ural: 1.5%

Postencephalitic syndrome associated with TBE Frequency and severity of TBE associated postencephalitic syndrome are related to: TBE virus subtype: European < Siberian/Far Eastern (?) Severity of acute illness

Conclusion: Clinical presentation and pathogenesis

Severe forms of TBE are associated with: - Age

- Severity of illness in the acute stage

- Low neutralising antibodies at onset

- Low early CSF IgM response

- Sequelae present after 1 year indicates a poor prognosis

- Disputed: TBEV subtype: European < Siberian/Far Eastern

C Christian Lüttich, 2007

Thank you !