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1 Tick borne encephalitis in Europe Sara Gredmark Russ Presentation on the 13th ESCMID Summer School th July 2014, Sigtuna, Sweden

2 Tick Borne Encephalitis virus TBEV belongs to the flavivirus family (other viruses; Dengue, Yellow fever virus, West Nile virus) Single stranded RNA genome (11 kb) of positive polarity Single polyprotein Transmitted to humans by ticks cases each year (mainly in Russia) 5 Structural Non-structural 3 C M E NS1 NS prm 2A virus capsule NS 2B NS 3 NS NS 4A 4B protein cleavage and transcription NS

3 Ticks - TBE Ixodes ricinus (European) Ixodes persulcatus (Far Eastern) Egg, larvea, nymph, adult Female tick Male tick Picture Bert Gutafsson, Adult female after blood meal Picture Lars-Åke Janzon, From

4 Life cycle of ticks Adult 3 years From L. Lindquist Nymph 2000 egg Competent hosts 2 1 Larvae Co-feeding transmission Accidental host Disease

5 Co-feeding Larvae and nymph feed from the same animal Differences for transmission of infectious agent of importance Picture: G Hasle From Manfield et al., (2009). Journal of General Virology 90;

6 Tick saliva and transmission of infections Anti-hemostasis factors Reduce pain and itch Anti-inflammatory Possible Immunomodulators Encounter host complement lyse spirochaetes Macrophages and Dendritic cells trigger inflammation and the immune response Facilitates transmission of Lyme and TBE Lyme transmitted after 24 hours TBE transmitted within minutes Illustration from Joppe W.R. Hovius Journal of Investigative Dermatology (2009)

7 Epidemiology TBE Vector: Ixodes ricinus or Ixodes persulcatus Uncommon: Unpasteurized milk Reservoir: The tick are the main carrier co-feeding and long life-time for the tick (larvae --> adult). The field mouse is a chronic carrier and might transfer TBE to the fetus. TBEV prevalence in ticks is usually about 1-3% in endemic areas, but could be up to 10% in certain areas and in certain parts in Russia 30%. Less <1% of the ticks in Southern Sweden are TBE infected. Sero prevalence in humans in highly endemic areas in the Archipelago in Stockholm is 14-22% of which 1/4-1/3 been hospitalized for TBE (studies from the early 90-ies)

8 Subtypes of TBE and endemic areas L. Lindquist et al Lancet 2008; 371:

9 TBE endemic areas in Europe From:

10 TBE Incidence in Europe From:

11 Incidence of TBE in Sweden Jaeson et al (2012), Parasites & Vectors 5:

12 Increased incidence of TBE in Sweden : n= : n=904 Jaenson et al (2012), Parasites & Vectors 5:184

13 TBE cases Age and Sex Sweden 2012

14 New TBE cases (month) in Stockholms County (Mona Insulander Smittskydd Stockholm) Sweden

15 Magnitude of clinical symptoms Tick Borne Encephalitis: symptoms and outcome 7-14 days Viremic phase 33% of patients TBE reaches CNS hospitalization No detectable viral load Asymptomatic phase 7 days 7 days Few days up to months Low mortality from the European strain approximately 1-2 % Up to 40 % of patients suffering from TBE will have long lasting sequele such as paralysis, concentration problems, headache and decreased quality of life July 18,

16 Diagnostics Not specific symptoms for TBE During the first phase of the disease, the virus can be isolated from the blood (PCR) rare! Specific diagnosis usually depends on detection of specific IgM and IgG serum antibodies by ELISA. Vaccine failures or previously vaccinated population Difficult to diagnose because initially TBEV-IgG in absence of TBEV-IgM is assigned to vaccination. IgM response is delayed in previously vaccinated people. Use of paired serolgy 4 weeks after the first sample to confirm diagnosis

17 TBE case definition Febrile patient with clinical signs or symptoms of meningitis or meningoencephalitis, Mild to moderate elevation of cell counts in CSF, and The presence of serum IgM and/or IgG antibodies against the TBE virus

18 Different clinical disease severity in TBE infection Fever/Flu-like disease BENIGN FORM Meningitis Encephalitis SEVERE FORM Myelitis

19 Clinical disease severity Mild predominantly meningeal symptoms, including fever, headache, rigidity of the neck, and nausea. Moderate monofocal symptoms of the CNS and/or moderate diffuse brain dysfunction. Severe multifocal symptoms of the CNS and/or severe diffuse brain dysfunction. Encephalitic symptoms: altered consciousness, ataxia, dysphasia, tremor, seizures, and mono- or multifocal symptoms (moderate or severe disease)

20 Patients with severe TBE in different age groups (Southern Germany ) (n=656) Kaiser R. Brain, 1999

21 Treatment No specific treatment available for TBE Patients with severe CNS symptoms closely monitored as coma and paralysis may develop rapidly (patient usually worsening within 2-3 days after seeking medical attention). Symptomatic treatment e.g. adequate fluids/nutrition, pain killers Severe cases: artificial breathing assistance Regimens that previously have been used Corticosteroids BUT has been associated with longer hospital stay and worse outcome compared to patient who only receives symptomatic treatment Passive immunization with specific immunoglobulins against TBE may aggravate the disease

22 Clinical follow-up of adult TBE patients in Sweden and Lithuania 1/3 permanent sequelae to a varying degree at follow-up 1-5 years after the infection About 10% severe neurological sequelae Approximately 1% mortality 2-6% permanent paresis Mickienė A et al. Clin Infect Dis. 2002;35: Günther G et al. Clin Diagn Virol 1997;8:17-29

23 Outcome at 1 year after onset of TBE Mickienė A et al. Clin Infect Dis. 2002;35: by the Infectious Diseases Society of America

24 TBE in children In general: higher percentage of meningitis as compared to adults Less severe disease Less severe long-term sequelae Less mortality (only occasitional reports)

25 Long-term follow up of swedish children with TBE (2-7 years post infection) Mild TBE (n = 30) Moderate TBE (n = 11) Severe TBE (n = 25) Full total IQ score and mean Index scores on the 4 subscales: Verbal Comprehension Index, Perceptual Reasoning Index, 2/3 of the children experienced residual problems Working memory Index, and Processing Speed Index > 1/3 of the children were reported by parents or teachers to have problems with executive functioning mainly in areas involving initiating and organizing activities and Åsa Fowler, The journal of Pediatrics, Jan working memory

26 TBE in children studies from Stockholm 10/124 children with neurologic symptoms attending the Pediatric Emergency were included prospectively and 10/124 (8%) were diagnosed with TBE and 21/124 (16.8%) were diagnosed with neuroborreliosis (Sundin et al, 2011) The children displayed an indistinct medical history and presented with nonspecific signs such as malaise/fatigue and headache. One-year follow up of these children showed that pediatric TBE results in long-lasting residual symptoms and neurologic deficits affecting daily life. (Mona-Lisa Engman et al, 2012) Children usually have vague symptoms in TBE (headaches, nausea, fever, tiredness) (Hansson et al, 2011) TBE most likely underdiagnosed in children

27 How can we prevent TBE? Avoid being bit by a tick Inspect the body multiple times a day. Take off the tick before it has attached, the tick can crawl around for a long time before it finds a good spot on the body. Ticks should be removed promptly. The longer it is attached the higher the chance of disease Insect repellants might help for a short time, however ticks are not mosquitoes. Vaccination

28 TBE Vaccines in Europe Formaldehyde inactivated whole virus of the European TBEV subtype grown in chicken embryo cell culture contains adjuvans (Aluminiumhydroxid) Intra muscular injection Encepur (Novartis) - strain K μg Encepur from 12 years of age Encepur Junior <12 years of age, half antigen content FSME Immun (Baxter) - strain Neudörfl 2.4 μg FSME Immun (Baxter). From 16 years of age FSME Immun Junior. Children 1-15 years of age, half antigen content

29 Vaccination schedule Inactivated vaccines generates B-cell response and antibody protection Conventional primary vaccination schedule = 3 doses: Day Booster doses After 1-3 mo (max 12 mo) Well in advance for coming tick season FSME: 5-12 mo after dose 2 Encepur: 9-12 mo after dose 2 Dose 4 after 3 years. Thereafter every 5 years <60 years of age and every 3 years > 60 y Delayed booster is okay in healthy individuals (Askling HH, Vaccine 2012)

30 Adverse effects from the vaccine Fever is common, especially in children (25%) after dose 1. Usually below <39 C, short duration <24 tim Fever after following doses is uncommon (a few %) Mild local reaction at site of injection 10-15% (dose 1) Severe adverse vaccine effects are uncommon Neuritis 1/ doses Post-vaccinal encephalitis not more than expected backgound Vaccine made from virus grown in chicken embryo cell culture, not egg Vaccination during pregnancy not dangerous, but usually unneccessary!

31 Vaccination schedule for fast immunization FSME Immun: If there is a lack of time the intervall in between dose 1 and 2 can be shortened to 14 days. Following doses according to the normal schedule. Encepur: 4 dosez given day 0, 7, 21 and after months (before the coming TBE season) Thereafter dose 5 after 5 years (except for >60 years; 3 years according to recommendations)! Avoid the fast immunization schedule if possible (lower antibody levels after 2nd dose, less efficient in the elderly population)

32 Protection after TBE vaccination Seroconversion for both vaccines after 2 and 3 doses (>95%). Not known what antibody level is needed for protection for TBE. Antibody level is related to age, highest levels in children Population studies in Austria has shown that TBE vaccination has a protection level of >98% Studies only performed for FSME and not for Encepur, but serolgy wise no differences Vaccination in the elderly population (>60 y.o) or immunosuppressed Worse antibody response and increased risk of vaccine failure In the elderly population especially before dose number 4. (Rydgård Andersson, Vaccine 2010) 32

33 Numer of TBE cases in Austria (high level of immunized population) and Sweden and Czech Republic (low level of immunized population) Austria Sweden Czech Republic

34 Vaccination failures in Sweden after using recommended vaccination schedule cases cases cases cases cases (7) cases Diagnosis: paired serology; initially IgM negative; have IgG; look after 2-4 weeks for IgM and rising IgG, neutralizing antibodies or intrathecal antibodies From L. Lindquist

35 Type of stay when infected Permanent residence 2002: 24% 2003: 16% 2004: 34% 2007: 38% Length of stay < 1 week 17% 17% 1-3 weeks 15% 16% > 3 weeks 57% 49% Not known 11% 18% Summer residence 2002: 45% 2003: 49% 2004: 37% 2007: 38% From L. Lindquist

36 Vaccination in travellers / tourists ECDC people travelling from non-endemic areas to endemic areas if the visits are to include extensive outdoor activities also for shorter stays in highly endemic areas Countries that have endemic TBE: Czeck Republic, Austria, Schwitzerland, Slovenia, Slovakia, Hungary, Estionia, Latvia, Lithuania, Russia, Bella Russe, Albania: Longer stays (>4 w) during the summer year if not only in city environment. TBE in certain parts of the country: Sweden, Danmark, Finland, Poland, France, Italy, Croatia Longer stays (>4 w) in the endemic areas during the summer year if not only in city environment. Whoever wants to even if low risk. 1/3 of the cases in Sweden affects people after <3 weeks in high risk areas. Natural TBE infection provides life long immunity!