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Dr Ales Chrdle Ceske Budejovice Hospital, Czech Republic

Royal Liverpool University Hospital, UK

Tick-Borne Encephalitis

ESCMID Postgraduate Course Preparing for (Re-)Emerging Arbovirus Infections

21 March 2018

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Hard ticks

Ixodes ricinus – central Europe Ixodes persulcatus – Far East, Siberia Rodents, small mammals

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Tick borne encephalitis

Chrdle at el (2016) Tick-borne encephalitis: What travelers should know when visiting an endemic country, Human Vaccines & Immunotherapeutics, 12:10, 2694-2699

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TBE endemicity by counties

European Centre for Disease Prevention and Control. Epidemiological situation of tick-borne encephalitis in the European Union and European Free Trade Association countries. Stockholm: ECDC; 2012. doi 10.2900/62311

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Tick borne encephalitis South Bohemia: 100-200 TBE cases/year

Kříž B, Beneš Č. Situation in TBE incidence in Czech Republic till 2013. Available at: http://www.szu.cz/tema/prevence/klistova-encefalitida. Accesed on 4 May 2015.

Kollaritsch H, The current perspective on tick-borne encephalitis. Vaccine. 2011 Jun 20;29(28):4556-64. Epub 2011 May 5.

Czech Republic 600-1,000/year

C-E Europe + Russia

10,000 cases /year

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Not all ticks are infected equal

0.1 – 3% ticks infected Exceptionally up to 37% in I. persulcatus In Europe: risk of infection after a tick bite 1:25 – 1:1,000

Danielová, V., Daniel, M., Kříž, B. Tick-borne encephalitis in Europe. In: Ebert R. A., Progress in Encephalitis Research, Nova Science Publisher, New York. 2006; pp. 59 – 103.

Bormane, A., Lucenko, I., Duks, A., Mavtchoutko, V., Ranka, R., Salmina, K., et al. Vectors of tick-borne diseases and epidemiological situation in Latvia in 1993-2002. Int. J. Med. Microbiol. 2004;293 Suppl 37:36-47.

Süss, J. Epidemiology and ecology of TBE relevant to the production of effective vaccines. Vaccine 2003;21 Suppl 1:S19-35.

Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008 May 31;371(9627):1861-71. doi: 10.1016/S0140-6736(08)60800-4.

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Case 1

36M, previously fit and well Admitted with progressive severe headache and fever 7/7 No tick bite, but removed ticks from his dog Clammy, photophobia, mild neck stiffness Right arm weakness, very poor memory, shaky FBC, U+E, LFT, CRP all unremarkable

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CT head NAD, LP: 120 lymphocytes, protein 0.95

Case 1

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CT head NAD, LP: 120 lymphocytes, protein 0.95

Serology: TBE IgG +, IgM +++

2 days later – cough while drinking, some drooling, progressive weakness R shoulder>hand

Case 1

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MRI Brain/C spine nil pathology

HDU stay 7/7, NG feeding

SatO2 90% in room air, CXR clear - chest physio

Gradually improved and became much brighter

Home 4 weeks later, back to work after 6/12

Case 1

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Biphasic course of TBE

(Graphics by Patrik Kilian, adapted from Ruzek et al., 2013)

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Biphasic course of TBE

(Graphics by Patrik Kilian, adapted from Ruzek et al., 2013)

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Brain inflammation

Astrocytes and microglia - production of TNF-a, IFN-a, IL-1b, IL-6, IL-8, IL-12, IFN-g, IP-10

Neuronophagia Endothelial activation Perivascular infiltrates Activated microglia Histiocyte nodules Cytotoxic T cell infiltration

Breakdown of blood brain barrier due to inflammation Palus, M et al . J Gen Virol. 2014;95(Pt 11):2411-26. Palus, M J. Med. Virol 2016 Růžek D, Tick-Borne Encephalitis, Grada Publishing, Prague, 2015

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45M, local pharmacist, previously fit and well,

Loves fishing

End May: sore throat, temp. 37.5, headache, myalgia

WBC 2.8, Plt 110, CRP 20

ALT 80, GTT 45

TBE serology negative

After 5 days back to normal

Case 2

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Case 2

Mid June – spiking temps T 38-39 for a few days, severe headache, photophobia, nausea/vomiting, tremor upper limbs and eyelids Exam: very mild neck stiffness, mild tremor of fingers, poor finger-to-nose coordination/dysmetria Recalls a tick bite end May Not vaccinated against tick-borne encephalitis (TBE)

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Case 2

End May

June July

(Graphics by Ales Chrdle)

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0 hospitalization days

0 missed days at work

End December: fatigue, difficult to concentrate at work, regular headaches, sensitive to noise and light, irritability, mild tremor, erectile dysfunction

However, 1 miserable year of life and 1 broken marriage

Disease burden: DALY - 3.1 years per case

2% acute illness, 5% mortality, 93% disability Šmit R, Postma MJ, 2015, PlosONE 10(12):e0144988

DALY = disease associated life-years (lost years of good quality life due to illness)

Case 2

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Tick bite 70%, few unpasteurized milk/cheese Not related to the length of tick attachment (unlike Lyme)

Incubation 7-14 days (3-21) Clinical picture of TBE; a retrospective study of 493 cases - V. Chmelik, M. Bouzkova, L. Houserova, J. Zdvorak, I. Sirkova, I. Slamova, Z.Jerhotova, R. Trnovcova, A. Chrdle, V. Cihlova, Y. Jabali, J. Becvarova Zent Bl Bakteriol 1999; 289:583-584

Retrospective study 493 cases (5 years)

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Second phase: - meningitis 60% - encephalitis 35% - myelitis 5% mild elevation WBC, CRP CSF: WBC 5-700, protein 0.5-2.5, glu N, Ly 30-90% Serum Abs: 50% -ve at time of LP, 100% +ve after 10 days, minimum +ve Ab in CSF Clinical picture of TBE; a retrospective study of 493 cases - V. Chmelik, et al Zent Bl Bakteriol 1999; 289:583-584

MRI brain* - only 20% cases have visible MRI changes –mostly in basal ganglia and brainstem *Horger, M., Beck, R., Fenchel, M., Ernemann, U., Nägele, T., Brodoefel, H., Heckl, S. Imaging findings in tick-borne encephalitis with differential diagnostic considerations. AJR Am J Roentgol. 2012;199(2):420-7.

Retrospective study 493 cases

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Headaches, vertigo (more in the elderly) Fine tremor Poor concentration, sleep disturbances Postencephalitic syndrome 24% Long term neurological deficit 5-10% Mortality 1% Clinical picture of TBE; a retrospective study of 493 cases - V. Chmelik, et al Zent Bl Bakteriol 1999; 289:583-584

Retrospective study 493 cases - Post discharge

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66 years old farmer

Presented in September 2017

3 days fever, headache

1 day slightly confused and generally weak

ICU – weakness of upper limbs and slurred speech

Next day unable to cough and swallow

Case 3

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66 years old farmer

Day 2 of admission intubated, ventilated, early tracheostomy, off sedation

Weaning of ventilator in 8 days

Unable to swallow, poor coughing

Left diaphragm palsy

Proximal biplegia of upper limbs

Severe weakness of lower limbs

Case 3

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66 years old farmer

October – March 2018 – HDU - tracheostomy

Parenteral nutrition, then PEG feed

Repeat chest infections – bronchoscopic lavage of the left bronchi

General wasting

Fully alert throughout

Died March 15, 2018 of progressive respiratory failure, cause of death: fully preventable disease

Case 3

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Vaccination

Heinz FX, Field effectiveness of vaccination against tick-borne encephalitis Vaccine. 2007 Oct 23;25(43):7559-67 Kunze, U. (2015). "Tick-borne encephalitis as a notifiable disease--Status quo and the way forward. Report of the 17th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE)." Ticks Tick Borne Dis 6(5): 545-548.

Vaccination uptake in Austria (1 shot, complete course 53%) TBE incidence rate in CZ (where vaccination cover <20%) TBE incidence rate in Austria

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TBE vaccine safety

Ceske Budejovice Hospital, year 2000 Hospital staff and family members (2,500) Vaccination campaign EUR 0.70/dose (EUR 10/dose retail price in 2000) 5000 doses within one month Mostly sore arm, one-day fever No SAEs

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TBE risk reduction

Tick prevention – repellents, clothing Avoid unpasteurized milk Tick removal – beware of self-contamination

Gammons M, Salam G. Tick removal. Am Fam Physician. 2002 Aug 15;66(4):643-5. http://cks.nice.org.uk/immunizations-travel#!scenario:9

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What we know in therapy?

Studahl et al. Drugs. 2013, Lindquist, Lancet 2008 Mansfield et al. Journal of General Virology 2009

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What we would like to know in therapy?

Corticosteroids - Lithuanian study 2002: 133 cases of TBE, prospective observation study, no intervention Steroids use not in the design/methods Given at discretion of the medical team to 100% cases of severe, 70% moderate, and 40% mild disease Those on steroids had longer admission and recovery Strong selection bias / never repeated, no further intervention study Mickiene, A., et al. Tick borne Encephalitis in an Area of High Endemicity in Lithuania:

Disease Severity and Long-Term Prognosis. Clin. Inf. Dis. 2002;35:650-8

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What we would like to know in therapy?

In Austria/Germany/Baltic states: no corticosteroids Czech practice: selected cases with refractory headache/hyperpyrexia, paresis, somnolence, or other signs of raised intracranial pressure In supportive Rx despite diagnosis: corticosteroids have antiedematous, antiemetic, and antipyretic effect. Effective in refractory hiccups.

Duniewicz, M. et al. Corticoids in the Therapy of TBE and Other Viral Encephalitides. Cas Lek Cesk 1974;9,113(32):984-7.

Taba P et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 2017 Oct;24(10):1214-e61.

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What we would like to know in therapy?

Germany/Austria routine antibiotics Czech / only when coinfection Lyme >1%, Ehrlichia, Babesia Individual case reports Listeria, Coxiella, Ricketsia Broeker, M. Following a Tick Bite: Double Infections by Tick-Borne Encephalitis Virus and the Spirochetate Borrelia and other Potential Multiple Infections. Zoonoses and Public Health 2012;59:176-180

Theoretically high dose IVIG -Unpublished case of severe myeloradiculitis with triplegia, long tracheostomy weaning, and very good recovery after one year (independent in daily living) -Few case studies of other flaviviruses and one of TBE Růžek, D., Dobler, G., Niller, H. H. May early intervention with high dose intravenous immunoglobulin pose a potentially successful treatment for severe cases of tick-borne encephalitis? BMC Infect. Dis. 2013;13:306.

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What we would like to know in F/U post discharge?

Bedrest vs. Early neurorehabilitation Cognitive training Goal setting Coping strategies Patient support groups EEG – Biofeedback Mild learing disability - in children

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What we would like to know in prevention?

Austria has high vaccination coverage (58-95%), unlike the Czech Republic – (10-33%) Vaccination for travellers – risk similar to typhoid or P. vivax malaria in travellers to India (1:3,000-1:25,000 travellers) Rendi-Wagner P. Risk and Prevention of Tick-borne Encephalitis in Travelers. J Travel Med 2004; 11:307–312

Spreading to new regions due to climate change (Germany, Switzerland, Italy, the Netherlands)

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Summary – what we know

Epidemiology – viral illness by ticks, central and eastern Europe, Russia, northern China Clinical presentation – biphasic course, low mortality, significant long term disability, potential of co-infection Diagnostics – (delayed) serology, cross reaction Therapy – symptomatic, supportive, specialized centres Prevention – effective vaccination (+repellents) Chrdle at el (2016) Tick-borne encephalitis: What travelers should know when visiting an

endemic country, Human Vaccines & Immunotherapeutics, 12:10, 2694-2699

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Summary – what we would like to know

Epidemiology – new regions affected Clinical presentation – preventing development of severe neurological disability, immunosuppressed Diagnostics – TBEV PCR in urine, cytokine/T cell profile Therapy – immunomodulation, incl. steroids, directly acting drugs (HepC is a flavirus) Small molecules Neurorehabilitation Prevention – increase vaccination rate, travellers

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Useful reading Bogovic P, Strle F. Tick-borne encephalitis: A review of epidemiology, clinical characteristics, and management. World Journal of Clinical Cases : WJCC. 2015;3(5):430-441. doi:10.12998/wjcc.v3.i5.430. Chrdle at el (2016) Tick-borne encephalitis: What travelers should know when visiting an endemic country, Human Vaccines & Immunotherapeutics, 12:10, 2694-2699 Taba P et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 2017 Oct;24(10):1214-e61.