tick-borne encephalitis · serum abs: 50% -ve at time of lp, 100% +ve after 10 days, minimum +ve ab...
TRANSCRIPT
1
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
2
Hard ticks
Ixodes ricinus – central Europe Ixodes persulcatus – Far East, Siberia Rodents, small mammals
3
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
4
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
5
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
6
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.
7
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
8
CT head NAD, LP: 120 lymphocytes, protein 0.95
Case 1
9
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
10
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
11
Biphasic course of TBE
(Graphics by Patrik Kilian, adapted from Ruzek et al., 2013)
12
Biphasic course of TBE
(Graphics by Patrik Kilian, adapted from Ruzek et al., 2013)
13
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
14
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
15
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)
16
Case 2
End May
June July
(Graphics by Ales Chrdle)
17
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
18
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)
19
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
20
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
21
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
22
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
23
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
24
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
25
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
26
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
27
What we know in therapy?
Studahl et al. Drugs. 2013, Lindquist, Lancet 2008 Mansfield et al. Journal of General Virology 2009
28
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
29
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.
30
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.
31
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
32
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)
33
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
34
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
35
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.