- Email: [email protected]
Report of the 19th Annual Meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) – TBE in a changing world
Ticks and Tick-borne Diseases 9 (2018) 146–150
Contents lists available at ScienceDirect
Ticks and Tick-borne Diseases journal homepage: www.elsevier.com/locate/ttbdis
Report of the 19th Annual Meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) – TBE in a changing world
T
A R T I C L E I N F O
A B S T R A C T
Keywords: Tick-borne encephalitis TBE International Scientific Working Group on TickBorne Encephalitis Risk Vaccination Awareness
The 19th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) – a group of neurologists, general practitioners, clinicians, travel physicians, virologists, pediatricians and epidemiologists–was held under the title “TBE in a changing world”. Key topics within virology, current epidemiological developments and investigations, expansion of risk areas, clinical aspects and cases, traveling and mobility, vaccination rates, and latest news on vaccination were presented and extensively discussed. Over the past four decades, TBE has become a growing public health challenge in Europe and parts of Asia. It may be considered a complex eco-epidemiological system, characterized by an intricate interplay between the virus, ticks and tick hosts on the one hand and human exposure strongly influenced by socioeconomic conditions on the other hand. Although the facts are simple – vaccination is the best prevention – the socioeconomic conditions keep changing, and with them the ability or willingness of people to get vaccinated.
1. Introduction It has now been 19 years since the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) kicked off its first official meeting in 1998. Since then, scientists−including neurologists, general practitioners, clinicians, travel physicans, virologists, pediatricians, ecologists and epidemiologists–from more than 30 different European countries have convened annually to exchange the results of up-to-date research, identify obstacles to increasing vaccination rates, and shape feasible strategies to overcome them. In all these years, the main aims of the ISW-TBE have been promoting national and international scientific, medical and regulatory collaboration on TBE, stimulating and co-ordinating applied and basic research, contributing to training and educational programs in the field, providing high-quality information and promoting its appropriate distribution, promoting and aligning international standards on epidemiological surveillance, and defining and promoting proposals to harmonize national and international policies on prevention. Main goals that have been achieved by the ISW-TBE are, among others, an increased awareness of TBE in endemic and non-endemic countries, an increase of vaccination rates in various countries, getting TBE acknowledged and established as a travel-related risk, and building contact with the European Centre for Disease Prevention and Control (ECDC). By publishing annual conference reports, the ISW-TBE wants to keep the scientific community informed about current developments in the field (Kunze et al., 2004; Kunze et al., 2005; Kunze and the ISW-TBE, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016). Hence, this year’s conference was titled ‘TBE in a changing world’. The conference agenda was divided into seven sessions over one and a half days: ‘TBE in a changing world’, ‘Virology’, “Epidemiology and Environmental Factors” (including a Poster Walk), ‘Clinical aspects’, ‘New Findings’ and ‘Vaccines & Vaccination’. Selected subjects of the presentations and discussions during the conference are described in this report. 2. Session 1: keynote lecture 2.1. Living in a changing world – which role do vaccinations play? (Presentation by N. Barrett) Vaccines against infectious diseases have been one of the major success stories in medical history. Vaccination has saved millions of lives over the last 50 years. In the need for better vaccines the existing vaccines must be improved, the number of necessary shots reduced and vaccine delivery enhanced (nasal, oral, transdermal). The principles and the rationale of active and passive immunisation can be utilised in a range of non-infectious disease targets. As human life expectancy substantially increases, vaccination can make contributions to healthy aging with respect to oncology, neurodegenerative or metabolic diseases. There is still need for new prophylactic vaccines against a range of significant infectious diseases such as Respiratory syncytial virus, Group A Streptococcus or bacterial diarrheal diseases. Therapeutic vaccines will be an important development in the campaign to treat and cure chronic infectious diseases such as HIV (human immunodeficiency virus) and HBV (hepatitis B virus). Passive immunisation (hyperimmune globulin, monoclonal antibodies) may be an important prophylactic and therapeutic approach for nosocomial infections and selected emerging viral diseases. The development of novel immunological interventions (adjuvants, cell therapies, check-point inhibitors, etc.), in combination with standard therapies, may open the door to a new era of cancer treatment. A multitude of innovative combination therapies are being developed to overcome immune tolerance to tumor-associated antigens
http://dx.doi.org/10.1016/j.ttbdis.2017.08.009 Received 26 July 2017; Received in revised form 21 August 2017; Accepted 21 August 2017 Available online 30 August 2017 1877-959X/ © 2017 Elsevier GmbH. All rights reserved.
Ticks and Tick-borne Diseases 9 (2018) 146–150
and generate synergistic immune response in the form of effector T cells following vaccination; these combinations have the potential to make vaccines a highly potent therapeutic option for a multitude of cancer targets. Financing the availability of even the already existing vaccines will be a continuous major challenge in our rapidly changing developed world and even more in the developing countries. 3. Session 2: virology 3.1. Zika and Chikungunya today! New emerging flavi-and alphaviruses tomorrow? (Presentation by O. Kistner) More than 100 Alphavirus and Flavivirus species have been described over the last hundred years. Out of about 35 alphaviruses at least 10 can be pathogenic for humans, e.g. Chikungunya virus, Eastern/Venezuelan/Western equine encephalitis virus, Mayaro-virus, O’Nyong-Nyong-virus, RossRiver-virus and Sindbis-virus. Among more than 70 described flaiviviruses at least 40 are pathogenic for humans, e.g. tick-borne encephalitis virus (TBEV), Powassan virus, Kyasanur Forest disease virus (Monkey Fever), Murray Valley encephalitis virus, West Nile virus, Usutu virus, Yellow fever virus and Zika virus. Several (re-)emergences of Alphavirus and Flavivirus infections in humans have been reported in the last 20 years. In recent years, a couple of alphaviruses and flaviviruses re-emerged (e.g. Yellow fever virus), conquered new continents (e.g. West Nile virus, Zika virus, Chikungunya virus in the Americas) or increased their pathogenic potential from mild to more severe (e.g. Chikungunya virus, Murray Valley encephalitis virus, Zika virus). Furthermore, well-known alphaviruses and flaviviruses of remote regions appear to have increased their distribution (e.g. Chikungunya virus, Zika virus, Kyasanur Forest disease virus) or their human pathogenicity (e.g. Usutu virus). As a result of these developments, more diligent surveillance of human and animal alphaviruses and flaviviruses, further investigations on certain virological parameters (e.g. mutations) and ecological factors (expansion or change of vectors) and finally the development of new vaccines − including the introduction of robust and reliable production technologies − are crucial. Despite high morbidity and substantial mortalitiy only few vaccines against these viruses have been developed so far, namely TBEV, Japanese encephalitis virus, and Yellow fever virus vaccine. Vaccines under development or for restricted use include Equine encephalitis, Dengue, West Nile, Chikungunya, and Ross River. 4. Session 3: epidemiology & environmental factors 4.1. First human case of tick-borne encephalitis acquired in the Netherlands, July 2016 (Presentation by J.de Graaf and V. Hira) Autochthonous human TBE infection had not been reported in the Netherlands and all TBE cases in the Netherlands so far were considered imported from endemic regions. Shortly after the first report about Dutch TBEV-positive ticks by the Dutch National Institute for Public Health and Environment the first human case of TBE acquired in the Netherlands was detected (de Graaf et al., 2016). Even though the liquor was negative for anti-TBEV IgM antibodies, the high serum IgM and IgG levels in an unvaccinated patient, combined with a typical biphasic clinical course and TBEV detected in the tick collected from the patient (verified by qRT-PCR), confirmed the diagnosis of TBE. This clinical case confirms the repeated occurrence of TBE in so-called TBEV-free regions, consequently there is a clear need of increased awareness among health care workers with respect to surveillance and diagnosis of TBE in such areas. 4.2. Alimentary transmission of TBE in Slovakia (Presentation by R. Madar) As the consumption of unpasteurized milk and dairy products of goat, sheep and cow milk is very popular in Slovakia, outbreaks of alimentary aquired TBE have often occurred. The largest outbreak so far with 660 cases had happened in Rožňava, South-Eastern Slovakia, in 1951. In the past 5 years, 22 outbreaks in various parts of the country caused 148 alimentary cases. Thereby, alimentary cases are responsible for almost 23% of all TBE cases in Slovakia. 5. Session 4: postersession walk & TBE epidemiology overview 5.1. Poster walk: epidemiological update Europe The following countries presented an epidemiological update by a poster presentation: Austria, Czech Republic, Germany, Lithuania, Poland, Slovakia, Switzerland, and Sweden (Table 1). Altogether, with 1900 cases in 2016, a considerable increase was observed in these countries in comparison to 1258 cases in 2015. However, such annual fluctuations are well-known for TBE. The fact that 35 of 348 registered cases in Germany were reported outside of the known TBE risk areas is striking. 6. Session 5: clinical aspects 6.1. TBE MRI results and specific clinical presentation (Presentation by J. Zajkowska) The mechanism of blood-brain barrier (BBB) breakdown during TBE, as well as TBEV entry into the brain, is still unknown. In an in vitro BBB model, the virus crossed the BBB via a transcellular pathway without compromising the integrity of the cell monolayer. These results indicate that human microvascular endothelial cells may support TBEV entry into the brain without altering BBB integrity (Palus et al., 2017). Few autopsy reports of fatal TBE cases demonstrate that the most affected areas in the brain are the cerebral and cerebellar cortex, basal ganglia, thalamus, substantia nigra, pons, medulla oblongata, and the spinal cord (Gelpi et al., 2006). A recent pilot study revealed that glucose hypometabolism was present in 7 out of 10 TBE patients reflecting neuronal dysfunction in predilection areas of TBEV infiltration responsible for development of clinical signs and symptoms (Dietmann et al., 2016). To combine symptoms with lesions in the brain, the provision of a magnetic resonance imaging (MRI) is not obligatory, but it may support the 147
148
Highly endemic country; 500–1000 cases/ yr. 100–200 cases per year, spreading from east to west 50–100 cases/yr; (approx. 16% of the prevacc. era); risk areas spreading to alpine regions in the west
Czech Republic
b
a
121 71
89
348
215
202
565
348
150
Lithuania not mentioned because of lacking data. Robert Koch Institut: FSME: Risikogebiete in Deutschland.Epidemiologisches Bulletin. 17: 149–161, 2017.
Austria
Switzerland
Increase of risk areas within or nearby southern endemic areas
Germany
283
85 (among them 17 alimentary)
173 (among them 79 alimentary)
Highly endemic country; increase in the last 10 years; alimentary transmission as a major risk factor 90% of cases in 2 provinces in the northeast
Slovakia
Poland
269
238
Rising by ≈6% each year during the last 3 decades
Sweden
Clinical cases 2015
Clinical cases 2016
Overall trend
Countrya
Table 1 Epidemiology – Summary of Poster Presentations.
0.4 overall; 13.5 Podlaskie region (2016) 0- < 1.7 (49 risk areas) up to < 5,2 (49) up to 41.7 (48) 5-year Interval 2012−16)b 5.3 overall (2016), Southern Bohemia 16.9, Highland 12, Pilsen region 8.7 2.4 in 2016; up to 5 in high endemic regions 0.45 overall, 5 in the unvaccinated people
2.2 (2014) 1.6 (2015)
3.03 (ECDC) highest incidence in Uppsala with 12 cases in 2016
#
Incidence/year/ 100,000
Southern Styria, Southern Carynthia, Lower Austria, Tyrol
Canton of Thurgau
Southern Bavaria, Southern BadenWürttemberg; Hesse, South-eastern Thuringia Southern Bohemia region
Northeastern provinces
Northern & central regions
Around Stockholm close to the Baltic sea, eastern and middle parts of Lake Mälaren
Highly endemic areas
83 (2016) with at least one shot
23 (2009); 16.1 in the Pilsen region; significant differences in age groups 3–71% in different Cantons (3 doses)
School children 2012-16: 39 high-, 31 other-, 12 non risk areas
?
11 whole pop. (2008); 53 in the Stockholm region, at least one shot (Askling et al.,2015) Very low: 0.01 adults (2016) 0.2 < 15 yrs.
Vaccination coverage (%)
Ticks and Tick-borne Diseases 9 (2018) 146–150
Ticks and Tick-borne Diseases 9 (2018) 146–150
differential diagnosis of TBE specific symptoms. The maximum inflammatory changes correlate with the optimal detectability of the IgM and IgG antibodies in the CSF around the tenth day post infection, which suggests the optimal time of the MRI scan (Gelpi et al., 2005). Literature reveals that the majority of changes is located in deep structures such as thalamus and surroundings. TBEV has a specific affinity to the gray matter including the anterior horn cells. In about 10% of cases of TBE, patients develop myeloradiculitic symptoms with progressive flaccid weakness of limbs and trunk. However, only a small number of papers documents lesions in the spinal cord. In the latest study in the field, including 45 TBE patients with an available MRI of the brain, abnormalities could be identified in four cases (Pichler et al., 2017). The authors concluded that, overall, MRI brain lesions in TBE are rare and do not correlate with the course of the disease. Diffuse areas of signal hyperintensity in the crura cerebri appear suggestive of TBE. 7. Session 6: new findings 7.1. Dermacentor reticulatus: a vector on the rise (Presentation by G. Földvari) Ixodes ricinus and Ixodes persulcatus are the most prominent vectors for the TBEV. However, in recent years another tick has attracked interest by a growing number of scientists, physicians and veterinarians: Dermacentor reticulatus. A review which underlines the great spectrum of possible veterinary and public health threats by D. reticulatus, consolidated current knowledge on the systematics, ecology, geographical distribution and recent spread of the species (Földvári et al., 2016). Although much less frequently than I. ricinus, D. reticulatus adults bite humans and transmit several Rickettsia spp., Omsk haemorrhagic fever virus and TBEV (prevalence of TBEV can be up to 8.5% in questing D. reticulatus). Altogether D. reticulatus can transmit over 40 pathogenic agents (Rubel et al., 2016). It is a hard tick species existing in a broad range of habitat types and with extraordinary biological features such as a rapid developmental cycle or the ability to survive years of unfavourable conditions as an adult. The adult stage has a spring and an autumn activity peak but can also be active in mild winters. This tick has shown a rapid geographical spread in recent years (e.g. in Poland, Germany, Hungary, Slovakia, The Netherlands and Belgium). Some of its biological features are summer diapause in the unfed adult stage, overwintering of adults on the host, survival under water, cold hardiness, large blood meals (nymph and adult female), high reproduction rate, quick immature development, longevity and tolerance to starvation in the adult stage. 8. Session 7: vaccines & vaccination 8.1. Self-reported TBE vaccination coverage in europe: results from a cross-sectional study (Presentation by W. Erber) A household survey conducted in eleven European countries (CZ, GER, LTU, LVA, PL, EST, FIN, HUN, SVK, SVN, SWE; total 25,600 respondents) at the end of 2015 aimed to gain insight into the TBE vaccination status (vaccination coverage and compliance) and identifiy personal factors influencing the vaccination status. Across 10 countries (excluding Poland), awareness of TBE (total 83%, ranging from 41.8% in Germany to 95.2% in Latvia) was lower than awareness of influenza (98%), pneumonia (93%), and measles (92%). Of all respondents, 68% were aware of the TBE vaccine, and 25% had received ≥1 TBE injection. Vaccination rates were lowest in Finland and Slovakia (≈10%) and highest in Latvia (53%). Strongest motivators for vaccination were fear of TBE (38%) and residence/spending time in high-risk areas (31–35%). Strongest barriers for not taking vaccination were the assumption that vaccination is unnecessary (33%) and believing to be not at risk (23%). 9. Conclusion TBE is a good example for the fact that facing the true burden of a disease involves a close look, keen awareness, comprehensive surveillance, and international cooperation to look beyond natural foci and national borders. Increasing problem awareness also outside endemic regions still is one of the major challenges of the ISW-TBE, especially while living in a changing world with all its serious issues. TBE is underestimated both in children and adults in several areas of Europe, where, due to the absence of human cases, TBEV is thought to be non-existent. Finally, it is underestimated in travelers, because they often do not know about the risk, and diagnostic awareness in seemingly non-endemic countries is still low. Preventing TBE is easy, as highly effective vaccines are available. Vaccination is recommended to everyone living in or traveling to TBE endemic areas and getting exposed to ticks there. References Askling, H.H., Insulander, M., Hergens, M.P., Leval, A., 2015. Tick-borne encephalitis (TBE)-vaccination coverage and analysis of variables associated with vaccination, Sweden. Vaccine 33, 4962–4968. de Graaf, J.A., Reimerink, J.H.J., Voorn, G.P., bij de Vaate, E.A., de Vries, A., Rockx, B., Schuitemaker, A., Hira, V., 2016. First human case of tick-borne encephalitis virus infection acquired in the Netherlands, July 2016. Euro. Surveill. 21 (33) (pii=30318). Dietmann, A., Putzer, D., Beer, R., Helbok, R., Pfausler, B., Nordin, A.J., Virgolini, I., Grams, A.E., Schmutzhard, E., 2016. Cerebral glucose hypometabolism in tick-borne encephalitis, a pilot study in 10 patients. Int. J. Infect. Dis. 51, 73–77. Földvári, G., Široký, P., Szekeres, S., Majoros, G., Sprong, H., 2016. Dermacentor reticulatus: a vector on the rise. Parasit. Vectors 9, 314. Gelpi, E., Preusser, M., Garzuly, F., Holzmann, H., Heinz, F.X., Budka, H., 2005. Visualization of Central European tick-borne encephalitis infection in fatal human cases. J. Neuropathol. Exp. Neurol. 64, 506–512. Gelpi, E., Preusser, M., Laggner, U., Garzuly, F., Holzmann, H., Heinz, F.X., Budka, H., 2006. Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue. J. Neurovirol. 12, 322–327. Kunze, U., Asokliene, L., Bektimirov, T., Busse, A., Chmelik, V., Heinz, F.X., Hingst, V., Kadar, F., Kaiser, R., Kimmig, P., Kraigher, A., Krech, T., Linquist, L., Lucenko, I., Rosenfeldt, V., Ruscio, M., Sandell, B., Salzer, H., Strle, F., Süss, J., Zilmer, K., Mutz, I., 2004. Tick-borne encephalitis in Childhood – Consensus. Wien. Med. Wochenschr. 154, 242–245. Kunze, U., ISW-TBE, 2006. Tick-borne encephalitis – a european health challenge. Conference report of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Wien. Med. Wochenschr. 156, 376–378. Kunze, U., ISW-TBE, 2007. Tick-borne encephalitis: from epidemiology to vaccination recommendations in new issues – best practices. Conference report of the 9th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Wien. Med. Wochenschr. 157, 228–232. Kunze, U., ISW-TBE, 2008. Combating tick-borne encephalitis: vaccination rates on the rise. Wien. Med. Wochenschr. 158, 518–521. Kunze, U., ISW-TBE, 2009. TBE: from childhood to golden age: increased mobility–increased risk of contracting tick-borne encephalitis? Wien. Med. Wochenschr. 159, 301–305.
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Ticks and Tick-borne Diseases 9 (2018) 146–150 Kunze, U., ISW-TBE, 2010. TBE awareness and protection: the impact of epidemiology, changing lifestyle and environmental factors. Wien. Med. Wochenschr. 160, 252–255. Kunze, U., ISW-TBE, 2011. Tick-borne encephalitis: new paradigms in a changing vaccination environment. Wien. Med. Wochenschr. 161, 361–364. Kunze, U., ISW-TBE, 2012. Tick-borne encephalitis (TBE): an underestimated risk…. still. Report of the 14th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 3, 197–201. Kunze, U., ISW-TBE, 2013. Tick-borne encephalitis (TBE): TBE – a notifiable disease. report of the 15th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 4, 363–365. Kunze, U., ISW-TBE, 2014. Tick-borne encephalitis – a notifiable disease. review after one year. Report of the 16th annual meeting of the International Scientific Working Group on TickBorne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 456. Kunze, U., ISW-TBE, 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, 545–548. Kunze, U., ISW-TBE, 2016. Tick-borne encephalitis – still on the map. Report of the 18th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISWTBE). Ticks Tick-Borne Dis. 7, 911–914. Kunze, U., Baumhackl, U., Bretschneider, R., Chmelik, V., Grubeck-Loebenstein, B., Haglund, M., Heinz, F.X., Kaiser, R., Kimmig, P., Kunz, C., Kunze, M., Mickiene, A., Misic-Majerus, L., Randolph, S., Rieke, B., Stefanoff, P., Süss, J., Wimmer, R., 2005. The golden agers and tick-borne encephalitis. conference report and position paper of the Conference report and position paper of the International Scientific Working Group on Tick-Borne Encephalitis. Wien. Med. Wochenschr. 155, 289–294. Palus, M., Vancova, M., Sirmarova, J., Elsterova, J., Perner, J., Ruzek, D., 2017. Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood-brain barrier integrity. Virology 507, 110–122. Pichler, A., Sellner, J., Harutyunyan, G., Sonnleitner, A., Klobassa, D.S., Archelos-Garcia, J.J., Rock, H., Gattringer, T., Fazekas, F., 2017. Magnetic resonance imaging and clinical findings in adults with tick-borne encephalitis. J. Neurol. Sci. 375, 266–269. Rubel, F., Brugger, K., Pfeffer, M., Chitimia-Dobler, L., Didyk, Y.M., Leverenz, S., Dautel, H., Kahl, O., 2016. Geographical distribution of Dermacentor marginatus and Dermacentor reticulatus in Europe. Ticks Tick-Borne Dis. 7, 224–233. ⁎
Ursula Kunze , the ISW-TBE1 Institute for Social Medicine, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, A−1090 Vienna, Austria E-mail address: [email protected]
⁎
Corresponding author.
1 Horst Aspöck, Noel Barrett, Dietmar Beier, Livia Borsoi, Katharina Brugger, Lidia Chitimia-Dobler, Hans Dautel, Joris de Graaf, Daniel Desgrandchamps, Gerhard Dobler, Marco Drehmann, Willhelm Erber, Gabor Földvári, Silvius Frimmel, Martin Haditsch, Helena Hervius Askling, Vishal Hira, Marika Hjertqvist, Heidemarie Holzmann, Jukka Hytönen, Anu Jääskeläinen, Ahcan Jerneja, Eva Jilkova, Olaf Kahl, Guntis Karelis, Jana Kerlik, Otfried Kistner, Lenka Krbkova, Thomas Krech, Suvi Kuivanen, Michael Kunze, Michael Leschnik, Alexander Lindau, Ute Mackenstedt, Rasti Madar, Eyal Meltzer, Aukse Mickiene, Tomas Molèányi, Rainer Oehme, Anna Överby, Petr Pazdiora, Martin Pfeffer, Eva Maria Pöllabauer, Daiva Radizsauskiene, Franz Rubel, Maurizio Ruscio, Robert Steffen, Jochen Süss, Alberto Tomasi, Malin Veje, Jana Vogelsang, Melanie Walter, Ursula Wiedermann-Schmidt, Heinz-Josef Schmitt, Joanna Zajkowska, Dace Zavadska, Werner Zenz, Milda Zygutiene.
150
Contents lists available at ScienceDirect
Ticks and Tick-borne Diseases journal homepage: www.elsevier.com/locate/ttbdis
Report of the 19th Annual Meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) – TBE in a changing world
T
A R T I C L E I N F O
A B S T R A C T
Keywords: Tick-borne encephalitis TBE International Scientific Working Group on TickBorne Encephalitis Risk Vaccination Awareness
The 19th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) – a group of neurologists, general practitioners, clinicians, travel physicians, virologists, pediatricians and epidemiologists–was held under the title “TBE in a changing world”. Key topics within virology, current epidemiological developments and investigations, expansion of risk areas, clinical aspects and cases, traveling and mobility, vaccination rates, and latest news on vaccination were presented and extensively discussed. Over the past four decades, TBE has become a growing public health challenge in Europe and parts of Asia. It may be considered a complex eco-epidemiological system, characterized by an intricate interplay between the virus, ticks and tick hosts on the one hand and human exposure strongly influenced by socioeconomic conditions on the other hand. Although the facts are simple – vaccination is the best prevention – the socioeconomic conditions keep changing, and with them the ability or willingness of people to get vaccinated.
1. Introduction It has now been 19 years since the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) kicked off its first official meeting in 1998. Since then, scientists−including neurologists, general practitioners, clinicians, travel physicans, virologists, pediatricians, ecologists and epidemiologists–from more than 30 different European countries have convened annually to exchange the results of up-to-date research, identify obstacles to increasing vaccination rates, and shape feasible strategies to overcome them. In all these years, the main aims of the ISW-TBE have been promoting national and international scientific, medical and regulatory collaboration on TBE, stimulating and co-ordinating applied and basic research, contributing to training and educational programs in the field, providing high-quality information and promoting its appropriate distribution, promoting and aligning international standards on epidemiological surveillance, and defining and promoting proposals to harmonize national and international policies on prevention. Main goals that have been achieved by the ISW-TBE are, among others, an increased awareness of TBE in endemic and non-endemic countries, an increase of vaccination rates in various countries, getting TBE acknowledged and established as a travel-related risk, and building contact with the European Centre for Disease Prevention and Control (ECDC). By publishing annual conference reports, the ISW-TBE wants to keep the scientific community informed about current developments in the field (Kunze et al., 2004; Kunze et al., 2005; Kunze and the ISW-TBE, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016). Hence, this year’s conference was titled ‘TBE in a changing world’. The conference agenda was divided into seven sessions over one and a half days: ‘TBE in a changing world’, ‘Virology’, “Epidemiology and Environmental Factors” (including a Poster Walk), ‘Clinical aspects’, ‘New Findings’ and ‘Vaccines & Vaccination’. Selected subjects of the presentations and discussions during the conference are described in this report. 2. Session 1: keynote lecture 2.1. Living in a changing world – which role do vaccinations play? (Presentation by N. Barrett) Vaccines against infectious diseases have been one of the major success stories in medical history. Vaccination has saved millions of lives over the last 50 years. In the need for better vaccines the existing vaccines must be improved, the number of necessary shots reduced and vaccine delivery enhanced (nasal, oral, transdermal). The principles and the rationale of active and passive immunisation can be utilised in a range of non-infectious disease targets. As human life expectancy substantially increases, vaccination can make contributions to healthy aging with respect to oncology, neurodegenerative or metabolic diseases. There is still need for new prophylactic vaccines against a range of significant infectious diseases such as Respiratory syncytial virus, Group A Streptococcus or bacterial diarrheal diseases. Therapeutic vaccines will be an important development in the campaign to treat and cure chronic infectious diseases such as HIV (human immunodeficiency virus) and HBV (hepatitis B virus). Passive immunisation (hyperimmune globulin, monoclonal antibodies) may be an important prophylactic and therapeutic approach for nosocomial infections and selected emerging viral diseases. The development of novel immunological interventions (adjuvants, cell therapies, check-point inhibitors, etc.), in combination with standard therapies, may open the door to a new era of cancer treatment. A multitude of innovative combination therapies are being developed to overcome immune tolerance to tumor-associated antigens
http://dx.doi.org/10.1016/j.ttbdis.2017.08.009 Received 26 July 2017; Received in revised form 21 August 2017; Accepted 21 August 2017 Available online 30 August 2017 1877-959X/ © 2017 Elsevier GmbH. All rights reserved.
Ticks and Tick-borne Diseases 9 (2018) 146–150
and generate synergistic immune response in the form of effector T cells following vaccination; these combinations have the potential to make vaccines a highly potent therapeutic option for a multitude of cancer targets. Financing the availability of even the already existing vaccines will be a continuous major challenge in our rapidly changing developed world and even more in the developing countries. 3. Session 2: virology 3.1. Zika and Chikungunya today! New emerging flavi-and alphaviruses tomorrow? (Presentation by O. Kistner) More than 100 Alphavirus and Flavivirus species have been described over the last hundred years. Out of about 35 alphaviruses at least 10 can be pathogenic for humans, e.g. Chikungunya virus, Eastern/Venezuelan/Western equine encephalitis virus, Mayaro-virus, O’Nyong-Nyong-virus, RossRiver-virus and Sindbis-virus. Among more than 70 described flaiviviruses at least 40 are pathogenic for humans, e.g. tick-borne encephalitis virus (TBEV), Powassan virus, Kyasanur Forest disease virus (Monkey Fever), Murray Valley encephalitis virus, West Nile virus, Usutu virus, Yellow fever virus and Zika virus. Several (re-)emergences of Alphavirus and Flavivirus infections in humans have been reported in the last 20 years. In recent years, a couple of alphaviruses and flaviviruses re-emerged (e.g. Yellow fever virus), conquered new continents (e.g. West Nile virus, Zika virus, Chikungunya virus in the Americas) or increased their pathogenic potential from mild to more severe (e.g. Chikungunya virus, Murray Valley encephalitis virus, Zika virus). Furthermore, well-known alphaviruses and flaviviruses of remote regions appear to have increased their distribution (e.g. Chikungunya virus, Zika virus, Kyasanur Forest disease virus) or their human pathogenicity (e.g. Usutu virus). As a result of these developments, more diligent surveillance of human and animal alphaviruses and flaviviruses, further investigations on certain virological parameters (e.g. mutations) and ecological factors (expansion or change of vectors) and finally the development of new vaccines − including the introduction of robust and reliable production technologies − are crucial. Despite high morbidity and substantial mortalitiy only few vaccines against these viruses have been developed so far, namely TBEV, Japanese encephalitis virus, and Yellow fever virus vaccine. Vaccines under development or for restricted use include Equine encephalitis, Dengue, West Nile, Chikungunya, and Ross River. 4. Session 3: epidemiology & environmental factors 4.1. First human case of tick-borne encephalitis acquired in the Netherlands, July 2016 (Presentation by J.de Graaf and V. Hira) Autochthonous human TBE infection had not been reported in the Netherlands and all TBE cases in the Netherlands so far were considered imported from endemic regions. Shortly after the first report about Dutch TBEV-positive ticks by the Dutch National Institute for Public Health and Environment the first human case of TBE acquired in the Netherlands was detected (de Graaf et al., 2016). Even though the liquor was negative for anti-TBEV IgM antibodies, the high serum IgM and IgG levels in an unvaccinated patient, combined with a typical biphasic clinical course and TBEV detected in the tick collected from the patient (verified by qRT-PCR), confirmed the diagnosis of TBE. This clinical case confirms the repeated occurrence of TBE in so-called TBEV-free regions, consequently there is a clear need of increased awareness among health care workers with respect to surveillance and diagnosis of TBE in such areas. 4.2. Alimentary transmission of TBE in Slovakia (Presentation by R. Madar) As the consumption of unpasteurized milk and dairy products of goat, sheep and cow milk is very popular in Slovakia, outbreaks of alimentary aquired TBE have often occurred. The largest outbreak so far with 660 cases had happened in Rožňava, South-Eastern Slovakia, in 1951. In the past 5 years, 22 outbreaks in various parts of the country caused 148 alimentary cases. Thereby, alimentary cases are responsible for almost 23% of all TBE cases in Slovakia. 5. Session 4: postersession walk & TBE epidemiology overview 5.1. Poster walk: epidemiological update Europe The following countries presented an epidemiological update by a poster presentation: Austria, Czech Republic, Germany, Lithuania, Poland, Slovakia, Switzerland, and Sweden (Table 1). Altogether, with 1900 cases in 2016, a considerable increase was observed in these countries in comparison to 1258 cases in 2015. However, such annual fluctuations are well-known for TBE. The fact that 35 of 348 registered cases in Germany were reported outside of the known TBE risk areas is striking. 6. Session 5: clinical aspects 6.1. TBE MRI results and specific clinical presentation (Presentation by J. Zajkowska) The mechanism of blood-brain barrier (BBB) breakdown during TBE, as well as TBEV entry into the brain, is still unknown. In an in vitro BBB model, the virus crossed the BBB via a transcellular pathway without compromising the integrity of the cell monolayer. These results indicate that human microvascular endothelial cells may support TBEV entry into the brain without altering BBB integrity (Palus et al., 2017). Few autopsy reports of fatal TBE cases demonstrate that the most affected areas in the brain are the cerebral and cerebellar cortex, basal ganglia, thalamus, substantia nigra, pons, medulla oblongata, and the spinal cord (Gelpi et al., 2006). A recent pilot study revealed that glucose hypometabolism was present in 7 out of 10 TBE patients reflecting neuronal dysfunction in predilection areas of TBEV infiltration responsible for development of clinical signs and symptoms (Dietmann et al., 2016). To combine symptoms with lesions in the brain, the provision of a magnetic resonance imaging (MRI) is not obligatory, but it may support the 147
148
Highly endemic country; 500–1000 cases/ yr. 100–200 cases per year, spreading from east to west 50–100 cases/yr; (approx. 16% of the prevacc. era); risk areas spreading to alpine regions in the west
Czech Republic
b
a
121 71
89
348
215
202
565
348
150
Lithuania not mentioned because of lacking data. Robert Koch Institut: FSME: Risikogebiete in Deutschland.Epidemiologisches Bulletin. 17: 149–161, 2017.
Austria
Switzerland
Increase of risk areas within or nearby southern endemic areas
Germany
283
85 (among them 17 alimentary)
173 (among them 79 alimentary)
Highly endemic country; increase in the last 10 years; alimentary transmission as a major risk factor 90% of cases in 2 provinces in the northeast
Slovakia
Poland
269
238
Rising by ≈6% each year during the last 3 decades
Sweden
Clinical cases 2015
Clinical cases 2016
Overall trend
Countrya
Table 1 Epidemiology – Summary of Poster Presentations.
0.4 overall; 13.5 Podlaskie region (2016) 0- < 1.7 (49 risk areas) up to < 5,2 (49) up to 41.7 (48) 5-year Interval 2012−16)b 5.3 overall (2016), Southern Bohemia 16.9, Highland 12, Pilsen region 8.7 2.4 in 2016; up to 5 in high endemic regions 0.45 overall, 5 in the unvaccinated people
2.2 (2014) 1.6 (2015)
3.03 (ECDC) highest incidence in Uppsala with 12 cases in 2016
#
Incidence/year/ 100,000
Southern Styria, Southern Carynthia, Lower Austria, Tyrol
Canton of Thurgau
Southern Bavaria, Southern BadenWürttemberg; Hesse, South-eastern Thuringia Southern Bohemia region
Northeastern provinces
Northern & central regions
Around Stockholm close to the Baltic sea, eastern and middle parts of Lake Mälaren
Highly endemic areas
83 (2016) with at least one shot
23 (2009); 16.1 in the Pilsen region; significant differences in age groups 3–71% in different Cantons (3 doses)
School children 2012-16: 39 high-, 31 other-, 12 non risk areas
?
11 whole pop. (2008); 53 in the Stockholm region, at least one shot (Askling et al.,2015) Very low: 0.01 adults (2016) 0.2 < 15 yrs.
Vaccination coverage (%)
Ticks and Tick-borne Diseases 9 (2018) 146–150
Ticks and Tick-borne Diseases 9 (2018) 146–150
differential diagnosis of TBE specific symptoms. The maximum inflammatory changes correlate with the optimal detectability of the IgM and IgG antibodies in the CSF around the tenth day post infection, which suggests the optimal time of the MRI scan (Gelpi et al., 2005). Literature reveals that the majority of changes is located in deep structures such as thalamus and surroundings. TBEV has a specific affinity to the gray matter including the anterior horn cells. In about 10% of cases of TBE, patients develop myeloradiculitic symptoms with progressive flaccid weakness of limbs and trunk. However, only a small number of papers documents lesions in the spinal cord. In the latest study in the field, including 45 TBE patients with an available MRI of the brain, abnormalities could be identified in four cases (Pichler et al., 2017). The authors concluded that, overall, MRI brain lesions in TBE are rare and do not correlate with the course of the disease. Diffuse areas of signal hyperintensity in the crura cerebri appear suggestive of TBE. 7. Session 6: new findings 7.1. Dermacentor reticulatus: a vector on the rise (Presentation by G. Földvari) Ixodes ricinus and Ixodes persulcatus are the most prominent vectors for the TBEV. However, in recent years another tick has attracked interest by a growing number of scientists, physicians and veterinarians: Dermacentor reticulatus. A review which underlines the great spectrum of possible veterinary and public health threats by D. reticulatus, consolidated current knowledge on the systematics, ecology, geographical distribution and recent spread of the species (Földvári et al., 2016). Although much less frequently than I. ricinus, D. reticulatus adults bite humans and transmit several Rickettsia spp., Omsk haemorrhagic fever virus and TBEV (prevalence of TBEV can be up to 8.5% in questing D. reticulatus). Altogether D. reticulatus can transmit over 40 pathogenic agents (Rubel et al., 2016). It is a hard tick species existing in a broad range of habitat types and with extraordinary biological features such as a rapid developmental cycle or the ability to survive years of unfavourable conditions as an adult. The adult stage has a spring and an autumn activity peak but can also be active in mild winters. This tick has shown a rapid geographical spread in recent years (e.g. in Poland, Germany, Hungary, Slovakia, The Netherlands and Belgium). Some of its biological features are summer diapause in the unfed adult stage, overwintering of adults on the host, survival under water, cold hardiness, large blood meals (nymph and adult female), high reproduction rate, quick immature development, longevity and tolerance to starvation in the adult stage. 8. Session 7: vaccines & vaccination 8.1. Self-reported TBE vaccination coverage in europe: results from a cross-sectional study (Presentation by W. Erber) A household survey conducted in eleven European countries (CZ, GER, LTU, LVA, PL, EST, FIN, HUN, SVK, SVN, SWE; total 25,600 respondents) at the end of 2015 aimed to gain insight into the TBE vaccination status (vaccination coverage and compliance) and identifiy personal factors influencing the vaccination status. Across 10 countries (excluding Poland), awareness of TBE (total 83%, ranging from 41.8% in Germany to 95.2% in Latvia) was lower than awareness of influenza (98%), pneumonia (93%), and measles (92%). Of all respondents, 68% were aware of the TBE vaccine, and 25% had received ≥1 TBE injection. Vaccination rates were lowest in Finland and Slovakia (≈10%) and highest in Latvia (53%). Strongest motivators for vaccination were fear of TBE (38%) and residence/spending time in high-risk areas (31–35%). Strongest barriers for not taking vaccination were the assumption that vaccination is unnecessary (33%) and believing to be not at risk (23%). 9. Conclusion TBE is a good example for the fact that facing the true burden of a disease involves a close look, keen awareness, comprehensive surveillance, and international cooperation to look beyond natural foci and national borders. Increasing problem awareness also outside endemic regions still is one of the major challenges of the ISW-TBE, especially while living in a changing world with all its serious issues. TBE is underestimated both in children and adults in several areas of Europe, where, due to the absence of human cases, TBEV is thought to be non-existent. Finally, it is underestimated in travelers, because they often do not know about the risk, and diagnostic awareness in seemingly non-endemic countries is still low. Preventing TBE is easy, as highly effective vaccines are available. Vaccination is recommended to everyone living in or traveling to TBE endemic areas and getting exposed to ticks there. References Askling, H.H., Insulander, M., Hergens, M.P., Leval, A., 2015. Tick-borne encephalitis (TBE)-vaccination coverage and analysis of variables associated with vaccination, Sweden. Vaccine 33, 4962–4968. de Graaf, J.A., Reimerink, J.H.J., Voorn, G.P., bij de Vaate, E.A., de Vries, A., Rockx, B., Schuitemaker, A., Hira, V., 2016. First human case of tick-borne encephalitis virus infection acquired in the Netherlands, July 2016. Euro. Surveill. 21 (33) (pii=30318). Dietmann, A., Putzer, D., Beer, R., Helbok, R., Pfausler, B., Nordin, A.J., Virgolini, I., Grams, A.E., Schmutzhard, E., 2016. Cerebral glucose hypometabolism in tick-borne encephalitis, a pilot study in 10 patients. Int. J. Infect. Dis. 51, 73–77. Földvári, G., Široký, P., Szekeres, S., Majoros, G., Sprong, H., 2016. Dermacentor reticulatus: a vector on the rise. Parasit. Vectors 9, 314. Gelpi, E., Preusser, M., Garzuly, F., Holzmann, H., Heinz, F.X., Budka, H., 2005. Visualization of Central European tick-borne encephalitis infection in fatal human cases. J. Neuropathol. Exp. Neurol. 64, 506–512. Gelpi, E., Preusser, M., Laggner, U., Garzuly, F., Holzmann, H., Heinz, F.X., Budka, H., 2006. Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue. J. Neurovirol. 12, 322–327. Kunze, U., Asokliene, L., Bektimirov, T., Busse, A., Chmelik, V., Heinz, F.X., Hingst, V., Kadar, F., Kaiser, R., Kimmig, P., Kraigher, A., Krech, T., Linquist, L., Lucenko, I., Rosenfeldt, V., Ruscio, M., Sandell, B., Salzer, H., Strle, F., Süss, J., Zilmer, K., Mutz, I., 2004. Tick-borne encephalitis in Childhood – Consensus. Wien. Med. Wochenschr. 154, 242–245. Kunze, U., ISW-TBE, 2006. Tick-borne encephalitis – a european health challenge. Conference report of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Wien. Med. Wochenschr. 156, 376–378. Kunze, U., ISW-TBE, 2007. Tick-borne encephalitis: from epidemiology to vaccination recommendations in new issues – best practices. Conference report of the 9th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Wien. Med. Wochenschr. 157, 228–232. Kunze, U., ISW-TBE, 2008. Combating tick-borne encephalitis: vaccination rates on the rise. Wien. Med. Wochenschr. 158, 518–521. Kunze, U., ISW-TBE, 2009. TBE: from childhood to golden age: increased mobility–increased risk of contracting tick-borne encephalitis? Wien. Med. Wochenschr. 159, 301–305.
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Ticks and Tick-borne Diseases 9 (2018) 146–150 Kunze, U., ISW-TBE, 2010. TBE awareness and protection: the impact of epidemiology, changing lifestyle and environmental factors. Wien. Med. Wochenschr. 160, 252–255. Kunze, U., ISW-TBE, 2011. Tick-borne encephalitis: new paradigms in a changing vaccination environment. Wien. Med. Wochenschr. 161, 361–364. Kunze, U., ISW-TBE, 2012. Tick-borne encephalitis (TBE): an underestimated risk…. still. Report of the 14th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 3, 197–201. Kunze, U., ISW-TBE, 2013. Tick-borne encephalitis (TBE): TBE – a notifiable disease. report of the 15th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 4, 363–365. Kunze, U., ISW-TBE, 2014. Tick-borne encephalitis – a notifiable disease. review after one year. Report of the 16th annual meeting of the International Scientific Working Group on TickBorne Encephalitis (ISW-TBE). Ticks Tick-Borne Dis. 456. Kunze, U., ISW-TBE, 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, 545–548. Kunze, U., ISW-TBE, 2016. Tick-borne encephalitis – still on the map. Report of the 18th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISWTBE). Ticks Tick-Borne Dis. 7, 911–914. Kunze, U., Baumhackl, U., Bretschneider, R., Chmelik, V., Grubeck-Loebenstein, B., Haglund, M., Heinz, F.X., Kaiser, R., Kimmig, P., Kunz, C., Kunze, M., Mickiene, A., Misic-Majerus, L., Randolph, S., Rieke, B., Stefanoff, P., Süss, J., Wimmer, R., 2005. The golden agers and tick-borne encephalitis. conference report and position paper of the Conference report and position paper of the International Scientific Working Group on Tick-Borne Encephalitis. Wien. Med. Wochenschr. 155, 289–294. Palus, M., Vancova, M., Sirmarova, J., Elsterova, J., Perner, J., Ruzek, D., 2017. Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood-brain barrier integrity. Virology 507, 110–122. Pichler, A., Sellner, J., Harutyunyan, G., Sonnleitner, A., Klobassa, D.S., Archelos-Garcia, J.J., Rock, H., Gattringer, T., Fazekas, F., 2017. Magnetic resonance imaging and clinical findings in adults with tick-borne encephalitis. J. Neurol. Sci. 375, 266–269. Rubel, F., Brugger, K., Pfeffer, M., Chitimia-Dobler, L., Didyk, Y.M., Leverenz, S., Dautel, H., Kahl, O., 2016. Geographical distribution of Dermacentor marginatus and Dermacentor reticulatus in Europe. Ticks Tick-Borne Dis. 7, 224–233. ⁎
Ursula Kunze , the ISW-TBE1 Institute for Social Medicine, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, A−1090 Vienna, Austria E-mail address: [email protected]
⁎
Corresponding author.
1 Horst Aspöck, Noel Barrett, Dietmar Beier, Livia Borsoi, Katharina Brugger, Lidia Chitimia-Dobler, Hans Dautel, Joris de Graaf, Daniel Desgrandchamps, Gerhard Dobler, Marco Drehmann, Willhelm Erber, Gabor Földvári, Silvius Frimmel, Martin Haditsch, Helena Hervius Askling, Vishal Hira, Marika Hjertqvist, Heidemarie Holzmann, Jukka Hytönen, Anu Jääskeläinen, Ahcan Jerneja, Eva Jilkova, Olaf Kahl, Guntis Karelis, Jana Kerlik, Otfried Kistner, Lenka Krbkova, Thomas Krech, Suvi Kuivanen, Michael Kunze, Michael Leschnik, Alexander Lindau, Ute Mackenstedt, Rasti Madar, Eyal Meltzer, Aukse Mickiene, Tomas Molèányi, Rainer Oehme, Anna Överby, Petr Pazdiora, Martin Pfeffer, Eva Maria Pöllabauer, Daiva Radizsauskiene, Franz Rubel, Maurizio Ruscio, Robert Steffen, Jochen Süss, Alberto Tomasi, Malin Veje, Jana Vogelsang, Melanie Walter, Ursula Wiedermann-Schmidt, Heinz-Josef Schmitt, Joanna Zajkowska, Dace Zavadska, Werner Zenz, Milda Zygutiene.
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