Tick-Borne Encephalitis (TBE): A Risk Still Underestimated

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1 Issue Number: 6 Tick-Borne Encephalitis (TBE): A Risk Still Underestimated 14 th Annual Meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW- TBE); 2 3 February, Vienna, Austria It has now been 14 years since the ISW-TBE kicked off its first official meeting in Since then, no fewer than 760 expert scientists and practitioners have convened to exchange late-breaking research and shape feasible strategies to raise awareness of tick-borne encephalitis (TBE). Today, 14 meetings later, the risk of TBE is still underestimated in many parts of Europe, and indeed the world. Does this mean that we have been unsuccessful in fulfilling our mission? Not at all. We look back on years of refining our knowledge of the disease, its epidemiology, and the variables determining TBE vaccination uptake. Sometimes, however, seeing the true burden of an illness requires a keen awareness of the disease, tight surveillance, and international cooperation to look beyond natural foci and national borders. TBE is one such disease. Because the symptoms it displays at initial presentation are often unspecific, TBE will not be diagnosed unless specifically tested for in the laboratory. We cannot eliminate all of nature s inherent risks. A tick bite and the TBE virus it may transmit is one such risk. Yet, some risks are preventable. With a highly effective vaccine available for more than 30 years, TBE is one such risk. TBE is preventable. Let s prevent it. Immunization offers the most effective protection against tick-borne encephalitis. WHO Position Paper on Vaccines Against Tick-Borne Encephalitis, Professor Dr Michael Kunze Chairman of the ISW-TBE, Institute for Social Medicine, Medical University of Vienna

2 TBE virus: A Member of the Flaviviridae Family TBE: An Underestimated Risk in Children In his keynote address, Professor Franz Xaver Heinz from the Department of Virology, Medical University of Vienna, covered the spectrum from known to novel facts about a pathogen causing one of the most harmful central nervous system infections the TBE virus (TBEV). Together with Dengue or West Nile virus, TBEV belongs to the genus flavivirus of the flaviviridae family. The mature TBE virion is composed of 3 structural proteins, with E protein being the major viral antigen inducing neutralizing antibodies and a protective immune response. The identity of amino acids in the E protein between different flaviviruses is at least 40%, that between the 3 TBEV subtypes (i.e., European, Siberian, and Far Eastern) is approximately 95% (Figure 1). This similarity between flaviviruses has a number of clinically relevant consequences in terms of both crossreactivity and cross-protection. Figure 1: Relationship between flaviviruses based on amino acid sequence similarities of the E protein Image courtesy of Professor FX Heinz Cross-reactivity between flaviviruses: a diagnostic pitfall In the course of a TBEV infection, hospitalization generally does not take place until the beginning of the second phase of the disease, i.e., at a time when neurological symptoms first manifest and levels of anti-tbev IgM and IgG antibodies rise rapidly. 2 This, then, is also the time a diagnosis is first established, ideally through the demonstration of IgM and IgG antibodies using enzyme-linked immunoassay (ELISA). Because of the close antigenic relationship between TBEV and other flaviviruses, cross-reactive antibodies are induced by vaccinations or infections. This may pose a diagnostic challenge in people vaccinated against yellow fever or Japanese encephalitis and in travelers having acquired Dengue, West Nile, or other flavivirus infections. Professor Heinz and colleagues recently set out to characterize the level of cross-reactivity between different flaviviruses not only for IgG but also for IgM antibodies, i.e., the antibody isotype that is truly diagnostic because it marks a new infection. 3 The results of their study 3 show that ELISA testing for IgM is much more TBE-specific than IgG and that most of the potential problems of TBE serodiagnosis can be resolved by quantification of IgM antibodies in a single serum sample taken upon hospitalization. Cross-neutralization between TBEV subtypes confirmed The 3 TBEV subtypes have a similarity of about 95%. Cross-neutralization between the European, Siberian, and Far Eastern TBEV isolates has been known to occur, 4-7 but it was difficult to quantify. Orlinger et al. recently developed a hybrid virus model with viruses encoding the structural proteins from different TBEV isolates, while using a West Nile virus backbone. 8 They then tested clinical samples from individuals previously immunized with a complete 3-dose primary course of FSME-IMMUN against all of these TBEV hybrids to quantify their virus-neutralizing capacity. The study found similar neutralization titers against all TBEV hybrid viruses. 8 Meanwhile, Fritz et al. have confirmed these results in animal studies. 9 Together, these studies demonstrate that FSME-IMMUN, a TBEV vaccine based on the European subtype strain Neudörfl, induces equally potent protection against TBEV strains of the European, Far Eastern, and Siberian subtypes. Dr Mikael Sundin from the Division of Pediatrics of Karolinska Institutet and Astrid Lindgren Children s Hospital of Karolinska University Hospital, Sweden, opened his presentation by recalling what had originally spurred his interest in TBE: Many literature reports claim that TBE in childhood is a comparatively mild condition. Then came 2-year-old Nils, an otherwise healthy boy who presented with a 2-day history of fever (38.5 C) which quickly developed into a serious illness that ultimately turned out to be TBE. Recent findings from Sweden indicate that the incidence of TBE in children may be higher than previously thought. With symptoms mainly unspecific, TBE is unlikely to be found unless specifically sought. Accurate diagnoses are a precondition for assessing the long-term effects of TBE in the very young. In a recent retrospective Swedish study, 10 39/699 serologies from children <16 years of age (5.5%) were IgM-positive, consistent with a diagnosis of TBE. About 25% of children negative for anti-tbe IgM but positive for IgG had not previously had a flavivirus infection or been vaccinated, suggesting a subclinical TBEV infection. These results demonstrate that TBE is likely to be missed in a sizeable proportion of children. Although the symptoms in children were found to be diffuse, they did differ from children with diagnoses other than TBE (Figure 2). Figure 2: Symptoms in children with TBE and diagnoses other than TBE (adapted from Hansson ) In a subsequent prospective study, children <18 years seeking medical attention for neurologic complaints from the highly tick-endemic southwestern region of Stockholm County were offered anti- TBEV and anti-borrelia serologies. Inflammation parameters in blood and cerebrospinal fluid were also analyzed. 31/124 children (25%) had a tick-borne CNS infection, with TBE seen in 10 children (8%) and neuroborreliosis (NB) in 21 children (16.8%). As in the retrospective study (Figure 2),10 most children presented with nonspecific signs. The biphasic course, considered a typical feature of TBE, was relatively rare (20%). Serology was diagnostic, but lumbar puncture and routine clinical chemistry did not contribute to the diagnosis of TBE. With the southwestern region of Stockholm County covering about 100,000 children, the study result corresponds with a TBE incidence rate of about 10 per 100,000 a figure well above the incidence rate reported for Stockholm (3.71 per 100, ). Both studies indicate that TBE in children is often missed due to its unspecific clinical presentation. Therefore, in children having spent time in a TBE-endemic area and presenting with unspecific neurologic symptoms, anti- TBEV serology should be performed more frequently. 2 3

3 International Scientific Epidemiology today: Documenting human TBE cases: Not enough for a complete risk assessment TBE in Europe and Russia A bird s eye view on the epidemiological development of TBE over the past two decades was presented by Professor Jochen Süss from the National Reference Laboratory for Tick-Borne Diseases, Friedrich Loeffler Institute, Jena, Germany. Thus, in the 20 years from , no fewer than 169,292 cases of TBE were reported in Europe and Russia, 58,451 (35%) of these in Europe alone. The incidence rates of TBE per 100,000 population from 2001 to 2010 and the vaccination rates in selected European countries are illustrated in Figure 3. The less predictable the risk of TBE for the individual, the more important to guard against it. Yet, vaccination rates in many endemic countries or among travelers to endemic areas are still low (Figure 3), in part because the risk is underestimated. Figure 4: Number of TBE cases in selected European countries (A), Europe as a whole and Russia (B), , and comparison between the two decades vs Traditionally, the definition of TBE risk areas has relied on documenting the occurrence of autochthonous TBE cases in humans or animals. However, considering that some 70% of TBE infections are clinically inapparent, TBE case numbers are a rather weak surrogate marker. A In the district of Suhl (Figure 5), 3 autochthonous clinical human TBE cases had previously been reported, i.e., in 2003, 2006, and According to the definition of a TBE-endemic area by the Robert Koch-Institut (RKI),* Suhl is not a risk area for TBE. However, of 22 goat sera tested in 2009, 4.5% were anti-tbev antibody positive using NT. Although TBEV was not found among the 43 ticks tested, the potential exists for alimentary transmission of TBE to occur. Figure 5: Map of Germany with TBE risk areas as defined by Robert Koch-Institut* A high vaccination rate, too, may mask the true risk of TBE. For example, Austria is among the countries with the highest risk of TBE,13 even though the incidence rate per 100,000 of 0.88 (Figure 3) may suggest otherwise. This seeming yet favorable contradiction has been the result of a mass vaccination campaign initiated in 1981 and a vaccination rate that has meanwhile increased to 86% (2009). The incidence of TBE has fluctuated greatly (Figure 4A), confirming a statement that had earlier been made by Professor Franz Xaver Heinz, namely that annual incidences of TBE vary up to 3-fold over time. Whereas a decrease in case numbers to 64.9% was seen in the Baltic states between and , the Czech Republic, Germany, Poland, and Switzerland witnessed an increase to 144% (Figure 4A), and Scandinavia saw an increase to 200.6%, mainly due to the steep rise in Sweden. B Despite the wide variations seen from year to year and between countries, case numbers throughout Europe remained fairly constant between and (Figure 4B). By contrast, TBE case numbers in Russia decreased to 58.4% (Figure 4B) a development defying ready interpretation. Therefore, to more realistically capture the TBE risk situation, TBE case statistics need to be complemented by both direct methods of risk assessment, such as virus isolation and characterization using PCR technologies in ticks and vector animals, and indirect methods, such as screening for antitbev antibodies in both humans and nonmigratory sentinel animals, mainly goat, sheep, small mammals, or dogs. Saxony: testing of dog sera Suhl, Thuringia: testing of goat sera Research is indeed busy continuing to fill the white spots on the TBE map an ongoing exploration not without surprises. The marked fluctuations in TBE case numbers seen between tick seasons and endemic areas illustrate the complexity of tick-borne diseases as a system depending on a close interplay between varied biological and human factors. As a result, the risk of TBE for an individual in any given tick season is unpredictable, emphasizing the importance of preventive vaccination. Thuringia, Germany: Not a defined TBE risk area, yet seroprevalences in goats as high as 25% Figure 3: Incidence rates of TBE per 100,000 population ( ) and vaccination rates* in selected European countries Between 1991 and 2010, 4661 TBE cases were reported in Germany, 85.9% of which occurred in Bavaria and Baden-Wuerttemberg, 6.6% in Hesse, and 1.4% in Thuringia. According to Professor Süss, about 5% of these cases acquired their infection in what is actually defined as a non-risk area. A good reason to look beyond the surrogate. In 2009, Klaus et al. tested 828 goat sera in a number of foci in Thuringia. Of the 7 Thuringian administrative districts considered risk areas for TBE, a positive seroprevalence of 3.2% was found in only one. By contrast, of the 13 non-risk districts, 5 districts had *Vaccination rates shown are from the year 2007 in Switzerland, 2008 in Estonia, Germany, Latvia, Lithuania, and Sweden, and 2009 in Austria, the Czech Republic, and Slovenia (source: GfK) 4 seroprevalences ranging from 2.3% in Weimarer Land and 4.5% in Suhl to 25% in Gotha.14 Orange: TBE risk areas according to Robert Koch-Institut (RKI)* Yellow: districts with single autochthonous TBE cases Map courtesy of Like master, like dog: Seroprevalence study in dogs to shed light on TBE risk in Saxony With hardly any friendship running as long as that between man and dog, it seems only logical that dogs should be used as sentinel animals for TBE surveillance. Professor Martin Pfeffer from the Center of Veterinary Public Health, University of Leipzig, Germany, is setting out to determine the seroprevalence against TBEV in dogs in the German state of Saxony (Figure 5). * An administrative district is defined as a TBE risk area if the number of TBE cases reported in the administrative district OR in the district region (defined as the administrative district in questions plus all adjacent administrative districts) in the periods , , , , or is significantly (p<0.05) higher than the case number corresponding to an incidence rate of 1 per 100,000 population (Epidemiologisches Bulletin 2011;17:134). 5

4 International Scientific Moving low to the ground and at a perfect height for ticks to attach, dogs are thought to be times more likely to come into contact with pathogen-infected ticks.15 Just like humans, dogs mainly host nymphal and adult ticks (Figure 6). Seroprevalence studies have shown that dogs are highly susceptible to TBEV infection. Clinical manifestations seem to be rare but are severe and often fatal if they do occur,15 ranging from fever or altered consciousness and behavior to facial paresis, nystagmus, and dysphagia due to thalamic, cerebrocortical, and brainstem involvement.16 Figure 6: Schematic representation of the role of dogs in the ixodid life cycle First serologic evidence of TBE in Romania First serologic evidence of TBE in central and southern Italy In Romania, a risk for TBE has been reported for Transsylvania, but there have otherwise only been unconfirmed reports on clinical cases of TBE in Romania.19 In April and May 2011, Dr Olaf Kahl from tick-radar GmbH, Berlin, Germany, together with his colleagues Dr Lidia Chitimia and Doru Hristescu from Romania and Professor Jochen Süss from Germany, undertook two field trips to the Romanian counties of Sibiu and Muresş to flag for questing ticks, collect feeding ticks from goats, and take sheep and goat serum samples. The vegetation in both counties provides a very good tick habitat made up of meadows and forests with permanent and dense leaf litter. In Italy, TBE has mainly focused in the northeastern regions of Trentino-Alto Adige, Friuli-Venezia Giulia, and Veneto, where a total of 198 confirmed clinical cases were recorded between 1992 and In the same period, the incidence of TBE in these regions increased from 0.06 to 0.88 cases per 100,000 inhabitants.20 Since the 1990s, a series of serosurveillance studies have been performed in dogs, most recently in Denmark and Belgium. The Danish study analyzed sera from 125 dogs collected in 5 different regions, including the known TBE focus Bornholm, and found a prevalence of anti-tbev antibodies of 30% using ELISA and 4.8% using NT.17 In Belgium, a country not endemic for TBE, 1 of 880 dog sera tested was TBEV-seropositive;18 it was unclear where the TBEV infection had been acquired. Sibiu Total area flagged: 6260 m2 Yield: 1074 nymphs and 218 adult ticks Map: public domain With dogs usually en route together with their owners, seropositive dogs indicate that their human companions, too, were exposed to the risk of acquiring TBE. Saxony is among the German countries not considered endemic for TBE, with only single autochthonous cases reported so far. Yet, as in Thuringia, animal sera may tell a different tale. Wherever the TBE virus is proven to exist, both animals and humans are at risk of contracting TBE. 6 Red: currently known endemic areas, i.e., Trentino-Alto Adige, Friuli-Venezia Giulia, and Veneto Blue: Areas included in the human seroprevalence study Map: jpeg, public domain Image courtesy of Professor M Pfeffer All of the 2345 unfed Ixodes ricinus ticks were TBEV-negative on PCR. However, all sera collected from 10 goats in Sibiu were anti-tbev antibody positive in both ELISA and NT. Sera collected from 10 sheep in Mures county were positive in ELISA but negative in NT. These preliminary results provide first clear evidence of the occurrence of TBEV in Romania, warranting further studies on sentinel host sera and ticks in Sibiu and other Romanian countries. In Alsace, the French region located on the eastern border of France adjacent to Germany s RhinelandPalatinate, highly endemic Baden-Württemberg, and Switzerland, the first case of TBE was reported in In 1993, another 8 Alsatian cases, observed between 1985 and 1990, were reported. The development of TBE virus infection in France is almost synonymous with the development of TBE in Alsace. Two seroprevalence studies have indicated that TBE in eastern France may frequently go unrecognized. One survey conducted in 1989 among professional foresters in eastern France found that 8% were seropositive.22 In a 2008 study, the observed seroprevalence of anti-tbev antibodies among almost 3000 individuals was 3.4%, with the seroprevalence significantly higher in Alsace (5.5%; p<0.001).23 Photo courtesy of Dr Olaf Kahl Muresş Total area flagged: 4500 m2 Yield: 862 nymphs and 191 adult ticks Alsace TBE s French connection So far, TBEV has been isolated and identified only in regions where human cases have been reported.21 Therefore, the group of Professor Emanuele Montomoli from the Laboratory of Molecular Epidemiology, University of Siena, initiated a multicenter study to determine the prevalence of anti-tbev antibodies in children from 12 months of age, adults, and elderly individuals from across Italy. In 2010 and 2011, more than 7000 samples were collected. Although data analysis is still in progress, preliminary results obtained for south and central Italy have already yielded surprising results, with 1% 2% of samples testing positive in ELISA (confirmation using NT to exclude cross-reactivity still pending). The TBEV epidemiology in Tuscany, central Italy, and perhaps even in the south of the country, may well be similar to that seen in northeast Italy, which is today considered the most significant area of concern in terms of TBEV. Between 1968 and 1996, TBE cases in Alsace were analyzed retrospectively, explained Dr Yves Hansmann from the Infectious Disease Unit, Université Louis Pasteur in Strasbourg.24 Since 1996, cases have been recorded prospectively, with 3 of the 4 main hospitals in Alsace sending serum samples to the institute s lab. Samples positive for anti-tbev IgM antibodies are retained, and the treating physicians are asked to provide clinical, epidemiological, and biological data on the patient. Figure 7: Map of Alsace, including number of TBE cases and hospitals transferring sera to Université Louis Pasteur, Strasbourg ( ) n=99 Map courtesy of Dr Yves Hansmann Most cases of TBE have been contracted in two specific foci, i.e., in Neuhof forest south of Strasbourg, a popular leisure time destination for city dwellers, and in Guebwiller valley. Single cases have occurred across Alsace (Figure 7). Specific immunodiagnosis of TBE is not systematically requested in patients with meningitis or meningoencephalitis, not all Alsatian hospitals refer their samples to Université Louis Pasteur, and only cases requiring hospitalization are identified. Therefore, the case number presented is likely to underestimate the true burden of TBE in Alsace. 7

5 ISW-TBE and international organizations While Professor Hubert Hrabcik from the Permanent Mission of Austria to the United Nations in Switzerland, in his function as chair of the ECDC Management Board, gave an overview of the TBE program of the European Centre for Disease Prevention and Control (ECDC), Professor Herwig Kollaritsch from the Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna presented the outcome of a project having resulted from the cooperation between ISW-TBE and the World Health Organization (WHO) that he supported as an expert advisor, i.e., the first WHO Position Paper on Vaccines Against Tick-Borne Encephalitis published in In its report, WHO echoes many of the calls of ISW- TBE, such as inclusion of vaccination against TBE into regional or national immunization programs in highly endemic areas. Also, WHO encourages studies into the effectiveness of TBE priming vaccinations in elderly individuals, On the move: TBE in travelers Europeans not only make up the majority of international travelers (496.1 million in 2010, 52.8%), Europe is also the world s most important travel destination (476.6 million in 2010, 50.7%, Figure 8). 25 In 2011, international tourist arrivals grew by more than 4% to 980 million, with the biggest growth by region seen in Europe (+6%). 26 Figure 8: World Inbound Tourism: International Tourist Arrivals, 2001 (million) 26 offering vaccination to travelers from nonendemic to endemic areas, research into the need for and timing of booster vaccinations by age group, and standardization of clinical case definitions, reporting requirements, follow-up processes to identify long-term sequelae of TBE, and reagents to allow comparison of test results across laboratories. In endemic areas, information on the disease, its vectors, and its pathways of transmission should be readily available, e.g., in schools, doctor s offices, and tourist information material. By including TBE on their agenda, both organizations recognize that TBE, although endemic in specific areas across Europe, is an international challenge. At the same time, no fewer than 76.7% of tourists stay in their own region, and most trips take place in the summer months. 25 With Europe being by far the most popular travel destination and most trips taken during the summer, the number of TBE cases exported from endemic regions throughout Europe must be considerable. For example, based on the number of tourist overnight stays in Austria, it has been estimated that some 60 travel-associated cases of TBE may occur every summer. 27 So far, however, only single cases of travelrelated cases of TBE have been reported. 2011: Two Dutch travelers to Austria and Germany contract TBE Drs Natalie Cleton from the National Institute for Public Health and the Environment, Centre for Infectious Disease Control, and Erasmus Medical Center, Rotterdam, presented 2 cases of TBE in Dutch travelers to Austria and Germany in Between , 1.9 million Dutch nationals traveled to Austria, 4.6 million to Germany, and 830,000 to the Czech Republic. Every summer, 470,000 Dutch travellers take a trip to Austria, with around 6.4 million overnight stays. Considering that the likelihood for an unvaccinated traveler to acquire TBE in a highly endemic region has been estimated at 1:10,000, 28 an annual 20 TBE cases would be expected to be imported to the Netherlands from Austria alone. With only 2 cases of TBE from all destinations recorded in 2011, it is reasonable to suspect that TBE in Dutch travelers is underdiagnosed. Promoting healthy travel to TBE risk areas Because awareness of TBE at both the sending and the receiving ends of the travel continuum is low, DDr Martin Haditsch from TravelMedCenter Leonding and Hannover MVZ Laboratory GmbH led a TBE Travel Advisory Board (TBE-TAB) meeting to lay the groundwork for placing TBE travel medicine initiatives into a strategic planning context. With travel medicine experts mostly lacking specific know-how of TBE, the aim of the initiative is to bridge the gap between TBE experts on the one hand and travel medicine experts on the other, ultimately with a view to improving risk communication to travelers. What advice do governments, international, and regional organizations give to travelers? For the purpose of a systematic review of travel streams, the three forms of tourism defined by the United Nations come in handy. Inbound tourism. Although know-how of TBE in endemic areas is generally high, many touristreceiving countries, even those that are highly endemic for TBE, fail to give any advice at all to travelers. Outbound tourism. Awareness of TBE and TBE vaccination in non-endemic countries is generally low a fact also reflected in recommendations to tourists traveling to endemic countries. While most tourist-sending countries fail to inform their globe-trotting citizens, some recommend that TBE vaccination be offered to at-risk travelers only and yet others, such as the US Centers for Disease Control and Prevention (CDC), maintain that, because routine primary vaccination requires more than 6 months to complete, travelers may find avoiding ticks bites more practical than vaccination 29 advice that is not backed up by either scientific evidence or practicability. In 2010, for example, 715,000 United Kingdom nationals took a trip to Switzerland, 533,000 to Austria, and 218,000 to Sweden. In the visiting friends and relatives (VFRs) category, 1 million UK residents traveled to Poland in 2009, up from 139,000 in Many thousands of UK residents, therefore, may have been at risk of contracting TBE without even knowing. Domestic tourism. People traveling from nonendemic to endemic areas within a particular country are also at risk of contracting TBE and should be adequately informed a mostly neglected aspect. According to the World Tourist Organization of the United Nations (UNWTO), international travel will continue to increase, with arrivals expected to rise by 3% 4% in. In short, improving TBE risk communication will be on the agenda of TBE and travel medicine experts for some time to come. 8 9

6 Briefly noted Concluding Remark Lethal TBE: Predictors of Poor Prognosis In Poland, TBE occurs endemically, with cases reported every year, 90% of which from the northeastern provinces neighboring the Baltic states. Among occupationally exposed inhabitants of endemic eastern regions, the seroprevalence has been found to range from 25% 81%. Most severe cases are treated at Professor Joanna Zajkowska s Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Poland. Between , Professor Zajkowska and her team analyzed records of 890 TBE patients, 349 of whom (39%) suffered meningoencephalitis and 62 (7%) meningoencephalomyelitis. Nine patients (1%) of the series died as consequence of TBE. In an analysis of 5 cases with complete data, age, severity of disease at presentation, and a monophasic disease course emerged as predictors of poor prognosis. Additional risk factors were co- or superinfections as well as immunosuppression. Anti-TBEV IgM antibody levels obtained on admission were only weakly positive and therefore not clearly indicative of TBE. To shed further light on the predictors of poor prognosis in TBE, establishment of a multicenter registry of fatal TBE cases appears warranted. Czech Republic Five Key Factors to Increase TBE Vaccination Uptake In the Czech Republic, a vaccination rate of only 16% (2009) is pitted against a high TBE incidence rate of 6.19 per 100,000 ( ). According to Associate Professor Dr Rasti Madar, there are five key factors to increase TBE vaccination uptake and, hence, protection of the population against TBE. The first issue raised was related to the affordability of vaccination relative to household income, which may prohibit certain populations (such as elderly on retirement, the unemployed, etc.) from protecting themselves and their families against TBE. In an effort to increase the TBE vaccination rate, the Avenier group of 23 vaccination centers represented across the Czech Republic offered a 30% discount on the first TBE vaccine dose in This measure alone led to an increase in vaccinations by no less than 248% between February and March Similar observations were made for human papillomavirus vaccination (increase of 192% between February and March 2010). Thus, a discount on the first vaccination dose or partial reimbursement by health insurance companies could help increase the number of people protected against TBE. Other important measures to increase the TBE-protected population were to continue using reminder systems to help people remember when their next dose is due involve the entire family increase the knowledge of general practitioners of TBE, its epidemiology and consequences cooperate with the mass media to raise awareness of the disease. How little it takes to change a life Photo: Magnus Wennman Svante Lidén In 2008, Svante Lidén, widely traveled journalist of the renowned Swedish daily Aftonbladdet, contracted TBE. I d written thousands of articles, shaken hands with the likes of Nelson Mandela, Benazir Bhutto, Roger Moore, or Frank Zappa. So it went on. Year after exciting year. Until the beautiful summer of 2008, when a tick decided to have an unannounced meeting with me the most important and overwhelming encounter of my life. I became another person back in August A person I don t recognize. A person I can t get rid of but who leaves me no choice. A person I m still desperately trying to get to know. Today, I am slowly, slowly coming back from the gray darkness. There are even a few days when the sky seems clear. Is TBE still an underestimated risk? It seems to be in children, in whom TBE symptoms are often unspecific and unlikely to be correctly diagnosed unless anti-tbev serology is routinely performed in those with a relevant exposure history. It seems to be underestimated in adults, in whom the consequences of a TBEV infection tend to be more severe than in younger patients, at times even taking a lethal course. It seems to be an underestimated risk in many areas of Europe, where, for a lack of human cases, TBEV is thought to be absent but seroprevalences in animals suggest otherwise. It seems to be underestimated in travelers returning from endemic regions, perhaps because diagnostic awareness in non-endemic countries is still low. Another year of hard work lies ahead of us. Meanwhile, we take comfort in knowing that TBE is vaccine-preventable and the ISW group will continue in its efforts to raise TBE awareness and enhance our scientific understanding of TBE. Sincerely yours, Professor Michael Kunze I wish to thank my co-chairman Prof Hubert Hrabcik, as well as the speakers at this years meeting: Drs Natalie Cleton, DDr Martin Haditsch, Prof Yves Hansmann, Prof Franz Xaver Heinz, Dr Anu Jääskeläinen, Dr Olaf Kahl, Prof Herwig Kollaritsch, Prof Ursula Kunze, Svante Lidén, Dr Alexandra Löw-Baselli, Ass Prof Rastislav Madar, Prof Emanuele Montomoli, Prof Martin Pfeffer, Dr Michael Sundin, Prof Jochen Süss, and Dr Joanna Zajkowska. My thanks also go to the authors and presenters at this year s epidemiology poster session: Austria: FX Heinz Baltic countries (Lithuania, Latvia, Estonia): A Mickiene, et al. Czech Republic: E Jilkova Finland: A Jääskeläinen, et el. Germany: U Mackenstedt Hungary: Z Jelenik, et al. Poland: JM Zajkowska and M Kondrusik Russia: IY Izvekova and VV Provorova Slovakia: M Avdičovà, et al. Sweden: M Hjertqvist Switzerland: T Krech. Finally, I thank the participants in the TBE Travel Advisory Board meeting: Professor Eric Caumes (France), Sandra Grieve (United Kingdom), Professor Martin Grobusch (the Netherlands), DDr Martin Haditsch (chairman, Austria), Professor Tomas Jelinek (Germany), Professor Michael Kunze (Austria), and Professor Robert Steffen (Switzerland)

7 References 1. WHO. Weekly Epidemiological Record (WER) of the World Health Organization (WHO), available from: who.int/wer/en/. 2. Holzmann H. Diagnosis of tick-borne encephalitis. Vaccine 2003;21 Suppl 1: Stiasny K, Aberle JH, Chmelik V, Karrer U, Holzmann H, Heinz FX. Quantitative determination of IgM antibodies reduces the pitfalls in the serodiagnosis of tick-borne encephalitis. J Clin Virol (in press). 4. Chiba N, Osada M, Komoro K, Mizutani T, Kariwa H, Takashima I. Protection against tick-borne encephalitis virus isolated in Japan by active and passive immunization. Vaccine 1999;17: Klockmann U, Krivanec K, Stephenson JR, Hilfenhaus J. Protection against European isolates of tick-borne encephalitis virus after vaccination with a new tick-borne encephalitis vaccine. Vaccine 1991;9: Leonova GN, Ternovoi VA, Pavlenko EV, Maistrovskaya OS, Protopopova EV, Loktev VB. Evaluation of vaccine Encepur Adult for induction of human neutralizing antibodies against recent Far Eastern subtype strains of tick-borne encephalitis virus. Vaccine 2007;25: Holzmann H, Vorobyova MS, Ladyzhenskaya IP et al. Molecular epidemiology of tick-borne encephalitis virus: crossprotection between European and Far Eastern subtypes. Vaccine 1992;10: Orlinger KK, Hofmeister Y, Fritz R et al. A tick-borne encephalitis virus vaccine based on the European prototype strain induces broadly reactive cross-neutralizing antibodies in humans. J Infect Dis 2011;203: Fritz R, Orlinger KK, Hofmeister Y et al. Quantitative comparison of the cross-protection induced by tick-borne encephalitis virus vaccines based on European and Far Eastern virus subtypes. Vaccine ;30: Hansson ME, Orvell C, Engman ML et al. Tick-borne encephalitis in childhood: rare or missed? Pediatr Infect Dis J 2011;30: Sundin M, Hansson ME, Engman ML et al. Pediatric tickborne infections of the central nervous system in an endemic region of Sweden: a prospective evaluation of clinical manifestations. Eur J Pediatr Lundkvist A, Wallensten A, Vene S, Hjertqvist M. Tick-borne encephalitis increasing in Sweden, Euro Surveill 2011; Kunz C. TBE vaccination and the Austrian experience. Vaccine 2003;21 Suppl 1: Klaus C, Beer M, Saier R et al. Goats and sheep as sentinels for tick-borne encephalitis (TBE) virus - Epidemiological studies in areas endemic and non-endemic for TBE virus in Germany. Ticks Tick Borne Dis ;3: Pfeffer M, Dobler G. Tick-borne encephalitis virus in dogs--is this an issue? Parasit Vectors 2011;4: Leschnik MW, Kirtz GC, Thalhammer JG. Tick-borne encephalitis (TBE) in dogs. Int J Med Microbiol 2002;291 Suppl 33: Lindhe KE, Meldgaard DS, Jensen PM, Houser GA, Berendt M. Prevalence of tick-borne encephalitis virus antibodies in dogs from Denmark. Acta Vet Scand 2009;51: Roelandt S, Heyman P, De FM et al. Tick-borne encephalitis virus seropositive dog detected in belgium: screening of the canine population as sentinels for public health. Vector Borne Zoonotic Dis 2011;11: Suss J. Tick-borne encephalitis 2010: Epidemiology, risk areas, and virus strains in Europe and Asia-An overview. Ticks Tick Borne Dis 2011;2: Rizzoli A, Hauffe HC, Tagliapietra V, Neteler M, Rosa R. Forest structure and roe deer abundance predict tick-borne encephalitis risk in Italy. PLoS One 2009;4:e D Agaro P, Martinelli E, Burgnich P et al. Prevalence of tickborne encephalitis virus in Ixodes ricinus from a novel endemic area of North Eastern Italy. J Med Virol 2009;81: Collard M, Gut JP, Christmann D et al. [Tick-borne encephalitis in Alsace]. Rev Neurol (Paris) 1993;149: Thorin C, Rigaud E, Capek I et al. [Seroprevalence of Lyme Borreliosis and tick-borne encephalitis in workers at risk, in eastern France]. Med Mal Infect 2008;38: Hansmann Y, Pierre GJ, Remy V, Martinot M, Allard WM, Christmann D. Tick-borne encephalitis in eastern France. Scand J Infect Dis 2006;38: UN World Tourism Organization (UNTWO). Tourism Highlights Edition [ docpdf/unwtohighlights11enhr_1.pdf]. 26. UN World Tourism Organization (UNTWO). World Tourism Barometer [ 10 [Jan]. 27. Kunze U. Is there a need for a travel vaccination against tickborne encephalitis? Travel Med Infect Dis 2008;6: Rendi-Wagner P. Risk and prevention of tick-borne encephalitis in travelers. J Travel Med 2004;11: CDC. Travelers Health. Tickborne encephalitis [ International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) Text: Gabriele Berghammer the text clinic Graphics design: ad line Werbedesign Isabella Farnleitner Project no.: BS-VA-465 / April Supported by an unrestricted educational grant from Baxter AG. Baxter and FSME-IMMUN are trademarks of Baxter International Inc., its subsidiaries or affiliates.

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