Epidemiology and distribution of tick-borne encephalitis

Wien Med Wochenschr (2012) 162:230 238 DOI 10.1007/s10354-012-0100-5 Epidemiology and distribution of tick-borne encephalitis Gerhard Dobler, Dieter Gniel, Robert Petermann, Martin Pfeffer Received: 5 April 2012 / Accepted: 19 April 2012 / Published online: 15 June 2012 Springer-Verlag Wien 2012 Epidemiologie und Verbreitung der FSME Zusammenfassung Die Frühsommer-Meningoenzephalitis (FSME) ist die medizinisch wichtigste durch Zecken übertragene Virusinfektion in Eurasien. Ihr Verbreitungsgebiet reicht von Japan im Osten Asiens bis nach Frankreich im Westen Europas. In den zurückliegenden Jahren wurde ein Ausweitung der Verbreitungsgebiete in nördlicher Richtung in Nord-Russland, Schweden und Finnland beobachtet. Zecken spielen die wichtigste Rolle in der Übertragung des FSME-Virus auf Mensch und Tier. Allerdings kann die Infektion auch durch Virus-haltige Milch erfolgen. Die FSME spielt eine zunehmende Rolle in der Reisemedizin. Erkrankungsfälle treten in Regionen außerhalb der bekannten FSME-Verbreitungsgebiete auf. Daher sollte die FSME grundsätzlich bei allen entzündlichen Erkrankungen des Zentralen Nervensystems differenzialdiagnostisch ausgeschlossen werden Schlüsselwörter: Zecke, Frühsommer-Meningoenzephalitis, Epidemiologie, Inzidenz, Geographische Verbreitung Dr. G. Dobler, MD ( ) Department of Microbiology of the German Armed Forces, Neuherbergstr. 11, 80937 Munich, Germany e-mail: gerharddobler@bundeswehr.org D. Gniel, PhD Novartis Vaccines and Diagnostics GmbH, Marburg, Germany R. Petermann, PhD Baxter BioScience, Vienna, Austria Prof. Dr. M. Pfeffer, DVM, PhD Institute of Animal Hygiene and Public Veterinary Health, University of Leipzig, Leipzig, Germany Summary Tick-borne encephalitis (TBE) is the main tick-borne virus infection in Eurasia. It is prevalent across the entire continent from Japan to France and occurs in endemic foci. Expansion of prevalence in areas including northern Russia, Sweden, and Finland has been observed in recent years. Ticks are the most important vectors and may transmit the TBE virus to animals and humans. TBE can also be transmitted to humans in milk containing the virus. TBE has been implicated as a travel-acquired illness and there are isolated reports of its occurrence in countries outside the known areas of prevalence. Therefore, TBE should be included in the differential diagnosis for all central nervous system diseases inside or outside endemic areas. Keyword: Tick, Tick-borne encephalitis, Epidemiology, Incidence, Geographical distribution The pathogenic agent The virus that causes tick-borne encephalitis (TBE) is classified as a member of the Flaviviridae family on the basis of its structure and genetic makeup [1]. It is known internationally as tick-borne encephalitis virus (TBEV). The Flaviviridae family is subdivided into flaviviruses transmitted by ticks, flaviviruses transmitted by mosquitoes, and non-arthropod-borne viruses with no known vector. The group of tick-borne flaviviruses is further divided into a subgroup of mammal-associated flaviviruses and a subgroup of seabird-associated flaviviruses. The former group (mammal-associated flaviviruses) contains a number of viruses relevant to human health, including the Omsk hemorrhagic fever virus, Kyasanur forest disease virus, louping ill virus in sheep, Alkhumra virus, and the Powassan virus found in the North American continent. Mammal-associated and tick-borne flaviviruses are more closely related to each other than to flaviviruses of other subgroups and display an amino acid homology in excess of 75 %, while the amino acid homology with other flaviviruses is less than 50 % (Fig. 1). The TBE virus was first described as the cause of TBE by Zilber in 1937. Previously, however, Schneider (an Austrian) noticed a seasonal correlation for cases of aseptic 230 Epidemiology and distribution of tick-borne encephalitis

E-protein amino acid homology (%) 100 90 80 70 60 50 Dengue group Japanese encephalitis group Tick-borne encephalitis group DEN WN KUN MVE JE SLE YF POW LGT LI TBE 3 1 2 4 W S FE 96 93 91 94 85 89 82 77 77 78 77 78 72 74 69 62 46 53 40 40 44 Fig. 1 Phylogenetic relatedness of flaviviruses known to infect humans. DEN Dengue, WN West Nil, KUN Kunjin, MVE Murray Valley Encephalitis, JE Japanese Encephalitis, SLE meningitis [2, 3]. The virus is currently divided into three subtypes (Fig. 2). The Western subtype (TBE-W) is mainly prevalent in Europe, west of the Urals, but has also been identified in Siberia. A Siberian subtype (TBE-S) is mainly found in Siberia. One subgroup of the Siberian subtype is found in the Baltics, another in northern Finland and a third in north-western Russia [4, 5]. The east-west spread of the subtype has been shown to correlate with transport activities during the conquest of Siberia and later with the construction of an intercontinental road and the Trans-Siberian railway [5]. Finally, the Far-Eastern subtype (TBE-FE) is mainly found in far-eastern Asia and central and eastern Siberia. There are isolated reports of its occurrence in the Baltics (Fig. 2). Division into different subtypes is important for genetic research purposes. Moreover, the different virus subtypes can cause different clinical pictures (Table 1). The wide distribution of TBE and severe clinical manifestations of the condition have given rise to a number of names for the condition in the various regions in which it occurs. Among other names, TBE is called: Central European Encephalitis (CEE, international) Russian Spring Summer Encephalitis (RSSE, Russia) Taiga Encephalitis (Russia) Early Summer Meningo-Encephalitis (FSME, Germany) Diphasic Meningoencephalitis (Czech Republic) Bi-undulant Meningo-Encephalitis (Czech Republic, Germany) Diphasic Milk Fever (Czech Republic) Schneider s Disease (Austria) Saint Louis Encephalitis, YF Yellow Fever, POW Powassan, LGT Langat, LI Louping Ill, TBE Tick-borne Encephalitis. (Modified after [57]) Kumlingesjukan (Sweden) Roslagssjukan (Sweden) Ryssjukan (Sweden) Transmission The TBE virus belongs to a group of viruses called arboviruses (arthropod-borne viruses). The group is defined not by taxonomy but by ecology. According to the WHO definition, arboviruses are viruses which are transmitted in nature exclusively or mainly by bloodsucking arthropods [6]. Arthropods absorb the arbovirus from a vertebrate animal, i.e., the host, and can transmit it to new hosts during the next blood meal after a period of active replication in the arthropod. Other transmission routes are possible which support the actual natural cycle (see below). Ticks are arthropod vectors for the TBE virus. The main vector of the Western subtype is the castor bean tick (Ixodes ricinus) [7]. The most important vector of Siberian and Far-Eastern subtype is the taiga tick (Ixodes persulcatus). On the Japanese island of Hokkaido, it is Ixodes ovatus [8, 9]. Other metastriate tick species may transmit the TBE virus in certain ecological conditions. The virus has also been detected in defined biotopes in isolated cases from Haemaphysalis and Dermacentor species [7]. The epidemiological relevance of these species remains to be established. In the vast majority of cases, the former two Ixodes species can also function as vectors in transmitting the TBE virus to humans. In Ixodes ricinus, the TBE virus can persist ( be transmitted ) transstadially from one stage of development Epidemiology and distribution of tick-borne encephalitis 231

Fig. 2 Classification of TBE viruses. (Modified after [1]) Flaviviridae Tick-borne Mosquito-borne Non-vector Seabird-associated Mammal-associated TBE virus Western subtype Siberian subtype Far-Eastern subtype Table 1. Characteristics of the three known subtypes of the TBE virus [8, 58 60] Western subtype Siberian subtype Far-Eastern subtype Vector Ixodes ricinus Ixodes persulcatus Ixodes persulcatus Prodromal symptoms Frequent Rare Rare Symptom onset Subacute Acute Acute Course Biphasic Monophasic Monophasic Chronicity No Approx. 2 % Yes (frequency unknown) Age disposition Rarely seen in children; increasing incidence in Commonly seen in children Commonly seen in children older age groups Letality rate < 2 % Up to 5 % Up to 15 20 % to the next stage. This means that a tick, once infected, can excrete the virus for the rest of its life and is hence infectious throughout its lifespan. There is evidence of horizontal infection (from infected males to females) and vertical infection from infected females to the offspring (transovarial transmission) [10]. The relevance of these forms of transmission within the tick population has not been conclusively established. The TBE virus is absorbed into the tick s gastrointestinal tract following absorption with a blood meal. From the gastrointestinal tract, the virus enters the hemolymph (the tick s nonvascularized blood system) and migrates eventually into the tick s salivary glands. The TBE viruses are released with the saliva and enter the next host in that manner. This means that the virus can be transmitted from the start of the blood meal. This form of excretion is typical of arboviruses and differs fundamentally from the mechanism by which Borrelia is transmitted by ticks. The main natural hosts of the TBE virus are believed to be small mammals, rodents in particular. The yellownecked mouse (Apodemus flavicollis) and the bank vole (Myodes glareolus) are often implicated. Both species develop sufficient levels of viremia to be able to infect bloodsucking ticks during a blood meal [7]. The viremic phase lasts several days. Recent studies suggest that small rodents may develop persistent infections. TBE viruses may still be detected in the brain and internal organs after months [11]. This persistence is thought to be a way of ensuring survival of the TBE virus during the winter in endemic areas. The relevance of these study data in terms of the TBE virus transmission cycle is unclear as it has not yet been established whether this persistence may in fact form the starting point for further transmission to ticks. Alongside the two rodent species, other species of both genera, and other Muridae (true mice) and Microtinae (voles) act as natural hosts of the TBE virus in defined ecosystems [7]. Insectivores may also serve as natural hosts due to production of sufficiently high levels of viremia. The European hedgehog (Erinaceus europaeus) is also thought to be of importance as an intermediate host of TBE virus due to the high levels of infestation of these animals with a variety of tick species (Ixodes ricinus, Ixodes hexagonus, Haemaphysalis concinna) and because of the viremia levels reached [7]. Larger forest animals such as foxes, boars, and deer do not seem to be able to develop sufficient virus titers in the blood in order to transmit the TBE virus to new ticks. Like domestic animals (goats, sheep, cattle, dogs) they are not believed to play a role in maintaining the natural transmission cycle of the TBE virus. However, especially deer play a very prominent role in stabilizing and maintaining 232 Epidemiology and distribution of tick-borne encephalitis

main topic Fig. 3 Developmental stages of Ixodes ricinus (Ixodes spp.) with TBE virus transmission routes. Periphery via host viremia, circle from developmental stage to developmental stage, center nonviremic transmission via cofeeding First host (larvae): Small mammals Second host (nymphs): small & large mammals transstadial transstadial transovariell Third host (adults): small & large mammals tick populations at levels necessary for the transmission cycle (Fig. 3). In addition to viremic transmission, another route of transmission of rodents to ticks has been demonstrated by experiment. If noninfected ticks are placed on a small rodent for a blood meal in the immediate proximity of a virus-bearing tick, the virus is transmitted from the infected to the noninfected ticks without viremia being detected, or necessary, in the mouse. This form of transmission via cofeeding is also termed nonviremic transmission [12, 13]. Experimental data show that certain immunomodulatory effects of tick saliva (including enticing macrophages) appear to be important [14]. No robust study data are available on the relevance of this transmission method for the transmission cycle in nature. Nor has it been established whether nonviremic transmission might play a role in nonrodent animals (e.g. deer, wild boars, foxes). Like other flaviviruses, the TBE virus is excreted in the viremia phase by rodents, cloven-hoofed animals, and humans in the mother s milk. There is evidence that this may result in transmission of TBE virus to offspring in rodents. Infection of lambs via sheep s milk has also been demonstrated for the louping ill virus, which is very closely related to the TBE virus. Laboratory experiments in mice have shown efficient oral transmission of TBE virus by this infection pathway [15, 16]. Transmission via virus-containing milk and dairy products (nonpasteurized cheese, yoghurt, butter) to humans (alimentary infection) is discussed in the following section. 13 Alimentary infection via unpasteurized milk & dairy products Transmission to humans Humans acquire TBE infection mainly via tick bites. Because of transmission of the TBE virus in tick saliva from the start of a blood meal, TBE virus can be transmitted by ticks after a very brief blood meal. The TBE virus can also be transmitted to humans in virus-containing milk of grazers (cattle, sheep, and goats). Particularly in the period after World War II, there were massive TBE outbreaks due to ingestion of goat s milk (as a substitute for cow s milk, which was rare at the time). Thereafter, up to 30 % of all TBE cases in Russia were caused by transmission in milk [17]. The largest known outbreak of TBE was in 1954 in what was then Czechoslovakia when more than 600 people developed TBE infection via contaminated cow s and goat s milk. The disease was termed biphasic milk fever during this period. Repeated smaller outbreaks have been reported in the recent past in association with transmission via contaminated milk in various European countries (Baltics, Eastern Europe, and Austria), and there have been repeated episodes in Russia [18 25]. Studies in the Czech Republic show that between 0.9 (Czech Republic) and 9 % (Slovakian Republic) of all TBE infections in these countries are transmitted in goat s and cow s milk [24, 26]. According to Polish data from grazes in endemic areas of eastern Poland, sensitive methods (polymerase chain reaction) detect TBE virus contamination in up to one out of five samples of goat s and sheep s milk and one in 10 samples of cow s milk [27]. The vast majority of infections are transmitted via tick bites. The available observations suggest that infection via virus-containing milk and dairy products is more effective in the sense of a higher rate of manifestation of clinical disease than infection Epidemiology and distribution of tick-borne encephalitis 233

via ticks. It is not known whether this is due to more effective infection of the virus via the gastrointestinal tract or due to potentially higher infectious dose levels in milk. Kunz reported at least one case of transmission of TBE virus from an unvaccinated mother to her infant after birth via breast-feeding in Lithuania (Kunz, personal communication, 2002). Prior to the introduction of modern safety workbenches and vaccination, a number of lab infections were detected which suggest aerosolborne infection. Geographical spread The TBE virus in the form of its three subtypes is prevalent across the Eurasian continent. Distribution is not consistent, however. The TBE virus is prevalent in very small areas where it occurs in endemic foci. It circulates in ticks and rodents in those areas (see above). These endemic foci are believed to occur throughout the entire area of prevalence. There is some mixing of TBE virus genotypes between individual foci, as demonstrated by the detection of multiple genotypes from a single TBE focus [28]. Data on TBE distribution is inadequate and in some cases contradictory in many countries. Many countries, including Germany and Austria, record geographical prevalence of TBE on the basis of the incidence of human cases. For various reasons, this provides an inadequate reflection of TBE virus spread. For one, reporting habits differ for geographical and historical reasons [29]. For another, as indicated above, humans are dead-end hosts for TBE. Only reporting human cases therefore provides a distorted picture of the actual endemic situation. Another argument against a database of this kind is the fact that diagnostic workup of TBE by serology alone falsifies the endemic situation depending on the respective vaccination rates in the local population. This is not just due to TBE vaccination but also due to the strong serological cross-reactivity between flaviviruses (see Fig. 1), be it by corresponding vaccinations against Japanese encephalitis or cases of yellow fever or corresponding infections (especially with Dengue viruses) play a role too. Moreover, the location where the infection took place is not necessarily reported, usually only the patient s place of residence or location of the physician consulted to treat the case. Extensive research is necessary in order to determine the actual location of infection. Much research has been done in recent years into the risk factors for TBE infection in humans [30 32], but we do not know the actual circumstances underlying human infection with the TBE virus. Obviously, being bitten by an infectious tick is a necessary condition, but we do not know why the incidence varies so markedly even in known endemic areas. Hence, there is a gap in the medicinal and virological understanding of what constitutes an endemic or risk area. The medicinal approach is essentially pragmatic and only takes caseload into account, while 234 Epidemiology and distribution of tick-borne encephalitis failing to address the prevalence of the pathogenic agent as confirmed by other means. Recent studies in wild and domestic animals show that the TBE virus is more widespread than previously thought, and is prevalent in regions with no recorded instances of human disease to date [33]. Data on this aspect might enhance current reporting practice even if the test systems are not approved for domestic and wild animals. Long-distance spread of the TBE virus in virus-bearing ticks in bird plumage seems possible [34, 35]. Virus spread along natural landscape features (river valleys) likewise appears to be a possibility (Dobler, unpublished data). Anthropogenic factors (human travel and transport activities of any kind) have been postulated too in conjunction with socioeconomic trends in Eastern Europe following the transformation of political systems as well as lifestyle influences such as the back-to-nature movement, involving human interaction with hitherto unspoiled nature. Ecological changes in agriculture in Eastern Europe and Russia (from large collective farms back to smallholdings and the resultant improved living conditions for tick populations) seem to be a contributory factor [36, 37]. It has long been suspected that low-virulence and apathogenic TBE viruses occur in nature [38]. Definite genetic markers for virulence properties of the TBE virus have not been detected so far, so the default assumption has to be that all TBE virus strains in nature are pathogenic. From this point of view, the definition of prevalence of TBE based on cases of human infection needs to be changed to prevalence of the TBE virus. Endemic foci of TBE are identified on that basis by the following properties: Autochthonous occurrence of cases of human and/or animal infection TBE virus detected in ticks Specific anti-tbe virus antibodies detected in wild animals exhibiting habitat fidelity Specific anti-tbe virus antibodies detected in domestic animals exhibiting habitat fidelity Changes in known areas of prevalence have been observed in recent years (Fig. 4). This is surely due in part to increased diagnostic activity and studies on ticks. New endemic foci/areas have been documented in Mongolia, northern China and Denmark (mainland), in Kazakhstan at altitudes of 1,000 2,100 m, Kirgizstan, and also in isolated endemic areas of Armenia, Azerbaijan, and Uzbekistan [39 44; Dmitrovskij 2010, personal communication; Deryabin 2010, personal communication]. The launch of more extensive diagnostics has also resulted in an increase in recorded cases of TBE infection in Poland [45, 46]. Twenty-two European countries (76 %) took part in a TBE survey in a study conducted in 2008 [47]. Participation in a follow-up survey in 2011 rose to 28 countries [48]. This can be seen as an indication that awareness of TBE as a severe infectious disease is increasing in the countries of Europe. These surveys also show however that different definitions of TBE are applied from country to country, with the result that statistics on caseload

Fig. 4 The TBE belt (prevalence of TBE viruses) in ticks, animals, and humans and epidemiology are not fully comparable. For instance, TBE is a reportable disease in only 16 European countries at present, and a case definition is in place in only 10 countries [48]. However, actual changes in prevalence are evident too. A definite extension in vector prevalence and hence TBE virus over the past 20 years has been reported in the Czech Republic [49]. An outbreak of TBE related to consumption of goat s milk has been observed in Austria at an altitude of 1,564 m [23]. Currently, further changes in TBE prevalence at present are mainly seen in the extreme north. A definite progression of prevalence of Ixodes ricinus in a northerly direction is reported from Sweden and Finland. Models predict a significantly longer period of tick activity in the coming decades. The trend toward increasing geographical prevalence in northern regions is also evident in Russia. Northern expansion, an absolute increase in TBE caseload and a relative increase in caseload versus the rest of Russia since 2001 has been observed in the Archangelsk region [50]. This (horizontal and vertical) expansion of prevalence at the margins of the endemic area can also be seen for other vector-borne infectious diseases such as malaria [51]. Individual European countries may be subdivided on the basis of their TBE incidence into countries with a high incidence (> 5/100,000 inhabitants), countries with an intermediate incidence (1 5/100,000) and countries with a low incidence (< 1/100,000) (Table 2). Given the focal Table 2. TBE incidences in European countries and Russia based on 2009 data [48] with a high incidence (> 5/100,000) with an intermediate incidence (1 5/100,000) with a low incidence (< 1/100,000) with regional/ sporadic incidence with no reported autochthonous cases Estonia Russia Austria (vaccinated) Italy UK Slovenia Sweden Hungary Denmark Ireland Latvia Switzerland Poland Ukraine Spain Lithuania Slovakian Finland Romania Portugal Republic Czech Republic Belarus (?) Germany Greece Belgium Austria (nonvaccinated) France Bosnia Netherlands Croatia Serbia Luxembourg Norway Lichtenstein Malta France Bulgaria Turkey a a Presence of anti-tbe virus antibodies in a seroprevalence study and two possible cases of human infection in Turkey [61] Epidemiology and distribution of tick-borne encephalitis 235

and regional prevalence of TBE, this classification is not an accurate reflection of the situation in the individual regions. According to the existing system, Germany is classified as a low-endemicity area for TBE. However, the districts with the highest caseload in Bavaria (Schwandorf ) and Baden-Württemberg (Ortenaukreis) have incidence rates of 10/100,000 and 6.2/100,000, respectively, which would merit classification as high-incidence regions. According to this classification, Russia is an intermediate-incidence country. However, parts of Siberia (e.g. Tomsk, Krasnoyarsk, Kemerovo) have incidence rates of > 30/100,000. A striking feature here apart from a high rate of exposure among the population (lengthy and frequent periods outdoors with multiple tick bites owing to socioeconomic factors; Gniel, unpublished data) is the high level of virus prevalence in ticks, which ranges from 4 to 38 % and is subject to annual variation [52]. These areas of western Siberia are believed to have the highest rates of TBE prevalence in the world. Again, these endemic foci are leveled out to a large extent by providing incidence rates for the whole country. The absolute number of human cases and incidence are of relatively little value in regions where the population is immunized as a result of vaccination. The best example is Austria, where more than 80 % of the population is immunized against TBE. This can be seen in the number of cases reported annually, and the approximately 90 % decline in that number since vaccination was first launched (Department of Virology, University of Vienna). In contrast, however, the incidence in the nonvaccinated Austrian population did not change and is still high at 4 10/100,000 (Heinz, ISW 2011). By contrast, reported cases in the neighboring Czech Republic with its low vaccination rate have been stable during the same period with a slight upward trend. Hence, the number of infections actually occurring is not necessarily an indicator of TBE virus circulation in a territory. TBE incidence data and absolute case numbers for areas outside Europe are even less robust. Data on incidence and prevalence in the countries of Central Asia is fragmentary at best. This is mainly because reporting systems have not been implemented in the countries in question. Virology and serology data may be available on a locally restricted scale from aid projects but are not generated systematically. Many of the known TBE endemic areas are among the most popular European (and, increasingly, Asian) holiday destinations. As a result, there are sporadic reports of TBE infections acquired abroad. Approximately 3 9 % of annual TBE cases in Germany were acquired abroad (Robert Koch Institute, Epidemiological Bulletins, 2001 2011). In a recent development, infections are increasingly being imported to countries not previously identified as TBE source countries. Five cases of TBE imported from Europe or Asia were diagnosed in the USA in the 10-year period from 2000 to 2009 [53]. In 2011, TBE infection was diagnosed in two travelers returning to the Netherlands from Austria [54]. Statistical analyses of risk show that the risk of contracting TBE is 1:10,000 person-months for nonvaccinated tourists who spend 4 weeks in endemic areas of Austria, which is approximately equivalent to the risk of contracting malaria while traveling in India [55]. Taken in conjunction with other individual reports, these imported cases show that TBE may well present a risk of infection for visitors to endemic areas [56]. Hence, TBE should be included in health travel advisories in keeping up with its geographical and seasonal occurrence. Conflict of interest GD has no conflict of interest. DG is a full-time employee of Novartis Vaccines, a manufacturer of TBE vaccine. RP is a full-time employee of Baxter BioScience, a manufacturer of TBE vaccine. 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