Clinical epidemiology of human AE in Europe

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Research paper

Clinical epidemiology of human AE in Europe D.A. Vuitton ∗ , F. Demonmerot, J. Knapp, C. Richou, F. Grenouillet, A. Chauchet, L. Vuitton, S. Bresson-Hadni, L. Millon WHO-Collaborating Centre for Prevention and Treatment of Human Echinococcosis, and French National Centre for Alveolar Echinococcosis, UMR 6249 ‘Chrono-Environment’ and EA 3181 ‘Epithelial Carcinogenesis: Prevention and Prediction Factors’, University of Franche-Comté and University Hospital, 25030 Besanc¸on, France1

a r t i c l e

i n f o

Keywords: Alveolar echinococcosis Echinococcus multilocularis Epidemiology Immune suppression Cancer Chronic inflammatory diseases Europe

a b s t r a c t This review gives a critical update of the situation regarding alveolar echinococcosis (AE) in Europe in humans, based on existing publications and on findings of national and European surveillance systems. All sources point to an increase in human cases of AE in the “historic endemic areas” of Europe, namely Germany, Switzerland, Austria and France and to the emergence of human cases in countries where the disease had never been recognised until the end of the 20th century, especially in central-eastern and Baltic countries. Both increase and emergence could be only due to methodological biases; this point is discussed in the review. One explanation may be given by changes in the animal reservoir of the parasite, Echinococcus multilocularis (increase in the global population of foxes in Europe and its urbanisation, as well as a possible increased involvement of pet animals as definitive infectious hosts). The review also focuses onto 2 more original approaches: (1) how changes in therapeutic attitudes toward malignant and chronic inflammatory diseases may affect the epidemiology of AE in the future in Europe, since a recent survey of such cases in France showed the emergence of AE in patients with immune suppression since the beginning of the 21st century; (2) how setting a network of referral centres in Europe based on common studies on the care management of patients might contribute to a better knowledge of AE epidemiology in the future. © 2015 Published by Elsevier B.V.

1. Introduction It was expected that alveolar echinococcosis (AE), a liver cancerlike disease due to the infection by the larval stage of the parasite Echinococcus multilocularis, would disappear from Europe at the end of the 20th century because of (1) major improvement of public health sanitation, individual hygiene, and food safety measures; (2) decrease in the European population with occupational risks related to agriculture/animal breeding; (3) changes in behaviour of individuals due to urbanisation and better income. The prediction was proved wrong and the number of patients with AE looks to be both increasing in European countries where AE had been recognised since the middle of the 19th century and emerging in European countries where AE cases were not diagnosed before the end of the 20th century (Deplazes, 2006; Romig, 2009). AE is, nevertheless, a rare disease (Kern et al., 2003), and an accurate

∗ Corresponding author. WHO-Collaborating Centre for Prevention and Treatment of Human Echinococcosis, Dept. of Parasitology, Region and University Hospital, Boulevard Fleming, 25030 Besanc¸on, France. E-mail address: [email protected] (D.A. Vuitton). 1 http://cnr-echino-alveolaire-ccoms.univ-fcomte.fr/spip.php?article93.

assessment of its incidence and prevalence in European populations and of its potential changes in the future depends upon the establishment of a standardised, systematic and prospective recording of AE cases in humans at the European level. This has not been achieved yet. Waiting for unified European recording data, for the present review we performed a PubMed (MEDLINE) search of the literature on AE epidemiology in Europe from 1850 to the end of 2014 in order to critically evaluate the situation of each country regarding AE in humans and its trends. The search used the following keywords: ‘E. multilocularis’, ‘alveolar (or ‘multilocular’) echinococcosis’, ‘alveolar (or ‘multilocular’) hydatidosis’, ‘alveolar (or ‘multilocular’) hydatid disease’, ‘Echinococcus alveolaris’, ‘Alveococcus’ and ‘alveococcosis’ (3 key-words used in Russian literature), combined with ‘epidemiology’, ‘risk factors’, ‘prevalence’, ‘incidence’, ‘immunosuppression’. In addition, in order to disclose the first reported case of AE and the series of cases published in each country – before and after 1990 – we combined the previous keywords with the name of each individual country of Europe. When the original paper was either not available or in a language different from English, French, Spanish, Italian or German, the abstract was used if available. Whenever useful, published data were complemented by data published in theses and dissertations in French

http://dx.doi.org/10.1016/j.vetpar.2015.07.036 0304-4017/© 2015 Published by Elsevier B.V.

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and German, and in reports/opinions published by the European Commission (EC)-DG SANCO, European Centre for Disease Control (ECDC), and European Food Safety Authority (EFSA) (retrieved by web searches from the respective web sites), in abstracts published in the Proceedings of the International Symposium ‘Innovation for the management of echinococcosis’, Besanc¸on, France, March 2014 (Vuitton et al., 2014), and oral communications at the International ESCCAP Meeting ‘Echinococcosis in Europe’, Vilnius, Lithuania, October 2014 (unpublished Abstract Booklet), and by email request to those in charge of AE registries/observatories in European countries. 2. Human AE in Europe: a historical perspective From phylogenetic and paleo-ecological studies one can speculate that E. multilocularis was introduced in Europe by foxes during the last Pleistocene period (130,000–10,000 years ago). In the ice age, the initial spread of the parasite from Siberia to North America was certainly permitted by the Beringia land bridge (Nakao et al., 2009). The exact origin of the parasite in the northern hemisphere remains unknown. However, historically, Europe is no doubt the cradle of AE (Vuitton et al., 2003, 2011). Thanks to the observations made by the German and Swiss physicians and scientists Siebold, Buhl, Zeller, Meyer and Virchow, the parasitological status of AE lesions was established and distinction from cystic echinococcosis was founded when the first patients were found in the middle of the 19th century (Virchow, 1855; Perrin, 1932; Tappe and Frosch, 2007). The clear distinction between the 2 species, E. multilocularis and E. granulosus, would, however, be confirmed only one century later (in Vuitton et al., 2011). AE cases were rapidly recognised in the German and Swiss Jura, and the German, Austrian and French Alps before the end of 19th century (Posselt, 1906; Auer and Aspöck, 1991); as early as 1886, a total of 79 AE cases could be reported (Vierordt, 1886). In 1932, Maurice Perrin, an intern of Besanc¸on hospital, reported the 10 autochthonous cases which had formally been identified in France, including the first case diagnosed in 1890 and 9 other patients who lived in the endemic area of the east and northeastern parts of France (Perrin, 1932). The geographic distribution of AE in central Europe, strictly based on human cases, was nearly fixed for more than 100 years (Fig. 1). In Russia, the first AE case was diagnosed in 1879, followed by many others, in the Moscow area, the Volga region (Kazan), and in Siberia (Tomsk and Irkutsk regions); in 1928, among 642 cases identified in the world (418 in contiguous areas of Germany, Austria, France and Switzerland), 209 Russian cases could be recorded (Posselt, 1928). The first cases in Turkey were published in 1939 (in Altintas, 2003). The earliest reports of human AE in Poland dated from the 1950s (Sowiakowski, 1955; Głuszcz and Kalczak, 1960). The first 3 human Greek cases of AE were published in 1978 (Theodoropoulos et al., 1978). But some doubt remained about the real nature of the reported disease, because of the sympatric presence of cystic echinococcosis in both countries. Confirmation of the genome of E. multilocularis in human liver lesions of Polish patients, reported in 2003, has now unequivocally confirmed human infection by E. multilocularis in Poland (Myjak et al., 2003). Similar confirmation has not been given for Greece. 3. AE in humans in Europe in the 20th and 21st centuries: real increase or biases? 3.1. Epidemiological observations Any claim on the increase, emergence or re-emergence of a disease must be based on sound data, especially when its incidence is

low, and thus any judgment regarding AE should rely on an active collection of cases performed in all European countries. This was effective at the end of the 20th century within the framework of the European Commission (EC-DGXXIV/SANCO)-funded “EurEchinoReg” project. This academically-based study was a cornerstone for further epidemiological studies on AE in Europe (Kern et al., 2003). The period of inclusion began in 1982, after ultrasound and other modern imaging techniques were introduced, and also after benzimidazoles were proposed for the treatment of AE. With a common methodology, scientists involved in this study actively retrieved AE cases diagnosed in their respective countries, namely Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, the Netherlands, Poland, Slovakia, Switzerland and the United Kingdom. The registry included all confirmed new cases from January 1982 to December 2000 as well as cases with a diagnosis from earlier periods, provided the patients were alive in 1982. The total number of verified AE cases reported to the registry (i.e. prevalence of cases in the time period 1982–2000) was 559 [258 males (46.2%); 301 females (53.8%)]; 42.0% were diagnosed in France (235 cases), 23.6% in Germany (132 cases) and 21.1% in Switzerland (118 cases). Most residences were clustered in defined regions: central France, French Jura and Savoy, Swiss Jura and northeastern Switzerland, German Jura and Alps in southern Germany, and Austrian Alps in western Austria. In addition, a few cases were identified outside the historic endemic areas. Fifteen patients had acquired the infection outside their reporting country (including 7 patients originating from one of the neighbouring European countries). The new and most exciting findings were the 14 autochthonous cases reported from Poland (diagnosed between 1986 and 2000), the case from Greece and 3 cases from Belgium, a country where autochthonous cases had never been reported before (Kern et al., 2003). In the EurEchinoReg European survey, patients were diagnosed at a mean age of 52.5 years; the gender ratio was 1:1.2. Risk factors studied in 210 patients included vocational or part-time farming, gardening, forestry, or hunting in 61% of patients. Such risk factors, as well as average age (peak between 50 and 60 years) and gender ratio (between 0.8 and 1.2), have been confirmed in all studies performed in Europe, including in a German case-control study on risk factors (Kern et al., 2004) and in the more recent study based on the French population-based AE Registry: most at-risk populations lived in rural settings [odds ratio (OR) 66.67 for farmers and 6.98 for other rural people] or gardened in non-rural settings (OR 4.30) (Piarroux et al., 2011). Compared to Asia and especially western China where the highest incidence of AE is observed, the average age of occurrence is higher in Europe, patients are more often women in Asia, but the rural origin of patients is similar in both regions of the world (Vuitton et al., 2003). Thanks to the EC-DG RESEARCH-funded project “Echino-Risk” aimed at getting knowledge on animal E. multilocularis infection in Europe (Romig, 2009), autochthonous emergence of E. multilocularis infection in fox populations was confirmed in many European countries and an increased risk for human populations became a concern (Eckert and Deplazes, 1999, 2004; Deplazes, 2006). Within this context, several countries of central-eastern and northern Europe have described their first autochthonous AE cases and/or a marked increase in incident AE cases since the 1990s (Bruˇzinskaite˙ et al., 2007; Nahorski et al., 2013; Antolová et al., 2014). Such findings will be described in detail below. However, the discovery of cases in areas where AE was not diagnosed before the 1990s and the apparent increase in the number of human AE cases in the historically established ‘endemic areas’ of Europe (Schweiger et al., 2007) could be due to an absence of diagnosis or misdiagnosis in the past, or to uneven recording over the years; this raises the issue of methodological biases that have to be discussed first.

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Fig. 1. Historical map of the discovery of the first cases of alveolar echinococcosis in the various European countries. Green circles: historic endemic area; red circles: endemic areas discovered since the 1990s (question marks indicate the year of publication of a first report when diagnosis was not fully ascertained).

3.2. Methodological issues 3.2.1. Absence or under-diagnosis? Epidemiology of zoonoses in humans is influenced by the contact with the infectious agent/animal host, but also by technical and social advances. Among the latter, progress in diagnostic techniques is a major issue; population ageing and specificities in the health system of a country/region may also play a role. There was an apparent increase in the number of AE cases in Europe after 1970: 559 in the18 years between 1982 and 2000, i.e. 18 years (Kern et al., 2003) versus less than 1000 reported in more than one century [calculated from the reports published until 1900 (in Perrin, 1932) and the 844 cases published between 1900 and 1980 (Fesseler, 1990)]. This rise has been attributed to an increase in fox infection, related to the increase in intermediate host pop-

ulations (voles) due to changes in land use after European Union Common Agriculture Policy (Viel et al., 1999; Vuitton et al., 2003). However, this rise was certainly also due to major improvement in imaging techniques since 1970. Before the 1960s, diagnosis of AE relied upon surgery or necropsy findings (in Perrin, 1932; Miguet, 1973). Most identified AE cases were diagnosed by surgeons: either very advanced cases with biliary or infectious complications or cases at any stage found by chance at laparotomy performed for any other condition. Clinically, signs and symptoms of AE could easily be misdiagnosed as cirrhosis or liver cancer. In many cases, due to the absence of appropriate treatment for such diseases at that time, no specific diagnosis was established. In addition, access to care was not always easy for patients from the mountainous rural areas endemic in the disease. The situation markedly improved in most European countries after the Second World War. This might

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also have played a role in the recognition of cases. An increase in both yearly incidence and the number of asymptomatic cases at diagnosis between 1972 and 1982 and 1983–1993 in a French single-centre study supports the role of imaging methods in AE diagnosis thus, in its reported incidence after their introduction in clinical practice (Bresson-Hadni et al., 2000). In the same study, mass screening using serology generated a peak in incidences of asymptomatic patients in 1988 (Bresson-Hadni et al., 2000). However, in France the situation remained stable afterwards, until the middle of the 2000s (Piarroux et al., 2011), which was also observed at European level (Kern et al., 2003). It is often argued that emergence of AE cases after 1990 in Slovakia, Lithuania or Poland could have been due to an emerging interest in this disease, better imaging diagnosis and specific care management which was not undertaken during the Soviet Union era. These countries indeed previously belonged to a different system of social organisation and fully entered the European network of scientific research at the beginning of the 1990s (Kern et al., 2003). However, it may be stressed that this is not the case for Belgium or the Netherlands where the ‘first autochthonous cases’ were also reported after 1990 only (Delbecque et al., 2002; Kern et al., 2003; van Dommelen et al., 2012). On the other hand, since its discovery in Germany in the 1850s, AE has been easily diagnosed by European surgeons and pathologists. Publications in German, French, Russian and several other European languages in the 20 years since the discovery of the first AE case made the disease known by physicians all over Europe; the numerous reports at national or regional Academies, or the theses/dissertations on cases observed in the endemic areas testify that the knowledge on the disease was well disseminated (in Perrin, 1932; Vuitton et al., 2011). Before the 1970s Russian literature on AE was very prominent (in Miguet, 1973). In addition, before the 1980s systematic autopsy was common practice among hospitals/pathology departments across the Soviet Union and associated countries, as shown in 1975 for Czechoslovakia (Dobiás, 1975). Thus, the occurrence of AE cases until the 1970s, if any in a given country, should have easily emerged from surgical and/or necropsy reports. After 1970, ultrasound examination of the liver was widely available in all western European countries. Long asymptomatic, at its late stage AE is however, a severe disease which cannot be neglected by clinicians (Bresson-Hadni et al., 2000; Piarroux et al., 2011). Advanced AE, with jaundice or clinically palpable hepatomegaly (the main presenting symptoms) would have easily been recognised by abdominal ultrasound which became the key-exam for the differential diagnosis of jaundice and hepatomegaly (Coodley, 1970; Weill et al., 1978) and the diagnosis of AE as early as the 1970s (Weill et al., 1975). In 1985, the contribution of ultrasound and computed tomography examinations to the diagnosis of AE was already published in international journals in English, French and German (Mörl, 1982; Claudon et al., 1984; Didier et al., 1985), and equipment for ultrasonography was available in Eastern European countries (e.g. in Kovác, 1984). An increase in the ageing population all over Europe could also represent a bias; however, the age range of patients in the population-based registries has not changed; a slight increase in the age of some patients seems to be counterbalanced by the younger age of others (French Registry: updated data). 3.2.2. Geographical clustering of AE cases Another difficulty in the interpretation of epidemiological data for AE is the geographical clustering of human cases. In the so-called ‘endemic countries’ of Europe, whenever present in a country, AE is considered to be a very rare disease with average incidences of 0.03–0.20/100,000 inhabitants/year, with the highest incidence found in Switzerland (0.10–0.18/100,000 and no marked variation during a 36-year period, until 1997 when the disease became no

longer officially notifiable). These figures, however, do not actually reflect the situation of the population at risk. Far higher incidences, from 4.7–8.1 cases per 100,000 inhabitants/years, are observed in areas where humans are directly exposed to E. multilocularis infection (Kern et al., 2003; Piarroux et al., 2011, 2013). This is why no prevalence per 100,000 inhabitants for each endemic country (neither for all endemic countries nor all Europe) was given in the collaborative paper by Kern et al. (2003). The French study, using data from a population-based registry (Piarroux et al., 2013) confirmed that the main risk factor to present the disease was living in AE-endemic areas (relative risk 78.63): almost all AE patients lived in 22/96 ‘départements’ in northeastern, eastern and central France. Kulldorff spatial scan analysis, based on data from the same Registry collected from 1982 to 2011, disclosed at least 4 levels of disease clusters (Said-Ali et al., 2013). This kind of detailed study remains to be done at European level, where such a case-clustering is a very common and general finding in all countries. As the disease clusters in rural areas in very specific geographical/climatic entities (generally mid-mountain areas with long cold winters and high rain-fall) (Piarroux et al., 2013), epidemiological figures calculated with reference to the country’s population are particularly irrelevant in those countries with the biggest area and highest number of inhabitants such as Germany, France or Poland; they are more reliable in Switzerland, Austria, Lithuania or Latvia. Comparing data expressed at the country level among the various European states may thus, be extremely misleading. 4. Current situation in Europe: typology of countries regarding human cases of AE If we consider AE epidemiology and the status of human versus animal cases of E. multilocularis infection in European countries, in the past 20 years (period 1995–2015), 4 types of countries may be described. 4.1. Type 1: Neither human case nor animal E. multilocularis infection The first group of European countries includes those where no autochthonous human cases of AE have ever been published and where E. multilocularis has never been documented in animals. Some of them apply specific pet entry regulations, such as the UK, Malta, Iceland, Ireland, Finland and mainland Norway (Davidson and Robertson, 2012). In Norway, the parasite is however, present in the northern Norwegian Svalbard islands, a focus with Siberian genetic characteristics of the parasite which thus, appears not related to the ‘European’ focus of infection (Knapp et al., 2012). No specific investigations have ever been conducted in Spain and Portugal which also, at least theoretically, belong to this type, and to our knowledge, there are no reports regarding AE in humans from Bulgaria, Albania, Bosnia-Herzegovina, Kosovo, Croatia, and Macedonia, countries otherwise endemic for cystic echinococcosis. 4.2. Type 2: No human cases but animal E. multilocularis infection The second group of countries includes those where no autochthonous human cases of AE have ever been published and where E. multilocularis wild cycle in animals is active. Despite the presence of an autochthonous E. multilocularis cycle in foxes in northern Italy (Casulli et al., 2005, 2009) and human cases reported in the 19th century (in Posselt, 1928), no autochthonous human case has been reported in Italy for the past 50 years. In Serbia, infection of the beaver as intermediate host was reported recently, but ´ no human cases (Bobic´ et al., 2012; Cirovi c´ et al., 2012). No information has been available on AE epidemiology in Ukraine after the

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first human case was published in 1976 (Geller and Railian, 1976), although 36% of red foxes of western Ukraine are infected with the parasite (Kharchenko et al., 2008); in Belarus, foxes were also found infected in Belorussian Polesie, a region at the Ukrainian and Polish border (Shimalov and Shimalov, 2001). Until now, no human cases of AE have been formally reported in Sweden and Denmark, after first evidence of E. multilocularis infection in foxes was given in 2011 in southwestern Sweden (Osterman Lind et al., 2011; Uhlhorn et al., 2011) and in 2000 and in 2012 in Denmark (Kapel and Saeed, 2000; Enemark et al., 2013). There are so far no confirmed human cases of AE from Estonia where foxes and raccoon dogs have been found infected by E. multilocularis (Moks et al., 2005; Süld et al., 2014). Among 14 cases of echinococcosis in humans officially registered in Estonia, differentiation between AE and CE was not achieved, and only CE cases were published in detail (Marcinkute˙ et al., 2015). 4.3. Type 3: Both human AE cases and animal E. multilocularis infection in countries considered to be ‘AE-free’ before 1995 The third group of countries includes those where the disease was unknown in humans before and has been diagnosed occasionally in one or several patients after the end of the 20th century. Since 1999, human cases have been reported in Slovakia (Antolová et al., 2009), Slovenia (Logar et al., 2007), Romania (Sikó et al., 2011), Czech Republic (Hozáková-Lukácová et al., 2009) and Hungary (Horváth et al., 2008) (Fig. 1). In most of the ‘newly endemic’ countries of central-eastern Europe, the number of cases remains limited (Eckert, 1997; Sréter et al., 2003). These rather low numbers should not mask the fact that fox infection rate by E. multilocularis is fairly high in several areas of these countries. Because of the time lag between infection and AE diagnosis in humans, human incidence could markedly increase in the next few years, as is already observed in Slovakia (Antolová et al., 2014). In this country, the first 2 cases were observed in 2000, in the Zˇ ilina Region, in northwestern Slovakia, where 50% of foxes are infected, and 26 clinical cases were recorded from 2000 to 2013, most of them from the highly endemic areas, with 1/3 under 40 years (Zˇ ilina and Preˇsov, with 38% of foxes infected). A similar trend is also detected for the Czech Republic, with cases in young patients (Hozáková-Lukácová et al., 2009). In countries of northwestern Europe, the first case of AE in humans was diagnosed in the Netherlands in 2012 (van Dommelen et al., 2012). In Belgium where the first 3 cases had been diagnosed between 1996 and 1999 (Kern et al., 2003), 6 additional cases were reported between 2000 and 2013 (Detry et al., 2005; Keutgens et al., 2013; Landen et al., 2013). Although there are no published human cases in Sweden and Denmark, personal communication with scientists from these countries indicate that investigations are ongoing to ascertain the autochthonous origin of recently diagnosed AE patients; if confirmed, this would move these countries to the ‘Type 3’. In northeastern Europe/Baltic area, where the disease was either unknown or diagnosed very rarely until the end of the 20th century, the number of human cases has considerably increased within the decade 2000–2010. Despite a population close to 3 million inhabitants, Lithuania is now among the top 5 European countries regarding the total number of cases and likely to be ranked first for AE incidence at country level (Bruˇzinskaite˙ et al., 2007; Marcinkute˙ et al., 2015). From 1997 to July 2006, 80 AE cases were diagnosed at the reference hospitals for AE, in Vilnius, Lithuania; this trend was confirmed for the following years, with 16 more ˇ ¯ cases reported in 2007–2008 (Sark unas et al., 2010) and a total of 179 cases between 1997 and 2013 (Marcinkute˙ et al., 2015). The age of patients averaged 60 (range 21–83), 65.9% were women; 53/179 patients died within the 16-year observation period. Most AE patients originate from the northwestern and northeastern parts of Lithuania but cases have been recorded from many parts of the

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country, which suggests, together with findings in definitive and intermediate animal hosts, that the whole territory of Lithuania should currently be endemic for AE (Marcinkute˙ et al., 2015). With a population of 2 million inhabitants, Latvia where 29 AE human cases have been reported for the 1996–2010 period also belongs to the newly discovered endemic areas where the disease seems to be emerging fast (Tulin et al., 2012). In Poland, a systematic collection of AE cases by a consortium of Polish referral centres was published in 2013: in 1990–2011 a total of 121 AE cases (incidence 0.014/100,000/year) were diagnosed in this country of 38.5 million inhabitants. They included 12 cases reported to the EurEchinoReg and 27 (22.3%) cases found during field studies in endemic areas screened for human AE (Nahorski et al., 2013). Once again, very young patients were among the recorded cases (4 patients from 6 to 11 years old). Aggregation of 9 cases, all of them genetically related, in 4 families was observed. AE cases were observed in 12 among 16 provinces in Poland and were distributed unevenly; the largest number (65 cases, 53.7%) was recorded in the Varmia and Masuria province and in Podlaskie province (11 cases), in northeastern Poland, at the border of the Russian Kaliningrad enclave and Lithuania. Cases were also observed in the northwest (Baltic Sea) and west (German border) regions. As expected, the human case distribution is consistent with the known prevalence of E. multilocularis-infected foxes and also raccoon dog infection (Malczewski et al., 2008; Nahorski et al., 2013). During the last 20 years, a steady increase of AE cases in Poland was observed with some degree of acceleration after 2005 (Nahorski et al., 2013). 4.4. Type 4: Increase in both human AE cases and animal E. multilocularis infection in historic endemic areas Several studies document a recent upward trend in incidence in historic endemic areas. Changes in AE incidence may be reliably evaluated only in those countries where the case recording system has not changed for the past 20 years, i.e. Switzerland, France and Austria. In Switzerland, a more than twofold increase of the annual incidence was reported between the periods 1993–2000 (10–15 cases/year) and 2001–2005 (20–30 cases/year) (Schweiger et al., 2007) and the incidence stabilised at the highest level of 20–30 cases/year (for 8 million inhabitants) for the following years (Peter Deplazes, Institute of Parasitology, Zurich, personal communication). Similar observations have been made since the mid 2000s in France: the median number of incident cases increased from 14 until 2006 to 28 from 2007 to 2013, with peaks of incidence of 35 in 2009 and 37 in 2012 (for a country of 66 million inhabitants) (Chauchet et al., 2014; FrancEchino Registry, unpublished updated data reported to the InVS, ECDC and EFSA). Similar trends have been pointed out in Austria by the Austrian AE reference centre: while the median number of incident cases in Austria (8 million inhabitants) was 2 and 3 cases during 1991–2000 and 2001–2010, respectively, the registration of 13 new AE patients in 2011 was unexpected (Schneider et al., 2013). Since then, from 2011 to 2014, the average incidence stabilised at a median of 9 cases per year, which is 3 times that observed before (Herbert Auer, Austrian AE reference centre, unpublished updated data). In addition, changes in the geographic distribution of the AE cases in the various historical endemic countries have been observed. This was described for France: from the beginning of the 21st century, more cases have been observed in the Ardennes area (Belgian border) and in the southeastern part of the Massif Central (Aveyron) than in the past; and within the highly endemic area of Franche-Comté, the number of human cases has increased in the Haute-Saône ‘département’ while before 2000 the cases were mostly restricted to the Doubs ‘département’ (Piarroux et al., 2013; Said-Ali et al., 2013; and unpublished, updated data of the French

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AE Registry). Similar regional changes have been recently described for Austria by Austria’s National Reference Centre for Echinococcosis: data for the past 21 years show a continuous increase of cases in Vorarlberg which has become the first region in terms of AE incidence (7 cases in 2011), although it is the Austrian region with the lowest population (Auer and Aspöck, 1991; Schneider et al., 2013). 5. Increased incidence of human AE: increased E. multilocularis animal reservoir and/or increased human susceptibility in European populations? 5.1. Changes in E. multilocularis reservoir The recent unexpected increase in AE incidence may find its origin both in an increase and/or geographical extension of the animal reservoir of the parasite (Romig, 2009; Combes et al., 2012) and/or in an increase in human susceptibility to parasite infection, since the occurrence and development of the disease is influenced by the immune status of the host (Koch et al., 2003; Vuitton et al., 2006; Vuitton and Gottstein, 2010). The considerable increase in the fox populations in Europe, partly due to rabies vaccination but also to changes in lifestyle and occupation in rural areas, thus, in the general attitude of the society towards foxes, has certainly much contributed to the geographic dissemination of infected foxes and thus, to the increase in E. multilocularis infection pressure in the environment in most European countries (Eckert, 1997; Dubinsky et al., 2001, 2006; Schweiger et al., 2007; Takumi et al., 2008; Berke et al., 2008; Bagrade et al., 2008). Urbanisation of the source of infection is also an important trend over the last 20 years, with infected foxes present in the cities of all endemic areas (Hofer et al., 2000; Stieger et al., 2002; Deplazes et al., 2004; Fischer et al., 2005; Romig et al., 2006; Comte et al., 2013). However, despite remarkable isolated observations, a real significant shift to a more frequent ‘urban’ residence of the patients has not been evidenced yet by clinicians using sound longitudinal studies from reliable registries in Europe (Piarroux et al., 2011, 2013; Deplazes and Gottstein: personal communication). Involvement of dogs as definitive hosts also makes human populations closer to the infectious sources; such an influence has been well demonstrated in China (Craig et al., 2000; Bartholomot et al., 2002). Dog infection has been shown in countries with rapidly emergent AE such as Slovakia and Lithuania, highly suggesting a ‘domestic cycle’ (Antolová et al., 2009; Bruˇzinskaite˙ et al., 2009). Occasional E. multilocularis infection of pigs in Lithuania could also support this hypothesis. Simple calculations in endemic countries like Switzerland have stressed the elevated risk of human infection by pet dogs compared to foxes (Hegglin and Deplazes, 2013). The discovery of ‘family-clustered cases’, as was shown in France (Piarroux et al., 2011) and in Poland (Nahorski et al., 2013), may also support the involvement of dogs in infection, although genetic factors of susceptibility may play a role (Eiermann et al., 1998; Yang et al., 2006). The involvement of cats in the increased infection risk cannot totally be ruled out although worm fertility is not as often obtained in cats as it is in dogs (Kreidl et al., 1998; Petavy et al., 2000; Nonaka et al., 2008; Deplazes et al., 2011). Young age of several AE patients in newly endemic countries, which has been repeatedly mentioned in recent reports and described above, could be an indicator of important infection pressure in the environment, and of the role of domestic animals in transmission, as was suggested in China (Craig et al., 2000; Yang et al., 2008). 5.2. The emergence of AE in patients with immunosuppressive therapy On the other hand, a significant number of AE cases have been reported for the past 15 years in patients who received organ transplantation or were treated for malignant or chronic

Fig. 2. Magnetic nuclear resonance imaging T2-weighted images in an immunosuppressed patient. Huge sized-alveolar echinococcosis lesions, with numerous pathognomonic hyperdense microcysts found in the right and left lobes of the liver in a patient with therapeutic immune suppression. The patient presented with fatigue and right quadrant abdominal pain and got abdominal ultrasound examination.

inflammatory diseases (Gruener et al., 2008; Kayacan et al., 2008; Gaultier et al., 2009; Geyer et al., 2011; Weiner et al., 2011; Kern et al., 2011; Dentan et al., 2012). AE cases in patients with cancer, malignant haematological disorders, chronic inflammatory diseases, transplantation, and AIDS, before or at AE diagnosis, were extracted from the population-based AE French registry database (1982–2012) (Chauchet et al., 2014). Fifty patients were found with such immunosuppression (IS)-associated conditions among 509 AE cases diagnosed from 1982 to 2012. There was significantly higher progression in IS/AE than in non-IS/AE case incidence between the last 2 decades. Acquired therapeutic immunosuppression was the main factor for AE occurrence and its fast progression (Fig. 2). ISassociated conditions modified AE presentation: this and negative serology made diagnosis more problematic, delayed or erroneous, and generated wrong therapeutic interventions. As the proportion of subjects with IS conditions is increasing in Europe, because of treatment intensification in patients with chronic inflammatory diseases and malignant disorders, and the use of biotherapeutic agents, it is likely that the number of patients with accidental AEdetection will also increase. All physicians in the endemic areas should be aware of this new situation which might be even trickier in those countries where AE is currently emergent, because of the lack of awareness of physicians in general, and the possible confusion between metastatic and AE images by oncologists at the follow-up of patients. 6. Public health consequences of the disease and situation of AE data recording in Europe In the world, AE has been estimated to cause an annual loss of approximately 666,000 disability-adjusted life years (DALYs) (Torgerson et al., 2010). Currently the costs per AE patient in Europe average D 110,000 (Torgerson et al., 2008, 2010). In the historic endemic areas, patients are more often diagnosed at earlier stages of the disease than 40 years ago, thanks to the awareness of physicians (Bresson-Hadni et al., 2000; Piarroux et al., 2011); however, many patients continue to present at advanced stage of infection, especially in the ‘emerging’ endemic areas (Bruˇzinskaite˙ et al.,

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Table 1 Situation of the various European countries regarding the legal notification of (alveolar) echinococcosis, according to ‘The European Union Summary Report on Trends and Sources of Zoonoses, Zoonotic Agents and Food-borne Outbreaks in 2010’ (ECDC and EFSA, 2012; accessible through: http://www.efsa.europa.eu/en/efsajournal/pub/2597. htm). Country

Notifiable in humans

Notifiable in animals

Notifiable in food

Austria Belgiium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Ireland Italy Latvia Lithuania Luxembourg Malta Netherlands Poland Portugal Romania Slovakia Slovenia Spain Sweden United Kingdom Iceland Liechtenstein Norway Switzerland

Yes, since 2004 Yes <1999 V yes Yes, since 1969 Yes No Yes, since 1986 1995 Yes V Yes Yes Yes, since 1960 Yes, since 2004 – Yes, since 1999 Yes, since 1990 Yes Yes No Yes, since 1959/1997b Yes Yes Yes Yes, since 1977 Yes, since 1982 Yes, since 2004 Yes V – Yes Yes, since 2003 No

Yes, since 1994 Yes, since 1998 – – No Yes Yes, since 2000 Yes, since 1995a No Yes, since 2004 Yes, since 1980 No – Yes Yes Yes No – Yes – Yes Yes, since 1942 yesc Yes <1991d Yes, since 1994 Yes >30 years Yes, since 1998e – – Yes, since 1985 Yes, since 1966

Yes, since 1994 Yes, since 2004 – – – – Yes, since 2000 Yes, since 1995a – – – Yes, since 1984 no Yes, since 1964 Yes – – Yes – – – No Yes, since 2003 Yes, since 1994 Yes >30 years No – – Yes, since 1965f –

V: on a voluntary basis (not legally mandatory). a In Finland, notifiable also before 1995, but legislation changed in 1995. b In Poland, from 1959, registered together with other tapeworms, from 1997, registered separately. c In Slovakia, only clinical cases. d In Slovenia, the year of independence; however, this disease was notifiable before 1991. e In the United Kingdom, notifiable only under the Specified Animal Pathogens Order 1998. f Mandatory meat inspection for hydatid cysts.

2007; Nahorski et al., 2013). The relatively low number of patients is largely balanced by the life-long ABZ treatment, iterative hospital stays and major surgical operations including liver transplantation, which greatly increase the economic cost in high-income countries while impairing proper access to care in resource-constrained countries (Torgerson et al., 2010). Response to the new epidemiological challenges includes the establishment of (1) an accurate European Registry of human AE cases, (2) Referral Centres in endemic regions, and (3) a network of health professionals to better manage individual patients, to perform prospective studies and to deal with the occurrence of the disease in regions where it was previously absent.

6.1. Status of AE surveillance at the national level in Europe The Swiss system of AE case recording after mandatory notification was cancelled in 1997 currently relies on active retrieval of cases by 2 academic reference centres, in the Institutes of Parasitology of Zurich and Bern Medicine and Veterinary Medicine Schools respectively, with the collaboration of the parasitology department of the Swiss Tropical and Public Health Institute, Basel University, and of the clinical departments of university hospitals in charge of patient care management (Peter Deplazes, personal communication). This academic consortium has published several retrospective studies based on the national collection of cases (Ammann et al., 2004; Kadry et al., 2005; Stumpe et al., 2007; Torgerson et al., 2008; Frei et al., 2014).

In Germany, legal notification was established in 2001 to allow AE epidemiological surveillance all over the country (Robert Koch Institut, 2006). However, when evaluated and compared to other sources of case recording in Germany, such a formal notification has not proved to be fully efficient. A 3-source capture–recapture analysis (using proxy matching identifiers for detecting double or triple recording, since the legal notification is anonymous) showed that the national surveillance system failed to detect 67% of AE incident cases in Germany in the 2003–2005 period (Jorgensen et al., 2008). In Austria, human AE case recording for the past 40 years has mostly relied on academic studies (Auer and Aspöck, 1991; Kreidl et al., 1998; Kern et al., 2003; Schneider et al., 2013). Since January 1st 2014, all cases diagnosed in Austria have to be reported electronically to the national reference centre where laboratory as well as clinical information on each patient should be collected (Auer, personal communication). Since January 2013, a specialised outpatient clinic has been established in the Dept. of Infectious Diseases of the University Hospital, in Vienna, where patients may seek for advice or treatment, which will improve case recording in the future.1 In Poland, there is currently a legal obligation to report all AE cases to the State Epidemiological Sanitary Inspection. Based on information provided by five clinical centres the first attempt was made in 1998 to register AE cases within the framework of the

1 http://infektiologie-hygiene.universimed.com/artikel/spezialambulanzechinokokkose-%E2%80%93-klinik-diagnose-und-therapie.

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Fig. 3. European Alveolar Echinococcosis (AE) referral centre networking in the past 20 years. (A) Published multicentre studies on epidemiology (EurEchinoReg), epidemio-genetics (HLA studies), and care management (liver transplantation and per-endoscopic interventions) of patients with AE involved in published studies. Red dots: Kern et al. (2003); purple dots: Eiermann et al. (1998) and Zhang et al. (2003); light blue dots: Koch et al. (2003); dark blue dots: Ambregna et al. (2014), in preparation; communication at the United European Gastroenterology Week, Vienna, Austria (2014). (B) European Quality External Evaluation system for AE serology (coordination: WHO-Collaborating Centre for Prevention and Treatment of Human Echinococcosis and French National Centre for Alveolar Echinococcosis). Purple stars: participants since the preliminary study (2013); yellow stars: participants in the first French national study (2013); green stars: participants in the first European study (2014).

EurEchinoReg program (Kern et al., 2003). In 2003 in an effort to formalise and extend the registry, the Chief Sanitary Inspectorate (CSI) of Poland was asked to continue the National AE Registry. First data recorded by the Polish AE Registry were published in 2013 (Nahorski et al., 2013). A similar endeavour has been launched in Lithuania (Marcinkute˙ et al., 2015). In nearly all other countries, even though AE is a notifiable disease in most of them (Table 1), sound data come mostly from academic studies, since notified cases do not represent the totality of cases and because the details given for each case are not sufficient to allow research work on risk factors and their changes with time and/or to get correlations with animal/environmental data. So far, to our knowledge a population-based publicly-funded registry only exists in France, with a satisfactory level of completeness (Grenouillet et al., 2010; Charbonnier et al., 2014). There is no legal obligation for the notification of AE cases in France but the quality of AE case recording by the French National Reference Centre (CNR)2 is evaluated every year by the French National Institute for Disease Surveillance (InVS) which financially supports the registry. This French AE Registry was designed on the model of the WHO-qualified cancer registries and was approved by the Regional Committees for the Protection of People (CPP) in medical research and by the National Informatics and Liberty Commission (CNIL) regarding non-anonymous personal data; more than 99% of patients have agreed to provide such data. Case retrieval is based on spontaneous notification by the physicians of the FrancEchino Network, a consortium of professionals in charge of AE case management in all endemic regions (Fig. 3). This is completed each year, for the whole French territory including the so-called ‘non-endemic areas’, by an active research of cases from the parasitology and

2

http://cnr-echino-alveolaire-ccoms.univ-fcomte.fr/spip.php?article91.

pathology departments of public hospitals, from 2 medical biology laboratories which perform nearly 80% of parasite serology exams in the private sector, and from the public hospital pharmacies, in charge, legally, of providing albendazole to the patients with AE. Follow-up of cases is performed every 2 years, to assess mortality and its relationship with AE. A new database better adapted to easy data entry by the patients’ physicians, and to the use of the Registry for scientific research was designed in 2014 (Charbonnier et al., 2014). 6.2. Status of AE surveillance at the European level The EC has made notification of ‘echinococcosis’, both cystic and alveolar, mandatory for its member states, among other zoonoses, according to the Directive 2003/99/EC1.3 Data are collected from the National Institutes of Disease Surveillance or other similar institutions established by the member states, and they are published in the ‘Summary report on Trends and Sources of Zoonoses, Zoonotic Agents and Food-borne Outbreaks’ co-edited by the ECDC and the EFSA (ECDC and EFSA, 2012). However, the sources of epidemiological data and the modalities of data collection and expression are very diverse and markedly different between the various member states. The 2010 Summary Report concludes: ‘The number of human echinococcosis cases decreased slightly in 2010’. This assessment may sound amazing if it is compared to the conclusions of scientific publications on the subject and in the present Review. This might be partially explained by the fact that the EU Summary Report analyses data collected from governmental

3 Directive 2003/99/EC1 of the European Parliament and of the Council of 17 November 2003 on the monitoring of zoonoses and zoonotic agents, amending Council Decision 90/424/EEC and repealing Council Directive 92/117/EEC. OJ L 325, 12.12.2003, p. 31–40.

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sources without harmonised methodologies, including a frequent and regrettable confusion between E. multilocularis and E. granulosus. The species was declared “unknown” for 21% of cases. There was no differentiation between ‘autochthonous’ and ‘imported’ cases, a differentiation which is important for a proper understanding of the epidemiological situation of both cystic and alveolar echinococcosis, 2 very different diseases in terms of presentation and public health significance. In 2010, among non-member states, Switzerland and Norway also reported data on zoonoses to the ECDC and EFSA; however, data for echinococcosis were only available for Norway, not for Switzerland, the country with the highest incidence of AE cases in Europe. 7. How to better assess human epidemiology and fight against AE in Europe? Standardised registration and prospective follow-up protocols are essential to properly assess the epidemiology of the disease and its trends in all European countries. An appropriate surveillance scheme at European level is thus, absolutely necessary to set up similar case-collection frameworks and procedures in the various European countries. Such a surveillance scheme should clearly differentiate between E. multilocularis and E. granulosus infection, and between autochthonous and imported cases; it should include data on a prolonged follow-up of the patients to draw survival curves. It should also provide environmental data, data on animal intermediate and definitive hosts collected in a uniform manner, and analyse all data in a comprehensive way. National initiatives and academic attempts at networking clinical centres in university hospitals to perform retrospective studies on AE epidemiology and/or care management of AE patients (Fig. 3) should pave the way for a more reliable European AE recording system with commonly agreed standards, provided that appropriate funding is available (Charbonnier et al., 2014). The constitution of a common European Registry would also make prospective studies on selected cases possible to test for diagnosis or follow-up tools and for new therapeutic options (Kern, 2006; Vuitton and Bresson-Hadni, 2014). References Altintas, N., 2003. Past to present: echinococcosis in Turkey. Acta Trop. 85, 105–112. Ambregna S., Vuitton L., Koch S., Sulz M.C., Chevaux J.B., Darius Moradpour D., Bichard P., Prat F., Vanbiervliet G., Kull E., Richou C., Vuitton D.A., Bresson-Hadni, Per-endoscopic management of alveolar echinococcosis biliary complications: a European survey. UEG Week 2014, Vienna, Austria (abstract UEG14ABS-5252). Ammann, R.W., Renner, E.C., Gottstein, B., Grimm, F., Eckert, J., Renner, E.L., Swiss Echinococcosis Study Group, 2004. Immunosurveillance of alveolar echinococcosis by specific humoral and cellular immune tests: long-term analysis of the Swiss chemotherapy trial (1976–2001). J. Hepatol. 41, 551–559. ˇ Antolová, D., Miterpáková, M., Radonák, J., Hudaˇcková, D., Szilágyiová, M., Zˇ áˇcek, M., 2014. Alveolar echinococcosis in a highly endemic area of northern Slovakia between 2000 and 2013. Euro Surveill. 19, 34, Available online: http:// www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20882 ´ P., 2009. The first Antolová, D., Reiterová, K., Miterpáková, M., Dinkel, A., Dubinsky, finding of Echinococcus multilocularis in dogs in Slovakia: an emerging risk for spreading of infection. Zoonoses Public Health 56, 53–58. Auer, H., Aspöck, H., 1991. Incidence, prevalence and geographic distribution of human alveolar echinococcosis in Austria from 1854 to 1990. Parasitol. Res. 77, 430–436. ˇ ˇ Bagrade, G., Snábel, V., Romig, T., Ozolin¸sˇ , J., Hüttner, M., Miterpáková, M., Sevcová, ´ P., 2008. Echinococcus multilocularis is a frequent parasite of red D., Dubinsky, foxes (Vulpes vulpes) in Latvia. Helminthologia 45, 157–161. Bartholomot, G., Vuitton, D.A., Harraga, S., Shi, D.Z., Giraudoux, P., Barnish, G., Wang, Y.H., MacPherson, C.N., Craig, P.S., 2002. Combined ultrasound and serologic screening for hepatic alveolar echinococcosis in central China. Am. J. Trop. Med. Hyg. 66, 23–29. Berke, O., Romig, T., von Keyerlingk, M., 2008. Emergence of Echinococcus multilocularis among red foxes in northern Germany, 1991–2005. Vet. Parasitol. 155, 319–322. ´ B., Nikolic, ´ A., Radivojevic, ´ S.K., Klun, I., Djurkovic-Djakovi ´ ´ O., 2012. Bobic, c, Echinococcosis in Serbia: an issue for the 21st century? Foodborne Pathog. Dis. 9, 967–973.

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Bresson-Hadni, S., Vuitton, D.A., Bartholomot, B., Heyd, B., Godart, D., Meyer, J.P., Hrusovsky, S., Becker, M.C., Mantion, G., Lenys, D., Miguet, J.P., 2000. A twenty-year history of alveolar echinococcosis analysis of a series of 117 patients from eastern France. Eur. J. Gastroenterol. Hepatol. 12, 327–336. ˙ R., Marcinkute, ˙ A., Strupas, K., Sokolovas, V., Deplazes, P., Mathis, A., Bruˇzinskaite, ˇ ¯ unas, M., 2007. Alveolar echinococcosis, Lithuania. Emerg. Infect. Eddi, C., Sark Dis. 13, 1618–1619. ˇ ˙ R., Sark ¯ Bruˇzinskaite, unas, M., Torgerson, P.R., Mathis, A., Deplazes, P., 2009. Echinococcosis in pigs and intestinal infection with Echinococcus spp. in dogs in southwestern Lithuania. Vet. Parasitol. 160, 237–241. Casulli, A., Bart, J.M., Knapp, J., La Rosa, G., Dusher, G., Gottstein, B., Di Cerbo, A., Manfredi, M.T., Genchi, C., Piarroux, R., Pozio, E., 2009. Multi-locus microsatellite analysis supports the hypothesis of an autochthonous focus of Echinococcus multilocularis in northern Italy. Int. J. Parasitol. 39, 837–842. Casulli, A., Manfredi, M.T., La Rosa, G., Di Cerbo, A.R., Dinkel, A., Romig, T., Deplazes, P., Genchi, C., Pozio, E., 2005. Echinococcus multilocularis in red foxes (Vulpes vulpes) of the Italian Alpine region: is there a focus of autochthonous transmission? Int. J. Parasitol. 35, 1079–1083. Charbonnier, A., Knapp, J., Demonmerot, F., Bresson-Hadni, S., Raoul, F., Grenouillet, F., Millon, L., Vuitton, D.A., Damy, S., 2014. A new data management system for the French National Registry of human alveolar echinococcosis cases. Parasite 21, 69. Chauchet, A., Grenouillet, F., Knapp, J., Richou, C., Delabrousse, E., Dentan, C., Millon, L., Di Martino, V., Contreras, R., Deconinck, E., Blagosklonov, O., Vuitton, D.A., Bresson-Hadni, S., FrancEchino, N., etwork, 2014. Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppression-associated conditions. Clin. Infect. Dis. 59, 1095–1104. ´ ´ ´ D., Pavlovic, ´ I., Kuliˇsic, ´ Z., Ivetic, ´ V., Penezic, ´ A., Cosi ´ N., 2012. Echinococcus Cirovi c, c, multilocularis in the European beaver (Castor fibre L.) from Serbia: first report. Vet. Rec. 171, 100. Claudon, M., Chaulieu, C., Delgoffe, C., Desplechain, C., Thomas, D., Regent, D., Treheux, A., 1984. Role of echography in the diagnosis and monitoring of hepatic alveolar echinococcosis. J. Radiol., 773–780 (in French). Combes, B., Comte, S., Raton, V., Raoul, F., Boué, F., Umhang, G., Favier, S., Dunoyer, C., Woronoff, N., Giraudoux, P., 2012. Westward spread of Echinococcus multilocularis in foxes, France, 2005–2010. Emerg. Infect. Dis. 18, 2059–2062. Comte, S., Raton, V., Raoul, F., Hegglin, D., Giraudoux, P., Deplazes, P., Favier, S., Gottschek, D., Umhang, G., Boué, F., Combes, B., 2013. Fox baiting against Echinococcus multilocularis: contrasted achievements among two medium size cities. Prev. Vet. Med. 111, 147–155. Coodley, E.L., 1970. Diagnostic modalities in jaundice. Am. J. Gastroenterol. 54, 112–125. Craig, P.S., Giraudoux, P., Shi, D., Bartholomot, B., Barnish, G., Delattre, P., Quere, J.P., Harraga, S., Bao, G., Wang, Y., Lu, F., Ito, A., Vuitton, D.A., 2000. An epidemiological and ecological study of human alveolar echinococcosis transmission in south Gansu, China. Acta Trop. 77, 167–177. Davidson, R.K., Robertson, L.J., 2012. European pet travel: misleading information from veterinarians and government agencies. Zoonoses Public Health 59, 575–583. Delbecque, K., Detry, O., Hayette, M.P., Jeukens, T., Delvenne, P., Hardy, N., Delwaide, J., Demonty, J., Boverie, J., Demol, P., Hauwaert, C., Honoré, P., Boniver, J., Jacquet, N., 2002. A case of hepatic alveolar echinococcosis contracted in Belgium. Acta Gastroenterol. Belg. 65, 55–60. Dentan, C., Mazet, R., Gilson, M., Marchou-Lopez, S., Gaudin, P., 2012. Rheumatoid arthritis, alveolar echinococcosis, and rituximab: a case report. Joint Bone Spine 79, 325–327. Deplazes, P., 2006. Ecology and epidemiology of Echinococcus multilocularis in Europe. Parassitologia 48, 37–39. Deplazes, P., Hegglin, D., Gloor, S., Romig, T., 2004. Wilderness in the city: the urbanization of Echinococcus multilocularis. Trends Parasitol. 20, 77–84. Deplazes, P., van Knapen, F., Schweiger, A., Overgaauw, P.A., 2011. Role of pet dogs and cats in the transmission of helminthic zoonoses in Europe, with a focus on echinococcosis and toxocarosis. Vet. Parasitol. 182, 41–53. Detry, O., Honoré, C., Delwaide, J., Demonty, J., De Roover, A., Vivario, M., Thiry, A., Hayette, M.P., Belaïche, J., Meurisse, M., Honoré, P., 2005. Endemic alveolar echinococcosis in Southern Belgium? Acta Gastroenterol. Belg. 68, 1–4. Didier, D., Weiler, S., Rohmer, P., Lassegue, A., Deschamps, J.P., Vuitton, D., Miguet, J.P., Weill, F., 1985. Hepatic alveolar echinococcosis: correlative US and CT study. Radiology 154, 179–186. Dobiás, J., 1975. The frequency of autopsies and bioptic examinations in Czechoslovakia from 1964 to 1973. Zentralbl. Allg. Pathol. 119, 355–358 (in German). Dubinsky, P., Malczewski, A., Miterpakova, M., Gawor, J., Reiterova, K., 2006. Echinococcus multilocularis in the red fox Vulpes vulpes from the East Carpathian region of Poland and the Slovak Republic. J. Helminthol. 80, 243–247. Dubinsky, P., Várady, M., Reiterová, K., Miterpáková, M., Turceková, L., 2001. Prevalence of Echinococcus multilocularis in red foxes in the Slovak Republik. Helminthologia 38, 215–219. ECDC, EFSA, 2012. The European union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2010. EFSA J. 10, 2597, 442 pp http://www.efsa.europa.eu/en/efsajournal/pub/2597.htm Eckert, J., 1997. Epidemiology of Echinococcus multilocularis and E. granulosus in central Europe. Parassitologia 39, 337–344. Eckert, E., Deplazes, P., 1999. Alveolar echinococcosis in humans: the current situation in central Europe and the need for countermeasures. Parasitol. Today 15, 315–319.

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ARTICLE IN PRESS D.A. Vuitton et al. / Veterinary Parasitology xxx (2015) xxx–xxx

Eckert, J., Deplazes, P., 2004. Biological, epidemiological, and clinical aspects of echinococcosis, a zoonosis of increasing concern. Clin. Microbiol. Rev. 17, 107–135. Eiermann, T.H., Bettens, F., Tiberghien, P., Schmitz, K., Beurton, I., Bresson-Hadni, S., Ammann, R.W., Goldmann, S.F., Vuitton, D.A., Gottstein, B., Kern, P., 1998. HLA and alveolar echinococcosis. Tissue Antigens 52, 124–129. Enemark, H.L., Al-Sabi, M.N., Knapp, J., Staahl, M., Chríel, M., 2013. Detection of a high-endemic focus of Echinococcus multilocularis in red foxes in southern Denmark, January 2013. Euro Surveill. 18, 20420. Fesseler, M., 1990. Vergleich der Endemiegebiete von Echinococcus multilocularis und Tollwut in Mitteleuropa. In: Veterinary Doctoral Thesis. University of Zurich, Zurich, Switzerland. Fischer, C., Reperant, L.A., Weber, J.M., Hegglin, D., Deplazes, P., 2005. Echinococcus multilocularis infections of rural, residential and urban foxes (Vulpes vulpes) in the canton of Geneva, Switzerland. Parasite 12, 339–346. Frei, P., Misselwitz, B., Prakash, M.K., Schoepfer, A.M., Prinz Vavricka, B.M., Müllhaupt, B., Fried, M., Lehmann, K., Ammann, R.W., Vavricka, S.R., 2014. Late biliary complications in human alveolar echinococcosis are associated with high mortality. World J. Gastroenterol. 20, 5881–5888. Gaultier, J.B., Hot, A., Mauservey, C., Dumortier, J., Coppere, B., Ninet, J., 2009. Granulomatous liver disease as the presenting feature of alveolar echinococcosis in an hepatitis C infected cardiac transplant patient. Rev. Med. Interne 30, 812–815 (in French). Geller, I., Railian, N.I., 1976. 1st case of alveococcosis. Vrach. Delo 5, 147–148 (in Russian). Geyer, M., Wilpert, J., Wiech, T., Theilacker, C., Stubanus, M., Kramer-Zucker, A., Fischer, K.G., Drognitz, O., Frydrychowicz, A., Kern, W., Walz, G., Pisarski, P., 2011. Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient. Transpl. Infect. Dis. 13, 278–284. ˘ Głuszcz, A., Kalczak, M., 1960. Banblowiec wielokomorowy (Echinococcus ˘ ˘ wantroby [Echinococcus alveolaris—a alveolaris)— rzadka postac´ı banblowca rare form of the echinococcosis of the liver] [in Polish]. Pol. Tyg. Lek. 15, 559–562. Grenouillet, F., Knapp, J., Millon, L., Raton, V., Richou, C., Piarroux, M., Piarroux, R., Mantion, G., Vuitton, D.A., Bresson-Hadni, S., 2010. Human alveolar echinococcosis in France, update 2010. In: Zoonoses: for an Integrated Health Approach at Human-animal Interface. Bull. Epidémiol. Hebd., Hors-série, 14 Septembre 2010 (in French) http://www.invs.sante.fr/beh/2010/hs/beh hs.pdf Gruener, B.C.C., Brunetti, E., Menezes, C.N., Haerter, G., Grobusch, M.P., Kern, P., 2008. Accelerated larval growth of Echinococcus spp. in the immunodeficient host? (abstract). Am. J. Trop. Med. Hyg. 6, 118. Hegglin, D., Deplazes, P., 2013. Control of Echinococcus multilocularis: strategies, feasibility and cost-benefit analyses. Int. J. Parasitol. 43, 327–337. Hofer, S., Gloor, S., Müller, U., Mathis, A., Hegglin, D., Deplazes, P., 2000. High prevalence of Echinococcus multilocularis in urban red foxes (Vulpes vulpes) and voles (Arvicola terrestris) in the city of Zurich, Switzerland. Parasitology 120, 135–142. Horváth, A., Patonay, A., Bánhegyi, D., Szlávik, J., Balázs, G., Görög, D., Werling, K., 2008. The first case of human alveolar echinococcosis in Hungary. Orv. Hetil. 149, 795–799 (in Hungarian). ´ L., Hiemer, I., Denemark, L., Curík, Hozáková-Lukácová, L., Kolárová, L., Roznovsky, R., Dvorácková, J., 2009. Alveolar echinococcosis–a new emerging disease? Cas. Lek. Cesk. 148, 132–136 (in Czech). Jorgensen, P., an der Heiden, M., Kern, P., Schöneberg, I., Krause, G., Alpers, K., 2008. Underreporting of human alveolar echinococcosis, Germany. Emerg. Infect. Dis. 14, 935–937. Kadry, Z., Renner, E.C., Bachmann, L.M., Attigah, N., Renner, E.L., Ammann, R.W., Clavien, P.A., 2005. Evaluation of treatment and long-term follow-up in patients with hepatic alveolar echinococcosis. Br. J. Surg. 92, 1110–1116. Kapel, C.M.O., Saeed, I., 2000. Echinococcus multilocularis—a new zoonotic parasite in Denmark. Dansk Veterinaertidsskrift 83, 14–16. Kayacan, S.M., Vatansever, S., Temiz, S., Uslu, B., Kayacan, D., Akkaya, V., Erk, O., Saka, B., Karadag, A., Turkmen, K., Yakar, F., Guler, K., 2008. Alveolar echinococcosis localized in the liver, lung and brain. Chin. Med. J. (Engl.) 121, 90–92. Kern, P., Ammon, A., Kron, M., Sinn, G., Sander, S., Petersen, L.R., Gaus, W., Kern, P., 2004. Risk factors for alveolar echinococcosis in humans. Emerg. Infect. Dis. 10, 2088–2093. Kern, P., 2006. Medical treatment of echinococcosis under the guidance of Good Clinical Practice (GCP/ICH). Parasitol. Int. 55 (Suppl), S273–S282. Kern, P., Bardonnet, K., Renner, E., Auer, H., Pawlowski, Z., Ammann, R.W., Vuitton, D.A., Kern, P., European Echinococcosis Registry, 2003. European echinococcosis registry: human alveolar echinococcosis, Europe, 1982–2003. Emerg. Infect. Dis. 9, 343–349. Kern, P., Gruener, B., Wahlers, K., 2011. Diagnosis and course of echinococcocal diseases in the transplant setting. Transpl. Infect. Dis. 13, 217–221. Keutgens, A., Simoni, P., Detrembleur, N., Frippiat, F., Giot, J.B., Spirlet, F., Aghazarian, S., Descy, J., Meex, C., Huynen, P., Melin, P., Müller, N., Gottstein, B., Carlier, Y., Hayette, M.P., 2013. Fatal alveolar echinococcosis of the lumbar spine. J. Clin. Microbiol. 51, 688–691. Kharchenko, V.A., Kornyushin, V.V., Varodi, E.I., Malega, O.M., 2008. Occurrence of Echinococcus multilocularis (Cestoda, Taeniidae) in red foxes (Vulpes vulpes) from Western Ukraine. Acta Parasitol. 53, 36–40. Knapp, J., Staebler, S., Bart, J.M., Stien, A., Yoccoz, N.G., Drögemüller, C., Gottstein, B., Deplazes, P., 2012. Echinococcus multilocularis in Svalbard, Norway:

microsatellite genotyping to investigate the origin of a highly focal contamination. Infect. Genet. Evol. 12, 1270–1274. Koch, S., Bresson-Hadni, S., Miguet, J.P., Crumbach, J.P., Gillet, M., Mantion, G.A., Heyd, B., Vuitton, D.A., Minello, A., Kurtz, S., European, C., ollaborating, C., linicians, 2003. Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report. Transplantation 75, 856–863. Kovác, A., 1984. Development of abdominal ultrasonography in Czechoslovakia. Vnitr. Lek. 30, 699–703 (in Slovak). Kreidl, P., Allerberger, F., Judmaier, G., Auer, H., Aspöck, H., Hall, A.J., 1998. Domestic pets as risk factors for alveolar hydatid disease in Austria. Am. J. Epidemiol. 147, 978–981. Landen, S., Van de Sande, J., Berger, P., Ursaru, D., Baert, J., Delugeau, V., 2013. Alveolar echinococcosis in a Belgian urban dweller. Acta Gastroenterol. Belg. 76, 317–321. Logar, J., Soba, B., Lejko-Zupanc, T., Kotar, T., 2007. Human alveolar echinococcosis in Slovenia. Clin. Microbiol. Infect. 13, 544–546. Malczewski, A., Gawor, J., Malczewska, M., 2008. Infection of red foxes (Vulpes vulpes) with Echinococcus multilocularis during the years 2001–2004 in Poland. Parasitol. Res. 103, 501–505. ˇ ˙ A., Sark ¯ Marcinkute, unas, M., Moks, E., Saarma, U., Jokelainen, P., Bagrade, G., Laivacuma, S., Strupas, K., Sokolovas, V., Deplazes, P., 2015. Echinococcus infections in the Baltic region. Vet. Parasitol. (in press, same issue). Miguet, J.P. L’échinococcose alvéolaire en Franche-Comté (à propos de vingt cas). Medical Doctoral Thesis, University of Franche-Comté, Besanc¸on, France, N◦ 179, 1973, 191 pp. (in French). Moks, E., Saarma, U., Valdmann, H., 2005. Echinococcus multilocularis in Estonia. Emerg. Infect. Dis. 11, 1973–1974. Mörl, M., 1982. Echinococcosis. Rational diagnosis and therapy. Fortschr. Med. 100, 1131–1136 (in German). Myjak, P., Nahorski, W., Pietkiewicz, H., von Nickisch-Rosenegk, M., Stolarczyk, J., Kacprzak, E., Felczak-Korzybska, I., Szostakowska, B., Lucius, R., 2003. Molecular confirmation of human alveolar echinococcosis in Poland. Clin. Infect. Dis. 37, e121–e125. ´ Nahorski, W.L., Knap, J.P., Pawłowski, Z.S., Krawczyk, M., Polanski, J., Stefaniak, J., Patkowski, W., Szostakowska, B., Pietkiewicz, H., Grzeszczuk, A., ˛ E., Wnukowska, N., Paul, M., Kacprzak, E., Felczak-Korzybska, I., Gołab, Sokolewicz-Bobrowska, E., Ni´scigorska-Olsen, J., Czyrznikowska, A., Chomicz, L., Cielecka, D., Myjak, P., 2013. Human alveolar echinococcosis in Poland: 1990–2011. PLoS Negl. Trop. Dis. 7, e1986. Nakao, M., Xia, N., Okamoto, M., Yanagida, T., Sako, Y., Ito, A., 2009. Geographic pattern of genetic variation in the fox tapeworm Echinococcus multilocularis. Parasitol. Int. 58, 384–389. Nonaka, N., Hirokawa, H., Inoue, T., Nakao, R., Ganzorig, S., Kobayashi, F., Inagaki, M., Egoshi, K., Kamiya, M., Oku, Y., 2008. The first instance of a cat excreting Echinococcus multilocularis eggs in Japan. Parasitol. Int. 57, 519–520. Osterman Lind, E., Juremalm, M., Christensson, D., Widgren, S., Hallgren, G., Ågren, E.O., Uhlhorn, H., Lindberg, A., Cedersmyg, M., Wahlström, H., 2011. First detection of Echinococcus multilocularis in Sweden, February to March 2011. Euro Surveill. 16, 14. Perrin, M.L.H.M. L’échinococcose alvéolaire du foie, principalement chez l’homme en France. Medical Doctoral Thesis, University of Nancy, Nancy, France, N◦ 113, 1932, 232 pp. (in French). Petavy, A.F., Tenora, F., Deblock, S., Sergent, V., 2000. Echinococcus multilocularis in domestic cats in France. A potential risk factor for alveolar hydatid disease contamination in humans. Vet. Parasitol. 87, 151–156. Piarroux, M., Piarroux, R., Giorgi, R., Knapp, J., Bardonnet, K., Sudre, B., Watelet, J., Dumortier, J., Gérard, A., Beytout, J., Abergel, A., Mantion, G., Vuitton, D.A., Bresson-Hadni, S., 2011. Clinical features and evolution of alveolar echinococcosis in France from 1982 to 2007: results of a survey in 387 patients. J. Hepatol. 55, 1025–1033. Piarroux, M., Piarroux, R., Knapp, J., Bardonnet, K., Dumortier, J., Watelet, J., Gérard, A., Beytout, J., Abergel, A., Bresson-Hadni, S., Gaudart, J., FrancEchino Surveillance Network, 2013. Populations at risk for alveolar echinococcosis, France. Emerg. Infect. Dis. 19, 721–728. Posselt, A., 1906. Die stellung des Alveolarechinococcus. Münch. Med. Wochenschr. 53, 537–605. Posselt, A., 1928. Der Alveolarechinokokkus und seine Chirurgie. Neue Dtsch. Chirurg. Bruns. 40, 305–418 (in German). Robert Koch Institut, 2006. Epidemiologie der Fuchsbandwurmerkrankungen in Deutschland—daten des Echinokokkose Register. Epidemiol. Bull. (13 April/Nr. 15). Romig, T., 2009. Echinococcus multilocularis in Europe-state of the art. Vet. Res. Commun. 33 (Suppl. 1), 31–34. Romig, T., Thoma, D., Weible, A.K., 2006. Echinococcus multilocularis–a zoonosis of anthropogenic environments? J. Helminthol. 80, 207–212. Said-Ali, Z., Grenouillet, F., Knapp, J., Bresson-Hadni, S., Vuitton, D.A., Raoul, F., Richou, C., Millon, L., Giraudoux, P., FrancEchino Network, 2013. Detecting nested clusters of human alveolar echinococcosis. Parasitology 140, 1693–1700. ˇSarkunas, ˙ R., Marcinkute, ˙ A., Strupas, K., Sokolovas, V., Mathis, A., ¯ M., Bruˇzinskaite, Deplazes, P., 2010. Emerging alveolar echinococcosis (AE) in humans and high prevalence of Echinococcus multilocularis in foxes and raccoon dogs in Lithuania. Acta Vet. Scand. 52 (Suppl. 1), S11, Available at: http://www. actavetscand.com/content/52/S1/S11

Please cite this article in press as: Vuitton, D.A., et al., Clinical epidemiology of human AE in Europe. Vet. Parasitol. (2015), http://dx.doi.org/10.1016/j.vetpar.2015.07.036

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Schneider, R., Aspöck, H., Auer, H. 2013. Unexpected increase of alveolar echinococcosis, Austria, 2011. Emerg. Infect. Dis. 19, 475–477. Schweiger, A., Ammann, R.W., Candinas, D., Clavien, P.A., Eckert, J., Gottstein, B., Halkic, N., Muellhaupt, B., Prinz, B.M., Reichen, J., Tarr, P.E., Torgerson, P.R., Deplazes, P., 2007. Human alveolar echinococcosis after fox population increase, Switzerland. Emerg. Infect. Dis. 13, 878–882. Shimalov, V.V., Shimalov, V.T., 2001. Alveolar echinococcosis in Belorussian polesie. Parazitologiia 35, 145–148 (in Russian). Sikó, S.B., Deplazes, P., Ceica, C., Tivadar, C.S., Bogolin, I., Popescu, S., Cozma, V., 2011. Echinococcus multilocularis in southeastern Europe (Romania). Parasitol. Res. 108, 1093–1097. Sowiakowski, J., 1955. Echinococcus alveolaris [in Polish]. Pol. Tyg. Lek. 10, 46–52. Sréter, T., Széll, Z., Egyed, Z., Varga, I., 2003. Echinococcus multilocularis: an emerging pathogen in Hungary and Central Eastern Europe? Emerg. Infect. Dis. 9, 384–386. Stieger, C., Hegglin, D., Schwarzenbach, G., Mathis, A., Deplazes, P., 2002. Spatial and temporal aspects of urban transmission of Echinococcus multilocularis. Parasitology 124, 631–640. Stumpe, K.D., Renner-Schneiter, E.C., Kuenzle, A.K., Grimm, F., Kadry, Z., Clavien, P.A., Deplazes, P., von Schulthess, G.K., Muellhaupt, B., Ammann, R.W., Renner, E.L., 2007. F-fluorodeoxyglucose (FDG) positron-emission tomography of Echinococcus multilocularis liver lesions: prospective evaluation of its value for diagnosis and follow-up during benzimidazole therapy. Infection 35, 11–18. Süld, K., Valdmann, H., Laurimaa, L., Soe, E., Davison, J., Saarma, U., 2014. An invasive vector of zoonotic disease sustained by anthropogenic resources: the raccoon dog in northern Europe. PLoS One 9, e96358. Takumi, K., de Vries, A., Chu, M.L., Mulder, J., Teunis, P., van der Giessen, J., 2008. Evidence for an increasing presence of Echinococcus multilocularis in foxes in The Netherlands. Int. J. Parasitol. 38, 571–578. Tappe, D., Frosch, M., 2007. Rudolf Virchow and the recognition of alveolar echinococcosis, 1850s. Emerg. Infect. Dis. 13, 732–735. Theodoropoulos, G., Kolitsopoulos, A., Archimandritis, A., Melissinos, K., 1978. Echinococcose alvéolaire hépatique. Trois observations en Grèce. Presse Méd. 7, 3056. Torgerson, P.R., Keller, K., Magnotta, M., Ragland, N., 2010. The global burden of alveolar echinococcosis. PLoS Negl. Trop. Dis. 4, e722. Torgerson, P.R., Schweiger, A., Deplazes, P., Pohar, M., Reichen, J., Ammann, R.W., Tarr, P.E., Halkik, N., Müllhaupt, B., 2008. Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years. J. Hepatol. 49, 72–77. Tulin, A.I., Ribenieks, R., Pogodina, E.N., Stutska, R., Shavlovskis, I.A., Gardovskis, I.A., 2012. Diagnostics and surgical treatment of liver echinococcosis in Latvia. Vestn. Khir. Im. I. I Grek. 171, 38–44 (in Russian). Uhlhorn, H., Lindberg, A., Cedersmyg, M., Wahlström, H., 2011. First detection of Echinococcus multilocularis in Sweden, February to March 2011. Euro Surveill. 16, 14. van Dommelen, L., Stoot, J.H., Cappendijk, V.C., Abdul Hamid, M.A., Stelma, F.F., Kortbeek, L.M., van der Giessen, J., Oude Lashof, A.M., 2012. The first locally acquired human infection of Echinococcus multilocularis in The Netherlands. J. Clin. Microbiol. 50, 1818–1820.

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Viel, J.F., Giraudoux, P., Abrial, V., Bresson-Hadni, S., 1999. Water vole (Arvicola terrestris scherman) density as risk factor for human alveolar echinococcosis. Am. J. Trop. Med. Hyg. 61, 559–565. Vierordt, H., 1886. Abhandlung über den multilokulären Echinococcus. Akademische Verlagsbuchhandlung von J.C.B. Mohr. Freiburg (in German). Virchow, R., 1855. Die multiloculäre, ulcerirende Echinokokkengeschwulst der Leber. Verh. Physicalisch-Medicinischen Ges., 84–95 (in German). Vuitton, D.A., Bresson-Hadni, S., 2014. Alveolar echinococcosis: evaluation of therapeutic strategies. Expert Opin. Orphan Drugs 2, 67–86. Vuitton, D.A., Gottstein, B., 2010. Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay. J. Biomed. Biotechnol. 2010, 923193. Vuitton, D.A., Millon, L., Gottstein, B., Giraudoux, P., 2014. Proceedings of the International Symposium—–Innovation for the management of echinococcosis, Besanc¸on, March 27–29, 2014. Parasite 21, 28. Vuitton, D.A., Wang, Q., Zhou, H.X., Raoul, F., Knapp, J., Bresson-Hadni, S., Wen, H., Giraudoux, P., 2011. A historical view of alveolar echinococcosis, 160 years after the discovery of the first case in humans: part 1. What have we learnt on the distribution of the disease and on its parasitic agent? Chin. Med. J. (Engl.) 124, 2943–2953. Vuitton, D.A., Zhang, S.L., Yang, Y., Godot, V., Beurton, I., Mantion, G., Bresson-Hadni, S., 2006. Survival strategy of Echinococcus multilocularis in the human host. Parasitol. Int. 55, S51–S55. Vuitton, A., Zhou, H., Bresson-Hadni, S., Wang, Q., Piarroux, M., Raoul, F., Giraudoux, P., 2003. Epidemiology of alveolar echinococcosis with particular reference to China and Europe. Parasitology 127 (Suppl), S87–S107. Weill, F., Eisencher, A., Zeltner, F., 1978. Ultrasonic study of the normal and dilated biliary tree. The shotgun sign. Radiology 127, 221–224. Weill, F., Kraehenbuhl, J.R., Bourgoin, A., Miguet, J.P., Gillet, M., 1975. Aspects echo-tomographiques de l’échinococcose alvéolaire. Med. Chir. Dig. 4, 35–37 (in French). Weiner, S.M., Krenn, V., Koelbel, C., Hoffmann, H.G., Hinkeldey, K., Ockert, D., 2011. Echinococcus multilocularis infection and TNF inhibitor treatment in a patient with rheumatoid arthritis. Rheumatol. Int. 31, 1399–1400. Yang, Y.R., Craig, P.S., Vuitton, D.A., Williams, G.M., Sun, T., Liu, T.X., Boufana, B., Giraudoux, P., Teng, J., Li, Y., Huang, L., Zhang, W., Jones, M.K., McManus, D.P., 2008. Serological prevalence of echinococcosis and risk factors for infection among children in rural communities of southern Ningxia, China. Trop. Med. Int. Health 13, 1086–1094. Yang, Y.R., Ellis, M., Sun, T., Li, Z., Liu, X., Vuitton, D.A., Bartholomot, B., Giraudoux, P., Craig, P.S., Boufana, B., Wang, Y., Feng, X., Wen, H., Ito, A., McManus, D.P., 2006. Unique family clustering of human echinococcosis cases in a Chinese community. Am. J. Trop. Med. Hyg. 74, 487–494. Zhang, S., Penfornis, A., Harraga, S., Chabod, J., Beurton, I., Bresson-Hadni, S., Tiberghien, P., Kern, P., Vuitton, D.A., 2003. Polymorphisms of the TAP1 and TAP2 genes in human alveolar echinococcosis. Eur. J. Immunogenet. 30, 133–139.

Please cite this article in press as: Vuitton, D.A., et al., Clinical epidemiology of human AE in Europe. Vet. Parasitol. (2015), http://dx.doi.org/10.1016/j.vetpar.2015.07.036