Travel-associated hepatitis A in Europe, 2009 to 2015

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1 Reserch rticle Trvel-ssocited heptitis A in Europe, 2009 to 2015 Julien Beuté¹, Therese Westrell¹, Dniel Schmid², Luise Müller³, Jevgeni Epstein⁴, Mi Kontio⁵, Elisbeth Couturier⁶, Mirko Fber⁷, Kssini Mellou⁸, Mri-Louise Borg⁹, Ingrid Friesem 10, Line Vold 11, Ettore Severi 1,12 1. Europen Centre for Disese Prevention nd Control (ECDC), Stockholm, Sweden 2. Austrin Agency for Helth nd Food Sfety, Vienn, Austri 3. Sttens Serum Institut, Copenhgen, Denmrk 4. Helth Bord, Tllinn, Estoni 5. Ntionl Institute for Helth nd Welfre, Helsinki, Finlnd 6. Snté Publique Frnce, Sint-Murice, Frnce 7. Robert Koch Institut, Berlin, Germny 8. Hellenic Centre for Disese Control nd Prevention, Athens, Greece 9. Infectious Disese Prevention nd Control Unit, Msid, Mlt 10. Ntionl Institute for Public Helth nd the Environment, Bilthoven, The Netherlnds 11. Norwegin Institute of Public Helth, Oslo, Norwy 12. Krolinsk Institutet, Stockholm, Sweden Correspondence: Julien Beuté (julien.beute@ecdc.europ.eu) Cittion style for this rticle: Beuté Julien, Westrell Therese, Schmid Dniel, Müller Luise, Epstein Jevgeni, Kontio Mi, Couturier Elisbeth, Fber Mirko, Mellou Kssini, Borg Mri- Louise, Friesem Ingrid, Vold Line, Severi Ettore. Trvel-ssocited heptitis A in Europe, 2009 to Euro Surveill. 2018;23(22):pii= org/ / es Article submitted on 22 Aug 2017 / ccepted on 25 Jn 2018 / published on 31 My 2018 Bckground: Trvel to countries with high or intermedite heptitis A virus (HAV) endemicity is risk fctor for infection in residents of countries with low HAV endemicity. Aim: The objective of this study ws to estimte the risk for heptitis A mong Europen trvellers using surveillnce nd trvel denomintor dt. Methods: We retrieved heptitis A surveillnce dt from 13 Europen Union (EU)/ Europen Economic Are (EEA) countries with comprehensive surveillnce systems nd trvel denomintor dt from the Sttisticl Office of the Europen Union. A trvel-ssocited cse of heptitis A ws defined s ny cse reported s imported. Results: From 2009 to 2015, the 13 countries reported 18,839 confirmed cses of heptitis A, of which 5,233 (27.8%) were trvel-ssocited. Of these, 39.8% were mong children younger thn 15 yers. The overll risk ssocited with trvel brod decresed over the period t n nnul rte of 3.7% (95% confidence intervl (CI): ) from 0.70 cses per million nights in 2009 to 0.51 in The highest risk ws observed in trvellers to Afric (2.11 cses per million nights). Cses more likely to be reported s trvel-ssocited were mle nd of younger ge (< 25 yers). Conclusion: Trvel is still mjor risk fctor for HAV infection in the EU/EEA, lthough the risk of infection my hve slightly decresed in recent yers. Children younger thn 15 yers ccounted for lrge proportion of cses nd should be prioritised for vccintion. Bckground Heptitis A is one of the most common cuses of foodborne infection worldwide [1]. The disese spreds by fecl-orl trnsmission either by consumption of contminted food or person-to-person contct [2]. Although the globl burden of heptitis A hs decresed in the pst 20 yers [3], the World Helth Orgnistion (WHO) still defines most of the world s low- nd middle-income countries s experiencing high or intermedite heptitis A virus (HAV) endemicity [4]. In Europe, the incidence of heptitis A decresed substntilly [5,6] nd most countries in the Europen Union (EU)/ Europen Economic Are (EEA) currently experience low or very low HAV endemicity [7]. In such popultions with n incresing proportion of susceptible individuls, trvel is n importnt risk fctor for infection [2,6]. Europen trvellers to countries with high HAV endemicity re often infected when consuming contminted food items or drinks during trvel [8,9]. A similr epidemiology is observed in other highincome countries such s the United Sttes (US) where c 40% of ll heptitis A cses re trvel-ssocited [10]. The WHO nd most EU/EEA countries recommend HAV vccintion to Europen trvellers visiting countries with intermedite or high endemicity [11]. Nevertheless, findings from recent survey mong overses trvellers from Frnce, Germny, Itly, Spin, nd the United Kingdom (UK) suggested moderte vccine coverge ginst HAV with only hlf of the occsionl trvellers visiting endemic countries vccinted [12]. A popultion-bsed study crried out in Sweden showed tht the highest risk ws ssocited with trvel to Est Afric, the Middle Est nd the Indin subcontinent [13]. The highest risk ws found mong young children visiting friends nd reltives, s in 1

2 Figure 1 Risk of trvel-ssocited cses of heptitis A by million nights, 11 EU/EEA countries, (n = 4,705) Figure 2 Sesonlity of trvel-ssocited cses of heptitis A, 13 EU/EEA countries, (n = 5,218) Cses / million nights Risk Log. (Risk) Number of cses Yer 50 Austri, Denmrk, Estoni, Finlnd, Frnce, Germny, Greece, Hungry, Luxembourg, Mlt, Portugl. nother study crried out in the Netherlnds [14]. It is difficult to compre findings from studies performed t ntionl level for severl resons, including different dt sources, popultions nd methodologies. Pooling dt from severl countries improves sttisticl power nd llows for broder generlistion of the findings. The objectives of this study were to describe the epidemiology of trvel-ssocited heptitis A, to estimte the risk for heptitis A mong trvellers from EU/EEA countries nd to identify groups t higher risk to help trget nd prioritise interventions. Methods Heptitis A dt Surveillnce of heptitis A t the EU/EEA level is crried out by the Food- nd Wterborne Diseses nd Zoonoses Network (FWD-Net) under the coordintion of the Europen Centre for Disese Prevention nd Control (ECDC). The network comprises ll 28 EU Member Sttes, Icelnd nd Norwy, which nnully report heptitis A cses mong their residents to the Europen Surveillnce System (TESSy) dtbse hosted by ECDC. Cses re reported with set of vribles including ge, sex, importtion sttus nd probble country of infection. A trvel-ssocited cse of heptitis A is defined s ny cse reported s imported, i.e. infected following exposure outside the reporting country during time comptible with the incubtion period. For the purpose of this nlysis, we included dt from 13 EU/ EEA countries (Austri, Denmrk, Estoni, Finlnd, Frnce, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds, Norwy nd Portugl) for the yers 2009 to These countries (totl popultion: 223 million) hve comprehensive nd compulsory 0 Jn 2009 Jn 2010 Jn 2011 Number of cses Jn 2012 Jn 2013 Jn 2014 Jn month moving verge Austri, Denmrk, Estoni, Finlnd, Frnce, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds, Norwy, Portugl. Jn 2016 surveillnce systems for heptitis A nd reported csebsed heptitis A dt for t lest 80% of cses with known importtion sttus during the study period. We chose this threshold rbitrrily to obtin relible estimtes for the proportion of trvel-ssocited cses. In Denmrk, Luxembourg nd Portugl, surveillnce ws bsed on physicin reporting only, wheres it ws bsed on both lbortory nd physicin reporting in other countries [15]. The prticipting countries follow WHO recommendtions s most EU/EEA countries do, i.e. they vccinte groups t incresed risk of infection. In ddition, Greece hs since 2008 provided universl vccintion to ll children older thn 12 months [7]. We included cses with known importtion sttus who met the EU cse definition criteri for confirmed cse of heptitis A, i.e. ny person meeting the clinicl criteri nd the lbortory criteri (detection of HAV nucleic cid in serum or stool or HAV-specific ntibody response or detection of HAV ntigen in stool) [16]. Trvel dt We obtined trvel denomintor dt for the period from 2009 to 2015 from the Sttisticl Office of the Europen Union (Eurostt) [17]. We used the totl number of nights spent, by destintion country, which includes ll nights tht EU/EEA residents, ged 15 or older, spent in collective ccommodtion estblishment or in privte tourist ccommodtion for personl 2

3 Tble 1 Min chrcteristics of reported cses of heptitis A by trvel sttus, nd djusted predictors of trvel-ssocited heptitis A, 13 EU/EEA countries, (n = 18,839) Chrcteristic Non-trvel-ssocited cses Trvel-ssocited cses Univrite logistic regression Multivrible logistic regression b n % n % OR (95% CI) OR (95% CI) Totl 13, , Not included Not included Sex Mle 7, , ( ) 1.10 ( ) Femle 6, , Unknown c 10 Not included 1 Not included Not included Not included Age group (yers) < ( ) 1.59 ( ) , , ( ) 1.38 ( ) , ( ) 1.45 ( ) , , , ( ) 0.80 ( ) 65 1, ( ) 0.24 ( ) Unknown c 1 Not included 0 Not included Not included Not included Outcome Alive 8, , Not included Not included Ded Not included Not included Unknown c 4,807 Not included 2,796 Not included Not included Not included CI: confidence intervl; OR: odds rtio. Austri, Denmrk, Estoni, Finlnd, Frnce, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds, Norwy, Portugl. b Adjusted for yer nd reporting country with Frnce s reference. c Percentges exclude the unknown. or professionl purposes. In most countries, this informtion is collected through household surveys. The collection of dt should conform to the specifictions described in the Methodologicl mnul for tourism sttistics [18]. A country my pply weighting procedures ccording to the smpling design used. Since trvel nights were not vilble for ll combintions of the different countries of residence with the different destintion countries for ll yers, we estimted the totl number of nights from the men number of nights for the vilble yers multiplied by 7 (study period of 7 yers). Anlysis We compred trvel-ssocited cses of heptitis A with non-trvel-ssocited cses for min chrcteristics. We defined the risk for trvel-ssocited heptitis A s the rte of trvel-ssocited cses per million nights spent in given destintion (region or continent) by ll trvellers from the reporting country. We excluded Frnce from the nlysis by destintion becuse informtion on the probble country of infection ws not vilble. We lso excluded Estoni nd Norwy for this prt of the nlysis becuse trvel dt were missing for some destintions. We considered five min regions s destintions (Afric, Americ, Asi, Europe nd Oceni). Following Eurostt grouping, we divided Americ further into (i) North Americ nd (ii) Centrl nd South Americ (including Mexico). In Europe, we distinguished EU countries from other Europen countries (including Turkey). We clculted 95% confidence intervls (CI) for risk, ssuming Poisson distribution. To ssess the trend in the nnul risk for trvel-ssocited heptitis A over time, we estimted the nnul rte of chnge nd its 95% CI using log-liner regression of risk for trvel-ssocited heptitis A ssocited with overses trvel in the period from 2009 to We compred continuous vribles cross strt by Mnn Whitney U test. We compred ctegoricl vribles using the chi-squred or Fisher s exct tests with significnce level of less thn To further chrcterise trvel-ssocited heptitis A, we ssessed the ssocition of ge nd sex with the cses trvel sttus (dependent vrible) in logistic regression nlysis nd estimted djusted odds rtios (OR) nd 95% CI. Ethics sttement Heptitis A is prt of the 52 communicble diseses for which ECDC routinely collects, nlyses nd dissemintes surveillnce dt s stted by the Article 3 of its founding regultion. TESSy dt re pseudonymised 3

4 Tble 2 Number of nights spent on overses trips, by reporting country nd world region of destintion, 13 EU/EEA countries, (n = 9,638 million) Country n (million) Nights spent on overse trips Distribution by destintion (%) Afric Americ Asi Europe Oceni Austri Denmrk Estoni No dt Finlnd Frnce 1, Germny 4, Greece Hungry Luxembourg Mlt The Netherlnds b 1, Norwy c Portugl Totl 9, Austri, Denmrk, Estoni, Finlnd, Frnce, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds, Norwy, Portugl. b Number of nights only vilble for The figure used is n estimte bsed on the verge for vilble yers. c Number of nights only vilble for The figure used is n estimte bsed on the verge for vilble yers. nd processed for public interest in the re of public helth. Informed consent ws not required. Results In the period from 2009 to 2015, the 13 prticipting countries reported 20,556 confirmed cses of heptitis A, of which 18,839 (91.6%) hd known trvel sttus. Of these 18,839, 5,233 (27.8%) were trvelssocited (Tble 1). Four countries hd proportions of trvel-ssocited cses below 25%: Hungry (1.1%), Greece (11.3%), Estoni (17.0%) nd Mlt (22.7%). Of the 5,233 trvel-ssocited cses, 2,581 (49.3%) were reported with vilble informtion on the probble country of infection. When excluding Frnce, informtion on probble country of infection ws vilble for 2,581 (94.8%) of 2,723 trvel-ssocited cses. Demogrphics Of the 5,232 trvel-ssocited cses with known sex, 2,907 (55.6%) were mle giving mle-to-femle rtio of 1.3:1 (Tble 1). There ws non-significnt difference between the proportion of trvel-ssocited cses in mle compred with femle cses (28.3% vs 27.2%; p = 0.07). The mle-to-femle rtio ws lower in younger nd older ge groups (1.1:1 below 15 yers nd 1.0:1 t 65 yers nd bove), peking t 1.5:1 for those yers of ge. Of the 5,233 trvel-ssocited cses, 2,083 (39.8%) were children younger thn 15 yers. The proportion of trvel-ssocited cses in tht ge group ws below 30% in Mlt (17.0%), Hungry (17.0%) nd Estoni (4.4%). Of the 2,437 trvel-ssocited cse with known outcome, four died (0.2%). Trend nd sesonlity Over the study period, the verge nnul number of trvel-ssocited cses ws 748 (rnge: ). The highest numbers of trvel-ssocited cses were observed in 2009 nd 2013 with 867 nd 795 cses, respectively. Annul numbers of nights spent brod were vilble for ll countries nd ll yers except for the Netherlnds (only yers ) nd Norwy (only yers ). Between 2009 nd 2015, for the 11 countries with vilble dt on nights spent for ll yers, the overll nnul risk for heptitis A ssocited with overses trvel ws 0.58 cses per million nights. The logrithmic trendline showed decrese t n nnul rte of 3.7% (95% CI: ) from 0.70 cses per million nights in 2009 to 0.51 in 2015 (Figure 1). Of the 5,218 trvel-ssocited cses with known month of reporting, 2,016 (38.6%) were reported between August nd October, including 1,181 (22.6%) in the month of September lone (Figure 2). Of the 2,078 trvel-ssocited cses younger thn 15 yers for whom the month of reporting ws known, 1,235 (59.4%) were reported between August nd October. Trvel ptterns From 2009 to 2015, residents from the 13 prticipting countries spent c 9.6 billion nights brod (Tble 2). The most visited regions were Europe (78.4% of ll nights spent, including Turkey), Americ (8.5%) nd Asi (7.4%). Trvellers only spent 4.6% of their nights in Afric nd 1.1% in Oceni. Trvellers from Frnce nd Portugl spent lrger proportion (13.3% 4

5 Tble 3 Number of trvel-ssocited cses of heptitis A, number of nights spent nd risk by reporting country, 13 EU/EEA countries, (n = 5,233) Country Trvel-ssocited cses n % % <15 yers Nights (million) Cses/million nights (95% CI) Austri ( ) Denmrk ( ) Estoni ( ) Finlnd ( ) Frnce 2, , ( ) Germny 1, , ( ) Greece ( ) Hungry ( ) Luxembourg ( ) Mlt ( ) The Netherlnds , ( ) Norwy b ( ) Portugl ( ) Totl 5, , ( ) CI: confidence intervl. Number of nights only vilble for The figure used is n estimte bsed on the verge for vilble yers. b Number of nights only vilble for The figure used is n estimte bsed on the verge for vilble yers. nd 9.6%, respectively) of their nights in Afric compred with those from other countries. Trvellers from Denmrk, Finlnd nd Norwy spent 9.6% or more of their nights in Asi. Within Europe, most nights were spent in the EU (84.5%). This proportion ws below 80% for trvellers from Estoni (71.5%) nd Greece (58.4%). Overll, 63.8% of the nights spent in Americ were in North Americ. Nine of the 13 countries included hd risk between 0.20 nd 0.46 cses per million nights. Trvellers from Frnce (1.67 cses per million nights), Greece (1.03), Estoni (0.87) nd Portugl (0.73) hd higher risk (Tble 3). Of the 2,581 cses reported by 12 countries with informtion on probble country of infection (dt from Frnce excluded), 2,416 (93.6%) resided in the 10 countries for which trvel dt were vilble for ll destintions (trvel dt for Estoni nd Norwy were not vilble for ll destintions). Among these 2,416 cses, the overll risk for trvel-ssocited heptitis A ws 0.31 cses per million nights spent overses. The highest risks were observed with trvel to Afric (2.11 cses per million nights) nd Asi (1.25) (Tble 4). Trvel to Egypt, Turkey nd Morocco ccounted for 30.9% of ll trvel-ssocited cses reported with informtion on probble country of infection (Tble 5). While most cses returning from Turkey nd Morocco were reported in the period from August to October (64.2% nd 62.6%, respectively), 47.7% of cses returning from Egypt were reported between November nd Februry. Of note, of the 69 cses ssocited with trvel to Itly, 24 were reported in The proportion of cses younger thn 15 yers ws bove 70% for cses reported with trvel to Afghnistn, Ethiopi, Irq or Pkistn nd below 10% for cses who trvelled to Frnce, Greece, Spin nd Thilnd. The proportion of cses younger thn 15 yers ws noticebly low in trvellers to Egypt (14.7%) nd Indi (17.9%) compred with neighbouring countries such s Lebnon (45.0%) or Pkistn (73.6%). In the EU, this proportion ws higher in trvellers to Romni (29.4%), Bulgri (22.6%) nd Itly (20.3%) compred with other EU countries. Multivrible nlysis Mle trvellers were more likely thn femle trvellers to hve cquired their infection brod (djusted OR = 1.10; 95% CI: ) (Tble 1), nd younger cses were more likely to be trvel-ssocited thn older cses. Compred with those ged yers, children younger thn 5 yers were 60% more likely to be reported with probble infection brod (djusted OR = 1.59; 95% CI: ). Discussion Principl findings In the prticipting Europen countries, 27.8% of reported heptitis A cses were trvel-ssocited. Both 5

6 Tble 4 Number of trvel-ssocited cses of heptitis A, number of nights spent nd risk by trvel destintion, 10 EU/EEA countries, (n = 2,416) Region Trvel-ssocited cses n % % <15 yers Nights (million, estimte b ) Cses/million nights (95% CI) Totl (ll regions) 2, , ( ) Afric ( ) Americ North Americ ( ) Centrl nd South Americ c ( ) Asi ( ) Europe EU , ( ) Other Europen countries d ( ) Oceni ( ) CI: confidence intervl. Austri, Denmrk, Finlnd, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds nd Portugl. b The number of trvel-ssocited cses ws ggregted for the period 2009 to 2015, but trvel nights were not vilble for ll combintions of the different countries of residence with the different destintion countries for ll yers. We therefore estimted the totl number of nights from the men number of nights for the vilble yers multiplied by 7 (study period of 7 yers). c Including Mexico. d Including Turkey. this proportion nd the number of trvel-ssocited cses were stble over the study period. However, the risk for trvel-ssocited heptitis A per nights spent overses decresed. This is consistent with decreses reported from the Netherlnds [14] nd Denmrk in the 2000s [19]. The lrge number of cses reported in 2013 my hve been relted to lrge multistte food-borne outbrek with more thn 1,500 cses in the EU/EEA [20]. It is possible tht other outbreks lso plyed role in the fluctutions observed in these dt. More thn 60% of ll trvel-ssocited heptitis A cses were ssocited with trvel to Afric nd Asi, lthough these destintions ccounted for less thn 15% of ll nights spent overses. These findings re hrdly surprising becuse these two continents host most countries with high endemicity [4]. However, these estimtes t continentl level my msk importnt disprities. Some Europen countries re lso t moderte to high risk for HAV infection. Age nd sesonlity ppered to be relted to specific destintions. Pkistn ws ssocited with lrge proportion of cses younger thn 15 yers, most of whom were reported between August nd October. These children were most probbly ccompnying their prents during the summer vction. Conversely, Egypt, Indi nd most Europen countries were ssocited with more cses mong dults nd less pronounced sesonlity. This my be suggestive of leisure trvel without children or business trvel which is yer-round for some destintions. Interestingly, most countries of residency included in the nlysis hd comprble trvel ptterns nd estimted risks, suggesting tht some of these findings could be generlised to other Europen countries not included in this study. The higher risk observed in trvellers from Frnce nd Portugl, compred with other countries, could be prtly driven by higher proportion of nights spent in Afric, destintion where trvellers re t high risk of cquiring heptitis A. Similrly, trvellers from Estoni nd Greece hd high proportion of nights spent in Estern Europe nd Turkey, which re destintions of higher risk compred with Western Europe [4]. Strengths nd weknesses of the study This study included more thn 5,000 trvel-ssocited heptitis A cses reported by 13 countries. These countries ccount for more thn 40% of the EU/EEA popultion. Our findings provide good picture of the epidemiology of trvel-ssocited heptitis A in Europe in recent yers. However, this study hd some limittions. Firstly, lrge proportion of mild non-specific or entirely symptomtic heptitis A cses, especilly mong children, were probbly not cptured by the surveillnce systems. In ddition, given the long incubtion period of heptitis A nd the possibility of cse hving visited severl countries, countries my hve misclssified some of their cses, nd it is chllenging to ssess the effect of this type of error in our nlysis. Secondly, informtion on the probble country of infection ws not vilble for cses reported by Frnce, which ccounted for nerly hlf of trvel-ssocited cses reported over the study period. Thirdly, we excluded countries with low coverge of their surveillnce system (e.g. Itly) or low completeness of the trvel sttus (e.g. the UK). Fourthly, nights 6

7 Tble 5 Top destintions for trvel-ssocited heptitis A cses, 12 EU/EEA countries, (n = 2,581) Rnk Destintion country Region Trvel-ssocited cses n % % <15 yers 1 Turkey Other Europen countries Egypt Afric Morocco Afric Pkistn Asi Afghnistn Asi Indi Asi Syri Asi Spin EU Itly EU Lebnon Asi Nmibi Afric Romni EU Irq Asi Bulgri EU Frnce EU Ethiopi Afric Peru Centrl nd South Americ Croti Afric Philippines Asi Greece EU Thilnd Asi Other destintions Totl 2, Austri, Denmrk, Estoni, Finlnd, Germny, Greece, Hungry, Luxembourg, Mlt, the Netherlnds, Norwy nd Portugl. spent by EU/EEA residents younger thn 15 yers were not vilble. Although children re unlikely to trvel without their prents, we my hve overestimted the risk in destintions with lrge proportion of cses in children (e.g. Asi). Unfortuntely, trvel denomintor dt t country level were not vilble for most destintion countries outside Europe. Lstly, there were limittions relted to the trvel dt. These dt were collected mostly vi household survey [17] which is prone to recll bis. In ddition, number of nights spent in destintions with few trvellers (e.g. Oceni) cn show high vritions over time [17]. However, we think tht overll, these dt were relible with little vrition over the study period for most destintions considered in the nlysis. Informtion on trvel purpose nd probble route of infection were not vilble. Some uthors hve recommended recording the trvel purpose in order to inform public helth strtegies [21]. For exmple, people visiting friends nd reltives re t higher risk of cquiring trvel-ssocited infection [22-24]. However, visiting friends nd reltives my not be the sole purpose of the journey nd the clssicl definition of visiting friends nd reltives hs been chllenged [25]. Informtion on the probble route of infection my lso be useful for informing prevention strtegies s heptitis A infection cn lso be sexully trnsmitted nd men who hve sex with men re known risk group [26]. Comprison with other studies Our risk estimte (0.54 cses per million nights) is higher thn dt reported by Askling et l. who estimted risk of trvel-ssocited heptitis A of 0.61 cses per 100,000 trvel months (i.e cses per million nights) mong Swedish trvellers [13]. Our overll estimte ws probbly driven by Frnce, country whose trvellers spent more nights in Afric nd were shown to be less likely to be vccinted compred with other Europen trvellers [12]. As in our study, Askling t l. found higher risk ssocited with trvel to some prts of Afric nd Asi. The proportion of trvelssocited cses in our study (c 30%) ws lower thn in the US (c 40%) [10]. However, this overll proportion msks importnt disprities cross countries nd ws hevily influenced by countries reporting mny loclly cquired cses such s Hungry. Alongside Romni nd Slovki, Hungry ws one of the few EU/EEA countries with notifiction rte bove 10 cses per 100,000 popultion in 2014 [15]. In the lte 1990s, routine heptitis A vccintion of children ws 7

8 implemented in those sttes in the US with the highest incidence, leding to decreses in incidence mong younger ge groups [27]. It is possible tht this strtegy, implemented t locl level, hd lrge impct on domesticlly cquired cses overll by decresing HAV circultion in the US. The high proportion of infection in children returning from countries less frequented by tourists (e.g. Afghnistn, Irq or Pkistn) is very suggestive of trvel to visit friends nd reltives or recent immigrtion. This would confirm reports from Austrli where trvel-ssocited infections in children were more frequently ssocited with visiting friends nd reltives thn in dults [22]. The lrge number of refugees entering Europe in 2015 is unlikely to hve hd ny mjor effect on our findings becuse reports from Germny nd Greece suggested tht heptitis A cses in this popultion were only observed in lte 2015 nd 2016 [28,29]. Possible explntions nd implictions for clinicins nd policymkers During the period from 2009 to 2015, the notifiction rte of heptitis A cses in the EU/EEA ws firly stble t c three cses per 100,000 popultion, with the highest notifiction rte observed in children ged 5 14 yers. Our dt suggest tht the risk of trvel-ssocited cses decresed slightly over the period. A moleculr cluster nlysis crried out in the Netherlnds showed tht trvelling children were n importnt group for introduction nd further trnsmission of HAV [30]. HAV vccintion, for children of fmilies trvelling to countries of high or intermedite endemicity would probbly hve high impct on the number of trvel-ssocited heptitis A cses in Europe nd consequently on secondry loclly cquired cses. For exmple, HAV incidence in children of Moroccn or Turkish descent stedily declined fter the introduction of trgeted HAV vccintion progrmmes in the Netherlnds [31]. More generlly, heptitis A vccine is recommended for ll non-immune trvellers to countries of intermedite or high endemicity. Since single dose of heptitis A vccine provides high protection even when given shortly before deprture [32], ny increse in opportunities for vccintion would be beneficil (e.g. vccintion clinics t irports). However, the recent vccine shortges in some Europen countries my jeoprdise efforts to promote vccintion [33]. Studies exploring other fctors for not getting vccinted (risk perception, cost etc.) would lso help design effective public helth mesures [34]. Conclusion Trvel remins mjor risk fctor for HAV infection in the EU/EEA, lthough the risk of infection my hve slightly decresed over recent yers. This still represents considerble cuse of morbidity which could be voided since sfe, effective nd ffordble vccine is vilble. Children younger thn 15 yers ccount for lrge proportion of cses nd should be prioritised for vccintion, prticulrly when trvelling to visit reltives nd friends in HAV-endemic countries. Acknowledgements We re very grteful to our collegues in the FWD-Net who provided the dt. We prticulrly would like to cknowledge Sophie Quoilin (Belgium), Snj Kurečić Filipović nd Iv Pem Novosel (Croti), Jitk Cstkov nd Vrtislv Nemecek (Czech Republic), Sofie Gillesberg Riser (Denmrk), Irin Filippov (Estoni), Rusk Rimhnen-Finne (Finlnd), Anne- Mrie Roque-Afonso (Frnce), Kssini Gkolfinopoulou (Greece), Nimh Murphy (Irelnd), Stefni D Amto nd Ann Rit Ciccglione (Itly), Tny Melillo (Mlt), Bernrdo Guzmán Herrdor (Norwy), Piotr Polnski nd Ann Bumnn-Popczyk (Polnd), Mri Avdicov nd Jn Miks (Slovk Republic), Elen Vness Mrtínez nd Crmen Vrel (Spin). Conflict of interest None declred. Authors contributions JB conceived the study nd rn the nlysis. All uthors interpreted the results. 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