Hepatitis E virus: Assessment of the epidemiological situation in humans in Europe, 2014/15

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JournalofClinicalVirology82(2016)9–16

ContentslistsavailableatScienceDirect

Journal

of

Clinical

Virology

j o ur na l h o me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / j c v

Short

communication

Hepatitis

E

virus:

Assessment

of

the

epidemiological

situation

in

humans

in

Europe,

2014/15

夽

Cornelia

Adlhoch

a,∗

_,

_Ana

_Avellon

b

_,

_Sally

_A.

_Baylis

c

_,

_Anna

_R.

_Ciccaglione

d

_,

Elisabeth

Couturier

e

_,

_Rita

_de

_Sousa

f

_,

_Jevgenia

_Epˇstein

g

_,

_Steen

_Ethelberg

h

_,

_Mirko

_Faber

i

_,

Ágnes

Fehér

j

_,

_Samreen

_Ijaz

k

_,

_Heidi

_Lange

l

_,

_Zdenka

_{Mand’áková}

m

_,

_Kassiani

_Mellou

n

_,

Antons

Mozalevskis

o

_,

_Ruska

_{Rimhanen-Finne}

p

_,

_Valentina

_Rizzi

q

_,

_Bengü

_Said

k

_,

Lena

Sundqvist

r

_,

_Lelia

_Thornton

s

_,

_Maria

_E.

_Tosti

d

_,

_Wilfrid

_van

_Pelt

t

_,

_Esther

_Aspinall

u

_,

Dragoslav

Domanovic

a

_,

_Ettore

_Severi

a

_,

_Johanna

_Takkinen

a

_,

_Harry

_R.

_Dalton

v

a_European_Centre_for_Disease_Prevention_and_Control_(ECDC),_Stockholm,_Sweden b_Spanish_National_Centre_of_{Microbiology,}_Carlos_III_Institute_of_Health,_Madrid,_Spain c_{Paul-Ehrlich-Institut,}_Langen,_Germany

d_National_Institute_of_Health_(Istituto_Superiore_di_Sanità₋_ISS),_Rome,_Italy e_Institut_de_veille_sanitaire,_{Saint-Maurice,}_France

f_National_Institute_of_Health_Dr._Ricardo_Jorge,_Lisboa,_Portugal g_Health_Board,_Tallinn,_Estonia

h_Statens_Serum_Institut,_Copenhagen,_Denmark i_Robert_Koch_Institute,_Berlin,_Germany

j_National_Center_for_Epidemiology_(NCE),_Budapest,_Hungary

k_National_Infection_Service,_Public_Health_England,_London,_United_Kingdom l_Norwegian_Institute_of_Public_Health,_Oslo,_Norway

m_National_Institute_of_Public_Health,_Prague,_Czech_Republic n_Greek_Center_for_Disease_Prevention_and_Control,_Athens,_Greece

o_World_Health_Organization_(WHO),_Regional_Ofﬁce_for_Europe,_Copenhagen,_Denmark p_National_Institute_for_Health_and_Welfare_(THL),_Finland

q_European_Food_Safety_Authority_(EFSA),_Parma,_Italy r_Public_Health_Agency_of_Sweden,_Stockholm,_Sweden

s_Health_Service_Executive₋_Health_Protection_Surveillance_Centre,_Dublin,_Ireland t_National_Institute_for_Public_Health_and_the_Environment,_Bilthoven,_Netherlands u_National_Health_Services,_Health_Scotland,_Glasgow,_United_Kingdom

v_European_Centre_for_Environment_and_Human_Health,_University_of_Exeter,_United_Kingdom

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received23March2016 Accepted19June2016 Keywords: HepatitisEvirus

a

b

s

t

r

a

c

t

Background:HepatitisEvirus(HEV)isendemicinEU/EEAcountries,buttheunderstandingoftheburden oftheinfectioninhumansisinconsistentasthediseaseisnotunderEUsurveillancebutsubjectto nationalpolicies.

Abbreviations:EU/EEA,EuropeanUnionandEuropeanEconomicArea;MS,memberstate;HEV,HepatitisEvirus.

夽 RegionsinEU/EEAcountrieswereusedaccordingtohttp://eurovoc.europa.eu/drupal/?q=request&view=mt&mturi=http://eurovoc.europa.eu/100277&language=en. ValentinaRizziisemployedwiththeEuropeanFoodSafetyAuthority(EFSA)initsBIOCONTAMUnitthatprovidesscientificandadministrativesupporttoEFSA’s scien-tificactivitiesintheareamicrobiologicalriskassessment.Thepositionsandopinionspresentedinthisarticlearethoseoftheauthorsaloneandarenotintendedtorepresent theviewsorscientificworksofEFSA.

∗ Correspondingauthor.

E-mailaddresses:[email protected](C.Adlhoch),[email protected](A.Avellon),[email protected](S.A.Baylis),[email protected] (A.R.Ciccaglione),[email protected](E.Couturier),[email protected](R.deSousa),[email protected](J.Epˇstein),[email protected]

(S.Ethelberg),[email protected](M.Faber),[email protected](Á.Fehér),[email protected](S.Ijaz),[email protected](H.Lange),[email protected] (Z.Mand’áková),[email protected](K.Mellou),[email protected](A.Mozalevskis),ruska.rimhanen-ﬁnne@thl.ﬁ(R.Rimhanen-Finne),[email protected] (V.Rizzi),[email protected](B.Said),[email protected](L.Sundqvist),[email protected](L.Thornton),[email protected](M.E.Tosti), [email protected](W.vanPelt),[email protected](E.Aspinall),[email protected](D.Domanovic),[email protected] (E.Severi),[email protected](J.Takkinen),[email protected](H.R.Dalton).

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10 C.Adlhochetal./JournalofClinicalVirology82(2016)9–16 Europe

Epidemiology Surveillance Zoonoticinfections

Study:Countrieswereaskedtonominateexpertsandtocompleteastandardisedquestionnaireaboutthe epidemiologicalsituationandsurveillanceofHEVintheirrespectiveEU/EEAcountry.Thisstudyreviewed surveillancesystemsforhumancasesofHEVinEU/EEAcountriesandnominatedexpertsassessedthe epidemiologyinparticularexaminingtherecentincreaseinthenumberofautochthonouscases. Results:SurveillancesystemsandcasedeﬁnitionsacrossEU/EEAcountrieswereshowntobehighly vari-ableandtestingalgorithmswereunreliable.Largeincreasesofautochthonouscaseswerereportedfrom WesternEU/EEAcountrieswithlowercasenumbersseeninNorthernandSouthernEuropeancountries. Lackofclinicalawarenessandvariabilityintestingstrategiesmightaccountfortheobserveddifferences inhepatitisEincidenceacrossEU/EEAcountries.InfectionswerepredominantlycausedbyHEVgenotype 3,themostprevalentvirustypeintheanimalreservoirs.

Conclusion:Discussionsfromtheexpertgroupsupportedjointworkingacrosscountriestobettermonitor theepidemiologyandpossiblechangesinriskofvirusacquisitionataEuropeanlevel.Therewas agree-menttosharesurveillancestrategiesandalgorithmsbutalsoimportantlythecollationofHEVdatafrom humanandanimalpopulations.ThesedatacollectedataEuropeanlevelwouldservethe‘OneHealth’ approachtobetterinformingonhumanexposuretoHEV.

1. Objectives

HepatitisEvirus(HEV)isoneofthemostcommoncausesof hep-atitisworldwide[1].HEVisendemicinregionsofAsiaandAfrica whereitcausesanacuteself-limitinghepatitisinyoungadults, exceptinpregnantwomenwhohaveacasefatalityrateof approx-imately25%.Intheseregions,infectionisusuallylinkedtoHEV genotypes(gt)1and2whicharespreadfaecal-orallyvia contam-inatedwater,resultinginbothsporadiccasesandlargeoutbreaks

[1].

Untiladecadeago,casesofhepatitisEinEuropewerethoughtto berestrictedtotravellersreturningfromendemicareas.However, itisnowwell-establishedthatHEVisendemicintheEU/EEA[2]. Here,thevirusistransmittedzoonoticallywithinfectionslinked mainlytogt3viruses.CasesofacutehepatitisEcausedbyHEV gt3occurmainlyinoldermalesandchronicinfectionin immuno-suppressedindividuals,includingtransplantrecipients,havebeen recognised[1].Excessmortalityhasnotbeenobservedin preg-nantwomeninEU/EEA,butinfectioninpatientswithunderlying chronicliverdiseasehasareportedcasefatalityrateof27%[3]. However,theburdenofHEVinfectioninhumansinEuroperemains poorlydocumented.HEVinfectionisnotunderEUsurveillance,and reportingsystems,casedeﬁnitionsandpopulationsunder surveil-lancearesubjecttonationalpolicies,whichvaryacrosscountries. Nationalincidenceandprevalenceestimateshavebeenpreviously publishedfor a number of EU/EEA countries[4,5]. However, a comparativeEU-widesituationalanalysishasnotpreviouslybeen reported.Theaimofthisstudywastoelucidatetheemergence ofHEVinfectioninhumansacrosstheEU/EEAMemberStatesby reviewingthesurveillancesystemsandreportednumberof hep-atitisEcases.

2. Study

EU/EEA countrieswere invited to nominate national public healthexperts,clinicians,andexpertsinbloodsafetyworkingon HEV.Inaddition,astandardisedquestionnairecollected informa-tionaboutnationalsurveillancesystems,andreportednumberof casesofhepatitisE.

3. Results

Information on surveillance systems was available from 29 countries and experts from 17 countries contributed to the assessmentoftheepidemiologicalsituation.Aconsiderable

hetero-geneityinsurveillancearrangements,diagnostictestingalgorithms andcasedeﬁnitionsbetweencountrieswasnoted(Fig.1,Table).

In2014/15,increasingandlargenumbersofcasesofHEVwere reportedinFrance,Germany,England&Wales,theNetherlands, andincreasesinFinland,HungaryandItaly(Table1,Fig.2).

Data from France, Germany, England & Wales, and the NetherlandsindicatedmorehepatitisEcasenotiﬁcationsthan hep-atitisAcases(datanotshown).Considerablylowernumbersof casesofhepatitisEwereconﬁrmedinNorthernandSouthern Euro-peancountries(Table1).

InEU/EEA,infectionswerepredominantlyautochthonousand causedbyHEVgt3,themostprevalentvirustypeinhumansand animalreservoirsinEurope[6,7].VirusesdetectedinEngland& Walesbetween2003and2009weremainlygt3efg,whilebetween 2010and2013,gt3cvirusespredominatedinhumans.Incontrast, HEVfromUnitedKingdompigstestedin2013weregt3efg[8].A verysmallnumberofautochthonouscasescausedbygt4havebeen documentedinFranceandItaly.

Seroprevalencedatawereavailableinaminorityofcountries andshowedconsiderableheterogeneitypossiblyduetodifferences intheperformanceoftheassaysusedandinthecharacteristics ofthestudypopulationstudied(datanot shown).DataonHEV viraemiainblooddonationshavebeenreportedfromseveral coun-triesandshowedasimilarheterogeneity,rangingfrom1:762inthe Netherlandsto1:14,520inScotland[9,10].

4. Discussion

TherehasbeenacommontrendamongsttheWestern Euro-peancountriesofayearonyearincreaseinreportedhepatitisEcase numbers.Insomecountriesthesenumbershaveexceededreported hepatitisAcases.Thisincreasemayreﬂectatrueriseinthe inci-denceofhepatitisEinsomepartsofEuropesuggestingthatthere hasbeenachangeintheriskofacquiringHEV.Thisissupported bytheobservedincreaseinHEVRNAprevalenceinblooddonors overtimereportedfromEnglandandtheNetherlands[9,11–13]. Theincrease mayalsobedue toimprovedcase-ascertainment: cliniciansareincreasinglyawareofHEVasacauseofhepatitisin patientswithouta travelhistory,assuggested bytheincreased numbersoftestsperformedforHEVinthesecountries.InSpain andFrance,thenumberoftestedspecimensincreased simultane-ouslytotheriseofHEVcases,however,thepositivityrateremained constant(12%–17%inSpain).

The reason for the low numbers of cases in Northern and SouthernEuropeancountriesisunknown.Itcouldrelateto differ-encesinclinicalawareness,diagnostictestingalgorithms/criteria

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C. Adlhoch et al. / Journal of Clinical Virology 82 (2016) 9–16 11 Table1

CharacteristicsofhepatitisEsurveillancesystemsinparticipatingEU/EEAcountrieswithnumberofcasesandgenotype/subtype. Country IsHEVnotiﬁable?

(Year)

Surveillancethroughreference laboratory(period)

Casedeﬁnition/positivitycriteria Comments Numberofreportedcasesof HepatitisE(autochthonous) Predominant autochthonous HEV genotype/subtype Austria Yes 2014:17(15) 2015:36(30) Belgium Yes 2014:35 2015:65 Bulgaria No 2015:54 gt3 Croatia Yes 2014:0 2015:2 CzechRepublic Yes(2008) Laboratorydiagnosis

• Anti-HEVIgM,IgG • HEVRNAinserumandstool

2014:290(288) 2015:412(398)

Denmark No Yes DiagnosticsandtypingperformedatSSId_._HEV

scheduledtobecomenotiﬁablein2016.

2014:9 gt3

England&Wales Yes (2010)

Availableat:https://www.gov.uk/ government/publications/hepatitis-e- health-protection-response-to-reports-of-infection

Viralhepatitishasbeennotifiablesincethe 1980’s.HepatitisEhasbeennotifiablesince 2010.Nationalguidelinesoncasedefinition andtestingalgorithmsareestablished.

2014:886(729) 2015:848(694)

gt3c

Estonia Yes

(1997)

Firstcasenotiﬁedin2012. 2014:1 2015:1

gt3

Finland Yes

(1995)

Notiﬁcationcriteria:serology,PCR. Fromthebeginningof2016,thelaboratories areencouragedtonotifyonlyanti-HEV IgM-positivecases. 2014:11 2015:44 France No Yes (2002–2014) Diagnosticalgorithm Immunocompetent

• IgM(+)=recentinfectiontoconﬁrm byPCR

• IgM(−)=norecentinfection Immunocompromised

• IgM(+)andHEVRNA(+)=recentor activeinfection

Clearanceorpersistencebytestingfor HEVRNA

• IgM(−)andHEVRNA(−)=norecent infection

2014:1825(1813) gt3f

Germany Yes

(2001)

Notiﬁablearelaboratoryconﬁrmed cases(IgMorIgGincreaseinpaired samplesorPCR)withclinical symptoms.

2014:671 2015:1266

gt3c

Greece No Basedonarecentstudyoflaboratorycapacity

ofGreekhospitals,hospitallaboratoriesdonot testforHEV.

2003–2015:NoreportedclustersofHEV infection.

Hungary Yes

(1993)

Conﬁrmedcase:acuteviralhepatitis withpositiveanti-HEVIgM.

Reportsbasedonsyndromicsurveillance. Acuteviralhepatitisisnotiﬁable(infectious hepatitis),testingismandatorytodetermine aetiologysince1993.

2014:140(140) 2015:166(166)

gt3

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12 C. Adlhoch et al. / Journal of Clinical Virology 82 (2016) 9–16 Table1(Continued)

Country IsHEVnotiﬁable? (Year)

Surveillancethroughreference laboratory(period)

Casedeﬁnition/positivitycriteria Comments Numberofreportedcasesof HepatitisE(autochthonous) Predominant autochthonous HEV genotype/subtype Ireland Yes (2015Dec)

Clinicalcriteria:Notrelevantfor surveillancepurposes Laboratorycriteria: Acutecase:Atleastoneofthe followingtwo:

• HEVIgMandIgGantibodypositive • DetectionofHEVRNA

Chroniccase:HEVRNApersistingforat least3months.

2015:30e

Italy Yes

(2007)

Clinicalcriteria:acuteillness compatiblewithhepatitis,andALTa

>10timestheupperlimitofthe normalrange;

Serologicalcriteria:IgManti-HEV positive,IgManti-HBcb_negative,_IgM

anti-HAVc_negative._Cases_IgM

anti-HEVpositive,inabsenceofclinical signs,areincludedamong“acute hepatitisEcases”.

ItaliansurveillanceforHEVisvoluntaryand currentlycovers77%oftheItalianpopulation.

2014:18(15) 2015:22(16) gt3e,3c,3f Latvia Yes 2014:16(14) 2015:10(8) Lithuania No Luxembourg Yes Malta No Netherlands No Yes 2014:142 2015:200 gt3e(1%),3c (90%),3e(1%), 3f(8%) Norway No 2014:1 2015:6 Poland No 2014:6(4) 2015:2(2) Portugal Yes (2015)

Mostcasesareconﬁrmedbyserology. 0

Slovakia Yes 2014:16(14)

2015:27(24)

Slovenia Yes 2014:1(1)

2015:0

gt3 Spain No Yes(2006–2015) PCR-positiveorIgMandPCR-positive.

IgMpositivewithoutPCR:IgG seroconversionisneededfor conﬁrmation.

80%oftheterritoryiscovered. 2014:100 2015:105(103)

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C. Adlhoch et al. / Journal of Clinical Virology 82 (2016) 9–16 13 Sweden Yes (1993)

Suspectedcase:Clinicalillness compatiblewiththediagnosisandan epidemiologicallinktoa

laboratory-confirmedcase. Confirmedcase:A laboratory-confirmedcase

Laboratorycriteria(atleastoneofthe followingtwo):

• DetectionHEVspeciﬁc antibody-responseinserum indicatingcurrentinfection. • DetectionofHEVRNAinserumor

faeces.

2014:22(11) 2015:29(16)

Thedatashownareforthemostrecentyearavailable,2015datamightnotbecomplete.

a_ALT:_alanine_{aminotransferase.}

b _anti-HBc:_antibodies_to_hepatitis_B_core_antigen. c _HAV:_Hepatitis_A_virus.

d _Statens_Serum_Institut.

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14 C.Adlhochetal./JournalofClinicalVirology82(2016)9–16

Fig.1.EU/EEAcountriesreportingsystemforhepatitisEvirusinfection,2016.

orsurveillancesystems/practices.LessexposuretoHEVinsuch

countriesseemsunlikely,giventheestimatednumberofviaremic

blooddonorsinSpain[14]andtheveryhighseroprevalenceof

49%inblooddonorsincentralItaly(unpublisheddata).In addi-tiontodifferencesbetweencountries,theremaybedifferencesin viralpressurewithinageographicalregion.InEngland,HEV sero-prevalencewas12–16%and1:2848blooddonorswereviraemic, comparedtoScotlandwhereseroprevalencewas5%and1:14,520 donorswereviaremic[10,11,15].

Thenumberof laboratory-confirmed/notifiedcases isalmost invariablyanunderestimateoftrueincidenceandthis ‘tip-of-the-iceberg’effectislikelytobeparticularlypronouncedwithrespect toHEV[16,17].Poorclinicalawarenessofthedifferentialdiagnosis inpatientswithhepatitismightcontributetotheunderestimation ofsymptomaticinfection.HepatitisEmaybefrequently misdiag-nosedasdrug-inducedliverinjury[18].Finally,recentdatahave shownthatHEVinfectionmaypresentwitharangeofneurological symptoms,includingGuillain–Barrésyndrome,neuralgic amyotro-phyand meningo-encephalitis[19]. Such patientsarecurrently notroutinely tested for HEV. Thus, thenumbersof laboratory-confirmedcasesdocumentedherearelikelytobeunderestimates ofthetrueincidenceofclinicalcasesassuggestedbydataon num-bersofviraemicblooddonors.

Theincreasedawarenessandbettertestingsystemsmighthave contributed to the reported increase of locally acquired cases recently,butdoesnotexplaintherecentreplacementof predom-inantvirussubtypesgt3efgbygt3cinhumanswithacontinued circulationofgt3efginthelocalpigpopulationintheUnited King-dom,whileintheNetherlandsgt3cisdetectedinboth,humans andpigs.HEVishighlyprevalentinEuropeanpigherds[20]and consumptionofcontaminatedporkproductsisonemajorrisk fac-torforhumaninfection[17,21].Monitoringactivitiesinthefood productionchainforHEVneedtobeenhancedtoidentifysources

ofinfection.Tounderstandtherelationshipofhumanandanimal virustypesacrossEurope,traderelationsandthecompilationof foodingredientsshouldbereviewed.

OurunderstandingoftheepidemiologyofHEVanditsburden ofhumaninfectionsattheEU/EEAleveliscurrentlyinconsistent. Increasingnumbersoflaboratory-conﬁrmedautochthonouscases inmanyWesternEuropeancountriessuggestacommontrendand possiblycommonriskse.g. duetoeatinghabits.Clinical testing algorithmsandnumbersofdiagnosticassaysperformedneedtobe knowntobeabletoputthedataintoperspective.Acommon EU-widestrategytobetterunderstandcasenumbersanddetermine circulatingstrainsofthevirusacrosshumanandanimal popula-tionsemploying a‘OneHealth’approachare neededtoaddress theseissues.Thedevelopmentofajointsequencedatabase cov-eringalsoclinicaldatawouldbeonesuggestion.

Competinginterests Nonedeclared. Funding ECDC. Ethicalapproval Notrequired. Contributions

Allauthorsprovided contributiontotheresearcharticleand approvedtheﬁnalversion.

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C.Adlhochetal./JournalofClinicalVirology82(2016)9–16 15

Fig.2. Numberofreportedlaboratory-conﬁrmedcasesofhepatitisEvirus(HEV)bycountry,2006–2015*. *2015datanotcomplete.

CorneliaAdlhoch,coordinatedthework,interpretedthedata andledthewritingofthearticle.

AnaAvellon,providedSpanishdata,andcontributedtowriting ofthearticle.

SallyA.Baylis,providedinformationonserologyanddetection systemsandcontributedtothewritingoftheresearcharticle.

AnnaRitaCiccaglione,providedvirologicaldatafromItaly,and contributedtowritingofthearticle.

ElisabethCouturier,provideddatafromFrance.

RitadeSousa,providedPortuguesedataandcontributedtodata interpretation.

JevgeniaEpˇstein,provideddatafromEstoniaandcontributedto writingofthearticle.

SteenEthelberg,provideddatafromDenmarkandcontributed towritingofthearticle.

MirkoFaber,provideddatafromGermanyandcontributedto writingofthearticle.

ÁgnesFehér,provideddatafromHungaryandcontributedto writingofthearticle.

SamreenIjaz,provideddatafromUK,interpretationof virolog-icaldataandcontributedtowritingofthearticle.

HeidiLange, provideddata fromNorwayand contributed to writingofthearticle.

ZdenkaMand’áková,provideddatafromCzechRepublic. KasianiMellou,providedGreekdata.

AntonsMozalevskis,contributedtodatainterpretation. RuskaRimhanen-Finne,provideddatafromFinland,and con-tributedtowritingofthearticle.

ValentinaRizzi,contributedtodatainterpretation. BengüSaid,providedUKdataandwritingofthearticle.

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16 C.Adlhochetal./JournalofClinicalVirology82(2016)9–16

LenaSundqvist,provideddatafromSweden,anddata interpre-tation.

LeliaThornton,provideddatafromIreland,andcontributedto writingofthearticle.

MariaElenaTosti,providedepidemiologicaldatafromItaly. WilfridvanPelt,provideddatafromtheNetherlands,and con-tributedtothedatainterpretation.

Esther Aspinall, developed questionnaire and collection of surveillancedata.

DragoslavDomanovic,responsibleforbloodsafetydata. EttoreSeveri,contributiontoanalysisofdata.

JohannaTakkinen, contributiontointerpretationofdata and writingofthearticle.

HarryR.Dalton,providedclinicaldata,contributionto interpre-tationofdataandwritingofthearticle.

Acknowledgements

Theauthorsaregratefultothenationalpublichealthexpertsin Austria(DanielaSchmid),Belgium(StéphanieJacquinet,Stevenvan Gucht),Bulgaria(KremenaParmakova),Croatia(SanjaKureˇci ´c Fil-ipovi ´c),Iceland(ThorGudnason),Latvia(RitaKorotinska),Lithuania (Galina Zagrbneviene), Luxembourg (Patrick Hoffmann), Malta (TanyaMelillo),Poland(MałgorzataSadkowska-Todys),Portugal (PaulaVasconcelos),Romania (CNSCBTteam),Spain(Silvia Her-reraLeón),Slovakia(HelenaHudecová)andSlovenia(EvaGrilic) forprovidinginformationontherespectivenationalsurveillance systemforHEV.ECDCespeciallythankstoSharonHutchinsonfor hersupportindevelopingthequestionnaire.

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