Measles in Italy: Viral strains and crossing borders

Short

Communication

Measles

in

Italy:

Viral

strains

and

crossing

borders

Fabio

Magurano

*

,

Melissa

Baggieri

,

Francesca

Mazzilli

,

Paola

Bucci

,

Antonella

Marchi

_,

_Loredana

_Nicoletti

_,

_MoRoNet

_Group

a

NationalReferenceLaboratoryforMeaslesandRubella–DepartmentofInfectiousDiseases,IstitutoSuperiorediSanità,VialeReginaElena299,00161 Rome,Italy

b

MeaslesandRubellaItalianReferenceLaboratoryNetwork:AntonellaAmendola(UniversityofMilan,Italy);FaustoBaldanti(IRCCSPoliclinicoSanMatteo Foundation,Pavia,Italy);MariaRosariaCapobianchi(INMI“LazzaroSpallanzani”,Rome,Italy);MariaChironna(UniversityofBari,Italy);Pierlanfranco D’Agaro(UniversityofTrieste,Italy);TizianaLazzarotto(UniversityofBologna,Italy);KatiaMarinelli(UnitedHospitalofAncona,Italy);AndreaOrsi (UniversityofGenoa,Italy);GiorgioPalù(UniversityofPadova,Italy);FabioTramuto(UniversityHospitalofPalermo,Italy)

ARTICLE INFO

Articlehistory:

Received11September2018

Receivedinrevisedform5November2018 Accepted6November2018

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Outbreak Measles Genotypeidentification Surveillance ABSTRACT

In2017,Italyexperiencedoneofthelargestoutbreaksofmeaslesinrecentyears,with5404notifiedcases and4347confirmedcases.Afurther2029caseswerenotifiedduringthefirst6monthsof2018,and1516 ofthemwerelaboratory-confirmed.TheB3andD8genotypeswereidentifiedasthoseresponsibleforthe outbreak.Possibletransmissionroutescanbeestablishedbymonitoringthecirculatingmeaslesvirus strainsinsupportofthenationalhealthauthoritiestowarnpeopleandtravellers.

©2018TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Afterthelargeepidemicofmeaslesin2017,with5404notified casesand4347confirmedcases,betweenJanuary1andJune30, 2018,2029casesofmeasleswerereportedtotheItaliannational measlesandrubellasurveillancesystem.Ofthese,1516(75%)were laboratory-confirmed in accordance with the World Health Organization(WHO)guidelines,asdescribedpreviously(Istituto Superiore di Sanità (ISS), 2018a; Magurano et al., 2015). The outbreakreacheditspeakinthemonthofApril2018,with466 cases(Figure1),andshowedslightsignsofaturnaroundatthe timeofwritingthisarticle.

Among 2029 notified cases, 1516 (74.7%) were laboratory-con_firmedinaccordancewiththeWHOguidelines,bymolecular (n=540)orserologicalmethods (n=976), attheNational Refer-enceLaboratory(Maguranoetal.,2015)andtheNetworkofItalian Reference Laboratories for Measles and Rubella (MoRoNet) (IstitutoSuperiorediSanità(ISS),2018b).AmongthePCR-positive samples,338sequenceswereobtainedbyamplifyingafragmentof thecarboxyl-terminalcodingregionoftheNgene,includingthe 450-bpfragmentrecommendedforgenotyping(Maguranoetal., 2015; World Health Organization, 2012a), and were analysed

phylogenetically. All sequenceswere submitted tothe Measles NucleotideSurveillance(MeaNS)database(Rotaetal.,2011).

TheanalysisofthesequencesidentifiedinItalyduringthefirst halfof2018demonstratedtheco-circulationofgenotypesB3and D8,with272and66sequencesidentified,respectively.

BLASTanalysisinMeaNSestablishedthatamongthesequences belongingtogenotypeB3,157wereidenticaltotheWHOnamed strainMVs/Dublin.IRL/8.16,alsoresponsibleforseveraloutbreaks inEurope.MVs/Dublin.IRL/8.16hasbeencirculatinginItalysince 2017.EvidenceoftheintroductionofthisstraintoItalydatesback to the end of 2016, and it occurred as a result of several importations in NorthernItaly fromRomania, as supported by epidemiologicaldata.Fifty-nineB3sequenceswereidenticaltothe WHO strain MVs/SaintDenis.FRA/36.17/. This strain has been circulatingin Italysince 2017,but thereare noepidemiological datatosupportthehypothesisofimportationfromabroad.Ten sequenceswereidenticaltotheWHOstrainMVs/Ljubljana.SVN/ 27.17/. Evidence of importation from the Czech Republic was providedfornineofthesesequences.

Beyondthesevariants,theremaining46sequencesclassifiedas B3,butnotidenticaltoanyoftheWHOstrains,werecloselyrelated totheB3strainsincludedinFigure2:20werecloselyrelatedto strain MVs/Dublin.IRL/8.16, one to MVs/SaintDenis.FRA/36.17, eight to MVs/Islamabad.PAK/1.13/, and 17 to MVs/Kabul.AFG/ 20.2014/3.Forseveralofthesecases,evidenceofimportationwas

* Correspondingauthor.

E-mailaddresses:fabio.magurano@iss.it(F.Magurano),melissa.baggieri@iss.it

(M.Baggieri),francesca.mazzilli@iss.it(F.Mazzilli),paola.bucci@iss.it(P.Bucci),

antonella.marchi@iss.it(A.Marchi),loredana.nicoletti@iss.it(L.Nicoletti).

https://doi.org/10.1016/j.ijid.2018.11.005

1201-9712/©2018TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

InternationalJournalofInfectiousDiseases79(2019)199–201

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

established by epidemiological links to cases returning from abroad(countriesoforiginarereportedinFigure2inbrackets).

Amongthe66sequencesbelongingtogenotypeD8,15were identicaltoWHOnamedstrainMVs/GirSomnath.IND/42.16/,nine wereidenticaltoMVs/Herborn.DEU/05.17/,threetoMVs/Victoria. AUS/6.11/,andfourtoMVs/Cambridge.GBR/5.16/.Theintroduction of strain MVs/Herborn.DEU/05.17/into Italy dates back to two importationevents. The first eventwas linked tofour patients returning from England (February 2018). The second one was linkedtoapatientwhohadtravelledinSwitzerland(April2018). The named strain MVs/Victoria.AUS/6.11/was identified in two patientswhohadtravelledinThailand(May2018),suggestingthe introductionof this strainfromthe Orient.Named strainMVs/ GirSomnath.IND/42.16/wasidentifiedinapatientreturningfrom Germany.MVs/Cambridge.GBR/5.16/wasidentifiedintwopatients returningfromUkraine.

Theremaining35sequenceswerenotidenticaltoanyoftheD8 named strains. Twenty-two wereclosely related to MVs/Frank-furtMain.DEU/17.11, fourto MVs/Gadag.IND/02.13, four toMVs/ Victoria.AUS/6.11,twotoMVs/Thiruvananthapuram.IND/18.12,one toMVs/Herborn.DEU/05.17/,andtwotoMVs/Cambridge.GBR/5.16/ . Evidence of importations was established by epidemiological linkstopatientsreturning fromabroad (countriesof originare reportedinFigure2inbrackets).

According totheMeaNS database,manyEuropeancountries havereportedthedominanceofB3andD8measlesstrainsin2018. Italianepidemiologicaldataindicatethatseveralcasesofmeasles werecausedbystrainsimportedtoItalyfromtheCzechRepublic, Germany,Switzerland,France,India,andThailand,asshowninthe phylogenetictree(Figure2).

Measlesisahighlyinfectiousvaccine-preventablediseaseand isstilloneoftheleadingcausesofchildhoodmortalityglobally. TheWHOEuropeanRegion(WHO/Europe)hasadoptedthegoalof eliminating measles and rubella, but despite the significant progressmadetowardsthisgoal,theeliminationofmeaslesand rubella in the region is yet to be achieved (World Health Organization,2012b;Dattaetal.,2018;Adamoetal.,2017).

According tothelatestassessment bytheEuropeanRegional Verification Commission for Measles and Rubella Elimination (RVC) of June 2018, 43 of the region_’s 53 member states have interrupted the endemic spread of measles (based on 2017 reporting). The RVC has also stated concern over poordisease surveillanceandlowimmunizationcoverageinseveralcountries(

WorldHealthOrganization,2018a).

Member States of WHO/Europe submit monthly reports on suspected and confirmed measles and rubella cases identified throughtheirnationaldiseasesurveillancesystemstotheWHO. BetweenJanuary1andJune31,2018,41013casesofmeasleswere reportedtoWHO/EuropeorviatheEuropeanSurveillanceSystem ECDC/TESSy,accordingtoWHOEpiDatapublishedonAugust 1, 2018(WorldHealthOrganization,2018b).Eighty-fourpercentof allthecasesoccurredinUkraine(23070),Serbia(4954),France (2579),Greece(2130),andItaly(2029),accountingfor56%, 12%,6%, 5%,and5%,respectively.

Duringthesameperiod,atotalof1748measlesvirussequences werereportedbythereferencelaboratoriesoftheWHO/Europe, accordingtotheMeaNSdatabaseasofJuly19,2018.Thegenotypes identifiedthroughoutEuropewereB3(n=952),D8(n=790),D9 (n=5), and A (n=1). Genotype B3 included several lineages, comprising the more widespread WHO strain MVs/Dublin.IRL/ 8.16/ and other B3 named strain MVs/SaintDenis.FRA/36.17/. NamedstrainsbelongingtogenotypeD8wereMVs/GirSomnath. IND/42.16/, MVs/Herborn.DEU/05.17/, MVs/Cambridge.GBR/5.16/, MVs/Victoria.AUS/6.11/,andMVs/HuluLangat.MYS/26.11/.

Viruscharacterization(bysequencingandinformation about genotypes)isconsideredessentialtoverifythestatusofmeasles eliminationinEurope.Furthermore,monitoringofnamedstrains withepidemiologicalinformationforadequatecaseclassi_fication and characterization of the chains of transmission allows an understandingofthepictureofmeaslescirculation.Geneticdata describing virus variants represent a key component of the verification of elimination of indigenous measles. It is also an invaluabletool inpublichealth investigations,bothtoestablish whetherconnectionsexistbetweenconcurrentmeaslescasesand to indicate possible sources of importations from endemic countries,suchasItaly.

EpidemiologicaldatafromEuropeanmeaslessurveillanceshow thatmeaslesiscurrentlyendemicinseveralEuropeancountries. The analysis of epidemiological and genetic data from several ItaliancasesconfirmsthatItalyimportedmeaslesfromsomeof thesecountries(Figure2).Moreover,datafromMeaNSshowthat thenamedstrainMVs/Dublin.IRL/8.16/wasimportedfromItalyto Mexico(February2018)andtotheUSA(April2018).Thisstrainwas also identi_fied in the UK at the beginning of 2018 in patients returningfromItaly.Thisdemonstratesthatwhenunvaccinated individuals travel to endemic countries where outbreaks are ongoing,thecross-bordertransmissionbetweenmemberstatesof thesameWHOregionandbetweendifferentWHOregionsisan

Figure1.Reportedmeaslescasesbymonthofrashonset,Italy,January2016–June2018(n=8291). 200 F.Maguranoetal./InternationalJournalofInfectiousDiseases79(2019)199–201

expectedevent.Inthiscontext,thenamedstrainsidentifiedinItaly during2018cansupportmeaslessurveillanceincountriesinthe WHOEuropeanRegiontobetteridentifychainsof transmission outsideofItalyandmonitorthecirculationofthevirus.

Itisimportanttoraiseawarenessinthepopulationtothefact thatmeaslesiscirculatinginvariousEuropeancountriesandto encourage people to check their measles vaccination status, particularly before travelling abroad, especially in the summer whenthenumberofpeopletravellingincreases.

Two doses of measles-containing vaccine are 97% effective against measles. The target immunization coverage set by the WHOfortheseconddoseofmeasles-containingvaccineis95%; however,20of27Europeancountrieshaveratesbelowthatlevel,

including Italy (World Health Organization, 2017). European travellersshouldfollowtherecentmessageputoutbyEuropean Centre for Disease Prevention and Control (ECDC) reminding peopletochecktheirMMRstatusbeforetravelling,tofullyprotect a community from the disease, including persons who have contraindications tothevaccineor who do not respond tothe vaccine.

Acknowledgements

The authors wish tothank Dr Antonietta Filia, Dr Antonino Bella,DrMartinaDelManso,DrM.CristinaRotaattheInfectious Diseases Epidemiology Unitof the National Health Instituteto manageepidemiologicaldata;thestaffinlocalhealthauthorities involvedinoutbreaksinvestigation,samplingandreporting;Drs FrancescaRovida,SilviaBianchi,LiciaBordi,EleonoraLalle,Giulia Piccirilli, Anna Morea,Monia Pacenti of MoRoNet sub-national labs;AlessiaCaratelli,DanielaCasale,ValentinaCecchetti,Sabrina Tocchioforsecretariatactivities;PaoloDeLeo,AmbrogioCarleifor logisticactivity;DrEmilioD’UgoandAntonioGiurgolaforfriendly support. We are grateful toDrs E. Brown and David Williams (Public Health England, United Kingdom) for the support by Measles Nucleotide Surveillance (MeaNS) database; Ms Emilie Charpentierfor makingavailablesequencesidentifiedinSerbia. WeareespeciallygratefultoDrMyriamCorrineBenMamouofthe WHO/EuropeandDrStefaniaIannazzoofItalianMinistryofHealth forprovidingsupporttotheactivitiesoftheNationalReferenceLab andtoProfGiovanniRezzaforrevisethemanuscript.

Fundingsource None. Ethicalapproval

Approvalwasnotrequired. Conflictofinterest

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Figure2.PhylogenetictreeconstructedbyusingtheMaximumLikelihoodmethod based on the Kimura 2-parameter model. The evolutionary analyses were conducted in MEGA7.The percentage of treesin which the associated taxa clusteredtogetherisshownnexttothebranches.Thetreeisdrawntoscale,with branchlengthsmeasuredinthenumber ofsubstitutionspersite.Numberof identicalsequencesidentifiedinthesameprovincebythesameweekisreported.