Vaccine effectiveness against severe laboratory-confirmed influenza in children: results of two consecutive seasons in Italy

ContentslistsavailableatScienceDirect

Vaccine

jou rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e

Vaccine

effectiveness

against

severe

laboratory-confirmed

influenza

in

children:

Results

of

two

consecutive

seasons

in

Italy

Francesca

Menniti-Ippolito

_,

_Roberto

_Da

_Cas

_,

_Giuseppe

_Traversa

_,

_Carmela

_Santuccio

_,

Patrizia

Felicetti

_,

_Loriana

_Tartaglia

_,

_Francesco

_Trotta

_,

_Pasquale

_Di

_Pietro

_,

Paola

Barabino

_,

_Salvatore

_Renna

_,

_Laura

_Riceputi

_,

_Pier-Angelo

_Tovo

_,

_Clara

_Gabiano

_,

Antonio

Urbino

_,

_Luca

_Baroero

_,

_Daniele

_Le

_Serre

_,

_Silvia

_Virano

_,

_Giorgio

_Perilongo

_,

Marco

Daverio

_,

_Elisa

_Gnoato

_,

_Michela

_Maretti

_,

_Beatrice

_Galeazzo

_,

_Giulia

_Rubin

_,

Stefania

Scanferla

_,

_Liviana

_Da

_Dalt

_,

_Chiara

_Stefani

_,

_Claudia

_Zerbinati

_,

_Elena

_Chiappini

_,

Sara

Sollai

_,

_Maurizio

_De

_Martino

_,

_Francesco

_Mannelli

_,

_Sabrina

_Becciani

_,

Martina

Giacalone

_,

_Simona

_Montano

_,

_Giulia

_Remaschi

_,

_Alessia

_Stival

_,

Mario

Furbetta

_,

_Piera

_Abate

_,

_Ilaria

_Leonardi

_,

_Nicola

_Pirozzi

_,

_Umberto

_Raucci

_,

Antonino

Reale

_,

_Rossella

_Rossi

_,

_Cristina

_Russo

_,

_Livia

_Mancinelli

_,

_Onori

_Manuela

_,

Concato

Carlo

_,

_Nadia

_Mores

_,

_Costantino

_Romagnoli

_,

_Antonio

_Chiaretti

_,

Adele

Compagnone

_,

_Riccardo

_Riccardi

_,

_Giovanni

_Delogu

_,

_Michela

_Sali

_,

_Valentina

_Prete

_,

Vincenzo

Tipo

_,

_Michele

_Dinardo

_,

_Fabiana

_Auricchio

_,

_Teodoro

_Polimeno

_,

Giuseppe

Sodano

_,

_Alessandra

_Maccariello

_,

_Concita

_Rafaniello

_,

_Fortunata

_Fucà

_,

Eleonora

Di

Rosa

_,

_Domenica

_Altavilla

_,

_Anna

_Mecchio

_,

_Teresa

_Arrigo

_,

Italian

Multicentre

Study

Group

for

Drug

and

Vaccine

Safety

in

Children

b_{ItalianMedicinesAgency,Roma,Italy}

c_{GianninaGasliniPaediatricHospital,Genova,Italy} d_{ReginaMargheritaPaediatricHospital,Torino,Italy} e_{DepartmentofPaediatrics,UniversityofPadova,Italy} f_{DepartmentofPaediatrics,TrevisoHospital,Treviso,Italy} g_{AnnaMeyerChildren’sUniversityHospital,Firenze,Italy} h_{DepartmentofPaediatrics,UniversityHospital,Perugia,Italy}

i_{EmergencyDepartmentandVirologyUnit,BambinoGesùChildrenHospital,Roma,Italy} j_{Pharmacology,MicrobiologyandVirology,UniversitàCattolicaS.Cuore,Roma,Italy} k_{SantobonoPaediatricHospitalandVirologyUnit-Cotugno,Napoli,Italy}

l_{DepartmentofExperimentalMedicine,SecondUniversity,Napoli,Italy} m_{GiovanniDiCristinaPaediatricHospital,Palermo,Italy}

n_{DepartmentofPaediatric,Gynecologic,MicrobiologicandBiomedicalSciences,UniversityHospital,Messina,Italy}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received4December2013

Receivedinrevisedform20March2014 Accepted11June2014

Availableonline21June2014 Keywords:

Influenzavaccineeffectiveness Children

a

b

s

t

r

a

c

t

Objective:ToevaluatetheeffectivenessofseasonalinfluenzavaccineinpreventingEmergency

Depart-ment(ED)visitsandhospitalisationsforinfluenzalikeillness(ILI)inchildren.

Methods:Weconducted atest negativecase-controlstudyduring the2011–2012 and 2012–2013

influenzaseasons.Elevenpaediatrichospital/wardsinsevenItalianregionsparticipatedinthestudy.

ConsecutivechildrenvisitingtheEDwithanILI,asdiagnosedbythedoctoraccordingtothe

Euro-peanCentreforDiseaseControlcasedefinition,wereeligibleforthestudy.Datawerecollectedfrom

trainedpharmacists/physiciansbyinterviewingparentsduringtheEDvisit(orhospitaladmission)of

theirchildren.Aninfluenzamicrobiologicaltest(RT-PCR)wascarriedoutinallchildren.

∗ Correspondingauthor.NationalCentreofEpidemiology,SurveillanceandHealthPromotion,ItalianNationalInstituteofHealth,VialeReginaElena,29900161Rome, Italy.Tel.:+390649904252.

E-mailaddress:francesca.menniti@iss.it(F.Menniti-Ippolito).

http://dx.doi.org/10.1016/j.vaccine.2014.06.048

Case-controlstudy Laboratory-confirmedcases

Results:Seven-hundredandfourchildren,from6monthsto16yearsofage,wereenrolled:262children

testedpositiveforoneoftheinfluenzaviruses(cases)and442testednegative(controls).Caseswereolder

thancontrols(medianage46vs.29months),thoughwithasimilarprevalenceofchronicconditions.Only

25children(4%)werevaccinatedinthestudyperiod.Theoverallage-adjustedvaccineeffectiveness(VE)

was38%(95%confidenceinterval−52%to75%).AhigherVEwasestimatedforhospitalisedchildren(53%;

95%confidenceinterval−45%to85%).

Discussion:Thisstudysupportstheeffectivenessoftheseasonalinfluenzavaccineinpreventingvisitsto

theEDsandhospitalisationsforILIinchildren,althoughtheestimateswerenotstatisticallysignificant

andwithwideconfidenceintervals.Futuresystematicreviewsofavailabledatawillprovidemorerobust

evidenceforrecommendinginfluenzavaccinationinchildren.

©2014TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND

license(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

Seasonalinfluenzarepresentsanimportantcauseof morbid-ity and mortalityespecially for the risk of secondary bacterial infections, which is higher in children and elderly than in the generalpopulation.Theburdenofinfluenzaishighestinyoung chil-drenunder5yearsofagelikelyduetoimmunologicalimmaturity [1–3].

Increasingattack ratesduring epidemics leadtohigher out-patientvisitandhospitalisationrates[3–5].Influenza-associated hospitalisationratesarewelldescribedinchildrenwith underly-ingchronicconditions;howeveraccumulatingevidenceshowed thattheincreasedriskalsoaffectedotherwisehealthychildren[4]. Observationaldataindicatedthatalthoughchildrenwith underly-ingconditionsareathigherriskofdeath,themajorityofpaediatric deathsoccuramonghealthychildren[6].

The vaccination against influenza is recognised as an effec-tivepreventiveinterventionandeach countryisresponsiblefor nationalprograms andfor defining targetedrisk groups. Inthe majority of European countries, the influenza vaccine is rec-ommendedforchildren withunderlyingmedicalconditions.UK authorities announced planstoextendinfluenza vaccinationto allchildren aged2–16years from2014[7].Atpresent,Finland istheonlyEuropeancountrywhichhasimplementedtheroutine influenzavaccinationofhealthychildren(6monthsto<3years)[8]. InItaly, thecourseof influenzaepidemics generallyextends betweenDecember and April, witha peak in February [9] and eachyeartheMinistryofHealthpromotesavaccinationcampaign betweenmid-OctoberandDecember.Theofficialrecommendation identifiesatriskchildrenasatargetgroupforinfluenza vaccina-tion(providedfree ofcharge); onlysub-unit,splitorvirosomal seasonalvaccineformulationscanbeadministeredinchildren(6 monthsto17yearsofage)[10,11].Duringtheseasons2011–2012 and2012–2013,thecompositionofthevaccinesvariedonlyfor theBvirusstrain(B/Wisconsinin2011–2012,andB/Brisbanein 2012–2013), whereasthe A(H1N1)and A(H3N2) antigenswere presentinbothseasons.ThetwovaccinestrainsB/Wisconsinand B/Brisbanebelongtotwodifferentlineages,i.e.B-Yamagataand B-Victoriarespectively.

Mostoftheavailableevidenceontheefficacyand effective-nessofseasonalinfluenzavaccineinapaediatricsettingisderived fromclinicaltrialsandconcernsalmostentirelyhealthychildren [12–15].Althoughthesestudiesadoptedheterogeneousoutcome definitions(e.g.fromclinicallydefinedinfluenzalike-illness(ILI)in theoutpatientsettingtolaboratoryconfirmedhospitalisationsfor influenza),theyfoundefficacyestimatesofaround70%,higherthan thoseoneffectiveness(around40%).Despitethefactthatinfluenza vaccinationisprimarilyrecommendedinchildrenwith underly-ingconditions,insufficientevidenceisavailableinthispopulation. Moreover,theWorld Health Organization considersas a target groupforinfluenzaimmunisation,childrenfrom6to23months, eventhougheffectivenessdataarescanty[16].

The objective of this national study was to determine the effectivenessofseasonalinfluenzavaccinationagainst laboratory-confirmed influenza cases visiting the Emergency Department (hospitalised or not) in a large paediatric population over two consecutiveseasons(2011–2012and2012–2013)andtoprovide evidenceforvaccinationrecommendationsinItaly.

2. Methods

InItaly,since1999anactivesurveillanceondrugandvaccine safetyinchildrenhasbeenconductedinvariouspaediatric hospi-tals/wardslocatedthroughoutthecountry[17].Italianpaediatric hospitals/wardscanadmitchildrenfrom0to17yearsofage. Over-all,thenetworkincludes11sitesfromsevenregionsrepresentative of thewholeCountry, and around400,000 children visited the EDsoftheparticipatingcentreseachyear.Thenetwork organisa-tionfacilitatedthepromptsetupoftheinvestigationoninfluenza vaccineeffectivenessduringtheA/H1N1pandemic(in2009)and intwofollowinginfluenzaseasons(2011–2012and2012–2013). TheresultsoftheA/H1N1pandemicvaccinationcampaignwere reportedelsewhere[18].

ConsecutivechildrenvisitingtheEmergencyDepartments(ED) withanILI,asdiagnosedbythedoctorduringtheEDvisit,were eligible for the study. The ILI case definition for children was adaptedfromtheEuropeanCentreforDiseaseControl(ECDC)and usedforinfluenzasurveillanceinEuropesincethepandemic sea-son[19,20].Indetail,thefollowingdefinitionofILIwasadopted, forchildren >5years:suddenonset offever≥38◦_{C (forat least}

24h),inassociationwithatleastonerespiratorysymptom(cough, sorethroat,coryza),andatleastonegeneralsymptom(headache, asthenia,malaise).Forchildrenbetween6monthsand5years,in associationwithfever>38◦C,thefollowinggeneralsignsand symp-tomswereconsidered:inadequatedrinkingorfeeding,vomiting and/ordiarrhoea,respiratorysymptoms.Allchildrenhospitalised, or admittedtoa ShortStay Unit(upto24hobservation) were enrolled,andinsomeclinicalcentresalsochildrenvisitingtheED butnotadmittedtohospitalwereincluded.Sinceinfluenzavaccine isindicatedforchildrenaged>6months,youngerchildrenwerenot eligible.

Writteninformedconsentwasacquiredfromparents.Datawere collectedbytrainedpharmacists/physiciansbyinterviewing par-entsduringtheEDvisit(orhospitaladmission)oftheirchildren. Demographicdata,medicalhistoryofchronicconditions,dateof vaccinationandtypeofvaccinewerecollectedusingastructured questionnaire.Fortheassessmentofinfluenzavaccine effective-ness,childrenweredefinedasvaccinatediftheyhadreceivedat leastonedosemorethan14daysbeforesymptomonset.

Aninfluenza-confirmatorylaboratorytestwascarriedoutinall children.Theviruswasdetectedthroughnasopharyngealsample collection;stableviraltransportmediumwasaddedtoswabs. Spec-imenswerecollectedandanalysedbyusingareal-timereverse transcriptase-polymerasechainreaction(RT-PCR).In sixcentres

thetestswereanalysedininternallaboratories,whereastheothers sentthespecimenstocertifiedexternallaboratories.

Thefirstphaseofthestudywasperformedinthe2011–2012 influenza season and was used as a pilot study to refine the 2012–2013investigation.Inordertoconcentrateenrolmentand laboratorytestsintheepidemicperiodthecoordinatorcentregave thestart-uponthebasisofdataoninfluenzaepidemics inItaly providedfromtheNationalsurveillanceofILIincidence[9].The inclusionofchildrentookplacebetween1Februaryand31March 2012(forthe2011–2012season),andbetween14Januaryand15 March2013(forthe2012–2013season).Theinclusionperiodswere thesameforallcentres.

Datawereanalysed accordingtoatest-negativecase-control studydesign:allchildrenwithapositiveconfirmatorylaboratory test(tooneofthevirusescontainedintheseasonalvaccine)were includedas cases,whereascontrolswerechildrenwitha nega-tivetest.Foreffectivenessevaluation,oddsofinfluenzavaccination werecomparedincasesandcontrols.

2.1. Studysites

Thefollowingpaediatrichospitalsanddepartmentswere par-ticipating:GianninaGasliniPaediatricHospital(Genova);Regina MargheritaPaediatricHospital(Torino);DepartmentofPaediatrics, University of Padova; Paediatric Department, Treviso Hospital (Treviso); AnnaMeyer Children’s University Hospital(Firenze); Departmentof Paediatrics, Universityof Perugia; Pharmacology andPaediatricsandDevelopmentalNeuroscience,Università Cat-tolicaS.Cuore(Roma);BambinoGesùPaediatricHospital(Roma); Santobono-PausiliponPaediatricHospital-VirologicUnitCotugno (Napoli);GiovanniDiCristinaPaediatricHospital(Palermo); Uni-versity Hospital of Messina. A common study protocol was approvedbytheEthicsCommitteeofeachclinicalcentre.Thestudy wascoordinated bytheNationalCentreofEpidemiologyofthe NationalInstituteofHealthinRome.

2.2. Statisticalanalyses

DatawereanalysedwithSPSS(v.21.0).T-testwasusedto com-paremeans, Wilcoxon–Mann–Whitneynon-parametrictestwas usedtocomparemediansandChi-squaretestwasusedtocompare percentages.Adjustedoddsratios(ORs)and95%confidence inter-vals(CI)wereestimatedthroughalogisticregressionmodel.ORs wereadjustedforage,whichwasincludedinthelogisticmodel

asacontinuousvariable(inmonths).Weestimatedtheseasonal influenzavaccineeffectiveness(VE)as1minustheOR,expressed asapercentage.

3. Results

Amongthe773eligiblechildren,69(9%)wereexcluded(Fig.1). Themainreasonforexclusionwaslackofinformedconsenteither tocollectthenasopharyngealswab(n=25)ortobeincludedin thestudy(n=10).The704remainingchildrenwereclassifiedas cases(262childrentestedpositiveforoneoftheinfluenzaviruses) andcontrols(442childrenwhotestednegative).Thepercentage ofhospitalisedchildrenwas56%(n=148)amongcasesand75% (n=332)amongcontrols.Overall,theageoftheenrolledchildren rangedfrom6monthsto16years.

Theproportionofcasesrangedfrom12%to56%inthe11centres. In69%ofcasesand55%ofcontrolsthetestwasperformedthesame dayofsymptomonset.In97%ofcasesandin93%ofcontrolsthetest wascarriedoutwithin2days.Amongcases,Bviruswasdetected in126children(48%),A(H1N1)in59(23%),unspecifiedAvirusin 33(13%),A(H1N1)pdm09in22(8%)andA(H3N2)in22(8%).Inthe 2012–2013seasonthevirologyunitofoneclinicalcentrewasable tocharacterise40ofthe126casespositiveforinfluenzaBvirus: theyallresultedbelongingtoB/Yamagata/16/88lineage.

Casesand controlswere similar with regard to gender and prevalenceofchronicdiseases,whereasastatisticallysignificant differencewasobservedforage(46monthsincasesand29months incontrols)(Table1).

ThemediandurationofsymptomsbeforethevisittotheEDwas similarinthetwogroups(3daysvs.2),asitwastheleveloffever (medianof39◦Cinbothgroups).AccordingtotheILIdefinitionall childrenpresentedfever≥38◦_{C.Coughwasthemostfrequently}

associatedsymptominbothcasesandcontrols(85%vs.83%), fol-lowedbyrhinorrhea,malaise,sorethroatandasthenia.Vomitingor diarrhoeaweremorefrequentlyreportedinyoungerchildren(40% inpatientsupto5yearsand21%inolderones).Sixty-eightpercent ofchildrenwerehospitalisedthroughtheEDsandthemean dura-tionofhospitalisationwasnotstatisticallydifferentincasesand controls(3.6and4.3daysrespectively).

Only25children(4%)werevaccinatedagainstinfluenza:seven ofthe262casesand18ofthe442controls(theyhadbeen vacci-natedbetweenOctoberandmid-January).Thedateofvaccination wasnot available for six children (one case and five controls). However,itislikelythatthesechildrenwerevaccinatedatleast

25 pts: test not performed 13 pts: fever <38°C 10 pts: lack of consent

13 pts: discharged before interview 3 pts: parents not found

5 pts: other reasons

Patients excluded (N=69)

Patients included N=704 Eligible patients N=773

Negative laboratory test (Controls)

N=442 Positive laboratory test

(Cases) N=262

Table1

Maincharacteristicsofcasesandcontrols.

Cases Controls p

Number 262 442

Medianage,months(IR) 46(26–71) 29(15–54) <0.001

%females 45 47 0.78

Chronicdiseases:N.(%) 47(18) 67(15) 0.34

Durationofsymptoms beforeadmissiontoED, mediandays

3 2 0.01

SymptomsofILIatadmissiontoED

Fever,median◦C 39 39 0.13 Cough,N(%) 224(85) 365(83) 0.31 Rhinorrhea,N(%) 122(47) 217(49) 0.52 Malaise,N(%) 111(42) 166(38) 0.21 Sorethroat,N(%) 85(32) 135(31) 0.60 Asthenia,N(%) 62(24) 88(20) 0.24 Vomiting,N(%) 58(22) 130(29) 0.04 Diarrhoea,N(%) 27(10) 76(17) 0.01 Bronchitis,N(%) 22(8) 73(17) 0.002 Hospitalisation,N.(%) 148(56) 332(75) <0.001

Lengthofstaya_(mean,

days) 3.6 4.3 0.20 Typeofvirus,N(%) B 126(48) – A(H1N1) 58(23) – A(unspecified) 33(13) – A(H1N1)pdm09 22(8) – A(H3N2) 22(8) – IR:interquartilerange,ED:EmergencyDepartment.

a_{Amonghospitalisedchildren.}

14daysbeforehospitaladmission,since theywerehospitalised betweentheendofJanuaryandFebruary.Twelveoutofthe25 vac-cinatedchildren(46%)reportedachronicdisease(asthma,allergy, cardiomyopathy,spinalmuscularatrophy[SMA1or2], immunod-eficiency,aplasticanaemia,coeliacdisease,Westsyndrome).

Theoverall age-adjustedVEwas38% (95%CI:_−52%to75%) (Table2).AslightlylowerVEwasestimatedinthe2012–2013 sea-son(VE26%;95%CI:−153%to78%).Threeoutofsevenvaccinated childrenwerepositivetounspecifiedAvirus(onechild)orA/H3N2 virus(twochildren)inthe2011–2012season,whereasthe remain-ingfourvaccinatedcasesinthe2012–2013seasonwerepositive toBvirus.Ninechildren(onecaseandeightcontrols)receivedtwo dosesofthevaccineinthesameseason(VE79%;95%CI:−57%to 100%).

When theanalysis was restricted tohospitalised children a higherestimateofVE,withrespecttotheoverall,wasobtained (53%;95%CI−45%to85%).

4. Discussion

Ourstudyestimatedaround40%reductioninvisitstoEDsand hospitalisationsforILIinchildren,althoughnotstatistically signif-icantandwithwideconfidenceintervals.

Even thoughthe confidence intervalsof the estimates were largelyoverlapping,aslightlylowereffectivenesswasestimatedin thesecondyear.Thefourvaccinatedcasesinthe2012–2013season werepositivetotheBvirus.Datafromourstudyandvirological surveysperformedinItaly[21]showedthattheB/Yamagata lin-eagewascirculatinginthelatterseason(whereasB/Brisbanestrain, belongingtoadifferentlineage,wasincludedintheseasonal vac-cine),whichmayexplainthelowerVEofthe2012–2013vaccine withrespecttothe2011–2012,whentheA(H3N2)andA(H1N1) weremostlypresent.Thematchingbetweenthevaccineand circu-latingstrainsofinfluenzaseasonisarecognisedfactorinfluencing theVE[22].

Themainlimitationofthestudyderivesfromthelow vaccina-tioncoverageobservedintheItalianpaediatricpopulation(4%in thecontrolgroup).Thisproportionwassimilartothatobservedin Italyduringthe2009pandemic[23].Duetothefewvaccinated chil-drenitwasnotpossibletoperformstratifiedanalysesbyvariables ofinterest,suchastypeofvirus/vaccine,agegroups,presenceof chronicconditionsandpriorvaccinationstatus.Assumingastrue theestimateof efficacyin ourstudy,toreachstatistical signifi-canceweshouldhavehad(withalphaerrorof5%andpower80%), eithera25%proportionofvaccinatedchildrenorastudy popu-lationofILIlargerthan4000.However,thenumber ofchildren enrolledinourstudyislargeincomparisonwithotherrecently publishedarticles.IntheI-MOVEstudy,thepaediatricpopulation (1–14years)amountedto512childrenwhowereincludedinfive Europeancountries[24].

Theadoptedstudydesignallowstocontrolfortheconfounding effectofbaselineclinicalstatus.Thereasonreliesonthedefinition ofthecontrolgroup,consistingofchildrenwhotestednegativefor theinfluenzavirusvaccine[25].Itiswelldocumentedthatseveral conditionsincreasethelikelihoodofdevelopinganILIand repre-sent,atthesametime,anindicationforvaccination.Inourstudy, caseandcontrolsubjectsweresimilarwithreferencetothe preva-lenceof chronicconditions,butnot forsymptomsat onset.For

Table2

Vaccineeffectivenessinthetwoinfluenzaseasons.

Influenzavaccine CasesN(%) ControlsN(%) Total CrudeOR(95%CI) AdjVEa_(95%CI)

Yes 7(3) 18(4) 25 35%(−65%to77%) 38%(−52%to75%)

No 255(97) 424(96) 679

Total 262(100) 442(100) 704 Season2011–2012

Influenzavaccine CasesN(%) ControlsN(%) Total CrudeOR(95%CI) AdjVEa_(95%CI)

Yes 3(5) 10(8) 13 38%(−152%to89%) 41%(−126%to84%)

No 58(95) 119(92) 177

Total 61(100) 129(100) 190 Season2012–2013

Influenzavaccine CasesN(%) ControlsN(%) Total CrudeOR(95%CI) AdjVEa_(95%CI)

Yes 4(2) 8(3) 12 23%(−194%to83%) 26%(−153to78%)

No 197(98) 305(97) 502

Total 201(100) 313(100) 514

instance,vomitinganddiarrhoeaweremorefrequentincontrols. ThesesymptomsaremoreoftenassociatedwithILIpresentationin youngerchildren.Theagedifferenceisinlinewiththatobserved inotherEuropeancountries.IntheI-MOVEstudy,thedifferencein themeanagebetweencasesandcontrolsinthepaediatric popula-tion(1–14years)was1.5years,similartothedifferenceobserved inourstudy[24].

Almostallnasopharyngeal swabs were carriedout within 2 daysfromsymptomsonsettotheED,whichisassociatedwitha greaterspecificity.Thefactthatresultswereobtainedseveraldays afterhavingconductedthetest,excludesthepossibilitythatthe exposureinformationmayhavebeenbiasedbytheknowledgeof case/controlstatus(andconsequentlynorecallorascertainment biasmayhaveplayedarole).

In Italy, influenza vaccination remains an unmet prior-ity, as only 4% of children were vaccinated in the recent seasons [23]. Efforts should focus on paediatricians to dis-cuss the importance of influenza vaccination for preventing major complications in both at-risk and healthy children. Sys-tematic reviews and meta-analysis of existing studies may providethebasis for a newawareness onthepositive benefit-risk profile of the influenza vaccination even among healthy children.

Ourstudyprovidesadditionaldataontheeffectivenessofthe seasonalinfluenza vaccinationin preventingvisitstothe Emer-gencyDepartmentsandhospitalisationsforILI,andaddsfurther evidenceforvaccinationrecommendationsespeciallyinchildren. Funding

ThestudywaspartiallyfundedbytheItalianMedicinesAgency (AIFA).

References

[1]MontoAS,SullivanKM.Acuterespiratoryillnessinthecommunity,frequency ofillnessandtheagentsinvolved.EpidemiolInfect1993;110:145–60.

[2]Schanzer DL,Schwartz B. Impactofseasonalandpandemic influenzaon emergencydepartmentvisits,2003–2010,Ontario,Canada.AcadEmergMed 2013;20:388–97.

[3]RufBR,KnufM.Theburdenofseasonalandpandemicinfluenzaininfantsand children.EurJPediatr2013May10[Epubaheadofprint].

[4]IzurietaHS,ThompsonWW,KramarzP,ShayDK,DavisRL,DeStefanoF,etal. Influenzaandtheratesofhospitalizationforrespiratorydiseaseamonginfants andyoungchildren.NEnglJMed2000;342:232–9.

[5]PoehlingKA,EdwardsKM,WeinbergGA,SzilagyiP,StaatMA,IwaneMK,etal. Theunderrecognizedburdenofinfluenzainyoungchildren.NEnglJMed 2006;355:31–40.

[6]BhatN,WrightJG,BroderKR,MurrayEL,GreenbergME,GloverMJ,etal. Influenza-associateddeathsamongchildrenintheUnitedStates,2003–2004. NEnglJMed2005;353:2559–67.

[7]ThorsV,SmithC,FinnA.Shouldallchildrenbeimmunizedagainstinfluenza? ArchDisChild2013;98:846–9.

[8]HeikkinenT,TsoliaM,FinnA.Vaccinationofhealthychildrenagainstseasonal influenza:aEuropeanperspective.PediatrInfectDisJ2013;32:881–8.

[9]NationalCentreofEpidemiology—ItalianNationalInstituteofHealth (Cnesps-ISS). EpiCentro.FLUNEWS. Rome: Cnesps-ISS. http://www.epicentro.iss.it/ problemi/influenza/FluNews.asp[accessedMarch2014].

[10]MinisterodellaSalute.Prevenzioneecontrollodell’influenza:raccomandazioni per lastagione2011–2012. http://www.trovanorme.salute.gov.it/normsan-pdf/0000/394511.pdf[lastaccessedMarch2014].

[11]Ministero della Salute.Prevenzione e controllo dell’influenza: raccoman-dazioni per la stagione 2012–2013. http://www.trovanorme.salute.gov.it/ renderNormsanPdf.spring?codLeg=43909&parte=1&serie=&anno=0 [last accessedMarch2014].

[12]OsterholmMT,KelleyNS,SommerA,BelongiaEA.Efficacyandeffectiveness ofinfluenzavaccines:asystematicreviewandmeta-analysis.LancetInfectDis 2012;12:36–44.

[13]Jefferson T,Rivetti A,DiPietrantonij C,DemicheliV, FerroniE.Vaccines for preventinginfluenzainhealthychildren.CochraneDatabaseSystRev 2012;(8):1–227, http://dx.doi.org/10.1002/14651858.CD004879.pub4 [Art. no.:CD004879].

[14]RhorerJ,AmbroseCS,DickinsonS,HamiltonH,OlekaNA,MalinoskiFJ,etal. Efficacyofliveattenuatedinfluenzavaccineinchildren:ameta-analysisofnine randomizedclinicaltrials.Vaccine2009;27:1101–10.

[15]Lukˇsi ´cI,ClayS,FalconerR,PulanicD,RudanI,CampbellH,etal.Effectiveness ofseasonalinfluenzavaccinesinchildren—asystematicreviewand meta-analysis.CroatMedJ2013;54:135–45.

[16]VaccinesagainstinfluenzaWHOpositionpaper—November2012;87:461–76. http://www.who.int/wer/2012/wer8747.pdf[lastaccessedMarch2014]. [17]Raucci U, Rossi R, Da Cas R, Rafaniello C, Mores N, Bersani G, et al.

Stevens–Johnsonsyndromeassociatedwithdrugsandvaccinesinchildren: acase-controlstudy.PLoSOne2013;8:e16823.

[18]Italian MulticenterStudy GroupforDrugandVaccineSafetyinChildren. EffectivenessandsafetyoftheA-H1N1vaccineinchildren:ahospital-based case-controlstudy.BMJOpen2011;2:e670001.

[19]European Center for Disease Prevention and Control (ECDC). Influenza casedefinition;2013.http://www.ecdc.europa.eu/en/activities/surveillance/ EISN/surveillance/Pages/influenzacasedefinitions.aspx[lastaccessedMarch 2014].

[20]RizzoC,SeylerT,BellaA,RotaMC,D’AnconaF,GiannitelliS,etal.Vaccino influenzalepandemico:stimadell’efficaciasulcampoinItalia,2009–2010. Roma:IstitutoSuperiorediSanità;2012[RapportiISTISAN12/12].

[21]EuropeanCenterforDiseasePreventionandControl(ECDC).Influenzavirus characterization. Summary Europe; March 2013. http://ecdc.europa.eu/ en/publications/layouts/forms/PublicationDispForm.aspx [last accessed March2014].

[22]HeikkinenT,HeinoneS.Effectivenessandsafetyofinfluenzavaccinationin children:Europeanperspective.Vaccine2011;29:7529–34.

[23]NationalCentreofEpidemiology—ItalianNationalInstituteofHealth (Cnesps-ISS). EpiCentro.FLUNEWS. Rome: Cnesps-ISS. http://www.epicentro.iss.it/ focus/h1n1/archivioflunews.asp[lastaccessedMarch2014].

[24]ValencianoM,KisslingE,I-MOVECase-ControlStudyTeam.Earlyestimatesof seasonalinfluenzavaccineeffectivenessinEurope:resultsfromtheI-MOVE multicentrecase-controlstudy,2012/13.EuroSurveill2013;18,pii=20400.

[25]JacksonML,NelsonJC.Thetest-negativedesignforestimatinginfluenzavaccine effectiveness.Vaccine2013;31:2165–70.