Neonatal infections: Case definition and guidelines for data collection, analysis, and presentation of immunisation safety data

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Vaccine

jo u 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

Neonatal

infections:

Case

definition

and

guidelines

for

data

collection,

analysis,

and

presentation

of

immunisation

safety

data

夽

Stefania

Vergnano

_,

_Jim

_Buttery

_,

_Ben

_Cailes

_,

_Ravichandran

_{Chandrasekaran}

_,

Elena

Chiappini

_,

_Ebiere

_Clark

_,

_Clare

_Cutland

_,

_Solange

_Dourado

_de

_Andrade

_,

Alejandra

Esteves-Jaramillo

_,

_Javier

_Ruiz

_Guinazu

_,

_Chrissie

_Jones

_,

_Beate

_Kampmann

_,

Jay

King

_,

_Sonali

_Kochhar

_,

_Noni

_Macdonald

_,

_Alexandra

_Mangili

_,

Reinaldo

de

Menezes

Martins

_,

_César

_Velasco

_{Mu ˜}

_noz

_,

_Michael

_Padula

_,

_Flor

_M.

_{Mu ˜}

_noz

_,

James

Oleske

_,

_Melvin

_Sanicas

_,

_Elizabeth

_Schlaudecker

_,

_Hans

_Spiegel

_,

_Maja

_Subelj

_,

Lakshmi

Sukumaran

_,

_Beckie

_N.

_Tagbo

_,

_Karina

_A.

_Top

_,

_Dat

_Tran

_,

Paul

T.

Heath

_,

_The

_Brighton

_{Collaboration}

_Neonatal

_Infections

_Working

_Group

b_{MonashMedicalCentre,Clayton,Victoria3168,Australia} c_{MadrasMedicalCollege,India}

d_{MeyerChildren’sHospital,FlorenceUniversity,Italy} e_{EnhancedVigilanceSystems,UK}

f_{UniversityoftheWitwatersrand,WitsHealthConsortium,DST/NRFRespiratoryandMeningealPathogensResearchUnit(RMPRU),SouthAfrica} g_{Fundac¸ãodeMedicinaTropicalDr.HeitorVieiraDourado,Brazil}

h_{GlobalPharmacovigilance,SanofiPasteur,USA} i_{GSKVaccines,Wavre,Belgium}

j_{ImperialCollege,London,UK} k_{MRCUnit,TheGambia}

l_{GlobalHealthcareConsulting,India}

m_{DepartmentsofPaediatrics,DalhousieUniversity,Halifax,NS,Canada} n_{NovartisVaccine/GSKVaccines,USA}

o_{BioManguinhos/Fiocruz,Brazil}

p_{ISGlobal,BarcelonaCtr.Int.HealthRes.(CRESIB),UniversitaddeBarcelona,Spain}

q_{DivisionofNeonatology,TheChildren’sHospitalofPhiladelphiaandUniversityofPennsylvania,USA} r_{BaylorCollegeofMedicine,Houston,TX,USA}

s_{DepartmentofPediatrics,Rutgers–NewJerseyMedicalSchool,Newark,NJ,USA} t_{Bill&MelindaGatesFoundation,Seattle,WA,USA}

u_{DivisionofInfectiousDiseases,GlobalHealthCenter,CincinnatiChildren’sHospitalMedicalCenter,USA} v_{HenryJacksonFoundation,Bethesda,MD,USA}

w_{NationalInstituteofPublicHealth(NIJZ),Slovenia}

x_{CentersforDiseaseControlandPrevention,DivisionofPediatricInfectiousDiseases–EmoryUniversitySchoolofMedicine,USA} y_{InstituteofChildHealth,UniversityofNigeriaTeachingHospital,Nigeria}

z_{DivisionofInfectiousDiseases,DepartmentofPaediatrics,TheHospitalforSickChildren,UniversityofToronto,Canada}

夽 Disclaimer:Thefindings,opinionsandassertionscontainedinthisconsensusdocumentarethoseoftheindividualscientificprofessionalmembersoftheWorking Group.Theydonotnecessarilyrepresenttheofficialpositionsofeachparticipant’sorganisation(e.g.government,university,orcorporation).Specifically,thefindingsand conclusionsinthispaperarethoseoftheauthorsanddonotnecessarilyrepresenttheviewsoftheirrespectiveinstitutions.

∗ Correspondingauthor.

E-mailaddresses:contact@brightoncollaboration.org,secretariat@brightoncollaboration.org(P.T.Heath).

1 _{BrightonCollaborationhomepage:http://www.brightoncollaboration.org.}

http://dx.doi.org/10.1016/j.vaccine.2016.03.046

a

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t

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Possiblebacterialinfection Pneumonia Bronchiolitis Perinatal Newborn Adverseevent Immunisation Guidelines Casedefinition

a

b

s

t

r

a

c

t

Maternalvaccinationisanimportantareaofresearchandrequiresappropriateandinternationally

com-parabledefinitionsandsafetystandards.TheGAIAgroup,partoftheBrightonCollaborationwascreated

withthemandateofproposingstandardiseddefinitionsapplicabletomaternalvaccineresearch.This

studyproposesinternationaldefinitionsforneonatalinfections.

TheneonatalinfectionsGAIAworkinggroupperformedaliteraturereviewusingMedline,EMBASE

andtheCochranecollaborationandcollecteddefinitionsinuseinneonatalandpublichealthnetworks.

Thecommoncriteriaderivedfromtheextensivesearchformedthebasisforaconsensusprocessthat

resultedinthreeseparatedefinitionsforneonatalbloodstreaminfections(BSI),meningitisandlower

respiratorytractinfections(LRTI).Foreachdefinitionthreelevelsofevidenceareproposedtoensurethe

applicabilityofthedefinitionstodifferentsettings.

Recommendationsaboutdatacollection,analysisandpresentationarepresentedandharmonized

withtheBrightonCollaborationandGAIAformatandotherexistinginternationalstandardsforstudy

reporting.

©2016PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense(http://

creativecommons.org/licenses/by/4.0/).

1. Preamble

1.1. Needfordevelopingcasedefinitionsandguidelinesfordata collection,analysis,andpresentationforneonatalinfectionsasan adverseeventfollowingimmunisation

Consideringtheenormouspublichealthbenefitthatcan poten-tiallybederived byvaccinating womeninpregnancytoprotect theirnewbornsagainstspecificinfections,itisnowimperativeto establishsafetyandefficacystandardsinthisarea.Thisincludes theneedtodevelopdefinitionsforneonatalinfections.Such defi-nitionsneedtobeflexibleenoughtoreflectchangesinthepattern ofinfectionsthatmayoccurfollowingvaccinationandtoinclude infectionsaspossibleadverseevents[1,2].Consideringthat vacci-nationmaydelaytheonsetofinfectionsfromtheneonatalperiod tolaterininfancy,thedefinitionsalsoneedtobeapplicabletothe younginfant.

Providing standardised definitions of neonatal infections is equallyrelevantforglobaleffortstoaddresschildmortalitysince themajorityofdeathsinchildrenlessthanfiveyearsnowoccur intheneonatalperiodandneonatalinfectionsarethethirdmost commoncauseofdeathinnewborns[3].Themajorityofdeaths occurinlowandmiddle-incomecountries(LMIC)andtherefore standardiseddefinitionsforglobalusemustspecificallyreflectthe needsofLMICs.Globaldeathsfromneonatalsepsisandother infec-tionswereestimatedtobe328,000and342,000in1990and2013, respectively(age-standardiseddeathrates4.7and4.9per100,000, respectively)[4].Theothermostcommontypesoffatal neona-talinfectionsin2013werelowerrespiratoryinfections(196,500 deaths),diarrhoealdiseases(44,800),tetanus(26,000),meningitis (20,600),andmalaria(16,800)[4].

Avarietyofdefinitionsforneonatalinfectionshavebeen pro-posedandappliedinboth communityand hospitalstudies(for examplefromtheYoungInfantClinicalStudyGroup(YICSG))[5], oraspartofverbalautopsystudies[6].

Inhigh-incomecountries,neonatalintensivecarehasadvanced dramaticallyover the last decades.Neonatal infections cause a significantburden ofmorbidity and mortalityin the extremely preterm population in these settings. As a result, neonatal networksaroundtheworldhaveproducedmanycasedefinitions forinfections,especiallyfocusingonpreterminfants. Thebetter knowncase definitions arefromtheNationalInstituteof Child Health and Human Development Neonatal Research Network (NICHD) [7], Australian and New Zealand Neonatal Network (ANZNN) ( https://npesu.unsw.edu.au/data-collection/australian-new-zealand-neonatal-network-anznn),EuropeanNeonatal Net-work (ENN) [8], the Vermont-Oxford-Network (VON) (https:// public.vtoxford.org)andtheneonatalinfectionnetwork(neonIN;

www.neonin.org.uk). Some infectious disease networks have focusedspecificallyonhealthcare-associated infections,suchas neoKISS[9].Withasimilardrivetomonitoringhospitalassociated infections, otherorganisations suchasthe Centers forDiseases Control(CDC)[10],theEuropeanCentreforDiseaseControl(ECDC) (http://ecdc.europa.eu/en/healthtopics/Healthcare-associated infections/point-prevalence-survey/Pages/Point-prevalence-survey.aspx)and theEuropeanMedicine Agency(EMA)(http:// www.ema.europa.eu/docs/enGB/documentlibrary/Report/2010/ 12/WC500100199.pdf)haveproposedyetmoreneonatalinfection definitions.

In the neonatal period, theimmaturity of the immune sys-tem,particularlyinprematureinfants,confersdistinctiveclinical, physicalandoutcomecharacteristicstoinfectionscomparedwith otheragegroups:neonatesaremorevulnerabletoabroadrange ofpathogens,includingthoseofgenerallylowvirulencesuchas Listeria,paraechovirusesorCandida.Differentpathogenssuchas bacteria,viruses,fungior parasites oftenpresent in a clinically indistinguishablepatterninneonates,andlocalisedinfectionsmay presentwithsystemicsignsmakingtheclinicaldiagnosisdifficult andoftenimpossiblewithoutimagingconfirmationand/or labo-ratorysupport.Moreover,anumberofnon-infectioussyndromes, suchas respiratory distress syndromein the prematureinfant, inbornerrorsofmetabolismandcongenitalmalformationssuchas seriouscardiacanomalies,haveinitialclinicalpresentationssimilar tosevereinfections[11].

Even when laboratory tests are available, diagnostic tools toguide clinicians are limited.Traditional blood culture meth-ods lack sensitivity, particularly in neonates where only small samplescan be obtained. This leadstoa highnumber of neg-ative results, leaving a largepercentage of bacterial infections microbiologicallyunconfirmed[12].Whilstthediagnosisofsome entitiessuchasHIVandCMVhasbenefitedfromtheuseofnovel PCR-basedmoleculardiagnostictools,thishasnothappenedfor allneonatal infections.Interpretation ofmolecularresultsfrom non-sterile samples, such as nasopharyngeal aspirates, can be problematic[13].

Thelackofastandardisedclinicalorlaboratorydiagnosisfor neonatal infections explains the heterogeneity in the neonatal infectiondefinitionsincurrentuse,particularlyforprobable blood-streaminfections[14].

Thereiscurrentlynouniformlyaccepteddefinitionof neona-talinfectionsfollowingimmunizations.However,thedevelopment ofstandardiseddefinitionsisnowessentialinordertofacilitate comparabilityofdataandoutcomesacrossclinicaltrialsand epi-demiologicalsurveillancestudiesinwhichwomenhavereceived vaccinesinpregnancyaswellasotherclinicaltrialsand interven-tionsaimedatreducingneonatalmorbidityandmortality.

Available online 01 August 2016

1.2. Methodsforthedevelopmentofthecasedefinitionand guidelinesfordatacollection,analysis,andpresentationfor neonatalinfectionsasanadverseeventfollowingimmunisation

Followingtheprocessdescribed in theoverview paper[15], theBrighton Collaboration – GAIA: Neonatal Infections Working Group was formed in 2015 and included members with clini-cal, academic, public health, and vaccine industry background. The composition of the working and reference group as well asresultsof theweb-basedsurvey completedbythereference group with subsequent discussions in the Working Group can beviewedat:http://www.brightoncollaboration.org/internet/en/ index/workinggroups.html.

Toguidethedecision-makingforthecasedefinitionand guide-lines,a literaturesearchwasperformedusingMedline,Embase and the Cochrane Libraries, the search terms are available in Appendix1.

Thesearch resulted in theidentificationof 4422 references. Only references with full abstracts (in English language) were included.Allabstractswerescreenedforpossiblereportsof neona-talinfections.1205articleswithpotentiallyrelevantmaterialwere reviewedinmoredetail.Thisreviewresultedinadetailedsummary of 432articles,includinginformation onthe diagnosticcriteria orcasedefinitionsused.Casereports,editorialsandletterswere excluded.Whererelevanta descriptionofthevaccineused,the timeintervalsinceimmunisation,andanyothersymptomswere extracted.Multiplekeyreferenceswerehandsearchedand def-initions fromexisting neonatalnetworks, infectionsurveillance networksandwebsitesofpublichealthorganisationssuchasthe CentersforDiseaseControl(CDC),theEuropeanCentreforDisease Control(ECDC)andtheEuropeanMedicineAgency(EMA)werealso searchedforneonatalandperinatalinfectiondefinitions.

Acrossthedifferentmanuscriptsselected,a largenumber of definitionswerefoundwithavariablenumberandtypeof clin-ical, laboratory and microbiological criteria. The quality of the manuscriptswasheterogeneousbutthisreviewdidnotgradethe evidenceasitwasnot consideredtoberelevantforthetaskof extractingthedefinitionsused.

The definitions from the manuscripts were extracted and enteredintospreadsheetslistingclinical,laboratoryand radiolog-icalcriteriaby14membersofthegroupindependentlyandthen reviewedforconsistencybythecoordinator(SV).Thedatawere separatedaccordingtothesyndromedescribed:sepsis,meningitis andrespiratorytractinfectionsandcongenitalinfections. Percent-agesoftheclinicalandlaboratoryindicatorswerecalculated.The syndromeswerenotseparatedaccordingtosinglepathogensor classofpathogens.

The data extracted from the published literature were col-lectedrecognizingthelimitationthateachstudyreporteddifferent dataanddefinitionsfortheclinicalorlaboratorysignsandthese werenotalwaysspecifiednorclearlydescribed.Thestudiesfrom neonatalunitsinhigh-incomecountrieswerereportingboth clin-icalandlaboratoryconfirmedinfectionswhilecommunitystudies frommiddle-orlow-incomecountriesusedmostlyclinical def-initions. This heterogeneity made data extraction a somewhat subjective exercise. Proposed definitions for specific congenital infectionswerealsodiscussed,butwereeventuallyexcludedfrom this guidelineand recommendedfor considerationas aspecific groupofdefinitionsforafutureBrightoncollaborationWorking Group.

TheresultsofthisworkwerepresentedtotheWorkingGroup togetherwiththestandarddefinitionscurrentlyinusefromthe aforementionednetworksandthegroupdiscussedthedefinitions inaseriesofteleconferencesuntilconsensuswasobtained.

1.3. Rationaleforselecteddecisionsaboutthecasedefinitionof neonatalinfectionsasanadverseeventfollowingimmunisation

Forthepurposeofthisguidelinetheterm“infection”includes neonatalbacteraemiaandsepsis(ofearlyorlateonset),meningitis, pneumonia and otherrespiratory infectionssuchas bronchioli-tis,causedby bacteria,parasites,virusesorfungi.Localisedeye andearinfectionswereexcludedfromtheseguidelinesaswere encephalitis,urinarytractinfectionsandintestinalinfections.The term “neonatal” includesinfants from birth (day 0) up to and including28postnataldays.

The term“neonatal infection” was chosen toinclude differ-entinfectionsyndromesduringtheneonatalperiod(provenblood streaminfections,probablebloodstreaminfections,meningitisand respiratorytractinfections).

Ultimately,thegroupreachedagreementon3separate def-initions forneonatalinfections, each with3 ormore diagnostic levels.Itisimportanttoemphasisethatwithinthedefinition con-text,however,thediagnosticlevelsmustnotbemisunderstoodas reflectingdifferentgradesofclinicalseverity.Theyinsteadreflect diagnosticcertainty.Thecasedefinitionhasbeenformulatedsuch thattheLevelOnedefinitionishighlyspecificforthecondition. Asmaximumspecificitynormallyimpliesalossofsensitivity,one ortwoadditionaldiagnosticlevelshavebeenincludedinthe def-inition,offeringastepwiseincreaseofsensitivityfromlevelone tolevelthree,whileretaininganacceptablelevelofspecificityat alllevels.Inthiswayitishopedthatallpossiblecasesofneonatal infectionscanbecaptured,regardlessofthesettingorpopulation inwhichtheyarebeingassessed.Thisisofparticularrelevancein LMICswheretheresourcesavailabletoassessevents,e.g. labora-toryfacilities,maybemorelimited.

1.3.1. Rationaleforindividualcriteriaordecisionsmaderelated tothecasedefinition

1.3.1.1. Neonatalinvasivebloodstreaminfections. TheGAIA neona-talinfectionsWorkingGroupincludedinlevel1themicrobiological confirmationofinfectionasthisistherecogniseddiagnosticgold standard. Itwasdecidedtousetheterm“validated”methodof identificationbecauseitwasrecognisedthatthisisarapidly chang-ingfield,especiallywithregardtomoleculartests.Itishopedthat thiswillallowthedefinitiontobeasinclusiveaspossibleasthese methodscontinuetoadvance.

Thegroupoptedtoincludealistoforganismscommonly con-siderednon-pathogenic(oftencalled“skincommensals”),butstill capableofcausingopportunisticinfectionsincertainsituations,for example,inthepresenceofcentrallines,aswellasalistof recog-nisedpathogensinordertoreduceuncertaintyanddifferencesin reporting.

Thenumber ofclinicalcriteria waschosenbyreviewing the available definitions in the literature and by consensus.It was decidedtoincludealevel3definitionbasedsolelyonclinicalsigns andtakenfromasystematicreviewofstudiesthatreported clini-calsignspredictiveofsevereillnessesormortalityinyounginfants aged0–59days,endorsedbytheWorldHealthOrganization(WHO) [16].Thelimitedsetofclinicalsignsforwhichextensiveevidence supportingtheirvalueexistswasreportedtohavehighsensitivity andreasonablespecificity.Thisensuresthatthecasedefinitionhas relevanceinallpopulationsandsettings.

Withregardtothecriterionofabnormalwhitecellcount(WCC), it is recognised that ethnic variations exist, for example many AfricanAmericanshaveaWCCthatispersistentlybelowthenormal rangeforpeopleofEuropeandescent,aconditioncalled“benign ethnicneutropenia”[17].Thisshouldbeconsideredwhen evaluat-ingacase.

1.3.1.2. Neonatalmeningitis. Asabove,the GAIAneonatal infec-tions Working Group included in level 1 the microbiological confirmationofinfectionasthisistherecogniseddiagnosticgold standard.

Inrecognitionthatdelays inundertaking alumbar puncture maymean that antibiotics have already beengiven before CSF isobtained, which may make microbiologicalconfirmation less likely,thegroupincludedadefinitionbasedonthepresenceof CSFpleocytosis.CSFpleocytosiswasdefinedas_≥20cells/mm3_for ≤28day-oldsand≥10cells/mm3_{for29–89day-oldsbasedondata} fromlargestudies[18,19]withnoadjustmentmadefortraumatic taps[20].

1.3.1.3. Respiratorytractinfections(RTI). TheGAIAneonatal infec-tionsWorkingGroupprovideda singledefinitionforRTI which aimedtoincludebacterial,fungalandviralpathogenstoallowease ofuse.Thedifferentpathophysiologyofviralandbacterialorfungal infectionsisreflectedintheuseofdiagnosticimaging.Radiographic features(e.g.lobarinfiltrate)wereacceptedwithout microbiolog-icalconfirmationforbacterialandfungalinfections,butvirallow respiratorytractinfectionsrequiredlaboratoryconfirmation,even inthepresenceofX-rayfindingsconsistentwithaviral diagno-sis.

Thenumberofclinicalcriteriachosenarosefromtheconsensus ofthegroupaftercarefulreviewofavailableevidenceandcurrent definitionsinuse.

TheWorkingGroupwereawareoftheproposedWHOcandidate casedefinitionsforRSVvaccineefficacytrialsandbelievethatboth setsofguidelinesareconsistent.

1.3.2. Influenceoftreatmentonfulfilmentofcasedefinitions[21] Inthecontextofinfectiona responsetoantimicrobial treat-ment might be considered towards fulfilment of the neonatal infectionscasedefinition.However,theWorkingGroupdecided againstthis. A treatmentresponse or its failure is not in itself diagnosticandmaydependonvariables suchasclinicalstatus, timetoinitiationoftreatment,otherclinicalparametersandfor manyinfections,particularlyviral,notreatmentiscurrently avail-able.

Inflammatorymarkers wereincludedalthoughit was recog-nised that viral infections often are not accompanied by an inflammatory response and newborns often do not present a strong inflammatory response, particularly extremely preterm infants.

1.3.3. Timingpostimmunisation

Specifictimeframesforonsetofsymptomsfollowing immun-isationarenotincludedbecausetherearemanyfactorsthatmay influencetheimpactofvaccinationinpregnancyoneventsinthe newbornperiod.Suchfactorsincludethevaccinegiven,thelength ofgestationatvaccinationofthemotherandatbirth,the pres-enceof pre-existingimmunity andconcomitantillnesses inthe newborn.

Wepostulatethatadefinitiondesignedtobeasuitabletoolfor testingcausalrelationshipsrequiresascertainmentoftheoutcome independentfromtheexposure(e.g.immunisations).Therefore,to avoidselectionbias,arestrictivetimeintervalfromimmunisation totheonsetofneonatalinfectionsshouldnotbeanintegralpart ofsuchadefinition.Instead,wherefeasible,detailsofthisinterval shouldbeassessedandreportedasdescribedinthedatacollection guidelines.

Further,eventsoftenoccuroutside the controlledsetting of a clinicaltrialor hospital. In somesettings it maybe impossi-ble to obtaina cleartimeline of the event, particularlyin less developed or ruralsettings. In order to avoid selecting against

Table1

Neonatalinvasivebloodstreaminfections:bacterial/fungal/viral.

LEVEL1 LEVEL2 LEVEL3[22] Recognisedpathogena

identifiedusinga validatedmethod andfromanormally sterilesiteb Ifanorganism normallyconsidered non-pathogenicis isolatedfromblood culturesa_:Level1 requiresits identificationfromat least2bloodcultures takenfromtwo differentsites,orat2 differenttimes,PLUS 1ofthecriteriaas perlevel2of evidence

NotmeetingLevel1of evidence AND 3ormorecriteria: •Temperature≥37.5◦_Cor <35.5◦_Cf •Tachycardiad_ornewor morefrequentepisodesof bradycardiad

•Newormorefrequent episodesofapnead_or increasedoxygen requirementorincreased requirementfor ventilatorysupport •Lethargyormovingonly whenstimulatedor hypotoniaorirritability •Difficultyinfeedingor abdominaldistention •Pallororpoor perfusiond_{orhypotension}d •AbnormalWhiteCell Countd_{orI/Tratio>0.2} •Abnormalplateletcountd •Increasede_{inflammatory} markers(CRP,

procalcitonin) •Metabolicacidosisas definedbyabaseexcess (BE)d

NotmeetingLevel 1or2ofevidence AND 2ormoreofthe followingcriteria: •Temperature ≥37.5◦_Cor <35.5◦_Cf •Tachypnead_or severechest indrawingor gruntingor cyanosis •Changeinlevelof activity •Historyoffeeding difficulty •Historyof convulsions

a_{Seelistofpathogensandnon-pathogensinAppendix1.}

b_{Sterilesite:blood,sterileurine(catheterurineorsupra-pubicaspirate),pleural}

fluid,asciticfluid,broncho-alveolarlavage,bonebiopsy,synovialfluid.

d _{Definitions:Apnea:pauseinbreathing>20s;CRPorcalcitoninlevelsabovethe}

localnormalstandards;Tachypnea/fastbreathing:respiratoryrate>60breathsper minute;Tachycardia:heartrate>180beatsperminute;Bradycardia:heartrate <100beatsperminute;cPoorperfusion:CRT>2.d4000or>20,000×109_cells/L;Low

Platelets/Thrombocytopenia:<100,000×109_{/L;Metabolicacidosis:<−10mmol/L}

(−10mEq/L)

e_{Increasedaccordingtolocallydefinedandvalidatedreferenceranges.} f _{AlsorefertoBrightoncollaborationcasedefinitionforfever[23].}

such cases, the case definition avoids setting arbitrary time frames.

1.3.4. Differentiationfromother(similar/associated)disorders Usingthelevel2or3ofevidencethereisriskthattheabove definitionswillinclude otherneonatalpathologies suchas con-genitalheartdiseasesorinbornerrorsofmetabolismwithinthe bloodstreaminfections(BSI)andmeningitisdefinitionsoreven respiratorydistresssyndromeandtransienttachypneaofthe new-borninthemostprematureneonateswithintheRTIdefinition. Congenital malformations and inborn error of metabolism are relativelyrareeventshowever,anddistinctionbasedonclinical responsetotreatment,laboratoryinvestigationsandimagingmay bepossibleinmostsettings.

1.4. Guidelinesfordatacollection,analysisandpresentation Thecase definitionis accompanied byguidelines,which are structured accordingto thesteps of conducting a clinical trial, i.e.datacollection,analysisandpresentation.Neithercase defini-tionnorguidelinesareintendedtoguideorestablishcriteriafor managementofillinfants,children,oradults.Bothweredeveloped toimprovedatacomparability.

Table2

Bacterial/fungal/viralmeningitis.

LEVEL1 LEVEL2 LEVEL3a LEVEL3b

Recognisedpathogena_identified usingavalidatedmethodfrom cerebrospinalfluid(CSF) Ifanorganismnormally considerednon-pathogenicis identifiedfromtheCSF,LEVEL1 ofevidenceadditionallyrequires allLEVEL2criteria:i.e.CSF pleocytosisANDtemperature criteriaAND1ormoreclinical criteria

CSFpleocytosisd_{ORpositiveIgM} antibodiestoaspecificpathogeninthe CSF

AND

Recognisedpathogena_{identifiedusing} avalidatedmethodfromanormally sterilesiteb_{(otherthanCSF)}

AND Temperature≥37.5◦_Cor<35.5◦_Cc AND 1ormorecriteria: •Historyofconvulsions •Lethargyorirritability •Coma •Apnead •Bulgingfontanel •Neckstiffness CSFpleocytosisd AND

NOdpathogena_{identifiedusinga} validatedmethodfromanormally sterilesiteb AND Temperature≥37.5◦_Cor<35.5◦_Cc AND 3ormorecriteria: •Historyofconvulsions •Lethargyorirritability •Coma •Apnead •Bulgingfontanel •Neckstiffness

Nolumbarpuncturedoneorno sampleavailable AND Temperature≥37.5◦_Cor<35.5◦_Cc AND 4ormorecriteria: •Historyofconvulsions •Lethargyorirritability •Coma •Apnead •Bulgingfontanel •Neckstiffness

a_{Seelistofpathogensandnon-pathogensinAppendix1.}

b_{Sterilesite:blood,sterileurine(catheterurineorsupra-pubicaspirate),pleuralfluid,asciticfluid,broncho-alveolarlavage,bonebiopsy,synovialfluid.} c _{AlsorefertoBrightoncollaborationcasedefinitionforfever[23].}

d _{CSFpleocytosis:≥20cells/mm}3_{for<28day-oldsand≥10cells/mm}3_{for29–89day-olds.#i–89day-olds.} 1.5. Periodicreview

SimilartoallBrightonCollaborationcasedefinitionsand guide-lines,reviewofthedefinitionwithitsguidelinesisplannedona regularbasis(i.e.everythreetofiveyears)ormoreoftenifneeded. 2. Casedefinitionsofneonatalinfections

2.1. Neonatalinvasivebloodstreaminfections: bacterial/fungal/viral

Table1presentsthecasedefinitionforneonatalinvasiveblood StreamInfections:bacterial/fungal/viral.

2.2. Bacterial/fungal/viralmeningitis

Table2presentsthecase definitionfor bacterial/fungal/viral meningitis.

2.3. Respiratorybacterial/fungal/viralinfection

Table 3 presents the case definition for respiratory bacte-rial/fungal/viralinfection.

3. Guidelinesfordatacollection,analysisandpresentation ofneonatalinfections

ItwastheconsensusoftheBrightonCollaborationGAIA Neona-talInfectionsWorkingGrouptorecommendthefollowingguidelines to enable standardised data collection, analysis, and presenta-tionofinformationregarding neonatalinfectionsinthecontext of pregnancy vaccination. The availability of information may varydependinguponresources,geographicalregion,andwhether thesourceof information is a prospectiveclinicaltrial,a post-marketingsurveillanceorepidemiologicalstudy,oranindividual reportofaneonatalinfection.

Guidelines for the collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women

are also available and should be referred to for more generic guidance.

3.1. Datacollection

3.1.1. Sourceofinformation/reporter

Forallcasesand/orallstudyparticipants,asappropriate,the followinginformationshouldberecorded:

(1)Dateofreport.

(2)Name and contact information of person reporting2 _and/or

diagnosingtheeventasspecifiedbycountry-specificdata pro-tectionlaw.

(3)Nameandcontactinformationoftheinvestigatorresponsible forthesubject,asapplicable.

(4)Relationtothepatient(e.g.immuniser[clinician,nurse],family member[indicaterelationship],other).

3.1.2. Vaccinee/control

Forallcasesand/orallstudyparticipants,asappropriate,the followinginformationshouldberecorded:

3.1.2.1. Demographics.

(5)Case/study participant identifiers(e.g. firstname initial fol-lowed bylast nameinitial) or code (or in accordance with country-specificdataprotectionlaws).

(6)Dateofbirth,age,andsex.Withneonataldatadisaggregated fromolderinfants.

(7)Gestationalage,birthweightandmethodsusedfortheir assess-ment.

2_{Ifthereportingcentreisdifferentfromthevaccinatingcentre,appropriateand}

Table3

Respiratorybacterial/fungal/viralinfection.

LEVEL1 LEVEL2 LEVEL3[24,25]

Neworprogressiveorpersistentinfiltrateor shadowingorfluidintheintrapleuralcavityor interlobarfissureonchestX-ray

AND

Recognisedvirusc_{identifiedusingavalidatedassay} fromanupperrespiratorysample

OR

Recognisedpathogena_{identifiedusingavalidated} methodandfromanormallysterilesiteb

AND3ormorecriteria:

•Temperature≥37.5◦_Cor<35.5◦_Ce

•Tachypneac_{orNasalflaringorChestindrawingor} Grunting

•Desaturationsorincreasedoxygenrequirementsor increasedventilatorrequirementsoroxygen saturation<95%

•Apneasc

•IncreasedrespiratorysecretionsorIncreased suctioningrequirements

•Coughorwheezeorcrepitations

•IncreasedCRPorprocalcitonind

Neworprogressiveorpersistentinfiltrateor shadowingorfluidintheintrapleuralcavityor interlobarfissureonchestX-ray

AND4ormorecriteria:

•Temperature≥37.5◦_Cor<35.5◦_Ce •Tachypneac_{orNasalflaringorChest} indrawingorGrunting

•Desaturationsorincreasedoxygen requirementsorincreasedventilator requirementsoroxygensaturation<95% •Apneasc

•IncreasedrespiratorysecretionsorIncreased suctioningrequirements

•Coughorwheezeorcrepitations •IncreasedCRPorprocalcitonind

2ormorecriteria:

Difficultyin breathing/Tachypneac •Severechestindrawing •Nasalflaring •Grunting •Wheezing •Stridor •Fever

a_{Seelistofpathogensandnon-pathogensinAppendix1.}

b _{Sterilesite:blood,sterileurine(catheterurineorsupra-pubicaspirate),pleuralfluid,asciticfluid,broncho-alveolarlavage,bonebiopsy,synovialfluid.} c _{SeelistofdefinitionsinTable1.}

d _{Increasedaccordingtolocallydefinedandvalidatedreferenceranges.} e_{AlsorefertoBrightoncollaborationcasedefinitionforfever[23].}

3.1.2.2. Clinical and immunisation history. For all cases and/or allstudyparticipants,as appropriate,thefollowinginformation shouldberecorded:

(8)Mother: Maternal history of infections or risk factors for infections (e.g.GBScolonisation,peripartumfever), indica-tionwhetheranyantimicrobialswereusedinpregnancyor inlabour,typeandrouteofadministration;underlying dis-eases/disorders, type of deliveryand indicate whetherthe deliveryoccurredinafacilityorathome,describeobstetric careavailableintermsofbasicorcomprehensive; immunisa-tionreceivedinpregnancywithdates,type,batchandreaction forallinfections,availableserologyasapplicable,anyother medicationsuseduringpregnancyincludingnonprescription medications.

(9)Newborn:reportwhetherthenewbornwasadmittedto hos-pitalandthetypeoffacility(e.g.emergencydepartment,ward, neonatalunit)orwasinthecommunity.Indicatethelevelof neonatalcareavailable(e.g.ventilatorsupport)andgivethe

typeofneonatalcarestaffavailableandtheirleveloftraining, Indicatethepresenceofcentrallines,whetherthenewborn receivedsurgicalinterventionsandtheirtype.

(10)Newborn:Reportthemedicationhistory(other than treat-ment for the event described) including prescription and non-prescription medication as well as medication, topi-caltreatments,parenteral nutritionortreatmentwithlong half-life or long-term effect (e.g. immunoglobulins, blood transfusionandimmunosuppressants).

(11)Facility: indicate whethermicrobiology laboratory investi-gations are available and describe the methods used for bacterialidentificationorthemoleculartechniquesusedto identifyorganismsviral,fungal,parasiticorbacterial.Givean indicationofthequalitycontrolinplace.Indicatewhether bio-chemistry,haematologyandradiologyfacilitiesareavailable. (12)Immunisationhistory(i.e.previousimmunizationsandany adverse event following immunisation (AEFI)), in partic-ular occurrence of neonatal infection after a previous immunisation.

3.1.3. Detailsoftheimmunisation

Forallstudyparticipants,asappropriate,thefollowing informa-tionaboutpregnancyvaccinationshouldberecorded:

(13)Dateandtimeofimmunisation(s),gestationalageatthetime ofimmunisation.Contextofimmunisation(routineclinic, out-breaksituation,clinicaltrial,etc.)

(14)Descriptionofvaccine(s)(nameofvaccine,manufacturer,lot number,dose(e.g.0.25mL,0.5mL,etc.)andnumberofdoseif partofaseriesofimmunizationsagainstthesamedisease). (15)Theanatomicalsites(includingleftorrightside)ofall

immun-izations(e.g.vaccineAinproximalleftlateralthigh,vaccineB inleftdeltoid).

(16)Routeandmethodofadministration(e.g.intramuscular, intra-dermal,subcutaneous,and needle-free(includingtype and size),oral,intranasal,otherinjectiondevices).

(17)Needlelengthandgauge.

3.1.4. Theadverseevent

(18)For all cases at any level of diagnostic certainty and for reportedeventswithinsufficientevidence,thecriteria ful-filledtomeetthecasedefinitionshouldberecorded.

Specificallydocument:

(19)Clinicaldescriptionofsignsofneonatalinfectionandifthere wasconfirmationoftheinfection(i.e.positiveidentification usingvalidatedmethod).

(20)Date/timeofonset,3_{firstobservation}4_{anddiagnosis,}5_endof

episode6_{andfinaloutcome.}7

(21)Concurrentsignsanddiseases. (22)Measurement/testing

• Values and units of routinelymeasuredparameters (e.g. temperature,bloodpressure)–inparticularthoseindicating theseverityoftheevent;

• Methodofmeasurement(e.g.typeofthermometer,oralor otherroute,durationofmeasurement,etc.);

• Resultsoflaboratoryexaminations,surgicaland/or patho-logicalfindingsanddiagnosesifpresent.

(23)Treatment given for neonatal infection, especially antimi-crobials, including which antimicrobials (e.g. antibiotics, antivirals,immunoglobulins),dosingand durationof treat-ment.

(24)Outcome6_{atlastobservation.}

(25)Objective clinical evidence supporting classification of the eventas“serious”8

(26)Exposures from 24h before and after immunisation (e.g. food,environmental)consideredpotentiallyrelevanttothe reportedevent.

3_{Thedateand/ortimeofonsetisdefinedasthetimepostimmunisation,when}

thefirstsignorsymptomindicativeforneonatalinfectionoccurred.Thismayonly bepossibletodetermineinretrospect.

4_{Thedateand/ortimeoffirstobservationofthefirstsignorsymptomindicative}

forneonatalinfectioncanbeusedifdate/timeofonsetisnotknown.

5_{Thedateofdiagnosisofanepisodeisthedaypostimmunisationwhentheevent}

metthecasedefinitionatanylevel.

6_{Theendofanepisodeisdefinedasthetimetheeventnolongermeetsthecase}

definitionatthelowestlevelofthedefinition.

7_{E.g.recoverytopre-immunisationhealthstatus,spontaneousresolution,}

ther-apeuticintervention,persistenceoftheevent,sequelae,death.

8_{AnAEFIisdefinedasseriousbyinternationalstandardsifitmeetsoneor}

moreofthefollowingcriteria:(1)itresultsindeath,(2)islife-threatening,(3)it requiresinpatienthospitalisationorresultsinprolongationofexisting hospitalisa-tion,(4)resultsinpersistentorsignificantdisability/incapacity,(5)isacongenital anomaly/birthdefect,(6)isamedicallyimportanteventorreaction.

3.1.5. Miscellaneous/general

(27)Thedurationofsurveillanceforneonatalinfectionshouldbe predefinedbasedon

• Biologiccharacteristicsofthevaccinee.g.liveattenuated versusinactivatedcomponentvaccines;

• Biologiccharacteristicsofthevaccine-targeteddisease; • Biologiccharacteristicsofneonatalinfectionincluding

pat-ternsidentifiedinprevioustrials(e.g.early-phasetrials); and

• Biologiccharacteristicsofthevaccinee(e.g.nutritional sta-tus,underlyingdiseaselikeimmunosuppressingillness). (28)Thedurationoffollow-up reportedduringthesurveillance

periodshouldbepredefinedlikewise.Itshouldaimto con-tinuetoresolutionoftheevent.

(29)Methodsofdatacollectionshouldbeconsistentwithinand betweenstudygroups,ifapplicable.

(30)Follow-upofcasesshouldattempttoverifyandcompletethe informationcollectedasoutlinedindatacollectionguidelines. (31)Investigators of patients with neonatal infection should provideguidancetoreporterstooptimisethequalityand com-pletenessofinformationprovided.

(32)Reportsof neonatalinfectionshouldbecollected through-outthestudyperiodregardlessofthetimeelapsedbetween immunisationandtheadverseevent.Ifthisisnotfeasibledue tothestudydesign,thestudyperiodsduringwhichsafetydata arebeingcollectedshouldbeclearlydefined.

3.2. Dataanalysis

Thefollowingguidelinesrepresentadesirablestandardfor anal-ysisofdataonneonatalinfections toallowforcomparabilityof data,andarerecommendedinadditiontothedataanalysedforthe specificstudyquestionandsetting.

Reportedeventsshouldbeclassifiedinoneofthefollowingfive categoriesincludingthethreelevelsofdiagnosticcertainty.Events thatmeetthecasedefinitionshouldbeclassifiedaccordingtothe levelsof diagnosticcertaintyasspecifiedin thecase definition. Eventsthatdonot meetthecase definitionshouldbeclassified intheadditionalcategoriesforanalysis.

Eventclassificationin5categories9

• Eventmeetscasedefinition

(1)Level1:Criteriaasspecifiedintheneonatalinfectionscase definition(separatelyforBSI,meningitisandRTI)

(2)Level2:Criteriaasspecifiedintheneonatalinfectioncase definition(separatelyforBSI,meningitisandRTI)

(3)Level3:Criteriaasspecifiedintheneonatalinfectionscase definition(separatelyforBSI,meningitisandRTI)

• Eventdoesnotmeetcasedefinition Additionalcategoriesforanalysis

9_{Todeterminetheappropriatecategory,theusershouldfirstestablish,whether}

areportedeventmeetsthecriteriaforthelowestapplicablelevelofdiagnostic certainty,e.g.Levelthree.Ifthelowestapplicablelevelofdiagnosticcertaintyof thedefinitionismet,andthereisevidencethatthecriteriaofthenexthigherlevel ofdiagnosticcertaintyaremet,theeventshouldbeclassifiedinthenextcategory. Thisapproachshouldbecontinueduntilthehighestlevelofdiagnosticcertainty foragiveneventcouldbedetermined.Majorcriteriacanbeusedtosatisfythe requirementofminorcriteria.Ifthelowestlevelofthecasedefinitionisnotmet,it shouldberuledoutthatanyofthehigherlevelsofdiagnosticcertaintyaremetand theeventshouldbeclassifiedinadditionalcategoriesfourorfive.

(4)Reported neonatal infection (separately for BSI, meningi-tis and RTI) with insufficient evidence to meet the case definition10

(5)Notacaseofneonatalinfection11_{neitherBSI,meningitisor}

RTI

The interval between maternal immunisation and reported neonatal infection could be defined as the interval from the date/timeofimmunisationtothedate/timeofonset2 _ofthefirst

signsconsistentwiththedefinition.Thetimingofonsetofa neona-talinfectionmaybedefinedbytheageoftheinfantatthetimeof onsetusingspecificperiodsofinfancyasfollows:

Periodsofinfancyforageofclinicalrecognitionofaneonatal infection

Timeperiod Days

Prenatal <Day1oflife

Neonatala _1–27b

Earlyneonatala _1–6b

Lateneonatala _7–27

Postneonatal 28–364

a_{UseeitherNeonatalordivideintoearlyneonatalandlateneonatal.} b _{Day1=first24hoflife.}

Thedurationofapossibleneonatalinfectioncouldbeanalysed astheintervalbetweenthedate/timeofonset2_{ofthefirstsigns}

consistentwiththedefinitionandtheendofepisode5_and/orfinal

outcome6_{.Whateverstartandendingareused,theyshouldbeused}

consistentlywithinandacrossstudygroups.

Ifmorethanonemeasurementofaparticularcriterionistaken andrecorded,thevaluecorrespondingtothegreatestmagnitudeof theadverseexperiencecouldbeusedasthebasisforanalysis. Anal-ysismayalsoincludeothercharacteristicslikequalitativepatterns ofcriteriadefiningtheevent.

Thedistributionofdata(asnumeratoranddenominatordata) couldbeanalysed inpredefined increments(e.g.measured val-ues,times),whereapplicable.Incrementsspecifiedaboveshould beused.When onlya smallnumber of cases ispresented, the respectivevaluesortimecoursecanbepresentedindividually.

Dataonneonatal infections obtainedfromneonatesbornto womenvaccinated during pregnancyshouldbecompared with thoseobtainedfromanappropriatelyselectedand documented controlgroup(s)orknownbackgroundratesofneonatalinfections incomparablepopulations,andshouldbeanalysedbystudyarm anddosewherepossible,e.g.inprospectiveclinicaltrials. 3.3. Datapresentation

Theseguidelines representa desirable standard for the pre-sentationandpublicationofdataonneonatalinfectionsfollowing maternalimmunisation to allowfor comparabilityof data, and arerecommendedasanadditiontodatapresented forthe spe-cificstudyquestionandsetting.Additionally,itisrecommendedto refertoexistinggeneralguidelinesforthepresentationand pub-licationofrandomisedcontrolledtrials,systematicreviews,and meta-analysesofobservationalstudiesinepidemiology(e.g. state-mentsofConsolidatedStandardsofReportingTrials(CONSORT),of Improvingthequalityofreportsofmeta-analysesofrandomised controlled trials (QUORUM), and of Meta-analysis Of Observa-tional Studies in Epidemiology (MOOSE), respectively) and the

10 _{Iftheevidenceavailableforaneventisinsufficientbecauseinformationis}

missing,suchaneventshouldbecategorisedas“Reportedneonatalinfectionwith insufficientevidencetomeetthecasedefinition”.

11 _{Aneventdoesnotmeetthecasedefinitionifinvestigationrevealsanegative}

findingofanecessarycriterion(necessarycondition)fordiagnosis.Suchanevent shouldberejectedandclassifiedas“Notacaseofneonatalinfection”.

StrengtheningtheReportingofObservationalStudiesin Epidemi-ology(STROBE)andStrengtheningtheReportingofObservational StudiesinEpidemiologyforNewbornInfection(STROBE-NI) guide-lines(Fitchett,inpress)(http://www.equator-network.org).

Allreportedeventsofneonatalinfectionsshouldbepresented accordingtothecategorieslistedabove.

Dataonpossibleneonatalinfectionseventsshouldbepresented in accordancewithdata collectionguidelinesand dataanalysis guidelines.

Terms to describe neonatal infection such as “low-grade”, “mild”,“moderate”,“severe”or“significant”arehighlysubjective, pronetowideinterpretation,andshouldbeavoided,unlessclearly defined.

Data shouldbe presentedwith numerator and denominator (n/N)(andnotonlyinpercentages),ifavailable.Itshouldbeclearif thedenominatorrepresentsapopulationdenominator(livebirths) orneonatesadmittedtoafacility.Thesourceofthedenominator datashouldbereportedandcalculationsofestimatedescribed(e.g. manufacturerdataliketotaldosesdistributed,reportingthrough MinistryofHealth,coverage/populationbaseddata,etc.).

Theincidenceofcasesinthestudypopulationshouldbe pre-sentedandclearlyidentifiedassuchinthetext.

Ifthedistributionofdataisskewed,medianandinterquartile rangeareusuallythemoreappropriatestatisticaldescriptorsthan themean.However,themeanandstandarddeviationshouldalso beprovided.

Anypublicationofdataonneonatalinfectionshouldincludea detaileddescriptionofthemethodsusedfordatacollectionand analysisaspossible.Itisessentialtospecify:

• Thestudydesign;

• Themethod,frequencyanddurationofmonitoringforneonatal infection;

• Thetrialprofile,indicatingparticipantflowduringastudy includ-ingdrop-outsandwithdrawalstoindicatethesizeandnatureof therespectivegroupsunderinvestigation;

• Thetypeofsurveillance(e.g.passiveoractivesurveillance); • Thecharacteristicsof thesurveillancesystem(e.g.population

served,modeofreportsolicitation);

• Thesearchstrategyinsurveillancedatabases; • Comparisongroup(s),ifusedforanalysis;

• Theinstrument ofdatacollection(e.g.standardised question-naire,diarycard,reportform);

• Whetherthedayofimmunisationwasconsidered“dayone”or “dayzero”intheanalysis;

• Whetherthedateofonset2_{and/orthedateoffirstobservation}3

and/orthedateofdiagnosis4_{wasusedforanalysis;and}

• Useofthiscasedefinition,intheabstractormethodssectionof apublication.12

Acknowledgements

The authors are grateful for the support and helpful comments provided by the Brighton Collaboration (Jan Bon-hoeffer, JorgenBauwens) and the reference group(see https:// brightoncollaboration.org/public/what-we-do/setting-standards/ case-definitions/groups.html for reviewers), as well as other expertsconsultedaspartoftheprocess.Theauthorsarealso grate-fultotheBrightonCollaborationSecretariatandtothemembers oftheISPESpecialInterestGroupinVaccines(VAXSIG)fortheir reviewandconstructivecommentsonthisdocument.Finally,we

12_{Use of this document should preferably be referenced by}

refer-ring to the respective link on the Brighton Collaboration website

(http://www.brightoncollaboration.org). S. Vergnano et al. / Vaccine 34 (2016) 6038–6046

wouldliketoacknowledgetheGlobalAlignmentofImmunisation SafetyAssessmentinPregnancy(GAIA)project,fundedbytheBill andMelindaGatesFoundation.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.vaccine.2016.03. 046.

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