www .e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Original
Article
Clinical
and
bacteriological
characteristics
of
invasive
pneumococcal
disease
after
pneumococcal
10-valent
conjugate
vaccine
implementation
in
Salvador,
Brazil
Carolina
Regis
Leite
a,∗,
Jailton
Azevedo
b,
Vivian
Santos
Galvão
b,
Otávio
Moreno-Carvalho
c,
Joice
Neves
Reis
b,d,
Cristiana
Nascimento-Carvalho
aaFaculdadedeMedicinadaBahia,UniversidadeFederaldaBahia,Salvador,BA,Brazil bCentrodePesquisasGonc¸aloMoniz,Fundac¸ãoOswaldoCruz,Salvador,BA,Brazil cLaboratóriodelíquor–SINPEL/Fundac¸ãoJoséSilveira,Salvador,BA,Brazil dFaculdadedeFarmácia,UniversidadeFederaldaBahia,Salvador,BA,Brazil
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Articlehistory:
Received19July2015 Accepted9October2015
Availableonline17December2015
Keywords:
Streptococcuspneumoniae
Vaccine Epidemiology
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Invasivepneumococcaldiseaseisa relevantpublichealthprobleminBrazil, especially amongchildrenandtheelderly.InJuly/2010a10-valentpneumococcalconjugatevaccine wasintroducedtotheimmunizationscheduleofBrazilianchildrenundertwoyearsofage. BetweenJuly/2010andDecember/2013weconductedacase-seriesstudyoninvasive pneu-mococcaldiseaseinSalvador,Braziltodescribetheclinicalandbacteriologicalprofileof invasivepneumococcaldiseasecasesduringthepost-implementationperiod.Eighty-two caseswereeligible.Meanagewas31years(interquartilerange,3–42);17.1%and30.5%were under2yearsand5years,respectively.Pneumococcalmeningitis(n=64,78.1%),bacteraemic pneumococcalpneumonia(n=12,14.6%)andbacteraemia(n=6,7.3%)weretheclinical syn-dromesidentified.Thirty-threedifferentserotypeswerefound.Ofthese,serotype14(n=12, 14.6%)wasthemostcommon,followedby23F(n=10,12.2%),12F(n=8,9.8%),18C(n=5, 6.1%)and6B(n=5,6.1%).InvestigationsconductedinSalvadorinthepre-vaccineperiod didnotidentifyserotype12Fasoneofthemostprevalentserotypes.Increaseofserotype 12FwasobservedindifferentregionsofBrazil,inthepost-vaccineperiod.Amongchildren undertwoyearsofage,thetargetgroupfor10-valentpneumococcalconjugatevaccine,11 (78.6%)ofthe14isolatedstrainsofStreptococcuspneumoniaebelongedtovaccineserotypes; atleast50%ofthesechildrenwerenotvaccinated.Therelativelyrecentimplementationof
∗ Correspondingauthor.
E-mailaddress:[email protected](C.R.Leite).
http://dx.doi.org/10.1016/j.bjid.2015.10.005
10-valent pneumococcal conjugate vaccine in Brazil reinforces the need to maintain anactivesurveillanceofinvasivepneumococcaldiseasecases,consideringthepossible increaseofinvasivepneumococcaldiseasecasesrelatedtonon-vaccineserotypesandthe changesontheclinicalpresentationofthedisease.
©2015ElsevierEditoraLtda.Allrightsreserved.
Introduction
Streptococcuspneumoniaeisamajorcauseofmeningitis, bac-teraemicpneumoniaandsepsis,1 accountingforsignificant
morbidityandmortalityratesworldwide.2Invasive
pneumo-coccal disease (IPD) is a relevantpublic health problem in Brazil, especially among children and the elderly.3 In the
decadebeforetheimplementationof10-valent pneumococ-calconjugatevaccine(PCV10),S.pneumoniaewasresponsible for12%ofbacterialmeningitisinBrazilamongchildrenaged undertwoyearsandolderandadults.4
Pneumococcal 7-valent conjugate vaccine (PCV7) was licensedintheUnitedStatesin2000andaccountedfor sig-nificantreductioninincidenceandmortalityfromIPDinthe US.5AstudyconductedintheUSpresentedevidencethatthe
vaccineprovidesherdimmunity.5However,followupofIPDin
thesamecountryrevealedanincreasedincidenceofinvasive diseasecausedbyserotypesnotincludedinPCV7specially 19A,6aphenomenonnamedreplacement.Serotype
replace-mentledtothedevelopmentofvaccineswithlargerserotype coverage,7whicharecurrentlyavailable.
InBrazil,PCV7wasincorporatedintotheNational Immu-nizationProgramin2002,availableonlytochildrenunderfive yearsofageathighriskofpneumococcaldiseases.8InJuly
2010PCV10wasintroducedtotheimmunizationscheduleof Brazilianchildrenundertwoyearsofage.9Inadditiontothe
conjugatevaccines,pneumococcal23-valentpolysaccharide vaccine(PPV23)isofferedforindividualsovertwoyearsofage athighriskofpneumococcaldisease.8
Initialevaluation ofIPD after PCV10 implementation in Brazilwaspublishedin2013.Asignificantreductionin inci-denceofIPDcausedbyvaccineserotypeswasobservedamong children under two years ofage in the São Paulo Univer-sityHospital.10 Inthe same study,therewas nosignificant
changeinincidenceofIPDcausedbynon-vaccineserotypes. Declinesinhospitalizationsratesforpneumoniawerefound inthreemajorcitiesinBrazilintheyear2011.11Ashortperiod
ofobservationafterimplementationofPCV10,however,was emphasizedasalimitationinbothstudies.
ThesurveillanceofIPDandtherecognitionofserotypes thatcause greater morbidityandmortalityare essential to assesstheeffectivenessoftheimmunizationprograms.12,13
Additionally,thevaccinestatusandpresenceof comorbidi-tiesplayarole ontheoccurrenceofIPD.Documentationof IPDcasesisinsufficientindevelopingcountries.14Giventhe
lackofdataonIPDinthepost-vaccineperiodinBrazil,thereis astrongneedformorestudiesontheclinicalpresentationof thediseaseandprofileofinvasivestrains.Inthisregard,the objectiveofthisstudywastodescribetheclinicaland bacteri-ologicalprofileofIPDcasesdiagnosedbetweenJuly2010and
December2013inSalvador,Brazil,throughcase-seriesstudy onIPD.
Material
and
methods
Thiswasaretrospectiveobservationalstudy,witha prospec-tivecomponent. Between July2010andDecember 2013we conducted a case-series study on IPD in Salvador, Brazil, involvingtheHospitalCoutoMaia(HCM),thePaediatricCentre ProfessorHosannahdeOliveira(CPPHO)andtheCerebrospinal Fluid Laboratory (SINPEL). HCM is the referral hospitalfor infectiousdiseasesinthestate,mainlyforthepublichealth caresystem;CPPHOisthepediatricunitoftheFederal Uni-versityofBahiaHospital;SINPELperformscerebrospinalfluid (CSF)analysisofpatientsseeninthesupplementaryhealth caresysteminthecity ofSalvador.IPDcasesweredefined bytheisolationofpneumococcusfromanormallysterilesite (bloodorCSF).PatientswithdiagnosisofIPDwithpositiveCSF orbloodculturesforS.pneumoniaeinHCM,CPPHOorSINPEL, betweenJuly2010andDecember2013were includedinthe study.Patientsforwhomitwasnotpossibletoobtaincontact informationwereexcluded.
Samplesofbloodor CSFforculturewere obtainedfrom patientswithclinicalsuspicionofIPD,accordingtotheroutine ofthecentersinvolved.Basedontherecordofpositive cul-turesforS.pneumoniae,isolatesweresenttothePathologyand MolecularBiologyLaboratoryoftheResearchCentreGonc¸alo Moniz CPqGM/FIOCRUZ for confirmation. Identification of
S.pneumoniaewasperformedusingstandardbacteriological techniques,includingGramstain,colonymorphologyonagar mediawith5%ofsheepblood,optochinsusceptibility(5g Oxoiddisks)andbilesolubility.
Serotypingwasperformedbymultiplex-PCRasdescribed elsewhere.15,16Theisolateswithnegativeorequivocalresults
inmultiplex-PCRweresenttoAdolfoLutzInstitute(National Reference Laboratory, Ministry of Health) and subjected to Quellung reaction for definition of capsular serotype. All isolatesidentifiedasserogroup6wassubjectedto wciN6C-specificPCR,fortheidentificationofpotentialserotype6Cand 6Disolates.17
Clinicalanddemographicdata(age,dateofadmissionand diagnosis)werecollectedbyreviewofthemedicalchartsor fromthedatarecordedontherequestofculturesto laborato-ries.Patientswerecontactedbytelephoneandaskedtoe-mail photoofvaccinationcardtoconfirmtheuseofpneumococcal vaccinepriortotheepisodeofIPD.
VaccineserotypesarethoseincludedinPCV10(1,4,5,6B, 7F, 9V,14,18C,19Fand 23F);vaccine relatedserotypes(6A, 6A/B/C,6C,7C,9L/N,9N,18B,19A,23B)weredefinedasthose notincludedinPCV10,butsharingthesameserogroupwith
thevaccineserotypes;otherserotypeswereconsidered non-vaccinetypes.
Collecteddatawereenteredandanalyzedintheprogram SPSSversion 17.For description, proportionsofcategorical variablesandmeasuresofcentraltendencyanddispersionof continuousmeasurementsarepresented.
ThisprojectwasapprovedbytheEthicsCommitteeofthe FederalUniversityofBahiaSchoolofMedicine.
Results
and
discussion
DuringtheperiodfromJuly2010throughDecember2013,93 casesofIPDwereidentified.Ofthese,11(11.8%)wereexcluded becauseoftheunavailabilityofclinical,epidemiologicaland contact information, resulting in 82 patients, which com-prisethestudysample.Tendifferentserotypes(12F,18B,7F, 4,23F,6A,22F,6B, 34 and28A)were isolated from individ-ualsexcludedfromthestudy.Ofthese11excludedisolates, 4(36.4%)belongedtovaccineserotypes,3(27.3%)belonged tovaccine-relatedserotypesand4(36.4%)belongedto non-vaccineserotypes.Capsularserotypes,ageinformationand informationonclinical syndromeofpneumococcaldisease wereobtainedforall82casesofIPD.
Meanagewas31years(interquartilerange,3–42). Twenty-fivecases(30.5%)occurredinpatientsagedlessthan5years. Ofthese,14(56%)childrenwereunder2yearsofage.InBrazil, itwas observedpredominance ofchildrenundertwoyears amongcasesofIPDpreandpost-PCV10implementation.9,18
Inthiscontext,theintroductionofpneumococcalconjugate vaccines,whichconferserotype-specificimmunitytochildren undertwoyearsofage,isanimportantstrategyforthe pre-ventionofIPDinBrazil.
Pneumococcal meningitis (n=64, 78.1%), bacteraemic pneumococcal pneumonia (n=12, 14.6%) and bacteraemia (n=6%, 7.3%) were the clinical syndromes identified. An international surveillance system of IPD in Latin America also identifies predominance of meningitis in Brazil, dur-ingthe pre-vaccine period.19 Nevertheless,it isestablished
that amongIPD, pneumonia incidenceis higher than that ofmeningitis.1 InBrazil,blood culturecollection is
recom-mendedonlyforseverecasesofpneumonia,whenpatients are hospitalized.20 In contrast, in Brazil meningitis cases
shouldbenotifiedandallsuspectedcasesofmeningitismust besubmitted to blood culturecollection and cerebrospinal fluidcollectionforculture,unlessacontraindicationexists.21
Itispossiblethattheincidenceofpneumococcalpneumonia inBrazilisunderestimatedas aconsequenceofthese rec-ommendations,resultinginthepreponderanceofmeningitis observedinthisstudy.
PneumococcusstrainswereisolatedexclusivelyfromCSF in45cases(54.9%),exclusivelyfrombloodin20cases(24.4%) andfrombothbloodandCSFin17cases(20.7%).Demographic andclinicalcharacteristicsofthestudysampleareshownin
Table1.
Informationonuseofpneumococcalvaccinewasavailable in39cases.Ofthe82patients,9couldnotbecontacteddue tochangeoftelephonenumberoraddressand8declinedto inform.Amongthe14childrenunder2yearsofage,thetarget groupforPCV10,3(21.4%)had receivedPCV10priortothe
Table1–Demographicandclinicalcharacteristicsof82 casesofinvasivepneumococcaldiseaseinSalvador, Brazil,fromJuly2010throughDecember2013. Demographicandclinicalcharacteristic n(%) Age <2years 14(17.1) <5years 25(30.5) ≥5years 57(69.5) Hospital HCM 55(67.1) CPPHO 8(9.8) SINPEL 19(23.1)
SterilesiteofS.pneumoniaeisolation
Blood 20(24.4)
CSF 45(54.9)
BloodandCSF 17(20.7)
Clinicalsyndromeofpneumococcaldisease
Meningitis 64(78.1)
Pneumonia 12(14.6)
Bacteraemia 6(7.3)
episodeofIPD.Ofthesethreechildren,onlyonehadreceived an appropriate number of PCV10 doses forage (atotal of 4 doses) and the other two children had received asingle doseofPCV10.Threeserotypeswereisolated(3,6Band9L/N) fromchildrenundertwoyearsofagewhowerevaccinated. Serotype3wasisolatedfromthechildwhohadreceivedan appropriatenumberofPCV10doses.Amongthe68patients agedtwoyearsandabove,4(5.9%)werevaccinated;ofthese, twochildrenreceivedPCV10andtheremainingtwopatients receivedPPV23.Serotypes6Band14wereisolatedfromthe twochildrenagedtwoyearsandabovewhoreceivedPCV10; bothhadreceivedasingledoseofPCV10.Serotypes6Cand 13 were isolated from patients who received PPV23. The patientswhoreceivedPPV23wereadultsandhadindication forPPV23vaccinationbasedontheircomorbidities:onewas
Table2–Demographicandclinicalcharacteristicsof82 casesofinvasivepneumococcaldiseaseinSalvador, Brazil,fromJuly2010throughDecember2013,stratified byageatdiagnosis.
Demographicandclinical characteristic
Age
<2years(n=14) ≥2years(n=68)
n(%) n(%)
SterilesiteofS.pneumoniaeisolation
Blood 7(50.0) 13(19.1)
CSF 5(35.7) 40(58.8)
BloodandCSF 2(14.3) 15(22.1) Clinicalsyndromeofpneumococcaldisease
Meningitis 7(50.0) 57(83.8)
Pneumonia 7(50.0) 5(7.4)
Bacteraemia 0(0) 6(8.8)
Useofpneumococcalvaccine
No 7(50.0) 25(36.8)
Yes 3(21.4) 4(5.9)
Table3–DistributionofcapsularserotypesofS.pneumoniaeisolatedfromcasesofinvasivepneumococcaldiseasefrom July2010throughDecember2013accordingtotheinclusioninPCV10.
Age n Serotype(%)
Vaccineserotypea Vaccine-relatedserotypeb Non-vaccineserotypec
<2years 14 11(78.6) 1(7.1) 2(14.3)
≥2years 68 27(39.7) 11(16.2) 30(44.1)
Total 82 38(46.4) 12(14.6) 32(39.0)
a SerotypesincludedinPCV10:1,4,5,6B,7F,9V,14,18C,19Fand23F.
b SerotypesnotincludedinPCV10,butinthesameserogroupasvaccineserotypes. c SerotypesnotincludedinPCV10,andnotinthesameserogroupasvaccineserotype
anindividualwithHIVinfectionand theother onewas an individualwithcerebrospinalfluidleaks.Thepatientswith comorbiditiesare those who received PPV23. Demographic andclinicalcharacteristicsofstudysample,stratifiedbyage atdiagnosisareshowninTable2.
Thirty-three different serotypes were found. Of these, serotype14 (n=12,14.6%) wasthemostcommon,followed by23F(n=10,12.2%),12F(n=8,9.8%),18C(n=5,6.1%)and6B (n=5,6.1%).Serotype14wasalsopredominantintwostudies conductedduringthepre-vaccineperiod.18,22Inthesestudies,
themostprevalentnon-vaccineserotypeswere3and6A,and theconjugatepneumococcalvaccinesarebelievedtoprovide cross-protectiontoserotype6A.23 Unlikethepresent study,
inpreviousinvestigationsconductedinSalvadorserotype12F wasnotobservedasoneofthemostprevalentserotypes.18,22
Surveillance of IPD cases in post-vaccine period is essen-tialtodeterminetheinfluenceofserotypereplacementafter pneumococcalvaccination on theincrease ofserotype 12F, consideringthatcyclicalchangesintheincidenceofserotypes may be responsible for this increase.24 Serotype 12F was
observedasoneofthemostcommonserotypesinthe post-vaccineperiod,indifferentregionsofBrazil.10,25 Thisraises
thepossibilityofcurrentemergenceofthisserotype. Amongchildrenundertwoyearsofage,eightserotypes wereisolated.Ofthese,serotype14(n=4;28.6%)wasthemost common.In this age group,most (78.6%)ofthe 14 strains belongedtovaccineserotypes,exceptserotypes11A/D,3and 9L/N,withoneisolateeach.Theelevatedfrequencyofcases involvingvaccine-serotypesamongchildrenundertwoyears ofageaftertheuniversal implementationofPCV10maybe partlyexplainedbythelowvaccineuptakeinthestudy sam-ple,inwhichatleast50% ofchildrenwere notvaccinated. Ofthe 14casesofIPDinchildrenyoungerthan twoyears, 11(78.6%)occurredduringthefirstyearofimplementationof PCV10.Duringthisperiod,PCV10wasanewlyimplemented vaccineandthereforeunknowntothepopulation.Itwas nec-essarythatthoseresponsibleforchildrenwereinstructedby healthprofessionalsabouttheneedofpneumococcal vaccina-tionandthevaccineavailability.Thisimplementationperiod mayexplainthelowvaccine uptakeamongchildrenunder twoyearsofageinthestudysample.
Thirty-onedifferentserotypeswereisolatedfrom individ-ualstwoyearsofageandabove.Ofthese,14(n=8,11.8%),12F (n=8,11.8%)and23F(n=8,11.8%)werethemostcommon.In thisagegroup,mostisolates(n=30,44.1%)belongedto non-vaccineserotypes,apatternsimilartothatreportedduring
thepre-vaccineperiod.22Theserotypedistributionaccording
totheinclusioninPCV10isdescribedinTable3.
Consideringall agegroups,the mostfrequentserotypes isolatedfrombloodwere14(n=6,30%),6B(n=4,20%)and19A (n=2,10%).FromCSF,23F(n=9,20%),12F(n=6,13.3%)14(n=4, 8.9%)and18C(n=4,8.9%)werethemostprevalent.Diversity indistribution ofpneumococcal serotypesaccording tothe sterilesiteofisolationisalsodescribedbyotherauthorsand itisprobablyaconsequenceofindividualcharacteristicsof eachserotype.26Fosterandcolleaguesreportedthatserotype
12Fsignificantlyincreasestheriskofmeningitiscomparedto other IPD.27In thisstudy,theserotype 12Fwasthesecond
mostprevalentamongthoseisolatedfromCSF.
This study isbased on a non-probability sampling and thereforeitispossiblethatsomeresultspresentedherearean outcomeofselectionbias.Acase-series,however,isan appro-priatestudydesigntodescribetheclinicalandbacteriological characteristicsofIPD,themainobjectiveofthisinvestigation. Therelatively recent implementationofPCV10 inBrazil reinforcestheneedtomaintainanactivesurveillanceofIPD cases.MaintainingsurveillanceofIPDinSalvadoriscriticalto clarifytheroleofPCV10inchangesonserotypesincidence, consideringthepossibleincreaseofIPDcasesrelatedto non-vaccineserotypes.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
Wethank the professionalsofHospital CoutoMaia, Paedi-atricCentreProfessorHosannahdeOliveiraandCerebrospinal FluidLaboratory;andthepatientsandtheirfamilies.
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