Clinical and microbiological implications of invasive pneumococcal disease in hospitalized patients (1998–2013)

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Clinical

and

microbiological

implications

of

invasive

pneumococcal

disease

in

hospitalized

patients

(1998–2013)

夽

Marta

Inês

Cazentini

Medeiros

_,

_Bento

_Vidal

_de

_Moura

_Negrini

_,

Jorgete

Maria

e

Silva

_,

_Samanta

_Cristine

_Grassi

_Almeida

_,

Maria

Luiza

Leopoldo

Silva

Guerra

_,

_Denise

_de

_Andrade

a_{RegionalLaboratoryCenterVI,InstitutoAdolfoLutz,RibeirãoPreto,SP,Brazil}

b_{HospitalCenterofEpidemiology,HospitaldasClínicasdaFaculdadedeMedicinadeRibeirãoPreto,UniversidadedeSãoPaulo(USP),}

RibeirãoPreto,SP,Brazil

c_{CenterofBacteriology,InstitutoAdolfoLutz,SãoPaulo,SP,Brazil}

d_{EscoladeEnfermagemdeRibeirãoPreto,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received2October2015 Accepted25January2016 Availableonline16April2016

Keywords: Streptococcuspneumoniae Serotypes Death Comorbidity

a

b

s

t

r

a

c

t

Introduction:InfectionscausedbyStreptococcuspneumoniae(pneumococcus)stillrepresenta challengeforhealthsystemsaroundtheworld.

Objective:Theobjectiveofthisstudywastoassessmicrobiologicalandclinicalaspectsin hospitalizedpatientswithinvasivepneumococcusdiseasebetween1998and2013. Materialsandmethods: Thiswasaretrospectivestudythatanalyzedtheresultsof pneumo-coccusidentification,serotyping,andsusceptibilitytestingfoundintheAdolfoLutzInstitute databank.Personalvariables,medicalhistoryandclinicaloutcomeofpatientsadmittedwith invasivepneumococcaldiseasewereanalyzed.Thesewereobtainedfromrecordsofapublic teachinghospital–HospitaldasClínicasFaculdadedeMedicinaRibeirãoPreto.

Results:Thesamplecomprised332patients.Patientagerangedfromlessthanonemonthto 89yearsold(mean20.3years)andthesamplewaspredominatelymale.Pneumonia(67.8%) wasthemostcommondisease,accountingfor18.2%ofdeaths.Serotypes14,1,3,9V,6B,6A, 23F,19A,18C,19F,12F,and4werethemostcommon(75.3%).Mostpatients,or67.5%,were curedwithoutanycomplication(success),6.9%hadsometypeofsequela(failure),and25.6% died(failure).Inthecaseofdeathsduetomeningitis,strainsoffullypenicillinresistant pneumococcuswereisolated.Furthermore,68.2%ofpatientswhodiedpresentedsometype ofcomorbidity.The60andolderagegrouppresentedthemostsignificantassociation(Odds Ratio=4.2),withoutcomefailureregardlessofthepresenceofcomorbidity.Serotype18Cwas themostsignificantriskfactorbothinrawanalysis(OddsRatio=3.8)andwhenadjusted forcomorbidity(OddsRatio=5.0)orage(OddsRatio=5.4).Thesameoccurredwithserotype 12F(respectively,OddsRatio=5.1,OddsRatio=5.0,andOddsRatio=4.7)

夽_{Partofadoctoralthesis“SerotypesandantimicrobialresistanceprofileofStreptococcuspneumoniae:clinicalimplicationsforinvasive}

diseaseandthenationalimmunizationprogram”(1998–2013).

∗ _{Correspondingauthor.}

E-mailaddresses:micmedeiros@ial.sp.gov.br,micmedeiros@hotmail.com(M.I.C.Medeiros). http://dx.doi.org/10.1016/j.bjid.2016.01.011

1413-8670/©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Conclusion: ThepresentfindingshighlighttheimportanceofIPDamongyoungadultsand olderadults.Intheeraofconjugatevaccines,monitoringserotypesindifferentagegroups isessentialtoassesstheimpactandadequacyofimmunization.

©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Even with the possibility of immunoprevention of several serotypes,theWorldHealthOrganizationhasindicatedand estimated1.6milliondeathsperyearduetopneumococcus disease.Thedatademonstrategreaterprevalencein develop-ingcountriesand0.7–1millionchildrenlessthanfiveyearsof age.1_{IncountrieswithimmunizationforH.influenzaeserotype} b, pneumococcus has becomethe mostcommon cause of invasivedisease.2_{BasedondatafromtheHospital} Informa-tion System (HIS), Novaes,Sartori, and Soárez3 _foundthat therewere34,217hospitalizationsduetopneumococcal dis-easein theBrazilian UnifiedHealth System(SUS) between 2006and 2014.Thisfigurerepresented 0.1%ofthetotal of admissions,ofwhich64.8%werepneumococcalpneumonia. Astudyontheclinicalandepidemiologicalprofileofpatients withpneumoniaacquiredinthecommunityobservedamong individualsundertheageof60anelevatedpercentageofthe disease,inadditiontoworsenedclinicaloutcomes.Lethality waslow(4.9%)andconcentratedamongtheyouth.InBrazil, these patients are usually hospitalized in order to ensure accesstomedicationandclinicalfollow-up,especiallyinthe caseofolderadultsandindividualswithunderlyingchronic diseases.4 _{According to the Brazilian Ministry of Health,}5 between2000and2008pneumococcalmeningitisrepresented 11%ofbacterialmeningitisrecordedintheNotifiableDiseases InformationSystem(SINAN),withanaverageof1218cases peryearand30%lethality.Inordertominimizetheimpactof pneumococcaldisease,in2009theNationalAgencyofHealth Surveillance(ANIVSA)approvedtheuseofconjugate pneumo-coccalpolysaccharidevaccine(PVC)with10specificserotypes (PVC10)inchildrenundertheageoftwo.Thus,Brazilwasone ofthefirstcountriestoincludetheVPC10intheimmunization scheduleoftheNationalImmunizationProgram(PNI).6,7_The objectiveofthisstudywastoanalyzeclinicaland microbiolog-icalaspectsofpeoplehospitalizedwithIPDbetween1998and 2013,andthereforeevaluatetheoutcomeofcasesinrelation totheserogroups.

Materials

and

methods

Thiswasaretrospectivecross-sectionalstudythatanalyzed recordsfrom1998to2013.Theserecordscontainedtheresults of332isolatedpneumococcalstrainsinpatientswithinvasive pneumococcusdisease(IPD)hospitalizedintheRibeirãoPreto SchoolofMedicineTeachingHospital–UniversityofSãoPaulo (HCRP-USP),Brazil.Thepneumococcussamplesincludedin thisstudywereisolatedintheHCRPlaboratoryandsentto AdolfoLutz Institute inRibeirão Preto (IAL-RP) in order to

confirmthespecies,andthenforwardedtotheNational Lab-oratory ofPublicHealth(AdolfoLutz InstituteinSãoPaulo) forserotypingandtodeterminetheantimicrobial susceptibil-ityprofile.Towardthisend,microbiologicalinformationwas obtainedfromtheIAL-RParchivesandtheclinicalaspectsof patientsretrievedfromthesurveillancesystemofHCRP-USP epidemiologicalcenter.

Analysisandinferenceofresults

The information gathered was saved on an MS Excel XP spreadsheet and thenexported toSPSS(StatisticalPackage fortheSocialSciences),version19.0forstatisticalanalyses: descriptive analysisthrough absoluteand relative frequen-cies and then means, standard deviations, medians, and minimum and maximum values were calculated. Possible associationsbetweenoutcomes:success(curewithno com-plications) or failure (cure with complications or death). Thestudiedvariables(gender,age,presenceofcomorbidity, and themostcommonserotypes)were analyzedusing chi-squaretestand univariate(rawOR)and multiple(adjusted OR) logistic regression. Level of significance was set at p≤0.05.Thiswasaretrospectivestudy,withlimitations asso-ciated with the nature of information in quantitative and qualitative terms. Thepresent study was approved by the human subject research ethics committee, protocol CAAE: 26759714.80000.5393.

Results

Amongthe332patientswithIPD,agerangedfromlessthana monthto89yearsold,withmeanageof20.3(standard devi-ation=25.5years,median4years),withapredominanceof malepatients(61.1%).Themostcommonclinicaldiagnoses were pneumonia (67.8%), followed by meningitis and bac-teremia(22.9%).After2010,therewasasignificantreduction inthenumberofpneumococcuscasessentforidentification (Table1).Forty-twodifferentserotypesofS.pneumoniaewere identified,ofwhich75.3%,indecreasingorder,wereserotypes 14,1,3,9V,6A,6B,23F,19A,18C,19F,12F,and4withatleast 10 isolates. Furthermore, there was a progressive increase ofserotypes3and6A,whichwerepresent inthe13-valent conjugate pneucomococcalvaccine, and serotypes 12F and 18C(non-vaccine).Therewasareductioninserotypes14,1, and 23FincludedinVPC10(Table2). Theprevalenceofthe serogroupsvariedaccordingtoageofthepatients.Serogroup 14wasthemostcommoninchildrenyoungerthanfiveyears ofage, and serogroup3was the mostcommon inthe age rangegreaterthanfiveyearsold(Table3).Inchildrenyounger thanfiveyearsofage,intheperiodpriortotheVPC10,there

Table1–Demographiccharacteristicsandclinical diagnosisofpatientswithIPDregisteredintheHCRP Databank,1998–2013.

Variable Category No. %

Gender Male 203 61.1

Female 126 38.0

Unknown 3 0.9

Agegroup(years) <1 52 15.7

1–2 59 17.8 2–5 57 17.2 Subtotal<5 168 50.7 5–20 40 12.0 20–60 83 25.0 ≥60 39 11.7 Subtotal≥5 162 48.7 Unknown 2 0.6 Period 1998–2002 81 24.4 2003–2010 205 61.7 2011–2013 46 13.9 Disease Pneumonia 225 67.8 Meningitis 76 22.9 Bacteremia/septicemia 26 7.8 Others 5 1.5 Total 332 100.0

IPD,invasivepneumococcaldisease;HCRP,RibeirãoPretoTeaching Hospital.

wasaprevalenceofserogroups14(46.4%),1(8.6%),19A(6.6%), 6A(6.0%),and9V(4.6%)inhospitalizedpatients.After2010, serogroups6A(23.1%),14(23.1%)and3(23.1%)werethe pre-vailingserogroupsinthisagerange.Treatmentwassuccessful among67.5%ofpatients,withnocomplications,while32.5% ofcasesresultedintreatmentfailure,with25.6%deathsand 6.9%withsometypeofsequelae.OftheIPDcasesthatresulted indeath,68.2% (58/85)occurred inpatientsolder than five years ofage.Amongpatients less than fiveyears old,46% (17/37)ofthedeathswereassociatedwithmeningitisand9.8%

Table2–SerotypesofS.pneumoniaemostoftenisolated fromIPDpatientsregisteredintheHCRPDatabank, 1998–2013.

Serotypes Periods Total

1998–2002 2003–2010 2011–2013 No. % No. %a _{No. %}a _{No. %}a

14 31 38.3 51 25.0 3 6.4 85 25.6 1 7 8.6 17 8.3 0 0.0 24 7.2 3 2 2.5 16 7.8 5 10.6 23 6.9 9V 5 6.2 9 4.4 2 4.3 16 4.8 6A 3 3.7 10 4.9 3 6.4 16 4.8 6B 3 3.7 10 4.9 2 4.3 15 4.5 23F 3 3.7 12 5.9 0 0.0 15 4.5 19A 6 7.4 5 2.5 1 2.1 12 3.6 18C 5 6.2 4 2.0 2 4.3 11 3.3 19F 0 0.0 10 4.9 1 2.1 11 3.3 12F 0 0.0 4 2.0 6 12.8 10 3.0 4 1 1.2 8 3.9 1 2.1 10 3.0 Others 15 18.5 48 23.5 21 44.7 84 25.3 Total 81 100.0 204 100.0 47 100.0 332 100.0

a _{ReferstothetotalnumberofIPDcasesineachperiod.}

(4/41)withpneumonia.Ofthe85deaths(25.6%)duetoIPD, meningitiswasinvolvedin43.5%ofthecases,witha48.7% lethality rate (37/76)across all age groups. Ofall meningi-tisrelateddeaths,29.7%(11/37)occurredinchildrenyounger thanoneyear,and27.0%(10/37)inpatientswithagesbetween 20 and 59,representingalethality rateof21.2% (11/52)for patientslessthanoneyearold,and12.0%(10/83)amongthose aged20through59.Pneumoniaaccountedfor48.2%ofdeaths, witha lethalityrateof18.2% (41/225).Ofall deathsdueto pneumonia,21.2%(18/85)occurredinthe20–59agegroup,and 4%inpatientslessthanfiveyearsofage.Regardingthe antibi-oticsusceptibilityprofileofthestrains,9.4%(n=8)ofdeaths duetomeningitiswerecausedbypenicillin-resistantS. pneu-moniae(penicillinMIC≥0.125␮g/mL),representedbyserotypes

Table3–SerogroupsofS.pneumoniaemostcommonlyisolatedfrompatientswithinvasivepneumococcaldiseasewho wereassistedattheRegionalHealthCareNetwork13,accordingtotheageofthepatients,from1998to2013.

Serotypes Agerange(years) Total

<1 1–2 2–5 Subtotal<5 5–20 20–60 ≥60 Subtotal≥5 No. % No. %a _{No. %}a _{No. % No. %}a _{No. %}a _{No. %}a _{No. %}a _{No. %}

14 20 38.5 26 44.1 29 50.9 75 44.6 4 10.0 6 7.2 0 0.0 10 6.2 85 25.8 1 1 1.9 2 3.4 10 17.5 13 7.7 8 20.0 2 2.4 1 2.6 11 6.8 24 7.3 3 3 5.8 5 8.5 2 3.5 10 6.0 1 2.5 6 7.2 6 15.4 13 8.0 23 7.0 9V 2 3.8 4 6.8 1 1.8 7 4.2 2 5.0 4 4.8 3 7.7 9 5.5 16 4.8 6A 6 11.5 2 3.4 5 8.8 13 7.7 2 5.0 1 1.2 0 0.0 3 1.8 16 4.8 6B 4 7.7 3 5.1 0 0.0 7 4.2 0 0.0 5 6.0 3 7.7 8 4.9 15 4.5 23F 2 3.8 2 3.4 0 0.0 4 2.4 3 7.5 6 7.2 2 5.1 11 6.8 15 4.5 19A 6 11.5 3 5.1 1 1.7 10 5.9 0 0.0 1 1.2 1 2.6 2 1.2 12 3.6 18C 2 3.8 2 3.4 3 5.3 7 4.2 1 2.5 1 1.2 2 5.1 4 2.5 11 3.3 19F 0 0.0 0 0.0 2 3.5 2 1.2 3 7.5 4 4.8 2 5.1 9 5.5 11 3.3 12F 1 1.9 0 0.0 0 0.0 1 0.6 2 5.0 6 7.2 1 2.6 9 5.5 10 3.0 4 0 0.0 0 0.0 0 0.0 0 0.0 2 5.0 6 7.2 2 5.1 10 6.2 10 3.0 Others 5 9.6 10 16.9 4 7.0 19 11.3 12 30.0 35 42.2 16 41.0 64 39.5 83 25.1 Total 52 100.0 59 100.0 57 100.0 168 100.0 40 100.0 83 100.0 39 100.0 162 100.0 330 100.0

Table4–DemographiccharacteristicsandpresenceofcomorbidityamongIPDpatientsregisteredintheHCRPDatabank bycaseoutcome,1998–2013.

Variable Category Curenosequela Curewithsequela/death Total p-value

No. %a _{No. %}a _{No. %}

Gender Male 134 66.0 69 34.0 203 61.1 0.568 Female 87 69.0 39 31.0 126 38.0 Unknown 3 0.9 0 0.0 3 0.9 Age(years) <1 38 73.1 14 26.9 52 15.7 <0.001 1–2 44 74.6 15 25.4 59 17.8 2–5 48 84.2 9 15.8 57 17.2 Subtotal<5 130 77.4 38 22.6 168 50.6 5–20 35 87.5 5 12.5 40 12.0 20–60 44 53.0 39 47.0 83 25.0 ≥60 15 38.5 24 61.5 39 11.7 Subtotal≥5 94 58.0 68 42.0 162 48.7 Unknown 1 0.3 1 0.3 2 0.6 Comorbidity No 108 77.1 32 22.9 140 42.2 0.002 Yes 112 61.2 71 38.8 183 55.1 Unknown 4 44.4 5 55.6 9 2.7 Total 332 100.0

a _{Referstothetotalofeachcategory.}

IPD,invasivepneumococcaldisease;HCRP,RibeirãoPretoTeachingHospital.

14(3.5%,n=3),23F(2.4%,n=2),19A(1.2%,n=1),6B(1.2%,n=1), and 9V (1.2%,n=1). Atotal of68.2% ofpatients presented comorbidities, the most common being HIV/AIDS (27.6%), alcoholism,andcancer(17.2%).Serotypes12F,14,18C,9V,18A, 19A,and23Faccountedfor65%ofalldeathsdueto meningi-tis,whileserotypes3,14,9V,6B,23F,and19Fwereinvolved in63.4%ofdeathsduetopneumonia.Therewasno associa-tionbetweenpatientgenderandoutcomeintermsofsuccess orfailure(p=0.568).Regardingthepresenceofcomplications and death related topatient age, we found that the older thepatient,thehigherthepercentageofsequelaeanddeath (p<0.001).Furthermore,thepresenceofcomorbiditywas asso-ciatedwithoutcomefailure(p=0.002).Amongpatientswith nocomorbidities,22.9%presentedtreatmentfailure,whereas amongthose withcomorbiditiesthefailure ratewas38.8% (Table4).Ouranalysisofeachserotypewithatleast10 iso-latesinrelationtoclinicaloutcomesrevealednosignificant difference forserotypes 3,9V, 6B, 6A, 23F,19F,19A, and 4. Serotype18Chadthehighestfailureratewhencomparedwith non-18Cserotypes(63.6×31.5%;p=0.025).Thesamewastrue forserotype12F(70.0×31.4%;p=0.010).Serotype14presented thelowestfailureratewhencomparedtoallotherserotypes (17.1×37.6%; p=0.001), as well as serotype 1 (8.0×34.5%; p=0.006).Univariateanalysisdemonstratedthatpatientsless than20yearswereatthegreatestrisk.Afteradjustingforthe presenceofcomorbidities,ageorserotypeweresignificantly associatedwithtypeofoutcomeonlyinthosewith60yearsor more(OR=4.2)(Table4).Furthermore,serotypes14(p=0.001) and1(p=0.006)werelesslikelytoresultinfailure(OR=0.3and OR=0.2,respectively),regardlessofthe presenceof comor-bidities(OR=0.4andOR=0.2,respectively)(Table5).However, afteradjustingforage,thisassociationwasnolonger signif-icant(Table4).Inthepresentstudy,serotypes18C(p=0.025) and12F(p=0.010)resultedinthegreatestfailurerateswhen comparedtotheotherserotypes.Thepresenceof18C repre-sentedasignfiicantriskfactor,bothinunadjustedanalysis

(OR=3.8)andafteradjustingforcomorbidity(OR=5.0)orage (OR=5.4),asdidserotype12F(OR=5.1,OR=5.0,andOR=4.7, respectively)(Table6).

Discussion

Thereisavastamountofliteraturewithinformationonthe characteristicsofStreptococcuspneumoniaestrainsthatcause invasivedisease,especiallyrelatedtothedevelopmentofnew vaccines.Incountriesinwhichtheconjugatepneumococcal vaccine was included inthe immunizationschedule, there wasasharpdeclineinhospitalizationratesdueto pneumo-nia,especiallyamongchildrenundertheageofthreeyears.8 In developing countries, approximately 15 million children withpneumoniawerehospitalizedeveryyear9_{;thisIPDstands} outduetoitshighlethality.10_{Thereductionin} pneumococ-cussamplessentforidentificationafter2010wascompatible with thefindings ofAfonso and collaborators,7 _{who found} that one year afterthe implementation ofVPC10 in Brazil therewasadropinthenumberofhospitalizedchildrenwith pneumoniain the municipalities ofBelo Horizonte,Recife, andCuritiba.InBrazil,datafromthepublichealth informa-tion system(DATASUS) indicate pneumoniaas the leading causeofhospitaladmissions,withthegreatestoccurrenceat extremesofage,affectingapproximately2.1millionBrazilians peryear.11_{Consideringallagegroups,theincidencedensity} ofpneumococcalmeningitisinthestateofSãoPauloduring theperiodofthisstudyrangedbetween0.9and1.5/100,000 inhabitants.12 _{Itwas observedthat 68.2%ofdeathsamong} all oftheanalyzedIPDsoccurredinpatientsundertheage of five. The global lethality rate of IPDs in industrialized countries rangesfrom15% to20%amongadults,andfrom 30%to40%amongpatientswithcomorbidities,orolderadults whose immunological function iscompromised.13 _In Euro-peancountries,Navarro-Tornéetal.14_{reporteda15.9%death}

Table5–MostcommonserotypesofS.pneumoniaeincomparisontootherserotypesisolatedfromIPDpatients registeredintheHCRPDatabankbycaseoutcome,1998–2013.

Serotypes Curenosequela Curewithsequela/death Total p-value

No. %a _{No. %}a _{No. %}

14 68 82.9 14 17.1 82 100.0 0.001 Non-14 156 62.4 94 37.6 250 100.0 1 23 92.0 2 8.0 25 100.0 0.006 Non-1 201 65.5 106 34.5 307 100.0 3 14 58.3 10 41.7 24 100.0 0.321 Non-3 210 68.2 98 31.8 308 100.0 9V 9 52.9 8 47.1 17 100.0 0.189 Non-9V 215 68.3 100 31.7 315 100.0 6B 9 56.2 7 43.8 16 100.0 0.326 Non-6B 215 68.0 101 32.0 316 100.0 6A 12 80.0 3 20.0 15 100.0 0.289 Non-6A 212 66.9 105 33.1 317 100.0 23F 11 73.3 4 26.7 15 100.0 0.620 Non-23F 213 67.2 104 32.8 317 100.0 19F 5 45.5 6 54.5 11 100.0 0.113 Non-19F 219 68.2 102 31.8 321 100.0 19A 9 64.3 5 35.7 14 100.0 0.795 Non-19A 215 67.6 103 32.4 318 100.0 18C 4 36.4 7 63.6 11 100.0 0.025 Non-18C 220 68.5 101 31.5 321 100.0 12F 3 30.0 7 70.0 10 100.0 0.010 Non-12F 221 68.6 101 31.4 322 100.0 4 7 70.0 3 30.0 10 100.0 0.862 Non-4 217 67.4 105 32.6 322 100.0

a _{Referstothetotalofeachassessedserotype.}

IPD,invasivepneumococcaldisease;HCRP,RibeirãoPretoTeachingHospital.

rate due to pneumococcal meningitis, withan association betweenpenicillin-resistant ofS.pneumoniaeand increased riskofdeath.Inthepresentstudy,weobserveda43.5%rateof meningitis,with9.4%ofdeathsinvolvingpenicillin-resistant strainsofS.pneumoniae.InthecityofSalvador15_andinthe Amazonstate,16_{thedeathrateduetopneumococcal} menin-gitissurpassed37.0%and32.4%,respectively,inallagegroups. BasedonSINANdatafrom2001to2010,Grandoetal.17_found

thattheannualmeandeathrateduetopneumococcal menin-gitisinBrazilwas33.6%and31.3%inchildrenlessthanfive yearsoldandlessthanoneyearold,respectively.Inaddition topresentinghighmortalityrates,meningitisisalsoa seri-ousconcernduetotheassociationwithsevereneurological complications,aswellashightreatmentcosts.Edmondand collaborators,18 _{attributed serious sequelae to} pneumococ-calmeningitis,suchashydrocephalus,cognitiveandmotor

Table6–AdjustedanalysisoffactorsassociatedwithoutcomefailureamongpatientswithIPDregisteredintheHCRP Databank,1998–2013.

Variable Category RawOR ORadjustedforcomorbidity ORadjustedforage

Age (years) <1 1 1 1–2 0.9[0.4;2.2] 0.9[0.4;2.2] 2–5 0.5[0.2;1.3] 0.5[0.2;1.4] 5–20 0.4[0.2;1.2] 0.4[0.1;1.2] 20–60 2.4[1.1;5.1] 2.1[0.9;4.8] ≥60 4.3[1.8;10.6] 4.2[1.6;10.9] Serotype 18C Yes 3.8[1.1;13.3] 5.0[1.4;18.0] 5.4[1.4;20.9] No 1.0 1.0 1.0 12F Yes 5.1[1.3;20.1] 5.0[1.2;20.1] 4.7[1.1;21.3] No 1.0 1.0 1.0 14 Yes 0.3[0.2;0.6] 0.4[0.2;0.8] 0.5[0.3;1.1] No 1.0 1.0 1.0 1 Yes 0.2[0.1;0.7] 0.2[0.1;0.9] 0.3[0.1;1.2] No 1.0 1.0 1.0

deficits,hearingloss,behavioralproblems,andlearning dis-orders.Inthepresentinvestigation,therateofsequelaewas 6.9%.Kyawetal.19_{indicatedthat,intheUnitedStates,} pneu-mococcal disease in adults was associated with a higher incidenceamongpatientswithHIV/AIDS, alcoholism,heart disease,respiratorydiseases,anddiabetesmellitus.In accor-dancewiththeresultsobtainedinthepresentstudy,68.2% ofpatients who died presentedsome type ofcomorbidity, primarily HIV/AIDS. In Brazil, data on lethality of respira-torydiseasesarescarce.However,accordingtoCashat-Cruz etal.,20_{deathfromacuterespiratorydiseasesisamongthe} most common causes of death in the Americas, account-ingforapproximately40%ofcases.Thisstudydemonstrated thatpneumonia-relatedmortalitywashigh(48.2%),especially amongadults,andonly4%ofcasesinvolvedpatientsyounger thanfive.InSpain,mortalityrelatedtopneumococcal pneu-moniavariedfrom7.4%to13%dependendingonthepatient’s age.21 _{InPortugal, pneumoniais the second leading cause} ofdeathamong patientshospitalized withrespiratory dis-eases,witha 22%lethalityrate.22 _{In thepresent studyIPD} casesweremoreoftencausedbyserotypes18Cand12F, rep-resentingasignificantriskfactorforfailure.Severalauthors suggest that thedifferent serotypes possess havedifferent potentialtocauseinvasivedisease,indicatinganassociation betweenfataloutcomesforpneumococcaldiseaseand capsu-larserotypesofpneumococcus.14,23–27_{However,therewasa} variationinserotypesmorefrequentlyinvolvedinfatalcases, namelyserotypes 3,6B,9N, 19F,and7F described bythese authorsasthemostinvasiveandinvolvedinunfavorable out-comes;ontheotherhandserotype1presentedthelowestrisk ofdeath.Furthermore,theseauthorsalsofoundserotypes3, 6B,18C,and19Ftobeamongthemostfrequentlyinvolvedin patientdeaths.Inturn,serotypes1,7F,8,6A,and15showed norelationwithfatalcases.Inthiscontext,informationabout theriskassociatedwithdifferentserotypes,intermsof differ-entoutcomesofIPDs,allowsustoestimatetheexpectation beforenewvaccine formulas; forexample the inclusion of serotype3maynothelpreducing themorbidityassociated withIPD.24_{However,theresultsofthisstudyunderscorethe} influenceofageasariskfactorforacquiringIPD,corroborating thefindingsofNavarro-Torné,14_{whoindicatedthat} individ-ualsolderthan65hadahighertendencytodevelopserious pneumococcaldiseasesassociatedwithagreaterrateof mor-bidityandmortalitythanchildrenlessthanfiveyearsold.As observedinthepresentstudy,thehigherriskrelatedtoolder adultsisnotdependentonthepresenceofcomorbidities,as wasfoundinastudybySantoset al.,28 _{whodemonstrated} thatthepresenceofcomorbiditiesdidnotseemtoinfluence thefinaloutcomeofIPDs.Duetoimpairedsplenicfunction, immunosenescence,and changesinthe respiratorytract,29 olderadultsaremoresusceptibletopneumococcaldisease. InBrazil,theGeriatricVaccinationGuideline30_recommends the23-valentpneumococcalpolysaccharidevaccine(PPV23) andthe 13-valentpneumococcal conjugatevaccine (PVC13) forpatientsabovetheageof60orthosewho havespecific chronicunderlyingdiseases.However,the13-valentvaccineis notavailableforolderadultsthroughthenational immuniza-tionprogram,andisofferedonlybyprivatevaccinationclinics. Inturn,thePPV23isadministeredtoinstitutionalizedolder adultsand,whenmedicallyindicated,tothosewhoarepartof

thehigh-riskgroupforpneumococcalinfection.Inthissense, afterassessingthecostofPPV23inadultsaged60orolder, Tonolio Neto and colleagues31 _{found that, in Brazil,} incor-poratingthisvaccinetothenationalimmunizationprogram wouldbeverycost-effectivegiventhecostsofhospitalization andabsenteeism.However,despitetheevidencepointingto theeffectivenessoftheVPP23againstIPDs,32_{itseffectiveness} in preventing pneumoniain adultsand high-risk patients, for whom it is recommended,33 _{as well as its preventive} actioninimmunosuppressedpatients,isstillquestioned.34_In thiscontext,astudyconductedinGermanyconcludedthat in comparisonwiththe VPP23, theVPC13 was better indi-cated toreducethe burdenofpneumococcaldisease,even economically.35_{AnotherstudyconducedbyPolishresearchers} foundthatolderadultsabovetheageof65,regardlessofrisk forcontractingpneumococcalinfection,shouldbevaccinated withVPC13.36_{In2010,basedonthedataabout} pneumococ-calpneumoniainSpain,Lujaetal.37_{suggestedthatthenew} VPC13wouldresultinasharpdeclineinmortalityamongthe olderadultpopulation.Ardanuyandcollaborators38 empha-sizedtheimportanceofadministeringtheconjugatevaccine toadults,suggestingthattheVPC13shouldbeusedinSpain forthatagegroup.Corroboratingthedataofadouble-blind randomizedtrialconductedinHolland,whichfounda reduc-tion inpneumococcalpneumoniaamongolder adultsafter immunizationwithVPC13,39_Picazoetal.40_{foundthatVPC13} doesnotleadtothephenomenonofserotypereplacementas observedwiththe7-valentpneumococcalvaccine.Inlightof theaboveandthehighincidenceandmortalityrateofIPDs amongadultsandespeciallyolderadults,weemphasizethe needtoreviewvaccinationrecommendationsandprograms fortheseagegroups,especiallyconsideringtheincreasein serotypes3and6Aobservedinthepresentstudy.However, thereis controversysurrounding theeffectivenessofthese vaccines in adults,as well as the mostappropriatechoice forthis population.41 _{Inthis context,O’Brien}42 _highlighted theimportanceofimmunogenicitystudiestodeterminethe effectiveness of conjugate vaccines against pneumonia in adults,especiallyinthecontextofco-infectionwiththeH1N1 influenzavirus.

Conclusion

Thepneumococcusisolatesamongpatientshospitalizedwith invasivepneumococcaldiseasepresentedvariabilityinterms ofcirculatingserotypes.Thisemphasizestheimportanceof ongoingmonitoringofinvasivestrainsindifferent manifes-tationsofpneumococcaldisease,especiallyconsideringthe progressive increase in serotypes 3 and 6Apresent in the 13-valent conjugate pneumococcal vaccine, and serotypes 12F and 18C, which are non-vaccine serotypes. Serotypes 18Cand12Fweresignificantriskfactorsbothinunadjusted andadjustedanalysisforcomorbidityandage.Furthermore, regardingcaseoutcomes,25.6%resultedindeath,especially amongpatients with meningitis.Patients aged60 years or olderpresentedthemoststatisticallysignificantassociation (OR=4.2) with outcome failure, regardless of the presence of comorbidities.In light ofthis information we recognize the importanceofconductingsurveillancestudies thatcan

underpin the process of reviewing and making decisions regardingpublicpoliciesandimmunizationprogramsforall adultsand forolderadultsinparticular.Inaddition, inthe ageofconjugatevaccines,informationaboutthedistribution ofserotypesamongdifferentagegroupsisessentialtoassess theimpactandadequacyofimmunizationprograms.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgement

WewouldliketothanktheCoordinationfortheImprovement ofHigherEducationPersonnel(CAPES)forfundingthisstudy.

r

e

f

e

r

e

n

c

e

s

1. WorldHealthOrganization(WHO).Relevéépidémiologique hebdomadaire.Pneumococcalconjugatevaccinefor childhoodimmunization.WklyEpidemiolRecGeneva. 2007;12:93–104.Availableat:http://www.who.int/wer [accessed23.05.15].

2. Organizac¸ãoPanamericanadaSaúde(OPAS).Informe regionaldeSIREVAII,2009.TecnologiadeSaludparala CalidaddelaAtención(THR/HT).Washington,DC:OPS/OMS; 2010.Availableat:http://www.paho.org/hq/index.

php?option=comcontent&view=category&layout=blog&id= 3609&Itemid=3953[accessed20.06.14].

3. NovaesHMD,SartoriAMC,SoarezPC.Hospitalizationrates forpneumococcaldiseasesinBrazil.RevSaúdePublica. 2011;45:539–47.

4. DonalisioMR,ArcaCHM,MadureiraPR.Perfilclínico, epidemiológicoeetiológicodepacientescompneumonia adquiridanacomunidadeinternadosemumhospitalgeral damicrorregiãodeSumaré,SP.JBrasPneumol.2011;37:200–8. 5. MinistériodaSaúde.Propostaparaintroduc¸ãodavacina

pneumocócica10-valente(conjugada)nocalendáriobásico devacinac¸ãodacrianc¸a,incorporac¸ãomarc¸o.Brasília;2010. Availableat:http://portal.saude.gov.br/portal/arquivos/pdf/ intropneumococica10val040210verfinal.pdf[accessed 20.06.13].

6. MinistériodaSaúdedoBrasil.Coordenac¸ãoGeraldo ProgramadeImunizac¸ões:InformetécnicodaVacina pneumocócica10valente(conjugada);2010.Availableat: http://www.sgc.goias.gov.br/upload/links/arq723infotec.pdf [accessed04.06.15].

7. AfonsoET,MinamisavaR,BierrenbachAL,etal.Effectof 10-valentpneumococcalvaccineonpneumoniaamong children,Brazil.EmergInfectDis.2013;19:589–97.

8. GrijalvaCG,NuortiJP,ArbogastPG,MartinSW,EdwardsKM, GriffinMR.Declineinpneumoniaadmissionsafterroutine childhoodimmunizationwithpneumococcalconjugate vaccineintheUSA:atime-seriesanalysis.Lancet. 2007;369:1179–86.

9. RudanI,TomaskovicL,Boschi-PintoC,etal.Globalestimate oftheincidenceofclinicalpneumoniaamongchildrenunder fiveyearsofage.BullWorldHealthOrgan.2004;82:895–903. 10.O’BrienKL,WolfsonLJ,WattJP,etal.Burdenofdisease

causedbyStreptococcuspneumoniaeinchildrenyoungerthan5 years:globalestimates.Lancet.2009;374:893–902.

11.MinistériodaSaúdePortaldaSaúdeBrasília,2014.Available at:

http://datasus.saude.gov.br/noticias/atualizacoes/478- evitar-aglomeracoes-no-inverno-ajuda-a-prevenir-

pneumonia-doenca-que-afeta-mais-de-2-milhoes-de-brasileiros-por-ano-segundo-o-datasus [accessed02.09.15].

12.CentrodeVigilânciaEpidemiológica.Meningitispor Streptococcuspneumoniae;2015.Availableat:

http://www.cve.saude.sp.gov.br/htm/resp/menicpneu.htm [accessed10.08.15].

13.WorldHealthOrganization(WHO).23-valentpneumococcal polysaccharidevaccine–WHOpositionpaper.Wkly EpidemiolRecGeneva.2008;83:373–84.Availableat:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5934a3.htm [accessed04.05.15].

14.Navarro-TornéA,DiasJG,HrubaF,etal.Riskfactorsfordeath frominvasivepneumococcaldisease,Europe,2010.Emerg InfectDis.2015;21:417–25.

15.GouveiaEL,ReisJN,FlanneryB,etal.Clinicaloutcomeof pneumococcalmeningitisduringtheemergenceof

penicillin-resistantStreptococcuspneumoniae:anobservational study.InfectDis.2011;11.Availableat:

http://www.biomedcentral.com/1471-2334/11/323[accessed 14.05.15].

16.DamascenoACA,FarhatCK.FatoresPrognósticosde letalidadenasmeningitesbacterianasemcrianc¸asmenores dedoisanos.RevParaensedeMedicina.2008;22.Availableat: http://files.bvs.br/upload/S/0101-5907/2008/v22n3/a2279.pdf [accessed16.06.15].

17.GrandoIM,MoraesC,FlanneryB,etal.Impactodavacina pneumocócicaconjugada10-valentenameningite pneumocócicaemcrianc¸ascomatédoisanosdeidadeno Brasil.CadSaúdePública.2015;31:1–9.

18.EdmondK,ClarkA,KorczakVS,SandersonC,GriffithsUK, RudanI.Globalandregionalriskofdisablingsequelaefrom bacterialmeningitis:asystematicreviewandmeta-analysis. LancetInfectDis.2010;10:317–28.

19.KyawMH,RoseCEJr,FryAM,etal.Theinfluenceofchronic illnessesontheincidenceofinvasivepneumococcaldisease inadults.JInfectDis.2005;192:377–86.

20.Cashat-CruzM,Morales-AguirreJJ,Mendoza-AzpiriM. Respiratorytractinfectionsinchildrenindeveloping countries.SeminPediatrInfectDis.2005;6:84–92. 21.PicazoJJ,González-RomoF,RojasAG,etal.Consenso:

VacunaciónAntineumocócicaemelAdultoconPatologíade Base.RevEspQuimioter.2013;26:81–91.

22.AraújoAT.RelatóriodoObservatórioNacionaldeDoenc¸as Respiratóriasde2011.DesafioseOportunidadesemTempo deCrise.ObservatórioNacionaldeDoenc¸asRespiratórias (ONDR).Fundac¸ãoPortuguesadoPulmão;2011.Availableat: http://www.ondr.pt/RelatorioONDR2011.pdf[accessed 18.06.15].

23.BrueggemannAB,PetoTE,CrookDW,ButlerJC,Kristinsson KG,SprattBG.Temporalandgeographicstabilityofthe serogroupspecificinvasivediseasepotentialofStreptococcus pneumoniaeinchildren.JInfectDis.2004;190:1203–11. 24.InverarityD,LambK,DiggleM,etal.Deathorsurvivalfrom

invasivepneumococcaldiseaseinScotland:associationswith serogroupsandmultilocussequencetypes.JMedMicrobiol. 2011;60:793–802.

25.JansenAGSC,RodenburgGD,EndeAV,etal.Invasive pneumococcaldiseaseamongadults:associationsamong serotypes,diseasecharacteristics,andoutcome.ClinInfect Dis.2009;49:e23–9.

26.RückingerS,vonKriesR,SiedlerA,vanderLindenM. AssociationofserotypeofStreptococcuspneumoniaewithrisk ofsevereandfataloutcome.PediatrInfectDisJ.2009;28: 118–22.

27.WeinbergerDM,HarboeZB,SandersEA,etal.Associationof serotypewithriskofdeathduetopneumococcalpneumonia: ameta-analysis.ClinInfectDis.2010;51:692–9.

28.SantosSR,PassadoreLF,TakageEH,etal.Serotype distributionofStreptococcuspneumoniaeisolatedinBrazil beforeandafterten-pneumococcalconjugatevaccine implementation.Vaccine.2013;31:6150–4.

29.SimellB,LahdenkariM,ReunanenA,KäyhtyH,Väkeväinen M.Effectsofageingandgenderonnaturallyacquired antibodiestopneumococcalcapsularpolysaccharidesand virulence-associatedproteins.ClinVaccineImmunol. 2008;15:1391–7.

30.SociedadeBrasileiradeImunizac¸ões.GeriatriaGuiade Vacinac¸ão.RiodeJaneiro;2013/14.Availableat: http://sbgg.org.br/wp-content/uploads/2014/10/ guia-de-vacinas.pdf[accessed18.06.15].

31.TonolioNetoJ,deAraujoGT,GagliardiA,PinhoA,DurandL, FonsecaM.Cost-effectivenessanalysisofpneumococcal polysaccharidevaccinationfromage60inSãoPaulostate, Brazil.HumVaccin.2011;7:1037–47.

32.ÖrtqvistA.Pneumococcalvaccination:currentandfuture issues.EurRespirJ.2001;18:184–95.

33.HussA,ScottP,StuckAE,TrotterC,EggerM.Efficacyof pneumococcalvaccinationinadults:ameta-analysis.CMAJ. 2009;180:48–58.

34.SiemieniukRAC,GressonDB,GillMJ.Thepersistingburdenof invasivepneumococcaldiseaseinHIVpatient:an

observationalcohortstudy.InfectDis.2011;11:314.Available at:www.biomedcentral.com/81471-234/11/314[accessed 08.04.15].

35.KuhlmannA,TheidelU,PletzMW,vonderSchulenburgJM, etal.Potentialcost-effectivenessandbenefit-costratiosof adultpneumococcalvaccinationinGermany.HealthEcon Rev.2012;30:2–4.Availableat:

www.healtheconomicsreview.com/content/2/1/4[accessed 06.04.15].

36.GrzesiowskiP,Aguiar-Ibá ˜nezR,Kobry ´nA,DurandL,PuigPE. Cost-effectivenessofpolysaccharidepneumococcal vaccinationinpeopleaged65andaboveinPoland.Hum VaccinImmunother.2012;8:1382–94.

37.LujaM,GallegoM,BelmonteY,etal.Influenceof pneumococcalserotypegrouponoutcomeinadultswith bacteraemicpneumonia.EurRespirJ.2010;36:1073–9. 38.ArdanuyC,MarimónJM,CalatayudL,etal.Epidemiologyof

invasivepneumococcaldiseaseinolderpeopleinSpain (2007–2009):implicationsforfuturevaccinationstrategies. PLoSONE.2012;7:e43619.Availableat:

http://www.ncbi.nlm.nih.gov/pubmed/22928005[accessed 07.04.15].

39.BontenMJM,HuijtsSM,BolkenbaasM,etal.Polysaccharide conjugatevaccineagainstpneumococcalpneumoniain adults.NEnglJMed.2015;372:1114–25.

40.PicazoJJ,Ruiz-ContrerasJ,Casado-FloresJ,etal.Expansionof serotypecoverageintheuniversalpediatricvaccination calendar:short-termeffectsonage-andserotypedependent incidenceofinvasivepneumococcalclinicalpresentationsin Madrid,Spain.ClinVaccineImmunol.2013;20:1524–30. 41.MusherDM,SampathR,Rodrigues-BarradasMC.The

potentialroleforprotein-conjugatepneumococcalvaccinein adults:whatisthesupportingevidence?ClinInfectDis. 2011;52:633–40.

42.O’BrienKL.Pneumococcalconjugatevaccine,polysaccharide vaccine,orbothforadults?We’renotthereyet.ClinInfect Dis.2009;49:1326–8.

Erratum

In the article “Clinical and microbiological implications of invasive pneumococcal disease in hospitalized patients

(1998–2013)” [Braz J Infect Dis. 2016;20(3):242–249], in the authors list, where it reads Maria Luiza Leopoldo, Silva Guerra,

it should read Maria Luiza Leopoldo Silva Guerra. The online version of the article has already been corrected.