Bacteremic pneumococcal pneumonia: serotype distribution, antimicrobial susceptibility, severity scores, risk factors, and mortality in a single center in Chile

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

article

Bacteremic

pneumococcal

pneumonia:

serotype

distribution,

antimicrobial

susceptibility,

severity

scores,

risk

factors,

and

mortality

in

a

single

center

in

Chile

Alberto

Fica

_,

_Nicolás

_Bunster

_,

_Felipe

_Aliaga

_,

_Felipe

_Olivares

_,

_Lorena

_Porte

_,

Stephanie

Braun

_,

_Jeannette

_Dabanch

_,

_Juan

_Carlos

_Hormázabal

_,

_Antonio

_Hernández

_,

María

Guacolda

Benavides

a_{ServiciodeInfectología,HospitalMilitardeSantiago,Chile} b_{UnidadCoronaria,HospitalMilitardeSantiago,Chile}

c_{UnidaddePacientesCríticos,HospitalMilitardeSantiago,Chile} d_{ResidenteMedicinaInterna,HospitalMilitardeSantiago,Chile} e_{LaboratoriodeMicrobiología,HospitalMilitardeSantiago,Chile} f_{SubdepartamentodeMicrobiología,InstitutodeSaludPública,Chile} g_{ServiciodeEnfermedadesRespiratorias,HospitalMilitardeSantiago,Chile}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received28March2013 Accepted3June2013

Availableonline10October2013

Keywords:

Streptococcuspneumoniae

Bacteremia Serotyping

Microbialdrugresistance Riskfactors Mortality Elderly CURB-65 APACHEII PIRO

a

b

s

t

r

a

c

t

Aims: Bacteremic pneumococcal pneumonia (BPP) is a severe condition. To evaluate seasonaldistribution,mortality,serotypefrequencies,antimicrobialsusceptibility,and dif-ferentseverityscoresamongpatientswithBPP.

Patientsandmethods:Patientswereidentifiedbylaboratorydataandrestrictedtoadulthood. Standardmethodswereusedforserotypingandantimicrobialsusceptibility.Riskfactors wereanalyzedbyunivariateandmultivariatemethods.Severityscores(APACHEII,CURB-65 andCAPPIRO)werecomparedusingROCcurves.

Results:Sixtyeventsofcommunity-acquiredBPPoccurredbetween2005and2010.A sea-sonal patternwasdetected. Meanagewas72.1years old (81.4%≥60years).All hada predisposingfactor.Previousinfluenza(3.3%)orpneumococcalimmunization(1.7%)was infrequent.Admissiontocriticalunitswasrequiredby51.7%.Twenty-twoserotypeswere identifiedamong59strains.Onlyonestrainhadintermediateresistancetopenicillin(1.7%). In-hospitalmortalityreached33.3%.MultivariateanalysisidentifiedaCAPPIROscore>3(OR 29.7;IC954.7–187),age≥65years(OR42.1;IC952.2–796),andaplateletcount<100,000/␮L (OR10.9;IC951.2–96)assignificantindependentfactorsassociatedwithdeath.ROCcurve analysisdidnotrevealstatisticaldifferencesbetweenthethreeseverityscorestopredict death(AUC0.77–0.90).Theprognosticyieldforallofthemwaslimited(PositiveLikelihood Ratio:1.5–3.8).

Conclusions: BPPhadahighcase-fatalityrateinthisgroupofadultpatientswithno associ-ationtoresistantisolates,andalowimmunizationrecord.Threeindependentfactorswere relatedtodeathandtheprognosticyieldofdifferentseverityscoreswaslow.

©2013 ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthorat:ServiciodeInfectología,HospitalMilitardeSantiago,Av.Larraín9100,LaReina,Santiago,Chile.} E-mailaddresses:albertofi[email protected],afi[email protected](A.Fica).

1413-8670/$–seefrontmatter©2013 ElsevierEditoraLtda.Allrightsreserved. http://dx.doi.org/10.1016/j.bjid.2013.06.001

Introduction

Invasive infections due to Streptococcus pneumoniae are an importantcauseormorbidityandmortalitywithahigh dis-easeburden.1_{Inaddition,invasivediseasecaseswillprobably}

increase inthe nearfuture due to populationaging.2

Bac-teremic pneumococcal pneumonia represents an invasive diseasethatislinkedtoextremeagesandcomorbidities.3,4 It has sometimes been associated with a range of differ-entserotypes,antibioticresistanceanda highcase-fatality ratio.3,5–7_{Updatedinformationaboutantibioticresistanceand}

serotype distributionisneededforantimicrobialtreatment and to evaluate vaccine efficacy. However, data regarding serotypefrequenciesisscarceinadultsinseveralcountries of Latin America because it has mainly been focused on children.8,9 _{In addition, different severityscores havebeen}

appliedinpatientwithcommunity-acquiredpneumoniaorin thoseseriously-ill4,10,11_{butnotinaspecificgroupofpatients}

such as those with bacteremic pneumococcal pneumonia. Wereportthe resultofa 6-yearperiodretrospective study inpatientswithbacteremicpneumococcalpneumonia.The aimswere to examineseasonal distribution, patient’ char-acteristics, mortality rate, use of intensive care resources, serotypefrequencies,antimicrobialsusceptibility,and sever-ityscorespredictionyield.Riskfactorsassociatedtocritical careunitadmissionandmortality,werealsoexplored.

Patients

and

methods

RetrospectiveanddescriptivestudyperformedattheHospital MilitardeSantiago,Chile.Thisinstitutionisa250-bed gen-eralhospitalforactiveorretiredmilitarypersonnelandtheir relatives.

Inclusioncriteriaandvariablesincluded

Every adultpatient≥18 years, admittedbetween 2005and 2010withS.pneumoniaegrowinginbloodcultures,andwith respiratory symptoms and/or pneumonia was included. Potentialcaseswereidentifiedusingthemicrobiology labora-torydatabase.Medicalchartswerereviewedanddataonthe followingvariableswereobtained:co-morbidities(pulmonary diseases, cardiac disease, renal failure, diabetes mellitus), immunosuppression, alcoholism or tobacco consumption, influenza and pneumococcal vaccination coverage, clini-calmanifestations,physicalexamination,laboratoryvalues, chestX-rayand/orCTinformation,admissiontointermediate orcriticalcareunit,useofvasoactivedrugsorshock, antimi-crobialtherapy,steroiduseduringthefirst72hofadmission, length of stay (LOS) and hospital mortality. APACHE II, CURB-65 and CAP-PIRO severity scores were applied.10,11

Data on antimicrobial susceptibility and serotyping were included.Thelatterwasperformedinthenationalreference laboratory.Thefollowingoperativedefinitionswereapplied: tobacco consumption (any quantity of cigarettes per day in the last two years), alcohol consumption (any quantity

of ethanol consumption per day), shock (arterial systolic pressure<90mmHgwithnoresponsetofluidresuscitationor needforvasoactivedrugs),acuterenalinjury(serum creati-ninelevel>1.5mg/dLatadmissionor50%increaseabovethe baselinevalue),acuterespiratory distresssyndrome(ARDS: PaFiO2<200andbilateralinfiltrates),andcomplicatedpleural

effusion (purulent pleural fluid or bacteria on gram stain, requiringachesttubeorsurgicaldrainage).

Statisticalanalysis

Clinical information is presentedin a descriptive manner. Continuous variables were categorized to facilitate anal-yses. Potential factors linked to in-hospital mortality or intermediate-intensive careunit admission, were explored usingchi-squareortwo-sidedFisher’sexacttest.Univariate analysisincludingoddsratios(OR)wasperformed,adding0.5 to everycell inthe 2×2contingency tablewhennull cells were present. Multivariate analysiswas developedthrough binary logisticregression.ROCcurveswereappliedinorder tocomparedifferentnumericalvariablesassociatedtohigher in-hospitalmortality,andcutoffvalueswereestablished.The areasunderthecurve(AUC)fromdifferentpredictivescales werecomparedusingEpidatsoftware.

Results

From2005to2010,sixtyeventsofcommunity-acquired bac-teremic pneumococcal pneumoniaoccurred in59 patients. Onepatienthadtwoeventsthreeyearsapartfromeachother. In this case demographics, tobacco smoking, alcohol con-sumption and co-morbidities were counted once, but data onclinicalmanifestations,laboratory,radiologic,andvaccine coverage,werecountedseparately.

Neartwo-thirdsofpatientswerefemales.Meanagewas 72.1 years old (range20–96; Table1). Over80%of the sub-jectswas60yearsorolder,andhalfwasolderthan75years. Inaddition,onethirddeclaredtobaccosmokingandalmost 20%werealcoholconsumersbutadetailedcharacterization onthequantityusedwasnotpossible.Medicalmorbid con-ditionswerefrequentinthisseries, heartdisease,different pulmonaryconditions, diabetesmellitus,and chronicrenal failure predominated. All patients had apredisposing con-dition and 76% had co-morbidities. No patients with HIV infectionorsolidorbonemarrowtransplantationwere iden-tifiedinthisseries,andinfluenzaorpneumococcalvaccine coveragewasexceedinglyrare(Table1).

Bacteremic events were characterizedby a severe clini-cal condition reflected in the relative higher frequency of cyanosis,respiratoryrate>30min–1_{,andhypotension(Table2,}

whole group column). More than half had an APACHE II score>15pointsandtwo-thirdsaCAPPIROscore>2.Cough, fever,andlungsoundsintheformofralesorcrackleswere fre-quent(∼80%,Table2,wholegroup).Mostpatientspresented onetosevendaysofsymptomsbeforeadmission,butnear15% ofeventsstartedonthesamedayofhospitalization(Table2, wholegroup).

Table1–Generalfeaturesamongpatientswith community-acquiredbacteremicpneumococcal pneumoniaadmittedtoHospitalMilitardeSantiago, 2005–2010.

n(%)

Patients/events 59/60

Femalegender 38(64.4%)

Age>60yearsold 48(81.4%)

Age>75yearsold 31(52.5%)

Tobaccosmoking 22(37.3%)

Alcoholconsumption(anyquantity) 11(18.6%)

Co-morbidities

Heartdisease 28(47.5%)

COPD–chronicbronchitis 14(23.7%)

Asthma 1(1.7%)

Diffusepulmonarydisease 2(3.4%)

Anypulmonarycondition 17(28.8%)

Diabetesmellitus 15(25.4%)

Chronicrenalfailure 12(20.3%)

Chronicliverdisease 5(8.5%)

Anycomorbidity 45(76.3%)

Age>60yearsoldorco-morbidities 59(100.0%)

Influenzavaccine 2(3.3%)

Pneumococcalpolysaccharidevaccine 1(1.7%)

Asagroup(Table3,wholegroupcolumn),patientswith bacteremicpneumococcalpneumoniapresentedtachycardia, tachypnea, fever, leucocytosis, elevated C reactive protein, low serum albumin concentration, and respiratory failure with low PaFiO2 index together with increased values of

blood urea nitrogen and serum creatinine concentration. Tenpercenthad complicatedpleuraleffusion andrequired achest tube orsurgicaldrainage. Thirty percentpresented multilobar lung infiltrates and 57% ARDS (Table 2, whole group).

Microbiologicalcharacterization

Twenty-twoserotypeswereidentifiedamong59strains.One isolatewasuntypeableandonestrainwasnotanalyzed. Two-thirdsofthesamplewererepresentedbyninepredominant serotypes(14,7f,9v,12f,22f,6a,8,4,and1)(Table4).Other 13serotypesweredetectedonceortwiceinthisperiod(23a, 23f,5,6b,13,15f,17f,18f,19a,3,9n,poolr,33f).Mostfrequent serotypeswereevenlydistributedthroughthewholeperiod. Thesameserotypewasfoundinbothisolatesfromthepatient withtwobacteremicepisodes(serotype5).

E-testanddiskdiffusionwereusedtostudyantimicrobial susceptibility(Table5).MIC50andMIC90valuesforpenicillin,

amoxicillin and cefotaxime were remarkablylow and only onestrainwithintermediatesusceptibilitytopenicillinwas detected.Noresistantisolatestolevofloxacinorvancomycin wereidentifiedbythediskdiffusionmethod.

Placeofhospitalizationandevolution

Thirty-onepatientswereadmittedtoanintermediateor crit-icalcare unit(51.7%). Thirtyper cent ofbacteremic events requiredmechanicalventilation.Antimicrobialtherapywas

Table2–Clinicalmanifestationsandseverityscoresatadmissionof60eventsofbacteremicpneumococcalpneumonia. HospitalMilitardeSantiago,2005–2010.

Intermediateand criticalcareunits

Generalwards Wholegroup OddsRatio(95%CI)for significantdifferences betweencriticalunitsand

generalwards

Precedingupperrespiratorysymptoms 8/31(25.8%) 7/29(24.1%) 15/60(25.0%)

Dayswithsymptoms

<1day 5/31(16.1%) 3/29(10.3%) 8/60(13.3%) 1–3days 13/31(41.9%) 13/29(44.8%) 26/60(43.3%) 4–7days 11/31(35.5%) 12/29(41.4%) 23/60(38.3%) >7days 2/31(6.5%) 1/29(3.4%) 3/60(5.0%) Cough 28/31(90.3%) 20/29(69.0%) 48/60(80.0%) 4.2(1.0–17.5)p=0.05 Dyspnea 23/31(74.2%) 15/28(53.6%) 38/59(66.4%) Highfever(T>38◦C) 24/31(77.4%) 23/28(82.1%) 47/59(79.7%) Sputum 24/31(77.4%) 16/29(55.2%) 40/60(66.7%)

Cough+highfever+sputum 20/31(64.5%) 15/29(51.7%) 35/60(58.3%)

Cyanosis 8/31(25.8) 6/29(20.7%) 14/60(23.3%)

Hemoptysis 1/31(3.2% 0/28(0.0%) 1/59(1.7%)

Pulserate>100/min 20/31(64.5%) 10/29(34.5%) 30/60(50.0%) 3.4(1.2–9.9)p<0.05

Respiratoryrate≥30/min 24/31(77.4%) 7/29(24.1%) 31/60(51.75%) 10.7(3.2–35.6)p<0.001

Hypotension 13/31(41.9%) 6/29(20.7%) 19/60(31.7%)

Shock 11/31(35.5%) 0/29(0.0%) 11/60(18.3%) 33.1(1.8–593)p<0.001

Pulmonaryralesorcrackles 23/31(74.2%) 27/29(93.1%) 50/60(83.3%)

Multilobarlunginfiltrates 18/31(58.1%) 0/29(0.0%) 18/60(30%) 80.8(4.5–1443)p<0.001

Complicatedpleuraleffusion 4/31(12.9%) 2/29(6.9%) 6/60(10.0%)

ARDS 25/31(80.6%) 7/25(28.0%) 32/56(57.1%) 10.7(3.1–37.3)p<0.001

C-reactiveprotein>150mg/L 21/29(72.4%) 2/27(7.4%) 23/56(41.1%) 32.8(6.3–171)p<0.001

CURB-65score>2 22/31(71.0%) 10/29(34.5%) 32/60(53.3%) 4.6(1.6–13.8)p=0.005

APACHEscore>15 24/31(77.4%) 10/29(34.5%) 34/60(56.7%) 6.5(2.1–20.3)p<0.01

Table3–Physicalexamparameters,laboratoryvaluesandseverityscoresresultsamong60eventsofbacteremic pneumococcalpneumonia,HospitalMilitardeSantiago,2005–2010.

Variable Intermediateand

criticalcareunitmean (range)

n=31

Generalwardmean (range)

n=29

Wholegroupmean (range)

n=60

Significantdifferencesby Mann–Whitneytest betweencriticalunitsand

wards Meanarterialpressure

(mmHg)

79.4(53–147) 84.0(43–120) 81.6(43–147)

Diastolicbloodpressure (mmHg)

61.9(33–120) 68.3(30–100) 65.0(30–120)

Pulserate/min 108.6(60–148) 97.6(71–123) 103.3(60–148) <0.05

Respiratoryrate/min 32.8(18–45) 25.4(18–40) 29.2(18–45) <0.001

Axilartemperature(◦C) 37.5(36–39.6) 37.2(35–39.5) 37.4(35–39.6) Whitecellcount/␮L 13,544(1300–33,100) 13,186(2400–30,900) 13,371(1300–33,100)

Hematocrit(%) 35.8(17.0–48.0) 35.5(21.6–44.8) 35.7(17.0–48.0) Platelets/␮L 188,645(19,000–396,000) 200,896(21,000–457,000) 197,950(19,000–457,000) Creactiveprotein(mg/L) 180.8(34–306) 98.7(14.5–197) 141.2(14.5–306) <0.001 Serumalbumin(g/dL) 3.0(1.0–4.3) 3.2(1.8–4.5) 3.1(1.0–4.5) Serumsodium concentration(mEq/L) 136.8(128–146) 137.1(124–150) 137(124–150) Serumpotassium concentration(mEq/L) 3.8(2.6–5.2) 4.1(3.3–5.6) 4.0(2.6–5.6) <0.05

Bloodureanitrogen (mg/dL)

36.1(11–99) 32.7(6–138) 34.4(6–138)

Serumcreatininelevel (mg/dL) 1.5(0.4–5.5) 1.4(0.1–9.1) 1.4(0.1–9.1) ArterialpH 7.34(7.1–7.5) 7.4(7.2–7.5) 7.37(7.1–7.5) ArterialpCO2(mmHg) 39.5(22–76) 34.2(19.7–55) 37.1(19.7–76) Serumbicarbonate (mEq/L) 20.9(10–30) 22.2(11–30) 21.5(10–30) PaFiO2 158.2(51–268) 233.4(49–364) 191.8(49–364) 0.01 CURB-65score 3.1(1–5) 2.1(0–5) 2.6(0–5) <0.01

CAPPIROscore 4.0(1–6) 2.6(1–6) 3.4(1–6) <0.001

APACHEIIscore 20.7(5–41) 12.7(6–24) 16.8(5–41) <0.001

Glasgowscore 13.9(5–15) 14.3(11–15) 14.1(5–15)

startedthree tofourdaysaftersymptoms appeared(range 0–21, median3, IQR 1–5 days). All events were adequately treatedfromthestartaccordingtosusceptibilitystudies.In addition,40.7%(n=24)receivedcorticosteroidtherapyduring thefirst72hofhospitalization.Themeanaccumulateddose forthisperiodwasequivalentof151mgofprednisone(range 38–650mg).In-hospitalmortalityreached33.3%(20outof60

Table4–Serotypedistributionamong59strainsof Streptococcuspneumoniaeisolatedduringbacteremic events. Serotype N % Accumulated% 14 7 11.7 11.7 7f 6 10.0 21.7 9v 5 8.3 30.0 12f 4 6.7 36.7 22f 4 6.7 43.3 6a 4 6.7 50.0 8 4 6.7 56.7 4 3 5.0 61.7 1 3 5.0 66.7 Otherserotypes 18 30.0 96.7 Nontypeable 1 1.7 98.3 Notdone 1 1.7 100.0 Total 60 100.0

bacteremicevents).Lengthofstayrangedfromoneto93days (mean13.3days).

Riskfactorsassociatedtoadmissiontointermediateor criticalcareunit

Univariate analysis identified several factors significantly associated with admission to intermediate or critical care unit.Categoricalvariablessuchastobaccosmoking(OR3.1; 95% CI 1.0–9.5, p<0.05), cough (OR 4.2; 95% CI 1.0–17.5,

p=0.05), tachycardia(OR3.4;95% CI1.2–9.9,p<0.05), respi-ratory rate>30min–1 _{(OR 10.7; 95% CI 3.2–35.6, p<0.001),}

shock (OR 33.1; 95% CI 1.8–593, p<0.001), multilobar infil-trates (OR 80.8; 95% CI 4.5–1443, p<0.001), ARDS (OR10.7; 95%CI3.1–37.3,p<0.001),C-reactiveprotein>150mg/dL(OR 32.8;95%CI6.3–171,p<0.001),APACHEIIscore>15 (OR6.5; 95% CI 2.1–20.3, p<0.01), CURB-65 score>2 (OR 4.6; 95% CI 1.6–13.8, p=0.005), and CAP PIRO score>2 (OR 7.2; 95% CI 2–25, p<0.01) (Table 2) were associated to hospitaliza-tion in critical units. Thisassociation wasalsoestablished for the following continuous variables for higher values: pulse and respiratory rate, C-reactive protein, APACHE II score, CURB-65, CAP PIRO score (Table 3), and for lower values of PaFiO2 index and serum potassium

concentra-tion (Table 3). Multivariate analysis indicated that only a C-reactive value >150mg/L was independently associated

Table5–Antimicrobialsusceptibilitystudies.

MICbyE-test

Compound n Mean(range)(␮g/mL) MIC50(␮g/mL) MIC90(␮g/mL) Susceptiblen(%) Intermediaten(%)

Penicillin 60 0.21(0.004–4.0) 0.03 0.5 59(98.3%) 1(1.7%) Amoxicillin 42 0.17(0.004–2.0) 0.03 0.5 42(100%) 0(0%) Cefotaxime 59 0.12(0.002–1.0) 0.03 0.4 59(100%) 0(0%) Diskdiffusion Levofloxacin 55 56(100%) 0(0%) Vancomycin 58 59(100%) 0(0%)

with admission to these units (OR 17.6; 95% CI 1.8–109,

p<0.01).

Riskfactorsassociatedtoin-hospitalmortality

Twentypatientsdied in this seriesand univariateanalysis identified several associations (Table 6). Most relevant fac-torswereCURB-65score>2(OR39.5;95%CI4.7–327.0),CAP PIROscore>3(OR19.5;95%CI4.6–81.0),respiratoryrate>30 (OR18.7;95%CI 3.7–92.0),Glasgow score<15(OR13.8;95% CI 3.7–51.7), and age>65 years (OR 11.4; 95% CI 1.4–94.0). A LOS>14 days was significantly associated with reduced in-hospitalmortality(OR0.1;95%CI0.1–0.8). Corticosteroid therapy was not linked to any particular effect. Multivari-ateanalysisidentifiedCAPPIROscore>3,age≥65years,and plateletcount<100,000/␮Lasindependentfactorslinkedto higherin-hospitalmortality(Table6).

Severityscoresandin-hospitalmortality

Fig.1showsreceiveroperatingcharacteristiccurvesfor in-hospital mortality according to PIRO, APACHE II, CURB-65 scoresandage.CURB-65andCAPPIROscoressurpassedthe areaunderthecurve(AUC)predictionobtainedwithAPACHE IIorAgebutmatchedbetweenthem(Table7).Significant sta-tisticaldifferenceswerefoundbetweentheAUCofCURB-65 and age (p<0.01); alsowith CAPPIRO versusage (p<0.05). Survivalcurves at30daysinceadmissionusingastratified CAPPIROscore (≤3or >3)was statisticallysignificant (Log

Curb 65 A P 0,0 1,0 0,8 0,6 0,4 0,2 0,0 0,2 0,4 0,6 0,8 1,0 Age 1 - Specificity Sensitivity

Fig.1–ROCcurveofdifferentseverityscoresandageto predictin-hospitalmortality.A:APACHEIIscore,P:CAP PIROscore.

ranktestp<0.001)(Fig.2).Cut-offvaluesoptimizedwithROC analysisanddifferentstatisticsparametersaredisplayedin Table7.Sensitivityandspecificityregardingprognosticyield waslimited.Severityscoresweremoreusefulasnegative pre-dictivevaluesifthepatientwasbelowthecut-off.

Epidemiologicalaspects

Eventsdistributionshowedasporadicpatternalongthestudy ranging from 4 to 17 cases per year. There was a non-significant trend toward case reduction during this period (Pearson correlationcoefficient−0.46; p>0.05). Over40%of cases were hospitalizedbetween epidemiologicalweeks 14 and26(Fig.3).

Discussion

Theaimsofthis studywere toevaluateclinical, epidemio-logical,andmicrobiologicalfeatures,aswellaspredictorsof mortalityandcriticalcareunitadmissioninagroupofadult patientshospitalizedforbacteremicpneumococcal pneumo-nia.Severalfindingsdeserveattention.

From anepidemiologicalperspective,aseasonal pattern wasobservedwithahigherincidenceofcasesduringmid-fall andearlywinter(weeks14–26).Thisphenomenonhadbeen previouslydescribedinadults,associatedtoaprecedingviral respiratoryinfectionandairpollution,12_{andpeakincidence}

of bacteremic events coinciding with seasonal influenza in Santiago.13 _{Between 2000 and 2010 a decreasing trend}

of these bacteremic events was observed in parallel to a

CAP PIRO < 3 CAP PIRO > 3 0 5 10 15 20 25 30 1,0 0,8 0,6 0,4 0,2 0,0 Days Sur viv al fr action

Fig.2– Survivalcurveuntildischargestratifiedaccordingto CAPPIROscore.

Table6–Riskfactorsassociatedtoin-hospitalmortalityamong60eventsofbacteremicpneumococcalpneumonia. HospitalMilitardeSantiago,2005–2010.

Factor OddsRatio IC95 p

Univariateanalysis

Admissiontointermediateorcriticalcareunit 3.1 1.0–9.9 <0.05

Age≥65years 11.4 1.4–94.0 <0.01

Cyanosis 3.7 1.1–13.1 0.05

Respiratoryrate≥30/min 18.7 3.7–92.0 <0.001

Leukocytecount<7000/␮L 4.6 1.3–15.9 <0.05

Bloodplatelets<100,000/␮L 4.8 1.2–19.3 <0.05

Serumcreatinineovernormallimit 3.1 1.0–9.5 <0.05

Bloodureanitrogen>23mg/dL 6.0 1.7–21.2 <0.01

Serumalbumin<3.5g/dL 5.9 1.2–29.2 <0.05

PaFiO2<150 7.5 2.1–26.2 <0.01

ARDS 7.9 2.0–32 <0.01

CAPPIROscore>3 19.5 4.6–81.0 <0.001

CURB-65score>2 39.5 4.7–327.0 <0.001

Glasgowscore<15 13.8 3.7–51.7 <0.001

APACHEIIscore>15 7.7 1.9–30.4 <0.01

Lengthofstay>14days 0.1 0.1–0.8 <0.05

Multivariateanalysis

CAPPIROscore>3 29.7 4.7–187 <0.001

Age≥65years 42.1 2.2–796 <0.05

Bloodplatelets<100,000/␮L 10.9 1.2–96 <0.05

Table7–Cut-offvaluesanddiagnosticparametersfordifferentseverityscoresandageaspredictorsofin-hospital mortality.

Variable AUC(IC95) Cut-off Sensitivity Specificity PPV NPV LR+ LR−

CURB-65 0.901}*_{(0.83–0.97) >2 0.95 0.67 0.62 0.96 1.5 0.07}

PIROscore 0.868}*_{(0.77–0.96) >3 0.85 0.77 0.77 0.91 3.8 0.19}

APACHEII 0.769(0.64–0.88) >15 0.85 0.57 0.59 0.88 2.0 0.26

Age 0.691}*_{(0.57–0.83) ≥65y 0.95 0.35 0.42 0.93 1.5 0.14}

PPV,positivepredictivevalue;NPV,negativepredictivevalue;LR+,positivelikelihoodratio;LR−,negativelikelihoodratio.

∗ _{p<0.05forageversusCAPPIROscoreandp<0.01forageversusCURB-65.}

reductioninmortalityduetopneumoniaamongtheChilean elderlypatients(Pearsoncoefficient−0.70,datanotshown).14 Death rate due to pneumonia decreased from 324 to 222 per100,000inhabitantsinthisage group,and itispossible thatthedeclineobservedinourworkissomehowmirroring a global trendin Chile. This change isprobably related to multiplefactors,like,asteadilyincreaseininfluenzavaccine

doses. At present, 25% of the Chilean population is being immunizedforinfluenza(over4milliondoses).Inaddition, since2009anationalpolysaccharide23-valentpneumococcal immunization program is applied among elderly people, albeit with a reduced coverage of the targeted population (near 6%). Moreover, during the last decade a significant reductioninairpollutionhasoccurred inthemetropolitan

5 0 5 4 3 2 1 10 15 20 25 Epidemiological week 41.7%

Events by epidemiological week

30 35 40 45 50

area,15_{andatimely,lowcostaccesstomedicalattentionand}

antimicrobialtherapyisguaranteedforallagedpatientswith ATSIIcommunityacquiredpneumonia.Theseinterventions couldenhancethedecreasingtrendofthisconditioninthe future.Infantimmunizationwithpneumococcalconjugated vaccines can influence the frequencyof invasive pneumo-coccal disease inadults through its effect on colonization and transmission.16 _{A national immunization program for}

infantswitha 10-valentconjugated pneumococcal vaccine was launched inChile at the end of2010,but beyondthe studyperiodandcouldhavenotinfluencedonthisdecrease. Three quarters of our patients had co-morbidities and all had an older age or chronic diseases. The high preva-lenceofco-morbidconditionsisacommonfeatureinadult patientsaffectedbypneumococcalpneumoniawithor with-outbacteremia,underscoringtheimportanceofhostfactors in disease progression, and at the same time, probably explainingwhythebacteremicconditionhasnotbeenclearly associatedwith aworst prognosisthan caseswithout this condition.4,5,17,18 _{Thedeathtollobservedinourwork (33%)}

isinlinewithhostcharacteristic(30%)andsimilartofigures reportedinonegroupfromBrazil.5_{However,itishigherthan}

previousreportsfrom Chile(10.9and20%).3,4 _{Thiscould be}

relatedtotheolderagerangeofourpatients.

Most of the patients had a severe underlying clini-cal condition and almost 15% suffered an abrupt onset. Cyanosis,arespiratoryrate>30/min,andhypotensionwere relatively frequent. Laboratory parameters included renal (BUN∼30mg/dL)andrespiratoryfailure(PaFiO2∼190),

leuko-cytosis(∼13,000/␮L),elevatedC-reactiveprotein(∼140mg/L) andlowserumalbumin(∼3g/dL).Inaddition,multilobar infil-tratesweredetectedinalmostonethirdofthesubjectsand 10%requiredachesttubeorsurgeryduetopleuraleffusion. Thesefindingswerealsocommoninotherseries.3–5

Severalriskfactorshavebeenassociatedtoahigherrisk of death in adult patients with pneumococcal infections. However, results vary depending on the type of infec-tion(pneumonia,bacteremicornon-bacteremicconditions, meningitis),groupofpatients(general,HIV-infected,liver dis-ease, cancer patients), and comparison groups (influenza, patients affected byCAP but without microbiological diag-nosis, etc.).3–5,17–21 _{A common finding is the higher risk}

associatedtoolderage,co-morbiditiesandseverityof infec-tion.Deathrateinthebacteremicsubgrouphasbeenrelated tomalegender,renalfailure,acidosis,shock,ICUadmission, mechanical ventilation, high APACHE II score, leukopenia, leukocytosis,cancer,specificpneumococcalserotypes, inap-propriateinitialantimicrobialtherapy, andinfection witha non-susceptiblestrain.3,7,21–24 _{Inourwork,in-hospital}

mor-talitywasassociatedtothreeindependentfactors:age≥65 yearsold,CAPPIROscore>3,andaplateletcount<100,000/␮L. Thesefindingscameasnosurprisebecauseolderageisa rec-ognizedriskfactor,aCAPPIROscore>3representsaknown highriskgroupofpatientsaffectedbycommunity-acquired pneumonia,10 _{and thrombocytopenia has been}

occasion-allydescribed as arisk factor inbacteremicpatients.25 _All

together,theyreflectseverelyillpatientswithpredisposing conditions.

Theonlyindependentfactorassociatedwithintensiveor intermediatecareunitadmissionwasC-reactiveprotein.This

parametershowshighvaluesinpatientswithCAPand bac-teremiacomparedtothosewithoutthiscondition.6_Increased

valuesarealsoseeninsubjectswithCAPandsepsis6_andin

CAPcausedbyLegionellapneumophila,EnterobacteriaceaeorS. pneumoniae, but notincases associatedtovirusesor atyp-ical agents.6 _{Despite C-reactive protein notbe included in}

predictivescalesitcouldbeagood,simplebiomarkerof sever-ityinpatientswithbacteremicstreptococcalpneumoniathat deservemorestudies.However,itwillprobablynotbeof uni-versallyvalidbecauseofthelowervaluesreportedinpatients with severe viral infections,such as those withpandemic influenzaAH1N1.26

Threeseverityscoreswereanalyzedinthisworkbutthey didnodifferstatisticallyaccordingtotheAUCobservedinROC analysis.AsimilarAUCforthePIROscorereportedinpatients admittedtoICUwithCAPwasobservedinanotherstudy(0.86 vs.0.88)aswellasfortheAPACHEIIscore(0.77vs.0.75).10

Usingthesamecut-off(>3)fortheCAPPIROscoreappliedin theabovementionedreferencegaveasimilarsensitivityand specificity(85%vs.86%and,77%vs.79%). Thesepredictive scoresappeartohavesuboptimaltestpropertiesaswitnessed bytheirlimitedsensitivitiesandspecificities,andlow posi-tivepredictivevaluesandlikelihoodratios.Otherreportsfrom ChilehaveobtainedevenlowerAUCinthecaseofCURB-65 andotherpredictivescores.27_{Theselimitationssuggestthat}

thesescorescanbeanoptionwhilemanagingthesepatients onceadmitted,andclinicianscanprefertouseapredictive scalethatiseasiertocalculate.TheCURB-65scoreiscurrently usedinChileinanationalguidelineonCAPtodiscriminate andselectpatientsforappropriateambulatorytreatmentor admission.Inthiscase,thispredictivescoreisappliedonan ambulatorybasisandnotafteradmission.

Resultsof onerandomizedtrial and meta-analysis sug-gestthatcorticoidsmaybeofbenefitinseverely-illpatients

withCAP.28,29_{Wefoundthatduringthefirst72halmost40%}

ofthepatients receivedcorticoidtherapy, butnoreduction of in-hospital mortalitywas observed. According toa post hocanalysisofonerandomizedtrial,thebenefitonmortality appearstoberestrictedtoaspecificgroupofpatients charac-terizedbyhighcytokineandreducedcortisollevels.30

S. pneumoniae serotype frequencies have been scarcely described among adultpatients inLatin America.31,32 _This

information is highly necessary to evaluate the preven-tive potential of immunization programs, and changes or emergence of specific serotypes, especially after vaccine introduction.9,33_{Inacomprehensivesurveillancestudy}

con-ducted between 2000 and 2005 in several Latin America countries, 5657 pneumococcal strains from adult patients were serotyped.31_{Eleven ofthe13mostfrequentserotypes}

reportedinthatstudy,weredetectedinourseries.Thismatch isnotsurprisingsince33.5%ofthestrainsofthatsurveillance studycamefromChile.Accordingtoourfindingstheserotype coverage of the 23-valent polysaccharide vaccine and the 13-valentconjugatedvaccinewouldbe72%,and50%, respec-tively.Thesefiguresareratherdisappointingbecauseoneof themostacceptedpolyvalentpolysaccharidevaccinebenefits ispreciselytheprotectionagainstinvasiveformsofdisease, but isserotype specific.34,35 _{Thislimitation isenhancedby}

thelowimmunizationrecorddetectedinthiswork,eitherfor influenza,asapredisposingcondition,orforS.pneumoniae.A

nationalimmunizationprogramforthelatterwaslaunched in2009inChilefortheelderlypopulation,butcoveragestill remains low withless than 6%of the targetedpopulation vaccinatedby2011.Fiveserotypeshavebeenassociatedtoa higherriskofdeath(3,6A,6B,9N,19F)andthreetoalowerrisk

(1,7F,8).23,36,37_{Twenty-oneisolatesinourstudymatchedthese}

serotypesbutwedidnotfindassociationwithanadverse out-come (datanot shown). Ofinterest, onepatient with liver cirrhosishad arecurrentinfection with thesame serotype (serotype5)afterthreeyears.Althoughinfrequent,this phe-nomenonhasbeendescribedbefore.38

Lowprevalenceofantimicrobialresistanceamong pneu-mococcal isolates from adult patients in Chile has been a stable finding.39 _{Less than 1% of CSF or non-CSF}

iso-lateshaveshownresistancetopenicillinorthirdgeneration cephalosporins.Consequently,inappropriateinitialantibiotic therapydidnothaveacontributoryinfluenceintheoutcome ofourpatients,ashasbeendemonstratedinotherreports.7

Inconclusion,ourseriesofadultpatientsadmittedwith bacteremicpneumococcalpneumoniawascharacterizedby anolderageandahighprevalenceofcomorbidities,asevere clinicalcondition,frequenthospitalizationincriticalcarebeds (50%),andmechanicalventilation(30%).Someofthemhad an abrupt onset (13%) and previous immunization against influenza or S. pneumoniae was remarkably rare. Multilo-bar infiltrates were rather common (30%) and in-hospital mortality was high (33%). Cases were not associated to a fewpredominant serotypes,and no beta-lactam resistance wasobserved.MultivariateanalysisidentifiedC-reactive pro-tein>150mg/Lasthe onlyfactorassociatedtocritical care hospitalization. Inaddition, death riskwas linkedto three independentfactors:aseverity CAPPIROscore>3,age≥65 years, and platelet count<100,000/␮L. Thepredictive yield ofAPACHEII, CURB-65andCAPPIROscoreswasnot statis-tically different, but demonstrated suboptimal sensitivities andspecificitiesorpositivelikelihoodratios.Also,aseasonal patternwasobserved,withhigherincidenceofcasesduring mid-fallandearlywinter.Finally,anon-significantdecreasing trend of bacteremic pneumococcal pneumonia cases was observedthroughthestudyyearsthatparalleledareduction inmortalityduetopneumoniainelderlypatientsinChile.

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