www.jped.com.br
ORIGINAL
ARTICLE
Risk
factors
for
candidemia
mortality
in
hospitalized
children
夽
Fabio
Araujo
Motta
a,b,c,∗,
Libera
Maria
Dalla-Costa
b,c,d,
Marisol
Dominguez
Muro
b,c,d,
Mariana
Nadal
Cardoso
a,
Gledson
Luiz
Picharski
b,c,
Gregory
Jaeger
b,
Marion
Burger
eaHospitalPequenoPríncipe,Curitiba,PR,Brazil bFaculdadesPequenoPríncipe,Curitiba,PR,Brazil
cInstitutodePesquisaPeléPequenoPríncipe,Curitiba,PR,Brazil
dUniversidadeFederaldoParaná(UFPR),HospitaldeClínicas,Curitiba,PR,Brazil eSecretariaMunicipaldaSaúdedeCuritiba,Curitiba,PR,Brazil
Received12February2016;accepted11May2016 Availableonline3October2016
KEYWORDS Candidemia; Pediatricmortality; Bloodstream infection; Bloodculture
Abstract
Objective: Toevaluateriskfactorsassociatedwithdeathduetobloodstreaminfectioncaused byCandidaspp.inpediatricpatientsandevaluatetheresistancetothemainanti-fungalused inclinicalpractice.
Methods: Thisisacross-sectional,observational,analyticalstudywithretrospectivecollection thatincluded65hospitalizedpediatricpatientswithbloodstreaminfectionbyCandidaspp.A univariateanalysiswasperformedtoestimatetheassociationbetweenthecharacteristicsof thecandidemiapatientsanddeath.
Results: Theincidenceofcandidemiawas0.23casesper1000patients/day,withamortality rate of 32% (n=21). Clinical outcomessuch as sepsis and septic shock (p=0.001), comor-bidities suchasacuterenalinsufficiency(p=0.01),andriskssuchasmechanicalventilation (p=0.02)anddialysis(p=0.03)areassociatedwithincreasedmortalityinpediatricpatients. Theresistanceanddose-dependentsusceptibilityratesagainstfluconazolewere4.2%and2.1%, respectively.NoresistancetoamphotericinBandechinocandinwasidentified.
Conclusion: Datafromthisstudysuggestthatsepsisandsepticshock,acuterenalinsufficiency, andrisks likemechanicalventilationanddialysis areassociated withincreasedmortalityin pediatricpatients.Themortalityamongpatientswithcandidemiaishigh,andthereisnospecies
夽
Pleasecitethisarticleas:MottaFA,Dalla-CostaLM,MuroMD,CardosoMN,PicharskiGL,JaegerG,etal.Riskfactorsforcandidemia mortalityinhospitalizedchildren.JPediatr(RioJ).2017;93:165---71.
∗Correspondingauthor.
E-mail:fabio.motta.hpp@gmail.com(F.A.Motta).
http://dx.doi.org/10.1016/j.jped.2016.05.007
0021-7557/©2016SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND
differenceinmortalityrates.Regardingtheresistancerates,itisimportanttoemphasizethe presenceoflowresistanceinthisseries.
©2016SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
PALAVRAS-CHAVE Candidemia; Mortalidade pediátrica;
Infecc¸ãodacorrente sanguínea;
Hemocultura
Fatoresderiscodemortalidadeporcandidemiaemcrianc¸asinternadas
Resumo
Objetivo: Avaliarosfatoresderiscoassociadosaoóbitoporinfecc¸ãodacorrentesanguínea cau-sadapelaCandidasppempacientespediátricoseavaliararesistênciaaoprincipalantifúngico usadonapráticaclínica.
Métodos: Esteéumestudotransversal,observacionaleanalíticocomcoletaretrospectivaque incluiu65pacientespediátricosinternadoscominfecc¸ãodacorrentesanguíneaporCandida
spp.Foirealizadaumaanáliseunivariadaparaestimaraassociac¸ãoentreascaracterísticasdos pacientescomcandidemiaeoóbito.
Resultados: Aincidênciadecandidemiafoide0,23casosemcada1000pacientes/dia,comtaxa demortalidadede32%(n=21).Oresultadoclínicocomo sepseechoqueséptico(p=0,001), comorbidades como insuficiência renal aguda (p=0,01) e riscos como ventilac¸ão mecânica (p=0,02)ediálise(p=0,03)estãoassociadosaoaumentodamortalidadeempacientes pediátri-cos.Astaxasderesistênciaesusceptibilidadedose-dependentecontraofluconazolforamde 4,2%e 2,1%, respectivamente.Não foi identificadanenhuma resistência àanfotericina B e equinocandina.
Conclusão: Osdadosdenossoestudosugeremqueasepseechoqueséptico,insuficiênciarenal agudaeriscoscomoventilac¸ãomecânicaediáliseestãoassociadosaoaumentodamortalidade empacientespediátricos.Amortalidadeentrepacientescomcandidemiaéalta,enãohá nen-humadiferenc¸anastaxasdemortalidadeentreasespécies.Sobrearesistência,éimportante enfatizarapresenc¸adebaixaresistêncianestasérie.
©2016SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Este ´eumartigo OpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4. 0/).
Introduction
Infection by Candida spp. is a significant cause of mor-bidity and mortality among hospitalized children, with a mortality rate ranging from 10% to 47%1,2 Current changesin theprevalence ofCandidaspp. in Latin Amer-icaandBrazil have transitioned fromCandidaalbicans to non-C.albicans.3,4
A recent laboratory surveillance study presented the epidemiologyof candidemia in Latin America.This report draws attention to the high percentage of candidemia episodesamongchildren (approximately 45%), in contrast witha patient series publishedin Europe and the United States.5
Moststudiesofriskfactorsformortalityinpatientswith candidemia have focused on adult populations. However, risk factors for mortality identified in adults may not be relevant in pediatric patients, and studies defining these risks and resistance data in the pediatric population are alsolimited.1,5
Theobjectiveofthisstudywastoevaluateriskfactors associatedwithdeathduetobloodstreaminfectioncaused byCandidaspp.inpediatricpatientsandevaluatethe resis-tancetothemainanti-fungalusedinclinicalpractice.
Methods
Studysetting
This is a series of cases of pediatric patients with posi-tivebloodcultureforCandidaspp.conductedinatertiary carechildren’shospitalwith400 beds.Datafrompatients withagesranging from0 to18 yearswhopresented with candidemiawereverifiedaspositivebloodculturesfor Can-didainsamplescollectedfromperipheralveinorvascular catheter. The studied included patients hospitalizedfrom September2008uptoSeptember2011.
Studydesignandfungalsamples
In addition, to evaluate the presence of associated bacteremia (beforeand after candidemia) and persistent candidemia,potentialriskssuchasuseofmechanical ven-tilation, total parenteral nutrition, use of central venous catheter,anddialysiswerealsoconsidered.Thedatawere usedtoassesstherelativemortalityrisk,andtheantifungal treatmentanditseffects.
Theseverityofillnessatthetimeofcandidemiahasalso been reportedas arisk factor for mortality.The patients were evaluated for the presence of fever, hypotension, and/or septic shock signs (hypothermia or hyperthermia, alteredmentalstatus,andperipheralvasodilationor vaso-constriction)inaccordancewithcriteriaestablishedin2009 byBrieleyetal.6
Allsampleswerecollectedbeforetheadministrationof antifungaldrugstopatientspresentingfeverandsuspected offungemia,whounderwentantibiotictherapy,andhada prolongedhospitalstay.
Microbiologystudies
Blood cultures of all 65 cases were performed using a BD BACTEC 9120 Blood Culture System (Becton Dickin-son,FranklinLakes,USA).TheVitek-2system(bioMérieux, Durham, USA) was used for species identification. Sus-ceptibility tests to antifungals were performed in 47 samples.TestsforamphotericinB(Sigma---AldrichQuimica, Madri,Spain),fluconazole(Pfizer,Madrid,Spain), micafun-gin(Mycamine®;AstellasPharmaInc.,Toyama,Japan),and
anidulafungin (Ecalta-Pfizer, Kent, United Kingdom) were performedusingthebrothmicrodilutionmethodaccording totheM27-S4protocols(2012)oftheClinicalandLaboratory StandardsInstitute.7
Statisticalanalysis
A univariate analysis was performed to determine the associationbetween thecharacteristicsofthecandidemia patients and death. Categorical variables were compared by using Fisher’sexact test or the chi-squared test, with a significance level of p<0.05. Statistical analyses were performed using R software (R Foundation for Statistical Computing,Vienna,Austria).
Duetothecomplexityofthecombinationsandthesmall number of cases for some categories, the analysisof the variable‘‘priorpathologicalcondition’’wasperformedby usingpatientgroupswithatleastoneofthefollowing con-ditions:prematurity,positivehumanimmunodeficiencyvirus (HIV), heart failure, pulmonary disease, neurological dis-ease,transplantation,acuteandchronicrenalinsufficiency, mucositis,and/orcancer,foracomparisonwiththepatients withother isolated or associated pathological conditions. The sameapproachwasusedfor theanalysisof potential riskfactors(neutropenia,parenteralnutrition,mechanical ventilation,and/ordialysis).
ThestudywasapprovedbytheInstitutionalReviewBoard oftheHospital.
Table1 Speciesdistributionof65episodesofcandidemia identifiedbyVitek-2.
Species Numberofisolates Percentage
C.albicans 24 37%
C.parapsilosis 20 31%
C.tropicalis 5 8%
C.guilliermondii 3 5%
C.haemulonii 3 5%
C.krusei 2 3%
C.glabrata 2 3%
Othersa 6 12%
a Otherspecies---C.lusitaniae(1),C.pelliculosa(1);C.
inter-media(1),C.famata(1),C.norvegiensis(1);C.lipolytica(1).
Results
Thestudyincluded 65patientswithcandidemia,in accor-dancewiththeaforementionedinclusioncriteria.Themean agewas3.3years(SD±1.8)andmedian,1.5years(range, 0---15.7years).Thirty-eightepisodes(58.5%)ofcandidemia occurredinchildren youngerthan2years,includingeight newborns, and 27 episodes (41.5%) occurred in children olderthan2yearsold,whichincludeten(15.4%)inpreschool age.Thirty-seven (57%)of thepatients weremaleand28 (43%)werefemale.Theincidenceofcandidemia was0.23 casesper1000patients/dayand0.9casesper1000 admis-sions,withamortalityrateof32%(n=21).
AmicrobiologicalsummaryoftheCandidaspp.isolated ispresentedinTable1.OnlyoneCandidaspp.wasisolated fromeachcase,exceptonecaseofmixedCandidaspp.and bacteria-positivebloodcultures.
Uponconsiderationoftheclinicalsymptomsatthetime ofcandidemia,patientswhopresentedwithsepsisor sep-tic shock had an increased mortality rate, whereas the patients who only presented fever had a lower mortality rate(p=0.001).
Regarding pathological conditionsprior to candidemia, it wasnoted that patients with acute renal insufficiency, whetherornotincombinationwithotherpathological con-ditions,wereassociatedwithincreasedmortality(p=0.01). Risk factors like mechanical ventilation (p=0.03) and dialysis(p=0.02),whetherornotincombinationwithother factors, were associated with increased mortality in the analysis.
Table2summarizesthemaindemographicdataand clin-icalcharacteristicsofthepatientsassociatedwithdeathor survivaloutcomes.
Upon consideration of the variable blood culture con-ductedwithin30daysofcandidemia,asignificantp-value (p=0.001) demonstrated increasedmortality inthe group withpositivebloodcultureforCandidaspp.and/orbacteria. Aftertheinitiationof antifungaltreatment, controlblood cultures were collected from 55 of the 65 patients with candidemia,whiletheremainingpatientswereeither dis-chargedfromthehospital(n=3)or died(n=7)duringthe periodofcandidemiadiagnosis.
Table2 Demographicdata,clinicalcharacteristics,andclinicaloutcomeinhospitalizedpediatricpatientswithcandidemia. Variable Numberofpatients Percentageof
death(%)
p-Value
Survival Death Total(%)
Age 0.12
<28days(neonatal) 3 5 8(12.3) 62.5
28daysto2years 20 10 30(46.2) 33.3
>2years 21 6 27(41.5) 22.2
Identifiedspecies 0.79
C.albicans 17 7 24(36.9) 29.2
Otherspecies 27 14 41(63.1) 34.1
Associatedbacteremiapriororduring candidemia
0.52
Yes 11 3 14(21.5) 21.4
No 33 18 51(78.5) 35.3
Bloodcultureperformedwithin30daysafter candidemia
0.001
No 3 7 10(15.4) 70.0
Yes,negative 27 2 29(44.6) 6.9
Yes,positiveforbacteria 5 4 9(13.8) 44.4
Yes,positiveforCandidaofthesamespecies 9 8 17(22.1) 47.1
Hospitalunit 0.11
Non-ICU 25 7 32(49.2) 21.8
ICU 19 14 33(50.8) 42.4
Severityofillness(fever,hypotension,septic shock)
0.001
Other(hypotensionand/orsepticshock) 4 10 14(21.9) 71.4
Onlyfever 28 4 32(50) 12.5
Noneoftheabove 11 7 18(28.1) 38.9
Catheter(CVC,PICC,arterial,ortotally implantedcatheter)
0.78
Yes 30 13 43(66.2) 30.2
No 14 8 22(33.8) 36.4
Priorpathologicalconditionsa
Group1 0.71
Priorpathologicalconditionsexcept pulmonarydisease
36 16 52(83.9) 30.8
Atleastpulmonarydisease 6 4 10(16.1) 40.0
Group2 0.75
Priorpathologicalconditionsexcept neurologicaldisease
33 15 48(77.4) 31.3
Atleastneurologicaldisease 9 5 14(22.6) 35.7
Group3 0.27
Priorpathologicalconditionsexceptmucositis 37 15 52(83.9) 28.8
Atleastmucositis 5 5 10(16.1) 50.0
Group4 0.01
Priorpathologicalconditionsexceptacute renalinsufficiency
40 14 54(87.1) 25.9
Atleastacuterenalinsufficiency 2 6 8(12.9) 75.0
Group6 0.74
Priorpathologicalconditionsexceptcancer 34 15 49(79) 30.6
Atleastcancer 8 5 13(21) 38.5
Potentialriskfactors(RF)b
Group1 0.42
Other(parenteralnutrition,mechanical ventilation,and/ordialysis)
Table2 (Continued)
Variable Numberofpatients Percentageof death(%)
p-Value
Survival Death Total(%)
NoneoftheassessedRF 20 7 27(41.5) 25.9 Atleastcneutropenia 9 3 12(18.5) 25.0
Group2 0.39
Other(mechanicalventilation,dialysis, and/orneutropenia)
15 6 21(32.3) 28.6
NoneoftheassessedRF 20 7 27(41.5) 25.9
Atleastparenteralnutrition 9 8 17(26.2) 47.1
Group3 0.02
Other(parenteralnutrition,dialysis,and/or neutropenia)
13 2 15(23.1) 13.3
NoneoftheassessedRF 20 7 27(41.5) 25.9
Atleastmechanicalventilation 11 12 23(35.4) 52.2
Group4 0.03
Other(parenteralnutrition,mechanical ventilation,and/orneutropenia)
23 9 32(49.2) 28.1
NoneoftheassessedRF 20 7 27(41.5) 25.9
Atleastdialysis 1 5 6(9.2) 83.3
ICU,intensivecareunit;CVC,centralvenouscatheter;PICC,peripheralimplantedcentralcatheter.
a Priorpathologicalconditions:pulmonarydisease,prematurity,cancer,humanimmunodeficiencyvirus(HIV),heartdisease,
neurolog-icaldisease,transplantation,acuteandchronicrenalinsufficiency,mucositis,and/orneutropenia.
b Potentialriskfactors:parenteralnutrition,mechanicalventilation,dialysis,andneutropenia.
c Atleast:thepatienthasatleastoneriskfactorassessed,whetherornotcombinedwithotherfactors.
previousabdominalsurgery,whichhavenotbeenassociated withincreasedmortality.
Similarly, due to the increase of non-albicans spp. in recentyears,univariateanalysesbetweenthealbicansand
non-albicansspp.wereperformedandnoincreased
mortal-itywasobserved.
Antifungigramperformedon47Candidasamplesfounda dose-dependentsusceptibility tofluconazolein onestrain
of C. glabrata. One sample of isolated C. glabrata and
C. albicans presented resistance to fluconazole, with a
minimum inhibitory concentration (MIC) of 64g/mL and 32g/mL, respectively(Clinicaland Laboratory Standards Institute,CLSI;2012).7NoresistancetoamphotericinBand echinocandinwasidentifiedinthe47samplestested.
Therefore,theresistanceanddose-dependent suscepti-bilityrates againstfluconazolewere4.2%(2/47)and 2.1% (1/47),respectively.
In this series, the most frequently antifungal therapy used was amphotericin B deoxycholate (60.0%), followed by fluconazole (38.0%), either alone or in combination. Six patients (9.2%) received amphotericin Bdeoxycholate and fluconazole in combination, and five patients (7.6%) received fluconazole followed by amphotericin B deoxy-cholate.Liposomal amphotericin Bwasused intwo cases andcaspofungininonecase.
Discussion
Significantdatawereproducedregardingmortalityandrisk factorsfor mortalityin thisseriesof65pediatricpatients withinvasivecandidemia.
Therearefewworksthathavestudiedunselected pedi-atric populations with invasive candidiasis/candidemia in Europeand in Latin America. In 2012, Tragiannidiset al. published the first series of cases in Germany describ-ingmicrobiological and clinical epidemiology.8 Pasqualoto etal.,in2007,heldthefirstpublishedBrazilianstudyonrisk factorsformortalityinanunselectedpediatricpopulation.4 Thepresentseriesof65casesisthesecondBrazilian pub-lication,totheauthors’knowledge,regarding riskfactors formortalityinpediatricpatientswiththesame character-istics.
This study demonstrated that patients who presented exclusivelywithfeverhadalowermortalityratethanthose withseveresignssuchassepsisorsepticshockwithor with-out fever. These severe signs are per se considered risk factorsfordeath.Ontheotherhand,thepresenceoffever mayhaveattractedpersistentattentionofthephysiciansin chargetolookmore extensivelyfora causeand,inthese patients,allowed earlier diagnosis of candidemia, provid-ingthemwithappropriatemedications,leadingtoabetter outcome.
Apriorpathologicalconditionconsideredasanotherrisk factor for mortality was acute renal insufficiency, which increased patient mortality whether or not in combina-tionwithotherpathologicalconditions.Recently,Santolaya etal.showedthesameresultinaseriesofchildrenpatients fromLatinAmerica.9
analyzed pediatric mortality fromCandida infection have notdemonstratedtheassociationbetweendialysisand mor-tality,asthepresentstudyhas.
Hammoud etal.10 reportedthat persistent candidemia wasassociatedwithanincreasedriskofdeath.Incontrast, Robinsonetal.11 observedthatanincreasein theinterval betweenbloodcultureandthebeginningofantifungal ther-apy(>1day)innewbornswasassociatedwithanincreased incidenceof persistentcandidemia,thoughnotassociated withincreasedmortality.
Thepresentstudyshowedanincreasedmortalityinthe patientgroupwithapositiveblood culturewithin30days after candidemia, regardless whether the positive results wereforCandidaspp.and/orbacteria.Threepatientshad threepositivebloodculturesforCandida,takingonaverage tendaystoobtainnegativebloodcultures.However,there wasalimitationregardingtheabsenceofcatheter manage-ment information, and it is possible that this increase in mortalitycouldbelinkedwithcathetermaintenanceinthe patient.Even so,it isimportanttohighlightthatthatthe promptremovaloflineswithinitiationofantifungal treat-mentarethecornerstones ofmanagement,in additionto performingacontrolbloodcultureevery72hafterthefirst Candida-positiveresult,untiltwonegativebloodcultures.12 Analyzing mortality and Candida spp. showed no dif-ferencebetween albicansand non-albicans spp. However, previous studies have suggested that C. parapsilosis is a lessvirulentspecies,andC.parapsilosisfungemiainadults andchildren is associated withlowermortality than non-parapsilosiscandidemia.9,13,14Itisprobablethatthisresult ofnodifferencebetweenspeciesinthepresentstudyisdue tolowervirulenceattributedC.parapsilosisspp.,whichin thepresentseriesrepresented31%ofisolatedCandidaspp. Differently,Santolayaetal.linkedmortalitywithC.albicans inneonatesandC.tropicalisinchildren.7
Diseasescausedbyspeciescommonlyresistanttoazoles wereextremelyrareamongpediatriccandidemia.15 Inthis series,therewasonlyonecaseofdose-dependentreduced susceptibilityto fluconazol and twocases withfluconazol resistance.Nevertheless,mostpatients(60%)weretreated withamphotericin B deoxycholate and only 38% with flu-conazol (alone or in combination therapy), following the orientationofinstitutional protocol,sincea largenumber ofpatientshadfailedtherapy withfluconazoleinCandida sepsiscases.Echinocandinshavebeenrecentlyintroduced astreatmentinlife-threateningcases(after2012).Recently, Herkertetal.16 showeddisturbingCandidaresistancerates to echinocandins in a university hospital, reflecting the impactofextensive useoftheseantifungalagentsas pro-phylactics.
Thereweresomepotentiallimitationsinthisstudy.The firstlimitationisrelatedtothenumberofpatientsincluded, since this study wasconducted in one site only. Second, ideally more information regarding the candidemia diag-nosis would be available. In cases where the blood was obtained through the catheter, it is impossible to know whetherthis represents true candidemia or catheter col-onization.Besidesthis,itwouldbeimportanttoknowhow manypatients werediagnosedbyobtaining blood through thecatheter,aswellasthecathetermanagementonce can-didemiahadbeendiagnosed.Afterall,C.parapsilosiswas thesecondmostfrequentCandidaspp.inthisseries.
In conclusion, data from this study suggest that sep-sis and septic shock, acute renal insufficiency, and risks like mechanical ventilation and dialysis are associated with increased mortality in pediatric patients. The mor-tality among patients with candidemia is high, and there is no species difference in mortality rates. The results alsoconfirm theelevated incidenceofbloodstream infec-tionscausedbyCandidaspp.other thanCandidaalbicans. Regardingtheresistancerates,itisimportanttoemphasize thepresenceoflowresistanceinthisseries.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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