Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in

19 Pages·2015·1.98 MB·English

RESEARCHARTICLE
Meta-Analysis and Cost Comparison of
Empirical versus Pre-Emptive Antifungal
Strategies in Hematologic Malignancy
Patients with High-Risk Febrile Neutropenia
MonicaFung1,2☯*,JaneKim3‡,FranciscoM.Marty2,4,5‡,MichaëlSchwarzinger6,7,8‡,
SophiaKoo2,4,5☯
1 BethIsraelDeaconessMedicalCenter,DepartmentofInternalMedicine,Boston,Massachusetts,United
StatesofAmerica,2 HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3 Harvard
T.H.ChanSchoolofPublicHealth,DepartmentofHealthPolicyandManagement,Boston,Massachusetts,
UnitedStatesofAmerica,4 BrighamandWomen’sHospital,DivisionofInfectiousDiseases,Boston,
Massachusetts,UnitedStatesofAmerica,5 Dana-FarberCancerInstitute,Boston,Massachusetts,United
StatesofAmerica,6 TranslationalHealthEconomicsNetwork,Paris,France,7 DecisionSciencesin
InfectiousDisease:Prevention,Control,andCare,INSERM,IAME,Paris,France,8 UniversitéParisDiderot,
IAME,Paris,France
OPENACCESS ☯Theseauthorscontributedequallytothiswork.
‡Theseauthorsalsocontributedequallytothiswork.
Citation:FungM,KimJ,MartyFM,SchwarzingerM,
*[email protected]
KooS(2015)Meta-AnalysisandCostComparisonof
EmpiricalversusPre-EmptiveAntifungalStrategiesin
HematologicMalignancyPatientswithHigh-Risk
FebrileNeutropenia.PLoSONE10(11):e0140930. Abstract
doi:10.1371/journal.pone.0140930
Editor:DavidNFredricks,FredHutchinsonCancer
Center,UNITEDSTATES
Received:July21,2015 Background
Accepted:October1,2015 Invasivefungaldisease(IFD)causessignificantmorbidityandmortalityinhematologic
Published:November10,2015 malignancypatientswithhigh-riskfebrileneutropenia(FN).Thesepatientsthereforeoften
receiveempiricalantifungaltherapy.Diagnostictest-guidedpre-emptiveantifungaltherapy
Copyright:©2015Fungetal.Thisisanopen
accessarticledistributedunderthetermsofthe hasbeenevaluatedasanalternativetreatmentstrategyinthesepatients.
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany
medium,providedtheoriginalauthorandsourceare
credited. Methods
DataAvailabilityStatement:Allrelevantdataare Weconductedanelectronicsearchforliteraturecomparingempiricalversuspre-emptive
withinthepaperanditsSupportingInformationfiles. antifungalstrategiesinFNamongadulthematologicmalignancypatients.Wesystemati-
Funding:SophiaKooissupportedbyK23AI097225 callyreviewed9studies,includingrandomized-controlledtrials,cohortstudies,andfeasibil-
fromtheNationalInstituteofAllergyandInfectious itystudies.Randomandfixed-effectmodelswereusedtogeneratepooledrelativerisk
Diseases(http://www.niaid.nih.gov/).Thefunderhad
estimatesofIFDdetection,IFD-relatedmortality,overallmortality,andratesanddurationof
noroleinstudydesign,datacollectionandanalysis,
decisiontopublish,orpreparationofthemanuscript. antifungaltherapy.HeterogeneitywasmeasuredviaCochran’sQtest,I2statistic,and
MichaëlSchwarzingerisemployedbythecompany betweenstudyτ2.Incorporatingtheseparametersanddirectcostsofdrugsanddiagnostic
TranslationalHealthEconomicsNetwork.Thisfunder
testing,weconstructedacomparativecostingmodelforthetwostrategies.Weconducted
providedsupportintheformofsalaryforDr.
probabilisticsensitivityanalysisonpooledestimatesandone-waysensitivityanalyseson
Schwarzinger,butdidnothaveanyadditionalrolein
thestudydesign,datacollectionandanalysis, otherkeyparameterswithuncertainestimates.
PLOSONE|DOI:10.1371/journal.pone.0140930 November10,2015 1/19
EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
decisiontopublish,orpreparationofthemanuscript. Results
Thespecificrolesofthisauthorarearticulatedinthe
‘authorcontributions’section. Ninepublishedstudiesmetinclusioncriteria.Comparedtoempiricalantifungaltherapy,
pre-emptivestrategieswereassociatedwithsignificantlylowerantifungalexposure(RR
CompetingInterests:MichaëlSchwarzingeris
0.48,95%CI0.27–0.85)anddurationwithoutanincreaseinIFD-relatedmortality(RR0.82,
employedbythecompanyTranslationalHealth
EconomicsNetwork.Thisdoesnotaltertheauthors' 95%CI0.36–1.87)oroverallmortality(RR0.95,95%CI0.46–1.99).Thepre-emptivestrat-
adherencetoPLOSONEpoliciesonsharingdata egycost$324less(95%credibleinterval-$291.88to$418.65pre-emptivecomparedto
andmaterials.
empirical)thantheempiricalapproachperFNepisode.However,thecostdifferencewas
influencedbyrelativelysmallchangesincostsofantifungaltherapyanddiagnostictesting.
Conclusions
Comparedtoempiricalantifungaltherapy,pre-emptiveantifungaltherapyinpatientswith
high-riskFNmaydecreaseantifungalusewithoutincreasingmortality.Wedemonstratea
stateofeconomicequipoisebetweenempiricalanddiagnostic-directedpre-emptiveanti-
fungaltreatmentstrategies,influencedbysmallchangesincostofantifungaltherapyand
diagnostictesting,inthecurrentliterature.Thisworkemphasizestheneedforoptimization
ofexistingfungaldiagnosticstrategies,developmentofmoreefficientdiagnosticstrategies,
andlesstoxicandmorecost-effectiveantifungals.
Introduction
Invasivefungaldisease(IFD)isanimportantcauseofmorbidityanddeathinhematologic
malignancyorhematopoieticstem-celltransplantation(HSCT)patientswithhigh-riskfebrile
neutropenia(FN)[1–6].Theseinfectionsconferasubstantialeconomicburdendueto
increasedhospitalstaysanddrugcosts[7,8].
PromptinitiationofappropriateantifungaltherapyearlyinthecourseofIFDreducesIFD-
relatedmortality.BecauseoftheconsequencesofnottreatingIFDearlyandlimitationsin
existingIFDdiagnosticmethods,manypatientswithhigh-riskneutropeniaandpersistentor
recurrentfeversdespitebroad-spectrumantibiotictherapyreceiveempiricantifungaltherapy
[4,9].
EarlyIFDdiagnosisremainschallengingbecauseofthelowsensitivityandspecificityof
clinicalsymptoms,microbiologicalcultures,andradiologictoolsforIFD.Non-culture-based
techniqueshavebeendevelopedtoidentifyAspergillusspeciesandotherfungi,includingdetec-
tionofcirculatingAspergillusgalactomannan[10–12]andfungal(1!3)-β-D-glucanantigens
[13–15],andpolymerasechainreaction(PCR)assaystargetingAspergillusnucleicacid
sequences[16].Thesetests,inconjunctionwithhigh-resolutionchestcomputedtomography
(CT),arefrequentlyusedtodiagnoseIFDinpatientswithhigh-riskFN[17,18].
GiventhesedevelopmentsinIFDdiagnostictestingandthetoxicityandcostsofprolonged
antifungalexposure,diagnostictest-guidedpre-emptiveantifungaltherapyhasbeenevaluated
asanalternativestrategytoempiricalantifungaltherapy.Reservingantifungaltherapyforthe
subsetofpatientswhohaveearlyevidenceofIFDbycarefulclinicalassessmentsandserialfun-
galbiomarkerevaluationsmightreduceantifungaldruguseanditsattendanttoxicityandcosts
withoutincreasingIFD-relatedmorbidityormortality.
Studiesofvaryingdesignhaveevaluatedthefeasibilityandclinicaleffectivenessofempirical
andpre-emptiveapproachesforantifungaltherapyinFNpatients[19–23].Here,weuseasys-
tematicapproachtosummarizetheexistingliteratureonIFDoutcomesandantifungaluse
PLOSONE|DOI:10.1371/journal.pone.0140930 November10,2015 2/19
EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
withempiricalversuspre-emptiveantifungalstrategiesinhematologicmalignancyandHSCT
patientswithhigh-riskFN,andincorporatethesedataintoadecisionanalysismodeltocom-
paretherelativeeconomicburdenofthesetwostrategies.
Methods
SystematicReview/Meta-Analysis
Wesearchedelectronicallyforpublishedorpubliclypresentedscientificliteraturecomparing
empiricalandpre-emptivestrategiesfortreatingadulthematologypatientswithhigh-riskFN
[9].UsingPubMed,wesearchedforcombinationsoftermsincluding“invasivefungaldisease,”
“hematologicmalignancy,”“pre-emptive,”“diagnostic-directed,”“febrileneutropenia,”and
“antifungal”tofindpublishedliteraturefromJanuary1990toJune2015.Amanualsearchof
thereferencelistsofselectarticleswasalsoconducted.Wesearchedforabstractsfrommajor
scientificmeetings,includingtheInterscienceConferenceonAntimicrobialAgentsandChe-
motherapy,InfectiousDiseasesWeekConference,andtheInfectiousDiseaseSocietyofAmer-
ica(IDSA),AmericanSocietyofClinicalOncology,andAmericanSocietyofHematology
AnnualMeetings.Forconferenceabstractsmeetingoursearchcriteria,postersorpresentations
werereviewedtofacilitatedataabstraction.Thisstudyisnotincludedinasystematicreview
registry.
Datawereextractedindependentlybyprimaryresearchers,andcross-checkedbyother
investigators.OutcomesmeasuredincludedIFDdetection,IFD-relatedmortality,andratesof
“pre-IFDdiagnosis”empiricalantifungaltherapy,definedasantifungaltherapyadministered
priortothestartoftreatmentforincidentprobableorprovenIFD[24].Whentheseoutcomes
werenotexplicitlyreportedintheprimaryliterature,wecalculatedtheseparametersusing
reporteddata.WeusedMantel-Haenszel(M-H)fixed-effectsandDersimonian-Laird(D-L)
randomeffectsmodelstogeneratepooledestimatesofoutcomes,representedasrelativerisks
(RR)and95%confidenceintervals(95%CI)comparingpre-emptivetoempiricalstrategies.
WeassessedheterogeneitybycalculatingCochran'sQ,I-squared,andthebetween-study
variancetau-squared.Biaswasassessedatthestudylevel.Specifically,weusedtheCochrane
Collaboration’s“RiskofBias”tooltoassessbiasinrandomizedcontrolledstudiesandtheNew-
castle-OttawaScaletoassessforriskofbiasedinnon-randomizedstudies.Asobservational
studiesareathigherriskofbeingbiased,arestrictedanalysiswasconducted,onlyincluding
morerobustrandomized-controlledstudies.AllstatisticalanalyseswereconductedusingStata
13software.
CostComparison
Wecreatedadecisiontreemodel(TreeAgePro2015,TreeAgeSoftware,Inc,Williamstown,
MA)andconductedacostanalysiscomparingtwostrategiesforantifungaltherapyamong
neutropenicpatientswithhematologicmalignancyorHSCTathighriskforIFD:(1)anempir-
ical(fever-directed)approach,inwhichpatientsfebrileafter4daysofbroad-spectrumantibi-
oticsstartempiricalantifungals[9],and(2)apre-emptive(diagnostictest-based)approach,in
whichpatientsstartpre-emptiveantifungaltherapyiftheydevelopapositiveserumgalacto-
mannantestandpneumoniaonchestimaging.Patientsinbothgroupsreceivesubsequent
treatmentantifungalsiftheydevelopincidentprovenorprobableIFD[24].Specifically,we
reporttheincrementalcostdifference(in2014U.S.dollars)ofpre-emptiveversusempirical
treatmentstrategiesperpatientwithaprolongedFNepisode(startingat>4days)for(a)the
pre-emptiveorempiricalperiodaloneand(b)theoveralltreatmentperiod,includingtreat-
mentofincidentprovenorprobableIFD.
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EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Fig1showsthestructureofourcostcomparisonmodel.Basedonourmeta-analysis,we
assumednodifferenceinoverallIFD-relatedmorbidityormortalitybetweenthegroups.We
alsoassumednodifferenceinthediagnostictestingstrategybutdidassumeadifferenceinthe
detectionanddurationofpre-emptiveversusempiricalantifungalusepriortodiagnosisof
incidentIFD(basedonpooledRRestimatesfromourmeta-analysis).
Basedonoursystematicreviewandmeta-analysis,thediagnostictestingstrategyinboth
groupsconsistedoftwoserumgalactomannantestsperweekofFNbeyond4daysandone
high-resolutionchestCTperFNepisode.Basecasediagnostictestingassumptionsfactoredin
therealitythatmanyempiricalstrategiesincorporatediagnostictesting[20].Neutropenia
durationwasassumedtobe18daysinbothgroups[25–28],withinitiationofeitherempirical
orpre-emptiveantifungaltherapyafterthefirst4days.
AntifungalagentsinpatientswithprovenorprobableIFD,accordingto2008European
OrganizationforResearchandTreatmentofCancer/MycosesStudyGroup(EORTC/MSG)
consensusdefinitions[24],wereassumedtobethesameinthetwogroups.Thebasecase
choiceanddistributionofantifungalagentsforempiricalandpre-emptivetherapyandfor
treatmentofprovenorprobableIFDweredefinedbyIDSAtreatmentguidelinesfortreatment
ofinvasiveaspergillosis[4,9]andbyagroupofInfectiousDiseasesphysiciansandclinical
pharmacistswithexpertiseincaringforhematologyandHSCTpatientswithFNatBrigham
andWomen’sHospitalandDana-FarberCancerInstitute.Thedurationoftreatmentforinci-
dentIFDwasdefinedas12weeks(84days)[4,9].Importantly,toxicitywasnotincorporated
intothismodelgivenevidencefromoursystematicreviewshowingnosignificantdifferencein
amphotericin,echinocandin,orazole-relatedrenalorhepatictoxicitybetweenpatientsreceiv-
ingantifungaltherapyonanempiricalorpre-emptivebasis[29,30].
Fig1.Costcomparisonmodelofempiricalversuspre-emptiveantifungaltherapyinhigh-riskneutropenicpatients.
doi:10.1371/journal.pone.0140930.g001
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EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Otherwise,pertherandomizedtrialsinoursystematicreview[26,31],baselinecharacteris-
ticsofthetwoantifungaltherapygroups—age,gender,oncologicdiagnosis,andphaseofther-
apy(induction,relapse,consolidation,andtransplantation)—wereassumedtobesimilar.We
alsoassumedhealthcareutilizationandhealthoutcomesofthetwogroupsbeyondspecified
differencesintheantifungaltherapeuticstrategyandmeasuredclinicaloutcomesweresimilar.
Directcostsfordiagnosticimagingwerederivedfromapublicly-availabledatabaseon
healthcarecosts[32].ThecostofserumgalactomannantestingwasderivedfromtheBrigham
andWomen’sHospitalandDana-FarberCancerInstitutelaboratorycosts.Antifungaldrug
costswerebasedonaveragewholesalepricefromtheRedBook[32].
Weconductedaprobabilisticsensitivityanalysis(second-orderMonteCarlosimulation)
with10,000simulationsandlognormaldistributionsonpooledRRestimatesinourmodelto
calculate95%credibleintervalsfortheincrementalcostdifferencebetweenpre-emptiveand
empiricalantifungalstrategies.Wealsoconductedbest-andworst-caseanalysesarounddiag-
nostictestingstrategyandantifungaldrugcosts(usingtheleastandmostcostlyantifungal
agents).Finally,weconductedsensitivityanalysesusingonlyparametersderivedfromlarge
randomizedcontrolledtrialsofempiricalversuspreemptiveantifungalstrategies.
Results
SystematicReview/Meta-Analysis
Ourinitialqueryreturned172studies.Ofthese,tenpublishedarticlesmetourinclusioncrite-
ria,presentingprimaryliteraturecomparingempiricalandpre-emptiveantifungaltreatment
strategyinhematologicmalignancyorHSCTpatientswithhigh-riskFN.Onestudywasfur-
therexcludedduetouncertaintyaboutdataquality(Fig2).Twopresentationsfrominfectious
diseasesandmycologyconferencesmetourinclusioncriteria,butbothcorrespondedwithone
ofthetenpublishedarticles[26,28].Table1summarizesthedesignofthesestudiesandTables
2and3summarizethemeta-analysisresultsofthesereports[26,28–31,34–37].
Oftheninereportsmeetingourinclusioncriteria,fivewererandomizedtrials,twowere
prospectivefeasibilitystudies,onewasaprospectiveinterventionalstudy,andonewasaretro-
spectivecohortstudy.Studieswerepublishedorpresentedbetween2005–2013,withdatacol-
lectedfrom1998–2009.OurassessmentsoftheriskofbiasarepresentedinFigs3and4.
Despitevaryinggeographicsites,thepatientpopulationsofthesestudiesincludedadultswith
hematologicmalignancyundergoingintensivechemotherapyorHSCT
Includedstudiesconsistentlydefinedempiricalantifungaltherapyastheinitiationofanti-
fungaldrugsafteradefinednumberofconsecutivedayswithpersistentfebrileneutropenia.
However,therewassignificantvariationinthetrigger(clinicalsymptoms,chestimaging,
galactomannan,PCR,traditionalfungalcultures)forstartingantifungaltherapyinthepre-
emptivestudygroups,presentinganothertypeofbias.Themajority(9of10)incorporated
chestimagingfindingsintothetrigger.Theremainingstudy[34]usedapositivefungalPCRas
theonlytriggerforinitiatingpre-emptivetherapy.Fungalbiomarkers,eithergalactomannan
orfungalPCR,werealsoconsistentlyemployedinallstudiesaspartofthepre-emptive
approach,althoughtherewasvariabilityinwhetheroneorbothwereapplied[26,31].
OfsevenstudiesthatmeasuredandreportedIFDdetection,twofoundasignificantlyhigher
rateofIFDdetectioninthepre-emptivetherapygroup(Table2)[26,31].InthetrialbyMorri-
seyandcolleagues,forexample,IFDdetectionratewas4.1%withempiricaland19.5%with
pre-emptivemanagement.Comparedtostudiesthatdidnotfindasignificantdifferencein
IFDdetectionbetweenthetwoantifungalstrategies,thosethatdidwerebetterpoweredto
identifysuchadifferencewithlargersamplesizes.PooledRRforIFDdetectioncomparing
pre-emptivetoempiricalstrategieswas1.70(95%CI1.12–2.57)usingaM-Hfixed-effects
PLOSONE|DOI:10.1371/journal.pone.0140930 November10,2015 5/19
EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Fig2.PRISMAFlowDiagramofstudiesincludedinsystematicreviewandmeta-analysis.
doi:10.1371/journal.pone.0140930.g002
modeland1.47(95%CI0.55–3.96)withaD-Lrandom-effectsmodel,suggestingpotentially
increasedIFDdetectionwithpre-emptivestrategies(Fig5).Ofnote,therewassignificanthet-
erogeneitybetweenstudiesinIFDdetection(Cochran’sQp=0.008;I2=71.3%;τ2=0.810).
OfthefivestudiesreportingIFD-relatedmortality,nonefoundasignificantdifferencewith
empiricalversuspre-emptivemanagement(Fig6)andtherewasnodifferenceinIFD-related
mortalitypooledRRcomparingthetwogroups(M-HRR0.85,95%CI0.45–1.62;D-LRR
0.82,95%CI0.36–1.87).WefoundnosignificantheterogeneityamongindividualstudyRRsof
IFD-relatedmortality(Cochran’sQp=0.306;I2=17.0%;τ2=0.132).Whileonestudyidenti-
fiedasignificantdifferenceinoverallmortalitybetweenpre-emptiveandempiricalstrategies,
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EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Table1. Summaryofstudiescomparingempiricalversuspre-emptiveantifungaltherapyinhigh-riskfebrileneutropenicpatients.
Study Design Population Study Empirical Pre-emptive Diagnostic Antifungal Primary
Period Protocol Protocol Testing Endpoint
Morrissey Open-label AUSTRALIA 9/ Antifungal Antifungaldrug GM2x/week; AmB,L-AmB, Antifungal
2013[31] randomized (n=240)Patients 2005- drugstarted startedaftera Nested Voriconazole treatment
controlledtrial (cid:2)18years 11/ after singlepositive Aspergillus perAustralian within26
undergoing 2009 persistent GM,single PCR2x/week; consensus weeksof
allogeneicHSCT feverfor(cid:2)3 positivePCR ChestCTafter guidelines enrollment
orintensive consecutive result,orserially positiveGMor
chemotherapyfor days negativeresultsin PCR
AMLorALL patientswith
characteristic
chestCTfindings
Cordonnier Open-label FRANCE 4/ Antifungal Antifungaldrug GM2x/week; AmB,L-AmB, Differencein
2009[26] randomized (n=293)Patients 2003– drugstarted startedafter4 ChestX-ray Caspofungin, mortality14
non-inferiority (cid:2)18yearswith 2/2006 after4daysof daysofpersistent followedby Voriconazole daysafter
trial hematological persistent feverwithclinical/ ChestCT recoveryof
malignancy feveror imaging- neutropeniaor
scheduledfor recurrentfever documented after60daysof
chemotherapyor after4days pneumoniaor studyinclusion
autologousHSCT acutesinusitis,
expectedtohave mucositis,septic
prolonged shock,skinlesion
neutropenia suggestingIFD,
unexplainedCNS
symptoms,
periorbital
inflammation,
splenicorhepatic
abscess,severe
diarrhea,
Aspergillus
colonizationor
positiveserumGM
Hebart Open-label EUROPE 7/ Antifungal Antifungaldrug Non-nested L-AmB IFDDetection
2009[29] randomized (n=403)Patients 1998- drugstarted startedafter1 Aspergillusand 100daysafter
controlledtrial undergoing 6/2001 after(cid:2)5days positivePCR CandidaPCR; transplant
allogeneicHSCT offebrile resultordetection ChestCT;
without neutropeniaor ofpulmonary AbdominalCT;
amphotericin detectionof infiltrate Bloodcultures
allergyorexisting pulmonary
IFD infiltrate
Blennow Open-label SWEDEN(n=99) 4/ No PositivePCR Non-nested L-AmB 100day
2010[34] randomized Patients 2002- intervention randomizedto Aspergillusand survival;1year
trial undergoing 11/ AmB,patientswith Candidawhole IFDdetection;
RIC-HSCTwithout 2006 persistentfever bloodPCR IFDriskfactors
hypersensitivityto regardlessofPCR
AmB result
Tan2011 Open-label SINGAPORE 6/ Standardof Antifungalsstarted GM2x/week; Caspofungin, Proven/
[35] randomized (n=47,NE=52) 2006- care aftertwopositive ChestCTafter L-AmB,AmB, probableIFD
trial Patients(cid:2)12 10/ accordingto GMx2and/or positiveGM Voriconazole
yearswith 2007 institutional chestCT
hematologic guidelines, suggestiveofIFD
malignancy empirical
undergoing antibiotics
intensive allowedif
consolidative indicated
chemotherapyor
HSCT
(Continued)
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EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Table1. (Continued)
Study Design Population Study Empirical Pre-emptive Diagnostic Antifungal Primary
Period Protocol Protocol Testing Endpoint
Aguilar- Prospective SPAIN(n=66) 11/ Antifungal Ifnoidentifiedfoci ChestX-ray; AmB, IFDdetection;
Guisado interventional Patients(cid:2)16 2002- drugstartedin ofinfection,chest Bloodcultures; Voriconazole, IFD-related
2010[36] study yearspost- 2/2005 patientswith CT,abdominal ChestCTin Caspofungin mortality
chemotherapyor sepsis,or ultrasound,and thosewith
post-HSCT identifiedfoci bloodcultureswith abnormalChest
ofinfection,or initiationof X-ray;
perclinical antifungaltherapy Abdominal
discretionin ifdiagnosticwork- ultrasound
high-risk uppositive
patients
Oshima Retrospective JAPAN(n=124) 9/ Atthe Antifungaldrug GM;Beta-D AmB, Development
2007[30] chartreview Adultpatientswho 2002– discretionof startedafter(cid:2)7 glucan Micafungin, ofproven/
underwent 12/ theattending daysofpersistent Itraconazole, probableearly
allogeneicHSCT 2005 orrecurrentfebrile Voriconazole invasive
atauniversity neutropenia, aspergillosis
hospital positiveGM,and/
orinfiltratesor
nodulesonchest
X-rayorCT
Girmenia Prospective ITALY(n=146, 3/ — Antifungaldrug 3blood Voriconazole, Rateof
2010[28] feasibility NE=220) 2006– startedafter cultures;GM AmB,L-AmB, patients
study Patients(cid:2)18 2/2007 positiveblood for3 Caspofungin, receiving
yearswith culture,GM,and/ consecutive Fluconazole antifungal
hematologic orcharacteristic days;Chest therapy
malignancywho chestCTfindings CT;Other
underwent microbiologicor
chemotherapyor clinical
autologousHSCT examinations
anddeveloped asindicated
neutropenia(cid:2)7
days
Maertens Prospective BELGIUM(n=88, 1/ — Antifungal GM;ChestX- L-AmB Rateof
2005[37] feasibility NE=136) 2003- treatmentafter2 ray1-2x/week; antifungaluse;
study Patients(cid:2)16 1/2004 +consecutive Blood,sputum, IFDcases
yearsreceiving positive urine,stool
chemotherapyfor galactomannanor cultures
acuteleukemia/ withCTfindings
MDSor suggestiveofIFD
undergoing
myeloablative
allogenicHSCT
AML:Acutemyelogenousleukemia,ALL:Acutelymphocyticleukemia,NE:Febrileneutropenicepisodes,IFD:invasivefungaldisease,HSCT:
Hematopoieticstem-celltransplantation,RIC:reducedintensityconditioning,GM:Aspergillusgalactomannan,CT:Computedtomographyscan,PCR:
Polymerasechainreaction,AmB:amphotericinBdeoxycholate,L-AmB:liposomalamphotericinB
doi:10.1371/journal.pone.0140930.t001
withdecreasedmortalitywiththepre-emptivestrategy(RR0.16,95%CI0.04–0.71)[36],there
wasnodifferenceinthepooledRRofoverallmortalitybetweenthetwogroups(M-HRR0.99,
95%CI0.70–1.40;D-LRR0.95,95%CI0.46–1.99)(Fig7).Ofnote,therewassignificanthetero-
geneityinoverallmortalityrates(Cochran’sQp=0.05;I2=61.9%;τ2=0.328).
Fiveofsevenstudiesassessingantifungalusefoundasignificantdecreaseinantifungaluse
inthepre-emptivetherapygroup(Table3,Fig8)[25,26,28–30].Forexample,intheCordon-
niertrial,61.3%ofpatientsontheempiricalstrategyarmreceivedantifungalscomparedto
39.2%ofpatientsonthepre-emptivestrategyarm.Furthermore,amongpatientswhodid
receiveantifungals,thedurationofantifungalusewasshorterinthepre-emptivegroup[26],
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EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Table2. ComparisonofIFD-relatedoutcomesinempiricversuspre-emptiveantifungaltherapyinhigh-riskneutropenicpatients.
IFDDetection IFD-relatedMortality OverallMortality
Study RR(95%CI) Empiric Pre-emptive RR(95%CI) Empiric Pre-emptive RR(95% Empiric Pre-emptive
(%) (%) (%) (%) CI) (%) (%)
Morrissey2013[31] 4.76(1.87– 4.1(5/ 19.5(23/ 0.86(0.27– 4.9(6/ 4.2(5/118) 1.55(0.66– 6.6(8/122) 10.2(12/
12.10) 122) 118) 2.75) 122) 3.66) 118)
Cordonnier2009 3.41(1.14– 2.7(4/ 9.1(13/143) 7.34(0.38– 0.0(0/ 2.1(3/143) 1.84(0.55– 2.7(4/150) 4.9(7/143)
[26] 10.21) 150) 140.86) 150) 6.14)
Hebart2009[29] 0.99(0.52– 8.1(17/ 8.2(16/196) 0.82(0.36– 4.8(10/ 3.6(7/196) 0.99(0.64– 16.4(34/ 16.3(32/
1.91) 207) 1.87) 207) 1.55) 207) 196)
Blennow2010[34] — 0.0(0/8) 7.7(1/13) — — — — — —
Tan2011[35] 0.62(0.11– 12.0(3/ 7.4(2/27) — — — — — —
3.39) 25)
Aguilar-Guisado 0.09(0.01– 11.5(3/ 0.0(0/40) 0.13(0.01– 8.0(2/26) 0.0(0/40) 0.16(0.04– 30.7(8/26) 5.0(2/40)
2010[36] 1.75) 26) 2.64) 0.71)
Oshima2007[30] — 0.0(0/13) 3.3(2/60) — 0.0(0/13) 0.0(0/60) — — —
Girmenia2010[28] — — — — — — — — —
Maertens2005[37] — — — — — — — — —
M-HRR(95%CI) 1.70(1.12–2.57) 0.85(0.45–1.62) 0.99(0.70–1.40)
D-LRR(95%CI) 1.47(0.55–3.96) 0.82(0.36–1.87) 0.95(0.46–1.99)
Q=13.90(df=4),p=0.01 Q=3.62(df=3),p=0.31 Q=7.88(df=3),p=0.05
Heterogeneity I2=71.3% I2=17.0% I2=61.9%
Betweenstudyτ2=0.81 Betweenstudyτ2=0.13 Betweenstudyτ2=0.33
RR:relativerisk,CI:confidenceinterval,IFD:invasivefungaldisease,RR:relativerisk,CI:confidenceinterval,M-H:Mantel-Haenszelfixedeffectsmodel,
D-L:Dersimonian-Lairdrandomeffectsmodels,—dataunavailableandcannotbederivedfromthisstudy
doi:10.1371/journal.pone.0140930.t002
Table3. Comparisonofantifungaluseinempiricversuspre-emptiveantifungaltherapyinhigh-riskneutropenicpatients.
AntifungalUse AntifungalDuration(mean)
Study RR(95%CI) Empiric(%) Pre-emptive(%) Empiric(%) Pre-emptive(%) p
Morrissey2013[31] 0.48(0.29–0.79) 30.3(39/122) 23.7(18/118) — — —
Cordonnier2009[26] 0.64(0.50–0.81) 61.3(92/150) 39.2(56/143) 7.0days 4.5days <0.01
Hebart2009[29] 1.56(1.25–1.93) 36.7(76/207) 57.1(112/196) 84.2%(64/76)<30days 79.5%(89/112)<30days NS
Blennow2010[34] — — — — — —
Tan2011[35] 0.76(0.38–1.51) 44.0(11/25) 33.3(9/27) — — —
Aguilar-Guisado2010[36] — — — — — —
Oshima2007[30] 0.08(0.03–0.19) 100.0(13/13) 6.7(4/60) — — —
Girmenia2010[28] 0.57(0.42–0.77) 52.8(84/220) 30.1(48/220) — — —
Maertens2005[37] 0.22(0.11–0.43) 35.0(41/117) 7.7(9/117) — — —
M-HRR(95%CI) 0.72(0.63–0.81) —
D-LRR(95%CI) 0.48(0.27–0.85) —
Q=91.01(df=6),p(cid:3)0.01
Heterogeneity I2=93.4% —
Betweenstudyτ2=0.503
RR:relativerisk,CI:confidenceinterval,IFD:invasivefungaldisease,RR:relativerisk,CI:confidenceinterval,M-H:Mantel-Haenszelfixedeffectsmodel,
D-L:Dersimonian-Lairdrandomeffectsmodels,—dataunavailableandcannotbederivedfromthisstudy
doi:10.1371/journal.pone.0140930.t003
PLOSONE|DOI:10.1371/journal.pone.0140930 November10,2015 9/19
EmpiricalversusPreemptiveAntifungalsinHigh-RiskNeutropenicFever
Fig3.RiskofbiasinrandomizedstudiesasassessedbytheCochraneCollaboration’s“RiskofBias”tool.
doi:10.1371/journal.pone.0140930.g003
withanaverageantifungaldurationof7.0–11.2daysintheempiricalgroupand4.5–8.7daysin
thepre-emptivegroup.Notably,therewasnodifferenceinantifungaldrugtoxicity,either
renalorhepatic,orindiscontinuationofantifungaltherapybetweenthetwogroupsinanyof
thestudies.ThepooledRRofantifungalusewassignificantlylowerusingpre-emptivecom-
paredtoempiricalstrategies(M-HRR0.72,95%CI0.63–0.81;D-L0.48,95%CI0.27–0.85).Of
note,wedetectedstatisticalheterogeneityamongindividualRRsofantifungaldruguse
(Cochran’sQp<0.001;I2=93.4%;τ2=0.503).
Overall,theexistingliteraturedemonstratesthatpre-emptivediagnostic-testdriven
approachesmayincreaseIFDdetectionwithoutanincreaseinIFD-relatedoroverallmortality,
comparedtoempiricaltherapy.Themajorityofstudiesshowedareductionintheproportion
ofpatientsreceivingantifungalsanddurationofantifungalexposureusingapre-emptive
strategy.
CostComparisonModel
Tables4and5outlineclinicalandcostparametersincorporatedintothecost-comparison
analysis,respectively,andTable6summarizestheresultsofthismodel.Assumingsimilar
PLOSONE|DOI:10.1371/journal.pone.0140930 November10,2015 10/19