Galactomannan use in clinical practice: providing free testing is not the full answer

brazjinfectdis2018;22(1):37–40

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Galactomannan

use

in

clinical

practice:

providing

free

testing

is

not

the

full

answer

Jeniffer

S.

dos

Santos

_,

_Djuli

_M.

_Hermes

_,

_Alessandro

_C.

_Pasqualotto

a_{CentroUniversitárioRitterdosReis(UniRitter),PortoAlegre,RS,Brazil} b_{SantaCasadeMisericórdiadePortoAlegre,PortoAlegre,RS,Brazil}

c_{UniversidadeFederaldeCiênciasdaSaúdedePortoAlegre,PortoAlegre,RS,Brazil}

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Articlehistory:

Received27September2017 Accepted5November2017 Availableonline22November2017

Keywords: Aspergillus Aspergillosis Opportunisticinfections Diagnosis Tomography Neutropenia Immunosuppressed

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Introduction:Invasiveaspergillosisisaconditionassociatedwithahighmortalityratemostly duetodifficultiesinperforminganearlydiagnosis.Inrecentyears,galactomannan detec-tionhasmarkedlyimprovedthediagnosisofinvasiveaspergillosis,butverylittleisknown onhowphysiciansdealwiththistestinclinicalpractice.

Methods:Thiscross-sectionalstudyaimedtoanalyzetheindicationsfortheuseofserum galactomannaninalargeBrazilianhospital,between2015and2016.Nospecificprotocolwas inplaceforGMrequest.Wereviewedthemedicalrecordsofadult(>18years-old)patients whoweretestedforgalactomannanduetoonethefollowingindications:screening, diag-nosis,ortreatmentfollow-up.Additionalvariablesincludeddemographicdata,underlying diseases,presenceofneutropenia,anduseofpreviousantifungal(anti-Aspergillus)drugs. Results:Themeanageofthepatientswas51years-old(sd±15.8),and63.3%ofpatientswere male.Patientswithhematologicalmalignanciesaccountedfor60.1%ofthecases,mostly acutemyeloidleukemia(19.6%).Galactomannantestingwaspositivein12.2%ofpatients, including1.6%ofoccasionsinwhichthetestwasusedforscreeningpurposes,13.2%for diagnosis,and32.4%duringfollow-up.Mediantimeforchestimagingrequestwastwodays beforeGMtesting.Previousantifungaltherapywasreportedfor35.1%ofpatients,mostly amphotericinB(57.1%).

Conclusion: Thecorrectuseofgalactomannantestingisessentialforanearlydiagnosisof invasiveaspergillosis,whichmayimprovetheprognosisofthedisease.Wedemonstrated thatcliniciansusuallyaskforgalactomannanteststoconfirmimagingfindingsinpatients whofrequentlywereonantifungaldrugs,somethingthatcouldbeimprovedbymedical education.Weobservedalowfrequencyofgalactomannanuseforpreemptiveantifungal therapy(25.7%),whichisworryingconsideringthewell-knownbeneficialuseofGMtesting inthisscenario.

©2017SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](A.C.Pasqualotto). https://doi.org/10.1016/j.bjid.2017.11.002

1413-8670/©2017SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Introduction

Aspergillusspeciesareopportunisticcosmopolitanfungi,being importantcausesofinfectioninimmunosuppressedpatients, mainly neutropenicindividuals.1,2 _{These filamentous fungi} arealsobecomingincreasinglycommoninnon-neutropenic individuals,3,4 _{inadditiontobeingrecognizedasagentsofa} varietyofclinicalsyndromes.5_{Withtheincreaseoftreatments} usingimmunosuppressantsaswellasofchronicdiseases,an overallincrementinthefrequencyofpatientsunderhighrisk ofopportunisticmycoseshasbeenobserved.6

AmongstthemostcommondiseasescausedbyAspergillus spp., we canhighlight invasive aspergillosis(IA),7 _a condi-tionresponsibleforhighmortalityrates,inwhichdiagnosis isusuallydifficultandlate.8_{Severaltechniquesareusedfor} diagnosingIA,inparticularthedetectionofgalactomannan (GM),apolysaccharideofthewallofAspergillusspp.usedasa microbiologicalsubstituteforIAdiagnosis,9_{mostlyinserum} samples.10 _{Positive tests would characterize the patient as} havingaprobableIA,incombination withhostfactorsand imagingtests.1_{Asthistechniquehasconsiderablespecificity} andallowsforanearlydiagnosis,itisveryusefulforboththe selectionofpatientsneedingtherapyaswellasmonitoringof patientswithIA.11

InBrazilgalactomannantestingisprovidedfreeofcharge byapharmaceuticaldrugcompanytohospitalsthatconsume their antifungal drug. Our institution has provided physi-cians with GM testing for many years in both serum and bronchoalveolarlavagesamples,withnospecificprotocolfor testing.Inthiscontext,weperceivetheimportanceof char-acterizingtheclinicalscenariosinwhichGMserumtesting hasbeen usedinclinical practiceand how clinicians have correlatedGMresultswithchestimagingfindings.

Methods

Design,inclusionandexclusioncriteria

Thiswasacross-sectionalobservationalstudycarriedout dur-ingtheyears2015and2016inalarge(1200beds)tertiary-care hospital.Allmedicalrecordsofadult(≥18years)individuals testedforserumGMwereconsideredforstudy,including out-patientsandhospitalizedpatients.Patientswereexcludedif GMtestingwasnotperformedintheserum(e.g., bronchoalve-olarlavage),ifsampleswereobtainedinanotherinstitution, andifmedicalrecordswerenotavailableorincomplete.

Variablesandclinicalgroups

Clinical-demographicvariableswerestudiedandthesewere obtained from patient’s medical records. These variables included: sex,age, result (opticalindex)ofGM(considered positiveif≥0.5),underlinediseases,immunosuppressive con-ditions, presence and duration of neutropenia and use of corticosteroids.Wealsoobtainedinformationonfungal cul-ture request, in addition to previous (last week) use of anti-Aspergillus antifungal drugs. As per convention, neu-tropenia wasdefinedasaneutrophil countequalor below 500cells/mm3.

GMserumrequestsweredividedintothefollowinggroups: screening(individualsatriskofIAduetoimmunosuppression butwithnoevidenceofdisease);investigationforsuspectedIA (usefordiagnosticpurposesinindividualswithsignsand/or symptoms suggestive of IA);or use for therapeutic follow-up. In addition, it was evaluated whether the patient was treated because ofthe GM test result, and alsoif biopsies and/orimagingwereperformedtemporallyrelatedtoGM test-ing.Radiologicalfindings(e.g.,presenceofnodules,halosor groundglassinfiltrates)werealsodescribed.

Statisticalanalysis

Descriptive statistics were used to describe the data, and analysis of the results was performed using the statisti-calprogramSPSS® (version24.0).Qualitativevariables were comparedbychi-squaretestorFisher’stest,asappropriate. QuantitativevariableswereassessedbytheStudentttestor Mann–Whitneytest,dependingondatadistribution.p-Values ≤0.05wereconsideredstatisticallysignificant.

Ethicalapproval

TheprojectwasapprovedbytheEthicsandResearch Commit-teesoftheparticipantinstitutions,withnomajorcomments onthestudydesign.

Results

During the study period,245 serum GMsamples from 158 patients were evaluated, and 683 requests were excluded. Therewasamedianof1.5samplesperpatient,rangingfrom 1–10tests.Ofthe158testedpatients,43%wereevaluatedin 2015and 57% in2016. Therewas apredominance ofmale patients(63.3%),andthemeanagewas51years-old(standard deviation±15.8).

Regarding underlying diseases, 60.1% of patients had hematologicalmalignancies,mainlyacutemyeloidleukemia (19.6%).Inaddition,17.7%hadnon-Hodgkin’slymphomaand 8.2%acutelymphocyticleukemia.Still,16.5%wererecipients ofsolidorgantransplantsand3.2%wereHIVinfected.

ThemajorityofpatientsweretestedforGMfor diagnos-ticpurposes(46.5%),followedbyscreening(preemptiveuse; 25.7%)andtherapeuticfollow-up(15.1%).Table1showsthe distributionofunderlyingdiseasesaccordingtoGMindication (i.e.,screening,diagnosisorfollow-up).

Regarding the results ofserum GM, the median of the opticalindiceswas0.14,rangingfrom0.01to4.82.The over-all frequency of GM positivity was 12.2% (30/245), ranging from1.6%(screening)to13.2%(diagnosis)and32.4% (follow-up). Eighty-six samples (35.1%) were tested inthe context ofpriorantifungaluse,mainlyamphotericinB(57.1%ofthe total),voriconazole(32.9%),posaconazole(4.3%), anidulafun-gin(4.3%),anditraconazole(1.4%).Inonly20%(6/30)ofthe caseswithpositiveGMresults,GMtestingtriggeredtheonset ofantifungaltherapy.

ThemediantimebetweenarequestforserumGMandthe nexttestrequestwas26days,rangingfrom1to231days;46.9% (115/245)ofthepatientshadonlyonerequest,being44.0%in

brazj infect dis.2018;22(1):37–40

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Table1–Mainunderlyingdiseasesandpredisposingconditionsforinvasiveaspergillosis,asstratifiedbythereasonfor serumgalactomannanrequest.

Hematologicalneoplasia SOT HIV Neutropenia Steroids PositiveGM Total

n(%) n(%) n(%) n(%) n(%) n(%) n(%)

Preemptive 51(81.0) 3(4.8) 1(1.6) 37(58.7) 44.4(28) 1(1.6) 63(25.7) Diagnosis 73(64.0) 20(17.5) 1(0.9) 66(57.9) 54.4(62) 15(13.2) 114(46.5) Follow-up 28(75.7) 1(2.7) 2(5.4) 24(64.9) 54.1(20) 12(32.4) 37(15.1) GM,galactomannantesting;HIV,humanimmunodeficiencyvirus;SOT,solidorgantransplantation.

screening,51.7%indiagnosisand4.3%inthefollow-upgroup.

Regardingthe presenceand durationofneutropenia,mean

durationwassevendaysinallgroups.

Overall,chestimagingprecededGMrequestbyamedian

oftwodays(range,19daysbeforetosevendayslater).Chest

imagingwasrequestedbeforeGMbyamedianoftwodays

inbothdiagnosticandfollow-upgroups,andonedayinthe preemptive(screening)group.Regardingtheimagingfindings, therewasapredominanceofgroundglassinfiltratesand nod-ules,49.0%(102/208)and48.1%(100/208)respectively,whilst thehalosignalwaspresentinonly21.6%(45/208)ofepisodes ofGMtesting.

Discussion

Althoughthe GM testing iswidelyused fordiagnosing IA,

littleisknownabouthowphysiciansusethetestinclinical practice,particularly inthe context ofpreemptive antifun-gal therapy. Until now, health care professionals’ attitudes regardingthetimingoftherequestforchest imagingtests inrelationtotheGMtestinghadnotyetbeendocumentedin Brazil.Hereweshowedthatmostcliniciansmakeinadequate useoftheGMserumtesting,includingnotaskingforserial (i.e.,2–3timesweekly)testing,aswellasandnotusingthe testasatriggerforchestcomputedtomography(CT)request. Rather,physicianscommonlyaskforchestCTbeforeGM test-ing.Untilrecently,empiricantifungaltherapywaswidelyused forpatientswithprolongedneutropeniawhoremainedfebrile despitetheuseofbroad-spectrumantimicrobials.12_However, studiesinitiatedbyMaertensetal.13_{haveshownthatitis} pos-sibletomarkedlyreduceantifungaluseinthesepatientswith theuseoftestswithhighnegativepredictivevalue,suchas GM,intheso-calledpreemptiveantifungaltherapy.However, thepositivepredictivevalueoftheGMtestisknowntobe lowtomoderate,14_{reinforcingtheimportanceoftestingina} newsampletoincreasethetestpredictionofdisease.Inour study,only43patientsoutof158hadarepeatedGMtest,and GMpositivitywasonly1.6%intheclinicalscreeninggroup,a surprisinglylowfrequency.

Inourhospital,havingfreeGMtestingdoesnotseemto help physiciansmaking a proper diagnosis of IA. The fre-quency of a positive GM test was ridiculously low in the preemptivestrategy,whichmay berelatedtoaselectionof patientswithlowpre-testprobabilityofdisease(unlikely)or (morelikely)inadequateserialmonitoring.GMtestingwas fre-quentlyusedtodiagnosepatientswithIA,butchestCTwas (erroneously) usuallyrequested beforeGMwas tested, and manypatientsweretestesafterantifungaltherapyhadalredy

been initiated.That clearlyshowsthatadvocacyforhaving GMtesting inplace isnotenough toimprovethe outcome ofpatientsinfectedwithinvasivefungaldiseases–education ofhealthcareprovidersisalsocritical.Suchtrainingwould involveeducationaboutthehighnegativepredictivevalueof serumGMtesting(particularlyfortheneutropenicpatient), inaddition toreinforcingthe importanceofGMuse inthe preemptivestrategy.Inthatcase,apositiveserumGMresult shouldledphysicianstoorderachestCT,inordertoconfirm theresultsobtainedbyGMintheserum.

Conflicts

of

interest

Dr.Pasqualottohasconsultedand/orreceivedresearchgrants forPfizer,Gilead,UnitedMedical,MSD,andAstellas,all com-paniesthatproduceorcommercializeantifungaldrugs.

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