Rare severe mycotic infections in children receiving empirical caspofungin treatment for febrile neutropenia

(1)

braz j infect dis.2015;19(5):549–552

ww 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

Case

report

Rare

severe

mycotic

infections

in

children

receiving

empirical

caspofungin

treatment

for

febrile

neutropenia

Deniz

Yilmaz

Karapinar

a,∗

_,

_Nihal

_Karadas¸

a

_,

_Zühal

_Önder

_Sivis¸

a

_,

_Pinar

_Yazici

b

_,

Muhterem

Duyu

b

_,

_Dilek

_Metin

c

_,

_Bülent

_Karapinar

b

_,

_Yes¸im

_Aydinok

a

a_Children’s_Hospital,_Department_of_Pediatric_Hematology,_Ege_University_Faculty_of_Medicine,_{Bornova-˙Izmir,}_Turkey b_Children’s_Hospital,_Department_of_Pediatric_Intensive_Care,_Ege_University_Faculty_of_Medicine,_{Bornova-˙Izmir,}_Turkey c_Medical_{Microbiology,}_Ege_University_Faculty_of_Medicine,_{Bornova-˙Izmir,}_Turkey

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received30March2015

Accepted12June2015

Availableonline11August2015

Keywords:

Geotrichumcapitatum Trichosporonasahii

Invazivefungalinfection

Febrileneutropenia

a

b

s

t

r

a

c

t

Empiricalantifungaltherapyismostoftengiventopatientswithleukemia.However

break-throughfungalinfectionsunderantifungaltherapyarenotuncommon.Fourchildren,with

hematologicmalignantdiseasedevelopedmycoticbreakthroughinfectionswhileon

empir-icalcaspofungintreatmentforamedianof14(range11–19)days.Trichosporonasahiiwas

detectedinthebloodcultureoftwopatientsandGeotrichumcapitatumintheothertwo(one

patientalsohadpositivecerebrospinalﬂuidculture).Becausethepatients’clinicalsituation

worsened,voriconazolewasempiricallyaddedfortwopatientsthreeandﬁvedaysbefore

theagentwasdetected.Theﬁrststerilebloodculturewasobtained3–7daysof

voricona-zoletreatment.Allpatientsreachedclearculturesbutonepatientdied.Onepatientwith

centralnervoussysteminfectionwithG.capitatumhadsevereneurologicalsequelae.Very

severefungalinfectionscanoccurduringempiricalcaspofungintherapy.Therefore,patients

shouldbefollowedclosely.

Introduction

Invasive fungal infections (IFIs) have signiﬁcant impact on

leukemia patients’ survival.Although antifungal drugs are

empiricallygiventomostofthepatients,breakthroughfungal

infectionsarenotuncommon.1–5

∗ _{Corresponding}_author_at:₂₃₆_Sok._No:₁_Kat:₇_D:_21,_Baris_Apt._35040,_{Bayrakli-Izmir,}_Turkey.

E-mailaddress:dyilmazk@yahoo.com(D.YilmazKarapinar).

Trichosporoninfectionsareanincreasinglycommon

com-plicationofneutropeniaandotherconditionsassociatedwith

severeimmuncompromise.Theoutcomeofdisseminated

Tri-chosporoninfectionismostoftenpoor,andthefatalityrateis over70%.3,6–9_Recently_the_genus_Trichosporon_has_been

taxo-nomicallyrevised.Generally,twospecieshavebeenassociated

http://dx.doi.org/10.1016/j.bjid.2015.06.008

(2)

550

braz j infect dis.2015;19(5):549–552

withIFIsinhumans:TrichosporonbeigeliiandTrichosporon

cap-itatum.T.capitatum hasnowbeen reclassiﬁedasGeotrichum capitatumorBlastoschizomycescapitatus.T.beigeliinow

corre-spondstosixdifferentspecies.InvasiveTrichosporoninfections

areduetoT.asahiiinmostcases.6,7

Theincreaseduse of echinocandinsleads tosigniﬁcant

selective pressure, which favors opportunistic fungi, that

areresistanttotheseagents.Disseminatedtrichosporonosis

hasbeen reported inimmunocompromised patientsunder

echinocandin therapy.3,4,7–14 _Breakthrough _{trichosporonosis}

andG.capitatuminfectionsoccurredinfourchildrenon

empir-icalcaspofungintherapy.

Case

reports

Case1

A16-year-oldgirlwithacquiredverysevereaplasticanemia

(vSAA)receivedimmunosuppressivetherapy(IST)consisting

ofrabbitanti-thymocyteglobuline(ATG),cyclosporineA,

gran-ulocytecolony stimulatingfactor (GCSF), and prednisolone

afterreplacementofcentralvenouscatheter(CVC).Shehad

nohematologicalresponsetoIST.Sixmonthsafterdiagnosis

ofvSAAand44daysafterinitiationofIST,thepatientwas

stillonregularplateletanderythrocytetransfusion,hadvery

severeneutropenia,anddevelopedfebrileneutropenia(FN).

On6thdayofFNcaspofunginwasinitiatedasempirical

anti-fungal therapy.Shedevelopedmaculopapularrashon 11th

dayofcaspofungin treatment. Her clinical condition

wors-ened.Thepatientdevelopedhepatosplenomegaly(HSM)and

severerespiratorydistress.Shewasadmittedtothepediatric

intensive careunit (PICU), and required mechanical

venti-lation(MV).Bloodculturestaken15 daysafterinitiationof

caspofunginrevealedyeast,lateridentiﬁedasT.asahii.Table1

showstheminimalinhibitoryconcentration(MIC)of

antifun-gals.Voriconazole(VCZ)wasstarted.Althoughbloodcultures

werenegativesevendaysafterinitiationofVCZ,thepatient

clinicalconditiondidnotimprove.Fever,HSM,respiratory

fail-ure,andpancytopeniapersisted.Shedevelopedrenalfailure

andexpired13daysafterclearingbloodculture.

Case2

A5-year-oldgirlwithpre-Bcellacutelymphoblasticleukemia

(ALL)wasincludedinthestandardrisk(SR)armofALLIC-BFM

2002treatmentprotocol.ACVC wasinserted.On 42ndday

oftreatment(day0),shedevelopedFN (ANCwas12mm−3)

andempiricalcaspofunginwasstarted onday5thereafter.

Shepresented diarrhea and feeding intolerance.Leukemia

treatmentwas discontinuedon day 21 (63rd dayof

induc-tiontherapy).Disseminatedmaculopapularlesionsappeared

andshedevelopedsepsis.VCZ(4mg/kgevery12h)wasadded

totreatmentempiricallyonday26andthreedayslatershe

developedsevererespiratorydistress.CVCwasremoved.The

patientwastransferredtoPICU,requiringintubationandMV.

Culturesofthreebloodsamplesobtained19daysafter

initia-tionofcaspofungintreatmentandthreedaysbeforestarting

VCZyieldedyeasts,lateridentiﬁedasT.asahii.Theagentwas

sensitivetoVCZ(Table1).Althoughallbloodculturesbecame

negativeafterfourdaysofVCZtherapy,shedeveloped

sec-ondaryhemophagocytosis(HLH)andwastreatedaccordingto

HLH2004protocolfortwoweeks.Afterresolutionofclinical

and laboratoryﬁndingsrelatedtosecondary HLH,she

con-tinued to receive ALL IC-BFM 2002chemotherapyprotocol.

SecondaryantifungalprophylaxiswasadministeredwithVCZ

forsixmonthsandshecompletedthechemotherapyprotocol

withoutreactivationofT.asahii.

Case3

A2.5-year-oldboywithpre-BcellALLwasincludedinHRarm

ofALLIC-BFM2002treatmentprotocol.Aportcatheterwas

inserted.On22nddayoftreatment(day0),hedevelopedFN

(ANC was 12mm−3).Empirical caspofunginwas started on

day 4.He could notachieve hematologicremission byday

15(33rddayoftreatmentprotocol)andonday17,VCZwas

addedasasecondantifungalagentduetoworseningclinical

condition.Serumgalactomannantestwasfoundtobe

posi-tive.Bloodsamplesforcultureweretakenonday18(14thday

ofCaspofungintreatmentand1stdayofvoriconazole

treat-ment)yieldedyeasts,lateridentiﬁedasG.capitatum.Onday

19,caspofunginwasstoppedandliposomalamphotericinB

(LiAmB)wasstartedatthedoseof5mg/kg,thenthedosewas

increasedupto10mg/kg/day.Bloodcultureswerenegativeon

day23,eightdaysafterVCZinitiationandfourdaysofLiAmB.

CVCwasremovedandcultureofthecathetertipyieldedthe

samefungi.Antifungaltherapywascontinuedwithcombined

antifungalsforthreemonthswithoutreactivationofIFI.

Case4

A 2.5-year-old girl with pre-Bcell ALL was included inHR

arm ofALL IC-BFM2002treatment protocol afterinsertion

of CVC. She had central nervous system involvement. On

the 4th day (day 0) oftreatment, she developed FN (ANC

was 104mm−3). Empirical caspofungin was started on day

8.Feverdisappeared12daysthereafter.Aportcatheterwas

insertedonday15.Whileshewasstilloncaspofungin

treat-mentsheagaindevelopedfebrileneutropeniaonday17.On

day21,abdominalcomputerizedtomographyshowed

multi-plespleenandkidney hypodensenodularlesionswithless

than1cmdiameter.Onday25shedevelopedsevereagitation,

andcranialmagneticresonanceimaging(MRI)showed

mul-tiplediffusecorticalandsubcorticallesions.Onday29(33rd

dayoftreatment),bonemarrowaspirationrevealed

hemato-logicalremission,andintrathecaltreatmentwasgivenafter

cerebrospinalﬂuid(CSF)samplewastakenaccordingtothe

protocol. Two days later, on day 31, she developed status

epilepticus.ShewasthentransferredtoPICUandrequiredMV.

Serumgalactomannanantigentestwasfoundtobeweak

pos-itive.EmpiricalVCZ(8mg/kg/day)wasadded.Onday32,CSF

cultureyieldedyeasts,lateridentiﬁedasG.capitatum.

Anti-fungal susceptibility isshown inTable 1. Caspofungin was

stoppedandLiAmBwasstartedatthe doseof5mg/kg/day.

Catheter tip, peripheral blood, and urine cultures yielded

G. capitatum.Port catheterwasremoved.Afterfourdaysof

LiAmB and ﬁve daysof VCZall blood cultures were

nega-tive. However,cranial MRIshowed progressiveencephalitis

(3)

brazj infect dis.2015;19(5):549–552

551

Table1–Minimuminhibitoryconcentration(␮g/mL)ofantifungaldrugsdisplayedagainstisolate.

Patientno. Isolate(isolationsite) AmpB Fluconazole Itraconazole Voriconazole Posaconazole Caspofungin Amidalafungin

1 T.asahii (Blood) 1.5 3 0.032 0.094 >32 32 2 G.capitatum (Blood,CSF, urine) 0.032 4 0.064 0.064 0.125 >32 32 3 G.capitatum (Blood) 0.032 4 0.50 0.125 >32 6 4 T.asahii (Blood) 0.008 0.023 0.25 0.023 >32 32 6 G.capitatum (Blood) 0.75 3 0.9 0.125 >32 12

thereservoir yieldedG.capitatum.Intrathecal amphotericin Batthedoseof0.25mg/daywasgiven.TheﬁrststerileCSF culturewas achievedafter 16 days ofintravenousVCZ, 15 daysofLiAmB,andfourdaysofintrathecalamphotericinB. Despiteantibioticand antifungaltherapies,feverpersisted. CranialMRIshowedprogressiveencephalitis,external ventri-culardrainagewasinsertedandintrathecalAmBwasgivenfor 21days.SheweanedfromMV78daysthereafter.She contin-uedtoreceivecombinedantifungaltherapyfor267daysbut developedsevereneurologicalsequelae.

Discussion

IFIisasigniﬁcant causeofmorbidityandmortalityamong patientswithhematologicmalignancies.Empirical antifun-galtherapyishighlyrecommendedafterfourdaysofFNin thispopulation.CaspofunginandamphotericinBarethe sug-gestedantifungalagentsforempiricalthreraoy.15

InvasiveinfectionscausedbyTrichosporonspeciesarerare

butpotentiallyfatalcomplicationsoftheimmunosuppression

associatedwith treatmentof cancer.3,7 _Among_Trichosporon

species,G.capitatumhasemergedasararefungalpathogen

inrecentyears,particularlyinseverelyimmunocompromised

hosts.IFIcausedbythisagentisoftencharacterizedbya

mul-tiorganinvolvement witha fatalcourse despite antifungal

therapy.16–19 _The_incidence_of_G. _capitatum_infection _among

patientswithleukemia wasfoundtobe0.5%withacrude

mortalityrateof55%.Several studiescollectingcasesofG.

capitatuminfectionsinhematologicalpatientshaveshoweda

30-dayattributablemortalityrangingfrom40%to75%.

Caspofunginhasagoodfungistaticandfungicidalactivity

againstavarietyofyeasts,butdoesnotshowactivityagainst

G.capitatumandtheotherfungiofTrichosporonspecies.2–5,17

Thepresentedfourpatientswithhematologicmalignant

diseasedevelopedseverefungalbreakthroughinfectionswith

rarecausativeagents.AllofthepatientshadaCVC,verysevere

neutropenia,andwereinitiallytreatedwithbroad-spectrum

antibiotics.Sincefeverandsevereneutropeniapersistedinall

patients,empiricalchangesinantibioticcombinationswere

implementeddespitenoagentbeingisolatedinthecultures.

Atamedianofﬁvedays(range4–8days)ofFN,caspofungin

was started in all thesepatients, who had fever and

hep-atosplenomegaly.Cutaneousmaculopapularrashwasseenin

twopatients.Onehadstatusepilepticusandmultiplecerebral

abscessesatpresentationofmycoticinfection.Threeofthese

patientsrequiredintubationandMV,andwereadmittedatthe

PICU.

Becausethepatients’clinicalsituationworsened,intwo

patientsVCZwasaddedtoantifungaltherapyempiricallyone

andthreedaysbeforetheagentwasdetected.

Echinocandinsalonehavelittletonoactivityagainst

Tri-chosporonspp.andarenotrecommendedfortrichosporonosis

treatment.2–5_In_the_literature_almost_all_IFIs_caused_by_T._asahii

orG.capitatumoccurredasbreakthroughinfectioninpatients

whoreceivedantifungaltherapy,especiallyechinocandinsfor

atleastﬁvetosevendays.8–10

Fluconazole was used as the initial therapy in 85% of

19 patients with invasive trichosporonosis documented in

a single medical center in Taiwan, and the mortality rate

was42%.9_Suzuki_et_al.10_recently_evaluated_the_clinical_and

therapeuticaspectsof33casesofTrichosporonfungemia

doc-umented inpatientswithhematologicalmalignancies.The

authors clearly demonstrated that survival was longer for

patients treated withan azolethan forthose treatedwith

otherdrugs.Triazolesseemtohavebetterinvitroandinvivo

antifungal activity against Trichosporon spp. than

ampho-tericin B. VCZ also has excellent in vitro activity against

Trichosporonstrains andmay beuseful fortreating patients

withtrichosporonosis.3,6

Inconclusion,disseminatedtrichosporonosisandG.

capi-tatuminfectionshavebeenincreasinglyreportedworldwide.

Treatmentwithechinocandinsshouldbeacceptedasarisk

factor inimmunosuppressedpatients, especiallyin

institu-tionswheretheinfectionhadbeendetectedbefore.Prognosis

is limited, and antifungal regimens containing triazoles

appeartobethebesttherapeuticapproach.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.LafaurieM,LapaluJ,RaffouxE,etal.Highratebreakthrough invasiveaspergillosisamongpatientsreceivingcaspofungin forpersistentfeverandneutropenia.ClinMicrobiolInfect. 2010;16:1191–6.

2.WalshTJ,GrollA,HiemenzJ,FlemingR,RoilidesE,AnaissieE. Infectionsduetoemerginganduncommonmedically

(4)

552

braz j infect dis.2015;19(5):549–552

importantfungalpathogens.ClinMicrobiolInfect. 2004;10:44–6.

3. ArendrupMC,BoekhoutT,AkovaM,etal.ESCMIDandECMM jointclinicalguidelinesforthediagnosisandmanagementof rareinvasiveyeastinfections.ClinMicrobiolInfect.

2014;20:76–98.

4. ChanTS,GillH,HwangYY,etal.Breakthroughinvasive fungaldiseasesduringechinocandintreatmentinhigh-risk hospitalizedhematologicpatients.AnnHematol.

2014;93:493–8.

5. CairaM,TrecarichiEM,TumbarelloM,LeoneG,PaganoL. Uncommonyeastinfectionsinhematologicalpatients:from diagnosistotreatment.ExpertRevAntiInfectTher. 2011;9:1067–75.

6. ColomboAL,PadovanACB,ChavesGM.Currentknowledgeof Trichosporonspp.andtrichosporonosis.ClinMicrobiolRev. 2011;24:682–700.

7. MeyerMH,Letscher-BruV,WallerJ,LutzP,MarcellinL, HerbrechtR.ChronicdisseminatedTrichosporonasahii infectioninaleukemicchild.ClinInfectDis.2002;35:e22–5.

8. KontoyiannisDP,TorresHA,ChaguaM,etal.

Trichosporonosisinatertiarycarecancercenter:riskfactors, changingspectrumanddeterminantsofoutcome.ScandJ InfectDis.2004;36:564–9.

9. RuanSY,ChienJY,HsuehPR.Invasivetrichosporonosis causedbyTrichosporonasahiiandotherunusualTrichosporon speciesatamedicalcenterinTaiwan.ClinInfectDis. 2009;49:11–7.

10.SuzukiK,NakaseK,KyoT,etal.FatalTrichosporonfungemiain patientswithhematologicmalignancies.EurJHaematol. 2010;84:441–7.

11.LiaoY,HarmannT,ZhengT,YangRY,AoJH,WangWL. Breakthroughtrichosporonosisinpatientsreceiving

echinocandins:casereportandliteraturereview.ChinMedJ. 2012;125:2632–5.

12.SunHY,SinghN.Characterisationofbreakthroughinvasive mycosesinechinocandinrecipients:anevidence-based review.IntJAntimicrobAgents.2010;35:211–8.

13.BayramogluG,SonmezM,TosunI,AydinK,AydinF. BreakthroughTrichosporonasahiifungemiainneutropenic patientwithacuteleukemiawhilereceivingcaspofungin. Infection.2008;36:68–70.

14.Ozkaya-ParlakayA,Karadag-OncelE,CengizAB,etal. Trichosporonasahiisepsisinapatientwithpediatric malignancy.JMicrobiolImmunolInfect.2013;13,1684-1182.

15.MaertensJA,MaderoL,ReillyAF,etal.Arandomized,double blind,multicenterstudyofcaspofunginversusliposomal amphotericinBforempiricantifungaltherapyinpediatric patientswithpersistentfeverandneutropenia.PediatrInfect Dis.2010;29:415–20.

16.IkutaK,TorimotoY,YamamotoM,etal.Successfultreatment ofsystemicGeotrichumcapitatuminfectionbyliposomal amphotericinB,itraconazole,andvoriconazoleinJapanese man.InternMed.2010;49:2499–503.

17.FianchiL,MontiniL,CairaM,etal.Combinedvoriconazole pluscaspofungintherapyforthetreatmentofprobable geotrichumpneumoniainaleukemiapatient.Infection. 2008;36:65–7.

18.EtienneA,DatryA,GasparN,etal.Successfultreatmentof disseminatedGeotrichumcapitatuminfectionwitha combinationofcaspofunginandvoriconazoleinan immunocompromisedpatient.Mycoses.2008;51:270–2.

19.ChristakisG,PerlorentzouS,AslanidouM,MegalakakiA, VelegrakiA.FatalBlastoschizomycescapitatussepsisina neutropenicpatientwithacutemyeloidleukemia:ﬁrst documentedcasefromGreece.Mycoses.2004;48:216–20.