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
A
consensus
document
for
the
clinical
management
of
invasive
fungal
diseases
in
pediatric
patients
with
hematologic
cancer
and/or
undergoing
hematopoietic
stem
cell
transplantation
in
Brazilian
medical
centers
Fabianne
Carlesse
a,b,
Liane
Esteves
Daudt
c,
Adriana
Seber
d,e,
Álvaro
Pimenta
Dutra
f,
Analy
Salles
de
Azevedo
Melo
g,
Belinda
Simões
h,
Carla
Renata
Donato
Macedo
a,
Carmem
Bonfim
i,
Eliana
Benites
j,
Lauro
Gregianin
k,
Marjorie
Vieira
Batista
l,
Marcelo
Abramczyk
m,n,
Vivian
Tostes
o,
Henrique
Manoel
Lederman
a,
Maria
Lúcia
de
Martino
Lee
p,q,
Sandra
Loggetto
r,
Cláudio
Galvão
de
Castro
Junior
s,
Arnaldo
Lopes
Colombo
t,∗aInstitutodeOncologiaPediátrica,UNIFESP,SãoPaulo,SP,Brazil
bUniversidadeFederaldeSãoPaulo,EscolaPaulistadeMedicina(EPM),UNIFESP,SãoPaulo,SP,Brazil cUniversidadedoRioGrandedoSul,HospitaldasClínicasdePortoAlegre,PortoAlegre,RS,Brazil dHospitalSamaritanodeSãoPaulo,SãoPaulo,SP,Brazil
eABHH,Brazil
fSantaCasadeBeloHorizonte,BeloHorizonte,MG,Brazil
gUniversidadeFederaldeSãoPaulo-UNIFESP,LaboratórioEspecialdeMicologia(LEMI),SãoPaulo,SP,Brazil hHospitaldasClínicasdeRibeirãoPreto-USP,SãoPaulo,SP,Brazil
iHospitaldasClínicasdeCuritiba,Paraná,PR,Brazil jGREENDAC,Jundiaí,SãoPaulo,Brazil
kHospitaldasClínicasdePortoAlegre,PortoAlegre,RS,Brazil
lUniversidadedeSãoPaulo,FaculdadedeMedicina,HospitaldasClínicas,SãoPaulo,SP,Brazil mHospitalInfantilDarcyVargas,Morumbi,SP,Brazil
nUniversidadeFederaldeSãoPaulo,EscolaPaulistadeMedicina,DepartamentodePediatria,SãoPaulo,SP,Brazil oPro-ImagemmedicinadiagnósticaRibeirãoPreto,SP,Brazil
pHospitalSantaMarcelinaTUCA,SãoPaulo,SP,Brazil qHospitalIsraelitaAlbertEinstein,SãoPaulo,SP,Brazil rHospitalInfantilSabará,SãoPaulo,SP,Brazil sSantaCasadePortoAlegre,PortoAlegre,RS,Brazil
tUniversidadeFederaldeSãoPaulo,EscolaPaulistadeMedicina,DisciplinadeInfectologia,Brazil
∗ Correspondingauthor.
E-mailaddresses:fabiannecarlesse@graacc.org.br(F.Carlesse),ldaudt@hcpa.edu.br(L.E.Daudt),adrianaseber@yahoo.com(A.Seber), aloapd@hotmail.com(Á.P.Dutra),analysalles@gmail.com(A.S.Melo),bpsimoes@fmrp.usp.br(B.Simões),carladonatomacedo@uol.com.br (C.R.Macedo),carmembonfim@gmail.com(C.Bonfim),ecbenites@ig.com.br(E.Benites),lgregianin@hcpa.edu.br(L.Gregianin),
marjorie.vieira@hc.fm.usp.br (M.V. Batista), mabramczyk@ig.com.br (M. Abramczyk), vitostes@hotmail.com (V. Tostes), Henrique.lederman@gmail.com (H.M. Lederman), marialucialee@gmail.com (M.L. Lee), loggetto.sr@hotmail.com (S. Loggetto), cjgalvao@uol.com.br(C.GalvãodeCastroJunior),colomboal@terra.com.br(A.L.Colombo).
https://doi.org/10.1016/j.bjid.2019.09.005
1413-8670/©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Articlehistory:Received20April2019 Accepted28September2019 Availableonline16November2019
Keywords: Fungalinfections Children Cancer
a
b
s
t
r
a
c
t
Inthepresentpaperwesummarizethesuggestionsofamultidisciplinarygroupincluding expertsinpediatriconcologyandinfectiousdiseaseswhoreviewedthemedicalliterature toelaborateaconsensusdocument(CD)forthediagnosisandclinicalmanagementof inva-sivefungaldiseases(IFDs)inchildrenwithhematologiccancerandthosewhounderwent hematopoieticstem-celltransplantation.Allmajormulticenterstudiesdesignedto charac-terizetheepidemiologyofIFDsinchildrenwithcancer,aswellasallrandomizedclinical trialsaddressingempiricalandtargetedantifungaltherapywerereviewed.Intheabsence ofrandomizedclinicaltrials,thebestevidenceavailabletosupporttherecommendations wereselected.AlgorithmsforearlydiagnosisandbestclinicalmanagementofIFDsarealso presented.Thisdocumentsummarizespracticalrecommendationsthatwillcertainlyhelp pediatricianstobesttreattheirpatientssufferingofinvasivefungaldiseases.
©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction
Invasive fungal diseases (IFDs) have become an important
cause of morbidity and mortality in immunosuppressed
patients, especially those with cancer and/or undergoing hematopoieticstemcelltransplantation(HSCT).1,2
Pediatric patients are equally susceptible to IFD com-paredtothe adult population. However,thereare relevant differences in the physiology, presence of comorbidities, pharmacokineticandtolerancetoantifungals,treatment reg-imens,underlyingdiseasesevolution,populationsatriskand prognosisoffungal infections.Therefore, the extrapolation ofclinicalpracticesconsolidatedintheadultpopulationfor childrenissometimesinappropriate,makingitnecessaryto createspecificguidelinesfortheclinicalmanagementofIFD optimized forpediatricpatients assisted inourcountry.In ordertoproposealgorithmsforearlydiagnosisandbest clin-icalmanagementofIFDsinpediatric patientswereviewed all major multicenter studies designed to characterize the epidemiologyofIFDsinchildrenwithcancer,aswellasall randomizedclinicaltrialsaddressingempiricalandtargeted antifungal therapy. In the absence of randomized clinical trials,thebestevidenceavailabletosupportthe recommen-dationswereselected.
Epidemiology
of
invasive
fungal
diseases
in
cancer
TheincidenceofIFDsinthepediatricpopulationwith can-cerand/orundergoingallogeneicHSCTishighlyinfluenced bythe use ofprophylactic systemic antifungalagents, the availabilityoftestsandproceduresforearlierdiagnoses,the adoptedIFDdefinitions,populationdenominators,andlocal epidemiology.1,2
ThepediatricpatientsatgreatestriskfordevelopingIFD are childrenundergoing allogeneic HSCT,those withacute myeloid leukemia (AML) and cases ofrelapsed acute lym-phoblasticleukemia(ALL).3Childrenwithacuteleukemiasare
continuouslyexposedtomultipleriskfactorsforIFDandupto onethirdofthemmaydevelopIFDintheabsenceofantifungal prophylaxis.4–7
IFDsafterallogeneicHSCThaveabimodalpatternof inci-dencethatissecondarytothepresenceofdifferentriskfactors
over time after transplantation. The first phase of risk is basicallyrelatedtothestatusoftheunderlyingdisease,the immunosuppressionsecondarytotheconditioningregimen, intensityanddurationofneutropenia,andmucositisthattake placebeforestemcellengraftment.Pendingontheintensity and duration ofneutropenia, patients may exhibit suscep-tibility to yeastsor also molds.After the engraftment and recoveryofneutrophilcount,theriskoffungalinfectionsis mostlydependentofthepresenceofacuteandchronic graft-versus-hostdisease(GvHD).Asexpected,theuseofantifungal prophylaxisandtheuseofhighefficiencyparticulateairfilters (HEPA)substantiallydecreasetheriskoffungalinfections.2,8
Mortality due to IFDsvaries from 20% to 70%, depend-ingontheintensityoftheimmunosuppression,presenceof comorbidities,theavailabilityoftoolsforearlydiagnosis,the siteandseverityoftheinfection,aswellasthetimeto ini-tiatetherapyand antifungalregimensused. Lowersurvival rateisusuallyseeninpatientswithdisseminatedfungal dis-ease,centralnervoussystem(CNS)involvement,underlying diseaserefractorytothefirstregimenofchemotherapyand persistentneutropenia.8,9Duringperiodsofdeeper
immuno-suppression,useofantifungalprophylaxismaymitigatethe riskofacquiringIFD,reducingmorbidityandhighmortality ratesoftheseinfections.2,10
Itisimportanttoconsiderthatcostsofantifungal treat-ment are alwaysamatterofconcernbyhealthcarepolicy makers.However,economicanalysesinhealthcareshould consider notonlythe costofdifferentantifungalregimens, butalsotheirimpactintermsofreducinglengthof hospital-izationsandintensivecareadmissions,toxicity,useofblood products,anddelaysfordeliveringappropriate antineoplas-tictherapies,whichmayhamperthechancesofcuringthese children.11–13
Variables
that
may
modulate
the
risk
of
IFDs
in
cancer
patients
Age
AgeisanindependentriskfactorforIFDsinchildrenbeing treated for AML or undergoing HSCT.8,14 Younger children
recoveryafterbeingexposedtointensivechemotherapy.7,15–17
Thedifferencesaremoresignificantwhencomparingimmune responsesinextremepediatricages.ChildrenwithAMLtend tobeolder,anditmayalsocontributetotheirincidenceof IFDs.Inaddition,olderchildrenandadolescentsaremore
sus-ceptibletomucousmembraneinjurydue tochemotherapy
exposure,andmucositismayalsoincreasetheriskofIFDs.14
Neutropenia
TheriskofIFDsisdirectlyrelatedtotheintensityandduration oftheneutropenia.Chemotherapyfurtherimpairsneutrophil, macrophage,Band T-lymphocytefunction,alsodecreasing immunoglobulinproductionandopsonization.5,14,18
Aneutrophilcountlowerthan 500/mm3 forlonger than
10daysisanimportantriskfactorforIFDs,but the riskis highestwithcountsbelow100/mm3inpatientswith
malig-nantneoplasms,oncorticosteroidsandchemotherapy,10AML
induction,andearlypostHSCT.Alowlymphocytecountof lessthan100/mm3furtherincreasestheincidenceofIFDsin
neutropenicfebrile childrenafter chemotherapy.19 Theuse ofsomenewimmunosuppressors,asinfliximab,maybe,by itself,ariskfactorforinvasiveaspergillosis.20
Hostimpactofanti-neoplastictreatment
Theintensityofthechemotherapyregimeninpediatric oncol-ogyisdrivenbymanydifferentfactors,suchasproliferative index of the tumor, stage and phase of the disease, risk ofrelapse, and the dose-limiting toxicitiesofthe different chemotherapycombinations.ChildrenwithAML,relapsedor refractoryacuteleukemias(bothlymphoidandmyeloid),and undergoingHSCThavethehighestriskofdevelopingIFDs. Oncethesehigh-riskpatientsareidentified,theyshouldbe maintainedunderprotectiveenvironment, includingrooms with HEPA filter, clean water and diet free of food-borne fungal contamination. In addition, they should be submit-tedtoanintensiveworkuptoactively screenforIFDs,and differentregimensofantifungalprophylaxisshouldbealso considered.5–7,10,14,21,22Thetreatingteammustbeawarethat
thesechildrenarealsoataveryhighriskofbacterialandviral infections.22
InALL patients, steroids usedduring inductiontherapy amplify the negative impact of neutropenia by impairing
phagocytosis, neutrophil migration and humoral immune
response. The use of an equivalent prednisone dose of
2mg/kg/dayisassociatedwithahighriskofIFDs.3,8High-dose
antimetabolites,anthracyclines and intensive asparaginase regimens lead to rupture of the mucosal barriers in the gastrointestinal tract, further increasing the occurrence of IFDs.3,5,17,22InpatientsundergoingallogeneicHSCT,theuse
ofhigh-dosesteroidsforover10daysanditsprolongeduseto treatGvHDareadditionalriskfactorsforIFD.8
Even minimizing invasive procedures during treatment, suchasbonemarrowaspirates,cerebrospinalfluidcollections, peripheral venipunctures and insertion of central venous catheters,childrencontinuesusceptibletobloodstream inva-sionbytranslocationofendogenous microbiota.All efforts shouldbetakentowarrantthathealthworkersworkingwith
hematologicpatientswillbecommittedwithbestpractices forcontrollinginfectionsrelatedtohealthassistance.8,10
Impactofbroad-spectrumantibiotics
The overuse of broad-spectrum antibiotics for empirical
treatment of febrile neutropenia changes the
endoge-nousmicrobiota,favoringcolonizationbyfungalpathogens. Indeed, the use ofantibioticsfor morethan seven daysis associatedwithanincreasedriskofIFDs.6
Impactofcandidaantifungalprophylaxis
Theprolongeduseofprophylacticfluconazole,oftenindicated inhigh-riskpatients,substantiallydecreasestheincidenceof candidemia,usuallytolessthan1%,butitmaycontributeto aselectionoffluconazole-resistantfungalpathogenssuchas C.glabrataandC.krusei.8
ImpactofdiseasesrequiringHSCT
Theunderlyingdiagnosesofsevereaplasticanemia, includ-ingFanconianemia,12andrelapsedorrefractoryleukemia21
significantly increase the chance of developing IFDs after HSCT. Prolonged lengthof neutropenia and the aggressive chemotherapyreceivedbythesepatientsmayfurther com-poundtheriskforIFDs.
ImpactofspecificHSCT-relatedtreatmentstrategies
Reduced intensity and non-myeloablative conditioning
regimenshavealowerriskofIFDswhencomparedto conven-tional myeloablative regimens during the pre-engraftment period.Bonemarrowandumbilicalcordbloodasgraftsources havehigherriskofIFDsthanperipheralbloodstemcells.8,11
T-cell depletion of the marrow or peripheral blood grafts further increases the risk of all opportunistic infections, includingIFDs.23
Theimmunosuppressiveagents selectedtoprevent and treat GvHD represent a majorrisk factor forIFD in trans-planted patients after engraftment.9,21,24 The presence of
cytomegalovirus(CMV) reactivation may havean
immuno-suppressiveeffectthatcanincreasepatients’susceptibilityto
IFDs.Thismechanismofimmunosuppressionhasnotbeen
completely characterized, but it is not only secondary to ganciclovir-inducedneutropenia.Infact,itiswellestablished
that CMVhasa negativeimmunomodulatoryeffecton the
activityofneutrophilsandmacrophages.8,25–27Asignificant
increaseintheriskoffungalinfectionisobservedwhenthe patientisCMV-seropositive,comparedwithbothpatientand donorwithCMV-negativeserology(p<0.01).26
Protectiveenvironment
Handwashingisanimportantpartofpreventingfungal dis-eases. Candida parapsilosis infections have been associated with the exposure ofpatients to central venous catheteri-zationandthe useofparenteralnutrition.Inthisscenario, thetransmissionofthisagentcanoccurthroughthehands
ofhealthcareproviders,sincetheseorganismsarefrequently presentintheirhands.8
Itisveryimportanttominimizeexposuretoairborne fun-galpropagulesthroughouthospitalization,notonlyduringthe periodofneutropenia.8Ahighefficiencyparticulateair(HEPA)
filter,providinganairfiltrationrateofmorethan12exchanges perhour,ishighlyrecommendedinhospitalfacilities assist-ingallogeneicHSCTrecipientsandAMLpatientsinorderto decreasetheirriskfordevelopinginfectionsduetoairborne filamentousfungi.28
Etiology
of
invasive
fungal
infections
in
pediatric
cancer
patients
and
their
clinical
impact
Candidasppcontinuestoberesponsibleforthemajorityof IFDsamongonco-hematologicpediatricpatients.However,in thepastdecades,thenumberofpatientsinfectedby filamen-tousfungihasincreased,includingAspergillusspp,Mucorales, andFusariumspp.22,29–31
Thisnewepidemiologicalscenarioisprobablyrelatedto thewidespreaduseofprophylaxiswithfluconazole,the inten-sityofimmunosuppressionsecondarytonewchemotherapy regimensandthedevelopmentofbetterdiagnostictoolsfor fungalinfections.1,21,32
Theclinicalpresentationofcandidemiaisusuallyfeveror sepsisrefractorytobroadspectrumantibiotics.C.albicans,C. parapsilosisandC.tropicalisarethemostfrequentisolates. Dis-seminatedcandidemiaisreportedin10–20%ofthepediatric patients;severesepsisandsepticshockoccursin30%. Mor-talityratesvarybetween10%and25%andcanbeupto50% inpatientsadmittedtoanintensivecareunit.1,33,34
In the HSCTsetting, Candida spp infections are usually identifiedwithinthefirstmonthaftertransplantation, espe-ciallyinpatientswithseveremucositis,duringneutropenia orimmediatelyafterneutrophilrecovery.OtherIFDscanalso occurinthisperiod,buttheyareusuallyduetoairway colo-nizationandimmunosuppressionpriortothetransplant.21,32
Epidemiological studies of invasive Aspergillosis (IA)
in pediatrics are usually represented by single center
reports.1,4,8,35,36 Theprevalenceof aspergillosisin
hemato-logicpediatricpatientsrangearound5–10%inpatientswith AML,relapsed orrefractoryleukemias,and post allogeneic HSCT.AtStJudeHospital(Memphis,USA),thehighest inci-dencewasfoundinpatientswithMDS(8%).35Thelethality
raterangesfrom20%to50%,butitisupto80%afterallogeneic HSCT.4
A retrospective study of 485 pediatricHSCT patients at DukeUniversity(USA)reportedanincidenceofIAof5%,witha higherincidenceamongallogeneicHSCTrecipients36;similar
tothefindingsoftwoothersdatabasesfromtheUSA.11,14
ThefirstpeakintheincidenceofIAoccursbetweenD+15 andD+30 afterHSCTbecauseofprolongedneutropenia. A second peaktakes placebetween D+60 andD+180and is associatedwithchronicGvHDandwiththeuseof immuno-suppressivedrugs,especiallycorticosteroids.1,8,32,34,21,38
Fun-gal infections in the early period after transplantation are usually documented in scenarios of HLA incompatibility, intensemyeloablativeconditioning regimensaswellasthe
lackofprotectiveenvironmentforassistingthepatients.Late fungalinfectionsareusuallydocumentedinthepresenceof GvHD,expositiontohighsteroiddosesandinpatientswith CMVreactivation.Aprevioushistoryofmoldinfectionsmay alsoincreasetheriskofIFDafterHSCT.1,8,32,34,21,38
Similar to adults, most pediatric patients present with pulmonaryaspergillosis.Disseminationtoothersites, partic-ularlytheCNS,mayoccurinupto30%ofthecaseswitha latediagnosis.39Ofnote,cutaneouspresentationofIAappears
tobemorecommoninchildrenthaninadults,probablydue totraumaticlesionsfollowed bydirectinoculationoffungi orbecauseoffungemia.Theskinlesionsinitiallypresentas non-specificerythematousoredematousplaques,sometimes verypainful,mayprogresstonecroticulcers.Patientsatrisk offungalinfectionwithskinlesionsmustundergobiopsyand cultureofthelesions.36
IFDscausedbyfilamentousfungiotherthanAspergillus,i.e., Fusariumspp,Scedosporiumsppandagentsofmucormycosis mayhaveaclinicalpresentationverysimilartoaspergillosis. Inourcountry,specialattention mustbepaidtoinfections causedbyFusariumspp.Fusariummaybepresentinthe pre-transplant period as apparently innocent paronychia that mayfurtherprogresstofastbloodstream invasionand sep-sisifsuperficialinfectionwereleftuntreatedalongtheperiod ofimmunosuppressionofthepatient. InarecentBrazilian multicenterepidemiologicalstudyfusariosiswasoneofthe
mostcommonIFDdocumentedamonghigh-riskhematologic
patients,includingcasesofHSCT,MDSandAML.29Patients usuallydevelopfungemia, painfulskinpapulessurrounded byanerythematoushaloandcentralnecrosis,and pneumo-nia. Serumgalactomannanisoftenpositive, increasingthe confusionwithIA.40,41
The literatureofinvasivefusariosis ismostly relatedto adultpatients.However,aneverincreasingnumberofcases of invasive fusariosis has also been reported in pediatric patients.42,43
Diagnostic
tools
in
clinical
mycology
ConventionalmethodsforthediagnosisofIFDs
ThediagnosisofIFDinpatientswithmalignanthematologic diseaseand/orundergoingHSCTshouldtakeinto considera-tion thepresenceofspecificriskfactors,aswellasclinical, radiological, and microbiological findings. To optimize the sensitivityandaccuracyofthediagnosisoffungalinfections, moleculartests(PCRbasedmethodsandassaysfordetecting fungal antigens)shouldbeusedincombinationto conven-tionalmethods,aswellasdirectexamination,histopathology, andculture.44,45
Directexamination
Directmicroscopicexaminationofclinicalmaterialsisoneof themoststraightforwardmethods,simpleandusefulforthe diagnosisoffungalinfectionoftherespiratorytractandskin lesions,asreportedinpatientswithfusariosis.46Advantages
ofthismethodincludethelowcostand shortturn-around timeforprovidingresults,butitmayhaveasensitivitylower than 50%,especially inpatients alreadyreceiving systemic antifungalagents.44
Culture
Cultures playa fundamental role in the diagnosis of fun-galinfections,providinganaccuratecharacterizationofthe agent.However,sensitivityislow(<50%)andfinalresultsmay takemanydayspendingonthepathogen.Thevolumeofthe biologicsamplemay substantiallyimpactthe sensitivityof thetest whatshould beconsidered along thecollection of thesamplesaccordingwiththebottleused(neonates<4kg: 1mL;pediatric: 4–13.9kg:3mL,14–24.9kg:10mland adults or>25kg:20mL).47Automatedbloodculturesystems,suchas
BactecTM(BDInstruments,USA)andBacT/Alert® (bioMérieux,
Brazil)havesensitivityaround50%forinvasivecandidiasis.48
Theidentification offungiatspecieslevel ismandatory forthe adequate characterizationof the IFD epidemiology ineach center, as well as toallow the adequate selection ofstrategies forprophylaxis, controland treatment ofthe infection.Theidentificationoffilamentous fungiisusually basedontheanalysisofthemicro-morphological character-istics of the reproductive mycelium ofthe mold pathogen isolatedinculture.Accuratespeciesidentification ofmolds is highly dependent on the combination of data provided bycolonymicromorphologyexaminationandsequencingof specificDNA target regions, astrategy thatmay allow dis-criminationofgeneticcloselyrelatedspecies.Morerecently, commercialsystemsbasedonproteomicanalysisperformed byMatrixAssociatedLaserDesorption-Ionization—Timeof Flight(MALDI-TOF)havebeenintegratedtotheroutineof clin-icallaboratoriesprovidingaccurateautomatedidentification ofyeastandmoldswithinfewminutes.49–51
Histopathology
ThegoldstandardforthediagnosticofIFDcausedbyamold isthehistopathologicdemonstrationoftissueinvasionbya filamentousfungicomplementedbycultureofthe biologic samplewithaccurateidentificationofthepathogen.However, tissuebiopsiesarenotfrequentlyperformedinhematologic patientsduetothecoexistenceofcoagulopathies, thrombo-cytopenia,neutropeniaandclinicalinstabilities,suchas res-piratoryfailure.Whenavailable,thetissuesampleshouldbe culturedandsentforhistopathologicalevaluationwith hema-toxylinandeosin(HE)andspecificstainingforfungi(periodic acidShiff(PAS)and/orGrocottstain(methenamine-silver).44
Roleofbiomarkersformycologicaldiagnosis
During episodes of IFDs, fungal antigens can be released into the bloodstream before the appearance of any clini-calorradiologicalabnormalitiesinasubstantialnumberof patients. Biological samples collected for the detection of fungalbiomarkersinserumor bronchoalveolarlavagemay provideanearlierdiagnosisofIFDinpatientswithmalignant hematologicaldiseasesand/orundergoingHSCT.44,52
Detectionofgalactomannan(GM)inbiologicalfluids
GMisapolysaccharidepresentinlargeamountsinthecell walloftheAspergillusspp.Itisreleasedintoinfectedhost tis-suesduringthehyphaegrowth.Despiteitsrelevanceforthe diagnosisofinvasiveaspergillosis,thisantigenisalsopresent inotherfungal agentsand cangeneratepositive resultsin
infectionscausedbyFusariumspandHistoplasmacapsulatum, amongothers.53
In Brazil, the sandwich-type immunoenzymatic assay
(ELISA,PlateliaTMAspergillus,RioRad,France)iscommercially
available for detecting this antigen. Final results may be obtainedafterapproximatelythreehours,muchfasterthan tissueculture.Galactomannandetectioninbiologicsamples fromhigh-riskpatientshasbeenusedwithgreatsuccessto aidintheearlydiagnosisofIA.54
In adults, in a significant number of patients, circulat-ing GM maybe detectedatamedian offiveto eightdays beforeclinicalandradiologicalmanifestationsofaspergillosis. Basedonseveralstudies,GMpositivityinserum, bronchoalve-olarlavagefluid,orcerebrospinalfluidhasbeenacceptedas mycologicalcriteriaofIAintherevisedEuropean Organiza-tion forResearchand TreatmentofCancer/InvasiveFungal InfectionsCooperative Groupand bythe National Institute ofAllergy and InfectiousDiseases MycosesStudyGroup— EORTC/MSG.55 False-positive and false-negativeresults can
occurforseveralreasons(Table1).53Lowersensitivityrates
aredocumentedinnon-neutropenicpatients,without onco-hematological diseases,aswellasinpatientsonanti-mold antifungalprophylaxis.57,58
ArecentsystematicreviewaddressingtheaccuracyofGM inpediatricpatientsanalyzedresultsof10studiesinwhich GMwasusedforscreeningoffungalinfectionsinhigh-risk patientsandeightstudiesevaluatingGMasadiagnostictoolin thepresenceofspecificclinical/radiologicalfindings. Exclud-ingcasesofpossibleIFD,onlyfivestudiesforeachoneofthe settings(screeningversusdiagnosis)remainedinthepooled analysisofspecificityandsensitivity.InthecohortwhereGM assaywasusedforscreeningIA,specificityandsensitivity val-ueswere91%[95%confidenceinterval(CI):86–94%]and68% (95%CI:51–81%),respectively.Otherwise,inthesettingwhere GMwasrequestedonlyatthemomentofdiagnosis,specificity andsensitivityvalueswere85%(95%CI:51–97%)and89%(95% CI:79–95%),respectively.59
The positive predictive values (PPVs) in children were ratherlowandrangedbetween0and100%ineachsetting, whilethenegativepredictivevalues(NPVs)wereconsiderably higher,rangingfrom85to100%andfrom70to100%inthe screeninganddiagnosticsetting,respectively.59
Data on GM in pediatric patients are still controversial to supportageneral recommendations forthe clinical use ofthis biomarkerforscreeningofaspergillosisinhigh-risk patients.60 Somemedicalcenters startedto useserum GM
monitorizationofhigh-riskpatientsaspartoftheirstrategy forpreemptivetreatmentofaspergillosis.61Experiencewith
GMscreeningofpediatricpatientsisstillscarcetoprovide anygeneralrecommendation.
Galactommanantestpositivity
Two consecutive serum samplesexhibiting galactomannan
index ≥0.5 or one result ≥0.7 are suggestive of IA. For bronchoalveolarlavage(BAL)samples,thecutoffitisstill con-troversial:themanufacturerconsidersanindex≥0.5inthe BALaspositive,butmostmeta-analysesandpediatricstudies suggestthatapositiveresultrequiresGMindex≥0.8or1.0in theBAL.1,51,52,53
Table1–Factorsthatcanleadtofalse-positiveandfalse-negativeresultswiththegalactomannantest.63
False-positive(andcross-reactions) False-negative
Biochemicalalterations Presenceofanti-Aspergillusantibodies formingimmunecomplexes Bilirubin≥20mg/L
Triglycerides≥200mg/dL Hemoglobin≥500mg/dL
Useofcytotoxicchemotherapeuticagents(promotingdamagetothe intestinalmucosa)
Storageofsamplesatroomtemperaturefora prolongedperiodbeforeprocessing
Graftversushostdiseaseandautoreactiveantibodies Highserumalbuminlevels
BacteremiabyPseudomonasspp.orEscherichiacoli Presenceofgalactomannan-degradingenzymesin biologicalmaterial
Useof-lactamssuchaspiperacillin-tazobactam, amoxicillin/clavulanicacid
Prioruseofantifungalagents
IFIsbyotherfungi: ChronicgranulomatousdiseaseandJob’s syndrome(hyperimmunoglobulinE) Fusarium Cryptococcus Histoplasma Penicilium Alternaria Paecilomyces Geotricum Yarrowialipolytica
Alterationsofintestinalmucosa(intakeofcerealandcowmilk) Lackofneutropenia NeonatescolonizedbyBifidobacteriumspp.
Gluconate-containingPlasma-Lyte
Otherintravenousfluidscontaininggluconate Possiblycardboardorsoybeanprotein
1,3ˇ-d-glucan(BDG)
BDG is a polysaccharide found in large quantities in the cell wall of several pathogenic fungi including Candida spp., Fusarium spp, Aspergillus spp, and agents of endemic mycoses. The presence of BDG in blood or other biologi-cal fluids can be a serological marker of fungal sepsis in patientswithcandidemia, aspergillosis,fusariosis,or infec-tions caused by Pneumocystis jiroveci, Acremonium spp. or Saccharomyces spp. It is important to mention that this testisnegativeininfections causedbyCryptococcusandall Mucorales.44,63
Alimitationofthistestisthelargenumberofconditions thatmaygeneratefalse-positiveresultsandthesmallnumber ofstudies addressingtherelevanceofthis testinpediatric populations.59,64
InBrazil,ANVISAapprovedtheFungitell® commercialtest (AssociatesofCapeCod,Inc.)forclinicaluse.Inadults,results
below 60pg/ml are considered negative, values between
60−80pg/mlinconclusive(suggestingtherepetitioninanew sample)and>80pg/mlisconsideredpositive.Inpatientsat risk ofIFD, different authors recommend serum collection twiceaweek.
Recently the Dynamiker Fungus (1-3)-B-d-Glucan Assay (DinamikerBiotechnology(Tianjin)CO.,LTD,Popular Repub-licofChina)hasbeenapprovedbyANVISAforIFIdiagnosis. AlthoughitsperformanceisequivalenttoFungitel,itis sel-domusedinBrazil.65
Cutoffvaluesof(1-3)-B-d-Glucancommercialtestsfor diag-nosingfungalinfectionsinpediatricpatientsarenotyetwell validated.64,66
Usingimagesasadiagnostictool
Imagingtestsareusefultoolsforevaluatingpatientswith sus-pectedIFD,especiallywithinvolvementoftherespiratorytract andcentralnervoussystem.Duetolimitationsinsensitivity ofconventionalchestX-ray(CXR)todetectIFDin immuno-compromisedpatients,CTscansarestronglyrecommended forscreeningpatientsatrisk.
Prospective studies conducted in adult patients have demonstrated thatCT scans can detect pneumoniaearlier thanCXR.Indeed,whenCTscanissystematicallyperformed inpatientsathighriskforIFDitmayprovideearlierdiagnosis of invasive pulmonary aspergillosis with improvement in prognosis.67,68
Imagingforinvestigationofneutropenicpatientswith persistentfever
Accordingtothe2017guidelinesonclinicalmanagementof children with febrile neutropenia, imaging studies, includ-ing chestCTscanoradequate imagingofthe symptomatic organ/system,shouldbeperformedintheevaluationof chil-dren considered tobeathigh-riskfordeveloping IFD, who remain febrile and neutropenic formorethan 96hdespite adequateantibioticcoverage.10,60
Thereislittledataontheevaluationofchildrensuspected ofsinonasalIFD.Notably,childrenwithlessthantwoyearsof agedonothavesufficientpneumatizationofthesinus cavi-ties,andthus,sinusimagingisrarelyinformativeinthisage range.Theroleofroutineabdominalimagingisuncertainin patientswithpersistentfebrileneutropenia,andimagingof abdominallesionsmaygeneratefalselynegativeresults.60
Imagingforcheckingpatientswithpulmonaryinfections Imagingfindingsininfantswithpulmonaryinvolvementcan differfromthoseinolderchildrenandadults.
Candidainvolvementofthelungsisrareinthissettingof patients.Thefewcasesreportedinthispopulationare typ-ically secondary to hematogenous dissemination and lung lesionsareusuallyrepresentedbyinfarctions,homogeneous consolidationssuchasbacteriallobarpneumoniaorpresence ofmass-likeroundedimageswithorwithoutcentralnecrosis, asoccurwithAspergillus.69
The image spectrum of pulmonary aspergilosis may
includeground-glassappearance,smallnodules,larger nod-ulestosegmentalorlobarconsolidations,andinvasionofthe ribcage.Hilarlymphnodeenlargementandsmallpleural effu-sionsmayoccur.70
Thepresenceofsmallnodulesorconsolidationswith sur-roundingground-glassarea,knownasthehalosign,resulting fromperilesionalhemorrhage,secondarytoangio-invasion, suggests angio-invasive aspergillosis in the neutropenic patient. Thehalo sign is mostcommonly reported in pul-monaryaspergillosisbutisnotpathognomonicofthisfungal infectionandmayoccursecondarytootherconditions. Cavi-tationandaircrescentformationmightoccurmorefrequently inolderchildrenand adultswithaspergillosis, when com-paredtoyoungerchildren.68,71,72
Thelargest seriesreportingaspergillosisinchildrenwas collect byBurgos et al.in 2008,addressing 188 pulmonary radiographicfindings generatedwith110patientswith
pul-monarydiseasewherenodulesweredocumentedin59%of
thecases.Noduleswerelessfrequentlyseenintheyoungest childrencomparedtotheolderagegroups:noduleswereseen in38.7%(12of31)ofthe0-to5-year-oldscomparedwith71.8% (28of39)and62.5%(25of40)ofthe6-to12-year-oldand 13-year-oldgroups,respectively.Onlythree(2.2%)of110patients showedtheaircrescentsign,andnoneofthemwasreported withinthegroupwith0-to5-year-olds.4,72
Interms ofobtainingaccuratediagnosisoffungal infec-tions,itismandatorytocorrelateradiologicalfindingswith clinical presentation, the host immunity status, results of fungalbiomarkers,anddataprovidedbyconventional micro-biologyassays.10,44
Thereiscurrently greatconcernregardingthe radiation doseoftheradiologicalexams,asthesepatientsundergo mul-tipleexaminationsthroughoutthefollow-upperiod.
Chronicdisseminatedcandidiasisorhepatosplenic candidiasis(CDC)
CDCisapersistentCandidainfectionoftheliver,spleen,and others organs that may follow candidemia in neutropenic patientsafterrecoveryofneutropenia.73 Whenrestrictedto
the liveror spleen, this entity isoften referredto as hep-atospleniccandidiasis(HSC).44
Ultrasonography(USG)remainsausefultoolfordetecting andmonitoringCDC.74Themainadvantageofthismethodis
thelackofnephrotoxicityandradiationexposuretoperform theexam,butitsmainlimitationisthatUSGmightnotdetect smalllesions.TheuseofcontrastwithUSGmightimprove theyieldofUSGfordetectingfungallesionsthatare repre-sentedbydisseminatedhypoecogenicsmalllesions.Atypical findingofCDClesionsintheliveristhebull’seyeortarget
patternwithperipheralhypoecogenichaloencirclingacentral hyperechogeniccore.73
MRIseemstobesuperiortoCTinidentifyingliverlesions associatedwithCDC;itssensitivityis100%andspecificityis 96%whentheappropriatetechniquesareused.75,76Themajor
drawback ofMRIuseiscostand availability.Inthisregard, contrast-enhancedbiphasicCTorUSGremaincredible imag-ingmodalitiesforpatientswithsuspectedCDC.77
Patientswithsinusinfection
Itisimportantto emphasizethatCT imagingtestscannot demonstratetheparanasalsinusesinvolvementinpatients withearly-stageAspergillusrhinosinusitis,whose diseaseis restrictedtothenasalcavity.
AcuteAspergillusinfectionoftheparanasalsinusesappears
in CT images as nonspecific dense opacification of the
airspaces. Bone erosionis often absent or present onlyat latestageofinfection andshouldnotbeconsidereda nec-essaryfindingforearlydiagnosisofacuteAspergillussinusitis. Ethmoidal sinusitiswithinvolvementofanorbitcan occur in the absence of bony erosion of the lamina papyracea. Alsoconsistentwiththisobservationisthatethmoidalsinus aspergillosiscaninvolvethemedialrectusmuscleoftheorbit whilethelaminapapyracearemainsintact.Increased diame-teronaCTscanandelevatedsignalintensityonT2-weighted imagingwilldelineatethemedialrectusinfection.Similarly, aspergillosis of the frontal sinuses can be associatedwith infectionofthefrontallobeswithouterosionofthewallsof thefrontalbone.Maxillarysinusaspergillosiscaninvadethe palatinevesselsandresultinnecrosisofthehardpalate.66,78
Theedemasignal ofthe paranasalsinusesmucosa cor-respondstotheSTIRhypersignalandT1hyposignal.When thissignalismodifiedtoSTIRhyposignalandT1hypersignal (heavyfungimaterial),itisdiagnosticofIFD.Thesignofthe fatoftheposteriorwallofmaxillarysinusshouldalsotobe evaluatedtocharacterizetheextentofthedisease.79
PatientswithCNSinfection
In the pediatric cancer population, Aspergillus spp may infecttheCNSviahematogenousdisseminationtothebrain parenchyma,seeding ofCSF,or bydirectextensionfrom a sinusfungalinfection,resultinginaclinicalpresentationthat includescerebritis,abscess,meningitis,andventriculitis.80,81
Patterns ofCNS aspergillosisidentified inneuroimaging inimmunocompromisedpatientsinclude(1)multipleareas ofhypodensity(CT)orhyperintensity (T2-weightedMRI)in the cortex and/or subcortical white matter corresponding tothromboembolic infarctionwithorwithout hemorrhage; (2) multipleintracerebral ring-enhancinglesions consistent with abscesses with a low signal (T2-weighted MRI); and (3)duralenhancementassociatedwithenhancinglesionsin the adjacent paranasal sinusstructure or calvariaor dural enhancementoftheopticsheathwithassociatedopticnerve andintraorbitalfatenhancement.82
Inarecentreviewof29childrensubmittedtohematologic stemcelltransplantationwhodevelopedIFDbymold,itwas foundthat20%ofthepatientsdidnotpresentanyneurological symptomsatthetimeimagingresultssuggestedthe involve-ment ofCNS by the fungal infection. Notably,all patients inthisseriespresentedatleastonesiteoffungalinfection
besidestheCNS,mostlythelungs.Basedontheirexperience theauthorssuggestedthatfacingaseverely immunocompro-misedpatientwithdiagnosis ofIMD atanysiteweshould consideradiagnosticworkupincludingimagesofCNS.83
Fur-therstudiesarenecessarytoconfirmifthisstrategyisreally cost-effectiveinclinicalpractice.
Frequencyofimagecontrol
Thisis ahighly controversialissue that should be consid-eredonacasebycasebasis.For patientswithpneumonia andsinusitis,ifthereisaclearclinicalimprovementofthe children, a new CT scan should not be considered before two weeks of treatment. In case of clinical deterioration
and failure of response, a new imaging may be
consid-ered at any time.84 We were not able to find robust data
to support any general recommendation on specific times
for imaging control of patients with fungal sinusitis or CNSinfection.66,70,78,85 Oncethe diagnosisofhepatosplenic
IFD has been established, patient should be submitted to
sequential imaging (every 30–60 days) to document
com-pleteresolutionofthelesions.Anewimageandbiochemical tests should be requested at any time in case of clinical deterioration.85,86
Strategies
for
diagnosing
IFD
in
pediatric
cancer
patients
The combination of different diagnostic tests is th best strategyforevaluatinghigh-riskpatientsandresultsshould be interpreted after considering a combination of vari-ables: status of the underlying disease, exposure to risk factors,clinicalpresentation,availabilityofprotecting envi-ronment for taking care of the patient, epidemiology of each medical center, as well as patient exposure to
dif-ferent regimens of antifungal prophylaxis or empirical
therapy.44
Inadults,GM,BDGandfungalPCRarethetoolsusedto earlydiagnoseIFD.However,onlyGMandBDGwere incorpo-ratedintothecriteriafordefinitionofopportunisticIFDand invasiveaspergillosis,accordingtoEORTC/MSG.55
The use of these tests in pediatrics remains highly
questionable as previously mentioned. A recent
system-aticreviewand meta-analysisaddressingthe useoffungal
biomarkers in pediatric cancer and HSCT concluded that
fungal biomarkers may present poor PPVs when used as
screening tools during neutropenia or periods of GVHD.59
Otherwise, recently, Santolaya et al. showed good clinical
results using GM in combination with imaging for
driv-ing antifungal therapy in pediatric patients with febrile neutropenia.61
Accordingtodataobtainedwithadultptientswith hema-tologicmalignancies,incasethecliniciandecides forearly diagnostic-drivenapproach(preemptiveantifungaltherapy) for initiating antifungaltherapy, a sequential collection of
serum samples (at least twice a week) for detecting GM
inhigh-risk patients for IFDis recommended tocheck for early diagnosis of IA.10 Otherwise, there is a lack of data
supporting the efficacy ofthis strategyin pediatric cancer patients.10
Intheabsenceofgoodscientificevidencetosupportthe preemptiveantifungalapproachinpediatricpatients,the lat-estguidelinesforfebrileneutropeniainchildrenwithcancer recommendthecombinationofimagingandfungal biomark-ersonlytoinvestigatehighriskpediatricpatientswithsigns, symptomsand/orclinicalinstability.60
Ofnote,innon-neutropenicpatients,inviewofthelimited sensitivityofserumGMfordiagnosingaspergillosis,anegative resultofthisbiomarkerwillnotruleoutthepossibilityofthe disease.Inthisparticularsetting,itisbettertoconsiderthe detectionofGMinBALsamplewherethesensitivityofthetest increasestoatleast80%.59
Disease-definingcriteriaaccordingtoEORTC-MSG
(Euro-pean Organization for Research and Treatment of
Can-cer/InvasiveFungalInfectionsCooperativeGroupandbythe NationalInstituteofAllergyandInfectiousDiseasesMycoses StudyGroup)
ThedefinitionofacaseofIFDisbasedonacombination ofevidencesinvolvinghostfactors,clinicaldataand myco-logical criteria.Themainhostfactors tobeconsidered are thepresenceofneutropenia,exposuretoallogeneicstemcell transplant, treatmentwithhigh-dosecorticosteroidsand/or Tcellimmunosuppressants.Theclinicalcriteriarelymostly onimagesoflowerrespiratorytractfungaldisease(nodules, presenceofhalosign,air-crescentsignorcavityonCTscan), sinonasal and CNS infection. The mycological criteria are basedonthepresenceoffungalelementsondirectmicroscopy orcytologyexamination,isolationoffungalpathogenin cul-ture ofnormally sterilebiologic samples,histopathologyof tissue samples, and positive fungal biomarkers as galac-tomannan antigendetectedinserumorinbronchoalveolar lavagefluid.55
Thecertaintycategoriesofdiagnosisaredefinedas pos-sible,probableandproven,pendingonthekindofevidence supportingthediagnosis.ProbableIFDrequiresthepresence ofahostfactor,aclinicalcriterion,andamycologicalcriterion notrelatedtohistopathologyoftheinfectedorgan.Casesthat meetthecriteriaforahostfactorandaclinicalcriterionbutfor whichmycologicalcriteriaareabsentareconsideredpossible IFD.ThecriteriaforprovenIFDincludesculturefromsterile materialorhistopathologicstudyofaspecimenobtainedby needleaspirationorbiopsyinwhichhyphaeareseen accom-paniedbyevidenceofassociatedtissuedamage.Severalseries ofstudiesconductedinadultcancerpatientshavesuggested thatalargeproportionofcasesclassifiedas ¨probable ¨are con-firmedbydiagnosisafterdeath,unlikethe ¨possible ¨casesthat aremostlyotherdiseases.86,87
Basedontheirexperienceanddataavailableinthe med-icalliterature,thepresentpanelofspecialistsorganizedtwo diagramsandalgorithmsfortheclinicalmanagementof pedi-atriconcologypatientsunderhighriskfordevelopingIFD(see Figs.1and2).
Notably,candidemiaisusuallydocumentedbythe pres-ence of a positive blood culture. Fusariosis is usually
documented by the presence of the pathogen in blood
culture(sensitivitycloseto60%),directexaminationand cul-ture of skin lesions ofmaterial from the respiratory tract.
Skin lesions Respiratory symptoms Neurological symptoms Pain and/or ocular edema
Adapt the investigation strategy according with clinical findings and
Risk stratification
Bood cultures Serum Galactomannan
Skin Lesion RespiratorySymptoms
Ocular pain And/or Facial edema Neurological symptoms Biopsy Direct exam Culture Histopathology Positive Candidaspp Mould Fundoscopy Abdominal USG Paranasal CT Thorax CT Paranasal CT
Thorax CT Cranial CT
Absence of intracranial hypertension Spinal Fluid Direct exam Culture Galactomannan ENT evaluation Orbit CT Paranasal sinus CT Nasofibroscopy CT Sugestive of DFI + Serum GM + CT Sugestive of DFI + Serum GM Neg Sinusitis-Consider surgical cleaning and culturing +histology
Evaluate possibility of BAL-Biopsy Direct exam Culture and Histology Symptomatic high-risk patients for IFD
In case of lesions: Direct exam
Culture Histology
Fig.1–StrategyforearlydiagnosisofIFDsinhigh-riskpatientswithfeverfollowedbyclinicalmanifestations. CT,computerizedtomography;IFD,invasivefungaldisease;BAL,bronchoalveolarlavage;ENT,otolaryngologist.
AML Relapsed ALL Allogeneic HSCT
Check GM results ParanThorax CTasal CT
GM + Thorax CT +
GM–Thorax Sinus CT +
GM– Thorax and Paranasal CT–
Start treatment targeting Aspergillosis
Evaluate possibility to perform BAL (GM)-BAL and Sinus direct examination,
culturing and/or biopsy for diagnosis
Consider Empirical Treatment and stop if all
results are negative for fungal elements
Investigate others sources of
fever
Febrile neutropenia for >96h despite broad spectrum ATB
Fig.2–StrategyfordiagnosisonpatientsatriskforIFDwithfebrileneutropeniafor>96hdespitebroadspectrumATB. AML,acutemyeloidleukemia;HSCT,hematopoieticsteamcelltransplantation;GM,galactomannan;CT,computerized tomography.
Mucormycosisisusuallydocumentedbythepresenceoflarge and non-septate hyphae in cytology or biopsy of infected tissuesamplesoncecultureshavelow sensitivityand fun-galbiomarkersare usuallynegative.Aspergillosisisusually detectedbythecombinationofGMinserumand/orBAL sam-pleofhigh-riskpatientsexhibitingimagescompatible with fungalinvolvementinrespiratorytract.44
Different
strategies
for
antifungal
therapy
of
IFD
Antifungalprophylaxis
ProphylaxisagainstinvasiveCandidainfectionswith flucona-zole is recommended for all pediatric patients with acute
myeloidleukemia,recurrentacuteleucemia,allogeneicHSCT andhigh-riskacutelymphoblasticleukemia.Local epidemi-ologyand patient-specificriskfactors,suchascomorbidity or specific treatment modalities, are important considera-tionsforthechoiceofanappropriateantifungalprophylactic strategy.10
Recent guidelines recommend mould-active antifungal
prophylaxis,mainlywithnewtriazoles,forhighrisk hema-tological malignancies and HSCT transplant recipients.84,85
Posaconazoleprophylaxis canbe usedfor patientsover 13 yearsold.88Ingeneral,anti-mouldprophylaxisareonly
cost-effectiveinpatientswithincidenceratesofinvasivemould infectionshigherthan 7–10%.Otherwise, itincreasescosts, toxicityandtheriskofantifungalresistance.1,10,85
Empiricantifungaltherapyversusdiagnostic-driven
antifungaltreatment
Empiricalantifungaltherapyhasbeenacommonpracticein granulocytopenicchildrenwithpersistentfeverdespitefour daysofappropriateempiricalantibacterialtherapy.This strat-egyshouldbeconsideredonlyforhigh-riskgranulocytopenic childrenwithnewlydiagnosedorrecurrentacuteleukemia andinthoseundergoingallogeneicHSCT.Antifungaltherapy shouldbeuseduptotheresolutionofgranulocytopeniain spiteoftheabsenceofdocumentedIFD.Alleffortsmustbe donetoelucidatethediagnosisinordertoreduceunnecessary exposureofpatientstoantifungaltherapy.10
Multiplestudies conducted inadultpopulation indicate that monitoring serum GM and Aspergillus-PCR inpatients
with acute leukemia or myelodysplasia and HSCT
recipi-entsduringneutropeniaisuseful fortheearly diagnosisof IA.WhencombinedwithaggressiveCTscanningofsinuses andlungs,thisstrategymaysafelyreplacetheconventional regimenofempiricalantifungaltherapydrivenbyfebrile neu-tropeniarefractorytoantibioticsincancerpatients.53,70,85,89,90
Unfortunately,itisstillunclearifthisstrategymaybe success-fullyextrapolatedforpediatriccancerpatients.
Recently,Santolayaetal.performedaprospective multi-centerrandomizedtrialinSantiago,Chile.Childrenpresenting withpersistenthigh-riskFNwererandomizedtoempiricalor pre-emptiveantifungaltherapy.Theyincluded149children, 73 received empiricaltherapy and 76 pre-emptivetherapy. Only32/76(42%)received antifungaltherapyin thisgroup. Theoverallmortalitywassimilarinbothgroups,IFD mortal-itywasthesame(3%);pre-emptivetherapywasaseffective asempiricalantifungaltherapyinthesechildren.61Thiswas
thefirstprospective,multicenter,randomizedstudy compar-ingstandardversuspre-emptiveantifungaltherapyinHRFN childrenwithprolongedfever andneutropenia. More stud-iesperformedwithpediatricpatientsarenecessarybeforewe establishanyrobustrecommendationfortheroutineuseof pre-emptiveantifungaltherapyinthissetting.
Antifungaltherapyofpatientswithdocumentedfungal
infections
Invasiveaspergillosis
Voriconazolehas been considered byseveral guidelines as thetreatmentofchoiceforthiscondition,butmonitoringof
drug plasmalevelsisrecommendedtooptimizeantifungal therapy.10,84,85,91Inordertoavoidtoxicityandoptimize
clini-calresults,thetargetplasmaticconcentrationofvoriconazole shouldremainistherangeof1–5mg/L.92Liposomal
ampho-tericinB,initiallyat3mg/kg/day,isanacceptablealternative forpatientsagedlessthantwoyearsold,aswellasfacingany contraindicationforvoriconazoleuse.10
There isnoevidencetosupporttheuse ofcombination antifungal therapy for treating children with aspergillosis. Recently,Isavuconazolewasfoundtobeequallyefficientand less toxic than voriconazole ina randomizedclinical trial performedwithadultpatients.93Sofar,therearenoclinical studiesaddressingtheuseofisavuconzoleinchildrenwithIA. Invasivefusariosis
ThegenusFusariumcontainsmanyspeciesandiswidely dis-tributedinnature.Humanfusariosismanifestsassuperficial infections (dermatomycosis and onychomycosis), localized subcutaneousinfectionsand,inseverelyimmunosuppressed patients,sinus,lungordisseminateddisease.40,94Therapeutic
outcomesarepoorduetounderlyingsevere immunosuppres-sionandsuboptimalsusceptibilityofthepathogentoalmost allantifungals.TheEuropeanSocietyofClinicalMicrobiology and InfectiousDiseases/European ConfederationofMedical Mycologyguidelines fortreatmentofraremould infections recommends the use of voriconazole as the best alterna-tiveforfusariosis,beinglipidformulationsofAMBaccepted as alternative choices.95,96 Considering the concerns with
voriconazoleplasmalevelsinchildren,combinationtherapy of amphotericinB lipid formulation with voriconazolehas beenextensivelyusedbyseveralmedicalcenters.42,43,94
Invasivemucormycosis
Theoptimaltreatmentofmucormycosishasnotbeendefined, duetothe lackofappropriateprospectiveandrandomized clinicaltrials.AmphotericinBdeoxycholate(AmB-d)at max-imum tolerabledoses(1–1.5mg/kg/day)washistoricallythe antifungal treatment of choice prior to the availability of lessnephrotoxiclipidformulationsofamphotericinB.Lipid formulations ofAMB, startingat5mg/kg/day, arenow pre-ferred as first-line therapy, with a higher initial dose of 10mg/kg/dayrecommendedincasesofCNSdiseasebysome investigators.97
Based on observational data, posaconazole may have a roleinpatientswhorequireongoingmaintenancetherapy.97
Maintenancetherapy isindicated inpatientswith residual tissue-basedinfectionorwithriskfactorsthatarenot read-ilymodifiable.Inthesepatients,therapeuticdrugmonitoring should be performed where possible.Given the paucityof high-quality evidenceandtheuncertainefficacyand safety ofthisstrategy, combinationpolyene-echinocandintherapy cannotcurrentlyberecommended.Similartoadults,surgery combinedwithantifungaltherapyisamajorfactortoincrease survival.97
Invasivecandidiasis
Patients should be initially treated with echinocandins as suggested by most guidelines published recently.98–101
Considering the lack of data on the safety and efficacy
Table2–TreatmentofInvasiveCandidiasis(adaptedfromGroll2014andColombo-2013).10,101
Recommendations Comments
Fluconazole 8–12mg/kg/dayIV Fungistaticactivity(checkforpersistent candidemia).
1x/day(Max: 800mg/day)
Avoidusingforneutropenicpatientsand criticallyillpatients.
NotrecommendedforC.kruseiandC.glabrata
infections. Voriconazole 2–12yearsor12–14yearsandweight
<40kg:(IV):9mg/kg/doseonD12x/day and8mg/kg/dose2x/dayonsubsequent days
Fungistaticactivity.
(Oral):9mg/kg/dose2x/day ConsiderindicationforpatientswithCNS infections.
>15yearsor12–14yearsandweight >40kg:
ActiveagainstC.krusei.
(IV):6mg/kg/doseonD12x/dayand 4mg/kg/dose2x/dayonsubsequentdays
Notapprovedforclinicaluseinchildren<2 years.
(Oral):200mg2x/day Targetserumlevel1–5mg/L. Caspofungin 70mg/m2(IV)onD1 Fungicidalactivity.
50mg/m2(IV)onsubsequentdays HighMICsforC.parapsilosisareprobablynot clinicallyrelevant(checkforpersistentcandidemia).
Micafungin 2–4mg/kg/dayIV Fungicidalactivity.
1x/dia HighMICsforC.parapsilosisareprobablynot clinicallyrelevant(checkforpersistentcandidemia).
>50kg:100–200mg Liposomal
AmphotericinB
3mg/kg/dayIV Fungicidalactivity.
1x/day Usuallyconsideredforpatientswithdeep-seated infectionsorCandidainfectionsrefractoryto otheralternatives.
AmphotericinBlipid complex
5mg/kg/day Fungicidalactivity.
IV1x/day Lowlevelofevidenceforitsclinicalusedueto thelackofrandomizedclinicaltrials.
Usuallyconsideredforpatientswithdeep-seated infectionsorCandidainfectionsrefractoryto otheralternatives.
Table3–TreatmentofInvasiveAspergilosis(adaptedfromGrolletal.,2014).10
Recommendations Comments
Voriconazole 2–12yearsor12–14yearsandweight <40kg:(IV):9mg/kg/doseonD12x/day and8mg/kg/dose2x/dayonsubsequent days.
Recommendationbasedonphase3 studiesinadults.
(Oral):9mg/kg/dose2x/day. Treatmentofchoiceforinfections involvingtheCNS.
>15yearsor12–14yearsandweight >40kg:
Therapeuticclasschangeis recommendedinpatientsthatuse triazolewithanti-fungalactivityagainst filamentousfungusforprophylaxis. (IV):6mg/kg/doseonD12x/dayand
4mg/kg/dose2x/dayonsubsequentdays. (Oral):200mg2x/day. Liposomal AmphotericinB 3mg/kg/dayIV 1x/day AmphotericinBlipid complex 5mg/kg/day IV1x/day
AntifungalCombinationTherapy Echinocandinassociatedwithpolyeneor triazole
Absenceofrobustdatatomakeany recommendation.
micafunginrepresentthemostappropriateoptionsfor chil-drenamongtheechinocandins.FormulationsofAMBarealso considered as alternative, especially in patients with CNS infectionsorendocarditis.99–101
After initial course of therapy with broad spectrum
antifungals, step-down therapy with fluconazole may be
consideredafterclinicalstabilizationandfacingthecorrect
identification of the pathogen. Treatment with
flucona-zole is not recommended for infections by Candida krusei and Candida glabrata, since C. krusei is inherently resis-tant, and C. glabrata has low susceptibility to this agent (Tables2–5).99,100
Table4–TreatmentofInvasiveMucormycosis(adaptedfromGroll,2014).10
Recommendations Comments
AmphotericinBlipidcomplex 5–7.5mg/kg/day Recommendationsimilartothatofthe adultpopulation.
IV1x/day Liposomal
amphotericinB
5–10mg/kg/dayIV Recommendationsimilartothatofthe adultpopulation.
1x/day GivepreferencetothisdrugoverABLC AmphBinpatientswithCNSinfectionor thosewithrenalinsufficiency.
Antifungalcombinationtherapy LipidAmphotericinassociatedwith echinocandinorposaconazole.
Lackofevidencethatthisstrategymay worksinchildren
Posaconazole 800mg/dayorally Approvedforpatientsoverthan13years old.
2xor4x/day Scarcepharmacokineticstudiesin patientsunder13years.
Withnolevelofevidence Serumlevelistobemonitored–Target: 0.7–1.5mg/L.
Patientsover13yearsofage
Table5–TreatmentofInvasiveFusariosis(adaptedfromGroll,2014).10
Recommendations Comments
Voriconazole 2–12yearsor12–14yearsandweight <50kg:(IV):9mg/kg/doseonD12x/day and8mg/kg/dose2x/dayonsubsequent days.
Recommendationsarebasedonseriesof casestreatedwiththisdrug.
(Oral):9mg/kg/dose2x/day. >15yearsor12–14yearsandweight >50kg:
(IV):6mg/kg/doseonD12x/dayand 4mg/kg/dose2x/dayonsubsequentdays. (Oral):200mg2x/day.
Posaconazole 800mg/dayorally InBraziltabletsandIVformulationsare notavailable;
2xor4x/day Drugbioavailabilityisstronglyimpactby feedingandgastricpH.
Onlypatientsover13yearsofage AmphotericinBlipid
complex
5mg/kg/dayIV Recommendationsarebasedonseriesof casestreatedwiththisdrug.
1x/day
LiposomalamphotericinB 3–5mg/kg/dayIV Recommendationsarebasedonseriesof casestreatedwiththisdrug.
1x/day
Patientswith hepatosplenic candidiasisusuallyrequires severalweeksor monthsoftherapywhatusuallydemands inductionwithechinocandinsfollowedbylongperiodsof flu-conazoleuptocompleteresolutionoflesions.99–101
Conflicts
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interest
Theauthorsdeclarenoconflictsofinterest.
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