braz j infect dis.2013;17(1):102–105
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
w w w .e l s e v i e r . c o m / l o c a t e / b j i d
Case
report
Posaconazole
as
rescue
therapy
in
African
histoplasmosis
Daniel
Gonc¸alves
∗,
Catarina
Ferraz
a,
Luisa
Vaz
bServic¸odePediatriadoCentroHospitalardeSãoJoão,Porto,Portugal
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Articlehistory:
Received16March2012 Accepted11June2012 Availableonline9January2013
Keywords:
Posaconazole Histoplasmosis Salvagetherapy
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AfricanhistoplasmosisisagranulomatousmycosiscausedbyHistoplasmacapsulatumvar. duboisii.Treatment isusuallyextrapolatedfromguidelinesforclassicalhistoplasmosis, andincludes2–4weeksofamphotericinBfollowedbyastep-downmaintenancetherapy withitraconazole.Pediatricusageofposaconazole,anoralsecond-generationazole,remains off-label,butrecentsurveysshowthatitissafeandwelltoleratedinchildren.Wereport acaseofdisseminatedAfricanhistoplasmosisina12-year-oldboy fromGuinea-Bissau. TherapywithamphotericinBanditraconazoleledtoaprogressiveclinicaldeterioration. Adramaticandlastingimprovementwasobservedusingposaconazole.Hecompleted12 monthsoftherapy.Norelapsewasnotedduringor3monthsaftertreatment.Wereport thatposaconazolemay be a safe and efficacious drug in thesalvage management of disseminatedAH,eitherinpatientswithdiseaserefractorytoconventionalanti-fungal therapy, or in patients whose serious adverse effects of first-line drugs preclude its use.
©2013ElsevierEditoraLtda.Allrightsreserved.
Introduction
Histoplasmosis is a granulomatous disease caused by the dimorphicfungusHistoplasmacapsulatum.Therearetwo rec-ognized subspecies of this fungus pathogenic to humans, namelyHistoplasmacapsulatumvar.capsulatum(Hcc)and Histo-plasmacapsulatumvar.duboisii(Hcd).Classicalhistoplasmosis iscausedbytheformer,andisendemicinNorthandLatin America.InfectionbyHcd isendemic inCentraland West AfricaandMadagascar,1andisresponsibleforAfrican
histo-plasmosis (AH). All reported cases of AH in Europe are importedfromendemicareas.2
∗ Correspondingauthor.Tel.:+351912328391;fax:+351225025766.
E-mailaddresses:danieldiasgoncalves@gmail.com(D.Gonc¸alves),ferraz.catarina@gmail.com(C.Ferraz),luisagvaz@netcabo.pt
(L.Vaz).
a Tel.:+351910528939;fax:+351225025766. b Tel.:+351934500014;fax:+351225025766.
InhaledH.capsulatumconidiaresultinsubclinicalinfection inthemajorityofexposedindividuals,butdisseminated dis-easeisnotuncommon.ThemainclinicalfeaturesofAHare involvementoftheskin,subcutaneoustissues,lymphnodes andbones,andrarelythelungsandotherinternalorgans.3
TreatmentofAHisusuallyextrapolatedfrom the guide-linesoftheInfectiousDiseasesSocietyofAmericaestablished forclassicalhistoplasmosis,4andincludes2–4weeksof
lipo-somalamphotericinBfollowedbyastep-downmaintenance therapywithoralitraconazoleforatleast12months.
Posaconazole, an oral second-generation azole, was approved by FDA in 2006for prophylaxis of invasive Can-didaandAspergillusinfectionsinadultimmunocompromised
1413-8670/$–seefrontmatter©2013ElsevierEditoraLtda.Allrightsreserved.
brazj infect dis.2013;17(1):102–105
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hosts.Pediatricusageofposaconazolehasbeendescribedin somesmallseries,anditsuseremainsoff-label.Recent sur-veysinwhichposaconazolewasusedassalvagetherapyshow thatitissafeandwelltoleratedinchildren3–17yearsold.5,6
Wereportthefirstcaseofposaconazoleusageassalvage therapyinAfricanhistoplasmosis.
Case
presentation
A12-year-oldAfricanboyfromGuinea-Bissauwasreferredto ourhospitalwithapresumptivediagnosisoflymphoma.Upon review,hehada2-yearhistoryofmultiplenodularformations incervical,axillary,andinguinalregions,whichwere enlarg-ingwithtime,andwereassociatedwithcutaneousfistulas. Hehadnofever,weightlossorrespiratorysymptoms.Hehad beentreatedinhishomecountrywithlarge-spectrum antibi-oticsforseveralweekswithoutanyclinicalimprovement.
Onphysicalexaminationheappearedpale,butwasfully conscious,andhadnormalvitalsigns.Cervical,axillary,and inguinalnodularformationsweredischargingayellowishpus. Therewerenoabdominalpalpablemasses.Theotherphysical examinationwasunremarkable.
Initial workup revealed anemia (hemoglobin=7.2g/dL), leucocytosis (15,860/L) with neutrophilia, thrombocytosis (967,000/L), and elevated C-reactive protein (98.3mg/L). Liverandkidneyfunctiontestswerenormal.Evaluationfor immunologicprofiledidnotshowanyevidenceof immuno-suppressionandhumanimmunodeficiencyvirustestingwas negative.Computerizedtomography(CT)ofthechestrevealed acondensationintheleftlowerlobewithperipheral micron-odules and hilar calcifications. Abdominal ultrasound was normal.
Onday3,hestarteda6-monthcourseofanti-tuberculous therapyduetoapositivepolymerasechainreaction(PCR) sam-pleofMycobacteriumtuberculosis(Mt)inagastricaspirate.This infectionwaslaterconfirmedbyapositivesputumculture. Meanwhile,acervicalnodularbiopsyrevealednecroticareas alongwithotherscontainingnumeroushistiocyteswith mul-tinucleatedgiantcells,polymorphicinflammatoryinfiltrate, andnumerousuninucleatethick-walledlargeyeasts,budding fromanarrowbase(Fig.1,arrow).Basedonthismorphology, adiagnosisofHcdinfectionwasmadeandhebegantherapy withliposomalamphotericinB(5mg/kg/day).Histoplasmosis waslaterconfirmedbymultiplepositiveswabculturesofthe exudates.After4weeksofamphotericinBtherapy, hewas switchedtooralitraconazole(10mg/kg/day).Atthisstage,a smallclinical improvementwasobserved, withonlyminor reductioninthesizeoflymphadenopathies.Inthefollowing weeks,thepatientclinical statuswasrapidlydeteriorating, withenlargementofthepreviouslynotedadenopathies,along withappearanceofnewcutaneousfistulas.Apainful supra-pubicabdominalmassappeared,andabdominalCTidentified numerousnewretroperitoneal lymphadenopathiesand left hydronephrosisduetodirectcompressionoftheureter(Fig.2). AmphotericinBwasrestarted,withnoapparentclinical ben-efit.
After approval by our hospital’s ethics committee, posaconazole therapy was started, at a dosage of 400mg twicedaily.Adramaticandlastingimprovement,bothclinical
Fig.1–Histologyfromacervicalnodule– remarkthe presenceofnumerousuninucleatethick-walledlarge yeastsHistoplasmacapsulatumvar.duboisii(Hcd)along withnumeroushistiocytes(HE– 400×).BelowaGrocott staindisplaysthethickwalloftheyeastsaswellasthe budding(600×).
(Fig. 3A-D) and biochemical, was observed. Imagiologic control2monthsafterintroductionofposaconazole demon-strated resolutionofhydronephrosisand onlyminor(1cm) lymphadenopathies.Atday127ofposaconazoletherapy, com-pletecicatrizationofallskinlesionswasachieved(Fig.3).Our patientcompleted12monthsoftherapywithposaconazole. Norelapsewasnotedduringor3monthsaftertreatment.
Discussion
Thiscaseillustratesthemanychallengesthatcliniciansface when treating conditions more common in tropical areas. Despiteitsrarity,AHshouldbekeptinmindasapossible diag-nosisinAfrica-bornpatientswhohavecompatiblesigns or symptoms,particularlyinvolvingtheskinandlymphnodes.
ThepathogenesisofAHremainsunclear.Themainrouteof acquisitioncouldbeairbornecontaminationfromthesoiland, rarely,directinoculation.7Inthiscase,wecouldnotidentify
thesourceofcontamination.AH,asobservedinourpatient, isusuallynotassociatedwithimmunosuppression.7
Fungalcultureremainsthegoldstandardfordiagnosisof histoplasmosis,butishamperedbytheslowgrowthofthis microorganism.Inourpatient,histologicalanalysisrevealing granulomasandfungiwithingiantcellswasthekeyforarapid diagnosis.Weshouldnotethattheobservedgiantcell granu-lomatosiscouldalsosuggesttuberculosis,butthehistological presenceofyeasts, the negativityofPCR forMycobacterium
inthehistologysample,andtheabsenceofclinical improve-mentwithanti-tuberculoustherapysuggestthattuberculosis
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braz j infect dis.2013;17(1):102–105Fig.2–Abdominalcomputerizedtomographyshowingmultipleretroperitoneallymphadenopathies.
Fig.3–Cervicalnodularformationsatdays4(A)and22(B)ofposaconazoletherapy,alongwithcervical(C)andinguinal(D) regionsaftercompletecicatrization.
brazj infect dis.2013;17(1):102–105
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wasnotresponsibleforthecutaneousandabdominalmasses. Tuberculosisisnowadaysaglobalemergency,responsiblefor 1.7milliondeaths/year.8 InGuinea-Bissau it isanendemic
infection,with a prevalenceof 134/100,000,as shown in a recent cross-sectional survey.9 In our patient, tuberculosis
mighthavecontributedtoAHinfection,butwecannot estab-lishanycausalrelationshipwiththesetwoentities.
InthepreviouslydescribedcasesofAH,themostcommon therapeuticregimensincludedamphotericinBand ketocona-zole,fluconazoleor itraconazole. In someofthesereports, thediseaseprovedfatal,eitherduetoits naturalcourseor duetosideeffects,mainlyassociatedwithamphotericinB.10
Posaconazole,though already successfully used as salvage therapyinclassicalhistoplasmosis,11hasneverbeenusedin
refractoryAH.
Although firm recommendations regarding use of the newerazolesinhistoplasmosiscannotbemade, posacona-zoleappearstobeapotentialvaluabletreatmentoption,even incomparisonwithestablishedeffectiveagentssuchas itra-conazole.Inmurinemodels infectedwithHistoplasmaspp., althoughtheminimalinhibitoryconcentrationfor itracona-zoleandposaconazolewassimilar,posaconazolewasatleast 10 timesmoreeffective than itraconazoleinreducing fun-gal burden.12 Moreover, itraconazole, being a substrate for
cytochromeP4503A4(CYP3A4),hasagreaterpropensityfor druginteractions.13Thisalsomighthavecontributedto
itra-conazolefailureinourpatient,sincehewasbeingtreatedwith theantituberculosisdrugrifampicin,aninducerofCYP3A4.14
Pharmacokineticandefficacydataforposaconazoleusage inpediatricpatientsarestillvery limited,15 but evenusing
highdoses(400mgtwicedaily),itprovidedaveryfast, sta-ble,andsafetherapyinourpatient.However,morestudies areneeded tooptimizeposaconazoledosageand lengthof therapyinpediatricpatients.
Inconclusion,wereportthatposaconazolemaybesafeand efficaciousinthesalvagemanagementofdisseminatedAH, eitherinpatientswithdiseaserefractorytoconventional anti-fungaltherapy,orinpatientswhoseseriousadverseeffectsor druginteractionsoffirst-linedrugsprecludeitsuse.
Conflict
of
interest
Allauthorsdeclaretohavenoconflictofinterest.
Acknowledgements
TheauthorsaregratefultoDra.HelenaBarrocafromour Hos-pital’sDepartment ofPathologyfor providingthe histology imagesforthisarticle.
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s
1. WheatLJ.Histoplasmosis:areviewfromcliniciansfrom non-endemicareas.Mycoses.2006;49:274–82.
2.ManfrediR,MazzoniA,NanettiA,ChiodoF.Histoplasmosis capsulateandduboisiiinEurope:theimpactoftheHIV pandemic,travelandimmigration.EurJEpidemiol. 1994;10:675–81.
3. GugnaniHC,Muotoe-OkaforF.Africanhistoplasmosis:a review.RevIberoamMicol.1997;14:155–9.
4. WheatLJ,FreifeldAG,KleimanMB,etal.Clinicalpractice guidelinesforthemanagementofpatientswith histoplasmosis:2007updatebytheInfectiousDiseases SocietyofAmerica.ClinInfectDis.2007;45:
807–25.
5.KrishnaG,Sansone-ParsonsA,MartinhoM,etal. Posaconazoleplasmaconcentrationsinjuvenilepatients withinvasivefungalinfection.AntimicrobAgents Chemother.2007;51:812–8.
6.LehrnbecherT,AttarbaschiA,DuerkenM,etal.Posaconazole salvagetreatmentinpaediatricpatients:amulticentre survey.EurJClinMicrobiolInfectDis.2010;29: 1043–5.
7. LoulergueP,BastidesF,BaudouinV,etal.Literaturereview andcasehistoriesofHistoplasmacapsulatumvar.duboisii
infectionsinHIV-infectedpatients.EmergInfectDis. 2007;13:1647–52.
8.WorldHealthOrganization.Globaltuberculosiscontrol– surveillance,planning,financing.WorldHealthOrganization; 2008.WHO/HTM/TB/2008.393.
9.Bjerregaard-AndersenM,daSilvaZJ,RavnP,etal.
Tuberculosisburdeninanurbanpopulation:acrosssectional tuberculosissurveyfromGuineaBissau.BMCInfectDis. 2010;10:96.
10.RakotoariveloRA,RazafimahefaSH,AndrianiainaHD, RandriaMJD.Unehistoplasmoseafricainechezunpatient malgacheimmunocompétent.BullSocPatholExot. 2010;103:19–21.
11.RestrepoA,TobónA,ClarkB,etal.Salvagetreatmentof histoplasmosiswithposaconazole.JInfect.2007;54: 319–27.
12.ConnollyP,WheatJ,Schnizlein-BickC,etal.Comparisonofa newtriazoleantifungalagent,Schering56592,with
itraconazoleandamphotericinBfortreatmentof histoplasmosisinimmunocompetentmice.Antimicrob AgentsChemother.1999;43:322–8.
13.KontoyiannisDP.Invasivemycoses:strategiesforeffective management.AmJMed.2012;1251Suppl.:S25–38.
14.NakamotoT,HaseI,ImaokaS,etal.QuantitativeRT-PCRfor CYP3A4mRNAinhumanperipherallymphocytes:induction ofCYP3A4inlymphocytesandinliverbyrifampicin. Pharmacogenetics.2000;10:571–5.
15.CesaroS,MilanoGM,AversaF.Retrospectivesurveyonthe off-labeluseofposaconazoleinpediatrichematology patients.EurJClinMicrobiolInfectDis.2011;30:595–6.