Cutaneous mucormycosis in advanced HIV disease

brazjinfectdis2016;20(6):637–640

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

Case

report

Cutaneous

mucormycosis

in

advanced

HIV

disease

José

Moreira

_,

_Felipe

_Ridolfi

_,

_Rodrigo

_Almeida-Paes

_,

_Andrea

_Varon

_,

Cristiane

C.

Lamas

a_{InstitutoNacionaldeSaúde,MinistériodaSaúde,Maputo,Mozambique}

b_{Fundac¸ãoOswaldoCruz(FIOCRUZ),InstitutoNacionaldeInfectologiaEvandroChagas,LaboratóriodePesquisaClinicaemDSTe}

AIDS,RiodeJaneiro,RJ,Brazil

c_{Fundac¸ãoOswaldoCruz(FIOCRUZ),InstitutoNacionaldeInfectologiaEvandroChagas,RiodeJaneiro,RJ,Brazil}

d_{Fundac¸ãoOswaldoCruz(FIOCRUZ),InstitutoNacionaldeInfectologiaEvandroChagas,LaboratóriodeMicologia,RiodeJaneiro,RJ,}

Brazil

e_{InstitutoNacionaldeCardiologia,RiodeJaneiro,RJ,Brazil} f_{UniversidadedoGrandeRio(Unigranrio),RiodeJaneiro,Brazil}

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Articlehistory:

Received3March2016 Accepted22June2016 Availableonline26July2016

Keywords: HIV Mucormycosis Rhizopus AIDS

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Angionvasivemucormycosisisanemergingfungaldiseaseknowntoaffectmainly diabet-icsorsubjectswithprofoundneutropenia.Infectionusuallyoccursthroughtheinhalation route,butcutaneousinoculationmayoccuraftertraumaorburns.However, mucormyco-sisremainsunusualinHIVinfection.Wereportafatalcaseofcutaneousmucormycosis duetoRhizopusarrhizusinvolvingthescalpfollowingherpeszosterinfection.Thepatient wasa42-year-oldmanwithadvancedAIDSfailingonsalvageantiretroviraltherapy.The funguswasdiagnosedonthebasisofhistopathologyandculture.Ourcaseemphasizesthe needtoconsidermucormycosisinthedifferentialdiagnosisofnecroticcutaneouslesions inpatientswithlate-stageHIVdisease.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Introduction

Invasive fungal infections represent a major cause of morbimortality in AIDS patients.1 _{Pneumocystosis,} cryp-tococcosis, and histoplasmosis are typically seen in HIV-infected patients with profound immune suppression (e.g. CD4+<200cells). Therapidexpansion ofantiretroviral ther-apy has contributed to a reduction in the incidence of these fungal infections. However, mucormycosis remains infrequently seen in patients whose only risk factor is

∗ _{Correspondingauthor.}

E-mailaddress:jose.moreira@ini.fiocruz.br(J.Moreira).

HIV infection, and few cases have been reported in the literature describing this rare association.2,3 _{In a recent} systematic review of 929 reported cases of mucormyco-sis, HIV infection was the attributed risk factor in just 2% but was associatedwith ahigher mortality rate.4 Sim-ilarly, in a study of 1630 autopsies conducted in AIDS patients from 1984 to 2002, mucormycosis was detected in only two cases.5 _{Herein, we report a fatal case of} cutaneous mucormycosis due to Rhizopus arrhizus in an AIDSpatientfailingsalvagecombinationantiretroviral ther-apy.

http://dx.doi.org/10.1016/j.bjid.2016.06.004

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

638

Case

report

A42-year-old male was admittedto our center with com-plaintsofasevere headache foramonth,accompaniedby scalprednessanddifficultyinmakingfacialmovements.His past medical history included chronic HIV infection, with poor adherence to antiretroviral drugs. He was diagnosed withHIVinfectionin2008,hadbeenonseveral antiretrovi-raldrugsandhislatestregimenwasacombinationof3TC, DRV/r,RAL,andMVQ.Themostrecentimmunovirologypanel showedCD4+ T-cellcountof2cells/mm3andHIVviralload of57.147copies/mL.Onemonthpriortopresentation,hewas seeninthewalk-inoutpatientclinicforacutesinusitisand facialherpeszoster;levofloxacin,prednisone,andvalacyclovir wereprescribed.Theconditiondeterioratedwiththe develop-mentofbilateralfacialpalsy,diffusefacialedemaandmultiple fistulaswithpurulentdischargesoverthescalp.Upon admis-sion,acomputedtomography(CT)scanofthebrainshowed airfluidlevelsandmucosalthickeningintheleft maxillary andsphenoidsinuses,obliterationoftheposteriorright eth-moidcells,andadiffuseincreaseofthefacialsubcutaneous tissuewithanorganizedcollectioninthelefttemporalregion. Nobrainparenchymalesionswerenoted.

Broad-spectrum antibiotics were started and blood cul-turesformycobacteria, fungiand bacteria weredrawn.On examination,hewasunderweight(BMI:15.9kg/m2_)and ane-mic,butvitalsignswere normal.Neurologicalexamination showedbilateralseventhcranialnervepalsy.Anareaof infil-trativeedemaandcellulitisinthescalpandforeheadregion wasvisiblecoupledwithmultiplebackescharslesions,some ofthemdrainingserupurulentdischarge(Fig.1).Aspiratesof

Fig.1–Featuresonadmission:infiltrativelesionsand cellulitisconcentratedinforeheadandscalpregion; multipleulcerscoveredwithblackeschar,draining seropurulentsecretion;seventhnervepalsy.

Fig.2–MicroscopicexaminationofRhizopusarrhizus: unbranchedsporangiosporeswithcollapsedcolumellaand rhizoids.Bar:100␮m.

scalp lesionsand ascalpbiopsy were performedand sam-ples were cultured inSabouraud dextroseAgar2%(Biolog, Brazil)andMycobioticAgar(Becton,DickinsonandCompany, USA).Cultureswerekeptat25◦C.Fungalidentificationwas performedbymorphophysiologicaltests,suchasmacroscopic andmicroscopyanalysis,andthermo-tolerance.Microscopic fungalaspectswereevaluatedunderaZeissPrimoStarlight microscope. Afterfour days, gray colonieswithcotton-like dense growth were observed. Microscopic aspects of the fungus included broad-hyphae with a few septa; rhizoids producedunderunbranchedsporangioporesthatterminated withdarkround sporangia(60–200␮m diameter)producing browntoblacksporangiospores(around6␮mlength)(Fig.2). Histopathologyshowedachronicnecrotizingandsuppurative granulomatousdermatitiswithnumerouscoenocytic (asep-tate)hyphae (Fig. 3). Thefunguswasable togrowat30◦C and 37◦C,but notat45◦C.Thefunguswas thenidentified asR.arrhizus.Bloodculturestakenathospitaladmissionwere negative.

Initialtreatmentwasintravenousoxacillinandceftazidime resultedinpartiallyimprovementofthesubcutaneousedema and erythema. Treatment with intravenous deoxycolate amphotericin B (1mg/kg/d) was then started on day 7 of admission.DespitesomeimprovementafteramphotericinB

Fig.3–Histopathology(hematoxylin–eosin)ofscalp biopsy:chronicnecrotizingandsuppurativegranulomatous dermatitiswithnumerouscoenocytic(aseptate)hyphae.

brazj infect dis.2016;20(6):637–640

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Fig.4–Day10afteradmission:persistenceof

erythematouslesionsdispersedoverthescalpregion.Note thetinyulcerscoveredbyblackeschars.

administration,thefacialpalsyandscalppurulentdrainage remained(Fig.4).Duringhospitalization,recurrentepisodes ofsevere neutropeniawere observedand improved bythe additionofgranulocytecolony-stimulantfactor. Inparallel, thepatientdevelopedseveralepisodesofcatheter-associated sepsis due to Pseudomonas aeruginosa, Methicillin-resistant

Staphylococcus aureus, and ESBL-producing Klebsiella pneu-moniae. A repeat CT scan after 6-weeks of antibiotic and antifungal therapy still showed mucosal thickening and a smallfluidlevelintheleftmaxillarysinus,extensive opaci-ficationofsphenoidalsinusandasmallbonediscontinuity oftheintersphenoidalsinus.Thepatientwasunsuitablefor sinusbiopsyduetotheongoingbloodstreaminfections.After eightweeksoffollow-up,thepatienthadreceiveda cumu-lativedoseof2gofamphotericinB.Thepatientdiedonthe 49thdayofhospitaladmissionandthe41stdayofantifungal therapy.

Discussion

Mucormycosis is an emergent fungal infection which

affectsasubstantialproportionofimmunosuppressedhosts, especially diabetics, those with hematological malignancy and recipients of bone marrow transplants. Fungi are

comprised of two main subphyla – Mucormycotina and

Entomophthoromycotina.6_{Diseasecausedbymembersofthe} Mucormycotinaplayanincreasingroleintheclinicalsettings especiallyinimmunocompromisedpatients.Theusualsites ofinfectionreflectportalsofentryandincludesinuses,lungs andskin.

Cutaneous involvement occurs in almost 20% of cases involvingpatientswithoutunderlyingimmunosuppression.4 The three main forms are superficial, nodular, and gan-grenous.Themechanismofacquisitionisthoughttobefrom inoculationofspores intoinjured skin. Moreover, hospital-relatedproceduressuchascatheterinsertion,injectionsites, adhesiontapes,woodentonguedepressors,ostomybags,and contaminated cotton clothes are some of the risk factors previouslydescribed.7_{Casesofpost-traumatic,suchasroad}

trafficaccidents,scorpionandspiderbites,andburnsin oth-erwise healthy individuals have also been reported in the literature.8–12 _{Theclinical presentationconsistsofasingle,} painfulareaofcellulitis,whichoftenprogressintoecthyma. Necrosismaydeveloprapidlyandsubsequentdissemination toadjacenttissuemayfollow.Thesefeaturesarehallmarksof mucormycosisattributablemainlytoangioinvasionand sub-sequenttissuethrombosis.

Here, we described an AIDS patient with cutaneous mucormycosisduetoR.arrhizus,diagnosedbasedona posi-tiveskinhistopathologyandconfirmedbyculture.Inaddition, wehypothesizedthatdisseminationoftheinfectionto sub-cutaneoustissueandthentothesinuses(thelattersuggested bythetemporalrelationandtheradiologicalfeaturesinthe absenceoftheothercommoncausesofsinusitis)didoccur.

Eventhoughwecouldnotperformanendoscopic evalu-ationofthesinusestomakeaprecisediagnosis,itislikely thatthesinusitiswasalsoduetomucormycosis.Inaddition, wearguethattheherpeticlesionsledtotissueischemiaand actedasapossibleportalofentryandacontributingfactorto thecutaneousmucormycosissuperinfection.

HIV-associated mucormycosisdoes occur predominantly inrelatively young males,withlower CD4+ _{cell countsbut} withoutthetraditionalriskfactorslinkedtomucormycosis.13 In some cases, there are underlying predisposing factors suchas transientepisodes ofneutropeniaand intravenous injections drug abuse. Mucormycosis has been the initial presentation ofHIV infection and, insomecases, unusual manifestations have been described.14 _{Co-infection with} otheropportunisticdiseasessuchascytomegalovirus vasculi-tis, Pneumocystis jirovecii pneumonia, and Kaposi’s sarcoma resultedincomplicatedcasesastheirpresencecontributes toincreasedvirulenceinthediseaseprocess.15 _Multi-organ dissemination does occur.16 _{Due tothe difficulty in} distin-guishing mucormycosis from other angioinvasive diseases (e.g.diseasescausedbyAspergillus,Fusarium,Pseudallescheria),

cliniciansshouldalwaysconsidermucormycosisinthe differ-entialdiagnosisinpatientswithadvancedAIDS.Collectively, those factsdraw attention totheimportance of mucormy-cosis asanemergent severeopportunistic pathogen inthe late-stageofHIVinfection.

Mortalityratesformucormycosisvarybetween38and66%; however,thereislargevariationdependingontheunderlying condition,siteofinfection,speciesinvolved,andregimenof antifungalsadministered.4,17,18_{Forinstance,infectiondueto}

Cunninghamellaspecies, disseminateddisease,active malig-nancy, andmonocytopenia were independentpredictors of pooroutcome,whereassalvageposaconazole-basedtherapy andneutrophilcountrecoverywerepredictiveofafavorable outcome.4,17

Acombinationofsurgicaldebridementcoupledwith fungi-cidal therapy improve patient outcomes.6 _{Amphotericin B} remainsthedrugofchoice.Posaconazolehasbeenusedas asalvagetherapyinextensiveandrefractorycases.6_Recently, anopen-labelphase3studyofisavuconazole–anew broad-spectrumtriazole–fortreatmentofmucormycosis,showed thatisavuconazoleimprovestreatmentsuccessinupto36%of patientswithprimaryorrefractorydisease.19_Themain advan-tagesofisavuconazoleoverotherantifungalagentsinclude the availability ofa water-solubleintravenousformulation,

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excellent oral bioavailability, predictable pharmacokinetics, andfewersideeffects.20_{Besidesadministrationofantifungal} therapy,itisvitaltopromptlyreversetheunderlyingrisk fac-torsthattriggeredmucormycosis(e.g.neutropenia,diabetes mellitus,corticosteroids).Inourcase,treatmentwith gran-ulocytecolony-stimulatingfactor wasintroducedtoreverse neutropenia.

The lipid-based formulations of amphotericin B have becometheantifungalsofchoiceforthetreatmentofinvasive fungal infections duetoless renal toxicity, fewer infusion-relatedreactionsandprovisionofhigherdosesoverashorter period of time compared to conventional amphotericin B. Wewere unableto providethose formulations inour case becauseofrestricteddrugavailabilityduetohighdrugprices. However,webelievethatourreportrepresentsareallife sit-uation and mirrors the current challenges facing Brazilian medicalinstitutions.Provisionofthemosteffectiveandsafe amphotericinBformulationsinthetreatmentof mucormyco-sis,especiallyinthedevelopingworld,needstobeurgently addressed.

Our patient presented severe immunosuppression and transientepisodesofneutropeniaoccurredpriortoand dur-ing hospitalization, possiblycontributingto mucormycosis. Thepatientalsoreceivedhigh-dose steroidtherapyfortwo weeks,whenherpeszosterandsinusitisweretreatedbefore admission.Despitetheextensivesinusitisshowedonrepeat CT scans, we were unable to perform sinus drainage and debridementbecausethepatientwascritically-illandseverely undernourished,whichcontraindicatedsurgery.Promptsinus andskindebridementmighthaveallowedabetteroutcomein thiscase.

Inconclusion,ourcasehighlightstheimportanceof main-tainingahigh index ofsuspicion formucormycosisinthe impairedhost,especiallythoseatlatestageAIDS,presenting withnecroticcutaneouslesions.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Wewishtoacknowledgethesupportofthemedicaland nurs-ingstaffatInstitutoNacionaldeInfectologiaEvandroChagas forthededicatedcareofthispatient.Moreover,wethankFabio Santosforhishelpinfungusidentification.

José Moreira is supported by a scholarship from Pro-grama de Estudantes-Convênio de Pós-graduac¸ão (PEC-PG, CAPES/CNPQ).

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