Chronic skull osteomyelitis due to Cryptococcus neoformans: first case report in an HIV-infected patient

brazjinfectdis2018;22(6):499–502

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

Chronic

skull

osteomyelitis

due

to

Cryptococcus

neoformans:

first

case

report

in

an

HIV-infected

patient

Natanael

Sutikno

Adiwardana

_,

_Juliana

_de

_Angelo

_Morás

_,

_Leandro

_Lombo

_Bernardo

_,

Giselle

Burlamaqui

Klautau

_,

_Wladimir

_Queiroz

_,

_Jose

_Ernesto

_Vidal

a_{InstitutodeInfectologiaEmilioRibas,ProgramadeResidênciaMedica,SãoPaulo,SP,Brazil} b_{InstitutodeInfectologiaEmilioRibas,DepartamentodeDoenc¸asInfecciosas,SãoPaulo,SP,Brazil} c_{InstitutodeInfectologiaEmilioRibas,DepartamentodeNeurologia,SãoPaulo,SP,Brazil}

d_{UniversidadedeSãoPaulo,HospitaldasClínicasdaFaculdadedeMedicina(HCFM-USP),DepartamentodeDoenc¸aseInfecciosas,São}

Paulo,SP,Brazil

e_{UniversidadedeSãoPaulo,InstitutodeMedicinaTropical,LaboratóriodeInvestigac¸ãoMédica,SãoPaulo,SP,Brazil}

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Articlehistory:

Received28September2018 Accepted16November2018 Availableonline6December2018

Keywords: Cryptococcusneoformans Osteomyelitis Skull HIV

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OsteomyelitisduetoCryptococcusneoformansaredescribedinmostly10%ofpatientswith disseminatedcryptococcosis,beingdirectinoculationevenmoreuncommon.Wereportthe caseofanHIV-infectedpatientwithhistoryofrecurringitchingonhisscalpandrepetitive localtrauma.Foreighteenmonths,henoticedapainfulandslowgrowinglumponhisscalp. Hewassubmittedtoanexcisionalbiopsyofthelesionbutnoetiologicaldiagnosiswas iden-tified.Afterthisprocedure,thepost-surgicalwoundnevercompletelyhealed.Atadmission, thepatientpresentednauseaandheadacheforthreedaysandanopenorificeintohisskull. InvestigationsconfirmedmeningitisandskullosteomyelitiscausedbyCryptococcus neofor-mans.Hewastreatedwithbonedebridementandcombinedsystemicantifungals,showing goodclinicalandlaboratorialoutcome.Cryptococcaldiseaseshouldbeincludedinthe dif-ferentialdiagnosesofchronicosteomyelitisinHIV-infectedpatientsandtraumaisapossible sourceofinfection.

©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

Globally,invasivefungalinfectionsareresponsibleforahigh burden ofmortality and morbidity, especially in immuno-compromisedindividuals.1_{Cryptococcosisaccountsforupto} 200,000deaths peryear and its mortalitymay reach up to

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](N.S.Adiwardana).

70%atthreemonthsafterdiagnosis,mainlyinsub-Saharan Africa.2

Theetiologicagentisayeast-like,encapsulated, oval-to-spherical shapedfungus commonlyfound insoil and bird excreta,especiallyfrompigeons.Classically,inhaledfungus maytriggerlimitedtowidelydisseminateddisease,most com-monlymanifestingaspulmonaryandcentralnervousillness throughhematogenous and lymphangyticspread.3 _{Thus, it} maypracticallyaffectanyorganandcauseseveraldiseases, includingosteomyelitis.

https://doi.org/10.1016/j.bjid.2018.11.004

1413-8670/©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Fig.1–(A)ExternalaspectofthescalpandskulllesioninanHIV-infectedpatientwithchronicskullosteomyelitisdueto

Cryptococcusneoformans;(B)computedtomographyscanofthepatient’sskullatadmissionshowingparamenyngeal

reactionwithosteolyticparieto-occipitalerosion;(C)three-dimensionalreconstructionofthecraniallesion;(D) Grocott-Gomorimethenamine-silverstainshowingfungalstructurescompatiblewithCryptococcus.

Cryptococcalosteomyelitis is anuncommon manifesta-tion of disseminated disease. Skeletal cryptococcosis was describedinpatientswithclassicalimmunodeficienciesbut alsoinpatientswithrelativeimmunodeficienciesorwithout anydetectableimmunesystemsuppression.3

Thejointsmostcommonlyaffectedbycryptococcosisare theknees,elbows,hips,wristsandankles.Ontheotherhand, thebonesmostfrequentlyaffectedincryptococcosisarethe vertebrae, skull, femur and ribs.3 _{HIV-related cryptococcal} meningitisisthemostfrequentcauseofopportunistic menin-gitis and skeletal involvement israrely described.3 _{In this} study,wereportanHIV-infectedpatientwithchronicskull osteomyelitisduetoCryptococcusneoformans.

Case

report

Hereinwereportthecaseofa48-yearoldmalepatientwith HIVdiagnosis,lymphocyteT-CD4+cellcountof55cells/mm3

and undetectable viral load count for over the last five years of admittance. He presented a history of chronic smoking,grade IIIobesity, hypertension,chronic atrial fib-rillation,dyslipidemia,peripheralobstructivearterialdisease andlipodystrophy.Heregularlyreceivedtenofovirdisoproxil fumarate,lamivudineanddolutegravir,metoprolol,losartan, aspirin,cotrimoxazoleandatorvastatin.Heworkedasa sales-manandlivedinanurbanareaofSãoPaulo,Brazilandowned

threeCalopsitabirds,twodogsandthreecats.Hehadahistory ofrecurringitchingonhisscalpassociatedwithaself-inflicted localtraumawithapen.Eighteenmonthspriortohis admis-sion,henoticedalumponhisscalp,withagradualincrease inswellingandlocalpain.Hewassubmittedtoanexcisional biopsy of abulging occipital-parietallesion. Theresultsof thebiopsywereunspecificandnoetiologicaldiagnosiswas identified.Afterthisprocedure,thepost-surgicalwoundnever completelyhealed.Thepatientwasadmittedtoourservice, atertiary levelhospitalinSãoPaulo,Brazil,withheadache andnauseaforthreedays.Atadmission,adeep-seated ulcer-atedlesionoftheskullwasobserved,affectingdeepplanes, downtotheboneplate,intherightmedialparietalarea,with honey-coloredcrustandasmallamountofserous-green dis-chargedrainingthroughtheformedorifice(Fig.1A).Following anexamination,thefirstcranialcomputedtomography(CT) scanshowedacontinuitysolutionbetweenskinandregion of parameningeal space, with accumulation of extradural substance,besidessignsofchronicosteolysiswithlow resorp-tion,compatible withchronicosteomyelitis (Fig. 1Band C). Thecerebrospinalfluid(CSF)analysisrevealed121cells/mm3

(78%neutrophils),proteinsof365mg/dL,glucoseof25mg/dL, and negativeIndiaink. Thepatientwasthen submittedto neurosurgicalprocedurewithsubcutaneoustissueandbone debridement.Acryptococcalantigentestusinglateral flow assayinwholebloodwaspositive,andasecondCSFanalysis

brazj infect dis.2018;22(6):499–502

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Fig.2–(A)One-weekpost-operativewoundaftersurgicaldebridementofchronicskullosteomyelitisinanHIV-infected patient.(B)Three-weekpost-operativewoundaspect.

showed75cells/mm3_{(90%neutrophils),proteinsof250mg/dL,}

glucoseof36mg/dL,negativeIndiainkandpositive cryptococ-calantigentestusinglateralflowassay.Inbonetissue,direct fungalexamwascompatiblewithyeastofCryptococcusand cultureshowedC.neoformans(Fig.1D).Inaddition,CSF cul-tureconfirmedthepresenceofthisfungus.ChestX-rayand CTwerenormal.ThepatientreceivedamphotericinB deoxy-cholate50mg/dayand5-fluocytosine100mg/kg/day.Afterfive days, there was significant improvement of all symptoms. Nevertheless,after15daysoftreatment,thepatientpresented acuterenalinjuryandanemia.Thus,hisantifungaltreatment waschangedtoamphotericinlipidcomplexandfluconazole 800mg/day.Finally,after29daysoftreatment,thepatientwas asymptomaticandshowednegativefungalculturesofhisCSF, beingdischargedandusingfluconazole400mg/dayupto com-plete10weeksoftreatmentandswitchingtoonfluconazole 200mg/day. Thesurgicalwound showed signs ofadequate cicatrizationthroughouthospitalizationandlateronduring followup, without complications(Fig. 2Aand B).Oneyear later,thepatientremainedasymptomaticwithaT-CD4+ lym-phocytecellcountof41cells/mm3_{andundetectableviralload.}

Discussion

Tothebestofourknowledge,thepresentreportrepresents the first caseofanHIV-infectedpatient withchronic skull osteomyelitisduetoC.neoformans.

Skeletalinfectionsasmanifestationsofcryptococcal dis-ease are described in only 5% to 10% of patients with disseminated disease. In the skull, its manifestations are even scarcer. Until 2011, there were only 14 similar cases published.3_{Themostclassicalclinicalmanifestationofskull} osteomyelitis byCryptococcus consists ofa progressive soft exophytic or swollen masses, withor without pain, some-times with fever and evolving from acute onset to three years of development,3 consistent with the history of our patient.

Direct inoculation is an uncommon form of origin of cryptococcalbonedisease,withonlyfourcasesdescribed pre-viously in the literature.1 _{In our case, a history of direct} repetitivetraumaandthe chronologyofclinical manifesta-tionsmaysuggestthatskulldiseaseprecededmeningealand bloodstream involvement. Notwithstanding, the possibility

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that areactivation of alatent reservoirin a long-standing immunosuppressedHIVpatientshouldalsobeconsidered.

Interestingly, our patient maintains severe immuno-suppression despite regular antiretroviral treatment and sustainedundetectableviralload.Thisfactmayhaveallowed the progression of the disease after the repetitive skull trauma or the reactivation of a latent reservoir, as cited before.

In HIV patients, meningitis is the main manifestation ofcryptococcosisandcauses highmortality,particularly in developingcountries.SkeletalcryptococcosisinHIV-infected patientshasbeendescribedonlyinfourpatients:twocases involvingtheknee,oneonthelumbarvertebraeandthelast onthesternum,elbowandribs.3,4

Skeletalcryptococcosisisadiagnosticchallenge. Erythro-cytesedimentationrateisusuallyhigh.Diagnosisisusually confirmedbyopen biopsies(∼70%)followed byother inva-sivemethodssuchasaspiration(∼25%),incisionanddrainage (∼6%).Nowadays,itisrecommended toprioritizeaspiration over open biopsies when possible to minimize invasive-ness.Bone,serumandCSFculturestodiagnosecryptococcal osteomyelitis appear to be highly sensitive rate (∼100%).3 Latexantigen and lateral flowassay are recommended for disseminatedandmeningealinvolvement.Lateralflowassay performedinwholebloodisanimportantpoint-of-caretool and was the first positive test in our patient. Radiological imaginginskeletalcryptococcosisisusuallyaltered(∼85%of cases).3Tomographicfindingsmayshowwell-defined, irreg-ular lyticlesions ranging from twotofive cmin diameter, sometimesshowingbonesequestrum,alsosuggestingdura materinvolvementinhalfofthem.4_{Periostealreactioncan} appearinsomecases(∼15%),and osteomyelitisisarather commonfindinginmostscannedpatients(∼65%).3_Aswith othercasesofosteomyelitis,followuprequiresserial radio-logicalimaging.3

There is no standardized treatment for cryptococcal osteomyelitis. Based on the experience with other forms

of cryptococcosis and using the principles of bacterial osteomyelitis management, bothsurgical debridement and prolongedcombinedantifungaltherapyseemstobe reason-able.Inthisregard,ourpatienthadundergonesurgeryand fourweeksofinductiontherapy.

Inconclusion,cryptococcaldiseaseshouldbeincludedin the differential diagnoses of chronic osteomyelitis in HIV-infectedpatientsandrepetitivetraumaisapossiblesource ofdirectinoculationofC.neoformans.

Funding

Thisresearchdidnotreceiveanyspecificgrantfromfunding agenciesinthepublic,commercial,ornot-for-profitsectors.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1.PudipeddiA,LiuK,WatsonG,DavisR,StrasserS.Cryptococcal osteomyelitisoftheskullinalivertransplantpatient.Transpl InfectDis.2016,http://dx.doi.org/10.1111/tid.12602.Accepted June26,2016.

2.LimperAH,AdenisA,LeT,HarrisonTS.Fungalinfectionsin HIV/AIDs.LancetInfectDis.2017,

http://dx.doi.org/10.1016/S1473-3099(17)30303-1.Published onlineJuly31,2017.

3.ZhouHX,LuL,ChuT,etal.Skeletalcryptococcosisfrom1977 to2013.FrontMicrobiol.2015,

http://dx.doi.org/10.3389/fmicb.2014.00740.Publishedonline January14,2015.

4.CorralJE,LimaS,QuezadaJ,SamayoaB,ArathoonE. Cryptococcalosteomyelitisoftheskull.MedMycol. 2011;49:667–71.PublishedonlineFebruary8,2011.