OfficialreprintfromUpToDate

www.uptodate.com2016UpToDate

Cryptococcusneoformansinfectionoutsidethecentralnervoussystem

Authors: GaryMCox,MD,JohnRPerfect,MD
SectionEditors: CarolAKauffman,MD,SheldonLKaplan,MD
DeputyEditor: JenniferMitty,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:May28,2015.

INTRODUCTIONCryptococcusneoformanspneumoniaandinfectionoutsidethecentralnervoussystem
inimmunocompetentandimmunocompromisedpatientswillbereviewedhere.

ThemicrobiologyandepidemiologyofC.neoformansinfectionarepresentedseparately.C.neoformans
meningoencephalitisandCryptococcusgattiiinfectionarealsodiscussedelsewhere.(See"Microbiologyand
epidemiologyofCryptococcusneoformansinfection"and"Epidemiology,clinicalmanifestations,and
diagnosisofCryptococcusneoformansmeningoencephalitisinHIVinfectedpatients"and"Clinical
manifestationsanddiagnosisofCryptococcusneoformansmeningoencephalitisinHIVseronegativepatients"
and"TreatmentofCryptococcusneoformansmeningoencephalitisinHIVinfectedpatients"and"Treatmentof
CryptococcusneoformansmeningoencephalitisanddisseminatedinfectioninHIVseronegativepatients"and
"Cryptococcusgattiiinfection:Microbiology,epidemiology,andpathogenesis"and"Cryptococcusgattii
infection:Clinicalfeaturesanddiagnosis"and"Cryptococcusgattiiinfection:Treatment".)

PULMONARYINFECTIONINIMMUNOCOMPETENTADULTS

ClinicalmanifestationsHumanslikelybecomeinfectedwithC.neoformansbyinhalingthebasidiospore
formofthefungusorsmall,poorlyencapsulatedyeasts.Basidiosporesaresmallerthantheyeastforms
obtainedfromclinicalsamplesandhavemuchsmallerpolysaccharidecapsules,facilitatingdepositioninthe
alveoliandterminalbronchiolesafterinhalation[1].Followinginhalation,C.neoformanslikelycauseafocal
pneumonitisthatmayormaynotbesymptomatic.Theimmunestatusisthemostimportantdeterminantof
thesubsequentcourseoftheinfection(eg,whetherthepneumonitisresolvesorprogressestosymptomatic
dissemination)[2,3].

AlargesegmentofthepopulationhasbeenexposedtoC.neoformans[4].Subclinicalprimaryinfectionsare
commonandmostareasymptomatic.Postmortemstudiesonimmunocompetentpersonswithoutantecedent
respiratorycomplaintshavedemonstratedsmallareasofgranulomatousinflammationinthelung
parenchymaand/orhilarlymphnodesduetoC.neoformans[5,6].Thefociaregenerallysmallerthanthose
seenintuberculosisanddonotappeartocalcifyasfrequentlyasseenwithhistoplasmosis.Infectioncan
persistinalatentstateifthehostimmunesystembecomescompromised,organismsmaybeliberatedfrom
thegranulomatouscomplexesandcauseactiveinfection.

Therearealsodescriptionsofpulmonarycryptococcosisinapparentlyimmunocompetentpatients[7,8].Ina
reviewofapproximately90immunocompetenthostswithpulmonarycryptococcosis,32percentofthe
patientswereasymptomatic,andpulmonaryinfectionwasdiscoveredasanincidentalfinding[7].
Asymptomaticpatientswithchestradiographfindingssuspiciousformalignancywhoundergobiopsyare
occasionallyfoundtohavecryptococcosis.

Thefactorsthatdeterminewhetheranexposedpersondevelopssymptomaticinfectionareuncertainbutmay
includetheinoculumoffungi(eg,burdenofexposure)and/orvirulencefactorsoftheinfectingstrain.
Commonsymptomsincludecough,sputumproduction,hemoptysis,dyspnea,chestpain,fever,malaise,
nightsweats,andweightloss[7,911].Lesscommonsymptomsincluderashandgastrointestinalcomplaints.
Raremanifestationsincludeobstructionofthesuperiorvenacava,Pancoastsyndromeduetogranulomatous
inflammationfromthehostresponsetoC.neoformans,eosinophilicpneumonia,andextensionfromthelung
tothechestwall[1215].

DiagnosisDiagnostictoolsforpulmonarycryptococcosisincludehistology,fungalculture,serum
cryptococcalantigen,andradiography.

CultureandhistologyVisualizationofencapsulatedyeastformsinsputum,bronchoalveolarlavageor
tissuespecimensissuggestiveofcryptococcalpulmonaryinfection.Thediagnosisisestablishedbyculturing
theorganismfromsputumoranotherspecimen.Biopsyspecimensofasymptomaticnodulesmayhaveyeast
onhistopathologicinspectionbuttheculturemaybenegative.

Associatedpleuraleffusionsareusuallyexudative[16,17].Yeastformsmaybeseeninthepleuraleffusion,
andculturesareusuallypositive.

Routinebloodculturesareappropriateforpatientswhohaveextensiveinfiltratesand/orsystemicsymptoms.

CryptococcalantigenSerumcryptococcalantigenshouldbeperformed.Althoughpositiveresultsare
oftenfoundinimmunocompromisedhostswithC.neoformanspneumonia,antigendetectionisnotasensitive
testfordiagnosisofpulmonaryinfectioninimmunocompetentpatients.However,antigentestingmaybe
moreusefulfordiagnosisofcryptococcalpneumoniaduetoC.gattiiamongimmunocompetenthostsin
regionswhereC.gattiiisendemic(eg,Australia)orhascausedoutbreaksofdisease(eg,theUnitedStates
PacificNorthwestandBritishColumbia).(See"Cryptococcusgattiiinfection:Clinicalfeaturesanddiagnosis",
sectionon'Cryptococcalantigen'.)

Thereisnoroleformonitoringserumcryptococcalantigentiterstodeterminedurationoftherapyineither
immunosuppressedorimmunocompetenthosts.

RadiographyRadiographicfeaturesofpulmonarycryptococcosisinimmunocompetentpatientsare
variable.Themostcommonfindingsaresolitaryorfewwelldefined,noncalcifiednodulesthatareoften
pleuralbased(image1)[1820].Otherradiographicfindingsincludelobarinfiltrates,hilarandmediastinal
adenopathy,andpleuraleffusions[16,17,2124].Inacaseseriesof12immunocompetenthosts,10patients
hadnodulesandmasses(eightwereperipheral)threehadcavitation[25].

LumbarpunctureDisseminationfromthelungstothecentralnervoussystem(CNS)in
immunocompetentpatientsisrare,androutinelumbarpuncturetoevaluateforcryptococcal
meningoencephalitisisgenerallynotnecessary[26].ImmunocompetenthostswithnoCNSsymptomsand
lowserumcryptococcalantigentiter(<1:512)neednotundergolumbarpuncture.However,lumbarpuncture
iswarrantedforpatientswithneurologicsymptomsoranunderlyingconditionthatpredisposesto
dissemination.Lumbarpunctureisalsoappropriateforimmunocompetentpatientswithaveryhighserum
cryptococcalantigentiter(>1:512)suchpatientsappeartohaveahigherburdenofinfectionwithriskfor
extrapulmonaryspreadandseedingofthecentralnervoussystem.

TreatmentThegoaloftreatmentistocontrolsignsandsymptomsofcryptococcalpneumoniaand
minimizeriskofdisseminationtothecentralnervoussystem[27].Literatureformanagementofpulmonary
cryptococcalinfectionconsistsofretrospectivereportstheapproachisextrapolatedfromliteraturedescribing
managementofpatientswithHIVinfectionandCNSdisease[9,2831].

Pleuraleffusionsrarelyrequiredrainage[16,17].Surgicalexcisionofinfectedpulmonarytissueisonly
indicatedincasesofmassesthatimpingeonadjacentstructures[12,13].

ThemanagementofC.gattiiinfectionisdiscussedseparately.(See"Cryptococcusgattiiinfection:
Treatment".)

AntifungaltherapyPatientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)or
disseminateddisease(eg,atleasttwononcontiguoussites)oracryptococcalantigentiter1:512(aknown
poorprognosticfactor[32])shouldbemanagedasoutlinedseparately.(See"TreatmentofCryptococcus
neoformansmeningoencephalitisanddisseminatedinfectioninHIVseronegativepatients".)

BasedonextrapolationfromliteraturedescribingmanagementofpatientswithHIVinfection,treatmentfor
immunocompetentpatientswithmildtomoderatepulmonarycryptococcosisintheabsenceofdiffuse
pulmonaryinfiltratesordisseminatedinfectionconsistsoffluconazole(400mg[6mg/kg]orallydaily)for6to
12months(table1)[27].Iffluconazoleisnotavailableoriscontraindicated,acceptablealternativesinclude
itraconazole(loadingdosesof200mgorallythreetimesdailyforthreedays,then200mgorallytwicedaily),
voriconazole(loadingdosesof6mg/kgintravenously[IV]twicedailyor400mgorallytwicedailyonthefirst
day,then200mgorallytwicedaily)orposaconazoledelayedreleasetablets(loadingdosesof300mgorally
twicedailyonthefirstday,then300mgorallyoncedaily),althoughthereareminimaldataavailable
regardingthelatteragents.

Asymptomaticpatientswhohavecryptococcalinfectiondiagnosedincidentallyinthesettingofpulmonary
noduleresectiontoruleoutmalignancyandwhohavenegativeculturesandcryptococcalantigentitersmay
notrequireantifungaltherapy.Therearereportsofimmunocompetent,asymptomaticpatientswithpositive
culture,serology,and/orhistopathologywhoimprovedradiographicallywithobservationaloneintheabsence
ofantifungaltherapy[9,29,31].

Asymptomaticpatientswithdetectableserumcryptococcalantigenprobablyhaveaverylowlikelihoodof
symptomaticsystemicdissemination.However,treatmentwithfluconazoleisappropriatesinceitislikelytobe
curativeandtheriskofadverseeffectsislow[27].

Thereisnoroleformonitoringserumcryptococcalantigentiterstoguidedurationoftherapy.

SurgeryOccasionally,localizedcryptococcalinfectionsofthelungnotrespondingtomedicaltherapy
mayneedsurgicalresectionforcure[27].

PULMONARYINFECTIONINIMMUNOCOMPROMISEDADULTSMostcasesofpulmonary
cryptococcosisintheimmunocompromisedhostarelikelyduetoreactivationoflatentinfection.However,
primaryinfectioninanavehostorreinfectionwithanewstrainisalsopossible.Immunocompromisedhosts
withpulmonarycryptococcosisgenerallyhavemoresymptomsthanimmunocompetenthostsandaremore
likelytopresentwithextrapulmonarydisease.

ConditionsthatincreaseriskforpulmonarycryptococcosisincludeHIVinfection,malignancies,stemcelland
solidorgantransplantation,cirrhosis,renalfailure,chroniclungdisease,diabetes,Cushing'ssyndrome,
sarcoidosis,andtreatmentwithglucocorticoidsortumornecrosisfactoralphaantagonists[9,31,3339].
CryptococcalpneumoniainalungtransplantpatientduetoasymptomaticC.neoformanscarriageinthe
donorlunghasalsobeenreported[40].

Clinicalmanifestations

HIVnegativepatientsClinicalmanifestationsduetopulmonarycryptococcosisrangefrom
asymptomaticpneumoniatoacuterespiratoryfailure[9,28,31,41].Among34immunocompromisedpatients
withcryptococcalpneumonia,28developedextrapulmonarydisease[31].Themostcommonsymptomswere
fever(63percent),chestpain(44percent),dyspnea(27percent),cough(17percent),andhemoptysis(7
percent).

Cryptococcalpneumoniaandacuterespiratorydistresssyndrome(ARDS)occurmorefrequentlyamong
organtransplantrecipientsthanotherhosts[28,42,43].Inthissetting,ARDSisoftenassociatedwith
disseminatedinfectionmortalityishighandurgenttreatmentisrequired[28,41].Suchpatientsshouldbe
managedasoutlinedseparatelyforcryptococcalmeningoencephalitis.(See"TreatmentofCryptococcus
neoformansmeningoencephalitisanddisseminatedinfectioninHIVseronegativepatients".)

HIVpositivepatientsThepresentationofpulmonarycryptococcosisinpatientswithHIVismoreacute
andseverethaninotherhosts.Theseverityofsymptomsandextentofdisseminationareinversely
proportionaltotheCD4lymphocytecountmostsymptomaticcasesoccurinpatientswithCD4countsless
than100/microL.

Clinicalmanifestationsincludefever(81to94percent),cough(63to71percent),dyspnea(5to50percent),
andheadache(41percent)[37].SomepatientsarehypoxicsomepresentwithARDS.Disseminationfrom
thelungstothecentralnervoussystemoccursin65to94percentofcasesofHIVassociatedpulmonary
cryptococcosis[30,37,44,45].

Otheropportunisticinfectionswithmanifestationssimilartopulmonarycryptococcosisincludethosedueto
Pneumocystisjirovecii,Mycobacteriumaviumcomplex,Mycobacteriumtuberculosis,cytomegalovirus,and
Histoplasmacapsulatum[37,45].

DiagnosisDiagnostictoolsforpulmonarycryptococcosisincludehistology,fungalculture,serum
cryptococcalantigen,andradiography.

Evaluationofimmunocompromisedpatientswithpulmonarycryptococcosisshouldincludeevaluationfor
disseminatedinfectionthisincludesbloodandcerebrospinalfluid(CSF)culturesaswellasbloodandCSF
cryptococcalpolysaccharideantigentesting[32].

CryptococcalantigenTheserumcryptococcalantigenispositiveinvirtuallyallpatientswithHIV
infectionandpulmonarycryptococcosisandin56to70percentofpatientswithotherunderlying
immunocompromisingconditions[9,30,35,36,46].Therefore,itisanexcellentscreeningtestin
immunocompromisedpatientswithrespiratorysymptoms.Falsepositiveserumcryptococcalantigentests
canoccurinthesettingofinfectionsduetothefungusTrichosporonasahii(formerlyT.beigelii)orthe
bacterialgeneraStomatococcusorCapnocytophaga[4749].Falsenegativeserumcryptococcalantigen
testscanoccurwithsamplesthatcontainalargeamountofantigen(theprozonephenomenon)ifthe
laboratoryisusingalatexagglutinationassayanddoesn'tpretreatthesamplewithpronase[50].

Insolidorgantransplantrecipientswithpulmonarycryptococcosis,apositiveserumcryptococcalantigentest
frequentlyreflectsadvancedlunginvolvementand/orextrapulmonarydisease,suchasfungemiaorcentral
nervoussysteminfection[51].Inoneseriesincludingsolidorgantransplantrecipients,apositiveserum
cryptococcalantigentiterwasdocumentedin38percentofpatientswithpulmonarycryptococcosis[29].Ina
prospectivestudyof60solidorgantransplantrecipientswithpulmonarycryptococcosis,positiveserum
cryptococcalantigenresultswereobservedin84percentofthosewithanypulmonaryinvolvementthetest
waspositivein73percentofthosewithdiseaselimitedtothelungs[51].However,anegativecryptococcal
antigenresultdoesnotexcludethediagnosisofcryptococcosis.

Giventhehighrateofextrapulmonarydiseaseamongimmunocompromisedpatientswithcryptococcal
pneumonia,apositiveserumcryptococcalantigenresultshouldpromptinvestigationfordisseminated
infectionwithbloodculture,CSFcryptococcalantigenassay,andCSFculture[32].Positiveresultsshould
promptmanagementasoutlinedseparately.(See"TreatmentofCryptococcusneoformans
meningoencephalitisanddisseminatedinfectioninHIVseronegativepatients"and"Epidemiology,clinical
manifestations,anddiagnosisofCryptococcusneoformansmeningoencephalitisinHIVinfectedpatients".)

CultureandhistologyCultureofexpectoratedsputumsamplesisoftenpositivein
immunocompromisedpatients.C.neoformansinrespiratorytractspecimensfromtransplantpatientsshould
beconsideredtorepresentatruepathogen.BronchoscopymaybeindicatedinpatientswithadvancedHIV
infectiontoruleoutotheropportunisticinfections[52].

Biopsyisnecessaryonlyifmalignancyissuspected.Histologycanhelptoestablishthediagnosisby
demonstratingencapsulatedyeastforms(picture1).

Routinebloodculturesareappropriateforpatientswithsevereimmunosuppression,extensiveinfiltrates,
and/orsystemicsymptoms.
 RadiographyRadiographicfindingsareusuallymoreseverethanthoseseeninapparently
immunocompetentpatients.(See'Radiography'above.)

InpatientswithHIV,alveolarinfiltrates,lymphadenopathy,masslesions,andsmallpleuraleffusionshave
beendescribed[37].InterstitialinfiltratesmaymimictheradiographicpresentationofP.jiroveciipneumonia
[37,53].(See"ClinicalpresentationanddiagnosisofPneumocystispulmonaryinfectioninHIVinfected
patients".)

LumbarpunctureLumbarpuncturetoevaluateforcryptococcalmeningoencephalitisiswarrantedfor
patientswithneurologicsymptomsoranunderlyingconditionthatpredisposestodissemination.Inastudyof
HIVseronegativepatientswithpulmonarycryptococcaldisease,thosewithdisseminateddiseaseweremore
likelytohavecirrhosis,headache,weightloss,fever,alteredmentalstatus,and/ortobereceivinghighdose
glucocorticoids[26].

Althoughthedefinitionoftheimmunocompromisedstateisimprecise,alumbarpuncturetoruleoutcentral
nervoussystemdiseaseshouldbeperformedinthosewithpulmonarycryptococcosiswhoareconsideredto
beimmunosuppressedevenintheabsenceofneurologicsignsorsymptoms.Suchpatientsappeartohavea
higherburdenofinfectionwithriskforextrapulmonaryspreadandseedingofthecentralnervoussystem.
(See"ClinicalmanifestationsanddiagnosisofCryptococcusneoformansmeningoencephalitisinHIV
seronegativepatients".)

Treatment

AntifungaltherapyPatientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)or
disseminateddisease(eg,atleasttwononcontiguoussites)oraserumcryptococcalantigentiter1:512(a
knownpoorprognosticfactor[32])shouldbemanagedasoutlinedseparately.(See"Treatmentof
CryptococcusneoformansmeningoencephalitisanddisseminatedinfectioninHIVseronegativepatients".)

Theoptimaltreatmentofcryptococcalpneumoniaisuncertainmanagementisextrapolatedfromliterature
describingmanagementofpatientswithHIVinfectionandcentralnervoussystemdisease[9,29,30].In
general,treatmentforimmunocompromisedpatientswithmildtomoderatepulmonarycryptococcosisinthe
absenceofdiffusepulmonaryinfiltratesordisseminatedinfectionconsistsoffluconazole(400mg[6mg/kg]
orallydaily)for6to12months(table1)[27].Iffluconazoleisnotavailableorcontraindicated,acceptable
alternativesincludeitraconazole(loadingdosesof200mgorallythreetimesdailyforthreedays,then200mg
orallytwicedaily),voriconazole(loadingdosesof6mg/kgintravenouslytwicedailyor400mgorallytwice
dailyonthefirstday,then200mgorallytwicedaily),andposaconazoledelayedreleasetables(loading
dosesof300mgorallytwicedailyonthefirstday,then300mgorallyoncedaily)[54,55],althoughthereare
minimaldataforthelatteragents.

Theefficacyofthisapproachwasillustratedinastudyof39solidorgantransplantrecipientswithextraneural
cryptococcosiswhoreceivedfluconazoleoraregimencontainingamphotericinBthemortalitywas
comparable(10to11percent)[56].Among109HIVnegativeimmunocompromisedpatientswithpulmonary
cryptococcosistreatedwithfluconazole,the12monthsurvivalwas95percent[9].Inaretrospectivereviewof
14solidorgantransplantrecipientswithextraneuralcryptococcosiswhoreceivedfluconazoleasprimary
therapyforamedianof60days,notherapeuticfailureswereobserved[56].

HIVinfectedpatientsshouldcontinuechronicsuppressivetherapywith200mgperdayoffluconazole.In
patientswithHIVwhoarereceivinghighlyactiveantiretroviraltherapyandhaveCD4count>100
cells/microL,suppressedviralload,andacryptococcalantigentiter1:512thatisnotincreasing,itmaybe
reasonabletodiscontinuemaintenancefluconazoleafteroneyearoftreatment[57].

Patientswhohaverespondedtotherapyforpulmonarycryptococcosisandsubsequentlymustundergo
chemotherapyorintensivetherapyforgraftrejectionwithintwoyearsofthediagnosisshouldbetreatedwith
fluconazolewhilereceivingsuchtherapytopreventrecurrentcryptococcalinfection.
Thereisnoroleformonitoringserumcryptococcalantigentiterstodeterminedurationoftherapy.

SurgeryOccasionally,localizedcryptococcalinfectionsofthelungnotrespondingtomedicaltherapy
mayneedsurgicalresectionforcure[27].

PULMONARYINFECTIONINPREGNANTWOMENTherehavebeencasesofcryptococcalpneumonia
describedinpregnancy,althoughthereareinsufficientepidemiologicdatatoimplicatepregnancyasa
predisposingcondition[58].

Patientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)ordisseminateddisease(eg,at
leasttwononcontiguoussitesorcryptococcalantigentiter1:512)shouldbemanagedasoutlinedseparately.
(See"TreatmentofCryptococcusneoformansmeningoencephalitisanddisseminatedinfectioninHIV
seronegativepatients",sectionon'Pregnantwomen'.)

Pregnantwomenwithstablepulmonarycryptococcosisshouldbefollowedclosely,andtherapywith
fluconazolecanbeginfollowingdelivery[27].Immunereconstitutioninflammatorysyndromecanoccurinthe
postpartumperiod[5961].Indeed,nearlyhalfoftheCryptococcuscasesreportedinpregnancypresented
withsymptomaticdiseaseinthethirdtrimesterorpostpartumperiod[58].(See"Immunereconstitution
inflammatorysyndrome".)

PULMONARYINFECTIONINCHILDRENCryptococcushasbeenreportedinchildrenwithprimary
immunodeficienciessuchashyperimmunoglobulinMsyndromeandseverecombinedimmunodeficiency
syndrome,aswellaschildrenwithHIV,connectivetissuediseases,andsolidorgantransplantrecipients.
Cryptococcosishasalsobeendescribedinchildrenwithnorecognizedimmunodeficiency.

Patientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)ordisseminateddisease(eg,at
leasttwononcontiguoussitesorserumcryptococcalantigentiter1:512)shouldbemanagedasoutlined
separately.(See"TreatmentofCryptococcusneoformansmeningoencephalitisanddisseminatedinfectionin
HIVseronegativepatients",sectionon'Children'.)

Treatmentofchildrenwithmildtomoderatepulmonarycryptococcosisconsistsoffluconazole(6to12mg/kg
perdayorally)for6to12months[27].

NONMENINGEAL,NONPULMONARYCRYPTOCOCCOSIS

ClinicalmanifestationsNonmeningeal,nonpulmonarycryptococcosisgenerallyreflectsdisseminated
infection,evenifclinicalmanifestationsareconfinedtoasingleanatomicsite(suchasskin,softtissue,or
osteoarticularinfection).

Cryptococcalskinlesionsareseeninupto15percentofpatientswithdisseminatedinfectiontheymanifest
aspapules(picture2),plaques,purpura,ulcers,cellulitis,superficialplaques,abscesses,andsinustracts
[62,63].PatientswithadvancedHIVinfectionmayhaveumbilicatedpapulesresemblingmolluscum
contagiosumintransplantpatients,cellulitismayoccurwithoutevidenceofdissemination.Althoughthe
majorityofcryptococcalskinlesionsresultfromdisseminatedinfection,primarycryptococcalskininfections
bydirectinoculationmayoccur[64].

Cryptococcallesionsoftheskeletalsystemoccurin<10percentofpatientswithdisseminateddisease[65].
Thevertebraearethemostcommonsiteofosteoarticularinfection.Radiographytypicallydemonstratesa
wellcircumscribedosteolyticlesionresemblingmalignancy.Septicarthritisisrare.

Cryptococcalinfectioncaninvolveanybodysiteorstructurefollowingdissemination,includingtheliver,
lymphnodes,peritoneum,urogenitaltract,adrenalglands,andeyes.Involvementoftheeyesfrequently
reflectscentralnervoussystem(CNS)infection,whichshouldbesoughtinallcases[66].Theprostatemay
serveasareservoirofinfection[67].(See"ClinicalmanifestationsanddiagnosisofCryptococcus
neoformansmeningoencephalitisinHIVseronegativepatients".)
Among175solidorgantransplantrecipientswithcryptococcosis,ninepatients(5percent)presentedvery
earlyfollowingtransplantation(definedas30daysposttransplantmean5.7daysposttransplant)[68].
Patientswhopresentedveryearlyweremorelikelytohavediseaseatunusuallocations,includinginthe
transplantedallograftorinthesurgicalfossa.Theselocationssuggestthattheinfectionsweredonorderived.
Fiveoftheninepatients(56percent)withveryearlyonsetdiseasewerelivertransplantrecipientscompared
with43of166patients(26percent)withdiseaseoccurring>30daysposttransplant[68],suggestingthat
someofthesepatientsmayhavehadunrecognizedinfectionpriortotransplantationasaresultofthe
impairedhostdefensesthataccompanycirrhosis[69].

TreatmentPatientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)ordisseminated
disease(eg,atleasttwononcontiguoussitesorcryptococcalantigentiter1:512)shouldbemanagedas
outlinedseparately.(See"TreatmentofCryptococcusneoformansmeningoencephalitisanddisseminated
infectioninHIVseronegativepatients".)

TherearenostudiesevaluatingtreatmentofcryptococcalinfectioninvolvingsitesotherthanlungsandCNS.
Ingeneral,infectionatasinglesiteintheabsenceofCNSdisease,fungemiaorriskfactorsfor
immunosuppressionmaybemanagedwithfluconazole(400mg[6mg/kg]orallyoncedaily)for6to12
months[27,70,71].

Managementofocularinfectionsmustbemanagedinconsultationwithophthalmologicexpertiseandtailored
toindividualcircumstancesdependingontheextentofeyestructureinvolvementandwhetherCNS
involvementhasbeendocumented.Therapeuticpossibilitiesincludesystemictherapywithhighpenetration
intotheeyesuchasfluconazoleorflucytosineand/oradjunctiveintravitrealamphotericinBdeoxycholate.

SUMMARYANDRECOMMENDATIONS

AlargesegmentofthepopulationhasbeenexposedtoCryptococcusneoformans.Subclinicalprimary
infectionsarecommon,andmostareasymptomatic.Infectioncanpersistinalatentstateifthehost
immunesystembecomescompromised,organismsmaybeliberatedfromthegranulomatouscomplexes
andcauseactiveinfection.Symptomaticpulmonarycryptococcosiscanalsooccurinapparently
immunocompetentpatients.(See'Pulmonaryinfectioninimmunocompetentadults'aboveand
'Pulmonaryinfectioninimmunocompromisedadults'above.)

Clinicalmanifestationsduetocryptococcalpneumoniarangefromasymptomaticpneumoniatoacute
respiratoryfailure.ThepresentationofpulmonarycryptococcosisinpatientswithHIVismoreacuteand
severethaninotherhosts.MostsymptomaticcasesoccurinpatientswithCD4countslessthan100
cells/microL.(See'HIVpositivepatients'above.)

Thediagnosisofcryptococcalpneumoniainimmunocompetenthostsisestablishedbyculturingthe
organismfromsputumoranotherspecimen.Visualizationofencapsulatedyeastformsinsputum,
bronchoalveolarlavage,ortissuespecimensissuggestiveofcryptococcalpulmonaryinfection.Themost
commonradiographicfindingsaresolitaryorfewwelldefined,noncalcifiednodules.Lumbarpunctureis
warrantedforpatientswithneurologicsymptomsandforpatientswithserumcryptococcalantigentiter
>1:512.(See'Diagnosis'above.)

Theserumcryptococcalantigentiterisoftenpositiveinimmunocompromisedpatientswithcryptococcal
pneumonia.Cultureofrespiratoryspecimensisalsoausefultool.Alumbarpuncturetoruleoutcentral
nervoussystemdiseaseshouldbeperformedinthosewithpulmonarycryptococcosiswhoare
consideredtobeimmunosuppressedevenintheabsenceofneurologicsignsorsymptoms.(See
'Diagnosis'above.)

Wesuggestthatpatientswithmildtomoderatepulmonarycryptococcosisintheabsenceofdiffuse
pulmonaryinfiltratesordisseminatedinfectionbetreatedwithfluconazole(Grade2B).Dosingis
fluconazole400mg(6mg/kg)orallyoncedailyfor6to12months(table1).(See'Antifungaltherapy'
above.)
 Patientswithseverepulmonarydisease(eg,diffusepulmonaryinfiltrates)ordisseminateddisease(eg,
atleasttwononcontiguoussitesorcryptococcalantigentiter1:512)shouldbemanagedasoutlined
separately.(See"TreatmentofCryptococcusneoformansmeningoencephalitisanddisseminated
infectioninHIVseronegativepatients".)

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REFERENCES

1.VelagapudiR,HsuehYP,GeunesBoyerS,etal.SporesasinfectiouspropagulesofCryptococcus
neoformans.InfectImmun200977:4345.
2.SalkowskiCA,BalishE.Roleofnaturalkillercellsinresistancetosystemiccryptococcosis.JLeukoc
Biol199150:151.
3.HuffnagleGB,TraynorTR,McDonaldRA,etal.LeukocyterecruitmentduringpulmonaryCryptococcus
neoformansinfection.Immunopharmacology200048:231.
4.GoldmanDL,KhineH,AbadiJ,etal.SerologicevidenceforCryptococcusneoformansinfectioninearly
childhood.Pediatrics2001107:E66.
5.BAKERRD,HAUGENRK.Tissuechangesandtissuediagnosisincryptococcosisastudyof26cases.
AmJClinPathol195525:14.
6.BakerRD.Theprimarypulmonarylymphnodecomplexofcrytptococcosis.AmJClinPathol1976
65:83.
7.CampbellGD.Primarypulmonarycryptococcosis.AmRevRespirDis196694:236.
8.ChuHQ,LiHP,HeGJ.Analysisof23casesofpulmonarycryptococcosis.ChinMedJ(Engl)2004
117:1425.
9.PappasPG,PerfectJR,CloudGA,etal.Cryptococcosisinhumanimmunodeficiencyvirusnegative
patientsintheeraofeffectiveazoletherapy.ClinInfectDis200133:690.
10.ChangWC,TzaoC,HsuHH,etal.Pulmonarycryptococcosis:comparisonofclinicalandradiographic
characteristicsinimmunocompetentandimmunocompromisedpatients.Chest2006129:333.
11.ShirleyRM,BaddleyJW.Cryptococcallungdisease.CurrOpinPulmMed200915:254.
12.MenonA,RajamaniR.Giant'cryptococcoma'ofthelung.BrJDisChest197670:269.
13.MitchellDH,SorrellTC.Pancoast'ssyndromeduetopulmonaryinfectionwithCryptococcus
neoformansvarietygattii.ClinInfectDis199214:1142.
14.StarrJC,CheH,MontgomeryJ.Cryptococcalpneumoniasimulatingchroniceosinophilicpneumonia.
SouthMedJ199588:845.
15.MitsuokaS,KanazawaH.ImagesinThorax.Anuniquecaseofprimarypulmonarycryptococcosiswith
extensivechestwallinvasion.Thorax200560:86.
16.McAllisterCK,DavisCEJr,OgnibeneAJ,CarpenterJL.Cryptococcalpleuropulmonarydisease:
infectionofthepleuralfluidintheabsenceofdisseminatedcryptococcosis.Casereport.MilMed1984
149:684.
17.YoungEJ,HirshDD,FainsteinV,WilliamsTW.PleuraleffusionsduetoCryptococcusneoformans:a
reviewoftheliteratureandreportoftwocaseswithcryptococcalantigendeterminations.AmRevRespir
Dis1980121:743.
18.ZlupkoGM,FochlerFJ,GoldschmidtZH.Pulmonarycryptococcosispresentingwithmultiplepulmonary
nodules.Chest198077:575.
19.LindellRM,HartmanTE,NadrousHF,RyuJH.Pulmonarycryptococcosis:CTfindingsin
immunocompetentpatients.Radiology2005236:326.
20.YangCJ,HwangJJ,WangTH,etal.Clinicalandradiographicpresentationsofpulmonary
cryptococcosisinimmunocompetentpatients.ScandJInfectDis200638:788.
21.HuntKK,EnquistRW,BowenTE.Multiplepulmonarynoduleswithcentralcavitation.Chest1976
69:529.
22.FeiginDS.Pulmonarycryptococcosis:radiologicpathologiccorrelatesofitsthreeforms.AJRAmJ
Roentgenol1983141:1262.
23.KhouryMB,GodwinJD,RavinCE,etal.Thoraciccryptococcosis:immunologiccompetenceand
radiologicappearance.AJRAmJRoentgenol1984142:893.
24.MurataK,KhanA,HermanPG.Pulmonaryparenchymaldisease:evaluationwithhighresolutionCT.
Radiology1989170:629.
25.FoxDL,MllerNL.Pulmonarycryptococcosisinimmunocompetentpatients:CTfindingsin12patients.
AJRAmJRoentgenol2005185:622.
26.BaddleyJW,PerfectJR,OsterRA,etal.PulmonarycryptococcosisinpatientswithoutHIVinfection:
factorsassociatedwithdisseminateddisease.EurJClinMicrobiolInfectDis200827:937.
27.PerfectJR,DismukesWE,DromerF,etal.Clinicalpracticeguidelinesforthemanagementof
cryptococcaldisease:2010updatebytheinfectiousdiseasessocietyofamerica.ClinInfectDis2010
50:291.
28.VilchezRA,LindenP,LacomisJ,etal.Acuterespiratoryfailureassociatedwithpulmonary
cryptococcosisinnonaidspatients.Chest2001119:1865.
29.AbergJA,MundyLM,PowderlyWG.PulmonarycryptococcosisinpatientswithoutHIVinfection.Chest
1999115:734.
30.MeyohasMC,RouxP,BollensD,etal.Pulmonarycryptococcosis:localizedanddisseminated
infectionsin27patientswithAIDS.ClinInfectDis199521:628.
31.KerkeringTM,DumaRJ,ShadomyS.Theevolutionofpulmonarycryptococcosis:clinicalimplications
fromastudyof41patientswithandwithoutcompromisinghostfactors.AnnInternMed198194:611.
32.DromerF,MathoulinPlissierS,LaunayO,etal.Determinantsofdiseasepresentationandoutcome
duringcryptococcosis:theCryptoA/Dstudy.PLoSMed20074:e21.
33.WhitleyTH,GraybillJR,AlfordRH.Pulmonarycryptococcosisinchroniclymphocyticleukemia.South
MedJ197669:33.
34.KramerM,CorradoML,BacciV,etal.PulmonarycryptococcosisandCushing'ssyndrome.ArchIntern
Med1983143:2179.
35.FinkeR,StrobelES,KroepelinT,etal.Disseminatedcryptococcosisinapatientwithmalignant
lymphoma.Mycoses1988Suppl1:102.
36.ChristophI.PulmonaryCryptococcusneoformansanddisseminatedNocardiabrasiliensisinan
immunocompromisedhost.Casereport.NCMedJ199051:219.
37.CameronML,BartlettJA,GallisHA,WaskinHA.Manifestationsofpulmonarycryptococcosisinpatients
withacquiredimmunodeficiencysyndrome.RevInfectDis199113:64.
38.ArendSM,KuijperEJ,AllaartCF,etal.Cavitatingpneumoniaaftertreatmentwithinfliximaband
prednisone.EurJClinMicrobiolInfectDis200423:638.
39.SunHY,WagenerMM,SinghN.Cryptococcosisinsolidorgan,hematopoieticstemcell,andtissue
transplantrecipients:evidencebasedevolvingtrends.ClinInfectDis200948:1566.
40.KanjSS,WeltyWolfK,MaddenJ,etal.Fungalinfectionsinlungandheartlungtransplantrecipients.
Reportof9casesandreviewoftheliterature.Medicine(Baltimore)199675:142.
41.VisnegarwalaF,GravissEA,LackeCE,etal.Acuterespiratoryfailureassociatedwithcryptococcosisin
patientswithAIDS:analysisofpredictivefactors.ClinInfectDis199827:1231.
42.SinghN,AlexanderBD,LortholaryO,etal.Cryptococcusneoformansinorgantransplantrecipients:
impactofcalcineurininhibitoragentsonmortality.JInfectDis2007195:756.
43.ShaariahW,MoradZ,SuleimanAB.Cryptococcosisinrenaltransplantrecipients.TransplantProc
199224:1898.
44.WasserL,TalaveraW.PulmonarycryptococcosisinAIDS.Chest198792:692.
45.ClarkRA,GreerDL,ValainisGT,HyslopNE.CryptococcusneoformanspulmonaryinfectioninHIV1
infectedpatients.JAcquirImmuneDeficSyndr19903:480.
46.JensenWA,RoseRM,HammerSM,KarchmerAW.Serologicdiagnosisoffocalpneumoniacausedby
Cryptococcusneoformans.AmRevRespirDis1985132:189.
47.ChanockSJ,ToltzisP,WilsonC.CrossreactivitybetweenStomatococcusmucilaginosusandlatex
agglutinationforcryptococcalantigen.Lancet1993342:1119.
48.McManusEJ,JonesJM.DetectionofaTrichosporonbeigeliiantigencrossreactivewithCryptococcus
neoformanscapsularpolysaccharideinserumfromapatientwithdisseminatedTrichosporoninfection.
JClinMicrobiol198521:681.
49.WesterinkMA,AmsterdamD,PetellRJ,etal.SepticemiaduetoDF2.Causeofafalsepositive
cryptococcallatexagglutinationresult.AmJMed198783:155.
50.TannerDC,WeinsteinMP,FedorciwB,etal.Comparisonofcommercialkitsfordetectionof
cryptococcalantigen.JClinMicrobiol199432:1680.
51.SinghN,AlexanderBD,LortholaryO,etal.Pulmonarycryptococcosisinsolidorgantransplant
recipients:clinicalrelevanceofserumcryptococcalantigen.ClinInfectDis200846:e12.
52.MalabongaVM,BastiJ,KamholzSL.Utilityofbronchoscopicsamplingtechniquesforcryptococcal
diseaseinAIDS.Chest199199:370.
53.FriedmanEP,MillerRF,SevernA,etal.Cryptococcalpneumoniainpatientswiththeacquired
immunodeficiencysyndrome.ClinRadiol199550:756.
54.PerfectJR,MarrKA,WalshTJ,etal.Voriconazoletreatmentforlesscommon,emerging,orrefractory
fungalinfections.ClinInfectDis200336:1122.
55.RaadII,GraybillJR,BustamanteAB,etal.Safetyoflongtermoralposaconazoleuseinthetreatment
ofrefractoryinvasivefungalinfections.ClinInfectDis200642:1726.
56.DromerF,MathoulinS,DupontB,LaporteA.EpidemiologyofcryptococcosisinFrance:a9yearsurvey
(19851993).FrenchCryptococcosisStudyGroup.ClinInfectDis199623:82.
57.MartnezE,GarcaViejoMA,MarcosMA,etal.Discontinuationofsecondaryprophylaxisfor
cryptococcalmeningitisinHIVinfectedpatientsrespondingtohighlyactiveantiretroviraltherapy.AIDS
200014:2615.
58.ElyEW,PeacockJEJr,HaponikEF,WashburnRG.Cryptococcalpneumoniacomplicatingpregnancy.
Medicine(Baltimore)199877:153.
59.CosteasPA,KoumouliA,GiantsiouKyriakouA,etal.Th2/Th3cytokinegenotypesareassociatedwith
pregnancyloss.HumImmunol200465:135.
60.AnnapureddySR,MastersonSW,DavidHG,GreigJR.PostpartumosteomyelitisduetoCryptococcus
neoformans.ScandJInfectDis200739:354.
61.SinghN,PerfectJR.Immunereconstitutionsyndromeandexacerbationofinfectionsafterpregnancy.
ClinInfectDis200745:1192.
62.MitchellTG,PerfectJR.CryptococcosisintheeraofAIDS100yearsafterthediscoveryof
Cryptococcusneoformans.ClinMicrobiolRev19958:515.
63.DingYG,FangH.Edematouserythema,subcutaneousplaques,andseverepaininthelower
extremitiesinanimmunocompromisedpatient.JAMA2013309:1632.
 64.NeuvilleS,DromerF,MorinO,etal.Primarycutaneouscryptococcosis:adistinctclinicalentity.Clin
InfectDis200336:337.
65.BehrmanRE,MasciJR,NicholasP.Cryptococcalskeletalinfections:casereportandreview.RevInfect
Dis199012:181.
66.CrumpJR,ElnerSG,ElnerVM,KauffmanCA.Cryptococcalendophthalmitis:casereportandreview.
ClinInfectDis199214:1069.
67.LarsenRA,BozzetteS,McCutchanJA,etal.PersistentCryptococcusneoformansinfectionofthe
prostateaftersuccessfultreatmentofmeningitis.CaliforniaCollaborativeTreatmentGroup.AnnIntern
Med1989111:125.
68.SunHY,AlexanderBD,LortholaryO,etal.Unrecognizedpretransplantanddonorderivedcryptococcal
diseaseinorgantransplantrecipients.ClinInfectDis201051:1062.
69.SinghN,HusainS,DeVeraM,etal.CryptococcusneoformansInfectioninPatientsWithCirrhosis,
IncludingLiverTransplantCandidates.Medicine(Baltimore)200483:188.
70.SinghN,LortholaryO,AlexanderBD,etal.Antifungalmanagementpracticesandevolutionofinfection
inorgantransplantrecipientswithcryptococcusneoformansinfection.Transplantation200580:1033.
71.SinghN,GayowskiT,MarinoIR.Successfultreatmentofdisseminatedcryptococcosisinaliver
transplantrecipientwithfluconazoleandflucytosine,analloralregimen.TransplInt199811:63.

Topic2421Version18.0
GRAPHICS

Transversecomputedtomographyscanin46yearoldwoman
showsseveralnodulesinthelungbases(7mmthicksection)

Mostofthenoduleshavesmoothmargins.

Reproducedwithpermissionfrom:LindellR,HartmanT,NadrousH,etal.Pulmonary
Cryptococcosis:CTfindingsinimmunocompetentpatients.Radiology2005236:326.Copyright
2005RadiologicalSocietyofNorthAmerica.

Graphic64815Version3.0
Antifungaltreatmentrecommendationsfornonmeningealcryptococcosis

Initial
Patientgroup antifungal Duration
regimen

Immunosuppressedpatientsandimmunocompetentpatientswithmildto Fluconazole(400mg 6to12

moderatepulmonarycryptococcosis perday) months

Immunosuppressedpatients*andimmunocompetentpatientswithsevere SameasCNS 12months

pulmonarycryptococcosis disease

Patientswithnonmeningeal,nonpulmonarycryptococcosis
Patientswithcryptococcemia SameasCNSdisease 12months
PatientsforwhomCNSdiseasehasbeenruledoutwithnofungemia,withasingle Fluconazole400mg 6to12
siteofinfection,andwithnoimmunosuppressiveriskfactors perday months

CNS:centralnervoussystem.
*ShoulddirectlyruleoutCNSdiseasewithlumbarpuncture.

Reproducedwithpermissionfrom:PerfectJR,DisnukesWE,DromerF,etal.Clinicalpracticeguidelinesforthe
managementofcryptococcaldisease:2010updatebytheInfectiousDiseasesSocietyofAmerica.ClinInfectDis2010
50:291.Copyright2010UniversityofChicagoPress.

http://www.journals.uchicago.edu/
Graphic82028Version2.0
PleuralbiopsywithCryptococcus

Hematoxylinandeosinstainofapleuralbiopsyspecimenfromapatientwith
cryptococcalpneumonia.

Reproducedwithpermissionfrom:CartwrightE,RouphaelN,JainS,IlksoyN.Pleural
EffusioninaPatientwithAIDS.ClinInfectDis200846:1887.Copyright2008
UniversityofChicagoPress.

Graphic64561Version2.0
Disseminatedcryptococcosis

Multipleumbilicatedpapulesarepresentonthefaceofthispatientwith
cryptococcosis.Thelesionsresemblemolluscumcontagiosum.

Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.

Graphic69214Version3.0
Contributor Disclosures
Gary M Cox, MD Nothing to disclose John R Perfect, MD Grant/Research/Clinical Trial Support: Merck
[Antifungal agents (Posaconazole; Isavconazole; AmBisome)]; Astellas [Antifungal agents (Posaconazole;
Isavconazole; AmBisome)]. Consultant/Advisory Boards:Merck [Antifungal agents (Posaconazole;
Isavconazole; AmBisome)]; Astellas [Antifungal agents (Posaconazole; Isavconazole; AmBisome)]. Carol A
Kauman, MD Nothing to disclose Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pzer [S.
pneumoniae (PCV13, Linezolid)]; Cubist [S. aureus (Tedizolid)]; Forest Lab [Osteomyelitis (Ceftaroline)].
Consultant/Advisory Boards: Pzer [S. pneumoniae (PCV13, Linezolid); S. aureus (vaccine development)];
Theravance [S. aureus (Telavancin)]. Jennifer Mitty, MD, MPH Nothing to disclose

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