dr. tetty aman nasution, m med sc departemen mikrobiologi...

Cryptococcus neoformansCryptococcus neoformansypyp

Dr. Tetty Aman Nasution, M Med ScDr. Tetty Aman Nasution, M Med ScDepartemen Mikrobiologi FKDepartemen Mikrobiologi FK--USUUSU

MEDANMEDAN

Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformansSuatuSuatu yeast,yeast, ovaloval,, dengandengan kapsulkapsulyy gg ppkarbohidratkarbohidrat yangyang tebaltebal dlmdlm kulturkultur && cairancairandidi j ij i tid ktid k b if tb if t di fikdi fikdidi jaringan,jaringan, tidaktidak bersifatbersifat dimorfikdimorfik

TermasukTermasuk infeksiinfeksi jamurjamur opportunistikopportunistikjj pppp

TheThe mostmost commoncommon lifelife--threateningthreatening fungalfungaldiseasedisease inin AIDSAIDS patientspatients

Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformansInvasive fungal infection Invasive fungal infection Increasingly prevalent with increasing numbers of Increasingly prevalent with increasing numbers of immunocompromised patients.immunocompromised patients.An encapsulated yeastAn encapsulated yeastAn encapsulated yeastAn encapsulated yeastC. neoformans C. neoformans major pathogenic member of the major pathogenic member of the genusgenusS b l ifi d i t 4S b l ifi d i t 4 tt d 2d 2 i tii tiSub classified into 4 Sub classified into 4 serotypesserotypes and 2 and 2 varietiesvarieties

Serotypes based upon capsular agglutination Serotypes based upon capsular agglutination reactions, types A, B, C, Dreactions, types A, B, C, DSerotype A now classified asSerotype A now classified as variety grubiivariety grubiiSerotypes B + CSerotypes B + C variety gattiivariety gattiiSerot pe DSerot pe D ariet neoformansariet neoformansSerotype DSerotype D variety neoformansvariety neoformans

Cryptococcus neoformansCryptococcus neoformans --lif llif llifecyclelifecycle

Exists in asexual and sexual forms, with theExists in asexual and sexual forms, with theExists in asexual and sexual forms, with the Exists in asexual and sexual forms, with the asexual form existing as a yeast, which asexual form existing as a yeast, which reproduces by budding, the only form associated reproduces by budding, the only form associated with human infection.with human infection.Produces white mucoid colonies in vitro which Produces white mucoid colonies in vitro which become visible within 48 hoursbecome visible within 48 hoursThick capsule visible in India ink suspension .Thick capsule visible in India ink suspension .Capsule has important antiphagocytic propertiesCapsule has important antiphagocytic properties

Infeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur Opportunistik

PenyebabPenyebabPenyebabPenyebabJamurJamur saprophytesaprophyte didi alamalam atauatau jugajugasebagaisebagai normalnormal floraflora dlmdlm tubuhtubuh manusiamanusia

HostHost yangyang dikenaidikenaiHostHost yangyang dikenaidikenaiImmunosupresi, immunodefisensi, Immunosupresi, immunodefisensi, keganasankeganasan

Infeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur OpportunistikInfeksi Jamur Opportunistik

CandidiasisCandidiasisCryptococcosisCryptococcosisAspergillosisAspergillosisZygomycosisZygomycosis

******ANY fungus found in nature may give rise to ANY fungus found in nature may give rise to opportunistic mycosesopportunistic mycoses ******opportunistic mycosesopportunistic mycoses ******

CRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSIS

Kadang2 dpt terjadi pada orang normalKadang2 dpt terjadi pada orang normal


Kadang2 dpt terjadi pada orang normalKadang2 dpt terjadi pada orang normal

Infeksi terjadi secara exogenousInfeksi terjadi secara exogenousj gj g

PathogenesisPathogenesis :: inhalasi yeasts melalui inhalasi yeasts melalui saluran pernapasansaluran pernapasan

Dapat bersifat asimptomatikDapat bersifat asimptomatikDapat bersifat asimptomatikDapat bersifat asimptomatik


Gejala pada paruGejala pada paru paruparu non spesifiknon spesifik


Gejala pada paruGejala pada paru--paru paru non spesifik, non spesifik, bisa tjd pneumonia.bisa tjd pneumonia.

Jika tjd pd orang normal Jika tjd pd orang normal penghirupan penghirupan yeast dlm jumlah yg banyakyeast dlm jumlah yg banyak penyakitpenyakityeast dlm jumlah yg banyak yeast dlm jumlah yg banyak penyakit penyakit sistemik progresif.sistemik progresif.

Cryptococcus neoformansCryptococcus neoformansMorfologi & IdentifikasiMorfologi & Identifikasi

Natural reservoirNatural reservoir::Natural reservoirNatural reservoir::Soil/tanah, bird droppings/tinja burung Soil/tanah, bird droppings/tinja burung (terutama merpati) yang sudah mengering(terutama merpati) yang sudah mengering(terutama merpati) yang sudah mengering(terutama merpati) yang sudah mengering

MicroscopicMicroscopic: : Bentuk: bulat atau oval, diameter Bentuk: bulat atau oval, diameter 44--1212μμm, sering bertunasm, sering bertunasμμ , g, gEncapsulated yeast Encapsulated yeast ( terlihat dgn menggunakan India ink)( terlihat dgn menggunakan India ink)( terlihat dgn menggunakan India ink)( terlihat dgn menggunakan India ink)

Cryptococcus neoformansCryptococcus neoformans --llecologyecology

Var grubii and var neoformansVar grubii and var neoformansgg

Found worldwide in soil contaminated by bird Found worldwide in soil contaminated by bird droppings (chickens and pigeons) roosting sitesdroppings (chickens and pigeons) roosting sitesdroppings (chickens and pigeons), roosting sites droppings (chickens and pigeons), roosting sites and rotting vegetationand rotting vegetationPigeons do not become infected, inhibited by body Pigeons do not become infected, inhibited by body t t f 40t t f 40 oo CCtemperature of > 40 temperature of > 40 o o CCCryptococcus can be found in pigeon GI tractCryptococcus can be found in pigeon GI tractOutbreaks of disease not associated with pigeonOutbreaks of disease not associated with pigeonOutbreaks of disease not associated with pigeon Outbreaks of disease not associated with pigeon roosting areasroosting areas

Cryptococcus neoformansCryptococcus neoformans --llecologyecology

Var gattiiVar gattiiVar gattiiVar gattiiNever cultured from bird guanoNever cultured from bird guanoFlowering river red gums (Flowering river red gums (EucalyptusEucalyptusFlowering river red gums (Flowering river red gums (Eucalyptus Eucalyptus camaldulensiscamaldulensis) and forest red gums () and forest red gums (E. E. tereticornis)tereticornis)))These trees have been widely exported These trees have been widely exported around the worldaround the world

Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformans

MacroscopicMacroscopic::

Morfologi & IdentifikasiMorfologi & IdentifikasiMorfologi & IdentifikasiMorfologi & Identifikasi

MacroscopicMacroscopic::Pada Saboroud Dextrose Agar (SDA), suhu kamar Pada Saboroud Dextrose Agar (SDA), suhu kamar

koloni kecoklatankoloni kecoklatan mucoid dan mengkilatmucoid dan mengkilatkoloni kecoklatan, koloni kecoklatan, mucoid, dan mengkilatmucoid, dan mengkilatKultur tidak meragi karbohidratKultur tidak meragi karbohidratMengasimilasi glukosa, maltosa, sukrosa, Mengasimilasi glukosa, maltosa, sukrosa, galaktosa, tetapi laktosa galaktosa, tetapi laktosa tidaktidakUrea dihidrolisisUrea dihidrolisis


SerotypesSerotypes::


SerotypesSerotypes::

4 tipe serologik polisakarida kapsul (A,B,C,D)4 tipe serologik polisakarida kapsul (A,B,C,D)4 tipe serologik polisakarida kapsul (A,B,C,D) 4 tipe serologik polisakarida kapsul (A,B,C,D)

kebanyakan adalah serotype Akebanyakan adalah serotype A

Antigen kapsul dapat larut dlm cairan spinal, Antigen kapsul dapat larut dlm cairan spinal,

serum atau air kemihserum atau air kemihserum, atau air kemihserum, atau air kemih


D t k i d ti ifik t h dD t k i d ti ifik t h d


Deteksi dengan antiserum spesifik terhadap Deteksi dengan antiserum spesifik terhadap karbohidrat yaitu Latex Particle Agglutination karbohidrat yaitu Latex Particle Agglutination TestTestCara kerja: partikel latex yang telah dilapisi Cara kerja: partikel latex yang telah dilapisi j p y g pj p y g pAntibodi spesifik akan teragglutinasi dengan Antibodi spesifik akan teragglutinasi dengan antigen homolog dari yeast yang diperiksaantigen homolog dari yeast yang diperiksaantigen homolog dari yeast yang diperiksaantigen homolog dari yeast yang diperiksa

Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformansPathogenicity factorsPathogenicity factors::

Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformansPathogenicity factorsPathogenicity factors::

a.a. Antigen pada kapsulAntigen pada kapsul

b.b. Menghasilkan pigmen coklat pd bird seed Menghasilkan pigmen coklat pd bird seed agar/ caffeic acid mediumagar/ caffeic acid medium tanda diagnostiktanda diagnostikagar/ caffeic acid medium agar/ caffeic acid medium tanda diagnostiktanda diagnostik

c.c. Tumbuh baik pd suhu 37Tumbuh baik pd suhu 37°°C dlm perbenihan C dlm perbenihan bi tdk d ikl h k i idbi tdk d ikl h k i idbiasa yg tdk mengandung sikloheksimidbiasa yg tdk mengandung sikloheksimid

Clinical ManifestationsClinical ManifestationsClinical ManifestationsClinical ManifestationsPulmonary cryptococcosisPulmonary cryptococcosis

Asymptomatic carriage may occur in healthy people as well as Asymptomatic carriage may occur in healthy people as well as those with chronic lung diseasethose with chronic lung diseasethose with chronic lung diseasethose with chronic lung diseaseMay experience a self limited pneumoniaMay experience a self limited pneumoniaInvasive chronic pulmonary disease may occur and may Invasive chronic pulmonary disease may occur and may disseminate to the CNSdisseminate to the CNSdisseminate to the CNSdisseminate to the CNS

CNS diseaseCNS diseaseM i iti (85%) i h liti tM i iti (85%) i h liti tMeningitis (85%), meningoencephalitis, cryptococcomaMeningitis (85%), meningoencephalitis, cryptococcomaGenerally symptoms more insidious and of longer duration in the Generally symptoms more insidious and of longer duration in the nonnon--immunosuppressedimmunosuppressedHi h b d f i i AIDS ith i bl i fl tHi h b d f i i AIDS ith i bl i fl tHigher burden of organisms in AIDS, with variable inflammatory Higher burden of organisms in AIDS, with variable inflammatory response, which parallels degree of immunosuppressionresponse, which parallels degree of immunosuppression

Clinical manifestationsClinical manifestationsClinical manifestationsClinical manifestations

Cutaneous cryptococcosisCutaneous cryptococcosisypypUlcerated or nodular lesions Ulcerated or nodular lesions –– usually poor prognosis in usually poor prognosis in disseminated diseasedisseminated diseaseCellulitisCellulitis

Bone and joint diseaseBone and joint diseaseLytic lesions in up to 10% with disseminated diseaseLytic lesions in up to 10% with disseminated disease

Ocular cryptococcosisOcular cryptococcosisOcular cryptococcosisOcular cryptococcosisRare, other than pressure effectsRare, other than pressure effects

Genitourinary diseaseGenitourinary diseaseProstate acts as sanctuary site in immunosuppressedProstate acts as sanctuary site in immunosuppressed

CRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISGambaran KlinikGambaran KlinikGambaran KlinikGambaran Klinik

11 PULMONARY :PULMONARY :1.1. PULMONARY :PULMONARY :Asimptomatik, gejala paru non spesifik, sub Asimptomatik, gejala paru non spesifik, sub kli ikkli ikklinik.klinik.

2.2. DISSEMINATED :DISSEMINATED :Meningitis acute/chronic Meningitis acute/chronic gejala mirip gejala mirip tumor otak abses otak peny degeneratiftumor otak abses otak peny degeneratiftumor otak, abses otak, peny. degeneratif tumor otak, abses otak, peny. degeneratif SSP, meningitis mycobacteria atau jamurSSP, meningitis mycobacteria atau jamur

CRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISGambaran KlinikGambaran KlinikGambaran KlinikGambaran Klinik

2.2. DISSEMINATED :DISSEMINATED :

Lesi pada paruLesi pada paru paru kulit dan organparu kulit dan organLesi pada paruLesi pada paru--paru, kulit, dan organparu, kulit, dan organ--organ lainorgan lain

Manifestasi klinis yg Manifestasi klinis yg paling seringpaling sering : : meningitis kronik, berkembang lambat,meningitis kronik, berkembang lambat,meningitis kronik, berkembang lambat, meningitis kronik, berkembang lambat, remisi spontan, terjadi beberapa kali remisi spontan, terjadi beberapa kali k b ik b ieksaserbasi.eksaserbasi.

Diagnosis Diagnosis C fC fCryptococcus neoformansCryptococcus neoformans

High index of suspicion neededHigh index of suspicion neededHigh index of suspicion neededHigh index of suspicion neededLumbar puctureLumbar pucture

Measure + record opening pressureMeasure + record opening pressureRepeat at least fortnightly during therapy and daily ifRepeat at least fortnightly during therapy and daily ifRepeat at least fortnightly during therapy and daily if Repeat at least fortnightly during therapy and daily if pressure > 25 cmHpressure > 25 cmH22OOIndia ink examinationIndia ink examinationCSF WCC (usually mononuclears) typically low (< 50) in CSF WCC (usually mononuclears) typically low (< 50) in th ith d d i ith ith d d i ithose with advanced immunosuppressionthose with advanced immunosuppressionCSF glucose + protein often only minimally abnormalCSF glucose + protein often only minimally abnormalCryptococcal antigen assayCryptococcal antigen assay

Rapid diagnostic testRapid diagnostic testRapid diagnostic testRapid diagnostic testRare false positivesRare false positivesTitre generally correlates to organism burdenTitre generally correlates to organism burdenSerum assay useful screen in AIDS patientsSerum assay useful screen in AIDS patientsSerum assay useful screen in AIDS patientsSerum assay useful screen in AIDS patients

Diagnosis Diagnosis C fC fCryptococcus neoformansCryptococcus neoformans

Extraneural culturesExtraneural culturesOccasionally positive from another site Occasionally positive from another site Full evaluation needed to exclude disseminated Full evaluation needed to exclude disseminated disease, or CNS diseasedisease, or CNS disease

Radiology Radiology Detection of cryptococcomasDetection of cryptococcomasDetection of cryptococcomasDetection of cryptococcomasMay detect hydrocephalus May detect hydrocephalus --> need for shunt> need for shunt

CRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISDiagnosisDiagnosis

CRYPTOCOCCOSISCRYPTOCOCCOSISDiagnosisDiagnosis

Bahan spesimen: Bahan spesimen: Cairan spinal (CSF)Cairan spinal (CSF)Cairan spinal (CSF),Cairan spinal (CSF),Sputum, Sputum, Aspirasi dari lesi kulit, Aspirasi dari lesi kulit, Exudat, Exudat, udat,udat,Air kemih, Air kemih, SerumSerumSerumSerum


PemeriksaanPemeriksaan

DiagnosisDiagnosisDiagnosisDiagnosis

PemeriksaanPemeriksaan::* dalam keadaan * dalam keadaan basah basah : :

direct examinationdirect examination, atau dengan , atau dengan India India inkink (kapsul terlihat besar menonjol di(kapsul terlihat besar menonjol diinkink (kapsul terlihat besar, menonjol di (kapsul terlihat besar, menonjol di sekitar sel bertunas, tdk berwarna)sekitar sel bertunas, tdk berwarna)

* d l k d* d l k d k ik i* dalam keadaan * dalam keadaan kering kering : : pewarnaan pewarnaan immunoflouresensiimmunoflouresensi



Kultur Kultur Saboroud Agar (SDA),Saboroud Agar (SDA),

b ih l ib ih l i ikl h k i id (ikl h k i id ( ))perbenihan lain perbenihan lain sikloheksimid (sikloheksimid (--))



SerologySerologydeteksi kapsul antigen didalam cairan spinaldeteksi kapsul antigen didalam cairan spinaldeteksi kapsul antigen didalam cairan spinal deteksi kapsul antigen didalam cairan spinal dan serum dengan Latex Particle Agglutination dan serum dengan Latex Particle Agglutination T tT t tittit A tiA ti kk i ii iTest Test titer titer AntigenAntigen akan akan meninggimeninggi

**Cara serologis ini, 90% positif pada pasien Cara serologis ini, 90% positif pada pasien meningitis kriptokokosismeningitis kriptokokosis

CRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISCRYPTOCOCCOSISPengobatanPengobatan

CRYPTOCOCCOSISCRYPTOCOCCOSISPengobatanPengobatan

Kombinasi Amphotericin B + flucytosine Kombinasi Amphotericin B + flucytosine p yp ypengobatan pilihan untuk meningitis pengobatan pilihan untuk meningitis k i t k kk ik i t k kk ikriptokokkosiskriptokokkosis



Walaupun Amphotericin B dpt Walaupun Amphotericin B dpt menyembuhkan sebagian besar pasien menyembuhkan sebagian besar pasien meningitis kriptokokkosis, ttp penghentianmeningitis kriptokokkosis, ttp penghentianmeningitis kriptokokkosis, ttp penghentian meningitis kriptokokkosis, ttp penghentian Amphotericin B pada pasien AIDS dgn Amphotericin B pada pasien AIDS dgn kriptokokkosis akan menyebabkan kriptokokkosis akan menyebabkan kekambuhan.kekambuhan.



Flukonazol dapat memasuki cairan CSF Flukonazol dapat memasuki cairan CSF dengan baikdengan baik meningitis kriptokokkosismeningitis kriptokokkosisdengan baik dengan baik meningitis kriptokokkosismeningitis kriptokokkosis

Ketokonazol tdk berguna utk pasien Ketokonazol tdk berguna utk pasien dengan meningitis kriptokokkosisdengan meningitis kriptokokkosis

Pada pasien AIDSPada pasien AIDS terapi supresifterapi supresifPada pasien AIDS Pada pasien AIDS terapi supresif terapi supresif jangka panjang dengan flukonazol oraljangka panjang dengan flukonazol oral

CryptococcusCryptococcus -- epidemiologyepidemiologyCryptococcus Cryptococcus epidemiologyepidemiology

Increasing proportions of patients have an Increasing proportions of patients have an g p p pg p p punderlying immune deficiency underlying immune deficiency –– virtually all virtually all var var neoformans neoformans or or var grubiivar grubii

HIV/AIDSHIV/AIDSHIV/AIDSHIV/AIDSAccounts for up to 50% cryptococcal infectionsAccounts for up to 50% cryptococcal infectionsCDCD 4 < 2004 < 200Incidence has declined in Australia since advent HAARTIncidence has declined in Australia since advent HAART

Prolonged steroid therapyProlonged steroid therapyOrgan transplantationOrgan transplantationOrgan transplantationOrgan transplantationMalignancyMalignancySarcoidosis Sarcoidosis

Cryptococcus neoformans var Cryptococcus neoformans var gattiigattii

In contrast toIn contrast to var neoformansvar neoformans,, var gattiivar gattiiIn contrast to In contrast to var neoformansvar neoformans, , var gattiivar gattiigeographically restricted:geographically restricted:

Australia, PNGAustralia, PNGN. Africa and MediterraneanN. Africa and MediterraneanIndia, SE AsiaIndia, SE AsiaMexico, Brazil, Paraguay, S CaliforniaMexico, Brazil, Paraguay, S California, , g y,, , g y,

Commonly Commonly nonnon--immunocompromisedimmunocompromised hostshostsLarge mass lesions (cryptococcomas) common,Large mass lesions (cryptococcomas) common,Large mass lesions (cryptococcomas) common, Large mass lesions (cryptococcomas) common, resulting in significant morbidity.resulting in significant morbidity.

Epidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & Pencegahan

Sumber utama infeksi: kotoran burungSumber utama infeksi: kotoran burungSumber utama infeksi: kotoran burung Sumber utama infeksi: kotoran burung (terutama merpati) yang mengandung (terutama merpati) yang mengandung CryptococcusCryptococcus

Organisme tumbuh subur dalam ekskretaOrganisme tumbuh subur dalam ekskretaOrganisme tumbuh subur dalam ekskreta Organisme tumbuh subur dalam ekskreta burung merpati (nitrogenous waste burung merpati (nitrogenous waste creatinine) ttp b r ng tsb tidak terinfeksicreatinine) ttp b r ng tsb tidak terinfeksicreatinine), ttp burung tsb tidak terinfeksi.creatinine), ttp burung tsb tidak terinfeksi.

Epidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & PencegahanEpidemiologi & Pencegahan

Cara pengendalian: pengurangan populasi Cara pengendalian: pengurangan populasi

burung merpati & dekontaminasi tempat burung merpati & dekontaminasi tempat

burung bersarang dengan alkaliburung bersarang dengan alkali

Budding yeastBudding yeastCryptococcus neoformansCryptococcus neoformansCryptococcus neoformansCryptococcus neoformans

Cryptococcus neoformansCryptococcus neoformans

Tortora et.al; Figure 22.14

dr. tetty aman nasution, m med sc departemen mikrobiologi...

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