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Hidup di Ujung Tanduk Gara-Gara Jamur di Otak
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KASUS - Edisi Januari 2007 (Vol.6 No.6), oleh andra
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Ilustrasi Kasus
Pasien laki-laki, 28 tahun, datang ke rumah sakit dengan keluhan sakit kepala bertambah berat sejak 1 bulan sebelum masuk rumah sakit (SMRS). Sakit kepala terasa seperti diremas-remas hampir di seluruh bagian kepala; rasa berputar tidak ada; makan obat jenis parasetamol tidak ada perbaikan; sakit kepala membuat pasien tidak dapat tidur. Bila sakit kepala timbul akan disertai dengan muntah. Muntah tidak menyemprot; keluar isi makanan; tidak ada darah.
Tiga hari SMRS, pasien mengalami kejang-kejang sekitar 3-5 kali per hari; selama 10 menit; kejang berhenti sendiri; setelah kejang berhenti pasien tidak sadar; kejang ditandai dengan mata yang mendelik ke atas sedangkan tangan dan kaki tidak ikut kelojotan; kejang ini baru pertama kali dialami pasien; riwayat kejang waktu kecil tidak ada. Pandangan mata kabur. Tidak ditemukan adanya riwayat kelumpuhan pada anggota tubuh. Tengkuk terasa sakit. Tidak ada riwayat trauma. Buang air besar dan buang air kecil normal.
Satu tahun SMRS, pasien punya riwayat batuk lama. Batuk berdahak; pernah mengeluarkan darah sebanyak 1x; sesak nafas tidak ada; demam tidak ada; ada penurunan nafsu makan; ada penurunan berat badan. Akhir tahun 2005, pasien berobat ke rumah sakit ”S” karena batuk tersebut. Diagnosis dari RS ”S” tidak diketahui pasien dan keluarga, hanya dikatakan bukan sakit berat; obat yang diberikan tidak ada yang membuat kencing warna merah; lama minum obat hanya 2 minggu.
Bulan Januari 2006, pasien dikatakan sakit paru oleh puskesmas ”TT”. Kemudian saat berobat di puskesmas tersebut, pasien diberi tahu oleh petugas kesehatan disana untuk berobat ke klinik ”B” agar mendapat pengobatan gratis. Disana pasien diminta untuk melakukan pemeriksaan darah di RS ”C” karena dicurigai mengidap HIV. Hasil pemeriksaan menunjukkan HIV positif. Pasien diberi obat HIV dan paru. Setelah minum obat paru (obat menyebabkan kencing warna merah) selama 3,5 bulan, pasien berhenti sendiri karena sudah merasa lebih baik.
Riwayat seks bebas ada; transfusi darah disangkal; obat terlarang dan suntik disangkal. Pasien juga memiliki riwayat keluar cairan dari telinga 15 tahun lalu, tidak pernah diobati dan berhenti sendiri. Pasien memelihara 4 ekor anjing di rumah.
Pemeriksaan fisik menunjukkan tanda vital pasien baik. Oral thrush (+). Paru terdengar rhonki +/+ basah kasar. Lain-lain dalam batas normal. Status neurologis pasien menunjukkan GCS 15; pupil bulat, anisokor, 4 mm/3 mm; kaku kuduk (+); hemiparesis nervus VII dekstra sentral; fungsi motorik dan sensorik baik.
Pada laboratorium dijumpai peningkatan laju endap darah (40 mm). Pemeriksaan liquor didapatkan peningkatan protein (0,78 g/L), None (-), Pandi (+), sel mononuklear 75%, polimorfonuklear 25%, dan Kriptokokus (+) dengan tinta India. Anti-TB (+), HbsAg (-), anti-HCV (-), anti toxoplasma IgG 0, anti-CMV IgG 391, anti-CMV IgM (-), sel T CD4 16.
CT-Scan kepala brain window tanpa dan dengan kontras memberi kesan adanya mastoiditis bilateral dengan kecurigaan serebritis. Sementara itu, thorax posterior-anterior menunjukkan pneumonia.
Diagnosis yang ditegakkan pada pasien ini adalah meningoensefalitis kritpokokus.
Pendahuluan
Kriptokokosis termasuk penyakit infeksi yang jarang diderita oleh orang sehat. Umumnya, kriptokokosis mudah dialami pada penderita dengan sistem imun yang rendah, contohnya HIV, seperti halnya pada kasus diatas. Di sisi lain, menurut penelitian oleh Tiksnadi A dkk yang dimuat dalam Neurona 2004, etiologi terbanyak komplikasi susunan saraf pusat pada penderita HIV adalah toxoplasma.
Di Indonesia, menurut data September 2002, dari jumlah penduduk tahun 2001 sekitar 214.840.000, diperkirakan terdapat penderita (baik anak-anak maupun dewasa) HIV/AIDS sekitar 130.000 jiwa, sebagian besar bersamaan dengan penyalahgunaan narkoba. Prevalensi HIV pada pasien yang dirawat di Rumah Sakit Ketergantungan Obat (RSKO) di Jakarta adalah 18% (1999), 40% (2000) dan 48% (2001). Prevalensi HIV positif pada pengguna narkoba suntik di Indonesia diperkirakan antara 50-90%. Beberapa laporan menyebutkan bahwa angka kejadian HIV yang mengenai susunan saraf pusat (SSP) adalah sekitar 40%, bahkan terdapat laporan neuropatologik yang menemukan kelainan pada 90% spesimen posmortem penderita HIV yang diperiksa. Angka kejadian ini semakin meningkat apabila disertai penyalahgunaan narkoba suntik. Meningkatnya jumlah penderita HIV disertai tingkat penyalahgunaan narkoba yang semakin tinggi, maka diperkirakan jumlah penderita dengan komplikasi neurologi juga akan semakin tinggi dan sering dijumpai.
Menurut laporan dari Rumah Sakit Penyakit Tropis di Ho Chi Minh, Vietnam, jumlah penderita HIV yang mengalami kriptokokosis terus meningkat setiap tahunnya. Di Thailand, prevalensi meningitis kriptokosis sebesar 18,5% pada pasien HIV dan menjadi penyebab infekasi oportunistik tersering pada SSP.
Kondisi lain selain HIV yang juga menjadi faktor predisposisi kriptokokosis adalah pasien yang menjalani terapi imunosupresif paska transplantasi organ, sarkoidosis, penyakit limfoproliferatif, hipogammaglobulinemia, terapi kortikosteroid, systemic lupus erythematosus (SLE), sirosis, dan dialisis peritoneal.
Patofisiologi
Cryptococcus neoformans menyebar secara hematogen ke sistem saraf pusat dari fokus di paru yang mana biasa bersifat subklinis. Tidak ada pneumonitis ditemukan pada 85% pasien dengan penyakit kriptokokal di SSP. Selain, paru-paru dan SSP, kriptokokus juga menyerang kulit, tulang dan saluran kelamin. Meninges merupakan tempat yang paling sering. Sebabnya masih belum jelas, tetapi beberapa teori telah dikemukakan seperti sifat antigen kapsul kriptokokus di cairan serebrospinal yang terbatas sehingga reaksi inflamasi tidak terinduksi. Selain itu cairan serebrospinal juga merupakan media pertumbuhan yang baik, mungkin disebabkan karena kandungan dopamin dan neurotransmiter lain di cairan serebrospinal dn tidak adanya protein yang toksik bagi kriptokokus. Penyakit ini biasanya berkembang bila kadar limfosit T helper CD4 berada dibawah 100 sel/mm3. Pada tahap ini, makrofag juga tidak berfungsi dengan baik.
Gejala Klinis
Gejala klinis yang paling sering dialami adalah sakit kepala, disusul kemudian oleh demam. Gejala klinis lain adalah mual, muntah, lemas, gangguan memori, dan penurunan kesadaran (stupor atau koma).
Dari pemeriksaan fisik pada pasien ditemukan penurunan kesadaran (apatis), kaku kuduk dan gangguan saraf kranialis nervus VII dextra sentral. Oleh karena itu, dipikirkan pasien mengalami meningoensefalitis. Sakit kepala progresif akibat tumor dapat disingkirkan karena pada pasien ditemukan tanda rangsang meningeal positif.
Diagnosis
Diagnosis definitif pada meningitis kriptokokus memerlukan pungsi lumbal yang disertai dengan pengukuran opening pressure. Cairan serebrospinal yang telah dipungsi selanjutnya diuji dengan pewarnaan tinta India atau dikultur. Hasil pemeriksaan cairan serebrospinal adalah leukositosis mononuklear ringan (50-500 sel/mL), protein >500-1000 mg/dL atau normal, dan glukosa sedikit menurun. Hasil itu mencerminkan meningoensefalitis kronik.
Cairan serebrospinal yang telah diwarnai dengan tinta India dilihat di bawah mikroskop dengan pembesaran kuat (minyak emersi). Yang terlihat adalah sel ragi yang berbentuk halo disekelilingnya. Adanya halo tersebut dikarenakan kapsul glukuronoxylomannan. Sensitivitas tes tinta India mencapai 75%. Akan tetapi, jumlah koloni sel ragi <104 colony forming units (CFU) akan menyulitkan deteksi sehingga diperlukan kultur atau tes antigen kriptokokus. Selain itu, perlu juga dilakukan pemeriksaan tes basil tahan asam terhadap bakteri Mycobacterium tuberculosis untuk mengeksklusi meningitis tuberkulosis.
Kultur cairan serebrospinal dilakukan pada agar darah atau Sabouraud pada suhu 35oC. Kultur lebih sensitif daripada tinta India dengan sensitivitas mencapai 90%.
Tes antigen kriptokokus sangat sensitif dan spesifik. Sensitivitasnya dapat mencapai lebih dari 90%. Tes antigen kriptokokus dirancang untuk menilai secara kualitatif apakah seseorang positif menderita kriptokokus, bukan kuantitatif (jumlah bakteri). Di samping itu, dapat pula digunakan untuk menilai respon pengobatan.
Fase-Fase Terapi
Berdasarkan pedoman terapi meningitis kriptokokus yang disusun oleh Saag dkk, seperti dilansir dari Clinical Infection and Disease 2000, terdapat 3 fase terapi yaitu fase induksi, konsolidasi, dan pemeliharaan. [Tabel 1] Kombinasi amfoterisin B dan flusitosine dianjurkan menjadi obat lini pertama pada fase induksi (2 minggu). Penelitian oleh van de Horst dkk dalam N Engl J Med 1997 menyimpulkan, eliminasi kriptokokus akan lebih cepat pada pasien yang mendapat kombinasi amfoterisin B dengan flusitosin daripada amfoterisin B saja. Selanjutnya, flukonazole diberikan pada fase konsolidasi (8 minggu). Setelah dua fase itu terlaksana, fase selanjutnya adalah fase pemeliharaan dimana jangka waktunya dapat seumur hidup. Akan tetapi, dapat dihentikan apabila CD4 >100 sel/mL. Risiko relaps pada fase pemeliharaan adalah sekitar 2%.
Amfoterisin B bersifat fungisidal. Resistensi secara in vitro masih jarang ditemukan. Efek samping yang paling dikhawatirkan adalah nefrotoksisitas, tetapi sifatnya reversible apabila dosis total tidak melebihi 4 gr. Nefrotoksisitas dapat tereksaserbasi apabila pasien mengalami kekurangan natrium. Untuk mencegah keadaan itu, pasien sebaiknya mendapatkan infus NaCl 0,9% selama pengobatan amfoterisin B. Bioavailabilitas amfoterisin B buruk pada pemberian oral sehingga harus diberikan secara intravena. Amfoterisin B menyebabkan kerusakan membran melalui ikatan sterol pada sel membran. Selain itu, amfoterisin B juga diduga merangsang fungsi makrofag. Pemberian intratekal dianjurkan hanya sebagai terapi salvage pada pasien relaps.
Flusitosine adalah analog nukleotida. Secara in vitro, ditemukan kerja yang sinergis dengan amfoterisin B. Pada studi acak oleh Horst dkk dilaporkan bahwa eliminasi kriptokokus pada cairan serebrospinal lebih cepat pada pasien yang diberikan flusitosine dan amfoterisin B daripada amfoterisin B saja. Flusitosine akan diubah menjadi fluoro-urasil pada sel jamur, dan merupakan zat aktif dari obat itu. Toleransi pengobatan yang kurang baik dan resistensi yang cenderung meningkat menjadi alasan flusitosine tidak digunakan sebagai monoterapi.
Golongan azole mempunyai potensi, tolerabilitas, dan penetrasi pada cairan serebrospinal yang baik. Mekanismenya berlawanan dengan amfoterisin B yaitu menghambat pembentukan sterol sehingga efek terapi akan kurang baik apabila keduanya digunakan secara kombinasi meski percobaan pada hewan belum membuktikan hal tersebut.
Sementara itu, terapi meningoensefalitis kriptokokus berdasarkan Standard of Procedure Rumah Sakit Cipto Mangunkusumo (RSCM) agak berbeda dengan yang dikemukakan Saag dkk. [Tabel 2]
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Tabel 1. Practice Guidelines for the Management of Cryptococcal Disease
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Tabel 2. Terapi Meningoensefalitis Kriptokokus
Berdasarkan Standard of Procedure RSCM
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Fase Induksi
selama 2 minggu yaitu amfoterisin B 0,7 mg/kgBB/hr IV
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Hari 1
Dosis percobaan: 1 mg amfoterisin B dimasukkan dalam 350 ml dextrose 5% diberikan sebagai infus intravena dalam jangka waktu 4 jam. Selama pemberian, monitor tanda vital setiap 30 menit. Amfoterisin B tidak boleh dilarutkan dengan NaCl 0,9% karena dapat mengkristal.
Dosis selanjutnya: amfoterisin B 0,3 mg/kg dimasukkan dlm 500 ml dekstrosa 5% diberikan secara infus intravena dalam jangka waktu 6 jam.
Hari 2-14
Dosis amfoterisin B 0,7-1 mg/kg dimasukkan dalam 500 ml dextrose 5% diberikan secara infus intravena dalam jangka waktu 6 jam. Setelah pemberian amfoterisin B selesai, infus dapat diganti sesuai dengan kebutuhan pasien.
Ukur balans cairan setiap hari:
Tiap 2 hari : periksa protein urin, ur/cr, dan elektrolit (Na,K,Mg)
Tiap minggu : periksa darah lengkap dan fungsi hati
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Fase Konsolidasi
Selama 8-10 minggu yaitu flukonazol 400 mg/hari
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Tabel 3. Tatalaksana Tekanan Intrakranial Meningkat
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Bila opening pressure >25 mmH2O pada pungsi lumbal dapat dilakukan:
Pungsi lumbal berulang
Pemasangan lumbar drain atau VP shunt
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Prognosis
Meningitis kriptokokus akan berakibat fatal bila tidak diobati. Dengan pengobatan, angka ketahanan hidup akan bertambah tetapi risiko kematian tetap tinggi antara 5,5-46%. Sebagian kecil pasien meninggal dalam 6 minggu pertama setelah diagnosis tanpa pengobatan. Sedangkan sebagian yang lain dapat hidup lebih hingga 18 bulan lebih lama. Angka kekambuhan setelah pengobatan cukup tinggi, sebesar 30-50%. Toksisitas obat sering terjadi yaitu mencapai 60% pasien. Maka dari itu, hidup serasa di ujung tanduk gara-gara jamur!
(Felix)
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Seperti tercetak di Majalah Farmacia Edisi Januari 2007 , Halaman: 66 (962 hits)
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INFEKSI JAMUR PADA SUSUNAN SARAF PUSAT
Dr ISKANDAR JAPARDI
Fakultas Kedokteran
Bagian Bedah
Umniversitas Sumatera Utara
2002 digitized by USU digital library
BEBERAPA JENIS JAMUR PENYEBAB INFEKSI SUSUNAN SARAF
PUSAT
1. Cryptococcus neofarmans
Cryptococcus neofarmans adalah jamur seperti ragi (yeast like fungus) yang
ada dimana-mana di seluruh dunia. Jamur ini menyebabkan penyakit jamur
sistemik yang disebut cryptococcosis, dahulu dikenal dengan nama Torula
histolitica. Jamur ini paling dikenal sebagai penyebab utama meningitis jamur
dan merupakan penyebab terbanyak morbiditas dan mortalitas pasien dengan
gangguan imunitas. Cryptococcus neofarmans dapat ditemukan pada kotoran
burung (terutama merpati), tanah, binatang juga pada kelompok manusia
(colonized human).
Gejalanya seperti meningitis klasik yang melibatkan meningitis secara difus.
Dengan adanya AIDS, insiden cryptococcal meningitis meningkat drastis. Di
Amerika, meningitis ini termasuk lima besar penyebab infeksi oportunistik
pada pasien AIDS.
a. Mikologi
Cryptococcus neofarmans merupakan yeast like fungus. Pada jaringan
yang terinfeksi organisme ini membentuk kapsul polisakarida yang
merupakan antigenpenting yang dapat mempengaruhi tubuh host. Kapsul
ini terdiri dari empat serotipe antigen yang telah dapat diisolasi yairu
A,B,C dan D. Berdasarkan antigen kapsul ini Cryptococcus neofarmans
dibagi menjadi dua subgroup, V.neofarmans var neofarmans (serotipe A
dan D) dan C.neofarmans var gatti (serotipe B dan C). Serotipe A
merupakan serotipe yang paling sering diisolasi dan yang terutama di
Amerika. Serotipe D biasanya ditemukan di Eropa, B dan C ditemukan di
daerah tropis dan subtropis. Pada pasien AIDS serotipe yang paling sering
ditemukan aialah serotipe B dan C.
Serotipe B dan C dapat pula menginfeksi manusia (nonimmunosupressant
host) dan lebih banyak menginvasi parenkim otak
menyebabkan lesi massa yang disebut toruloma.
Isolasi jamur dapat dilakukan dengan membuat sediaan cairan
serebrospinal yang dicampur dengan tinta India kemudian diperiksa pada
mikroskop. Ukuran diameter yeast 4-6 ìm dengan kapsul berukuran 1-30
ìm. Jika pemeriksaan ini dilakukan dengan hati-hati maka dapat positif
pada lebih kurang setengah kasus meningitis cryptococcal, dan lebih tinggi
pada penderita AIDS. Perhitungan kwantitatif pasien meningitis daro 103-
107 count forming unit (CFU) perdarahan milimeter cairan serebrospinal.
Patogenesis dan Patofisiologi
Infeksi pertama terbanyak terjadi akibat inhalasi yeast dari lingkungan
sekitar. Pada saat dalam tubuh host Cryptococcus membentuk kapsul
polisakarida yang besar yang resisten terhadap fagositosis. Produksi
kapsul distimulasi oleh konsentrasi fisiologis karbondioksida dalamparu.
Keadaan ini meyebabkan jamur ini beradaptasi sangat baik dalam host
mamalia. Reaksi inflamasi ini menghasilkan reaksi kompleks primer paru
kelenjar limfe (primary lung lymp node complex) yang biasanya
membatasi penyebaran organisme.Kebanyakan infeksi paru ini tanpa
gejala, tetapi secara klinis dapat terjadi seperti gejala pneumonia pada
infeksi pertama dengan gejala yang bervariasi beratnya. Keadaan ini
biasanya membaik perlahan dalam beberapa minggu atau bulan dengan
atau tanpa pengobatan. Pada pasien lainnya dapat terbentuk lesi
pulmonar fokal atau nodular. Cryptococcus dapat dorman dalam paru atau
limfenodus sampai pertahanan host melemah.
Cryptococcus neofarmans dapat menyebar dari paru dan limfenodus
torakal ke aliran darah terutama pada host yang sistem kekebalannya
terganggu. Keadaan ini dapat terjadi selama infeksi primer atau selama
masa reaktivasi bertahun-tahun kemudian. Jika terjadi infeksi jauh, maka
tempat yang paling sering terkena adalah susunan saraf pusat. Keadaan
dimana predileksi infeksi ini terutama pada ruang subarakhnoid, belum
dapat diterangkan.
Ada beberapa faktor yang berperanan dalam patogenesis infeksi
Cryptococcus neofarmans pada susunan saraf pusat. Jamur ini
mempunyai beberapa fenotif karakteristik yang diaktakan berhubungan
dengan invasi pada susunan saraf pusat seperti, produksi phenoloxidase,
adanya kapsul polisakarida,dan kemampuan untuk berkembang dengan
cepat pada suhu tubuh host.Informasi terakhir mengatakan bahwa
melanin bertindak sebagai antioksidan yang melindungi organisme ini dari
mekanisme pertahanan tubuh host. Faktor karakteristik lainnya yaitu
kemampuan kapsul untuk melindungi jamur dari pertahanan tubuh
terutama fagositosis dankemampuan jamur untuk hidup dan berkembang
pada suhu tubuh manusia.
c. Patologi
Ada tiga pola dasar infeksi jamur pada susunan saraf pusat yaitu,
meningitis kronis,vaskulitis daninvasi parenkimal.pada infeksi Cryptococcal
jaringan otak menunjukkan adanya meningitis kronis pada leptomeningen
bsal yang dapat menebal dan mengeras oleh reaksi jaringan penyokong
dandpt mengobstruksi aliran likuor dari foramen Luschka dan Magendi
sehingga terjadi hidrosefalus. Pada jaringan otak terdapat substansi
gelatinosa pada ruang subarakhnoid dan kista kecil didalam parenkim y
terletak terutama pada ganglia basilis pada distribusi arteri
lentikulostriata. Lesi parenkimal terdiri dari agregasi atau gliosis. Infiltrat
meningen terdiri dari sel-sel ingflamasi dan fibroblast yang bercampur
dengan Cryptococcus. Bentuk granuloma tidak sering ditemukan pada
beberapa kasus terlihat reaksi inflamasi kronis danreaksi granulomatosa
sama dengan yang terlihat pada M.tuberculosa dengan segala bentuk
komplikasinya.
Menurut Prockop,perubahan susunan saraf pusat termasuk infiltrasi
meningen oleh sel mononuklear dan organisma. Organisma ini dapat
tersebar pada parenkim otak dengan reaksi inflamasi yang minimal atau
tanpa reaksi inflamasi. Kadang-kadang terdapat abses pada jaringan otak
dan granuloma pada meningen otak dan medula spinalis.
Gejala klinis infeksi jamur pada susunan saraf pusat tidak spesifik seperti
akibat infeksi bakteri. Pasien paling sering mengalami gejala sindroma
meningitis atau sebagai meningitis yang tidak ada perbaikan atau semakin
progresif selama observasi (paling kurang empat minggu). Manifestasi
klinis lainnya berupa kombinasi beberapa gejala seperti demam, nyeri
kepala, letargi, confise, mual, muntah, kaku kuduk atau defisit neurologik.
Sering kali hanya satu atau dua gejala utama yang dapat ditemukan pada
gejala awal. Misalnya pasien datang ke klinis hanya dengan keluhan
demensia subakut tanpa gejala lainnya.
Waktu terjadinya penyakit sangat vital dan penting dalam
mempertimbangkan diagnosis meningitis jamur. Beberapa kasus sebagai
meningitis akut,kebanyakan subakut dan beberapa kronis.
Gambaran klinis selain meningitis yang sering ditemukan yaitu gambaran
ensefalitis. Sering kali pasien didagnosa sebagai meningitis TBC sampai
akhirnya ditemukan diagnosa yang benar dengan ditemukannya jamur
dalamcr serebrospinal. Diagnosa meningitis jamur dapat ditegakkan
dengan kultur dalam medium sabouraud. Granuloma besar pada
serebrum, serebrum atau batang otak memberikan gejala seperti space
occupaying lesion lainnya. Diagnosa granuloma dapat ditegakkan dari
pemeriksaan CT scan dan MRI.
d. Diagnosa
Diagnosa ditegakkan berdasarkan gejala klinis dan pemeriksaan tambahan
seperti, laboratorium cairan serebrospinal. Gambaran cairan serebrospinal
infeksi Cryptococcus sama dengan meningitis tuberkulosa. Tekanan
biasanya meningkat terdapat peningkatan jumlah sel dari 10-500
sel/mm3. protein meningkat dan glukosa menurun biasanya sekitar 15-
35 mg. Diagnosa dapat dibuat dengan menemukan organisme ini dalam
cairan serebrospinal dengan pewarnaan tinta India, kultur dalam media
sabouraud dan berasarkan hasil inokulasi pada hewan percobaan. Jamur
ini juga dapat dikultur dari urine, darah, fases, sputum dan sum-sum
tulang. Pemeriksaan antigen Cryptococcus pada serum dan cairan
serebrospinal dapat menegakkan diagnosa, dapat dikultur dari urine,
darah, feses, sputum dan sum-sum tulang.
e. Terapi
Terapi dengan amphotericin B memperlihatkan hasil yang baik.
Amphotericin B diberikan tiap hari intravena dengan dosis 0,5
mg/kg,diberikan enam sampai sepuluh minggu, tergantung dari perbaikan
klinis danekmbalinya cairan serebrospinal kearah normal. Peneliti lain
memberikan amphotericin B dengan 5-flurocytosine 150 mg/kg perhari
(dalam 4 dosis). Kombinasi ini memberikan hasil yang lebih baik.
f. Prognosa
Pada pasien yang tidak diobati, biasanya fatal dalam beberapa bulan
tetapi kadang-kadang menetap sampai beberapa tahun dengan
rekuren,remisi dan eksaserbasi. Kadang-kadang jamur pada cairan
serebrospinal ditemukan selama tiga tahun atau lebih. Telah dipalorkan
beberapa kasus yang sembuh spontan.
Journal of Clinical Microbiology, July 2005, p. 3548-3550, Vol. 43, No. 7
0095-1137/05/$08.00+0 doi:10.1128/JCM.43.7.3548-3550.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
First Case of Human Cryptococcosis Due to Cryptococcus neoformans var. gattii in Spain
A 60-year-old heterosexual Spanish farmer came to the Hospital General de Alicante in July 2003, having suffered for several days from cephalalgia and somnolence. He had never traveled abroad. A diabetes mellitus type 2 identified 2 years previously was the only clinical antecedent of interest. Human immunodeficiency virus serology was investigated with repeated negative results. General and neurological exploration included computerized tomography scanning, which disclosed a brain mass lesion in basal ganglions. Capsulated yeasts were seen in a stereotaxic brain puncture sample, and Cryptococcus neoformans was suspected to be the causative agent. C. neoformans capsular antigen was detected in blood and cerebrospinal fluid (CSF) several times during the process (maximum values detected, 1/256 and 1/32, respectively). The yeast was cultured from a surgical drainage sample of the brain abscess. Species identification was carried out on the basis of microscopic morphology, growth at 37°C, a urease test, phenoloxydase production, and the carbohydrate assimilation pattern (Auxacolor; Bio-Rad). Further testing such as canavanina glycine bromothimol blue agar growth, serotype determination (Cryptocheck test; Iatron), and genotype analysis revealed that the strain was C. neoformans var. gatti serotype B. The strain identification and serotype were confirmed in another mycology laboratory (IMIM, Barcelona, Spain). Two antifungal drug sensitivity tests were performed (Sensititre and Etest). Both tests showed low amphotericin B (AMB) and ketoconazole MICs but different results with fluconazole (MICsensititre, 8 µg/ml; MICEtest, 64 µg/ml) and 5-flucytosine (MICsensititre, 2 µg/ml; MICEtest, 32 µg/ml). Voriconazole was only tested with the Sensititre test (MICsensititre, 12 µg/ml). Genotype analysis consisted of the study of five molecular DNA targets: internal transcribed spacer-5.8S rRNA gene sequence analysis (36), 5S rRNA gene and URA5 gene restriction fragment length polymorphism (RFLP) analysis (24), and amplification patterns of two highly repeated minisatellite sequences (M13 and GACA4) (14, 24). Nucleotide sequence analysis of the internal transcribed spacer-5.8S rRNA gene confirmed the identification at a species level by comparing it to ribosomal sequence databases (EMBL and GenBank). RFLP of the URA5 gene showed a VGI molecular type (Fig. 1) which is characteristic of C. neoformans var. gattii. RFLP 5S rRNA gene and minisatellite amplification of M13 and GACA4 also displayed molecular patterns attributable to C. neoformans var. gattii strains (14, 24).
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FIG. 1. Agarose gel electrophoresis of DNA obtained by PCR amplification of the URA5 gene (A) and subsequent RFLP fingerprinting after DNA enzymatic digestion (B). Lanes 1, molecular ruler; lanes 2, DNA obtained from C. neoformans-cultured cells; lanes 3, DNA obtained from the clinical sample (cryptococcoma drainage).
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Some different antifungal therapies were followed, depending on the clinical evolution and the antigen levels (serum and CSF). Intravenous AMB at 200 mg/day (Ambisome) was the first choice, but fluconazole (400 mg/12 h) and AMB at 400 mg/day combined with 5 flucytosine (2.5g/6 h) were also prescribed. Three months after diagnosis, neurological symptoms and serum and CSF positive antigen detection persisted. Therefore, intra-abscess amphotericin B deoxicolate was administrated by a surgical procedure, and a symptomatic improvement was rapidly detected. Although during the next 3 months serum antigen detection remained positive at low levels (1/16), 6 months after diagnosis, the serum level increased again to 1/64. Therefore, oral voriconazole was prescribed as a maintenance therapy. At present the patient is asymptomatic, and serum remained negative for C. neoformans antigen for more than 6 months.
An extensive sampling of the patient’s area of work was carried out, including different soil samples, bird droppings, and vegetal tissues from all the tree species around; no eucalyptus was seen in the area. Some Cryptococcus and other yeast species were found, but, unfortunately, none of them corresponded to C. neoformans. Moreover, the patient’s family reported the presence of a species of parrot in the house next door. Our interest in visiting the neighbors and taking samples of the parrot’s feces was misunderstood, and they therefore got rid of the parrot, together with the possibility of studying a putative source of the infection (30, 32, 35).
Cryptococcosis is an infectious disease caused by the yeast C. neoformans. It presents different clinical manifestations and a wide range of severity, depending not only on the patient’s risk factors but also on the yeast variety involved. This microorganism was traditionally described as a unique species, C. neoformans, that included two pathogenic varieties, C. neoformans var. neoformans and C. neoformans var. gattii. Important differences between the two varieties have recently raised C. neoformans var. gattii to species status as Cryptococcus gattii (20).
Cryptococcosis from C. neoformans var. neoformans infection is cosmopolite. Patients are commonly immunocompromised, mostly with a cellular immunity alteration, as in human immunodeficiency virus-infected individuals. C. neoformans var. gattii is believed to behave more aggressively than C. neoformans var. neoformans and to cause infections in immunocompetent patients more frequently (8). Until now, this yeast was considered to be restricted to warm areas (tropical and subtropical climates), but this statement is under discussion after the recent outbreak of cryptococcosis infection by C. gattii in the temperate climate of Vancouver Island (British Columbia, Canada) (18). Both pathogenic varieties also show different natural habitats. C. neoformans var. neoformans is widely associated with bird feces, with a strong presence in pigeon excreta (19). The association of C. neoformans var. gattii with eucalyptus trees has been demonstrated (13), and some strains have also been isolated from a wide range of different natural sources, including some tropical birds (2, 12, 16, 23, 26, 27). Cryptococcoma is not the usual clinical presentation of the disease, although a number of cases were described in countries all over the world, including Spain (28). They usually appear in the literature as case reports because of their low incidence. They are more common in immunocompetent hosts and usually have a better prognosis than disseminated cryptococcosis (17, 22).
In Spain, Cryptococcus and cryptococcosis have already been studied by some authors with various points of view (3, 25). The presence of the yeast in relation to birds has been demonstrated in different studies and in various locations (11, 15, 29). Some reports on human and animal cryptococcosis have also been reported since 1971 (1). Among these studies, the first report of the presence of C. neoformans var. gattii in our country is remarkable (4). In 1998, 13 strains of C. neoformans var. gattii were isolated from the tissues of different dead goats. All of them suffered from invasive disease. At that time, a national epidemiological study for human cryptococcosis had just started in Spain (10). During a 6-year period (1998 to 2003) all strains found in the human study (a total of 64) belonged to C. neoformans var. neoformans until July 2003, when the present case came to our laboratory.
Finding the source of the infection is very important to clarify whether it could be an autochthonous infection or an imported case. Some published cases of C. neoformans var. gattii cryptococcosis outside the area of endemicity (5, 6, 31, 33, 34) had a clear source of infection. Most of them occurred in patients who had traveled to Australia or South America. For some others, without a probable contact with eucalyptus trees and without any prior travel, the source remains uncertain. An exceptional situation has recently been described in Vancouver Island (Canada). An extended cryptococcosis outbreak of C. gattii involved some locations on the east coast of the island, and a large number of humans and animals were affected. The exhaustive environmental sampling carried out in the area allowed the detection of the possible natural reservoirs of the disease. The yeast was present in some tree hollows, soils, and other materials (18). This fact marks an important change in the understanding of the geographical distribution and natural life cycle of C. gattii and highlights the importance of finding the source of the infection. In order to demonstrate the presence of the yeast in our patient’s environment, a total of 43 samples were taken all around his working area. Samples included vegetal material from different tree species (not including eucalyptus), different kinds of soils, and some pigeon droppings. As with other works focused on the isolation of C. neoformans var. gattii from eucalyptus and other trees outside the zones of endemicity (7, 9, 21), until now the presence of the yeast in the natural environment has not been proved. All these findings encouraged the search for a C. gattii environmental niche in Spain.
CASE REPORT
PRIMARY CUTANEOUS CRYPTOCOCCOSIS DUE TO Cryptococcus neoformans var. gattii
SEROTYPE B, IN AN IMMUNOCOMPETENT PATIENT
Carlos da Silva LACAZ(1), Elisabeth Maria HEINS-VACCARI(1), Giovanna L. HERNÁNDEZ-ARRIAGADA(1), Eduardo Lacaz MARTINS(2), Célia A.L. PREARO(2),
Simone Miwa CORIM(1) & Marilena dos Anjos MARTINS(3)
SUMMARY
The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized
on the left forearm, caused by Cryptococcus neoformans var. gattii serotype B. Oral treatment with fluconazole was successful.
A review of the literature showed the rarity of this localization in HIV-negative patients. In contrast, skin lesions frequently occurs
in HIV-positive patients, with Cryptococcus neoformans var. neoformans serotype A predominating as the etiological agent.
In this paper, the pathogenicity of C. neoformans to skin lesions in patients immunocompromised or not, is discussed, showing
the efficacy of fluconazole for the treatment of these processes.
KEYWORDS: Cryptococcus neoformans var. gattii; Serotype B; Immunocompetent patient; Cutaneous cryptococcosis.
INTRODUCTION
Cryptococcosis is a fungal infection caused by two varieties of
Cryptococcus neoformans, with five serotypes. We traditionally consider
the varieties C. neoformans var. neoformans (serotypes A, D and AD)
and C. neoformans var. gattii (serotypes B and C) (LACAZ et al. 1991)12.
According to some researchers, C. neoformans var. grubii represents
strains of serotype A, var. neoformans (serotypes D e AD) and var. gattii
(serotypes B and C) (FRANZOT et al., 1999)7. Based on sequential
analysis of intergenic rDNA spaces, DIAZ et al., (2001)6 consider two
pathogenic varieties: C. neoformans (serotypes A, D and AD) and C.
bacillisporus (serotypes B and C), the latter corresponding to C.
neoformans var. gattii.
The sexual states of C. neoformans are assigned to Filobasidiella,
with the species neoformans and bacillispora. A heterothallic yeast, C.
neoformans presents two types of conjugating hyphae: _ and a (KWONCHUNG
& BENNETT, 1992; TAKEO et al. 1993)10,25.
A capsulated yeast, C. neoformans (SANFELICE, 1894) Vuillemin,
1901 can be isolated in a relatively easy manner, making possible the
study of its sexuality and of its antigenic and genetic structure.
Current research has been mainly directed at the study of the genome
of C. neoformans, its life cycle and ecological niche (LAZERA et al.,
2000; MONTENEGRO & PAULA, 2000)13,17.
C. neoformans var. gattii has been isolated in Brazil by several
investigators, mainly from hollow trees (LAZERA et al., 2000)13 but
also from soil and plant detritus (LAZERA et al., 1998)14.
BARRETO DE OLIVEIRA (2001)2 observed that 40 of 58 serotyped
strains (70%) were serotype A, 10 (17%) serotype B, 5 (8%) serotype D,
2 (3%) serotype C, and 1 (2%) serotype AD. C. neoformans var.
neoformans serotype A predominates in Brazil, followed by the variety
gattii, serotype B at lower frequency.
Cryptococcosis has been reported to be associated with AIDS in
most cases, or with other immunodeficiencies, being rarely observed in
immunocompetent patients (KWON-CHUNG & BENNETT, 1992;
SPEED & DUNT, 1995)10,24. According to SEVERO et al. (1999)23,
cryptococcosis induced by C. neoformans var. neoformans usually occurs
in immunocompromised patients and C. neoformans var. gattii occurs
in immunocompetent subjects.
Financial support: FAPESP
(1) Laboratório de Micologia Médica do Instituto de Medicina Tropical de São Paulo e LIM-53 do Departamento de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da
Universidade de São Paulo, São Paulo, SP, Brasil
(2) Clínica Dermatológica da Faculdade de Medicina do ABC, Santo André, SP, Brasil
(3) Laboratório de Micologia Médica do Instituto Adolfo Lutz, São Paulo, SP, Brasil.
LACAZ, C.S.; HEINS-VACCARI, E.M.; HERNÁNDEZ-ARRIAGADA, G.L.; MARTINS, E.L.; PREARO, C.A.L.; CORIM, S.M. & MARTINS, M.A. – Primary cutaneous cryptococcosis
due to Cryptococcus neoformans var. gattii serotype B, in an immunocompetent patient. Rev. Inst. Med. trop. S. Paulo, 44(4):225-228, 2002.
In a study on immunosuppressed Wistar rats, ALMEIDA FILHO
(2001)1 observed that C. neoformans var. neoformans, serotype A, is
more virulent to these animals than var. gattii, serotype B.
MITCHELL & PERFECT (1995)16, in a review of cryptococcosis
during the AIDS era, reported that this fungal infection is causing great
suffering to mankind.
CASE REPORT
T.U, patient attended in the Faculty of Medicine of ABC, Santo
André, São Paulo, 65 years old, a male seller borned in Japan and living
in São Bernardo do Campo, presented an extensive ulceration with
erythematous borders and irregular infiltrates on the left forearm starting
50 days before his consultation (Fig. 1). According to the patient, the
lesion had started with a macula that progressed to ulceration.
The culture of the lesion was positive for Cryptococcus neoformans
var. gattii, serotype B (Fig. 2). Histopathological examination was positive
for C. neoformans (mucicarmin method) (Fig. 3). A chest X-ray was
normal. A search for anti-HIV antibodies was negative. Blood count
and cerebrospinal fluid were normal. A latex test applied to serum for
the detection of circulating Cryptococcus neoformans antigen was
positive. Skull tomography showed no alterations and digestive
tomography revealed mild erosive gastritis. Glucose: 70 mg/dL;
Creatinine: 0.8 mg/dL. Treatment with fluconazole, 150 mg/3 capsules
a day, led to a complete cure within 45 days (Fig. 4).
DISCUSSION
Cutaneous cryptococcosis in its generalized forms, especially in
patients with AIDS, presents multiple lesions, most of them simulating
molluscum contagiosum. Acneiform, nodular, or herpetiform lesions,
or cellulitis are frequently recorded (LACAZ et al., 1991; RICCHI et
al., 1991; MANRIQUE et al., 1992)12,15,20. HECKER & WEINBERG
(2001)9 recorded one case of cutaneous cryptococcosis simulating a
cheloid in a man with AIDS.
Fig. 1 - Left forearm with an extensive ulceration with erythematous borders and irregular
infiltrates.
Fig. 3 - Histopathological slides positive for C. neoformans (mucicarmin methd, 500x).
Fig. 4 - Left forearm after 45 days therapy.
Fig. 2 - C. neoformans var. gattii – Culture on Sabouraud dextrose agar, incubated at 25 °C,
3 days.
In the case described here, a hypothesis that might be raised is that
the site of entry of the fungus was by inhalation of small yeast propagula,
probably its basidiospores, that were first installed in the lungs and were
radiologically undetectable, followed by skin lesion (KWON-CHUNG
& BENNETT, 1992)10. Direct examination of biopsy with a drop of
India ink, showed yeast cells with capsules. The fungus isolated from
the lesion was identified as C. neoformans var. gattii, serotype B.
The literature reports marked dermotropism of the so-called grubii
variety of C. neoformans, serotype A (FRANZOT et al., 1999)7. We
should point out the absence of trauma preceding the lesion and of any
detected immunosuppression.
According to RODRIGUES et al. (1999)21, when the host is
immunocompromised, C. neoformans cells try to escape the defenses of
the organism by producing sialic acid, capsulated polysaccharides,
melanin, mannitol and phospholipase. In contrast, in immunocompetent
hosts the mechanisms of pathogenicity have not been carefully clarified.
In cryptococcosis, melanin seems to interfere with the virulence of the
yeast, with great tropism for the central nervous system, rich in
catecholamines.
PAPPAS et al. (2001)18 conducted a review study in the United States
involving 15 American Medical Centers from 1990 to 1996 and a total
of 306 patients with cryptococcosis, all of them HIV negative. Of these,
109 presented pulmonary lesions, 157 central nervous system lesions,
and 40 lesions located at other sites. Fluconazole was administered to
approximately 2/3 of the patients, with therapeutic success in 74% of
them.
BOHNE et al. (1996)3 reported an erysipela-like lesion induced by
C. neoformans in a female patient with sarcoidosis after a traumatic
injury, which was treated with corticoids. This patient was treated
successfully with itraconazole.
HAMANN et al. (1997)8, in Australia, reported an immunocompetent
patient with cellulitis induced by C. neoformans var. gattii.
PATEL et al. (2000)19 reported a case of cutaneous cryptococcosis
involving an immunocompetent elderly woman (85 years of age) induced
by C. neoformans which was cured with fluconazole.
VELEGRAKI et al. (2001)26, in Greece, reported two cases of
cryptococcosis induced by C. neoformans var. gattii serotype B, one
involving an HIV-positive patient and the other a patient with systemic
lupus erythematosus.
SEVERO et al. (1999)23 in Rio Grande do Sul (Brazil), reported
three cases of cryptococcosis induced by C. neoformans var. gattii,
affecting HIV-positive patients. SEVERO et al. (2001)22 also reported a
case of cutaneous cryptococcosis induced by C. neoformans var. gattii
in an immunocompetent host.
In Teresina (Piauí), C. neoformans var. gattii is the causal agent of
cryptococcosis in 91.2% of HIV-negative patients (CAVALCANTI,
1997)4. This variety has been found in Belém (Pará) as an agent of
pediatric neurocryptococcosis (CORRÊA, 2001)5.
In Brazil, the serotypes of C. neoformans strains predominantly
belongs to A, followed by B (LACAZ & RODRIGUES, 1983)11. For the
patient reported here, we emphasize the excellent therapeutic result
obtained after 45 days of fluconazole treatment.
RESUMO
Criptococose cutânea primária causada por Cryptococcus
neoformans var. gattii sorotipo B em paciente
imunocomprometido
Os autores registram em paciente do sexo masculino, vendedor
ambulante sem qualquer doença de base, lesão cutânea extensa, localizada
no antebraço esquerdo, sob forma ulcerada, provocada pelo Cryptococcus
neoformans var. gattii sorotipo B. Sucesso terapêutico com fluconazol,
por via oral.
Revisão da literatura foi realizada, mostrando raridade de tal
localização em pacientes HIV-negativos. Já em pacientes HIV-positivos,
lesões cutâneas ocorrem com freqüência, predominando como agente
etiológico o Cryptococcus neoformans var. neoformans, sorotipo A.
A patogenicidade do C. neoformans nas lesões cutâneas é discutida
em pacientes imunocomprometidos ou não, mostrando a eficácia do
fluconazol no tratamento de tais processos.
REFERÊNCIAS
1. ALMEIDA FILHO, O.M. de – Avaliação da virulência de Cryptococcus neoformans
(Vuillemin, 1901) variedade neoformans (Vuillemin, 1901) e var. gattii
(Vanbreuseghem & Takashiro, 1970) em ratos imunossuprimidos. Rio Claro,
2001. (Tese de Doutorado – Universidade Estadual Paulista).
2. BARRETO DE OLIVEIRA, M.T. – Sorotipos, diversidade genética, determinação de
“mating – types” em amostras ambientais e clínicas de Cryptococcus neoformans
isoladas no Brasil. São Paulo, 2001. (Tese de Doutorado – Instituto de Ciências
Biomédicas da Universidade de São Paulo).
3. BOHNE, T.; SANDER, A.; PFISTER-WARTHA, A. & SCHÖPF, E. – Primary cutaneous
cryptococcosis following trauma of the right forearm. Mycoses, 39: 457-459, 1996.
4. CAVALCANTI, M. dos A.S. – Criptococose sistêmica endêmica pela variedade gattii
no meio Norte do Brasil. Teresina, 1997. (Tese de Doutorado – Universidade Federal
do Piauí).
5. CORRÊA, M. do P.S.C. – Neurocriptococose pediátrica no Estado do Pará: espectro
de achados tomográficos na infecção por Cryptococcus neoformans var. gattii.
Belém, 2001. (Dissertação de Mestrado – Universidade Federal do Pará).
6. DIAZ, M.R.; BOEKHOUT, T.; THEELEN, B. & FELL, J.W. – Molecular sequence
analysis of the intergenic spacer (IGS) associated with rDNA of the two varieties of
the pathogenic yeast C. neoformans. System. appl. Microbiol., 23: 535-545, 2000.
7. FRANZOT, S.P.; SALKIN, I.F. & CASADEVALL, A.F. – Cryptococcus neoformans var.
grubii: separate varietal status for Cryptococcus neoformans serotype A isolates. J.
clin. Microbiol., 37: 838-840, 1999.
8. HAMANN, I.D.; GILLESPIE, R.J. & FERGUSON, J.K. – Primary cryptococcal cellulitis
caused by Cryptococcus neoformans var. gattii in immunocompetent host. Aust. J.
Derm., 38: 29-32, 1997.
9. HECKER, M.S. & WEINBERG, J.M. – Cutaneous cryptococcosis mimicking keloid.
Dermatology, 202: 78-79, 2001.
Cryptococcus neoformans produces a chronic or subacute pulmonary, systemic or meningeal infection and is recovered, most frequently, from patients with immunosuppression. In patients with HIV infection it is one of the common causes of meningitis.[1] In India, though isolated cases of Cryptococcus have been reported from different centres,[2],[3],[4],[5] no case has been reported from in and around Amritsar. We are reporting two cases of Cryptococcal meningitis for the first time in acquired immunodeficiency syndrome(AIDS) patients from Govt. Medical College Amritsar .
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Case 1
A fiftyfive year old man with HIV infection was admitted in the medical ward of Guru Nanak Dev hospital with complaints of headache, fever (38-38.50 C) and neck rigidity for the last 21 days. CSF obtained by Lumbar puncture was received in the department of Microbiology. Wet mount, Gram staining and India ink preparation revealed 4-7µm, round budding yeasts with capsule and 8-10 lymphocytes per high power field. CSF was cultured by standard procedures.[6] Creamy white colonies were seen on Sabouraud dextrose agar medium. The identification and pathogenicity of Cryptococcus neoformans was established by growth at 370 C ,urease production and mouse pathogenicity test. Antigen detection was also done and titre ,both in CSF and serum, was 2048. The patient responded to antifungal treatment (amphoterecin B and fluconazol) within 3 days.
Case 2
Fortytwo years old lady (HIV positive) was admitted with chest infection, fever 380 C and headache for the last six weeks and neck rigidity for the last fifteen days. Wet mount, Gram staining and India ink preparation of the CSF showed 4-7µm, round budding yeast cells with capsule. 5-6 lymphocytes were also seen per high power field. Culture on Sabouraud dextrose agar showed the growth of Cryptococcus. Identification and pathogenicity were established as in the above case. Both in serum and CSF, the antigen titre was done. Antigen titre in serum was 132 and in CSF it was more than 32. As this patient had chest infection, sputum was also cultured which was negative for Cryptococcus neoformans. Response to treatment is not known as the patient left against medical advice.
Section 3. Summaries of Infectious Diseases
Cryptococcus neoformans Infections
(Cryptococcosis)
Clinical Manifestations
Etiology
Epidemiology
Diagnostic Tests
Treatment
Isolation of the Hospitalized Patient
Control Measures
CLINICAL MANIFESTATIONS: Primary infection is acquired by inhalation of aerosolized fungal elements from contaminated soil and often is asymptomatic or mild. Pulmonary disease, when symptomatic, is characterized by cough, chest pain, and constitutional symptoms. Chest radiographs may reveal a solitary nodule or mass or focal or diffuse infiltrates. Hematogenous dissemination to the central nervous system, bones, skin, and other sites can occur, but dissemination is rare in children without defects in cell-mediated immunity (eg, children with leukemia, systemic lupus erythematosis, chronic cutaneous candidiasis, congenital immunodeficiency, or acquired immunodeficiency syndrome [AIDS] or people who have undergone solid organ transplantation). Usually, several sites are infected, but manifestations of involvement of one site predominate. Cryptococcal meningitis, the most common and serious form of cryptococcal disease, often follows an indolent course. Symptoms are characteristic of meningitis, meningoencephalitis, or space-occupying lesions but may manifest only as behavioral changes. Cryptococcal fungemia without apparent organ involvement occurs in patients with human immunodeficiency virus (HIV) infection, but in children it is rare.
ETIOLOGY: Cryptococcus neoformans, an encapsulated yeast that grows at 37°C (98°F), is, with rare exceptions, the only species of the genus Cryptococcus considered to be a human pathogen.
EPIDEMIOLOGY: Cryptococcus neoformans var neoformans is isolated primarily from soil contaminated with bird droppings and causes most human infections, especially infections in immunocompromised hosts. Cryptococcus neoformans var gattii occurs most commonly in tropical and subtropical regions, and for unknown reasons, rarely causes disease in immunocompromised people. Person-to-person transmission does not occur. Cryptococcus species infect 5% to 10% of adults with AIDS, but infection is rare in HIV-infected children.
The incubation period is unknown.
DIAGNOSTIC TESTS: Encapsulated yeast cells can be visualized using India ink or other stains of cerebrospinal fluid (CSF) specimens containing 103 or more colony-forming units of yeast per mL. Definitive diagnosis requires isolation of the organism from body fluid or tissue specimens. Blood should be cultured by lysis-centrifugation. Media containing cycloheximide, which inhibits growth of C neoformans, should not be used. Sabouraud dextrose agar is optimal for isolation of Cryptococcus from sputum, bronchopulmonary lavage, tissue, or CSF specimens. Use of Niger seed (birdseed) can increase the rate of detection in sputum and urine specimens. Few organisms may be present in the CSF specimen, and a large quantity of CSF may be needed to recover the organism. The latex agglutination test and enzyme immunoassay for detection of cryptococcal capsular polysaccharide antigen in serum or CSF specimens are excellent rapid diagnostic tests. Antigen is detected in CSF or serum specimens from more than 90% of patients with cryptococcal meningitis.
TREATMENT: Amphotericin B (see Drugs for Invasive and Other Serious Fungal Infections, p 780), in combination with oral flucytosine or fluconazole, is indicated as initial therapy for patients with meningeal and other serious cryptococcal infections. Serum flucytosine concentrations should be maintained between 40 and 60 µg/mL. Patients with meningitis should receive combination therapy for at least 2 weeks, and then fluconazole (10 mg/kg per day) can be used for a minimum of 10 weeks. (see related erratum) Alternatively, the amphotericin B and flucytosine combination can be continued for 6 to 10 weeks. Lipid formulations of amphotericin B can be substituted for conventional amphotericin B in children with renal impairment. A lumbar puncture should be performed after 2 weeks of therapy. The 20% to 40% of patients in whom culture is positive at 2 weeks will require a more prolonged treatment course. When infection is refractory to systemic therapy, intrathecal or intraventricular amphotericin B may be required. Patients with less severe disease may be treated with fluconazole or itraconazole, but data on use of these drugs for children with C neoformans infection are limited. Another potential treatment option for HIV-infected patients with less severe disease is combination therapy with fluconazole and flucytosine; the toxicity associated with this regimen often limits its usefulness. Increased intracranial pressure frequently occurs despite microbiologic response and often is associated with clinical deterioration. Symptomatic elevation of intracranial pressure initially is managed with repeated lumbar punctures.
Children with HIV infection who have completed initial therapy for cryptococcosis should receive lifelong suppressive therapy with fluconazole daily. Oral itraconazole daily or amphotericin B 1 to 3 times weekly are alternatives. Data regarding discontinuing this secondary prophylaxis after immune reconstitution as a consequence of highly active antiretroviral therapy are available for adults but not for children.
ISOLATION OF THE HOSPITALIZED PATIENT: Standard precautions are recommended.
CONTROL MEASURES: None.
Cryptococcus neoformans Infections (Cryptococcosis) Images
Etiology Images See Text
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Image 035_01. Cryptococcus neoformans Infections (Cryptococcosis). C neoformans, thin-walled encapsulated yeast in cerebrospinal fluid (india ink preparation, original magnification of cerebrospinal fluid x 450).
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Image 035_18. Cryptococcus neoformans Infections (Cryptococcosis). Pictured is a Sabouraud dextrose agar slant culture of the fungus Cryptococcus neoformans grown at 37°C. Life-threatening infections caused by the encapsulated fungal pathogen Cryptococcus neoformans have been increasing steadily over the past 10 years because of the onset of AIDS, and the expanded use of immunosuppressive drugs.
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Clinical Manifestations Images See Text
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Image 035_20. Cryptococcus neoformans Infections (Cryptococcosis). Cryptococcosis of lung in patient with AIDS. Mucicarmine stain. Histopathology of lung shows widened alveolar septum containing a few inflammatory cells and numerous yeasts of Cryptococcus neoformans. The inner layer of the yeast capsule stains red.
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Image 035_16. Cryptococcus neoformans Infections (Cryptococcosis). This micrograph depicts the histopathologic changes associated with cryptococcosis of the lung using Mucicarmine stain. Cryptococcosis, caused by the fungal pathogen Cryptococcus neoformans is transmitted through inhalation of airborne yeast cells and/or biospores. At risk are the immunocompromised, especially those with HIV infection.
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Image 035_19. Cryptococcus neoformans Infections (Cryptococcosis). Cryptococcosis of lung in patient with AIDS. Methenamine silver stain. Histopathology of lung shows numerous extracellular yeasts of Cryptococcus neoformans within an alveolar space. Yeasts show narrow-base budding and characteristic variation in size.
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Image 035_22. Cryptococcus neoformans Infections (Cryptococcosis). This micrograph depicts histopathologic changes due to cryptococcosis of the lung revealing a large fibrocaseous nodule. Cryptococcosis is transmitted through inhalation of airborne yeast cells and/or biospores. At risk are the immunocompromised, especially those with HIV infection. Note the fibrocaseous nodule which contains C neoformans organisms.
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Image 035_03. Cryptococcus neoformans Infections (Cryptococcosis). Cryptococcosis of the liver (original magnification X810) in an immunodeficient patient with disseminated disease. The mucinous capsules are prominent.
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http://aapredbook.aappublications.org/cgi/content/full/2006/1/3.3
asam manis hidupku..
