acute systemic histoplasmosis associated with chorioretinitis in an.docx

8/14/2019 Acute systemic histoplasmosis associated with chorioretinitis in an.docx

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HISTOPLASMOSIS AKUT SISTEMIK TERKAIT DENGAN

CHORIORETINITIS PADA REMAJA IMUNOCOMPETENT

Abstrak

Histoplasmosis adalah penyakit endemik, mikosis sistemik yang disebabkan oleh jamur dimorfik

HistoplasmaCapsulatum. Sebuah minoritas pasien menderita asimtomatik chorioretinitis yang

dikenal sebagai Presumed Ocular Histoplasmosis Syndrome (POHS), yang biasanya dikaitkan

dengan jaringan parut dan atrofi peripapillary chorioretinal dan kadang-kadang dengan

neovaskularisasi choroidal sekunder pada maculopathy.

Kami melaporkan kasus akut chorioretinitis bilateral berat yang berhubungan dengan

penyebaran H. capsulatum pada remaja imunokompeten di daerah endemik. Chorioretinitis

tersebut tidak merespone pada pemberian terapi antijamur sistemik, namun kedua penyakit

sistemik dan lesi mata terobati dengan penambahan steroid sistemik.

Pengenalan

Histoplasmosis adalah endemic, mikosis sistemik yang disebabkan oleh jamur dimorfik

Histoplasma Capsulatum. Bentuk miselium dari mikroorganisme umumnya ditemukan dalam

debu dan tanah di daerah lembah Sungai Mississippi dan lembah Sungai Ohio. Sekitar 70%

penduduk yang hidup di daerah endemik yang terkena jamur dan bereaksi positif terhadap test

kulit histoplasmin antigen. Infeksi primer ini biasa di sebabkan karena inhalasi spora. Perjalanan

penyakit sangat tergantung pada jumlah microconidiae yang terhirup dan status kekebalan dari

host. Pada host yang imunokompeten, infeksi primer cenderung tidak menunjukkan gejala atau

ringan dan biasanya remits spontan.

Beberapa pasien terjangkit Presumed Ocular Histoplasmosis Syndrome (POHS), yang

berhubungan dengan temuan trias klasik berikut: Bukti perkembangan, sebelum korioretinitis

dari perifer chorioretinal bekas luka dan atrofi peripapillary, dan pada sebagian kecil pasien,

neovaskularisasi choroidal sekunder pada jaringan parut chorioretinal. Sebaliknya, bentuk


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penyebaran progresif penyakit ini biasanya terlihat pada pasien dengan inhalasi spora besar

atau immunodeficiency. Kasus fulminan dapat terjadi dengan gangguan pernapasan, syok,

koagulasi intravaskular diseminata, dan kegagalan multi organ.

Tes diagnostik yang berguna mencakup tes serologis untuk antibodi anti-histoplasma dan

antigen polisakarida Histoplasma (HPA), noda perak pada bagian jaringan atau cairan tubuh,

dan kultur darah, sumsum tulang, cairan bronchoalveolar lavage, dan jaringan atau cairan

tubuh lainnya diduga terinfeksi berdasarkan temuan klinis. Amfoterisin B dan itrakonazol yang

paling sering digunakan untuk mengobati infeksi secara klinis signifikan.

Kami melaporkan kasus yang tidak biasa dari acute ocular histoplasmosis dan penyebaran

infeksi pada remaja imunocompetent dengan keterlibatan beberapa organ, termasuk

korioretinitis bilateral untuk terapi antijamur sistemik. Manifestasi klinis akut dari penyakit

teratasi dengan penambahan terapi steroid sistemik.

Laporan Kasus

Seorang bocah 16 tahun Afrika Amerika berobat kepada dokter anak dengan riwayat dua

minggu malaise umum, lesi kulit berjerawat, dan floaters bilateral, buruk di mata kiri. Dia

diobati dengan klindamisin untuk infeksi bakteri yang diduga menimbulka demam tinggi

spiking-(Tmax 105 F), dispnea, dan keadaan memburuk sehingga rawat inap. Pasien tidak

sedang dalam penggunaan obat lainnya saat datang berobat ke Rumah Sakit Anak LeBonheur di

Memphis, Tennessee. Catatan medis penyakit lalunya dan catatan medis pada mata biasa saja.

Pada awal pemeriksaan ophthalmologis, ketajaman visual tidak dikoreksi adalah 20/20 pada

mata kanan dan 20/20-3 di mata kiri. Pergerakan extraokular dan tekanan intraokular adalah

normal, kedua reflek pupil baik. Pada pemeriksaan slit lamp, ditemukan dua keratic presipitat

berukuran kecil pada kornea kiri. Pada pemeriksaan fundus, mata kanan pasien menunjukkan

saraf optik , kutub posterior, dan pembuluh darah yang normal. Ada dua daerah kecil

chorioretinitis, ukuran diameter disk sekitar 1 / 4, di pinggiran inferotemporal tanpa atasnya

vitritis. Mata kiri menunjukkan penyebaran, chorioretinitis multifokal melibatkan retina dan


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koroid di kutub posterior dan pinggiran, dengan kumpulan putih seperti salju di pinggiran

hidung. Intravena angiografi fluorescein itu sangat jinak, menunjukkan tidak adanya kebocoran

dalam tahap awal dan hanya vaskulitis ringan dibuktikan dengan pewarnaan selubung

perivaskular dan fokus di tahap selanjutnya, dengan temuan hanya peradangan retina yang

minimal di samping dari fokus Choroidal terbesar (Gambar 1 ).

Pasien awalnya dirawat selama tiga hari dengan vankomisin dan klindamisin untuk infeksi

bakteri yang diduga sebelumnya. Kultur darah negatif, dan antibiotik dihentikan. Sejak

pemeriksaan ophthalmologis yang mengarah jamur sebagai penyebabnya, diberikan

amfoterisin B intravena liposomal 375 mg sekali / hari dimulai bersama-sama dengan asiklovir

intravena 750 mg dua kali / hari, sambil menunggu hasil serologi. Titer serologi Histoplasma

oleh fiksasi komplemen yang ditunjukkan untuk menjadi nyata meningkat (1:512, positif> 1:8).

Selanjutnya, H. capsulatum M-band pengujian kembali positif, menunjukkan infeksi aktif atau

baru terinfeksi. Asiklovir dihentikan setelah 3 hari, dan amfoterisin B dengan vorikonazol mulai

diberikan. Selama pengobatan dengan antimikroba, kondisi pasien terus memburuk, dengan

demam tinggi dan gangguan pernapasan meningkat.

Terjadi efusi pleura bilateral, sehingga membutuhkan drainase cairan. Tes diagnostik cairan

pleura mengungkapkan transudate, negatif untuk bakteri atau jamur, termasuk H. capsulatum.

Pemeriksaan lebih lanjut rematologi ekstensif negatif. Pemeriksaan imunologi berupa IgA, IgG,

IgM, dan IgE serta jumlah darah putih normal dan diferensial memberikan hasil normal.

Pemeriksaan lebih lanjut mengungkapkan penyakit menular HIV yang negatif serologi dengan

ELISA. Pengujian lebih lanjut adalah negatif untuk toksoplasmosis, tuberkulosis, sarkoidosis, dan

sifilis. Biopsi dari lesi kulit menunjukkan folikulitis pustular, negatif untuk bakteri atau jamur,

termasuk H. capsulatum. Meskipun satu minggu terapi antimikroba termasuk terapi antijamur

sistemik, kondisi pasien terus memburuk dan steroid intravena dimulai. Pasien menanggapi

dengan cepat terhadap pengobatan steroid, dengan resolusi demam dan perbaikan dalam

gejala pernapasan nya dalam waktu dua belas jam. Pasien diizinkan pulang beberapa hari

kemudian dengan pemberian obat itrakonazol dan obat prednison selama enam minggu dosis

tapering off.


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Pasien terlihat di Eye Institute Hamilton satu bulan setelah presentasi awal dan tercatat hanya

memiliki satu focal spot sisa dari chorioretinitis yg aktif dalam retina perifer mata kiri. Tiga

bulan kemudian pasien asimtomatik, ada resolusi lengkap dari semua lesi aktif dengan hanya

retinal pigmen epitel (RPE) perubahan ini (Gambar 2). Atrofi epitel pigmen retina yang

dihasilkan jauh lebih kecil dari yangdiharapkan untuk tingkat chorioretinitis dilihat pada presentasi

awal, dan tidak "menekan keluar" bekas luka chorioretinal.

Gambar 1

A. Kutup posterior dari mata kiri pada saat presentasi menunjukkan fokus inflamasi tersebar

dan kabut vitreous ringan.

B. Resolusi peradangan setelah perawatan.

C. Mata kiri pada presentasi menunjukkan banyak diskrit dan lesi chorioretinitis multifokal di

pinggiran hidung pertengahan (panah kuning).

D. Fluorescein angiogram dari bidang yang sama menunjukkan hanya kebocoran pewarna jejak

di lokasi lesi padat (panah kuning).
http://www.djo.harvard.edu/files/9278_1567.jpg


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Gambar 2

A. Pertengahan pinggiran-inferior dari mata kiri pada saat presentasi menunjukkan penyebaran

lesi diskrit dan lesi multifocal chorioretinitis.

B. Resolusi peradangan di bidang yang sama setelah pengobatan. Sebuah bekas luka RPE yang

sudah ada sebelumnya ditampilkan di lapangan (lingkaran kuning). Hanya jejak perubahan RPE

(putih persegi) dan selubung pembuluh darah (kuning panah) terlihat di lokasi lesi padat setelah

resolusi, sebagian besar lesi diselesaikan tanpa bukti perubahan pigmen atau bekas luka.

C. Superior pertengahan pinggiran mata kiri pada saat presentasi.

D. Mata kiri setelah resolusi lesi chorioretinal menunjukkan tidak ada perubahan jaringan parutdi akhir (panah putih menandai titik cabang pembuluh darah).

Diskusi

Manifestasi okular dari histoplasmosis diduga menghasilkan hasil jaringan parut fokal

chorioretinal setelah infeksi sistemik dan respon inflamasi mereda. Temuan umum termasuk


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menekan keluar lesi chorioretinal atropi, atrofi peripapillary, dan tidak adanya peradangan

vitreous. Neovaskularisasi Choroidal adalah penyebab paling umum kehilangan penglihatan dan

diperkirakan mempengaruhi dari 5% dari mata yang terkena. Multifocal korioretinitis

diperkirakan terjadi pada pasien dengan kekebalan yang cukup untuk melokalisasi dan

merespon terhadap infeksi H. capsulatum.

Lesi chorioretinal umumnya kecil (


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pasien ini memiliki HLA-B7 atau HLA-DRw2 histokompatibilitas kompleks antigen (1,3) H.

capsulatum. Telah diamati tidak memiliki kultur dari mata enucleated pasien yang terkena.

Pada pasien imunokompeten seperti ini, mungkin korioretinitis merupakan proses kekebalan

yang dimediasi. Telah diusulkan bahwa mekanisme ini dimediasi kekebalan korioretinitis adalah

deposisi antigen di koroid dari fokus paru atau lainnya. Untuk sebagian besar kasus, yang

menyelesaikan korioretinitis spontan dan antijamur dan atau sistemik steroid pengobatan

mungkin tidak diperlukan. Pasien kami adalah imunokompeten tetapi gagal untuk merespon

terhadap terapi antijamur sistemik, namun, ia menanggapi secara dramatis untuk terapi

steroid, menunjukkan proses penyakit terutama kekebalan dimediasi.

Dalam presentasi kasus yang tidak biasa seperti ini, hasil pemeriksaan sistemik menyeluruh

harus dilakukan untuk menyingkirkan penyebab lain dari uveitis granulomatosa multifokal

posterior, termasuk uveitis simpatik, TB, toksoplasmosis, sarkoidosis, dan proses infeksi dan

inflamasi lainnya. Status imunologi pasien merupakan pertimbangan penting dalam

menentukan diagnosis diferensial, pemeriksaan berikutnya, dan manajemen.

Presentasi penyakit pada pasien ini sangat asimetris, hanya dengan fokus perifer beberapa di

mata kanan, tetapi parah, disebarluaskan, dan penyakit multifokal di mata kiri. Perbedaanteropong tersebut dapat menjelaskan asimetri bekas luka POHS sering terlihat pada pasien

yang tinggal di daerah endemik. Meskipun adanya lesi multifokal chorioretinal di mata kiri,

pasien tidak mengembangkan luka klasik chorioretinal atrofik biasanya terkait dengan POHS.

Kami tidak, bagaimanapun, mengidentifikasi area yang jarang dari perubahan pigmen pada

tingkat RPE di lokasi fokus chorioretinal paling parah (Gambar 2B, D).

Acute systemic histoplasmosis associated with chorioretinitis in an immunocompetent adolescent

Digital Journal of Ophthalmology 2011

Volume 17, Number 3


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August 16, 2011

Brian T. Fowler, MD* | Department of Ophthalmology, Hamilton Eye Institute, Memphis,

Tennessee

Christopher Shen, MD* | Department of Ophthalmology, Hamilton Eye Institute, Memphis,

Tennessee

Joseph Mastellone | Department of Ophthalmology, Hamilton Eye Institute, Memphis, Tennessee

Edward Chaum, MD | Departments of Ophthalmology and Pediatrics, Hamilton Eye Institute and

University of Tennessee Health Science Center, Memphis, Tennessee

Abstract

Histoplasmosis is an endemic, systemic mycosis caused by the dimorphic fungus Histoplasma

capsulatum. A minority of patients develop asymptomatic chorioretinitis known as presumed

ocular histoplasmosis syndrome (POHS), which is typically associated with chorioretinal scarring

and peripapillary atrophy and occasionally with choroidal neovascularization secondary to

maculopathy. We report a case of acute severe bilateral chorioretinitis associated with

disseminated H. capsulatumin an immunocompetent adolescent boy living in an endemic area.

The chorioretinitis did not respond to systemic antifungal therapy, but both his systemic illness

and ocular lesions resolved with the addition of systemic steroids.

Introduction

Histoplasmosis is an endemic, systemic mycosis caused by the dimorphic fungus Histoplasma

capsulatum. The mycelial form of the microorganism is commonly found in the dust and soil of

the Mississippi River valley and Ohio River valley regions.(1) Approximately 70% of the

population living in endemic areas are exposed to the fungus and react positively to a

histoplasmin skin antigen challenge.(2) Primary infection is usually due to spore inhalation. The

course of the disease largely depends on the number of inhaled microconidiae and the immune

status of the host. In immunocompetent hosts, primary infection tends to be asymptomatic or

mild and usually remits spontaneously.(1) Some patients develop presumed ocular
mailto:[email protected]:[email protected]


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histoplasmosis syndrome (POHS), which is associated with the following classic triad of findings:

evidence of a prior chorioretinitis, development of peripheral chorioretinal scars, and

peripapillary atrophy, and, in a small proportion of patients, choroidal neovascularization

secondary to chorioretinal scarring.(3) In contrast, the disseminated progressive form of the

disease is typically seen in patients with massive spore inhalation or immunodeficiency.

Fulminant cases can present with respiratory distress, shock, disseminated intravascular

coagulation, and multiple organ failure.(1) Useful diagnostic tests include serologic tests for

anti-Histoplasma antibodies and Histoplasma polysaccharide antigen (HPA), silver stains of

tissue sections or body fluids, and cultures from blood, bone marrow, bronchoalveolar lavage

fluid, and other tissues or bodily fluids suspected to be infected based on clinical findings.(3,4)

Amphotericin B and itraconazole are most frequently used to treat clinically significant

infections.

We report an unusual case of acute ocular histoplasmosis and disseminated infection in an

immunocompetent adolescent presenting with multiple organ involvement, including bilateral

chorioretinitis refractory to systemic antifungal therapy. The acute clinical manifestations of the

disease resolved with the addition of systemic steroid therapy.

Case report

A 16-year-old African American boy presented to his pediatrician with a two-week history of

general malaise, pustular skin lesions, and bilateral floaters, worse in the left eye. He was

treated with clindamycin for presumed bacterial infection until the onset of high-spiking fevers

(Tmax105F), dyspnea, and worsening malaise prompted hospitalization. The patient was on no

other medications at the time of admission to LeBonheur Childrens Hospital in Memphis,

Tennessee. His past medical and past ocular history were unremarkable.

On initial ophthalmological examination, uncorrected visual acuity was 20/20 in the right eye

and 20/20-3 in the left eye. Extraocular motility and intraocular pressure were normal, and the

pupils were equally reactive. The anterior segment slit-lamp examination was unremarkable


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with the exception of two small fine keratic precipitates on the left cornea. On dilated fundus

examination, the patients right eye showed a normal-appearing optic nerve, posterior pole,

and vasculature. There were two small areas of chorioretinitis, approximately 1/4 disc diameter

in size, in the inferotemporal periphery without overlying vitritis. The left eye showed a

disseminated, multifocal chorioretinitis involving the retina and choroid in the posterior pole

and periphery, with snow-banking in the nasal periphery. Intravenous fluorescein angiography

was remarkably benign, demonstrating an absence of leakage in the early phase and only a mild

vasculitis evidenced by perivascular sheathing and focal staining in later phases, with findings of

only minimal retinal inflammation at the site of the largest choroidal foci (Figure 1).

The patient was initially treated for three days with vancomycin and clindamycin for presumed

bacterial infection. Blood cultures were negative, and antibiotics were discontinued. Since the

ophthalmological examination was suggestive of fungal etiology, intravenous liposomal

amphotericin B 375 mg once/day was started together with intravenous acyclovir 750 mg

twice/day, pending serology results. Histoplasma serology titers by complement fixation were

demonstrated to be markedly elevated (1:512, positive >1:8). Further, H. capsulatumM-band

testing returned positive, indicating active or recent infection. Acyclovir was discontinued after

3 days, and amphotericin B with voriconazole was initiated. During treatment withantimicrobials, the patients condition continued to worsen, with high fevers and increasing

respiratory distress. The etiology was large bilateral pleural effusions, requiring drainage of

fluid. Diagnostic testing of the pleural fluid revealed a transudate, negative for bacteria or fungi,

including H. capsulatum. Further extensive rheumatologic workup was negative. Immunologic

workup revealed normal IgA, IgG, IgM, and IgE as well as a normal white blood count and

differential. Infectious disease workup further revealed negative HIV serology by ELISA. Further

testing was negative for toxoplasmosis, tuberculosis, sarcoidosis, and syphilis. Biopsy of the skinlesions showed pustular folliculitis, negative for bacteria or fungus, including H. capsulatum.

Despite one week of antimicrobial therapy including systemic antifungal therapy, the patients

condition continued to worsen and intravenous steroids were started. The patient responded

rapidly to steroid treatment, with resolution of fever and improvement in his respiratory


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symptoms beginning within twelve hours. The patient was discharged several days later on

itraconazole and a six-week prednisone taper.

The patient was seen at the Hamilton Eye Institute one month following his initial presentation

and was noted to have only one focal spot of residual active chorioretinitis in the peripheral

retina of the left eye. Three months later the patient was asymptomatic; there was complete

resolution of all active lesions, with only subtle retinal pigment epithelial (RPE) changes present

(Figure 2). The resultant retinal pigment epithelium atrophy was far less than would be

expected for the degree of chorioretinitis seen at initial presentation, and no punched out

chorioretinal scars developed.

Figure 1

A, Posterior pole of the left eye at the time of

presentation showing scattered inflammatory

foci and mild vitreous haze. B, Resolution of

the inflammation after treatment. C, Left eye

at presentation showing many discrete and

multifocal chorioretinal lesions in the nasal

mid-periphery (yellow arrows). D,

Fluorescein angiogram of the same field

showing only trace dye leakage at the sites of

denser lesions (yellow arrows).


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immunocompetent siblings.(8) Our patient presented with symptomatic active chorioretinitis

prior to the development of severe systemic pulmonary and dermatologic disease. The lesions

seen on the initial fundus examination were consistent with chorioretinal lesions seen in

previous case reports; however, the chorioretinitis described in our patient was unusual in that

it was more severe, diffuse, and also associated with significant systemic disease

manifestations. Interestingly, the multifocal choroidal lesions did not scar and form the classic

punched out choroidal lesions typically described in POHS. This mirrors the relatively benign

findings seen on the initial fluorescein angiography.

POHS is considered "presumed" ocular histoplasmosis because the causal relationship between

the fungus and the eye disease has not been definitively proven. In immunocompromised

patients, disseminated chorioretinitis due to H. capsulatumduring the active phase of infection

has previously been described in the literature, with ocular histopathological examination

confirming the presence of budding yeast characteristic of H. capsulatumin the choroid, retina,

and central retinal vein.(3) A reproducible model of histoplasma choroiditis may be induced in

primates by the injection of live H. capsulatumorganisms via the internal carotid artery. In this

model, variation in the severity of disease correlates with the size of innoculum and site of

injection.(9) In a review of the clinical spectrum and treatment of classic histoplasmosis, theincidence of chorioretinitis is estimated to be between 1 to 10% in endemic areas,

predominantly affecting patients between 30 and 40 years of age. Most of these patients

possess the HLA-B7 or HLA-DRw2 histocompatibility complex antigen.(1,3) H. capsulatumhas

neither been observed nor cultured from the enucleated eyes of affected patients. In

immunocompetent patients such as these, chorioretinitis may be an immune-mediated

process. It has been proposed that the mechanism of this immune-mediated chorioretinitis is

secondary to deposition of antigens in the choroid from pulmonary or other foci.(1,3) For themajority of cases, the chorioretinitis resolves spontaneously and antifungal and/or systemic

steroid treatment might not be required. Our patient was immunocompetent but failed to

respond to systemic antifungal therapy; however, he responded dramatically to steroid

therapy, suggesting a primarily immune-mediated disease process.


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In unusual case presentations such as this, a thorough systemic workup should be undertaken

to exclude other causes of multifocal granulomatous posterior uveitis, including sympathetic

uveitis, tuberculosis, toxoplasmosis, sarcoidosis, and other infectious and inflammatory

processes. The patients immunologic statusis an important consideration in determining the

differential diagnosis, subsequent workup, and management.

The disease presentation in this patient was remarkably asymmetric, with just a few peripheral

foci in the right eye, but severe, disseminated, and multifocal disease in the left eye. Such

binocular disparity may account for the asymmetry of POHS scars commonly seen in patients

living in endemic areas. Despite the presence of multifocal chorioretinal lesions in the left eye,

the patient did not develop the classical atrophic chorioretinal scars typically associated with

POHS. We did, however, identify rare areas of pigmentary changes at the level of the RPE at the

site of the most severe chorioretinal foci (Figure 2B, D).

Literature Search

PubMed (1980 to present) and Google Scholar were searched using the following keywords:

histoplasmosis, chorioretinitis, and retina.

*These authors contributed equally to this work.

Acknowledgments

Supported in part by an unrestricted UTHSC departmental grant from Research to Prevent

Blindness, New York, NY, the Plough Foundation, Memphis, TN, and the UTHSC Hamilton Eye

Institute NEI Core Grant for Vision Research (P30 EY013080). Dr. Chaum is an RPB Senior

Scientist.


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LAMPIRAN


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acute systemic histoplasmosis associated with chorioretinitis in an.docx

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