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Histoplasma Capsulatum in the Eye
Histoplasma Capsulatum in the Eye RICHARD SCHOLZ, MD,* W. RICHARD GREEN, MD,* ROBERT KUTYS, BA,t JOHN SUTHERLAND, MD,t RICHARD D. RICHARDS, MDt
Abstract: The ocular pathologic findings in an immunosuppressed patient who died of disseminated histoplasmosis are described. Histoplasma capsulatum was found in large numbers within the endothelial cells of the choroid, in one area each of the ciliary body and trabecular meshwork. There was a minimal inflammatory response. No granulomas were noted. Previously reported cases of ocular histoplasmosis in immunosuppressed patients are similar in that, with one exception, granulomatous inflammation was not demonstrated. Thirteen eyes in which histoplasma organisms have been found in the eye are reviewed. [Key words: histoplasmosis, immunosuppression, ocular histoplasmosis, ocular histoplasmosis syndrome.] Ophthalmology 91: 1100-1104, 1984
The presence of Histoplasma capsulatum in the human eye has been demonstrated in 13 cases. 1- 13 Five of these cases had the clinical findings seen in the ocular histoplasmosis syndrome: peripapillary scarring, peripheral punched-out lesions, and a disciform macular scar. 2•6•7·10·11'14 Midperipheral chorioretinal scars were observed histopathologically in one eye. 11 In five cases, the patients had systemic histoplasmosis3- 5•13 and one case occurred in an individual who had an extraocular focus of infection with histoplasmosis. 1 An additional case had a presumed extraocular focus. 9 In two cases, the eyes were suspected of harboring melanomas2 •11 and in one the lesion was considered to be a metastatic tumor. 8 The lesions were found to be choroidal granulomas containing organisms consistent with H. capsu/atum. The ability of H. capsulatum to both invade the eye and to cause granulomatous disease seems well established. We report a case of disseminated histoplasmosis with choroidal involvement in a severely immunocompromised host who failed to produce an ocular inflammatory response despite widespread dissemination of the organisms in the choroid and one focus in the ciliary body.
From the Eye Pathology, Laboratory, Wilmer Ophthalmological Institute, and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland* and the Departments of Pathologyt and Ophthalmology,:j: University of Maryland School of Medicine, Baltimore, Maryland. Reprint requests to W. Richard Green, MD, Eye Pathology Laboratory, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205.
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CASE REPORT A 39-year-old man was admitted to the hospital on October 27, 1981 complaining ofthree days of upper and mid-abdominal pain and vomiting. Medical history was remarkable for chronic alcoholism and heroin abuse which led to heroin nephropathy and subsequent renal failure requiring renal transplantation. A cadaveric transplantation was performed in 1979. Because of chronic rejection, azothioprine and prednisone therapy was required. Multiple episodes of pancreatitis had been experienced since 1978, the most recent in June 1981. Culture-proven cavitary tuberculosis was treated in June 1981, with a right upper lobectomy, isoniazid, and rifampin. Because of druginduced hepatitis, the rifampin was discontinued and ethambutol 900 mg four times daily was begun. In July 1981 the patient was examined by one ofthe authors (R.D.R.). The visual acuity was 20/25 in both eyes secondary to early posterior subcapsular cataractous changes thought to possibly be the result of steroid therapy. The fundus was normal. There was no evidence of inflammatory disease in the choroid or vitreous. In August, 1981 because of an abnormal infiltrate on the chest x-ray and a spiking fever, the patient was admitted to the hospital. While in the hospital, the patient's fever ran as high as 103 o, occurring without his appearing toxic. Infectious disease consultants thought that tuberculosis was the most likely cause of the fever, but a search for other causes was instituted. Bone scan, liver-spleen scan, computerized tomography (CT) of the head and abdomen, bone-marrow biopsy, and aspirate were all unremarkable. A biopsy of the lung infiltrate was refused. Trimethoprim-sulfasoxisole and erythromycin therapy was initiated as empirical treatment for Pneumocystis carinii and
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Legionnaire's disease, respectively. No fever was experienced for three days, but then the patient again became febrile. He was discharged at the beginning of September 1981. At the time of admission in October 1981, the medications were ethambutol 950 mg, isoniazid 300 mg, azothioprine 25 mg, and prednisone lO mg four times daily. The temperature was 101.2°, pulse 120, respiratory rate 30, and blood pressure 130/90. Physical exam was remarkable for decreased bowel sounds and tenderness and rigidity of the abdomen. Remarkable laboratory findings were: a hemoglobin of 10, a white blood count of 2.6K and an amylase of 452. The chest x-ray revealed no change from previous films. The assessment was chronic pancreatitis, chronic renal transplant rejection, dehydration, and anemia. A computed tomograph did not indicate pancreatic enlargement, but did show a lesion compatible with a pseudocyst of the tail of the pancreas. During the next week the patient remained febrile. Blood cultures, ultrasound of the abdomen, and a gallium scan were all unremarkable. Intravenous hyperalimentation was begun on November 11, 1981. As all cultures remained negative, the possibility of a drug fever was considered, and the ethambutol was discontinued for four days. This produced no change and a similar trial of discontinuation of the isoniazid also failed to produce any change. The patient became stuporous, and a lumbar puncture was performed. All cultures of the CSF were negative, as were the stains for bacteria and acid-fast bacilli. The india ink preparation and VDRL were negative. On November 16, cultures of the urine were positive for cytomegalovirus. The opinion of a virologist was that the culture may or may not have been significant and there was no effective treatment should the virus be the cause of the patient's illness. Because of increasing lethargy, a decrease in blood pressure and a persistent fever, all of which seemed to indicate sepsis, the patient was transferred to the Intensive Care Unit on November 16. Blood cultures were positive for Staphylococcus epidermidis. Treatment was with vancomycin, and despite adequate blood levels and minimum inhibitory concentrations, the fever did not subside. As the hematocrit dropped and the fever persisted on adequate antibiotic therapy, endocarditis was considered. Adrenal insufficiency was also considered in view of the long course of steroid therapy, and intravenous steroid therapy was initiated. Despite all these measures, the patient's course was progressively downhill and he died on December 2, 1981 following a hypotensive episode and a grand mal seizure. At postmortem examination Histoplasma capsulatum was demonstrated in lungs, liver, spleen, transplanted kidney, bone marrow, lymph nodes, adrenal glands, and in the intestinal tract. Postmortem lung cultures grew Histoplasma cap$ulatum. Postmortem blood cultures were also positive for coagulasenegative staphylococcus, and gram positive cocci were found in the pancreas.
RESULTS The microscopic findings were similar in both eyes. Organisms, 2 to 6 1-1-m in size, were seen within the cytoplasm of hyperplastic endothelial cells of choroidal arteries, veins (Figs 1, 2) and choriocapillaris. The organisms were round and contained a central nucleus that stained with periodic acid-Schiff reagent (Figs 2, 3). The capsule of the organisms stained with Gomori
methanamine silver stain (Fig 4). Increased stammg time intensified the staining of the organisms (Fig 5). A small number of chronic inflammatory cells was present. No granulomas or necrosis were noted. Serial sections in the plane of the pupil, optic nerve head, and macula were obtained and the only additional finding was the presence of a small number of organisms in one area of the ciliary body and the trabecular meshwork of the left eye. Electron micrographs of the choroid showed multiple intracellular organisms that were round to oval in shape (Fig 6). The organisms measured 1.5 to 2 ~tm in diameter and were surrounded by a capsule. The capsule measured 900 to 1200 nm in thickness. Beneath the capsule was a membrane consisting of two layers separated by a space of approximately 50 to 70 nm within the organism itself. There was a nucleus of approximately one ~tm, numerous free ribosomes, and vacuoles, some of which contained electron-dense debris and mitochondria. The surrounding cytoplasm contained numerous degenerated organisms containing electron-dense material and dilated endoplasmic reticulum.
DISCUSSION The association between H. capsulatum and ocular disease is now well established. Intraocular organisms consistent with H. capsulatum have been demonstrated in 13 previously reported or presented cases. In one additional case, positive indirect immunofluorescence to histoplasma antigen was observed in the eye of a patient with the features of the ocular histoplasmosis syndrome. 15 Histopathologic study of ocular lesions in eyes with the features of the ocular histoplasmosis syndrome, but without demonstrable intraocular organisms, has been performed in a number ofinstances. 14•16- 21 These studies have generally shown macular disciform scars of various sizes, choroidal neovascularization, often with extension under the retinal pigment epithelium and the periphery of the lesion with little or no inflammation in the choroid. The peripheral lesions uniformly show a scar that involves the inner aspect of the choroid and outer aspects of the retina. Discontinuity of Bruch's membrane is evident in most of the peripheral and peripapillary lesions, and in some instances, hyperplastic retinal pigment epithelium, and rarely, glial cells, extend into the choroid in the scarred area. Lesions in the periphery do not show neovascularization, although a chorioretinal vascular anastomosis was seen in one peripherallesion. 21 The histopathology of the eyes with both organisms consistent with H. capsulatum2•6 •1•10•11 •14 or immunopathologic evidence of H. capsulatum antigen 15 and features of the ocular histoplasmosis syndrome has been described in six cases. One case is referred by two authors. 2 •14 In the case presented by Duke 11 as "granuloma of the choroid of unknown etiology," subsequent ll01
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study showed the granuloma to contain organisms consistent with H. capsulatum. No peripapillary scarring was noted, but peripheral punched-out lesions were found in addition to the granuloma. The granuloma was located in the choroid in the macular area. Bruch's membrane, retinal pigment epithelium, and the outer layers of the retina were absent in the central area of the granuloma. A similar case was reported by Maumenee 2 and Ryan. 14 An eye enucleated for what was thought to be a melanoma, but which proved to be a granuloma, was later shown to contain H. cqpsulatum. The fellow eye contained peripheral punched-out lesions on subsequent clinical examination. 14 The case described by Roth6 concerned two eyes from a patient who had died of heart failure and in whom H. capsulatum was found not only in the eyes but also in the lung. The eyes contained disciform macular lesions, peripheral punched-out lesions and peripapillary scarring. Organisms were demonstrated in both macular lesions, in the punched-out peripheral lesions and in one peripapillary lesion. The disciform macular lesions were fibrovascular masses containing areas of necrosis and granulomatous inflammation. The overlying pigment epithelium was disrupted. No choroidal neovascularization was observed but breaks in Bruch's membrane were noted. Lymphocytic infiltration of the choroid was seen. The case described by Khalil 10 is similar. A 33-yearold man was diagnosed as having ocular histoplasmosis in the right eye on the basis of a positive histoplasmin skin test, an old nodular granuloma in the lower lobe of the right lung, and a macular scar. Nine years later the right eye was removed because of a large melanoma. Both eyes contained peripapillary chorioretinal lesions with irregular pigmentation and multiple mid peripheral lesions. Histopathologic study of the right eye showed multiple chorioretinallesions in the macula, peripapillary area, and in the mid periphery. These lesions were grouped into three types: active granulomatous inflammation, nongranulomatous inflammation, and localized chorioretinal scars. H. capsulatum was identified by periodic acid-Schiff and Gomori methenamine silver stains. Dead organisms were identified by electron microscopy. Makley7 described a 53-year-old woman who had her left eye enucleated because of a malignant melanoma. Prior to the development of the tumor, she had been diagnosed as having a central choroiditis that left a macular scar. When the choroiditis was active, a histoplasmin skin test was positive. Peripapillary scarring and peripheral punched-out spots were observed in the fellow eye. Histopathologic examination of the enucleated eye was remarkable for melanoma of the choroid, a macular chorioretinal scar, and a mid peripheral chorioretinal scar that contained organisms consistent with H. capsulatum. Six of the seven cases in which H. capsulatum was demonstrated intraocularly but the features of the ocular histoplasmosis syndrome were absent, were all cases in 1102
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which systemic histoplasmosis or an active extraocular focus of histoplasmosis were present. 1•3- 5•12•13 In one case, an extraocular focus was not sought because the patient declined diagnostic studies. 9 In one case 13 the diagnosis was established by cytopathologic examination of vitreous and by culture. Hoefnagels and Pijpers 1 reported a case of panophthalmitis leading to enucleation. A primary infection by H. capsulatum in the gingiva was proven by biopsy and culture. The eye became painful and without light perception. It was enucleated and a panophthalmitis demonstrated. There was intense granulomatous inflammation found subconjunctivally, in the area of Schlemm's canal and in the iris, ciliary body, and retina. Organisms were found subconjunctivally, in the anterior chamber, iris, posterior chamber, ciliary body, and retina. No organisms were found in the choroid. Goldstein and Buettner12 reported a case quite similar to the one just described. A 37-year-old man with recurrent systemic histoplasmosis developed an intense panophthalmitis leading to enucleation. Histopathologic examination was remarkable for an intense necrotizing granulomatous iridocyclitis with numerous organisms. The choroid contained only a mild inflammatory infiltrate and no organisms. Craig and Suie4 reported a case of fatal disseminated histoplasmosis in a 22-year-old woman who was being treated for lupus erythematosis with immunosuppressive drugs. She was noted to have small white retinal lesions near each optic nerve head. At autopsy, H. capsulatum was found within macrophages in the choroid. Klintworth et al 3 reported a case of multifocal granulomatous choroiditis in a 14-year-old boy who died of disseminated histoplasmosis. The patient developed adrenal insufficiency eight years after the original diagnosis had been established. Clinical examination of the eyes disclosed "small white drusenoid bodies in the macular area of the left eye." Postmortem sections through these lesions showed them to be choroidal granulomas containing both intracellular and extracellular organisms typical of H. capsulatum. H. capsulatum was isolated from the bone marrow, skin, lymph nodes, and cerebrospinal fluid during life and from the brain postmortem. Schwarz et al 5 reported finding H. capsulatum in the eye of a 3-year-old boy who died of disseminated histoplasmosis. Histiocytes containing H. capsulatum were found in capillaries of the optic nerve in extraocular muscle, the sclera, and the retina. The choroidal vessels were engorged with histiocytes containing H. capsulatum. Font8 has reported a solitary chorioretinal granuloma in a child with aniridia and Wilm's tumor. The eye came to enucleation after radiation for what was considered to be metastatic tumor. The lesion was found to be a necrotizing choroidal granuloma that was surrounded by a palisading of fibroblasts and epithelioid cells. Organisms compatible with H. capsulatum were seen with the Gomori methanamine silver stain. Zimmerman9 presented a case of intraocular histoplasmosis leading to phthisis bulbi. The patient had
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Fig 1. Top left, nodule of hyperplastic endothelium of choroidal vein with histoplasma organisms present (paraphenylenediamine; phase-contrast, X 153). Fig 2. Top right, nodule of hyperplastic endothelium in choroidal vein (periodic acid-Schiff, X96). Fig 3. Second row left, higher power of endothelial cell nodule with organisms present in cytoplasm of endothelial cells (periodic acidSchiff, X384). Fig 4. Second row right, demonstration of organisms in choroidal vascular endothelium after exposure to solution of 5% silver nitrate and 3% methanamine silver for 60 minutes (Gomori methanamine silver, X384). Fig 5. Bottom left, demonstration of organisms after exposure to silver solution for 90 minutes (Gomori methanamine silver, X384).
recurrent high fevers of undetermined etiology, and developed phthisis following intractable iritis. The intraocular contents were necrotic and contained acute suppurative and chronic granulomatous inflammation. H. capsulatum was found throughout the tissues using special stains. Further investigations to determine the source of the infection were refused by the patient. Carroll and Franklin 13 reported the case of a 62-yearold man with chronic uveitis and a past history of diabetes mellitus, hypertension, and biopsy-proven systemic histoplasmosis. The uveitis did not respond to amphotericin B therapy and a diagnostic vitrectomy was
performed. Cytopathologic evaluation of the vitreous aspirate disclosed organisms consistent with H. capsulatum. Font8 has pointed out that proven ocular involvement with H. capsulatum falls into three groups: ( 1) disseminated histoplasmosis with uveal and/or retinal involvement, (2) solitary histoplasmic chorioretinal granuloma, and (3) the ocular histoplasmosis syndrome. The case reported here is quite similar to several of the previously reported cases of disseminated histoplasmosis with uveal and/or retinal involvement. Three of the five previously reported cases in this category had 1103
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recurrent systemic antigenic stimulation are factors in the syndrome is also unknown.
REFERENCES
Fig 6. Oval and round Histoplasma capsulatum with cell wall (arrowheads), plasma membrane (arrows), and nucleus (N) (original magnifications: upper X26,000; lower X38,000).
documented impairment of the immune system and/or treatment with immunosuppressive drugs. 3•4 •12 In two cases the patient's immune system was not investigated.5·13 In no previously reported case have the organisms been seen proliferating in the endothelial cells of the choroid. In Darling's22 original description of the disease, he described the organisms as occurring "in enormous numbers in the tissue, generally intracellularly in large mononuclear endothelial cells in the liver, spleen and lymph nodes." The patients who develop the ocular histoplasmosis syndrome do not have detectable systemic disease. This suggests that the development of peripheral and peripapillary lesions and submacular granulomas with neovascularization may require the presence of an intact immune system. The relationship between the presence of H. capsulatum in the choroid during subclinical systemic infection and the development of the syndrome remains unclear. Whether persistence of organisms or histoplasma antigen within ocular lesions, as well as
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1. Hoefnagels KLJ, Pijpers PM. Histoplasma capsulatum in a human eye. Am J Ophthalmol 1967; 63:715-23. 2. Maumenee AE. Clinical entities in "uveitis": an approach to the study of intraocular inflammation. Am J Ophthalmol 1970; 69:1-27. 3. Klintworth GK, Hollingsworth AS, Lusman PA, Bradford WD. Gran· ulomatous choroiditis in a case of disseminated histoplasmosis; histologic demonstrations of Histoplasma capsulatum in choroidal lesions. Arch Ophthalmol1973; 90:45-8; 1974; 91:237. 4. Craig EL, Suie T. Histoplasma capsulatum in human ocular tissue. Arch Ophthalmol1974; 91:285-9. 5. Schwarz J, Salfelder K, Viloria HJE. Histoplasma capsulatum in vessels of the choroid. Ann Ophthalmol 1977; 9:633-6. 6. Roth AM. Histoplasma capsulatum in the presumed ocular histo· plasmosis syndrome. Am J Ophthalmol1977; 84:293-8. 7. Makley TA. Presumed histoplasma chorioretinitis. Case presented at the Verhoef! Society Meeting, April 23-24, 1977. 8. Font RL. Histoplasma chorioretinal granuloma in a child with aniridia and Wilm's tumor. Case presented at the Association of Ophthalmic Alumni of the Armed Forces lrfstitute of Pathology-Eighth Biennial Meeting, June 22-23, 1979. 9. Zimmerman LE. Histoplasma endophthalmitis. Case presented at the Verhoef! Society Meeting, April 26-27, 1979. 10. Khalil MK. Histopathology of presumed ocular histoplasmosis. Am J Ophthalmol 1982; 94:369-76. 11. Duke JR. Granuloma of the choroid of unknown etiology. Case presented at the Ophthalmic Pathology Club Meeting, March 2021, 1961. 12. Goldstein BG, Buettner H. Histoplasmic endophthalmitis; a clinicopathologic correlation. Arch Ophthalmol 1983; 101:774-7. 13. Carroll OM, Franklin RM. Vitreous biopsy in uveitis of unknown cause. Retina 1981; 1:245-51. 14. Ryan SJ. Histopathological correlates of presumed ocular histoplasmosis. lnt Ophthalmol Clin 1975; 15(3):125-37. 15. Irvine AR, Spencer WH, Hogan MJ, et al. Presumed chronic ocular histoplasmosis syndrome: a clinical-pathological case report. Trans Am Ophthalmol Soc 1976; 74:91-106. 16. Meredith TA, Green WR, Key SN Ill, et al. Ocular histoplasmosis: clinicopathologic correlation of 3 cases. Surv Ophthalmol 1977; 22: 189-205. 17. Key SN Ill, Green WR, Maumenee AE. Pathology of macular lesion of ocular histoplasmosis: its pathogenetic and therapeutic implications. In: Brockhurst RJ, Boruchoff SA, Hutchinson BT, Lessell S, eds. Controversy in Ophthalmology. Philadelphia: WB Saunders, 1977; 732-47. 18. Makley TA Jr, Craig EL, Long JW. Histopathology of presumed ocular histoplasmosis. Palestra Oftalmol Panam 1977; 1:71-82. 19. Sheffer A, Green WR, Fine SL, Kincaid M. Presumed ocular histoplasmosis syndrome; a clinicopathologic correlation of a treated case. Arch Ophthalmol 1980; 98:335-40. 20. Makley TA. Presumed ocular histoplasmosis syndrome. Histologic findings in an early case. Case presented at the Verhoef! Society, Washington, DC, April 23-24, 1983. 21. Green WR. Uvea. In: Spencer WH, Zimmerman LE, eds. Ophthalmic Pathology; A Textbook and Atlas, 3d ed. Philadelphia: WB Saunders, 1984, In Press. 22. Darling ST. The morphology of the parasite (Histoplasma capsulatum) and the lesions of histoplasmosis, a fatal disease of tropical America. J Exp Med 1909; 11:515-31.
Abstract: The ocular pathologic findings in an immunosuppressed patient who died of disseminated histoplasmosis are described. Histoplasma capsulatum was found in large numbers within the endothelial cells of the choroid, in one area each of the ciliary body and trabecular meshwork. There was a minimal inflammatory response. No granulomas were noted. Previously reported cases of ocular histoplasmosis in immunosuppressed patients are similar in that, with one exception, granulomatous inflammation was not demonstrated. Thirteen eyes in which histoplasma organisms have been found in the eye are reviewed. [Key words: histoplasmosis, immunosuppression, ocular histoplasmosis, ocular histoplasmosis syndrome.] Ophthalmology 91: 1100-1104, 1984
The presence of Histoplasma capsulatum in the human eye has been demonstrated in 13 cases. 1- 13 Five of these cases had the clinical findings seen in the ocular histoplasmosis syndrome: peripapillary scarring, peripheral punched-out lesions, and a disciform macular scar. 2•6•7·10·11'14 Midperipheral chorioretinal scars were observed histopathologically in one eye. 11 In five cases, the patients had systemic histoplasmosis3- 5•13 and one case occurred in an individual who had an extraocular focus of infection with histoplasmosis. 1 An additional case had a presumed extraocular focus. 9 In two cases, the eyes were suspected of harboring melanomas2 •11 and in one the lesion was considered to be a metastatic tumor. 8 The lesions were found to be choroidal granulomas containing organisms consistent with H. capsu/atum. The ability of H. capsulatum to both invade the eye and to cause granulomatous disease seems well established. We report a case of disseminated histoplasmosis with choroidal involvement in a severely immunocompromised host who failed to produce an ocular inflammatory response despite widespread dissemination of the organisms in the choroid and one focus in the ciliary body.
From the Eye Pathology, Laboratory, Wilmer Ophthalmological Institute, and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland* and the Departments of Pathologyt and Ophthalmology,:j: University of Maryland School of Medicine, Baltimore, Maryland. Reprint requests to W. Richard Green, MD, Eye Pathology Laboratory, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205.
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CASE REPORT A 39-year-old man was admitted to the hospital on October 27, 1981 complaining ofthree days of upper and mid-abdominal pain and vomiting. Medical history was remarkable for chronic alcoholism and heroin abuse which led to heroin nephropathy and subsequent renal failure requiring renal transplantation. A cadaveric transplantation was performed in 1979. Because of chronic rejection, azothioprine and prednisone therapy was required. Multiple episodes of pancreatitis had been experienced since 1978, the most recent in June 1981. Culture-proven cavitary tuberculosis was treated in June 1981, with a right upper lobectomy, isoniazid, and rifampin. Because of druginduced hepatitis, the rifampin was discontinued and ethambutol 900 mg four times daily was begun. In July 1981 the patient was examined by one ofthe authors (R.D.R.). The visual acuity was 20/25 in both eyes secondary to early posterior subcapsular cataractous changes thought to possibly be the result of steroid therapy. The fundus was normal. There was no evidence of inflammatory disease in the choroid or vitreous. In August, 1981 because of an abnormal infiltrate on the chest x-ray and a spiking fever, the patient was admitted to the hospital. While in the hospital, the patient's fever ran as high as 103 o, occurring without his appearing toxic. Infectious disease consultants thought that tuberculosis was the most likely cause of the fever, but a search for other causes was instituted. Bone scan, liver-spleen scan, computerized tomography (CT) of the head and abdomen, bone-marrow biopsy, and aspirate were all unremarkable. A biopsy of the lung infiltrate was refused. Trimethoprim-sulfasoxisole and erythromycin therapy was initiated as empirical treatment for Pneumocystis carinii and
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et al •
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Legionnaire's disease, respectively. No fever was experienced for three days, but then the patient again became febrile. He was discharged at the beginning of September 1981. At the time of admission in October 1981, the medications were ethambutol 950 mg, isoniazid 300 mg, azothioprine 25 mg, and prednisone lO mg four times daily. The temperature was 101.2°, pulse 120, respiratory rate 30, and blood pressure 130/90. Physical exam was remarkable for decreased bowel sounds and tenderness and rigidity of the abdomen. Remarkable laboratory findings were: a hemoglobin of 10, a white blood count of 2.6K and an amylase of 452. The chest x-ray revealed no change from previous films. The assessment was chronic pancreatitis, chronic renal transplant rejection, dehydration, and anemia. A computed tomograph did not indicate pancreatic enlargement, but did show a lesion compatible with a pseudocyst of the tail of the pancreas. During the next week the patient remained febrile. Blood cultures, ultrasound of the abdomen, and a gallium scan were all unremarkable. Intravenous hyperalimentation was begun on November 11, 1981. As all cultures remained negative, the possibility of a drug fever was considered, and the ethambutol was discontinued for four days. This produced no change and a similar trial of discontinuation of the isoniazid also failed to produce any change. The patient became stuporous, and a lumbar puncture was performed. All cultures of the CSF were negative, as were the stains for bacteria and acid-fast bacilli. The india ink preparation and VDRL were negative. On November 16, cultures of the urine were positive for cytomegalovirus. The opinion of a virologist was that the culture may or may not have been significant and there was no effective treatment should the virus be the cause of the patient's illness. Because of increasing lethargy, a decrease in blood pressure and a persistent fever, all of which seemed to indicate sepsis, the patient was transferred to the Intensive Care Unit on November 16. Blood cultures were positive for Staphylococcus epidermidis. Treatment was with vancomycin, and despite adequate blood levels and minimum inhibitory concentrations, the fever did not subside. As the hematocrit dropped and the fever persisted on adequate antibiotic therapy, endocarditis was considered. Adrenal insufficiency was also considered in view of the long course of steroid therapy, and intravenous steroid therapy was initiated. Despite all these measures, the patient's course was progressively downhill and he died on December 2, 1981 following a hypotensive episode and a grand mal seizure. At postmortem examination Histoplasma capsulatum was demonstrated in lungs, liver, spleen, transplanted kidney, bone marrow, lymph nodes, adrenal glands, and in the intestinal tract. Postmortem lung cultures grew Histoplasma cap$ulatum. Postmortem blood cultures were also positive for coagulasenegative staphylococcus, and gram positive cocci were found in the pancreas.
RESULTS The microscopic findings were similar in both eyes. Organisms, 2 to 6 1-1-m in size, were seen within the cytoplasm of hyperplastic endothelial cells of choroidal arteries, veins (Figs 1, 2) and choriocapillaris. The organisms were round and contained a central nucleus that stained with periodic acid-Schiff reagent (Figs 2, 3). The capsule of the organisms stained with Gomori
methanamine silver stain (Fig 4). Increased stammg time intensified the staining of the organisms (Fig 5). A small number of chronic inflammatory cells was present. No granulomas or necrosis were noted. Serial sections in the plane of the pupil, optic nerve head, and macula were obtained and the only additional finding was the presence of a small number of organisms in one area of the ciliary body and the trabecular meshwork of the left eye. Electron micrographs of the choroid showed multiple intracellular organisms that were round to oval in shape (Fig 6). The organisms measured 1.5 to 2 ~tm in diameter and were surrounded by a capsule. The capsule measured 900 to 1200 nm in thickness. Beneath the capsule was a membrane consisting of two layers separated by a space of approximately 50 to 70 nm within the organism itself. There was a nucleus of approximately one ~tm, numerous free ribosomes, and vacuoles, some of which contained electron-dense debris and mitochondria. The surrounding cytoplasm contained numerous degenerated organisms containing electron-dense material and dilated endoplasmic reticulum.
DISCUSSION The association between H. capsulatum and ocular disease is now well established. Intraocular organisms consistent with H. capsulatum have been demonstrated in 13 previously reported or presented cases. In one additional case, positive indirect immunofluorescence to histoplasma antigen was observed in the eye of a patient with the features of the ocular histoplasmosis syndrome. 15 Histopathologic study of ocular lesions in eyes with the features of the ocular histoplasmosis syndrome, but without demonstrable intraocular organisms, has been performed in a number ofinstances. 14•16- 21 These studies have generally shown macular disciform scars of various sizes, choroidal neovascularization, often with extension under the retinal pigment epithelium and the periphery of the lesion with little or no inflammation in the choroid. The peripheral lesions uniformly show a scar that involves the inner aspect of the choroid and outer aspects of the retina. Discontinuity of Bruch's membrane is evident in most of the peripheral and peripapillary lesions, and in some instances, hyperplastic retinal pigment epithelium, and rarely, glial cells, extend into the choroid in the scarred area. Lesions in the periphery do not show neovascularization, although a chorioretinal vascular anastomosis was seen in one peripherallesion. 21 The histopathology of the eyes with both organisms consistent with H. capsulatum2•6 •1•10•11 •14 or immunopathologic evidence of H. capsulatum antigen 15 and features of the ocular histoplasmosis syndrome has been described in six cases. One case is referred by two authors. 2 •14 In the case presented by Duke 11 as "granuloma of the choroid of unknown etiology," subsequent ll01
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study showed the granuloma to contain organisms consistent with H. capsulatum. No peripapillary scarring was noted, but peripheral punched-out lesions were found in addition to the granuloma. The granuloma was located in the choroid in the macular area. Bruch's membrane, retinal pigment epithelium, and the outer layers of the retina were absent in the central area of the granuloma. A similar case was reported by Maumenee 2 and Ryan. 14 An eye enucleated for what was thought to be a melanoma, but which proved to be a granuloma, was later shown to contain H. cqpsulatum. The fellow eye contained peripheral punched-out lesions on subsequent clinical examination. 14 The case described by Roth6 concerned two eyes from a patient who had died of heart failure and in whom H. capsulatum was found not only in the eyes but also in the lung. The eyes contained disciform macular lesions, peripheral punched-out lesions and peripapillary scarring. Organisms were demonstrated in both macular lesions, in the punched-out peripheral lesions and in one peripapillary lesion. The disciform macular lesions were fibrovascular masses containing areas of necrosis and granulomatous inflammation. The overlying pigment epithelium was disrupted. No choroidal neovascularization was observed but breaks in Bruch's membrane were noted. Lymphocytic infiltration of the choroid was seen. The case described by Khalil 10 is similar. A 33-yearold man was diagnosed as having ocular histoplasmosis in the right eye on the basis of a positive histoplasmin skin test, an old nodular granuloma in the lower lobe of the right lung, and a macular scar. Nine years later the right eye was removed because of a large melanoma. Both eyes contained peripapillary chorioretinal lesions with irregular pigmentation and multiple mid peripheral lesions. Histopathologic study of the right eye showed multiple chorioretinallesions in the macula, peripapillary area, and in the mid periphery. These lesions were grouped into three types: active granulomatous inflammation, nongranulomatous inflammation, and localized chorioretinal scars. H. capsulatum was identified by periodic acid-Schiff and Gomori methenamine silver stains. Dead organisms were identified by electron microscopy. Makley7 described a 53-year-old woman who had her left eye enucleated because of a malignant melanoma. Prior to the development of the tumor, she had been diagnosed as having a central choroiditis that left a macular scar. When the choroiditis was active, a histoplasmin skin test was positive. Peripapillary scarring and peripheral punched-out spots were observed in the fellow eye. Histopathologic examination of the enucleated eye was remarkable for melanoma of the choroid, a macular chorioretinal scar, and a mid peripheral chorioretinal scar that contained organisms consistent with H. capsulatum. Six of the seven cases in which H. capsulatum was demonstrated intraocularly but the features of the ocular histoplasmosis syndrome were absent, were all cases in 1102
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which systemic histoplasmosis or an active extraocular focus of histoplasmosis were present. 1•3- 5•12•13 In one case, an extraocular focus was not sought because the patient declined diagnostic studies. 9 In one case 13 the diagnosis was established by cytopathologic examination of vitreous and by culture. Hoefnagels and Pijpers 1 reported a case of panophthalmitis leading to enucleation. A primary infection by H. capsulatum in the gingiva was proven by biopsy and culture. The eye became painful and without light perception. It was enucleated and a panophthalmitis demonstrated. There was intense granulomatous inflammation found subconjunctivally, in the area of Schlemm's canal and in the iris, ciliary body, and retina. Organisms were found subconjunctivally, in the anterior chamber, iris, posterior chamber, ciliary body, and retina. No organisms were found in the choroid. Goldstein and Buettner12 reported a case quite similar to the one just described. A 37-year-old man with recurrent systemic histoplasmosis developed an intense panophthalmitis leading to enucleation. Histopathologic examination was remarkable for an intense necrotizing granulomatous iridocyclitis with numerous organisms. The choroid contained only a mild inflammatory infiltrate and no organisms. Craig and Suie4 reported a case of fatal disseminated histoplasmosis in a 22-year-old woman who was being treated for lupus erythematosis with immunosuppressive drugs. She was noted to have small white retinal lesions near each optic nerve head. At autopsy, H. capsulatum was found within macrophages in the choroid. Klintworth et al 3 reported a case of multifocal granulomatous choroiditis in a 14-year-old boy who died of disseminated histoplasmosis. The patient developed adrenal insufficiency eight years after the original diagnosis had been established. Clinical examination of the eyes disclosed "small white drusenoid bodies in the macular area of the left eye." Postmortem sections through these lesions showed them to be choroidal granulomas containing both intracellular and extracellular organisms typical of H. capsulatum. H. capsulatum was isolated from the bone marrow, skin, lymph nodes, and cerebrospinal fluid during life and from the brain postmortem. Schwarz et al 5 reported finding H. capsulatum in the eye of a 3-year-old boy who died of disseminated histoplasmosis. Histiocytes containing H. capsulatum were found in capillaries of the optic nerve in extraocular muscle, the sclera, and the retina. The choroidal vessels were engorged with histiocytes containing H. capsulatum. Font8 has reported a solitary chorioretinal granuloma in a child with aniridia and Wilm's tumor. The eye came to enucleation after radiation for what was considered to be metastatic tumor. The lesion was found to be a necrotizing choroidal granuloma that was surrounded by a palisading of fibroblasts and epithelioid cells. Organisms compatible with H. capsulatum were seen with the Gomori methanamine silver stain. Zimmerman9 presented a case of intraocular histoplasmosis leading to phthisis bulbi. The patient had
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HISTOPLASMA CAPSULATUM
Fig 1. Top left, nodule of hyperplastic endothelium of choroidal vein with histoplasma organisms present (paraphenylenediamine; phase-contrast, X 153). Fig 2. Top right, nodule of hyperplastic endothelium in choroidal vein (periodic acid-Schiff, X96). Fig 3. Second row left, higher power of endothelial cell nodule with organisms present in cytoplasm of endothelial cells (periodic acidSchiff, X384). Fig 4. Second row right, demonstration of organisms in choroidal vascular endothelium after exposure to solution of 5% silver nitrate and 3% methanamine silver for 60 minutes (Gomori methanamine silver, X384). Fig 5. Bottom left, demonstration of organisms after exposure to silver solution for 90 minutes (Gomori methanamine silver, X384).
recurrent high fevers of undetermined etiology, and developed phthisis following intractable iritis. The intraocular contents were necrotic and contained acute suppurative and chronic granulomatous inflammation. H. capsulatum was found throughout the tissues using special stains. Further investigations to determine the source of the infection were refused by the patient. Carroll and Franklin 13 reported the case of a 62-yearold man with chronic uveitis and a past history of diabetes mellitus, hypertension, and biopsy-proven systemic histoplasmosis. The uveitis did not respond to amphotericin B therapy and a diagnostic vitrectomy was
performed. Cytopathologic evaluation of the vitreous aspirate disclosed organisms consistent with H. capsulatum. Font8 has pointed out that proven ocular involvement with H. capsulatum falls into three groups: ( 1) disseminated histoplasmosis with uveal and/or retinal involvement, (2) solitary histoplasmic chorioretinal granuloma, and (3) the ocular histoplasmosis syndrome. The case reported here is quite similar to several of the previously reported cases of disseminated histoplasmosis with uveal and/or retinal involvement. Three of the five previously reported cases in this category had 1103
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recurrent systemic antigenic stimulation are factors in the syndrome is also unknown.
REFERENCES
Fig 6. Oval and round Histoplasma capsulatum with cell wall (arrowheads), plasma membrane (arrows), and nucleus (N) (original magnifications: upper X26,000; lower X38,000).
documented impairment of the immune system and/or treatment with immunosuppressive drugs. 3•4 •12 In two cases the patient's immune system was not investigated.5·13 In no previously reported case have the organisms been seen proliferating in the endothelial cells of the choroid. In Darling's22 original description of the disease, he described the organisms as occurring "in enormous numbers in the tissue, generally intracellularly in large mononuclear endothelial cells in the liver, spleen and lymph nodes." The patients who develop the ocular histoplasmosis syndrome do not have detectable systemic disease. This suggests that the development of peripheral and peripapillary lesions and submacular granulomas with neovascularization may require the presence of an intact immune system. The relationship between the presence of H. capsulatum in the choroid during subclinical systemic infection and the development of the syndrome remains unclear. Whether persistence of organisms or histoplasma antigen within ocular lesions, as well as
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1. Hoefnagels KLJ, Pijpers PM. Histoplasma capsulatum in a human eye. Am J Ophthalmol 1967; 63:715-23. 2. Maumenee AE. Clinical entities in "uveitis": an approach to the study of intraocular inflammation. Am J Ophthalmol 1970; 69:1-27. 3. Klintworth GK, Hollingsworth AS, Lusman PA, Bradford WD. Gran· ulomatous choroiditis in a case of disseminated histoplasmosis; histologic demonstrations of Histoplasma capsulatum in choroidal lesions. Arch Ophthalmol1973; 90:45-8; 1974; 91:237. 4. Craig EL, Suie T. Histoplasma capsulatum in human ocular tissue. Arch Ophthalmol1974; 91:285-9. 5. Schwarz J, Salfelder K, Viloria HJE. Histoplasma capsulatum in vessels of the choroid. Ann Ophthalmol 1977; 9:633-6. 6. Roth AM. Histoplasma capsulatum in the presumed ocular histo· plasmosis syndrome. Am J Ophthalmol1977; 84:293-8. 7. Makley TA. Presumed histoplasma chorioretinitis. Case presented at the Verhoef! Society Meeting, April 23-24, 1977. 8. Font RL. Histoplasma chorioretinal granuloma in a child with aniridia and Wilm's tumor. Case presented at the Association of Ophthalmic Alumni of the Armed Forces lrfstitute of Pathology-Eighth Biennial Meeting, June 22-23, 1979. 9. Zimmerman LE. Histoplasma endophthalmitis. Case presented at the Verhoef! Society Meeting, April 26-27, 1979. 10. Khalil MK. Histopathology of presumed ocular histoplasmosis. Am J Ophthalmol 1982; 94:369-76. 11. Duke JR. Granuloma of the choroid of unknown etiology. Case presented at the Ophthalmic Pathology Club Meeting, March 2021, 1961. 12. Goldstein BG, Buettner H. Histoplasmic endophthalmitis; a clinicopathologic correlation. Arch Ophthalmol 1983; 101:774-7. 13. Carroll OM, Franklin RM. Vitreous biopsy in uveitis of unknown cause. Retina 1981; 1:245-51. 14. Ryan SJ. Histopathological correlates of presumed ocular histoplasmosis. lnt Ophthalmol Clin 1975; 15(3):125-37. 15. Irvine AR, Spencer WH, Hogan MJ, et al. Presumed chronic ocular histoplasmosis syndrome: a clinical-pathological case report. Trans Am Ophthalmol Soc 1976; 74:91-106. 16. Meredith TA, Green WR, Key SN Ill, et al. Ocular histoplasmosis: clinicopathologic correlation of 3 cases. Surv Ophthalmol 1977; 22: 189-205. 17. Key SN Ill, Green WR, Maumenee AE. Pathology of macular lesion of ocular histoplasmosis: its pathogenetic and therapeutic implications. In: Brockhurst RJ, Boruchoff SA, Hutchinson BT, Lessell S, eds. Controversy in Ophthalmology. Philadelphia: WB Saunders, 1977; 732-47. 18. Makley TA Jr, Craig EL, Long JW. Histopathology of presumed ocular histoplasmosis. Palestra Oftalmol Panam 1977; 1:71-82. 19. Sheffer A, Green WR, Fine SL, Kincaid M. Presumed ocular histoplasmosis syndrome; a clinicopathologic correlation of a treated case. Arch Ophthalmol 1980; 98:335-40. 20. Makley TA. Presumed ocular histoplasmosis syndrome. Histologic findings in an early case. Case presented at the Verhoef! Society, Washington, DC, April 23-24, 1983. 21. Green WR. Uvea. In: Spencer WH, Zimmerman LE, eds. Ophthalmic Pathology; A Textbook and Atlas, 3d ed. Philadelphia: WB Saunders, 1984, In Press. 22. Darling ST. The morphology of the parasite (Histoplasma capsulatum) and the lesions of histoplasmosis, a fatal disease of tropical America. J Exp Med 1909; 11:515-31.