Fig. 9.30 (a) Large focal choroidal granuloma (arrows) secondary to histoplasmosis. (b) Special stains showed

Histoplasma capsulatum (arrows). (Panel A reprinted with permission from Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967;63:Suppl:1–139; and Maumenee AE, Ryan SJ. Photocoagulation of disciform macular lesions in the ocu-

lar histoplasmosis syndrome. Am J Ophthalmol. 1973;75:13–16. Panel B reprinted with permission from Klintworth GK, Hollingsworth AS, Lusman PA, Bradford WD. Granulomatous choroiditis in a case of disseminated histoplasmosis. Histologic demonstration of Histoplasma capsulatum in choroidal lesions. Arch Ophthalmol. 1973;90:45–48)

Histoplasma Chorioretinitis

Histoplasma capsulatum is a dimorphic unencapsulated fungus with mycelial and yeastlike phases that often grows in soil around old chicken houses and areas harboring bats, such as caves [46]. The organism is endemic in southeastern and central United States and many parts of Central America and Asia. The organism gains access to the body by way of the respiratory tract through inhalation of spores.

Acute histoplasmosis is usually a benign subclinical or self-limited pulmonary illness [47]. Disseminated histoplasmosis is a rare condition in which the organism spreads by way of the bloodstream, producing lesions throughout the body.

Presumed ocular histoplasmosis syndrome (POHS) is a distinct clinical entity that is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy. This condition is believed to be secondary to exposure to Histoplasma capsulatum, although this fungus rarely has been isolated or cultured from an eye with the typically associated clinical findings.

Risk Factors

Rarely, disseminated infection occurs in normal adults without any immunologic defect [48]. Risk factors for histoplasmosis infection are:

•Residents or visitors to endemic areas

•Prior exposure to chickens, parakeets, or pigeons

•Incomplete development of immune defense mechanisms in infants [47]

•AIDS

•Iatrogenic immunosuppression, especially after kidney transplantation

•Immunocompromised patients

Pathogenesis

In a normal host, the initial infection is usually asymptomatic or feels like influenza. In a few patients, a chronic cavitary pulmonary disease may follow. In immunocompromised patients, a progressive, life-threatening, disseminated form can occur. Following initial infection, hematogenous spread to the rest of the body, including the eye, can occur. Histoplasma capsulatum may eventually seed the choroid to produce a multifocal granulomatous chorioretinitis that heals as atrophic histo scars (Fig. 9.30).

Clinical Features

The classic ocular disease is manifested with a triad of disseminated choroiditis (histo spots), maculopathy that may be associated with episodes of exudation and may occur with subretinal neovascularization, and peripapillary atrophy with pigmentary changes (Fig. 9.31) [49].

Ocular involvement in cases of disseminated histoplasmosis may manifest as retinitis, optic neuritis, or uveitis. The retinitis appears as multiple,

Fig. 9.31 (a) Disseminated choroiditis (histo spots), maculopathy, and peripapillary chorioretinal degenerative changes in a patient with the presumed ocular histoplasmosis syndrome. (b) Fundus photographs revealed serosanguinous retinal detachment with faint pigment halo in right macula of

a patient with the presumed ocular histoplasmosis syndrome. (Reprinted with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier: 2006; 366–774)

creamy white intraretinal and subretinal infiltrates and intraretinal hemorrhages (Fig. 9.32 panels A, B, and C). Active choroiditis appears as discrete, round, yellowish choroidal lesions. With time, the lesions resolve, leaving the typical “punched-out” atrophic scars that disrupt Bruch’s membrane. Reexposure to the histoplasmin antigen may account for the enlargement of old scars and the emergence of new scars (Figs. 9.33 and 9.34).

Diagnosis

Diagnosis is made by histology and culture of tissue specimens. The organism exists as yeasts within the host tissues, usually located within macrophages, and surrounded by granulomatous inflammation. Organisms are best visualized by stains specific for fungal elements such as periodic acid Schiff, Gomori methenamine silver, or Grocott silver stain. The morphology of the yeast is suggestive, but not diagnostic, as it can be confused with other fungi such as Candida glabrata,

Blastomyces dermatitidis, Penicillium marneffei, or Coccidioides immitis.

Culture is performed on routine fungal culture medium such as Sabouraud glucose agar (Fig. 9.32 panel D) or brain heart infusion agar. At 28–30°C, the organism grows as a white mold, with typical tuberculated macroconidia on microscopy. However, conversion to a yeast form after subculture at 35–37°C is required for diagnosis. Microscopy

then shows elliptical yeast cells, budding from the small end by a narrow base. Confirmation can also be made by immunofluorescent techniques, which detect specific exoantigens or nucleic acid probes, which detect Histoplasma- specific DNA. Serology is positive in as many as 75% of patients 6 weeks after the onset of acute disease, but antibodies can also be detected in up to 10% of asymptomatic individuals in endemic areas. Immunocompromised individuals often do not mount an antibody response. Skin testing using histoplasmin antigen is mainly used as an epidemiological tool. The organisms may also be isolated from vitreous aspirates obtained during pars plana vitrectomy.

Fluorescein angiography can show hyperfluorescence in the late phases of the study from choroidal neovascularization in patients with histoplasmosis (Fig. 9.35) [50]. Optical coherence tomography is useful in the identification of different types of choroidal neovascularization (type 1 or 2), accumulation of subretinal fluid, macular edema, and epiretinal membranes (Fig. 9.36). Chest radiography may show calcified lesions by histoplasmosis infection (Fig. 9.37).

Treatment

Amphotericin B or ketoconazole generally is recommended for treatment of disseminated histoplasmosis. Pars plana vitrectomy with

Fig. 9.32 Patient with ocular histoplasmosis. (a–b) Multiple, creamy white intraretinal and subretinal infiltrates. (c) Intraretinal and subretinal hemorrhages. (d) Histoplasma capsulatum. Yeast colonies in Sabouraud glucose agar. (Part D, reprinted with permission from

Gonzales CA, Scott IU, Chaudhry NA, Luu KM, Miller D, Murray TG, Davis JL. Endogenous endophthalmitis caused by Histoplasma capsulatum var. capsulatum: a case report and literature review. Ophthalmology. 2000;107:725–729)

Fig. 9.35 (a–b). Hyperfluorescence in the late phases of the fluorescein angiogram from choroidal neovascularization in patient with the presumed ocular histoplasmosis syn-

drome. (Modified and reprinted with permission from Gass JDM. Stereoscopic Atlas of Macular Diseases; Diagnosis and Treatment. 4th ed. St. Louis: Mosby, Inc. 1997)

Fig. 9.36 Type 2 choroidal neovascular membrane in a patient with a diagnosis of presumed ocular histoplasmosis syndrome. Fusiform hypereflectivity between the

retina and the retinal pigment epithelium complex on optical coherence tomography