Chapter 170 – Histoplasmosis
RAMANA S. MOORTHY
JAMES A. FOUNTAIN
• Histoplasmosis is a chronic intraocular inflammation induced by Histoplasma capsulatum, a diphasic fungus.
• Ocular histoplasmosis can appear as an endophthalmitis or solitary granuloma or, more commonly, as a syndrome characterized by peripheral “punched-out” chorioretinal scars, absence of inflammatory cells in the anterior chamber or vitreous, and positive histoplasmin skin test results.
• Peripapillary chorioretinal atrophy, choroidal neovascularization, and hemorrhagic macular lesions occur.
• The disease is endemic in the Ohio and Mississippi river valleys.
Histoplasma capsulatum is a diphasic, soil-borne fungus. Humans and other mammals inhale wind-blown soils and aerosolized bird droppings that contain these organisms and so become infected. These organisms infect the lungs and can be disseminated through the systemic circulation to other organs such as the liver, kidney, spleen, and the eye. H. capsulatum is responsible for three different forms of ocular involvement in humans :
• Endophthalmitis with diffuse uveal and retinal involvement from disseminated histoplasmosis
• Solitary chorioretinal granuloma
• Ocular histoplasmosis syndrome (OHS)
The Histoplasma organisms have been identified in ocular tissues in all three of these forms.
Histoplasmin endophthalmitis occurs mainly in immunocompromised patients, particularly those who have acquired immunodeficiency syndrome (AIDS). Symptoms can include floaters, decreased vision, and pain in the affected eye. Ophthalmic examination reveals conjunctival injection, anterior chamber flare and cells, yellow iris infiltrates, posterior synechiae, vitreous cells, and multiple, white, creamy foci of retinochoroiditis.  Diagnosis is based on the presence of active pulmonary or disseminated histoplasmosis and positive cultures from sputum, bronchial washings, and biopsy specimens from the anterior chamber or vitreous cavity. Complement fixation titers are elevated (>1:32) in disseminated disease. Histopathological evaluation of eyes with histoplasmic endophthalmitis demonstrates diffuse granulomatous inflammation that involves the entire uveal tract, focal retinal inflammation, and intracellular and extracellular H. capsulatum that are detected with periodic acid-Schiff and Gomori methenamine-silver (GMS) stains.  Prompt treatment with systemic amphotericin B or itraconazole is recommended in affected patients.
Solitary histoplasmic granuloma is an extremely rare condition found in immunocompromised patients. An identifiable primary source of histoplasmic infection may not be found in these patients who have a white, ill-defined choroidal lesion of variable size in one eye.  Inflammation of the vitreous cavity is variable. Histopathological evaluation shows a dense, granulomatous mass that contains lymphocytes and epithelioid and giant cells. Few histoplasma organisms are noted within the granuloma. Treatment with systemic amphotericin B should be considered if a granuloma appears to be growing or is associated with severe vitritis.
OHS is by far the most common form of ocular disease caused by H. capsulatum. It continues to be an important cause of central visual loss during the productive years of human life. The syndrome consists of peripapillary chorioretinal atrophy and scarring, peripheral “punched-out” chorioretinal scars, hemorrhagic macular lesions secondary to choroidal neovascularization, absence of anterior segment and vitreous inflammation, and yields a positive histoplasmin skin test result.
EPIDEMIOLOGY AND PATHOGENESIS
OHS is endemic in the Ohio and Mississippi river valleys of the eastern half of the United States. Up to 80 million people are at risk for the development of OHS in this part of the country. In endemic areas, 60% or more of the population may have positive histoplasmin skin tests. Approximately 5% of these patients who have positive skin tests have peripheral atrophic scars and peripapillary atrophy. Additionally, 95% or more of patients who have typical signs of OHS have positive histoplasmin skin test results. Although H. capsulatum has not been cultured from peripheral, atrophic chorioretinal scars or disciform macular scars, organisms have been demonstrated histopathologically in both.  These observations suggest that H. capsulatum causes OHS.
Genetic factors may be important in the pathogenesis of OHS, because patients with macular or peripapillary hemorrhagic lesions have a significantly higher prevalence of human lymphocyte antigen B-7 (HLA-B7) than the population at large. No significant increase in HLA-B7 occurs in patients who have only peripheral atrophic spots associated with OHS.
H. capsulatum may cause a subclinical systemic infection in patients in the endemic areas prior to the development of the typical ocular manifestations of OHS. This may be a self-limited upper respiratory tract illness. Subsequent routine radiological studies of patients in endemic areas may disclose asymptomatic pulmonary, hepatic, splenic, and renal granulomas.
Anterior segment and vitreous inflammation are notably absent. The characteristic fundus findings of OHS include:
• Small, oval to round, “punched-out” chorioretinal scars in the midperiphery or posterior pole ( Fig. 170-1 )
• A macular lesion that varies from atrophic scar to active choroidal neovascularization ( Fig. 170-2 ) to disciform scar
• Peripapillary atrophy or scarring ( Fig. 170-2 )
The peripheral chorioretinal lesions are discrete, “punched-out,” atrophic scars that are 0.2–0.6 disc diameters in size. They
Figure 170-1 Atrophic “punched-out” chorioretinal scars in the midperiphery in a patient who has ocular histoplasmosis syndrome.
often have pigmented borders and may be located in the midperiphery or in the posterior pole. The macular lesions may be hemorrhagic initially and associated with a pigment ring. An overlying serous retinal detachment or retinal pigment epithelial (RPE) detachment may occur. Subretinal hemorrhaging and fluid accumulation are due to the growth of a choroidal neovascular membrane (CNVM) into the sub-RPE or subretinal space. If untreated these lesions may evolve into disciform scars. The disciform lesion may appear yellowish to whitish, fibrotic, and associated with variable amounts of pigmentation. The size of the disciform macular scar can vary, depending upon the amount of serum and blood in the subretinal space prior to its development. Peripapillary scarring is associated with a thin area of chorioretinal atrophy adjacent to the optic nerve and a peripheral zone of hyperpigmentation at the edge farthest from the optic nerve (see Fig. 170-2 ). Choroidal neovascularization also may develop in the peripapillary area and result in peripapillary subretinal hemorrhage and serous retinal detachment, which may occasionally involve the macula. In addition to these three characteristic lesions, linear streak lesions at the equator have been found in up to 5% of patients with OHS ( Fig. 170-3 ). Equatorial linear streak lesions, however, also may be seen in idiopathic multifocal choroiditis.
Patients who have OHS generally are asymptomatic unless macular or peripapillary choroidal neovascularization causes metamorphopsia. This usually is followed by visual loss and the development of a small scotoma in the central or paracentral visual field. Patients who have OHS usually seek treatment for these symptoms between their third and sixth decades.
The diagnosis of OHS may be made by funduscopic examination alone. Skin testing with H. capsulatum antigen is not recommended because of the high prevalence of positive results in endemic areas and controversy as to whether the skin test may actually cause activation of otherwise quiet, atrophic chorioretinal scars.
Patients with known, asymptomatic OHS should be instructed to perform frequent Amsler’s chart self-monitoring for early detection of choroidal neovascularization. Patients who have OHS who have symptoms of metamorphopsia or scotoma should have fluorescein angiography performed. In asymptomatic patients fluorescein angiographic findings consist of late
Figure 170-2 Peripapillary scarring and macular, juxtafoveal choroidal neovascular membrane with surrounding subretinal hemorrhage in the eye of a patient who has ocular histoplasmosis syndrome.
Figure 170-3 Nasal equatorial linear streak lesion in the eye of a patient who has ocular histoplasmosis syndrome.
staining of the peripapillary scar, midperipheral atrophic spots, and atrophic macular scars. If clinical examination suggests the presence of subretinal fluid or a subretinal hemorrhage (see Fig. 170-2 ), fluorescein angiography demonstrates early hyperfluorescence and late leakage from a complex of lacy, small blood vessels in the subretinal space or subretinal pigment epithelial space ( Fig. 170-4 ). This is consistent with the diagnosis of choroidal neovascularization. Similar findings are seen on indocyanine green angiography, which may be helpful in delineating the CNVM when it is obscured by subretinal hemorrhage.
All of the syndromes listed in Box 170-1 , except myopic degeneration, have anterior segment and vitreous inflammation in association with the chorioretinal findings. Peripheral, “punched-out,” atrophic scars may be present in all of these syndromes. In sarcoidosis, the atrophic scars may be present throughout the fundus. In Vogt-Koyanagi-Harada syndrome and sympathetic
Figure 170-4 Arteriovenous phase fluorescein angiogram of extrafoveal choroidal neovascular membrane of the left eye. Note the leakage of fluorescein from the macular lesion, hypofluorescence due to blockage of choroidal fluorescence by surrounding subretinal hemorrhage, faint ring of subretinal fluid, and peripapillary staining.
Differential Diagnosis of Ocular Histoplasmosis Syndrome
Idiopathic multifocal choroiditis
ophthalmia, these lesions typically are located in the inferior mid- to far-peripheral retina. Atrophic and disciform macular scarring and peripapillary atrophy, scarring, and choroidal neovascularization also may occur in all of these syndromes.
Histopathology of peripheral lesions demonstrates the infiltration of lymphocytes. Caseating granulomatous foci with fibrohyaline scarring may be present. The granulomas may contain structures suggesting H. capsulatum.  
The macular lesions of OHS show disruption of Bruch’s membrane with ingrowth of a neovascular complex into the subretinal space ( Fig. 170-5 ). There may be an overlying serous retinal detachment and subretinal hemorrhage. A variable amount of lymphocytic infiltration may be present. The CNVM may appear only loosely adherent to the overlying photoreceptors and underlying native RPE. If left untreated, the subretinal hemorrhage and serum in the subretinal space may lead to proliferation and metaplasia of RPE into fibrovascular tissue that organizes into an inactive disciform plaque. Lymphocytes can sometimes become a prominent feature of the choroid adjacent to the subretinal scar. The peripapillary scar also demonstrates RPE proliferation and replacement of much of the choroid by fibrovascular tissue. Disruption of Bruch’s membrane and extensive destruction of the overlying photoreceptors also may occur in this area.
Surgically excised CNVMs demonstrate the expression of various growth factors—basic fibroblast growth factor, transforming growth factor ß-1, and procollagen. These growth factors may play a role in the development of choroidal neovascularization.
Figure 170-5 Histopathology of an “active” atrophic chorioretinal scar in ocular histoplasmosis syndrome. Note the lymphocytic infiltrate of the choroid, disruption of Bruch’s membrane and retinal pigment epithelium, and extension of inflammation from choriocapillaris into the subretinal space. Typical histoplasmin organisms are not demonstrated here but have been isolated from other lesions. (Courtesy of Yanoff M, Fine BS. Ocular pathology: a text and atlas, ed 5. St. Louis: Mosby; 2002:412.)
Most patients who have OHS are asymptomatic unless they develop choroidal neovascularization in the peripapillary or macular regions. Macular choroidal neovascularization may be subdivided into the following :
• Extrafoveal lesions, when the foveal edge is more than 200?mm from the center of the fovea
• Juxtafoveal lesions, when the foveal edge is 1–199?mm from the center of the fovea
• Subfoveal lesions, when any part of the membrane has clearly grown underneath the center of the fovea
Argon green or krypton red laser photocoagulation of extrafoveal and juxtafoveal lesions in ocular histoplasmosis is recommended. Untreated eyes with CNVM and ocular histoplasmosis have a 3–6 times greater risk of losing six or more lines of visual acuity than do treated eyes. Recurrent neovascularization has been observed in 26% of treated eyes within 5 years of the initial laser photocoagulation. Treatment using argon green or krypton red laser is equally efficacious with similar visual outcomes. Laser treatment is accomplished by using a 100–200?mm spot size of 0.2–0.5?sec duration, and enough power to attain a uniform whitening of the entire CNVM defined anatomically by fluorescein angiography. Treatment using laser photocoagulation is reassessed 2–4 weeks after the treatment; and fluorescein angiography is used to look for persistence or recurrence of choroidal neovascularization. Continued Amsler’s chart monitoring for the development of new metamorphopsia is important. Follow-up visits should be performed at 2, 3, and 6 months posttreatment.
Treatment of subfoveal CNVMs in OHS is less clear cut. Patients who have good visual acuity with subfoveal choroidal neovascularization should not be treated with laser photocoagulation because an immediate drop in visual acuity occurs, particularly if visual acuity is better than 20/200 (6/60). Up to 14% of eyes with subfoveal CNVMs retain visual acuity of 20/40 (6/12) or better without any treatment. Periocular depot injections of triamcinolone or dexamethasone or a course of oral corticosteroids for 3–4 weeks may be useful to limit the progression of subfoveal choroidal neovascularization in some patients. Subfoveal surgery to remove CNVMs in ocular histoplasmosis appears to be promising. However, surgery requires pars
plana vitrectomy, disinsertion and removal of the posterior hyaloid, a small retinotomy, and careful delamination, dissection, and removal of the CNVM from the subretinal space. With successful surgery, 85% of patients have stable vision between 3 and 12 months after surgery. Risks of surgery include intraocular hemorrhage, suprachoroidal hemorrhage, endophthalmitis, retinal detachment, and cataract. In addition, choroidal neovascularization may recur in 44% of cases within 13 months after surgery. Approximately 66% of these recurrences are subfoveal. Recurrences may warrant further surgery, laser photocoagulation, or merely observation. Other treatment options include limited macular translocation, especially in cases when subfoveal retinal pigment epithelial loss occurs during subfoveal surgery. Ocular photodynamic therapy using verteporfin, a second-generation lipophilic-amphiphilic photosensitizer, for subfoveal CNVMs is also promising. A preliminary study showed that visual improvement was even possible with this method. The Verteporfin in Ocular Histoplasmosis (VOH) study group recently completed a multicenter, uncontrolled, prospective clinical trial for choroidal neovascular membranes less than 5400?µm in greatest lesional dimension that extended under the geometric center of the foveal avascular zone. At the end of 1 year of follow-up, 25 patients had received an average of 2.9 treatments and 56% (14) has improved 7 or more ETDRS letters of visual acuity from baseline and 16% (4) had lost 8 or more letters. There are no systemic or ocular adverse events reported. The 2-year results are still pending.
COURSE AND OUTCOME
Patients who have OHS who do not develop macular complications of the disease enjoy excellent visual acuity and visual prognosis. Treatment of extrafoveal and juxtafoveal choroidal neovascularization with argon or krypton laser photocoagulation reduces the risk of serious visual loss by at least 50%. Extrafoveal choroidal neovascularization has an excellent visual prognosis after treatment. However, the visual prognosis for subfoveal choroidal neovascularization is guarded.
Patients who have a disciform scar or choroidal neovascularization in one eye and evidence of macular atrophic scars in the high-risk region (defined vertically between the temporal arcades, nasally by the temporal disc margin, and temporally by disc to fovea distance from the foveal center) in the fellow eye have approximately a 20% risk over a 2–3-year period of developing choroidal neovascularization in the macula of the fellow eye. Patients who do not have macular lesions are at significantly lower risk of developing choroidal neovascularization. However, de novo choroidal neovascularization has been reported in patients with OHS who did not appear to have macular scars.
Reactivation of inflammatory lesions may occur also in patients with OHS. This phenomenon dispels the notion of OHS being a static disease and may explain the development of new lesions and enlargement of old chorioretinal scars in patients with OHS. Patients with reactivation may complain of decreased vision and metamorphopsia. Reactivation usually is not accompanied by vitritis. Clinical examination may demonstrate mild graying of the choroid and/or RPE and thickening of the retina. Fluorescein angiography of reactivated lesions demonstrates progressive leakage with irregular borders without evidence of underlying CNVM. Patients may be treated with systemic itraconazole combined with oral corticosteroids, which also may be used alone. Most lesions improve within 4 to 12 weeks. Choroidal neovascularization only rarely occurs after several months at the site of these reactivated lesions.
Subfoveal choroidal neovascularization generally is associated with a poorer visual prognosis. More than 75% of patients who have subfoveal choroidal neovascularization have visual acuity of 20/100 (6/30) or worse after 3 years. However, up to 14% of eyes with subfoveal choroidal neovascularization may retain visual acuity of 20/40 (6/12) or better if the patient is less than 30 years of age, has small CNVMs, and has no visual loss secondary to OHS in the fellow eye. Patients who are older and who have more than 50% involvement of the foveal avascular zone at the time of diagnosis have a significantly greater likelihood of poorer visual outcomes with subfoveal choroidal neovascularization in OHS.
Spontaneous visual acuity recovery in patients who have central disciform scarring in OHS has been reported only when visual acuity drops to 20/80 (6/24) or worse in the fellow eye. Spontaneous visual recovery occurs more commonly in younger patients and patients who have smaller diameter disciform scars, shorter distances from the foveal center to adjacent normal retina, and shorter intervals of visual loss prior to visual loss in the fellow eye. Such visual acuity recovery also may occur from spontaneous involution of subfoveal choroidal neovascularization in some rare instances.
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