Background
Presumed ocular histoplasmosis syndrome (POHS) is a distinct clinical entity that is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy. [1] Vitritis typically is absent. 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.
Epidemiologic findings link the fungus to this condition. Based on skin tests in the United States, a similar geographic distribution of the fungal infection and POHS exists. Histoplasmin skin testing may exacerbate the ocular condition. Visual loss in POHS is secondary to the development of macular choroidal neovascularization (CNV).
Pathophysiology
H capsulatum is a dimorphic pathogenic fungus that often grows in soil around old chicken houses and areas harboring bats, such as caves. Large numbers of spores are dispersed into the air when contaminated soil is disturbed (eg, spelunking, raking). Exposure occurs when spores are inhaled.
In a normal host, the initial infection usually is 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. A focal granulomatous choroiditis is thought to occur. This phase seldom is observed in humans.
In an experimental nonhuman primate model, inoculation of the organism via the carotid artery results in an active choroiditis. These foci are observed as discrete, round, yellowish choroidal lesions. Six weeks after inoculation of the organisms, isolating the organisms by any histologic techniques was not possible. The inflammatory response probably destroyed the invading organisms. With time, the lesions resolve, leaving the typical "punched-out" atrophic scars that disrupt the Bruch membrane (see Physical). Reexposure to the histoplasmin antigen may account for the enlargement of old scars and the emergence of new scars.
Visual loss in POHS is secondary to the development of CNV. Pigment epithelium derived factor (PEDF) was found to have an inhibitory effect on ocular neovascularization. Another peptide, vascular endothelium growth factor (VEGF), is a well-known ocular angiogenic factor. The balance between antiangiogenic factors (eg, PEDF) and angiogenic factors (eg, VEGF) may determine the growth of CNV. This CNV usually grows in the subretinal space in a sheetlike fashion, not in the sub–retinal pigment epithelium (RPE) space. As the CNV grows, reactive hyperplastic RPE tries to surround and envelop the CNV. If successful, the CNV usually involutes.
Why CNV arises is unclear. Based on a case of a pregnant patient who developed a macular detachment during the third trimester, some propose that a type of vascular decompensation caused the CNV. [2] A lymphocytic choroidal infiltrate usually is found near histo spots. Some hypothesize that an allergic reaction to Histoplasma antigens is an important stimulus for CNV growth. A few propose that the infectious granuloma secondary to the fungus is responsible for CNV growth. Others state that damage to the Bruch membrane by itself is a strong stimulus for CNV.
Epidemiology
Frequency
United States
Presumed ocular histoplasmosis syndrome occurs in endemic areas of the United States, including the Ohio and Mississippi River Valleys (Indiana, Ohio, Illinois, Kentucky, Tennessee, and Mississippi) and parts of the mid-Atlantic region (Maryland, West Virginia, and Virginia). Approximately 200,000-500,000 new infections occur annually. [3]
In an endemic area, 90% of patients with POHS had a positive histoplasmin skin test. In Maryland, 4% of those infected with histoplasmosis had POHS. [4, 5, 6]
The incidence rate was 1.35/100,000, the prevalence rate was 0.064%, and macular neovascularization ocurred in 17.4% of eyes in Olmsted county in Minnesota during 2006-2015. Furthermore, 16.8% of the affected eyes had a visual acuity of < 20/40. [7]
Peripheral atrophic scars were present in 2% of people living in endemic areas; disciform scars were found in 0.1% of people. [8]
A clinical entity indistinguishable from POHS has been reported in a series of 10 patients from a nonendemic area, the Pacific Northwest. These patients tested negative to a lymphocyte stimulation assay with H capsulatum. Unlike series from the Midwest, all patients were female; 50% of them were myopic. The authors speculate that an atypical mycobacteria might be responsible for this entity. [9]
International
H capsulatum is endemic in the Caribbean, Central America, and South America. No reports of POHS from these areas have appeared in the literature. However, certain areas of India are endemic for systemic histoplasmosis. [10] Three cases of POHS recently were described in India. [11]
Patients with clinical findings indistinguishable from POHS have been reported in areas where H capsulatum is not found. These reports suggest that other agents can cause similar fundus findings as POHS. In the Netherlands and the United Kingdom, a clinical syndrome indistinguishable from POHS has been described. In the Dutch series by Suttorp-Schulten et al, a large number of female and myopic patients were reported. [12] Given that H capsulatum is not found in Europe, some European colleagues have proposed to change the name from POHS to multifocal choroidopathy. Other cases from Brazil and Morocco have also been described. [13, 14]
Mortality/Morbidity
POHS is an uncommon cause of visual loss.
The incidence and the prevalence in the blind population in Tennessee were reported to be 2.8% and 0.5%, respectively.
Race
Histoplasmin skin testing reveals that African Americans and Caucasians living in endemic areas are infected equally by H capsulatum. No difference is apparent between the prevalence of peripheral histo spots between these 2 groups. Caucasian patients are more likely than African Americans to develop macular CNV.
Some reports suggest an increased prevalence of POHS in patients with human leukocyte antigen B7 (HLA-B7) and human leukocyte antigen DRw2 (HLA-DRw2). Patients with HLA-DRw2 are more likely to have peripheral histo spots and disciform scarring, whereas patients with HLA-B7 are more likely to have peripheral histo spots.
Sex
No apparent gender predilection exists in the Midwest and the mid-Atlantic series according to Smith et al. [15]
In the series from the Netherlands by Suttorp-Schulten et al and in the series from the Pacific Northwest by Watzke et al, women seemed to be affected to a greater degree. [9, 12]
Age
Presumed ocular histoplasmosis syndrome usually affects patients aged 20-50 years; the average age is 35 years.
Prognosis
The average interval from the onset of symptoms between the first eye and the fellow eye was 4 years. According to the MPS, a 2% per year risk of developing CNV in the fellow eye exists. The risk depends on whether the fellow eye has peripapillary scarring (4% risk) or a macular atrophic spot (20-24% risk). [16]
The visual prognosis for patients with POHS depends on the development of CNV and its location with respect to the center of the fovea.
The MPS has shown that after 5 years of follow-up care, 12% of eyes with extrafoveal CNV that were photocoagulated had severe visual loss (loss of 6 lines or more) compared with 42% of eyes that were observed. [16, 17]
Of eyes with juxtafoveal CNV, 12% had severe visual loss compared with 28% of eyes that were observed. [18]
In the MPS, photocoagulation of peripapillary CNV reduced severe visual loss from 26% of control eyes to 14% of treated eyes.
Pilot studies of photocoagulation of subfoveal CNV by Fine et al were inconclusive. [19] The natural history of untreated subfoveal CNV shows that 14-23% of patients retain 20/40 or better visual acuity. Eyes with subfoveal CNV undergoing surgical excision were more likely to gain 20/40 if the preoperative vision was 20/100 or better. [20]
Patient Education
Once diagnosed with a maculopathy secondary to POHS, the patient is asked to self-monitor each eye with a near card and an Amsler grid.
If a disturbance is detected, prompt examination is encouraged.
