Presumed Ocular Histoplasmosis Syndrome (POHS) is a chorioretinal disease that occurs secondary to infection with the dimorphic fungus Histoplasma capsulatum, which lives in soil. Clinically, it is defined by a triad: (1) punched-out “histo spots”, (2) peripapillary atrophy (PPA), and (3) absence of vitritis. 1)
Because it is often difficult to culture or histologically confirm the organism from intraocular specimens, the term “presumed” has been used. However, cases with histological confirmation of H. capsulatum by Grocott’s methenamine silver (GMS) staining in acute infection have been reported. 1)
In the United States, the Ohio and Mississippi River valleys are endemic areas, with skin test positivity rates reaching about 60% among residents. However, only about 1.5% of skin test-positive individuals develop ocular lesions. Associations with HLA-DRw2 and HLA-B7 have been reported.
Japan is a non-endemic area, and POHS is treated as an imported infection. Soil contaminated with bird or bat droppings is the main source of infection, and infection occurs through inhalation of spores. 2)
Since Japan is a non-endemic area, POHS is mainly treated as an imported infection in patients with a history of travel or residence in endemic areas. Working in soil contaminated with bird or bat droppings can be a source of infection. 2)
In the stage of only choroidal lesions (histo spots, PPA), there are often no symptoms. When choroidal neovascularization develops, the following symptoms appear.
The characteristic findings of POHS are summarized below.
Histo spots
Definition: Round, punched-out, yellowish-white chorioretinal atrophic spots measuring 0.2 to 0.7 disc diameters.
Distribution: Multiple lesions from the macula to the periphery.
Significance: Macular lesions have a high risk (approximately 25%) of developing choroidal neovascularization and require close follow-up.
Peripapillary Atrophy (PPA)
Definition: Chorioretinal atrophy around the optic disc. One of the important components of POHS.
Choroidal neovascularization risk: The rate of choroidal neovascularization arising from PPA is approximately 4%.
Course: PPA alone often does not affect visual function.
Absence of Vitritis
Characteristic: An important feature of POHS is the absence of active inflammatory signs (vitreous haze, anterior chamber inflammation). 1)
Differential significance: When vitritis is present, other diseases (multiple evanescent white dot syndrome, punctate inner choroidopathy) should be actively differentiated.
Other findings include linear streaks in about 5% of cases. 1) When choroidal neovascularization occurs, hemorrhage, edema, and exudation are observed in the macula, directly causing visual impairment. Bilateral involvement occurs in about 60% of cases.
Many intraocular inflammatory diseases involve inflammatory cell infiltration into the vitreous, but in POHS, choroidal neovascularization occurs through an immunological mechanism after the acute phase of infection has resolved, so active inflammatory signs are absent. This combination of “choroidal atrophy and choroidal neovascularization without inflammation” forms the basis of the triad. 1)
Spores of H. capsulatum are inhaled via the respiratory tract, forming a primary infection focus in the lungs. Subsequently, they disseminate hematogenously throughout the body, reaching the choroid and forming granulomatous lesions. 1)2) Soil contaminated with bird (especially starlings and chickens) or bat feces is the main environmental source of spores. 2)
In immunocompetent individuals, acute pulmonary infection often runs a mild or asymptomatic course. On the other hand, in immunocompromised states such as after kidney transplantation, the risk of systemic dissemination increases, and extraocular lesions (e.g., conjunctival lesions) may occur. 2)
Risk factors for choroidal neovascularization associated with POHS are as follows.
There is no specific test for a definitive diagnosis of POHS; diagnosis is based on a combination of clinical findings.
The main tests and their characteristic findings are summarized below.
| Test | Characteristic Findings |
|---|---|
| Fluorescein Angiography (FA) | Window defects in atrophic spots, early staining of CNV1) |
| Optical Coherence Tomography (OCT) | Bruch’s membrane rupture, outer retinal atrophy, CNV morphology assessment1) |
| OCT Angiography (OCT-A) | Noninvasive evaluation of microvascular structure of CNV |
POHS has no single definitive test; diagnosis is based on the clinical triad (histo spots, PPA, absence of vitritis). Travel history to endemic areas and serological tests are used as adjuncts. In acute infection, biopsy with GMS staining to identify organisms may confirm the diagnosis. 1)
Treatment for POHS is indicated when CNV develops. In the absence of CNV, histo spots or PPA alone are managed with observation.
Currently, intravitreal anti-VEGF agents (VEGF inhibitors) are the first-line treatment for CNV. Multiple reports demonstrate efficacy; a study of 54 eyes with POHS-related CNV showed mean visual acuity improvement from 20/53 to 20/26.
Additionally, the HANDLE trial using aflibercept reported a mean gain of 19 letters in visual acuity with PRN (pro re nata) dosing.
The main anti-VEGF drugs used are as follows.
For extrafoveal lesions, laser photocoagulation based on the results of the Macular Photocoagulation Study (MPS) is an option. The MPS trial reported that laser treatment reduced the incidence of severe vision loss (6 or more lines) from 44% to 9%. However, it is not indicated for foveal lesions.
Photodynamic therapy may be used for subfoveal CNV. Reports indicate visual improvement in approximately 45% of cases. Since the advent of anti-VEGF drugs, PDT alone is less commonly used as a first-line treatment.
Antifungal agents (such as itraconazole) are ineffective for ocular lesions of POHS and are not used as standard treatment. This is because the ocular lesions are primarily due to immunological mechanisms rather than direct infectious invasion (see Pathophysiology). Systemic antifungal treatment may be required separately for disseminated histoplasmosis in immunocompromised patients. 2)
The main hypothesis regarding the pathogenesis of POHS is the sequence proposed by Gass: infection → granuloma formation → spontaneous elimination → scarring → hyperimmune response → CNVM formation. 1)
Evidence supporting the validity of the Gass hypothesis includes a case report of a 17-year-old immunocompetent male with acute choroidal lesions in whom OCT showed a Bruch’s membrane defect and GMS staining identified H. capsulatum. 1) Additionally, detection of Histoplasma DNA from POHS lesion tissue by Spencer et al. supports a direct link between infection and lesions. 3)
Granulomatous inflammation of the choroid causes breaks in Bruch’s membrane (the basement membrane complex beneath the retinal pigment epithelium). Through these breaks, choroidal neovascular buds invade the subretinal space, forming CNV. Plasma leakage and hemorrhage from CNV cause macular edema and exudation, leading to visual impairment.
CNV in POHS occurs not during the acute phase of infection but as a hyperimmune response after the infection has been eliminated. This explains why antifungal drugs are ineffective for ocular lesions. On the other hand, immunocompromised states (e.g., after kidney transplantation) increase the risk of direct progression of infection. 2) In conjunctival histoplasmosis after kidney transplantation, fungal elements have been confirmed by KOH, calcofluor, and Giemsa staining. 2)
Janetos et al. (2023) confirmed OCT findings of Bruch’s membrane penetration in acute choroidal lesions of a 17-year-old immunocompetent male, and histologically identified H. capsulatum by GMS staining. 1) Antifungal therapy with IV amphotericin B followed by itraconazole was administered, and after 6 months, atrophic scarring and improvement to 20/20 vision were observed. Combined with Spencer et al.’s detection of Histoplasma DNA, this report is noted as direct support for the Gass hypothesis. 3)
The HANDLE trial is a prospective study evaluating PRN (as-needed) dosing of aflibercept for POHS-related CNV, reporting favorable outcomes with a mean visual acuity improvement of 19 letters. It provides important evidence for optimizing anti-VEGF therapy protocols.
OCT-A is a technology that non-invasively visualizes the microvascular structure of CNV without fluorescein angiography. Its application to activity assessment and treatment response evaluation of POHS-related CNV is advancing, and it is expected to contribute to individualized treatment strategies.
