Presumed ocular histoplasmosis syndrome

Presumed ocular histoplasmosis syndrome is a chorioretinal disorder characterised by small peripheral atrophic scars, peripapillary atrophy, and macular choroidal neovascularisation in people who have lived in or travelled to regions where Histoplasma capsulatum is endemic

The adjective presumed reflects the fact that the diagnosis is inferred from a characteristic fundus picture and an exposure history, because the fungus is almost never cultured from the eye

Most affected people are asymptomatic and retain good vision, but a minority develop choroidal neovascularisation that can cause sudden metamorphopsia, scotoma, and permanent central visual loss if untreated

Terminology and classification

• Presumed ocular histoplasmosis syndrome is classified among the inflammatory chorioretinal disorders, although its infectious versus immune-mediated nature is still debated
• The clinical triad comprises multiple small, round, punched-out peripheral atrophic scars known as histo spots, peripapillary atrophy, and a macular lesion that is usually choroidal neovascularisation
• The condition is distinct from active disseminated or pulmonary histoplasmosis, which requires antifungal therapy and is diagnosed by culture, antigen testing, or serology
• ICD-10-CM previously provided the single code 115.92 for histoplasmosis retinitis, but this code was retired and ophthalmologists now report B39.9 for histoplasmosis together with H32 for chorioretinal disorders in diseases classified elsewhere
• Wikidata maps the entity to Q81430268, and the term ocular histoplasmosis syndrome is used interchangeably in the American and British literature
• Some authors regard the syndrome as part of the multifocal choroiditis spectrum rather than a distinct disease, a controversy that affects coding, trial design, and the interpretation of prevalence data

History

• Woods and Wahlen proposed the concept of presumed ocular histoplasmosis in 1959, linking characteristic choroidal scars in endemic-area residents to prior, often subclinical, histoplasma infection
• During the 1960s and 1970s, fluorescein angiography allowed clinicians to distinguish inactive histo spots from active choroidal neovascularisation and to document leakage
• Population surveys in the Ohio and Mississippi River valleys during the 1960s and 1970s found high rates of histoplasmin skin-test positivity and established the geographic distribution of the disease
• Indocyanine green angiography, introduced in the 1990s, improved the detection of occult choroidal neovascular membranes that were invisible on fluorescein angiography
• Optical coherence tomography, adopted in the 2000s, transformed the monitoring of subretinal fluid, intraretinal fluid, and macular fibrosis in treated and untreated eyes
• The anti-VEGF era began in 2006, when intravitreal ranibizumab and subsequently aflibercept and bevacizumab were shown to reduce leakage and improve or stabilise vision in histoplasmosis-related choroidal neovascularisation

Epidemiology

• The syndrome is most frequently reported in the Ohio and Mississippi River valleys of the United States, including parts of Missouri, Illinois, Indiana, Kentucky, Tennessee, Arkansas, and Ohio
• Histoplasmin skin-test surveys in these endemic areas have found positivity rates exceeding 80% in adults, indicating widespread prior exposure to the fungus
• Typical peripheral histo spots are far less common than skin-test positivity, and surveys in endemic communities have identified them in roughly 1% to 5% of adults
• Most people with histo spots never develop choroidal neovascularisation, and the proportion who do is estimated at a small minority, although estimates vary widely between clinic-based and population-based studies
• Choroidal neovascularisation usually presents between 20 and 50 years of age, decades after the initial exposure, and both sexes are affected approximately equally
• Bilateral involvement is common in patients who develop choroidal neovascularisation, and the fellow eye requires lifelong surveillance because a second lesion may appear years later
• The syndrome is also reported in Mexico, Central and South America, parts of Africa, and Asia, but it is under-recognised where histoplasmin testing is not routine
• Because the diagnosis is clinical and coded with two separate ICD-10-CM codes, administrative datasets underestimate incidence and cannot reliably track trends over time

Pathophysiology

• The prevailing model holds that inhaled Histoplasma capsulatum yeasts disseminate haematogenously during a transient fungemia and leave antigenic debris in the choroid, where a delayed hypersensitivity response produces small granulomatous lesions
• These lesions heal as the punched-out atrophic scars recognised clinically as histo spots, and similar inflammation adjacent to the optic nerve head produces peripapillary atrophy
• Choroidal neovascularisation arises when chronic low-grade inflammation and Bruch membrane disruption allow abnormal vessels to grow beneath the retina, driven by vascular endothelial growth factor
• The vitreous remains clear and there is no anterior segment inflammation, which is a key point that separates the syndrome from sarcoidosis, tuberculosis, and toxoplasmosis
• The fungus is not recoverable from aqueous or vitreous specimens in most cases, and the disease is therefore regarded as a post-infectious immunological sequela rather than a chronic active infection
• Reported associations with HLA-DR2 and DRB104 suggest that host immunogenetic factors influence which exposed individuals develop clinically significant lesions, but the associations are inconsistent across populations

Clinical features

• Most patients are entirely asymptomatic, and the characteristic scars are discovered during routine fundoscopy or screening for another ophthalmic condition
• When choroidal neovascularisation develops, patients report sudden central metamorphopsia, a positive scotoma, reduced reading acuity, or distorted straight lines
• Fundoscopy shows multiple small, round, yellowish-white or pigmented atrophic spots scattered in the mid-periphery, often with a pigmented halo, and peripapillary atrophy around the optic disc
• The macular lesion appears as a grey-green subretinal membrane, often with subretinal fluid, subretinal haemorrhage, or a disciform scar in late stages
• The anterior segment and vitreous are quiet, and there is no vitritis, which helps distinguish the syndrome from uveitic entities that produce similar chorioretinal scars
• Complications include recurrent or persistent choroidal neovascularisation, disciform scarring, central visual loss, and in a minority, development of a lesion in the fellow eye

Diagnosis

• Diagnosis is clinical and requires the combination of characteristic fundus findings, a history of residence or travel in an endemic area, and exclusion of other causes of multifocal chorioretinal scars
• Fluorescein angiography shows early hypofluorescence of inactive scars and late staining, whereas active choroidal neovascularisation shows early hyperfluorescence with leakage into the subretinal space
• Optical coherence tomography is essential for detecting subretinal fluid, intraretinal fluid, pigment epithelial detachment, and for monitoring response to treatment
• Indocyanine green angiography may reveal occult neovascular membranes and help distinguish the syndrome from other inflammatory chorioretinopathies when the diagnosis is uncertain
• Serology, antigen testing, and cultures are usually negative or unhelpful in presumed ocular histoplasmosis syndrome, and positive results would suggest active rather than presumed disease
• The differential diagnosis includes multifocal choroiditis with panuveitis, sarcoidosis, tuberculous choroiditis, toxoplasmosis, age-related macular degeneration, myopic choroidal neovascularisation, and angioid streaks
• The American Academy of Ophthalmology Preferred Practice Pattern for choroidal neovascularisation and NICE technology appraisal TA155 provide the framework used in many centres for investigating and treating neovascular macular disease

Management

• Asymptomatic histo spots and peripapillary atrophy require no treatment, only baseline documentation with widefield fundus photography and optical coherence tomography
• Active macular choroidal neovascularisation is treated with intravitreal anti-VEGF agents, most commonly ranibizumab, aflibercept, or bevacizumab, given as loading injections followed by treat-and-extend or pro re nata regimens
• Photodynamic therapy with verteporfin is an alternative for selected lesions, particularly those with a small classic component or those that respond poorly to anti-VEGF injections
• Focal laser photocoagulation may be considered for small, well-defined extrafoveal neovascular membranes, but it is unsuitable for subfoveal or juxtafoveal lesions because it destroys central retina
• Intravitreal corticosteroids such as triamcinolone acetonide are used occasionally as adjuncts for persistent inflammation, but they carry risks of cataract, ocular hypertension, and infection
• Systemic antifungal drugs are not indicated because the disease is a post-infectious immunological process and there is no evidence of active fungal replication in the eye
• Patients with unilateral choroidal neovascularisation need lifelong monitoring of the fellow eye, with home Amsler grid testing and periodic optical coherence tomography to detect early asymptomatic lesions
• Visual prognosis has improved substantially with anti-VEGF therapy, and many treated eyes maintain or regain reading vision, although recurrences and disciform scarring still cause long-term impairment in a substantial minority

Research and controversies

• Whether Histoplasma capsulatum is truly the cause of the syndrome, or merely a marker of exposure in a susceptible host, remains unresolved after more than six decades of investigation
• A study of the MICA gene found no association with presumed ocular histoplasmosis syndrome, undermining earlier suggestions that major histocompatibility complex variation explains susceptibility
• The boundary between the syndrome and multifocal choroiditis with panuveitis is contested, and some authors propose that many cases labelled as presumed ocular histoplasmosis are better classified as idiopathic multifocal choroiditis
• The optimal anti-VEGF agent, dosing interval, and duration of treatment for histoplasmosis-related choroidal neovascularisation have not been tested in dedicated randomised trials, so practice is extrapolated from neovascular age-related macular degeneration
• Geographic variation in exposure, diagnostic thresholds, and coding practice makes international comparison of incidence and outcomes difficult, and prospective population-based registries are needed