A color fundus photo from young man with a history of intravenous drug abuse with endogenous Aspergillus endophthalmitis shows vitreous haze and a confluent macular lesion with retinal hemorrhages (This image was published in Ophthalmology, Yanoff and Duker, Fungal Endophthalmitis, 735–739, Copyright Elsevier (2013))
In comparison with Candida, Aspergillus more commonly invades retinal and choroidal vasculature. As a result, retinal or choroidal vascular occlusion and exudative retinal detachment may be present with Aspergillus endophthalmitis and account for poorer visual outcomes compared with cases of Candida endophthalmitis .
20.5 Other Fungal Infections
Fusarium is a filamentous mold commonly found on plants and in soil. It is the most common fungal intraocular infection resulting from keratitis with contiguous spread from the ocular surface . During an outbreak of Fusarium keratitis occurring due to one brand of contact lenses from 2004 to 2006, 6 % of the keratitis patients progressed to endophthalmitis . It has also been reported as a rare cause of fungal endophthalmitis following cataract surgery .
Endogenous spread of Fusarium is infrequent, and those cases that have been reported are limited to immunocompromised patients with disseminated fungal infection. In immunocompromised patients, Fusarium may cause sinusitis, pneumonia, and cellulitis at sites of skin breakdown or onychomycosis. Ocular disease typically manifests as a more localized inflammation or fungal mass confined to the anterior chamber or anterior vitreous, but disease can extend to the posterior vitreous in severe cases. While rare, these cases are often severe, presenting with a robust inflammatory reaction in the anterior chamber, vitritis, and varying degrees of retinal ischemia and necrosis  (Fig. 20.2).
A color fundus photo from a 70-year-old female with Fusarium endophthalmitis. Note vitreous haze from vitritis and severe vasculitis. (Courtesy of Lucia Sobrin, MD) (This image was published in Ophthalmology, Yanoff and Duker, Fungal Endophthalmitis, 735–739, Copyright Elsevier (2013))
Histoplasma capsulatum is a thermally dimorphic fungus which grows as a mold in soil and as a yeast in human or animal hosts. When involved in eye infections, it typically affects a relatively young population, usually in the third or fourth decade of life. The fungus is endemic to the Central United States including the Ohio River Valley and Mississippi River Valley. Like many of the other fungal pathogens, its route of inoculation is most commonly through the respiratory tract. Humans usually acquire the infection via inhalation of spores (conidia) from soil that is contaminated with bat or bird droppings. While healthy patients may be asymptomatic, immunocompromised patients present with fever, pancytopenia, hepatosplenomegaly, and oropharyngeal or gastrointestinal lesions. Adrenal, brain, and skin lesions may additionally be seen in these patients . Ocular clinical manifestations include punched-out choroidal scars, peripapillary pigmented degeneration, and macular choroidal neovascularization (CNV) or disciform scarring. The ocular disease is marked by little or no vitreous inflammation. As most cases of ocular histoplasmosis occur in healthy patients who are largely asymptomatic, regular follow-up for the possible occurrence of CNV is required [17, 18].
Histoplasma capsulatum is a very rare cause of endogenous endophthalmitis and when present occurs mostly in immunocompromised patients, such as those with AIDS, causing severe visual loss. Endogenous Histoplasma endophthalmitis is usually characterized by a granulomatous chorioretinitis and rarely by subretinal  and intraretinal exudates and retinal detachment .
Coccidioides immitis is a dimorphic fungus found in dust in the endemic areas of the San Joaquin Valley of California, Arizona, and some parts of Central and South America. Agricultural and construction workers are among those at greatest risk for infection. Infection occurs through the inhalation of spores and in most patients leads to a self-limited disease. However, those patients who are re-exposed to the fungus may develop a chronic respiratory disease .
Coccidioides is a rare cause of endophthalmitis, and when it does cause intraocular infection, spread is hematogenous to the choroid. Cases of acute infection manifest with a multifocal choroiditis with scattered small lesions, vascular sheathing, exudative retinal detachment, and vitritis . Other patients may remain asymptomatic and present only with chorioretinal scars .
Cryptococcus neoformans is an encapsulated yeast causing opportunistic infection in AIDS patients or other severely immunocompromised patients. Pigeons play an important role in its pathogenesis as the Cryptococcus spores survive up to 2 years in pigeon droppings. Human infection is acquired via the respiratory tract through the inhalation of spores. The fungus is then disseminated hematogenously and has a predilection for the central nervous system, most commonly resulting in fungal meningitis . The organism reaches the eye either by direct extension from the optic nerve sheath or via hematogenous spread to the choroid. Ocular cryptococcosis is very rare, manifesting as a multifocal choroiditis with discrete, yellowish white lesions of differing size. Other manifestations include optic nerve edema, vascular sheathing, and exudative retinal detachment .
20.6 Diagnosis of Aspergillus and Other Fungal Infections
Early in the course of fungal infection, clinical manifestations may be subtle and variable, rendering a definitive diagnosis challenging. Therefore, the ability to make a prompt diagnosis of ocular fungal infection relies on a high index of suspicion and an appreciation of any predisposing conditions or risk factors that may make a patient more susceptible to fungal infection.
In the absence of an established source of infection or evidence of fungemia, it is important to obtain blood cultures as well as cultures from multiple sites and bodily fluids, including wounds and catheter tips. Cardiac imaging is recommended to rule out valvular vegetations which may be a source of septic emboli. A vitreous aspirate should be obtained and sent for special stains and culture. While this is the gold standard for the diagnosis of fungal endophthalmitis, the rates of positive cultures from vitreous sampling vary from 40 to 77 % . In general, vitreous samples taken from vitrectomy are more likely to produce a positive culture result compared to an anterior chamber or vitreous tap .
Once a fluid sample has been obtained, most organisms can be identified by direct microscopy. Aspergillus will appear as septate hyphae branching at 45° angles (Fig. 20.3). Several special stains allow for improved visualization of fungal elements. Potassium hydroxide or KOH dissolves human cells and calcofluor white stains the cell wall of the fungi causing them to fluoresce. Both of these stains allow for easier detection of fungal elements. Calcofluor white is particularly useful in cases of fungal endophthalmitis resulting from keratitis . Hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Gomori methenamine silver (GMS) are among the stains used to detect fungi in cytologic preparations . GMS is particularly helpful in cases of intraocular coccidioidomycosis, while India ink and mucicarmine are useful in cases where cryptococcal infection is suspected [21, 24] (Fig. 20.4).
Vitreous biopsy from a patient with Aspergillus endophthalmitis with multiple Aspergillus filaments in undiluted vitreous specimen staining with alcian blue (This image was published in Ophthalmology, Yanoff and Duker, Fungal Endophthalmitis, 735–739, Copyright Elsevier (2013))
Vitreous specimen from 69-year-old male with endogenous cryptococcal endophthalmitis. Note cryptococci staining with alcian blue (This image was published in Ophthalmology, Yanoff and Duker, Fungal Endophthalmitis, 735–739, Copyright Elsevier (2013))
In addition to these various stains, vitreous cultures should always be performed as they may aide in determining the susceptibility to various antifungal agents. More recent studies have shown polymerase chain reaction (PCR) detection of fungal species in vitreous samples to be highly specific and sensitive in the prompt diagnosis of fungal infection .