Contributor: Gordon K Klintworth
A wide variety of fungi are known to cause human disease and in many of these infections the ocular tissues may be involved. Factors predisposing to ocular fungal infection include penetrating ocular trauma (especially with plant, wood and vegetable matter), iatrogenic instrumentation, intravenous catherization, intravenous drug abuse, contaminated irrigating solutions or prosthetic devices (such as contact lenses, punctal occlusive plugs, aqueous shunt tubing, intraocular lenses), and scleral buckling materials, defective operating room air control, topical or systemic corticosteroids and other immunosuppressive agents, the treatment of local corneal diseases with topical antibiotics and corticosteroids, cataract extraction with excessive instrumentation, and keratoplasty with contaminated donor storage media). Fungal infections of the eye and its adnexa most often involve the cornea [keratitis - fungal].
Some fungi affecting the eye and orbital tissue have characteristic geographic distributions based on the environmental living conditions of the pathogen. Aspergillosis occurs more commonly in areas-with a hot, humid climate. Coccidioidomycosis is endemic in the Southwestern region of the United States, in Northwestern and Central Mexico, Venezuela, and in the Gran Chaco Plain of South America. Blastomycosis is found most frequently in the Southeastern United States, but also occurs in other areas of the United States, Canada, and Africa. Histoplasmosis due to Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys and the Appalachian Mountains in the United States. Histoplasmosis due to Histoplasma duboisii is found in Nigeria [Histoplasmosis duboisii].
A warm, moist climate and a rural agricultural environment exposes healthy eyes to fungi causing fungal keratitis [keratitis - fungal]. The pathogens differ strikingly within different geographic areas and fungal keratitis occurs infrequently in northern latitudes.
Airborne fungi belonging to the Zygomycetes, settle in the paranasal sinuses and readily enter the orbital tissues causing severe disease [zygomycosis] in susceptible hosts such individuals with diabetes mellitus, who are poorly controlled. Other fungal diseases that may affect the ocular tissues include sporotrichosis, cryptococcosis and rhinosporidiosis.
Some fungi affecting the eye and orbital tissue have characteristic geographic distributions based on the environmental living conditions of the pathogen. Aspergillosis, which may involve the orbit, for example, occurs more commonly in areas with a hot, humid climate. Coccidioides immitis is endemic in the Southwestern region of the United States, in Northwestern and Central Mexico, Venezuela, and in the Gran Chaco Plain of South America. Blastomyces dermatitidis (Ajellomyces dermatitidis), the causative agent of North American blastomycosis, is found most frequently in the Southeastern United States, but also occurs in other areas of the United States, Canada, and Africa. Histoplasma capsulatum (Emmonsiella capsulata) is endemic to the Ohio and Mississippi River valleys and the Appalachian Mountains in the United States causes a characteristic ocular syndrome (ocular histoplasmosis syndrome) in regions where it is endemic. Histoplasma duboisii is found in Nigeria.
Fungal keratitis is common and can be caused by more than 35 genera of fungi (including Aspergillus, Blastomyces dematitidis, Candida, Cephalosporium, and Fusarium). The causative agents vary with the geographic locale. Fungal keratitis is usually caused by saprophytic fungi in the setting of corneal trauma and an altered host resistance. Many cases follow prior treatment with antibiotics and topical corticosteroids. The clinical presentation of fungal keratitis is often identical to that of bacterial keratitis. A red painful eye is associated with photophobia, tearing, a mucopurent discharge, a foreign body sensation and decreased vision. A dense stromal infiltrate is present on examination. In contrast to bacteria fungi can not only infiltrate through the corneal stroma, but even penetrate Descemet's membrane to reach the anterior chamber. When this happens iritis, hypopyon and an endothelial plaque can become evident and the corneal perforation may occur. Because fungal keratitis is less common than bacterial keratitis, ophthalmologists usually treat corneal ulcers initially on the assumption that they are due to bacteria.
FROM PBOD c10
In a large series of suspected infectious keratitis from South Florida, fungi were recovered from 35% of patients from corneal scrapings. Fusarium solani was isolated in 57% of the cases, nonpigmented fungi in 21%, pigmented fungi in 15%, and yeasts in 10% of the cases. In contrast, from a large series from New York City, fungi were recovered from only 1% of cases of suspected microbial keratitis and were principally Candida sp. with infrequent examples due to Fusarium and one isolate was Cryptococcus. In a series of 19 cases from a ten year period in Minnesota, Candida sp. were isolated in 6, Aspergillus in 6, Alternaria in 4, and Fusarium in 3. Fusarium sp. are ubiquitous in air, soil, and organic waste and is the major fungal corneal pathogen in the southern United States . Fusarium solani is the single most common isolate and has been reported throughout the world. F. solani produces several complex toxins and destructive enzymes, which may result in severe, suppurative keratitis.
Aspergillus also produces various toxins. It may be the most common cause of fungal keratitis worldwide .
Corneal ulceration may also be caused by the action of proteolytic enzymes from Cephalosporium sp. This fungus is one of several agents causing suppurative skin lesions. Cephalosporium has been implicated in cases of post-surgical fungal endophthalmitis.
Candida is a ubiquitous yeast not directly linked to environmental factors for ocular infections as with the filamentous fungi. It is an extreme opportunist causing keratitis in eyes with predisposing alterations in host defenses including keratitis sicca, exposure keratitis, post-keratoplasty, viral keratitis, and with chronic corticosteroid usage. Trauma or environmental and agricultural exposures are not necessary factors in the pathogenesis of candidal keratitis. Candida is the most common ocular fungal pathogen, also causing diseases of the eyelids, conjunctiva, lacrimal drainage system, and retina.
Filamentous organisms usually infect normal eyes of healthy individuals who have sustained mild abrasions to the corneal epithelium typically with plant or vegetable matter. No other predisposing ocular or systemic immunologic diseases nor exogenous immunosuppressive therapy are required to establish filamentous fungal infections. In contrast, Candida and other yeasts cause opportunistic keratitis in compromised corneas of immunologically incompetent individuals.
The pathogenesis of the inflammatory reaction in fungal infections includes multiple factors including replicating and non-replicating fungi, mycotoxins, proteolytic enzymes, and soluble fungal antigens. Although many mycotoxins have been isolated from numerous fungi and yeasts, the precise role of them in corneal disease has not been fully elucidated. The severity of fungal keratitis varies due to the destructive potential of specific fungi. Fusarium causes a rapidly destructive keratitis while the less virulent Cephalosporium, Allescheria, Aspergillus, Penicillium, and Phialophora cause a more indolent keratitis. Fusarium has the ability to replicate at 35oC and releases a potent mycotoxin. The large hyphae escape phagocytic ingestion by neutrophils and may penetrate the stromal lamellae, as well as extend through Descemet's membrane into the anterior chamber.
The adverse effects of Candida and other yeasts may result from release of a proteolytic enzyme causing lysis of host cells. Yeasts may also transform from blastospores to a pseudohyphae and prevent effective phagocytosis by neutrophils.
The use of topical corticosteroids or other immunosuppressive agents, potentiates the invasive properties and virulence of fungi.
The salient clinical features of fungal keratitis are well described. The corneal surface typically appears gray or dirty-white with a dry, rough texture. Although such an appearance in the cornea is highly suggestive of a fungal infection, the specific pathogen can not be predicted. The margins are delicately irregular with feathery-like extensions beneath the intact epithelium into adjacent stroma. Focal areas of stromal infiltration or "satellite lesions" may exist apart from the central area corresponding to microabscesses.
Additional clinical features of fungal keratitis include conjunctival hyperemia, endothelial plaque formation with deposition of fibrinous material and neutrophils that may accumulate into hypopyon. The inflammatory reaction within the cornea may be less marked than in bacterial keratitis. Fungi tend to invade the corneal stroma and sometimes align in parallel to the lamellae of the collagen. The infection may produce extensive necrosis of the infected tissue as with certain strains of Fusarium and Cephalosporium due to the elaboration of proteolytic enzymes. The ability of hyphae to penetrate deeper layers of the corneal stroma accounts for frequent failure of lamellar keratectomy in the treatment of fungal keratitis.
Less commonly, an immune ring may be the principle clinical feature and mimic Herpes simplex keratitis or Acanthamoeba keratitis. Yeast keratitis typically occurring in the setting of a compromised cornea more closely resembles bacterial keratitis. In chronic cases there may be considerable necrosis with suppurative stromal inflammation and features indistinguishable from bacterial keratitis.
Superficial diagnostic corneal scrapings may fail to disclose organisms on microscopic examination in advanced fungal keratitis because hyphae are often absent in the superficial stroma. In deep fungal keratitis, a superficial keratectomy with deep corneal biopsy may be necessary to obtain diagnostic material. If neither scrapings nor keratectomy reveal the causative organisms, anterior chamber paracentesis for diagnostic smear and fungal culture have been suggested for deep mycotic keratitis. Gram and giemsa stains may be ineffective in detecting fungal elements on diagnostic corneal scrapings. In addition to the periodic acid-Schiff stain and the most specific Gomori methenamine silver stain, fluorescent dyes (calcofluor white and acridine orange) and an ink-potassium hydroxide preparation may be effective in distinguishing fungal elements on corneal smears.
Fungal culture with specific media should be performed in all cases of suspected mycotic keratitis. Most causative fungi readily grow within 48-72 hours. Certain pathogenic fungi may take as long as seven days to grow and some as long as two weeks. It is usually recommended that cultures be maintained for a period no less than 21 days. Most fungal pathogens readily grow on blood agar at 35oC, but Sabouraud's agar with gentamicin and without cycloheximide at room temperature is considered the most sensitive medium for the isolation of fungi.
A warm, moist climate and a rural agricultural environment may influence the sensitivity of healthy eyes to fungi and fungal infections. Fungal keratitis is infrequent in northern latitudes. In the United States, Aspergillus, Candida, Cephalosporium and Fusarium are the most frequently isolated genera. Many fungi are ubiquitous in air, soil, and organic waste. Fusarium sp. is the predominant cause of fungal keratitis in the southern United States.
The airborne fungi belonging to the Zygomycetes, settle in the paranasal sinuses and readily enter the orbital tissues causing severe disease in susceptible hosts such as poorly controlled diabetics.
The conjunctiva, eyelid or intraocular tissues may become locally infected by Sporothrix schenckii, a saprophyte found on plants, green vegetables, and grass. Ocular sporotrichosis has generally been a localized infection and this fungus rarely causes systemic disease after entering the body at a site of injury. Crytococcosis that may be aquired from pigeon droppings and unpasterized cow's milk can affect the eye.
Rhinosporidiosis, caused by the enigmatic Rhinosporidium seeberi most often involves the nasal mucosa producing vascularized polyps. The conjunctiva may also be affected. The disease has been detected in most countries except Australia and New Zealand, but is most prevalent in India and Sri Lanka. The mode of transmission of the etiologic agent, which has been neither grown in culture nor transmitted experimentally, remains unknown, but the handling of infected horses, cattle, pets, and other animals has been implicated. Water and dust are also suspected of spreading this noncontagious disease. A recent provocative review suggests that the disease is not due to fungus, but a storage disease due to the defective degradation of ingested tapioca.