Introduction
Fungal infections of the cornea are relatively infrequent in the developed world but cause a large proportion of keratitis in many parts of the developing world. Although these infections can cause devastating damage if allowed to progress unchecked, advances in antimicrobial therapy and surgical technique have improved their prognosis. Recognition and prompt, aggressive therapy of fungal infections are extremely important.
Epidemiology and Pathogenesis
Fungi are ubiquitous organisms that are recognized more frequently as ocular pathogens in agrarian, tropical countries than in the developed world. For clinical purposes, fungi can be classified on a morphological basis into filamentous, yeast, and diphasic forms. Filamentous organisms are multicellular with branched hyphae. Septate filamentous organisms, such as Fusarium and Aspergillus , have hyphae that are divided by cell walls. Other filamentous fungi, including Mucor and Rhizopus , are nonseptate. Septate filamentous fungi can be further divided into nonpigmented hyaline species (e.g., Fusarium , Aspergillus ) and pigmented dematiaceous species (e.g., Alternaria , Curvularia ). Yeasts, such as Candida and Cryptococcus , are unicellular fungi that reproduce by budding, but in tissue, they might develop elongated buds (pseudo-hyphae) or real hyphae. Dimorphic fungi, such as Histoplasma , Coccidioides , and Blastomyces , demonstrate both a yeast phase that occurs in tissues and a mycelial phase that appears on culture media and saprophytic surfaces.
The incidence of fungal keratitis in the United States has historically been quite low, but rates of Fusarium keratitis increased dramatically in the mid-2000s because of an epidemic related to a contact lens solution. Although the rate of Fusarium keratitis decreased after the solution was withdrawn from the market, microbiology laboratories have continued to detect elevated numbers of filamentous fungi. Fungal keratitis is more common in tropical climates. In these areas, septate filamentous fungi, most notably Fusarium and Aspergillus , are the most common causative organisms. In contrast, Candida is the predominant cause in more temperate climates.
The risk factors associated with fungal keratitis depend on the setting. In the tropics, corneal trauma, which might be trivial, frequently precedes infection. Concurrent contamination with plant material presents an increased risk for fungal keratitis. However, in colder climates, where Candida infections predominate, fungal infections are more commonly seen in patients with corneal pathology or with an ocular surface that is locally immunosuppressed by chronic corticosteroid use or systemic disease.
Clinical Features
Fungal infection tends to arise in traumatized, diseased, and immunocompromised corneas. The keratitis tends to be slowly progressive and insidious, but rapid infiltrate development does not rule out fungal infection. In some cases, the epithelium might heal over an intrastromal infiltrate that produces little inflammation and minimal discomfort. Conversely, inflammation might be so severe as to result in satellite lesions and hypopyon formation. The ulcer and infiltrate itself can assume protean appearances and might be indistinguishable from a bacterial ulcer. However, certain features suggest a filamentous fungal infection, including feathery edges or a dry, gray, elevated infiltrate and satellite lesions ( Fig. 4.13.1 ). Compared with other fungal pathogens, Aspergillus may be more likely to have a ring infiltrate, and dematiaceous fungi may be more likely to have a pigmented or raised infiltrate. Although a ring infiltrate and endothelial plaque are suggested as indicators of fungal keratitis, many cases do not demonstrate these features, which merely reflect corneal and anterior chamber inflammation.
Diagnosis
A high level of suspicion for nonbacterial keratitis must be maintained at all times, especially in those areas where the incidence of fungal keratitis is relatively high ( Fig. 4.13.2 ). Important historical elements include preexisting corneal disease, chronic corticosteroid use, trauma, contact lens wear, and recent surgery, including laser-assisted in situ keratomileusis (LASIK).
Definite diagnosis requires laboratory confirmation. Scrapings for stains and culture should be obtained as described for bacterial keratitis. If fungal infection is suspected after LASIK, the flap must be elevated to obtain samples. Smear diagnosis is primarily made with Giemsa or ink-potassium hydroxide stains, though fungal elements are also visible on Gram stain ( Fig. 4.13.3 ). Gomori’s methenamine silver stain is generally considered the stain that best demonstrates fungal organisms.
Culture media used to demonstrate fungal growth include Sabouraud’s agar, potato dextrose agar, and brain–heart infusion broth, although many fungi will grow on blood agar kept at room temperature. Most ocular fungal isolates demonstrate growth within 2–3 days, although it is prudent to wait 2 weeks before confirmation of no growth. Fungal susceptibility criteria are poorly standardized and not performed at most laboratories.
Corneal scrapings can be investigated with polymerase chain reaction techniques that target a common fungal ribosomal RNA (rRNA), although the high sensitivity of these methods carries the risk of false positives because of contamination, either at the site of corneal scraping or in the laboratory.
In vivo confocal microscopy can be used to detect fungal hyphae and is particularly useful for diagnosis of deep infections that cannot easily be scraped. Fungal filaments appear as highly reflective double-walled structures measuring between 3 and 8 µm.
Since some cases of keratitis may develop deep in the stroma with intact overlying corneal tissue, a deep corneal biopsy might be necessary to obtain tissue for laboratory studies ( Fig. 4.13.4 ).
Differential Diagnosis
For the differential diagnosis of fungal keratitis, see Box 4.12.1 . As a result of indolent progression and failure to respond to antibacterial medication, fungal keratitis often is misdiagnosed as herpetic or amebic disease. Fungal infection following LASIK must be differentiated from the sterile interface infiltration of post-LASIK diffuse lamellar keratitis and from infection caused by bacterial species.
Pathology
Destructive fungal infection is advanced by organism adherence, invasion, growth, and subsequent damage caused by direct toxicity and host response. The mycelia of filamentous organisms tend to extend along the corneal lamellae, whereas more virulent organisms can cross lamellae and even penetrate Descemet’s membrane, leading to intracameral infection. The inflammatory host response is similar to that described in bacterial infection, with both mycotic and host factors leading to an inflammatory cell infiltrate, necrosis, and neovascularization.
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