Medically important fungi are classified into three principal types based on macroscopic properties: filamentous fungi or molds, which produce cottony, feathery, or powdery aerial growth above culture media; yeasts, which produce creamy, opaque, pasty colonies on the surface of culture or media; and dimorphic fungi, which exhibit properties of yeasts when cultivated at 37°C and molds when grown at 25°C to 30°C.¹ Filamentous fungi are multicellular microorganisms joined together to produce tubelike filaments or hyphae. Filamentous fungi can be subdivided into septate (hyphate) organisms, which produce cross-walls or septa behind the tip of the growing hyphae during elongation, and nonseptate organisms, which do not form cross-walls. Septate fungi are either nonpigmented (Moniliacea) or pigmented (Dematiaceae). Although fungi can be further classified by cellular and molecular features, these taxonomic schemes are complex and are not essential to the laboratory identification or therapy of fungi important in corneal infections.

At least 70 genera of filamentous fungi (56), yeasts (11), and dimorphic fungi (3) have been reported to cause human keratitis^{2,3,4,5,6,7,8,9,10,11} (Table 1). The principal causes in the United States are the septate filamentous fungi, predominantly Alternaria, Aspergillus, Curvularia, and Fusarium and yeasts, predominantly Candida. Of importance to ophthalmologists are the differences in geographic prevalence, risk factors, pathogenesis, distinctive signs of keratitis, and antifungal susceptibility of filamentous fungi and yeasts. Fungi account for less than 5% of cases of microbial keratitis in developed countries and 10% to 15% or more in developing countries.¹²

Compiled from multiple sources including the Sid W. Richardson Ocular Microbiology Laboratory.

Comparable to other forms of microbial keratitis, initiation of fungal infection requires the presence viable microorganisms and a mechanism of corneal inoculation. Fungi cannot penetrate the intact corneal epithelium and do not enter the cornea from episcleral limbal vessels. The principal routes of inoculation are introduction concurrent with a penetrating or perforating wound, either mechanical injury or surgery, and introduction through an epithelial defect. Posttraumatic infections are caused principally by filamentous fungi in the United States. Fungal keratitis following penetrating keratoplasty is uncommon but may result from contaminated donor material or late inoculation in the presence of epithelial defects, sutures, and topical corticosteroids. Fungal keratitis has also occurred following radial keratotomy,^9,13,14 excimer laser photorefractive keratectomy,¹⁵ and laser-assisted in-situ keratomileusis (LASIK),¹⁶, ^17,18,19,20 either by intraoperative inoculation via contaminated instruments or subsequent introduction through an epithelial defect. Infection of pre-existing epithelial defects is caused primarily by the indigenous microflora of the conjunctiva and adnexa, predominantly Candida. Candida keratitis has also occurred in individuals abusing topical anesthetics,²¹ crack cocaine,²² and methamphetamine,²³ presumably resulting from the toxic effect on the structure and function of the corneal epithelium by the agents. Other routes of corneal inoculation, such as contiguous spread from fungal scleritis or extension through the endothelium in endophthalmitis, are extremely rare.

Contact lens wear is an uncommon risk factor in fungal keratitis.²⁴ Filamentous fungi cause most infections associated with cosmetic or aphakic refractive contact lens wear. Candida is the principal cause of keratitis secondary to therapeutic contact lens wear. Pathogenesis of these infections is probably enhanced by fungal contamination of contact lens cases and paraphernalia, by the ability of fungi to adhere to soft contact lenses, and by microtrauma to the corneal epithelium, which accompanies lens wear.

The precise events that follow adherence of fungi to the corneal epithelium or exposed deeper structures and replication of the organism to produce keratitis have not been defined. The intrinsic virulence of fungi relates to their ability to proliferate within corneal tissue, resist host defenses, and produce tissue damage.²⁵ Filamentous fungi proliferate within the corneal stroma without release of chemotactic substances, thereby delaying the beneficial, inhibitory phases of the host response. Filamentous fungi multiply by apical hyphal extension, whereas yeast multiply by budding or transformation from the blastophore to the pseudohyphal phase. The large size of the true hyphae of filamentous fungi and pseudohyphae of yeasts precludes complete ingestion by neutrophils and macrophages. Certain fungi secrete enzymes that degrade organic substances into soluble nutrients, which are passively absorbed or actively transported into the cell. Candida albicans contains a phospholipase A and lysophospholipase on the surface of blastospores, which may aid invasion of tissue. Similar mechanisms probably account for the ability of Fusarium solani and other filamentous fungi to ramify within the corneal stroma and penetrate Descemet’s membrane. Fungi also release various toxic substances, including proteases, hemolysins, and exotoxins. The role of mycotoxins in the pathogenesis of fungal keratitis has not been determined. Comparable to the pathogenesis of other forms of infectious microbial keratitis, the host response contributes to stromal destruction by release of lysosomal substances from polymorphonuclear leukocytes and other substances through a cascade of complex reactions.

The clinical diagnosis of fungal keratitis is based on analysis of risk factors and the distinctive signs of corneal infection. The principal risk factor for filamentous fungal keratitis is corneal trauma, most commonly in healthy individuals during some form of recreational or work activity outdoors. The frequency of injury with plant or dirt material, such as a tree branch or flying debris, is substantial evidence that the responsible organisms are inoculated into the cornea by the injuring material rather than by subsequent contamination of an epithelial defect by environmental organisms. Many infected individuals do not recall antecedent corneal injury, thereby suggesting that certain fungi invade the cornea through small asymptomatic breaks in the epithelial surface. Topical corticosteroids enhance the likelihood of replication of filamentous fungi but are not absolute requisites for infection.

The principal risk factors for yeast or Candida keratitis are protracted epithelial ulceration, penetrating keratoplasty, and therapeutic soft contact lens wear. Concurrent administration of topical corticosteroids enhances the replication of Candida through suppression of the host inflammatory response. Although polymicrobial keratitis is uncommon, risk factors for Candida are comparable to bacterial keratitis, and Candida is the most common genus among mixed bacterial and fungal keratitis.^26,27 Polyfungal keratitis is rare.¹⁴

The distinct biomicroscopic signs of infectious microbial keratitis are epithelial and stromal ulceration (vs. intact epithelium), necrotizing stromal inflammation (vs. nonnecrotizing inflammation), and single location (vs multifocal sites) of the stromal inflammation. These distinctive signs are determined by the strain (virulence) of the responsible organism(s); the mechanism of inoculation into the cornea; the time interval from inoculation to examination; the antecedent status of the cornea; antimicrobial or corticosteroid therapy; and other host factors, such as an ocular surface abnormality, tear dysfunction state, lid closure dysfunction, and immunosuppression. Other biomicroscopic signs are helpful in judging the severity of the inflammatory process but not the presence or type of infection. These include epithelial edema, stromal edema, loss of endothelial reflectivity (pseudoguttata), endothelial plaque, aqueous flare and cells, and hypopyon.

In the early stages of infection, filamentous fungi produce signs that are readily distinguishable from yeast or bacterial keratitis. The most distinctive sign is the presence of delicate, fine, feathery, opalescent, gray-white or yellow-white material in the anterior stroma, surrounded by scant cellular infiltrate or edema (Fig. 1). The epithelium may be intact. The overlying epithelium may be granular and the surface elevated and irregular in contour. Linear infiltrates typically extend into the adjacent stroma. Multiple discrete opacities may develop outside the perimeter of the principal focus of inflammation, either separated by clear stroma or linked by fine linear collections of inflammatory cells and material (Figs. 2 and 3). In the absence of inflammation in the adjacent stroma, branching hyphal fragments may be visualized by biomicroscopy (Figs. 4 and 5). Confocal microscopy may also detect hyphal elements within the stroma.^28,29 Peripheral infection resembles noninfectious marginal infiltrative and ulcerative keratitis (Fig. 6). Multifocal keratitis may develop after contact lens wear or injury by multiple projectiles (Fig. 7). In the early stages, iritis is present and the intraocular pressure remains normal. Inappropriate, empirical therapy of fungal keratitis with topical fluoroquinolone or aminoglycoside antibiotics may suppress or eliminate the superficial elements but allow extension of the organisms into the stroma because these agents may possess selective antifungal activity.^4,30,31

There is no distinguishing clinical sign by which to recognize the genus or species of the infectious filamentous fungus. F. solani is the most virulent organism and typically produces rapidly progressive infection characterized by epithelial and stromal ulceration, dense stromal necrosis, abundant cellular infiltrate, and edema in the adjacent stroma and hypopyon (Figs. 8 and 9). Delicate feathery components are transient. Individual hyphal fragments are rarely visualized. Infection by certain species of Aspergillus and Scedosporium (Figs. 10 and 11) resembles F. solani keratitis and progresses rapidly. Infection by less virulent organisms, such as Curvularia and Alternaria species, produces small, focal (less than 3-mm diameter) areas of nonnecrotizing stromal inflammation with delicate feathery borders (see Fig. 1 and Fig. 12). Macroscopic pigmentation may develop in keratitis caused by Alternaria, Curvularia, and other dematiaceous fungi (Fig. 13).^4,11,14 The central component may progress to dense, opaque, gray-white suppuration in the deep stroma without enlargement in total area and may be accompanied by mild inflammation in the adjacent stroma. Iritis is minimal to moderate. Infection caused by other, relatively less virulent organisms resembles herpes simplex or noninfectious keratitis (Fig. 14).

Keratitis caused by Nocardia, nontuberculous Mycobacterium, and other low-virulence bacteria resembles filamentous fungal keratitis by the presence of intact epithelium, multiple stromal infiltrates, and minimal inflammation in the adjacent stroma.

Candida infection typically produces epithelial ulceration, focal necrotizing stromal inflammation, moderate cellular infiltrate and edema in the adjacent stroma, and mild or moderate iritis in the early stages, indistinguishable from bacterial keratitis (Figs. 15, 16, and 17). Fungal elements cannot be detected by biomicroscopy. If untreated, the keratitis evolves to produce dense suppuration and necrosis of the deep stroma. Although multifocal suppuration may develop in polymicrobial keratitis, there is no distinctive sign of mixed Candida and bacterial infection (Fig. 18).

Advanced, severe filamentous fungal or yeast keratitis is indistinguishable from keratitis caused by virulent bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa. The area of epithelial and stromal ulceration is large. Dense, opaque, homogenous, yellow-white stromal necrosis develop and is surrounded by confluent cellular infiltrate and full-thickness stromal edema (Figs. 19, 20, 21). Hyphal elements may penetrate Descemet’s membrane and endothelium and be visualized in the anterior chamber. Fibrinous material accumulates over the endothelium, anterior chamber angle, and iris. Pain is typically severe. Secondary ocular hypertension may ensue. Progressive stromal necrosis leads to corneal perforation and, rarely, consecutive endophthalmitis.