Bacterial infections

Bacterial infections of the cornea often follow a disruption in corneal epithelial integrity resulting from contact lens wear, trauma, alteration in immunologic defenses (eg, use of topical or systemic immunosuppressive agents), preexisting corneal disease (eg, dry eye disease, exposure keratopathy), ocular medication toxicity, or contamination of ocular medications. Bacterial organisms commonly involved in corneal infections include Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae, as well as members of the family Enterobacteriaceae.

Figure 6-3 Bacterial corneal ulcer. A, Clinical photograph. B, H&E stain demonstrates acute necrotizing ulcerative keratitis, with necrosis and numerous neutrophils infiltrating the corneal stromal lamellae. C, Gram stain shows numerous gram-positive cocci (arrowheads).D, Keratoplasty specimen shows a scar from healed keratitis. Note the loss of Bowman layer (between arrowheads), stromal thinning with fibrosis (arrow), and compensatory epithelial thickening.

(Part A courtesy of Andrew J.W. Huang, MD; parts B and C courtesy of Tatyana Milman, MD; part D courtesy of George J. Harocopos, MD.)

Scrapings from infected corneas show collections of neutrophils admixed with necrotic debris. Gram stain may demonstrate the presence of microorganisms (Fig 6-3). A culture is helpful for accurate identification of specific organisms and for assessment of antibiotic sensitivities.

Herpes simplex virus keratitis

Herpes simplex virus (HSV) keratitis is usually a self-limited corneal epithelial infection, but it may have recurrent or chronic forms. HSV epithelial keratitis is characterized by a linear arborizing pattern of shallow ulceration and swelling of epithelial cells, known as a dendrite (Fig 6-4A), that reflects viral reactivation in the corneal nerves. Corneal scrapings obtained from a dendrite and prepared using Giemsa or hematoxylin-eosin (H&E) stain may reveal intranuclear viral inclusions. Viral culture and, especially, polymerase chain reaction (PCR) techniques are useful for confirmation of viral infection. Like the dendritic ulcer, a geographic ulcer is caused by replicating virus; however, it has a much larger epithelial defect, similar in appearance to a map. Metaherpetic (trophic) ulcer is the only form of epithelial ulceration that does not contain any live virus. These ulcers result from the inability of the epithelium to heal. Stromal and/or disciform keratitis (Fig 6-4B) may accompany or follow epithelial infection as an immune-mediated response directed against viral antigens but not necessarily with the presence of active replicating virus. Histologically, chronic inflammatory cells and blood vessels may be seen tracking between stromal lamellae, a phenomenon known as interstitial keratitis (IK) (Fig 6-4C), which is discussed later in this chapter. In some cases, stromal keratitis may demonstrate significant necrosis, resulting in stromal thinning and even full-thickness perforation. Endotheliitis may also occur, with a granulomatous reaction at the level of Descemet membrane (Fig 6-4D, E). Postherpetic neurotrophic keratopathy may result from corneal hypoesthesia or anesthesia; it is characterized histologically by marked loss of stromal keratocytes (Fig 6-4F).

Figure 6-4 Herpes simplex virus keratitis. Clinical photographs depicting dendritic (A) and stromal (disciform) (B) keratitis. Note the central stromal haze and thickening in B.C, Histology of a corneal button illustrating stromal keratitis with loss of Bowman layer (asterisk), stromal scarring and vascularization (arrowhead), and scattered chronic inflammatory cells (arrows).D, Higher-magnification photomicrograph shows a granulomatous reaction (area between arrows) in the region of Descemet membrane (arrowhead). Note the fibrous retrocorneal membrane (asterisk), scattered chronic inflammatory cells, and blood vessel (open arrow). E, Multinucleated giant cells (asterisks) located just anterior to Descemet membrane (arrowheads).F, Postherpetic neurotrophic keratopathy. Photomicrograph shows a featureless corneal stroma (asterisks) with very few keratocytes (arrow).

(Parts A and B courtesy of Anthony J. Lubniewski, MD; parts C and D courtesy of Tatyana Milman, MD; part E courtesy of Ralph C. Eagle Jr, MD; part F courtesy of Robert H. Rosa Jr, MD.)

Fungal keratitis

Fungal (mycotic) keratitis is often a complication of trauma, especially trauma involving plant or vegetable matter or microtrauma related to contact lens wear. Corticosteroid use, especially topical, is another major risk factor. Unlike most bacteria, some fungi can penetrate the cornea and extend through the Descemet membrane into the anterior chamber. The most common fungal organisms are the septate, filamentous fungi Aspergillus and Fusarium, and the yeast Candida. Cultures, particularly on Sabouraud agar, are helpful for accurate identification of specific fungi and for assessment of antifungal sensitivities. When cultures are negative and organism identity remains elusive, corneal biopsy may be considered. Histologic evaluation can demonstrate the presence of fungal microorganisms with the use of special stains such as Gomori or Grocott methenamine silver (GMS) (Fig 6-5) or PAS with diastase. Identification of the exact fungal species solely on the basis of histology is often difficult.

Acanthamoeba keratitis

Acanthamoeba protozoa most commonly cause infection in soft contact lens wearers who do not take appropriate precautions in cleaning and disinfecting their lenses or whose lenses come into contact with contaminated stagnant water (eg, as found in hot tubs or ponds). Tap water may also harbor Acanthamoeba in small numbers. Patients presenting with Acanthamoeba keratitis usually have severe eye pain caused by radial keratoneuritis. In the late stages of the disease, a corneal ring infiltrate may be present (Fig 6-6A). Special culture techniques and media, including nonnutrient blood agar layered with Escherichia coli, are required to grow Acanthamoeba but are not widely available. The microorganisms penetrate the deeper layers of the stroma and may be difficult to isolate from a superficial scraping. Because of these challenges, PCR-based methods for diagnosis of Acanthamoeba keratitis are becoming more widely used. Histologically, corneal epithelial scrapings, biopsy specimens, or corneal buttons may show cysts and trophozoites (Fig 6-6B). The organisms are generally visualized with routine H&E sections but may also be highlighted with PAS and GMS stains. Calcofluor white or acridine orange fluorescent stains may also be used.

Figure 6-5 Fusarium keratitis. A, Clinical photograph shows gray-white stromal infiltrate with feathery margins and satellite lesions (arrow). B, Grocott methenamine silver (GMS) stain of a corneal button demonstrates frequent fungal hyphae (black). Note that fungal hyphae have penetrated through Descemet membrane (arrow).

(Part A courtesy of Andrew J.W. Huang, MD; part B courtesy of George J. Harocopos, MD.)

Figure 6-6 Acanthamoeba keratitis. A, Clinical photograph depicting a corneal ring infiltrate and a small hypopyon. B, Histology of stromal organisms. Note the cyst (C) and trophozoite (T) forms. The cyst has a double wall (ie, endocyst and exocyst) (arrows).

(Part A courtesy of Sander Dubovy, MD.)

Infectious crystalline keratopathy

Infectious crystalline keratopathy (ICK) typically occurs in patients who are on long-term topical corticosteroid therapy—for example, following penetrating keratoplasty (PK). The infection typically arises along a suture track or a surgical wound. The most common etiologic microorganism is Streptococcus viridans (α-hemolytic Strep), but many other organisms have been reported, including bacteria, mycobacteria, and fungi. Chronic immunosuppression, when combined with properties of the organism’s glycocalyx (a glycoprotein and glycolipid covering that surrounds the cell membranes of some bacteria and sequesters the organism from the immune system), may promote growth of the organism in this condition. No true crystals are involved; rather, this condition derives its name from the crystalloid, feathery clinical appearance of the opacity (Fig 6-7A).

Figure 6-7 Infectious crystalline keratopathy. A, Clinical photograph depicting crystalline-appearing, feathery stromal infiltrate (arrow), with intact overlying epithelium. The infection arose along a suture track following repair of a corneal laceration. B, Gram stain demonstrates sequestrations of gram-positive cocci interposed between stromal collagen lamellae (arrows) without an appreciable inflammatory response.

(Part A courtesy of Anthony J. Lubniewski, MD; part B courtesy of Morton E. Smith, MD.)

In many cases, the diagnosis is missed clinically and is made histologically after failure of a corneal graft. Histologically, sequestrations of organisms are present within the interlamellar spaces of the stroma. Typically, the inflammatory cell infiltrate is insignificant. The organisms are sometimes apparent on H&E stain; they may also be highlighted with Gram, PAS, GMS, or acid-fast stain, depending on the etiologic agent (Fig 6-7B).

• Porter AJ, Lee GA, Jun AS. Infectious crystalline keratopathy. Surv Ophthalmol. 2018;63(4): 480–499.

Interstitial keratitis

In interstitial keratitis (IK), nonsuppurative inflammatory cells infiltrate the interlamellar spaces of the corneal stroma, often with vascularization. Typically, the overlying epithelium remains intact. The changes observed in IK are thought to result from an immunologic response to infectious microorganisms or their antigens. Transplacental infection of the fetus by Treponema pallidum (congenital syphilis) may cause IK (Fig 6-8A). Histologically, chronic syphilis-related (luetic) IK is characterized by the presence of stromal ghost vessels devoid of erythrocytes with surrounding stromal fibrosis and a variable degree of chronic inflammation. The Bowman layer and Descemet membrane are characteristically intact. In addition, the Descemet membrane may demonstrate focal multilaminated excrescences (Fig 6-8B) that are reminiscent of guttae (Latin for drops), droplike excrescences of Descemet membrane, observed in Fuchs endothelial corneal dystrophy (discussed later in this chapter).

Figure 6-8 Interstitial keratitis of congenital syphilis. A, Clinical photograph depicting a stromal opacity, with intact overlying epithelium. B, PAS stain shows ghost vessels (arrows) in the midstroma and deep stroma, with surrounding fibrosis and a sparse chronic inflammatory cell infiltrate. Descemet membrane is multilaminated and demonstrates nodular excrescences (arrowheads). Note the intact epithelium and Bowman layer.

(Part A courtesy of Anthony J. Lubniewski, MD; part B courtesy of Tatyana Milman, MD.)

Although congenital syphilis represents the “classic” cause of IK, the most common etiologic agent of IK is HSV (see Fig 6-4). Other microorganisms that can cause IK include Onchocerca volvulus, Mycobacterium tuberculosis, Mycobacterium leprae, Borrelia burgdorferi, and Epstein-Barr virus. See also BCSC Section 8, External Disease and Cornea.

Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.