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PATIENT CARE
Understanding the process of infiltrate formation can help you select an appropriate response. by Kathleen L. Krenzer, O.D., Ph.D., Boston When there is an insult to the corneal
surface, the limbal vasculature or the tear film respond by sending out inflammatory and/or immune cells to repair the damage. When enough of these cells aggregate in a region of the cornea, you can see them as clinically
identifiable infiltrates. This is where your work starts, because infiltrate formation can arise from either infectious or non-infectious conditions. Your challenge is the identify the etiology, then treat it accordingly. The
telltale symptoms of a corneal infiltrate include conjunctival hyperemia, discomfort or photophobia, and lacrimation.1-4 They occur because the corneal insult leads to the production of inflammatory mediators, which originate from
four sources: plasma enzyme systems (e.g. complement), lipid membrane metabolism (e.g. leukotriene B4), release of preformed molecules from lysosomes (e.g. lysozyme), or newly synthesized gene products (e.g. interleukin-1).
The Cornea
Thus, the corneal tissues are not under the surveillance of the immune system. This separation of the immune system and the cornea permits light to travel through the cornea. It also explains the decreased risk of graft rejection in keratoplasty procedures compared with other transplant procedures. However, the anterior surface of the eye does have some immunological protection. The preocular tear film contains the secretory IgA dimer which binds with foreign antigens in the tears and prevents the antigens from adhering to the ocular surface. Interestingly, the sIgA-antigen complex is not proinflammatory.5 The conjunctiva is the other primary source of immunological protection. It's part of the mucosal- associated lymphoid tissue (MALT) system, and contains not only a vascular system but also lymphatic drainage.11 Although the corneal stroma is a barrier to cells, conjunctival IgG moves rather freely in the corneal stroma.7
Insults to the cornea, however, disrupt this balance. The immune and inflammatory systems will move into the cornea to protect the integrity of the eye. This protective mechanism can have many clinical manifestations ranging from infiltrate to ulcer formation. Though protective, these processes often compromise the primary function of the eye by causing vascularization, scarring and/or perforation of the cornea. Non-Infectious Infiltrates
Since the first reports of a corneal infiltrate associated with contact lens wear, the study of sterile infiltrates has concentrated on contact lens wear. However, there are several other possible etiologies that promote the development of sterile infiltrates (see table, opposite). Researchers have not been able to pinpoint the pathogenesis of sterile marginal infiltrates. The process may involve different mechanisms, depending on the etiology of the insult. Some suspected reactions: hypoxic,13,14 toxic, antigen/antibody complex15,16 and delayed hypersensitivity-based.17 Here's a likely sequence of events: The insult instigates the production and/or release of proinflammatory mediators. These mediators then trigger a vasodilation and increased permeability of limbal vessels. White blood cells move to the site of the insult following chemotaxis between the edematous lamellae of the corneal stroma. The white blood cells aggregate in the anterior stroma at the site of the insult. This forms the clinically apparent gray-white infiltrate (figure 2). Polymorphonuclear leukocytes, lymphocytes, plasma cells and macrophages have been identified in corneal infiltrates from animal models and biopsies of sterile contact lens-associated peripheral ulcers.18 These cells can also elaborate inflammatory mediators. These mediators can diffuse anteriorly and cause a breakdown of the epithelium.19 Sterile Infiltrates in Lens Wear The prevalent finding was that extended wear of soft contact lenses carried the highest risk factor for sterile infiltrates. Extended wear of disposable lenses posed an even greater risk than conventional extended wear. Rigid gas permeable lenses carried the lowest risk for the development of sterile infiltrates. One hypothesis suggests that an amplified hypoxic response in the cornea when the eye is closed initiates the development of sterile infiltrates in extended wear.10,13,14 When the eye is closed during sleep, it appears that a subclinical inflammatory condition exists.24 There is an increase in proinflammatory mediators, which prepare the closed eye to better deal with microbial attack.10 During sleep, oxygen levels available to the corneal epithelium diminish and the palpebral conjunctival vascular supply becomes the primary source. This decrease of oxygen on the eye induces glycolytic metabolic pathways. The lactate that is subsequently produced leads to a decrease in stromal pH. This contributes to the mild corneal edema that occurs during sleep. Contact lens wear can also induce a drop in pH.25 One study showed a greater decrease in the pH in closed eyes with contact lenses than in open eyes with a contact lens. Both situations showed lower pH than that in open eyes without a contact lens. This study found the lowest pH in the corneal epithelium. This may result in cellular damage to the epithelial cells and activation of the inflammatory cascade.19 Additional evidence for the hypoxia theory is the clinical observation that infiltrates are more common in the superior quadrant where both the lid and the contact lens impede oxygen transmission to the cornea.2 Microbial toxins may be another cause of sterile infiltrates in contact lens wearers. Experimental topical instillation of a lipopolysaccharide coat of gram-negative bacteria into rabbit eyes has induced acute redness, infiltrates and ulcers in the absence of viable bacteria.26 Another study isolated significantly more gram-negative organisms from the lenses and solutions of contact lens subjects with red eye (CLARE) and infiltrates vs. those with no signs of ocular inflammation.27 The bacterial toxins may incite the inflammatory cascade by causing direct damage to cells, or by interacting with antibodies and recruiting the cell-mediated reactions. Sterile Infiltrates in Blepharitis The development of these marginal infiltrates in staphylococcal blepharitis may be due to a hypersensitivity reaction to protein A, peptidoglycan and/or ribitol teichoic acid, which are the three major components of the Staphylococcus aureus cell wall. Rabbit studies have shown that repeated instillation of S. aureus onto the ocular surface exacerbated the blepharitis and related infiltrates only in those animals that had been immunized with inactive S. aureus. Additionally, histological examination of the corneal manifestation of blepharitis failed to reveal any organisms with gram stain. This supports the idea that the corneal lesions were sterile. With prolonged topical administration of S. aureus, immunized rabbits developed a higher amount of anti-ribitol teichoic acid IgG and IgA in the cornea than immunized rabbits that did not receive topical S. aureus and non-immunized animals receiving topical challenge.26 The same groups with high corneal IgG developed phlyctenules and corneal infiltrates more often than the other group. This suggests that IgG and IgA may mediate the corneal response to S. aureus. A clinical study also examined the role of adaptive immunity in S. aureus-related keratitis. This study tested patients who had chronic blepharitis, either with or without corneal involvement, for cell-mediated responses to intradermal injection of S. aureus and protein A. Wheal size was then correlated with signs and symptoms of blepharitis. The researchers found no firm correlation between the wheal size and the signs and symptoms of blepharitis. They observed, however, that individuals with exaggerated wheal formation were more likely to benefit from treatment.17 Interestingly, antibody titers of tears and sera did not correlate with the severity of disease.
Mediators of Ocular Response Arachidonic acid (AA) is a fatty acid that is found as part of the phospholipid membrane, generally as part of phosphatidylcholine and phosphatidylinositol. Adverse cellular stimuli will activate enzymes (phospholipase) that cleave AA from the phospholipid backbone in the cell membrane. AA can then be metabolized by one of two major pathways: the cyclooxygenase pathway or the lipoxygenase pathway (figure 3, page 105). One or more of these metabolites can mediate all the signs and symptoms. Of the AA metabolites, leukotriene B4 (LTB4) appears to play a prominent role in the genesis of both the infiltrate and the ocular surface response.18,19 LTB4 can be generated in all cell layers of the cornea. Newly synthesized LTB4 released from damaged cornea cells diffuse from the area of damage to recruit inflammatory cells, particularly polymorphonuclear leukocytes, to the area of damage. Another lipid membrane-derived mediator, platelet activating factor (PAF), works in conjunction with LTB4 to recruit and activate inflammatory cells. This mediator also appears to have a prominent role in the generation of sterile infiltrates.18 Both these mediators are also vasoactive, producing vasodilation and increased vascular permeability. Another very potent vasoactive mediator, complement C3, was found to be elevated in the tears of a contact lens wearer with a sterile infiltrate.28 Two pathways by which these mediators reach the conjunctival blood vessels are possible. Due to the corneal edema and the separation of the stromal lamellae, these mediators might diffuse toward the limbal vasculature. In this scenario a sectorial injection might develop as a result of focal mediation of vasodilation of the limbal blood vessels most proximal to the infiltrate. An alternative is that these mediators release into the preocular tear film, potentially able to reach all the superficial conjunctival vessels exposed to the tears. In sufficient quantities, these mediators in the tears might cause a generalized conjunctival hyperemia to develop. Though lipid-membrane mediators clearly play a role in the generation of the infiltrates and the ocular response, antibodies also contribute. Several studies on animal models have demonstrated that IgG and IgA levels are elevated in both the tears and the cornea in a hypersensitivity reaction.15,29 If an antibody-antigen complex were to form, as is hypothesized in staphylococcal blepharitis,15 the complement may activate the plasma enzyme system via the classic pathway. Several of the mediators derived from the complement cascade, specifically C3a and C5a, are vasoactive. The sterile corneal infiltrate can develop from a number of both ocular and systemic etiologies. Whether hypoxic, toxic, traumatic or immunologically mediated, the initial stimulus appears to be damage to the cornea. The development of both the infiltrate and the ocular surface signs and symptoms are due to the inflammatory and immune reactions which may further interact with each other to produce the clinical picture. The clinical use of topical steroidal and non-steroidal anti-inflammatory agents interferes with these reactions and, in conjunction with eradication and/or modification of the initial stimulus, will promote the healing and resolution process.
Dr. Krenzer is an assistant professor at the New England College of Optometry. 1. Snyder C. Infiltrative keratitis with contact lens wear—a review. J Am Optom Assoc 1995;66:160-177. |
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The histology of a marginal infiltrate. An insult to the cornea (green arrow) will lead to the elaboration of proinflammatory mediators from the corneal epithelial cells and/or stromal keratocytes. The
mediators can spread via the tears or between the stromal lamellae (red arrows). Upon reaching the conjunctival vasculature, these mediators stimulate vasodilation, increase leakage and initiate migration
of white blood cells toward the site of the insult. The increased leakage leads to corneal stromal edema easing the path for the migration of cells (blue arrow). At the site of the insult, the inflammatory
and immune cells aggregate to form a clinically apparent infiltrate.
