Conjunctivitis and Drug Hypersensitivity
Helen K. Wu
Conjunctival inflammation may result from allergic and toxic reactions to medication and is common among external eye diseases. Particularly familiar is the clinical scenario in which the treatment of an underlying infection or dry eye condition creates worsening of the red eye, due to toxicity of the medication or to its preservatives. Failure to recognize this clinical picture may lead one to assume worsening of the underlying problem and to prescribe additional medications, which can further exacerbate the ocular irritation or inflammation. Knowledge of toxic and allergic reactions to medication helps identify a rational and targeted clinical approach to patients presenting with red eye and irritation.
Both toxicity and allergy may play a role in producing ocular symptoms, and may sometimes be difficult to distinguish. In general, toxicity implies damage to the ocular surface without accompanying ocular inflammation, whereas allergy results from either the type I anaphylactoid (Prausnitz-Küstner) reaction or a type IV delayed hypersensitivity reaction. In the immediate type I hypersensitivity response, allergen combines with immunoglobulin E (IgE) attached to mast cells or basophils, which degranulate and release histamine, prostaglandins and leukotrienes, and cytokines such as tumor necrosis factor (TNF), interleukin-4 (IL-4), and IL-5. In the delayed type IV hypersensitivity reaction, the antigen is presented to naive T lymphocytes, resulting in expansion of antigen-specific activated CD4+ T cells that produce a variety of cytokines. Although allergy generally requires repeated exposure to the drug and sensitization time, a toxic reaction may occur either immediately or over time.
SIGNS AND SYMPTOMS
The signs and symptoms of toxicity and allergy to medication may be similar. Symptoms of toxicity may include irritation, dryness, photophobia, pain, tearing, or blurry vision. The most common adverse reaction to topical medications is a toxic papillary keratoconjunctivitis. Although a papillary reaction is common with toxicity, follicles may also be seen. A purely follicular response of the conjunctiva may be seen typically with certain medications, including pilocarpine, dipivefrin, carbachol, scopolamine, neomycin, ketorolac tromethamine, gentamicin, sulfacetamide, and antiviral medications, among others. With toxicity, conjunctival hyperemia and chemosis tend to be more concentrated in the inferior interpalpebral zone, with relative sparing of the superior conjunctiva. There is typically an associated punctate keratopathy but severity of corneal involvement may extend to corneal ulceration. Pseudodendrites and persistent corneal epithelial defects with a rolled edge appearance may occur. In severe cases, keratinization of the ocular surface and conjunctival scarring may also result. Predisposing factors include dry eye, a compromised ocular surface, long-term drug exposure, intensified treatment, and additive drug toxicity (1).
In allergic conjunctivitis, itching is the most common symptom. Conjunctival injection, chemosis, and eyelid and periorbital swelling may occur. A white stringy mucous discharge is common. A papillary reaction of the conjunctiva is most common in allergy, and follicles are not typically seen as an isolated response. With contact hypersensitivity, hyperemia and swelling are seen predominantly around the eyelids and periorbital area, and the inflammation may be worse inferiorly where the medication tends to drip toward the cheek.
DIAGNOSTIC TESTS
Diagnostic techniques to distinguish an allergic response from a toxic reaction include the intradermal skin test, in which a wheal and flare reaction occurs shortly after injection of the antigen within the skin, or application of the substance into the conjunctiva, with immediate conjunctival injection, chemosis, itching and lid swelling. Patch testing may be helpful in diagnosing patients with contact hypersensitivity, but a detailed clinical history is crucial in making the diagnosis. Conjunctival scrapings may show eosinophils in allergic conjunctivitis. There are no specific tests for toxicity, although toxic large basophilic granules may be seen in cells obtained from conjunctival scraping.
KERATOCONJUNCTIVITIS RELATED TO TOPICAL MEDICATIONS
Topical medications are most likely to cause keratoconjunctivitis or contact dermatitis from the medication itself, or from the preservatives or other compounds added to the preparation. The following is a discussion of medications commonly associated with toxicity and hypersensitivity reactions.
Preservatives
Although preservatives, required in multiple dose containers, are important in reducing the incidence of ocular infections associated with topical medications, they may be associated with significant toxicity to the conjunctival and corneal epithelium. Allergic reactions are also common with certain preservatives, such as thimerosal. Benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorobutanol, ethylenediaminetetraacetic acid (EDTA), mercurial preservatives, paraben esters, phenylethyl alcohol, sodium benzoate, sodium propionate, and sorbic acid are preservatives that may be present in ophthalmic products. Sodium perborate is considered a less toxic preservative. Of these preservatives, benzalkonium chloride is one of the most common. This bactericidal quaternary ammonium agent may damage the corneal epithelial microvilli, with decreased adherence of the tear film to the cornea. It may increase the penetration of some medications through the corneal epithelium. In higher concentrations, it may severely damage the corneal endothelium. In addition to preservatives, a variety of chemicals may be added to ophthalmic products, including antioxidants, buffers, tonicity agents, and viscosity-increasing agents.
Contact lens wearers may be particularly at risk for allergy or toxicity from their solutions, which may include a variety of preservatives, including benzalkonium chloride, chlorhexidine, benzyl alcohol, polyaminopropyl biguanide, EDTA, and thimerosal. Because preservatives may bind to the contact lenses, toxicity may be amplified. Thimerosal, a mercury-containing preservative, is a particularly common cause of irritation, conjunctival hyperemia, and chemosis. Hypersensitivity reactions may occur in up to 10% of patients in the United States and up to 50% of patients in Japan. Clinical findings of thimerosal toxicity include redness, irritation, and epitheliopathy, which may range from faint opacities to coarser punctate lesions (2). The findings may be quite acute, mimicking adenoviral keratoconjunctivitis (3). Patients with delayed hypersensitivity to thimerosal may react to patch testing or intradermal injection (4). In patients with sensitivity to preservatives in contact lens solutions, hydrogen peroxide disinfection and preservative-free saline solution may ameliorate the symptoms. Daily disposable contact lenses are also a good alternative.
Mydriatics
In general, mydriatics are well tolerated, with transient burning and stinging upon instillation. The conjunctiva may become hyperemic, and mild punctate keratitis may be present. With prolonged use, however, atropine and homatropine may produce a contact dermatitis. An allergic response of the conjunctiva may produce papillary conjunctivitis, whereas toxicity may be associated with a follicular conjunctival response (5).
Glaucoma Medications
Glaucoma medications are widely prescribed and have virtually all been associated with local allergic or toxic reactions. They may cause ocular hyperemia and transient burning and stinging. Miotic agents, such as pilocarpine and carbachol, rarely cause allergy, although pilocarpine and carbachol may both cause conjunctival follicles. Pilocarpine may also be a cause of drug-induced ocular cicatricial pemphigoid. In patients on pilocarpine gel, a subtle diffuse superficial corneal haze may occur, persisting for several years even after cessation of the medication (6). Carbachol may result in corneal clouding and persistent bullous keratopathy. The benzalkonium chloride preservative in these medications may also be responsible for some of their side effects.
Timolol, a commonly prescribed beta-blocker, may cause a papillary or follicular conjunctival reaction, in addition to a contact dermatitis (7, 8, 9). Corneal findings may include a punctate epitheliopathy, pseudodendrites, and corneal anesthesia (10). A mild dry eye may result from decreased tear film breakup time and decreased tear secretion. Symblepharon formation and cicatrization of the conjunctiva may occur with long-term use, particularly in the inferior cul-de-sac.
Epinephrine is a topical sympathomimetic amine that is not commonly prescribed currently. It is frequently associated with reactive hyperemia. Cicatrizing conjunctival changes may occur over time, resembling ocular cicatricial pemphigoid. Blepharitis and meibomitis may occur, in addition to conjunctival epidermalization. Adrenochrome deposits in the conjunctiva, resembling dark brown or black spots, are common after prolonged use. These are the products of oxidation and polymerization of epinephrine. The cornea may appear black due to deposition of this material on a compromised corneal surface. Corneal epithelial toxicity or edema may also be observed. Use of epinephrine or any of its derivatives may induce an allergic reaction. Dipivefrin is generally much better tolerated than epinephrine, but may frequently induce a follicular conjunctivitis (11, 12, 13) as well as a contact dermatitis (13,14). Cicatrizing conjunctival changes may also occur with use of dipivefrin, but adrenochrome deposits are less frequently associated with dipivefrin compared to epinephrine (15).
Apraclonidine, an α2-adrenergic agonist, may also cause ocular allergic conjunctivitis and contact dermatitis in 20% to 50% of patients (16). It may also be associated with a follicular conjunctivitis (17). Brimonidine, a newer α2-adrenergic agonist, may also cause a follicular conjunctivitis. Like apraclonidine, it may cause an allergic contact dermatitis or conjunctivitis in up to 10% of patients (18). Cross-reactivity may be seen in approximately 10% to 20% of patients allergic to apraclonidine, but overall it is much better tolerated than apraclonidine (19,20).
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