Allergic Reaction to Phenylephrine
This careful review of past exam notes revealed that phenylephrine and Fluress were the only drops that had not been instilled at the October 2013 visit when no AE was reported. However, Fluress was an unlikely culprit since it was not instilled in October 2014, and the patient still experienced an AE. Therefore, the agent most likely responsible for the allergic reaction in the patient, as confirmed by a review of the past notes and by the aforementioned pharmacologic test, was deemed to be phenylephrine (Table).
Adverse reactions to topical ocular medications and specifically to diagnostic eye drops have long been recognized. Mathias, Camarasa, Barber, Ducombs, and Monsálvezhave reported on variations of conjunctivitis and periorbital erythema with positive patch testing to phenylephrine.1-5 Geyer and colleagues reported on a study of 21 patients who had blepharoconjunctivitis after instillation of phenylephrine.6 In this case study patient, severe keratoconjunctivitis was the clinical manifestation observed.
Villarreal and colleagues studied 31 patients who had a previous reaction to mydriatic drops. The study found that phenylephrine was the drug that most frequently caused an AE (93.5%).7 One patient reacted to the preservative thimerosal, and 1 patient reacted to benoxiprocaine. Tropicamide was demonstrated to be very well tolerated as none of the patients tested positive on either the patch test or the pharmacologic test.
Tropicamide is a nonselective muscarinic antagonist commonly used for mydriasis due to its fast onset and short duration.8 Adverse reactions to tropicamide are rare. Three studies reported on patients who had a positive patch test to tropicamide.9-11 However, the reaction was not provoked by direct instillation of tropicamide into the eye.
Common in-office topical anesthetics, proparacaine, tetracaine, benoxinate, and lidocaine also can cause AEs. Corneal toxicity is a well-known complication with topical anesthetic abuse, whereas allergic reactions are considered rare. The most common symptoms include stingingand discomfort upon instillation. Common signs include punctate corneal epithelial erosionsresulting indirectly from a decrease in reflex tearing, infrequent blinking, and increased tear evaporation.12 Topical anesthetics also inhibit the migration of corneal epithelial cells and cause direct damage to the cells that are present, leading to impaired healing and epithelial defects.13
Manifestations of allergic reaction to topical anesthetics can include conjunctival hyperemia and edema, edematous eyelids, and lacrimation. One published case described a 60-year-old woman who developed eczematous dermatitis of the eyelids after ophthalmic anesthetic drops were instilled prior to laser surgery. Patch testing showed a positive response to benzocaine 5%, proparacaine, and tetracaine 0.5%.14
Preservatives, in general, can cause an allergic reaction. Benzalkonium chloride’s (BAK) cytotoxic sequelae include possible trabecular cell death in glaucoma patients, disruption of tear film stability (even at low concentrations), and immune-allergenic properties. One article reported BAK as one of the 30 most frequent allergens causing allergic periorbital dermatitis.15 Benzalkonium chloride is used in most brands of phenylephrine. However, preservatives in this patient’s case were ruled out as instigating agents since both phenylephrine and tropicamide contain the same preservative, BAK 0.01%, yet this patient did not develop a reaction to tropicamide when used without phenylephrine. Expired medications also were not considered to be a factor as none of the medications used on the patient were indeed expired (the Malcom Randall VAMC clinic maintains a strict policy of discarding medications 28 days after being opened).
Although uncommon, phenylephrine sometimes has been found to cause a type 4 hypersensitivity reaction, also known as cell-mediated or delayed-type hypersensitivity.16 First, helper T cells secrete cytokines. Activation of cytokines recruits and activates cytotoxic T cells, monocytes, and macrophages, leading to inflammation of the surrounding tissue. Examples of cell-mediated hypersensitivity include reactions to the tuberculin skin test and to poison ivy.
Type 1 hypersensitivity reactions, also known as immediate or anaphylactic hypersensitivity reactions, are not triggered by phenylephrine. In this type of reaction, IgE binds to the mast cell on initial exposure to an allergen. On second exposure, the allergen binds to the IgE, causing the mast cell to release mediators of inflammation, triggering physiologic responses. Examples of this type of hypersensitivity include those seen with penicillin, bee stings, hay fever, bronchial asthma, and food allergies, for example, to shellfish.
A toxic reaction’s mechanism differs from that of a type 4 hypersensitivity reaction. Toxic reactions occur due to direct cytotoxicity of a drug caused by a low or high pH and either hyper- or hypo-osmolarity. Toxicity can lead to corneal and conjunctival cell necrosis or induce apoptosis, stimulating inflammatory reactions. Clinically, toxic reactions will present with follicles, whereas allergic reactions will present with papillae.
The definitive diagnostic methods used to determine the allergic agent causing ocular or periocular AEs are patch testing and conjunctival challenge.7 Mathias, Camarasa, Barber, Ducombs,and Monsálvezused patch testing to confirm phenylephrine as the allergic agent in their series of cases. Patch testing entails the application of a small amount of an allergic agent that is taped onto the skin. The allergic agent is confirmed if the patient has a dermal reaction, wherein the area patched will become erythematous. When patch testing is negative or inconclusive, a conjunctival challenge is performed by instillation of the suspected allergic agent into the eye with subsequent observation to determine whether a reaction occurs. The sequelae found in Villarreal’s study included itching, lacrimation, edema, erythema, and sometimes blepharitis.7
A direct conjunctival challenge with the suspected culprit was not pursued in this patient’s case due to the known severity of the potential resulting reaction. The authors instead chose an indirect method of determining the implicating agent and used the process of elimination to whittle down the most likely suspect. A challenge with the medications suspected not to be likely offenders was undertaken. This spared the patient a likely repeat of the AE he had just recovered from.
