Therapeutic Topics
Here's how to weed out the true drug-induced reactions from the mimics.
Mark B. Abelson, MD and Sarah A. Rosner Boston
Pharmocological agents have the potential to be double-edged swords. In addition to therapeutic effects, they can occasionally produce adverse effects as well, and drug-induced allergic reactions have been reported in 1 to 27 percent of cases (Iopadine). Awareness of signs and symptoms of DIAC and its differentiation from similar conditions will be helpful. Here are some tips for diagnosis and management of this perennial problem.
Clinical diagnosis
Characteristics of drug-induced allergic conjunctivitis include
itching, conjunctival injection, lid swelling and dermatitis.
Patients with drug-induced hypersensitivity reactions experience
moderate to severe itching on the eyelid(s) and/or eye globe(s).
Hyperemia is present to a greater extent in the inferior conjunctiva
than in the superior regions--often, the superior conjunctiva
isn't injected at all. Similarly, chemosis may be present, restricted
only to the inferior conjunctiva. Run-off of the drug out of the
eye may also produce dermatitis of the surrounding skin. In general,
the lower lid is more susceptible to irritation than the upper
because of pooling of the drug in the eye and run-off into the
lower lid. In some cases, the upper lid may appear to be completely
normal despite the irritation and redness in the lower part of
the eye.
Occasionally, the patient may show keratitis or follicles. These are not specifically associated with DIAC. There may also be corneal abnormalities such as marginal infiltrates. Allergic reactions require repeated exposure to the sensitizing agent and a sufficient amount of time to elapse for sensitization. The time period may range from immediately to 10 days to years, depending on the potency of the sensitizing agent and the susceptibility of the exposed individual. Allergy symptoms continue to worsen progressively until the patient stops using the drug.
Seasonal allergy and other potential confounders
Accurate diagnosis of DIAC is crucial in many cases, because a
misdiagnosis can lead to discontinuation of a potentially effective
drug. Unfortunately, DIAC is often misdiagnosed for several reasons.
First, there is the seasonal effect. If a person begins a new medication at the time that his seasonal allergies begin, their normal reaction to pollens in the air may be misdiagnosed as a drug allergy. On the other hand, a drug-induced allergic reaction itself can be misdiagnosed as seasonal allergies. Additionally, seasonal allergy may predispose people to having drug-induced allergic conjunctivitis reactions.
The symptoms of drug-induced allergic conjunctivitis may be confused with those of other eye diseases such as bacterial conjunctivitis, dry eye and reactive folliculosis (see Table 1). What's more, all drugs have the potential to be toxic to the ocular surface if given in large enough doses. Also, patients suffering from dry eye and contact lens wearers are more susceptible to drug toxicity at lower doses. However, eosinophils, the hallmark of late-phase allergic reactions, are absent in toxic reactions to drugs. Corneal toxicity can range from common, benign coarse punctate epithelial keratopathy to the more severe corneal ulcerative keratitis. However, DIAC corneal abnormalities are most commonly expressed as punctate marginal keratitis.
Ocular itching associated with inferior conjunctival hyperemia is the defining symptom of a DIAC reaction. The other hallmark of DIAC is a relentless progression--allergic symptoms will worsen until the drug is stopped. To confirm the presence of DIAC, stop the drug and let the patient recover from the reaction, then re-challenge him with the drug one to two weeks later. The DIAC patient will demonstrate the same symptoms exhibited before the termination of the drug. If the patient doesn't have any reaction to the drug, then he's suffering from either a seasonal allergy or some other ocular disease.
An example of misclassification of DIAC is the case of Alphagan, an intraocular pressure lowering agent. In a retrospective study, the incidence of drug-induced conjunctivitis in glaucoma patients using Alphagan was evaluated. A set of diagnostic criteria was used to identify drug-induced allergic conjunctivitis. The incidence of DIAC reported by the drug manufacturer in the insert was 12.7 percent. However, after re-evaluating the patients' records utilizing standard criteria for DIAC, incidence of DIAC was found to be 5.3 percent. Drug allergy to Alphagan was most commonly diagnosed as either reactive folliculosis or dry eye.
Treatment
Drug-induced allergic conjunctivitis is best treated by simply
discontinuing the offending medication.2 If the patient is taking
more than one medication, each may be stopped individually until
symptoms cease in order to identify the particular drug that's
behind the allergic reaction. Note that it may take as long as
two weeks for all symptoms to subside.3
There are three major symptoms of DIAC that you can treat: itching, redness, and dermatitis of surrounding skin (see Table 2). A 1-2% hydrocortisone cream may be used to treat dermatitis on the eyelid and skin around the eye. In most cases topical antihistamines such as Emadine (emedastine difumarate) or Livostin (levocabastine) relieve itching and redness if these symptoms are mild. Steroidal drugs, such as Alrex (loteprednol) and FML (fluoromethalone), are effective in treating redness and itching in severe cases. In general, the best treatment is to avoid all new drugs. However, this may not be feasible for all patients, depending on their level of discomfort.
Drug-induced allergic conjunctivitis can be a confounding condition, since it has many mimics and can be due to one or more medications. However, with these tips in mind, you can treat it effectively.
Table 1: Signs and Symptoms of Concomitant External Disease 1
| DISEASE | SIGNS AND SYMPTOMS | |
| Drug-Induced | Ocular itching (moderate-severe) | |
| Allergic Conjunctivitis | Inferior conjunctiva vasodilation | |
| Lid edema (lower more than upper) | ||
| +/- Dermatitis of lower lid | ||
| Relentless progression | ||
| Seasonal Allergic | Ocular itching | |
| Conjunctivitis | Conjunctival injection | |
| Lid edema | ||
| Tearing | ||
| Bacterial Conjunctivitis | Lids stuck together upon waking | |
| Visible discharge in tear film and/or caruncle | ||
| Conjunctival injection | ||
| Papillary reaction | ||
| Dry Eye | Ocular burning | |
| Mild conjunctival injection | ||
| (+) Rose Bengal staining and/or decreased | ||
| Schirmer test | ||
| Reactive Folliculosis | Follicle formation in inferior cul-de-sac | |
| Conjunctival injection | ||
| Minimal mucous discharge | ||
| +/- Mild lid pain | ||
The Allergic Response:
When drug-induced allergic conjunctivitis occurs, the body's immune
system displays two of the four major types of hypersensitivity
reactions: a type I immediate hypersensitivity reaction and a
type IV delayed hypersensitivity. A type I hypersensitivity reaction
occurs in seasonal and food allergies, while a type IV reaction
occurs in contact dermatitis, and vernal and atopic conjunctivitis.
The difference between the underlying mechanisms of type I and
type IV reactions lies in the two separate divisions of the immune
system: the humoral branch and the cellular branch.
The humoral response, which characterizes a type I reaction, involves the production and secretion by B cells of antigen-specific IgE antibodies. The antigen-specific IgE antibodies bind to the cell membrane of mast cells.
A type I immediate hypersensitivity reaction begins when antigen comes into contact with conjunctival mast cells. The antigen binds to two molecules of IgE antibody on the surface of mast cells and crosslinks them together. The binding of antigen induces a change in the mast cell's membrane that, in turn, triggers degranulation of the cell and the release of pharmacologically active mediators. The primary mediator released by mast cells is histamine. When released, histamine binds to two receptors, H1 and H2 on various target cells. Binding to H1 receptors results in increased permeability of venules, increased mucous secretion and nerve stimulation (itching). Binding of histamine to H2 receptors increases vasopermeability and dilation. The type I immediate hypersensitivity occurs within minutes of antigen contact with IgE antibodies.
The cellular response, which characterizes a type IV reaction, involves interaction between T cells, cytotoxic T lymphocytes and antigen. T cells secrete cytokines, which activate various phagocytic cells that destroy foreign invaders. Cytokines are small protein molecules that regulate the intensity and duration of an immune response. They control the recruitment and proliferation of various immune cells.4
Table 2: Treatment of Drug-Induced Allergic Conjunctivitis
| DRUG | CLASS | INDICATION |
| Alrex (loteprednol) | Steroid | Redness and itching |
| FML (fluorometholone) | Steroid | Ocular inflammation |
| Emadine | Topical antihistamine | Redness and itching |
| (emedastine difumarate) | ||
| Livostin (levocabastine) | Topical antihistamine | Redness and itching |
| OcuHist, Ophcon-A and | Antihistamine/ | Vasoconstriction |
| Naphcon-A | vasoconstrictor | |
| (pheniramine/naphazoline) | ||
| 1-2% Hydrocortisone cream | Corticosteroid | Dermatitis of eyelid and skin surrounding eye |
Dr. Abelson, an associate clinical professor of ophthalmology at the Harvard Medical School, consults in ophthalmic pharmaceuticals.
References
1. Abelson MB, Chapin M, Batoosingh A, Chen K, York J. A retrospective
examination of drug-induced allergy to Alphagan( and a proposal
for a new reporting system. (ARVO poster presentation) 1999.
2. Abelson MB, George MA, Garafalo C. Differential diagnosis of
ocular allergic disorders. Ann. Allergy 1993:70:95-113.
3. Abelson MB, Schaefer K. Conjunctivitis of allergic origin:
Immunologic mechanism and current approaches to therapy. Surv.
Ophthalmol 1993:38(suppl):115-132.
4. Kuby, J. Hypersensitive reactions. In Immunology. New York,
NY, W.H. Freeman and Company, 1997:413-439.