Managing the Complex Ocular Allergic Reaction

Understanding the pathophysiology of ocular allergic responses is paramount to determining optimal therapy. Here's a review.

By Gregory A. Caldwell, OD

Release Date:

March 2016

Expiration Date:

March 1, 2019

Goal Statement:

This course covers signs, symptoms and the treatment of ocular allergy.

Faculty/Editorial Board:

Dr. Gregory A. Caldwell, OD, is a 1995 graduate of the Pennsylvania College of Optometry who later completed a one-year residency in primary care and ocular disease at the Eye Institute in Philadelphia. He is a fellow of the American Academy of Optometry and a diplomate of the American Board of Optometry, and currently works in Duncansville and Johnstown, Pennsylvania as an ocular disease consultant.

Credit Statement:

This course is COPE approved for 1 hour of CE credit. COPE ID is 49332-AS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Caldwell has no financial interest in any products mentioned in this article.

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While a seemingly simple ailment, ocular allergy is, in fact, multifaceted, encompassing multiple diag-nostic categories differentiated by a complex cascade of inflammatory mediators, cytokines and other chemicals. As such, while grouping these disparate conditions into a single diagnostic category called “allergic conjunctivitis” can ease treatment selection, doing so can also result in therapeutic failure. Instead, approaching ocular allergy as a spectrum of different diseases—each with its own initiating factors, presentations and methods of management—can help clinicians select more appropriately targeted therapies to enhance the likelihood of resolution.

The human allergic response is classically considered an overreaction of the body’s immune system to foreign substances perceived as a threat to ocular health (i.e., allergens). Said substances are not necessarily pathogenic, but rather perceived as so.¹ In effect, an allergic reaction is a result of a beneficial immune response that has gone awry.

Allergies can be subdivided into four categories based on the cascade of events that comprise each reaction and the time it takes for them to occur. Of the four, Type I and Type IV are considered true ocular allergy. Immediate hypersensitivity reactions, or Type I ocular allergies, include seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis and atopic keratoconjunctivitis. Delayed hypersensitivity reactions, or Type IV ocular allergies, include contact dermatitis.

Moderate contact dermatitis secondary to application of topical 0.2% brimonidine tartrate solution.

The same patient one week later after discontinuing the topical 0.2% brimonidine tartrate solution and applying OTC hydrocortisone cream 1%.

A Type I allergic reaction begins with a sensitization phase in which the patient is exposed to the offending antigen. Additional re-exposure results in an early-phase response and subsequent late-phase response. The early response is the degranulation of the mast cell, which has preformed mediators—the most common being histamine. Most patients in this phase exhibit the hallmark symptom of itching in conjunction with mild conjunctival hyperemia, chemosis and a conjunctival papillary response. At times, a stringy white mucus or concurrent rhinitis is also present. Antihistamines and mast-cell stabilizers, or better yet agents that combine both properties, are the best treatment methods for the early phase.

The ensuing late-phase allergic response involves white blood cell (i.e., eosinophil and basophil) infiltration that results in cell-mediated cytotoxicity or tissue damage and edema. The late-phase reaction typically commences between four and six hours after sustained mast cell degranulation.^2,3 T-lymphocyte activation and infiltration of the conjunctival mucosa by eosinophils, neutrophils, monocytes and basophils are hallmarks of the late phase.^4,5 If intervention is initiated while the allergic reaction is predominately in the early phase, control can be achieved using anti-allergy products that have antihistamine and mast cell stabilizing effects. Once Type I allergies have progressed to the late phase, however, more potent anti-inflammatory agents in the form of topical corticosteroids or non-steroidal anti-inflammatory agents (NSAIDs) may be neces-sary to mitigate the inflammatory/immune response.

UNDERSTANDING THE PRESENTATION

Determining whether patients with seasonal or perennial allergic conjunctivitis are in the early or late phase can be completed using details from their patient history and results from a clinical exam. When performing the exam, note type, severity and duration of signs and symptoms: patients in the early phase present with itching and chemosis, while those in the late phase exhibit evidence of eosinophil and basophil infiltration and accumulation in the ocular tissues.

In the case of vernal kerato-conjunctivitis (VKC), which is seen primarily in children, the allergic reaction moves rapidly from the early to late phase. In this instance, the accumulation of eosinophils and basophils in the limbal area of the bulbar conjunctiva are known as Horner’s points or Trantas’ dots, and are a classic example of cell-mediated cytotoxicity or tissue damage.

Treatments for allergic conjunctivitis consist of reducing or eliminating the antigen when possible and prescribing pharmaceuticals to prevent or decrease the immune response; however, non-pharmacological interventions can also be beneficial as a first line of defense. Examples for managing both Type I early and late phases and Type IV hypersensitivities include:

Above: a presentation of severe contact dermatitis. Below: the same patient one week later after a six-day Medrol (methylprednisolone) Dosepak.

• Allergen/antigen avoidance. Using air conditioners and HEPA filters can prevent pollen from infiltrating indoor areas. Instructing patients to avoid outdoor activities during high pollen periods is also beneficial, though not always possible. Patients can track tree, grass and weed pollen counts and mold spore counts one of numerous smartphone apps; this may assist patients in reducing antigenic exposure.

• Artificial tears. Though these can flush away antigens from the ocular surface, sporadic use makes this option only marginally effective, especially in more severe cases. Excessive lacrimation in allergic conjunctivitis is an example of the body’s attempt to emulate this action.

• Cold compresses. Applying chilled temperatures triggers vaso-constriction and limits the eosinophilic response. Cold compresses may also have a psychological benefit, in that patients have something to occupy their hands with rather than scratching, which increases mast cell degranulation, eosinophil release and subsequently, severity of itching.

• Washing hair before going bed. Hair—particularly longer strands—acts as a filter to trap airborne allergens throughout the day. These allergens transfer to the pillow when the patient lies down and then into the eyes overnight. Rinsing hair before bed reduces and even eliminates this problem.

THE TYPE I ALLERGIC RESPONSE

Pharmacologic options for managing Type I acute phase allergic responses include:

• Prescription topical anti-histamine/mast-cell stabilizers. These agents employ multiple mechanisms of action to bring relief; antihistamine competes for and reversibly blocks histamine receptors in the conjunctiva and eyelids, while the mast-cell stabilization properties inhibit mast-cell degranulation. Most patients prefer to use antihistamine/mast-cell stabilizers instead of other options because of the rapid onset of relief they provide. Examples include Patanol (olopatadine hydrochloride 0.1%, Alcon), Pataday (olopatadine hydrochloride 0.2%, Alcon), Pazeo (olopatadine hydrochloride 0.7%, Alcon), Lastacaft (alcaftadine ophthalmic solution 0.25%, Allergan), Bepreve (bepotastine besilate 1.5%, Bausch + Lomb), Optivar (azelastine hydrochloride 0.05%, Meda Pharmaceuticals) and Elestat (epinastine hydrochloride 0.05%, Allergan).

• Over-the-counter (OTC) topical antihistamine/mast-cell stabilizers. Often more cost-effective than their prescription counter-parts, OTC topical antihistamine/ mast-cell stabilizers are also less effective due to their lower affinity for histamine receptors and inhibited mast-cell stabilization effects.⁷ However, they still maintain a place in many treatment regimens. Examples include Zaditor (ketotifen fumarate 0.025%, Alcon), Claritin Eye (ketotifen fumarate 0.025%, Bayer) and Alaway (ketotifen fumarate 0.035%, Bausch + Lomb).

• Topical mast-cell stabilizers/ cromones. When a patient cannot tolerate antihistamines due to allergy or severe dry eye, agents like Crolom (cromolyn sodium 4%, Bausch + Lomb), Alomide (lodoxamide tromethamine 0.1%, Alcon), and Alocril (nedocromil sodium 2%, Allergan) make suitable alternatives. Alamast (pemirolast potassium 0.1%, Vistakon) is another option, but is no longer available on the market. Note, these drugs’ mechanism of action is slow in comparison, and relief is delayed, compared to the aforementioned options. They are much less effective than dual-action medications due to their limited action.

• Topical antihistamines. Emadine (emedastine difumarate 0.05%, Alcon) is a single-agent antihistamine. It provides rapid relief like mast-cell stabilizers, but is limited in efficacy due to its single mechanism of action.

Dose Notes • Pazeo, Pataday and Lastacaft  are the only once-a-day prescription topical antihistamine/mast-cell stabilizers available.  • Pazeo and Lastacaft are indicated in patients two years of age and older.  • All topical antihistamine/ mast-cell stabilizers fall in the historic pregnancy category C except for Lastacaft, which is in the historic pregnancy category B. • Single-agent mast-cell stabilizers and single-agent antihistamines all fall in the historic pregnancy category B. • Lotemax gel does not require shaking, contains 70% less preservatives than its suspension and contains two moisturizers—propylene glycol and glycerin.10 • Topical NSAIDs inhibit cyclooxygenase, which blocks a segment of the arachidonic acid pathway. Thus, taking a topical antihistamine/mast-cell stabilizer in conjunction with topical NSAIDs would provide the most symptom relief. • If cyclosporine is used as an alternative, it will need to be combined with a topical antihistamine/mast-cell stabilizer to relieve symptoms.

• Topical NSAIDs. These may help with itching in the Type I acute allergic phase when other medications are not effective. Topical NSAIDs have analgesic and anti-inflammatory activity; this is why they are indicated for ocular pain and postoperative inflammation in patients who have undergone cataract extraction or corneal refractive surgery. In this case, the analge-sic benefit would help manage the itch (pain). Examples like Acular LS (ketorolac tromethamine 0.4%, Allergan), Xibrom (bromfenac 0.09%, Mylan), Voltaren (diclofenac 0.1%, Novartis) or Nevanac (nepafenac 0.1%, Alcon) could be used when needed.

Therapeutic options for managing a Type 1 late-phase allergic response include:

• Topical steroids. Corticosteroids inhibit the inflammatory process by stabilizing vascular membranes to decrease capillary dilation and permeability, which restricts eosinophils, basophils and macrophages from invading tissues. Corticosteroids function primarily by obstructing the ara-chidonic acid pathway via inhibition of phospholipase A2 to stop formation of the inflammatory mediators prostaglandin, thromboxane and leukotriene. Note: extended use can lead to elevated intraocular pressure in susceptible individuals.

An additional side effect of cataract formation is also especially prevalent with use of acetate or phosphate topical steroids; these include Pred Forte (prednisolone acetate suspension 1%, Allergan), Pred Mild (prednisolone acetate suspension 0.12%, Allergan), Durezol (difluprednate emulsion 0.05%, Alcon) and FML (fluorometholone suspension 0.1%, Allergan).

These higher-risk steroids are used in certain cases, such as when drug formularies may limit or dictate a treatment regimen. The release of newer generation site-specific or ester-based steroids like loteprednol etabonate have helped decrease many ocular complications associated with topical steroids; examples include Alrex (loteprednol etabonate suspension 0.2%, Bausch + Lomb), Lotemax (loteprednol etabonate suspension 0.5%, Bausch + Lomb) and Lotemax gel (loteprednol etabonate gel 0.5%, Bausch + Lomb). Still, monitoring for the above signs is key for protecting a patient from further adverse effects.

• Topical immunosuppressants. Cyclosporine offers potent immunosuppressive properties, reflecting its ability to block transcription of cytokine genes in activated T-cells. This makes cyclosporin A a highly potent inhibitor of T-cell activation and, as such, a potential alternative for patients unable to tolerate topical steroids, such as those with glaucoma.⁸ Cyclosporin A may also be used in conjunction with topical steroids, however.

Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) is one option for treatment of the late phase response. A second, not-yet-FDA-approved drug, lifitegrast (Shire)—being studied for the treatment of dry eye—may also have an off-label use in the late-phase allergic reaction due to its ability to inhibit T-cell migration and activation.⁹

• Oral NSAIDs. These are a good alternative when steroids are contraindicated; for example, in patients allergic to corticosteroids or those with glaucoma. As already mentioned, topical NSAIDs have analgesic and anti-inflammatory activity. The anti-inflammatory benefit is key in the late-phase as a means to relieve inflammation.

THE TYPE IV ALLERGIC RESPONSE

Type IV ocular allergies typically present as contact dermatitis on the upper and lower eyelids. The patient usually presents with itching, burning and red and scaly eyelids, often quickly following exposure to a noxious substance. When contact dermatitis is persistent, the eyelids typically thicken.

As such, more aggressive treatments supersede the supportive therapies mentioned above.

Therapeutic options for managing Type IV allergic response include:

• Topical steroids. The most appropriate treatment vehicle in mild to moderate contact dermatitis is cream or ointment. Examples include the ointment forms of Lotemax or FML, as well as OTC hydrocortisone 1% cream. Because limited options exist for topical corticosteroid ointments, it may be necessary to employ alternate preparations such as combination antibiotic/steroid ointments like Maxitrol (neomycin and polymyxin B sulfates and dexamethasone, Alcon) and Tobradex (tobramycin 0.3% and dexamethasone 0.05%, Alcon). Be aware, however, that some of these combination ointments may have antigenic properties themselves.

• Oral steroids. Severe contact dermatitis is most often responsive to a short course of oral corticosteroids. Oral prednisolone can be given, but methylprednisolone may work best to treat this ocular allergy. The latter is available as a six-day Medrol 4mg dose-pack.

The treatment of Type I and Type IV hypersensitivities has long been based on the known abilities of antihistamines, mast-cell stabilizers/cromones, NSAIDs, immuno-suppressants and corticosteroids. However, none of these drugs completely eliminate the clinical features of these allergic reactions; furthermore, current estimates sug-gest that at least 20% of the overall population suffers from some form of allergic conjunctivitis, many who do not seek treatment at all.¹¹ Identifying these patients in need is an opportunity to improve lives as well as our practices. The second step is to apply knowledge of how each individual drug works in combination with insights into the pathophysiological mechanisms of ocular allergy to refine your therapeutic strategy and increase success of resolution. So, get out there and prepare for allergy season!

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