Allergies (allergic rhinitis), the counterpart to allergic conjunctivitis, represent a significant problem for approximately 25% of the U.S. population¹ (i.e., more than 50 million people) and are responsible for about 10% of all doctor visits.^2,3 But, as eye care practitioners we should be even more concerned since 60% of allergic rhinitis patients manifest significant ocular symptoms associated with allergic conjunctivitis. In fact, allergic conjunctivitis appears to be directly related to allergic rhinitis manifestations and, less frequently, to asthma and eczema.⁴ Furthermore, the treatment of allergic rhinitis represents a $7.5 billion business, yet the market for treating allergic conjunctivitis with prescription products barely tops $300 million in the United States.

In addition to these numbers, we also know that more than 41 million bottles of OTC vasoconstrictor eye drops are used every year as a direct result of patients' self-diagnoses and treatment. Based on these numbers, the systemic treatment of the disease is presumed to alleviate the ocular symptoms of the disease, but as eye care practitioners we know that is not the case. A better clinical understanding of allergy in general and allergic conjunctivitis in particular may improve our ability to help these patients.

Degranulation
The classic ocular allergic response is a type I antigen-IgE-mediated hypersensitivity reaction. While allergy is an extremely complex process, in traditional terms, it initially requires the sensitization of a mast cell, its activation (degranulation) and release of mast-cell derived mediators, particularly histamine, which induce the signs and symptoms of allergy.

Degranulation can occur either mechanically (eye rubbing secondary to severe itching) or when an allergen binds to two separate IgE molecules creating a dimer formation that initiates a chain reaction in the mast cell plasma membrane^5,6 leading to an uptake of Ca⁺² by the mast cell.⁷ After a primed mast cell is re-exposed to an allergic stimulus it deregulates, exposing the tissue to a variety of pre-formed and newly formed inflammatory chemical mediators that initiate the allergic cascade.⁸

Histamine, released from the degranulation of mast cells, is the primary chemical mediator of the allergic response. In addition, some of these chemical mediators recruit other cells, such as eosinophils, which participate in the allergic response in more severe allergic disease.⁹ In most cases of seasonal allergy, however, eosinophils do not play a large role in the clinical presentation. In the eye, the allergic cascade results in signs of redness, tearing, swelling and itching. The most notable sign of ocular allergy is itch.

Mast Cell Heterogeneity
While mast cells exist throughout the body (eye, skin, lung, nasal mucosa and small intestine), it is important to appreciate that all mast cells are not alike. Human mast cells are readily differentiated into two subtypes based on their specific protease histochemistry: those that contain tryptase (MC_t) and those that contain tryptase and chymase (MC_tc).¹⁰ (See Figure 1.) More importantly, the tissue distribution of these mast cell subtypes is such that MCtc comprise 88% of the total mast cells in epithelial tissue, while lung tissue, nasal mucosa and the mucosa of the small intestine is comprised almost exclusively of MC_t.¹¹

Figure 1: Mast Cell Heterogeneity
	Connective Tissue Mast Cell (MCtc)	Mucosal Mast Cell (MCt)
Protease histochemistry	Tryptase and chymase	Tryptase
Location	Skin Serosal surfaces	Small intestinal mucosa Alveoli of lungs
Size	Large Uniform	Small Pleomorphic
Histamine content (pg/cell)	1-30	0.1-2.0
Inhibition of activation by disodium cromogylcate (Cromolyn)	Yes	No
Life span	> 40 days	< 40 days

There are more than 5000 mast cells per cm³ in the human conjunctiva and while they are located predominately in the substantia propria in a quiet eye, they are found in more superficial tissue layers in chronic allergic conditions. This makes the eye a highly reactive tissue from an allergy standpoint.

From an ocular standpoint, mast cells of the human conjunctiva are the MC_tc subtype and more closely resemble skin mast cells than those found in the nasal mucosa. Also, while the typical nasal and lung allergic response is biphasic, demonstrating a distinct relatively severe early phase reaction followed by a generally less severe late phase reaction, the ocular allergic response, in all but a few clinical conditions, is typically restricted to just an early phase reaction.

Mast cell heterogeneity is important because most drugs developed for allergic conjunctivitis were originally developed to treat the allergic cascade in the nasal mucosa (rhinitis) or in the lungs (asthma). And, drugs that target MC_t (rhinitis and asthma) are simply not as effective in the eye where MC_tc predominates.

Forms of Conjunctivitis
Clinically, conjunctivitis presents with three basic classifications: viral, bacterial and allergic. While each of these conditions has a unique clinical presentation, sometimes they can be difficult to differentiate. (See Figure 2). A key differentiating symptom for allergic conjunctivitis is 'breakthrough itching.' While more chronic conditions such as atopic keratoconjunctivitis (AKC),^12,13 vernal keratoconjunctivitis (VKC)¹⁴ and even giant papillary conjunctivitis (GPC)¹⁵ (GPC however is not really an allergic disease; it is due to repeated micro-trauma to the ocular surface) represent severe forms of ocular allergy with late phase reactions and tissue damage, allergic conjunctivitis (seasonal [SAC] and/or perennial [PAC] allergic conjunctivitis)¹⁶ represents the vast majority of allergic ocular disease.

SAC is typically associated with pollens and outdoor molds and primarily occurs seasonally in either the spring or fall. While PAC can be present all year long and is associated more with indoor molds, cockroaches, dust mites and pet dander it appears to be an extension of SAC based on the similarity of clinical symptoms and the immune mechanisms involved.¹⁷ Acute allergic conjunctivitis differs slightly from SAC and PAC in that it is usually just a 24 hour phenomenon. However, acute allergic conjunctivitis, SAC and PAC are caused by a response to environmental allergens and present with the hallmark signs of ocular allergy: hyperemia, chemosis, mucous discharge, lid edema, tearing and itching (see Figure 3).

Figure 3

To differentiate dry eye from allergy and bacterial conjunctivitis remember that burning is typically associated with dryness, itching with allergy and stickiness with bacterial conjunctivitis.

In more chronic forms of allergic conjunctivitis, such as VKC in children and AKC in adults, the following changes are evident: a persistent state of mast cell, eosinophil and lymphocyte activation; noted switching from connective-tissue to mucosal-type mast cells (although the connective-type still predominate); increased involvement of corneal pathology; and papillae development and fibrosis.¹⁸

Some evidence exists that AKC is a variant of VKC that affects an older population. Hence, tissue damage is more severe and these can be sight threatening conditions.⁸

GPC has primarily been associated with contact lens wear, although other mechan ical irritations (e.g., exposed sutures) of the upper tarsal plate have also been associated with the development of large diameter papillae. Fortunately, these conditions represent less than 5% of ocular allergic disease.

AKC is a potentially blinding disorder that is associated with a hereditary condition, called atopy, and presents with not only ocular disease, but skin abnormalities and respiratory tract dysfunction.¹⁹ While bilateral itching is a common complaint, burning is often a more prevalent symptom among these patients due to the chronic ocular surface inflammation that is present. Additional issues such as gelatinous nodules adjacent to the cornea,²⁰ Trantas' dots, conjunctival cicatrization with symblepharon and keratoconus can be present.¹⁹ Topical antihistamine/mast cell stabilizers for disruption of the allergic cascade and to reduce itching, non-steroidal anti-inflammatory drugs to reduce inflammation, and steroids to minimize tissue damage may all be required in the treatment of this disease.

Figure 4

VKC is a seasonally influenced allergic condition that effects children more commonly than adults and shows 2:1 predominance for males over females.²¹ Primarily two clinical forms of the disease (tarsal and limbal) exist, although a mixed form (tarsal/limbal) can develop. Giant, flattened tarsal plate papillae with significant mucous secretions characterize the tarsal form of the disease, while single or multiple gelatinous limbal infiltrates are pathognomonic of the limbal disease.²⁵ Intense itching with hot, tight, sensitive, photophobic eyes is characteristic of this disease pro-cess. Due to the significant presence of eosinophils in VKC,²² varying degrees of corneal ulceration are possible.²³

Since the potential complications of VKC can be so severe, aggressive treatment with steroids is often recommended for moderate to severe presentations, while antihistamine combination mast cell stabilizers and NSAIDs may be helpful in very mild forms of the disease or in adult patients who have demonstrated significant improvement after adolescence.²⁴

While GPC can develop from many circumstances (ocular prostheses,^25,26 exposed sutures,²⁷ and irregular corneal surfaces from foreign bodies including limbal dermoids²⁸ and filtering blebs ),²⁹ the problem occurs most frequently with contact lens wear.³⁰ Contact lens chemistry plays a role in the development of GPC; however, other factors such as edge design, surface properties, fitting characteristics, and replacement cycle are also important variables in the pathophysiology of GPC.³¹

Since both GPC and VKC involve mechanical trauma, it is not unusual for them to share common features such as hyperplastic nodules on the upper tarsal plate, excess mucus production and itching.³² Although antihistamine/mast cell stabilizers are effective in controlling the symptoms of GPC, often the best treatment is removal of the offending agent, be it an exposed suture or a contact lens. It should be noted that AKC, VKC and GPC all show moderately high amounts of eosinophils, but SAC does not.³³

Self-Medicating
The medical management of allergic conjunctivitis is multifactoral and ranges from non-pharmacologic, over-the-counter treatment to pharmacologic intervention. For relatively mild symptoms of ocular allergic disease, simple avoidance of the offending allergen is an effective treatment, but naturally this is also very difficult.³⁴

Tear substitutes and cold compresses have been the mainstay of non-pharmacologic treatment. Tear substitutes provide a barrier function preventing the allergen from reaching the mast cell and triggering the allergic cascade. Moreover, they serve to dilute and flush allergens and inflammatory mediators from the eye reducing the clinical response, while cold compresses minimize the itching and swelling. Both techniques, although highly effective, exhibit short-term activity, especially during the peak of allergy season.

Many over-the-counter antihistamine/decongestant preparations (e.g., Naphcon-A, Opcon-A and Visine-AC) are self-prescribed by patients and can provide rapid, but short-lived relief of symptoms. These vasoconstrictors are sympathomimetic alpha adrenergic agents and will reduce injection regardless of the causative agent by causing the conjunctival vessels to constrict, decreasing blood flow and resulting in shrinkage of the tissue.³⁵ Tachyphylaxis occurs with these agents and, with the short duration of action, re-appearance of symptoms may occur within 6 hours.³⁶

While antihistamine/decongestant drugs typically provide suboptimal concentrations of medication to adequately treat allergic eye disease, these OTC agents are also contraindicated for patients with narrow angle glaucoma, can cause mydriasis at low concentrations and are associated with discomfort upon instillation. Unfortunately, 90% of patients who suffer from allergic eye disease choose to self-medicate, despite the availability of more effective treatments.

Pharmacologic Treatment
The pharmacologic treatment of allergic eye disease includes the use of potent topical antihistamines, mast cell stabilizers, antihistamine/mast cell stabilizer combinations, NSAIDs and steroids. Early treatment of ocular allergy was directed toward minimizing the symptoms associated with histamines. Early antihistaminic drugs, such as levocabastine and emedastine, competitively and reversibly block H₁ receptors to relieve the itching and redness associated with allergy. Since they leave other pro-inflammatory mediators like prostaglandins and leukotrienes uninhibited, they only provide short-term symptomatic relief. When antihistamines are combined with vasoconstrictors they may help relieve the intense redness of the allergic cascade.

Mast cell stabilizing drugs are designed to stabilize the mast cell, preventing its degranulation and the subsequent release of histamine and other pro-inflammatory mediators. While the exact mechanism of action is still unknown, inhibition of Ca⁺² influx into the cell, membrane fluidity and the inhibition of phosphorylation of required proteins are some of the proposed actions.

Since it takes time for the cell membrane to become stable, loading doses are required and immediate symptomatic relief is not obtained from this class of drugs alone. In view of the fact that mast cell stabilizers have no effect once the inflammatory cascade has begun, long-term (7-14 days) application is typically required before symptoms abate.

This general class of drugs has no direct effect on vascular permeability, histaminic sites or anti-inflammatory actions.³⁷ Mast cell stabilizers merely stabilize the mast cell to prevent the further release of chemical mediators. Examples of single action mast cell stabilizer drugs are cromolyn sodium (Opticrom), lodoxamide tromethamine (Alomide), nedocromil sodium (Alocril) and permirolast (Alamast).

A relatively new class of mast cell stabilizer-antihistamine combination drugs--olopatadine HCL (Patanol), ketotifen fumarate (Zaditor) and azelastine (Opti-var)--addresses the issue of providing more immediate symptomatic relief. The combination of a potent antihistamine with a mast cell stabilizer quiets the eye while the mast cell stabilizer increases duration of action and, over time, prevents the release of inflammatory mediators, thereby reducing the allergic cascade.

Olopatadine has demonstrated action in multiple sites along the allergic cascade, including effects on IL-4, Th2 lymphocytes, and the reduction of the release of TNF-alpha thereby reducing upregulation of ICAM and in turn the attraction of eosinophils.³⁸ In addition, it demonstrates H₁-receptor site binding similar to that of levocabastine, which classically produces acute symptomatic relief for allergic hypersensitivity.^39,40

Ketotifen, another combination mast cell-antihistaminic drug has also been shown to inhibit the release of leukotrienes, inhibit eosinophil chemotaxis and suppress eosinophil activation by cytokines.⁴¹

Azelastine has demonstrated effects on suppressing release of mast cell mediators in cells from rat skin and human umbilical mast cells.⁴²

Drug Concentrations
When dealing with antihistamines for the treatment of allergic eye disease it is important to understand that antihistamines exhibit a biphasic effect on mast cells. This cytotoxic membrane effect causes histamine to actually be released at higher antihistamine concentrations, but not at lower concentrations of the drug.^43,44 Histamine release is thought to occur from non-specific membrane damage, possibly from the disru ption of membrane integrity as the amphipathic molecules insert themselves into the membrane.^45-48

Figure 5

For example, at low concentrations, pyrilamine, pheniramine, diphenyl hydramine and clemastine (all classic H1-receptor antagonists) inhibited histamine release, but at higher concentrations, even with more modern antihistamines (epinastine, ketotifen, azelastine) used topically in the eye, histamine was released in large quantities.⁴⁹ Because such large quantities of antihistamine are present secondary to the drug administration, the patient does not experience itching because the H1 receptor sites are blocked in spite of the cytotoxic effect of the drug and subsequent lysis of the cell membrane. Hence, when long-term allergy relief is necessary, it is beneficial to use a drug like olopatadine, which does not have cytotoxic membrane effects.

A study examined the effect of selected antihistamines (including desloratadine, olopatadine, ketotifen, azelastine and epinastine) on model membranes. It showed that these agents, except for olopatadine, caused disruption of the cellular membrane. The most common side effect of this class of drugs is transient headaches, which will occur in a small percentage of patients varying from <10% to 40% dependent on the agent.

Steroids and NSAIDS
Non-steroidal anti-inflammatory drugs (NSAIDs) like ketorolac (Acular) also have clinical indications to reduce ocular itching, but they are of questionable efficacy in the treatment of ocular allergy. Since NSAIDs inhibit the cyclooxygenase metabolic pathway, stopping production of prostaglandins and thromboxane, it does not affect preformed mediators, notably histamine, or the lipoxygenase pathway. Also, they can delay corneal healing by interfering with wound repair. A stinging sensation with topical application of NSAIDs is the most common adverse effect.⁵⁰

While the use of either hard steroids, such as prednisolone acetate (Pred Forte), or soft steroids, such as loteprednol 0.5% (Lotemax) and loteprednol 0.2% (Alrex), have significant anti-inflammatory indications in severe ocular allergic disease, they are primarily used for short term pulse therapy only in recalcitrant acute allergic conjunctivitis^51,52 or when other treatments are ineffective.⁵³ The potential side effects of cataract formation, increased intraocular pressure and the exacerbation of herpetic corneal lesions limit their long term use except in cases of VKC and on rare occasions with AKC. However, the potential development of shield ulcers in VKC and corneal melting in AKC require careful professional supervision.

Systemic Meds
From a patient perspective, a more frequently used treatment option is the use of either over-the-counter or prescribed systemic oral antihistamines. Unfortunately, this group of medications provides only minimal relief for allergic conjunctivitis and often can worsen ocular symptoms by drying the corneal surface as a consequence of reduced tear production. In one study for example, it was shown that Claritin causes clinically meaningful damage to the ocular surface due to its anti-muscarinic action and that both tear flow and tear volume is reduced from a 4-day dosage regimen.⁵⁴ Moreover, the addition of topical olopatadine to systemic Claritin therapy significantly reduced ocular itching associated with allergic conjunctivitis compared with treatment with Claritin alone, indicating that concomitant topical therapy is an important adjunct to systemic therapy for allergy-prone patients.⁵⁵

Although prescription intranasal steroidal inhalants are effective for allergic rhinitis symptoms, they have no effect on ocular symptoms. However, since there is such a close association between these two disease processes, practitioners should consider treating these patients for ocular allergic disease as well. In general terms, though, the question arises regarding the efficacy of systemic versus topical treatment for allergic eye disease. Since ocular allergy is primarily a topical problem, it is far better to treat this ocular allergy topically rather than systemically.

The most common adverse effect associated with oral H₁ antihistamines is sedation.⁵⁶ Not only can higher concentrations of drugs be delivered directly to the source of the problem, topically applied drugs also have less interaction with other systemic medications and fewer central nervous system side effects (e.g., sedation, dizziness, insomnia, nervousness or tinnitus).

Contact Lens Wear
Contact lens wear often complicates the diagnosis of allergic ocular disease. Allergy must be differentiated from GPC, contact lens fitting and/or solution related complications as well as systemically dry and contact lens-induced dry eye conditions. While itching is the hallmark symptom of an allergic reaction, it may be confused with foreign body sensation characteristic of contact lens wear.

The most significant of these issues is GPC since it results in abnormally large upper tarsal plate papillae, conjunctival hyperemia, excess mucus secretion, foreign body sensation and disruption of contact lens wear.⁵⁷ While GPC bears some clinical, physiological and etiological similarities to VKC, it is primarily associated with a combination of mechanical irritation and allergic factors⁵⁸ in response to contact lens wear and is reversible in most situations.^59,60 However, atopy also plays a significant role in a patient's predisposition to GPC.^61,62

Generally, GPC appears as rounded, more fleshy papillae (Figure 4), while VKC has a much more flattened appearance (Figure 5). Since mast cell degranulation is involved in the immunopathology of GPC, mast cell stabilizers^63-65 and antihistamine-mast cell stabilizer combination drugs⁶⁶ are generally very effective in the treatment of this disease. Compared with a placebo, olopatadine, when used for allergic contact lens wearers, increased wearing time by 2.1 hours longer with superior comfort from the signs and symptoms of seasonal allergic conjunctivitis, as induced by the CAC model.⁶⁷

A once a day topical allergy medication would potentially be more convenient for our contact lens wearing patients as they would use the drops at the same time they are inserting their contact lenses.

While contact lens materials themselves rarely cause allergic ocular reactions, some combinations of lenses and solutions can cause significant corneal irritation, which can be confused with ocular allergy symptoms. While allergic conjunctivitis may or may not be associated with contact lens wear, prophylactic application of antihistamine/ mast cell stabilizers during allergy season can significantly improve contact lens wearing comfort.

Successful Practice
From a business perspective, not addressing allergies in practice reduces a patient's general satisfaction with your practice including creating dissatisfaction with contact lens wear, displeasure with anti-reflective coatings and an increased interest in alternative procedures such as refractive surgery.

More importantly, patients will seek alternative sources for professional care if their clinical needs are not being met. The data shows that most patients will self-medicate with less effective OTC allergy drops and usually won't see their eye care professional for allergy, per se. Thus it is important to ask patients about their allergies, even if the primary reason for their visit is something else.

By proactively addressing allergic ocular disease you not only provide an additional income stream for your practice by increasing the number of billable primary care visits, but the increased patient flow will help build opportunities for referral and more solid relationships with existing patients.

References cited here are available at Review of Optometry OnLine, www.revoptom.com.

About the Authors