Allergy is a disease that affects as much as 45% of our patient population. It is estimated that of those who have allergies, 60% suffer from ocular allergy. Most of these cases involve periodic and/or seasonal bouts of itching, runny, stuffy nose and itchy red eyes. This widespread problem can have a profoundly negative effect on the lives of patients, from early childhood, in many cases, straight through to later life.

With such a broad range of clinical options available to practitioners, advances in the management of allergic conjunctivitis can be difficult to keep track of. The following article is intended as an update on the basic science underlying ocular allergy, new concepts in its clinical presentation, and as a guide to effectively managing allergy patients in your practice.

Ocular allergy overview

Although sometimes used interchangeably, atopy and allergy do not mean the same thing. Allergy occurs when an atopic individual presents with what is an unusual and heightened immune response to otherwise normal environmental substances, such as plant pollens or animal dander. Atopic individuals possess a genetic predisposition to allergy, but they do not necessarily manifest it clinically. Allergy is the hypersensitivity reaction that occurs when an atopic individual is re-exposed to a sensitizing allergen.

Genetic predisposition is a key factor in whether a patient will develop ocular allergy. If one parent is allergic, a person is four times more likely to manifest allergy. If both parents are allergic, a person is 10 times more likely to manifest allergy.

Environmental factors also play a role. The incidence of allergy is higher among populations in developed countries. Known as the "hygiene hypothesis," it is thought that exposure to increased pathogen loads minimize development of the kinds of T-cells responsible for atopic response, decreasing a child's propensity to manifest allergy.

Pollution is also suspected to contribute to higher rates of allergy. Aromatic hydrocarbons from diesel exhaust may be involved in enhancing the production of inflammatory agents in the eye. In terms of susceptibility to allergy, the eye is probably one of the most sensitive organs. By design, it is directly exposed to the environment as no other organ is.

Allergy often affects younger patients. Those with severe disease may develop severe signs such as facial malformation; many pediatric patients have a nasal crease due to vigorous nose rubbing. This is called the "allergic salute." Sinusitis and rhinitis are also associated with ocular allergy.

The allergic cascade represents a complex interplay of cells and messenger molecules. Allergic conjunctivitis is a type I hypersensitivity IgE-mediated reaction that consists of four phases: 1) sensitization; 2) mast cell activation and subsequent degranulation; 3) activation, or early-phase response; 4) and late-phase response.

Sensitization is the cocking of the gun, as it were. Langerhans cells, B cells and macrophages function as antigen-presenting cells (APC) in the conjunctival mucosal epithelium to process the antigens to which the conjunctiva becomes exposed, such as pollens, dust mite fecal particles, animal dander and other proteins. These processed antigens then form a major histocompatability complex, forcing naïve Th0 lymphocytes to differentiate into antigen specific Th2 lymphocytes.^1,2

These newly differentiated Th2 cells then release cytokines, which in turn stimulate B cells to produce IgE and suppress the development of Th-1-mediated delayed-type hypersensitivity reactions.³ Antigen-specific IgE then populates mast cells, bound to the cell surface by high-affinity receptors, completing the sensitization phase.

The second step is mast cell activation and subsequent degranulation. After sensitization, mast cells in the conjunctival mucosa carry specific IgE antibodies on their surface. Antigens in the air enter the tears, come into contact with the surface of the eye and bind to mast cells. Binding to specific IgE, an influx of calcium initiates mast-cell degranulation, with the subsequent release of both preformed and synthesized inflammatory mediators. The result is the classic signs and symptoms of allergy. The mast cell is the key player in allergic response. It stands silently as a sentinel of immune defense until it contacts an antigen that it has been sensitized to. Once that happens, a prototypical and predictable series of responses initiates.

The early phase of the disease occurs after mast cell degranulation. This is typified by the release of preformed and newly formed mediators such as histamine, tryptase, prostaglandins and leukotrienes. Increased histamine levels stimulate blood vessels, nerves, and mucus producing glands. This results in the characteristic signs and symptoms of allergic disease. Early-phase reaction is what is responsible for the classic ocular itching, conjunctival redness, chemosis, lid swelling and tearing associated with this condition. It is important to remember that in a larger sense, all of the signs and symptoms of allergy are attempts by the body to wash away the offending antigen and, secondarily, to mobilize defenses against it. There are many known mediators involved in the allergic response; histamine is still the foremost pro-inflammatory mediator that accounts for these signs and symptoms. It is important to note that garden-variety seasonal or perennial ocular allergy, the kinds most commonly seen in clinical settings, do not involve late-phase reactions or the presence of eosinophils or other cellular response.

When they occur, late-phase allergic reactions are more serious and are linked with problems such as asthma, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis. Therefore, it is important that we understand differences between the early and late phases of the disease. The late phase is cell mediated rather than localized, and late phase can be associated with frank tissue damage.

During late phase, an influx of cells contribute significantly to the signs and symptoms. Histamine can be released by both mast cells and basophils in the late phase by the action of histamine-releasing factors (HRFs). Mononuclear cells, neutrophils and eosinophils are some of the inflammatory cells that produce HRFs. The eosinophil is the central cell in the late phase of the allergic reaction and functions like a more aggressive but mobile mast cell. Clinically, late-phase reactions are most commonly encountered in nasal mucosa during bouts of rhinitis.

Eosinophils

An influx of eosinophils occurs in chronic allergic inflammation and produces profound changes in the conjunctival mucosa. Eosinophils are activated by interactions with other inflammatory cells, with mediators and possibly with IgE.

Activated eosinophils release very basic, highly charged polypeptides, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EPX), and eosinophil peroxidase (EPO). These proteins may bind to basement membrane proteoglycans and hyaluran to cause cellular disaggregation and epithelial desquamation. ECP and MBP are also epitheliotoxic and are involved in corneal damage that occurs in severe chronic allergic conditions--an example being the shield ulcers that occur in VKC. ECP and EPX tear levels are correlated with the clinical signs and symptoms of vernal and atopic keratoconjunctivitis disease and may be considered local markers of eosinophil activation.

Eosinophils are also an important source of leukotrienes, prostaglandins, cytokines and chemokines such as IL-3, IL-5, GM-CSF, eotaxin and RANTES, promoting eosinophil survival and chemoattraction. Adhesion molecules and chemokines are expressed in conjunctival mucosa during the allergic reaction and are induced by several cytokines

The importance of histamine

Histamine is produced in situ and stored in the cytoplasmic granules of mast cells and basophils. It can also be found in histaminergic neurons (and plays a pivotal role in neurotransmission), in parietal cells, in enterochromaffin-like cells, in platelets and in endothelial cells. Its effects are mediated by the activation of specific H1, H2 and H3 receptors, the last mainly being associated with the nervous system.

In its archetypal role in inflammation, histamine acts primarily as a vasoactive peptide that induces vasodilatation and increases vascular permeability. It also has a wide range of biological functions, such as gastric acid secretion, cell proliferation and tissue growth and repair. The H1 receptors are mostly responsible for the early-phase allergic reaction, increasing vascular permeability, inducing vasodilatation, the sensation of itching and pain, and bronchial smooth muscle contraction. Histamine also binds to H1 receptors on nociceptive type-C nerves that are extensively branched in the mucosa, leading to their activation and release of neuropeptides such as substance P.

However, the most potent effect involves the activation of pain centers in the brain responsible for the sensation of itching and congestion, and of systemic reflexes such as tearing and glandular secretion.

The explosive degranulation of mast cells induced by allergens leads to release of histamine and a complex cascade of mediators that may have synergistic effects on resident cells in tissues. Mast cell degranulation also induces activation of vascular endothelial cells and thus the expression of chemokines and adhesion molecules. These factors initiate the recruitment phase of inflammatory cells in the conjunctival mucosa. Mast cell activation can also be initiated by other stimuli including substance P, polyamines, opiates and a wide range of cytokines.

Histamine is not the only preformed allergy mediator; neutral proteases (chymase and tryptase), proteoglycans (heparin) and hydrolases also work to instigate, exacerbate and prolong the allergic response. Another part of the allergic cascade involves synthesis of newly formed mediators. Among these inflammatory mediators and chemo-attractants are prostaglandins, thromboxanes and leukotrienes. Seasonal allergic conjunctivitis is typically an acute, recurrent and self-limiting disorder modulated by enzymes such as histaminase released during mast cell degranulation.

Diagnosis and management

The diagnosis of allergic eye disease is generally straightforward. After years of television and magazine ads for allergy products, most patients know that red, itchy, watery eyes mean allergy. Patients often diagnosis themselves. However, there are occasions when allergy mimics other disorders (and vice versa) or occurs with another condition concurrently. Also keep in mind that the filtered environment of your office may reduce or eliminate many of the signs and symptoms that patients experience in their habitual environment. In establishing an allergy diagnosis, remember that allergic disease is hereditary, but its clinical expression can vary, even with exposure to the same allergen levels. Yet as a general rule, heightened allergy periods tend to worsen symptoms in any sensitive patient.

For most patients the best therapeutic strategy is to prescribe conservative, focused treatment. Avoid a scattershot approach that targets all possible causes; polypharmacy invites toxicity (it's also expensive). Identify the primary signs and symptoms, and establish the best diagnosis you can make even in the face of conflicting or equivocal data. Treat patients with the most effective medications and discontinue those that are less effective. These recommendations stand to reason, but bear repeating.

If necessary, stop all medications for a wash-out period, then reevaluate the patient. Communicate with the patient during this period to ensure that he or she is following directions properly. Discontinue antibiotics that have not worked, and consider other alternatives, if indicated.

We have seen an explosion in the number of medications available to treat ocular allergy in recent years. Many are available over-the-counter, and while patients frequently self-medicate, OTC products are usually less effective and have more side effects than prescription medications. An OTC product used unsupervised is also more likely to cause ocular irritation and inflammation.

Antihistamines are a mainstay of systemic allergy treatment. But systemic antihistamines tend to dry the ocular surface and exacerbate allergy due to diminished tear film volume. Even the newer, non-sedating systemic antihistamines are inadvisable for patients who suffer from ocular manifestations of allergy.⁴

Topical antihistamines are particularly effective at reducing itching and redness during acute allergy attacks. Because these drugs work by blocking histamine receptors, instruct patients to administer topical antihistamines at the first sign of itching to minimize the subsequent allergic response. Emadine (emadastine, Alcon Laboratories) and Livostin (levocabastine, Novartis Ophthalmics) are effective and fairly inexpensive topical antihistamines. However, qid dosing and a short duration of action limit their usefulness, especially for contact lens wearers. Emadine has an "up to qid" approval, and may be effective at lower doses. Even so, antihistamines have no effect on the other inflammatory mediators of allergy.

Recent research suggests that overuse of antihistamines may actually increase inflammation due to mast cell degranulation subsequent to mast cell membrane lysis.⁵ This dose-dependent effect apparently occurs with almost all medications that have antihistamine effects. The exception is Patanol (olopatadine, Alcon Laboratories), which seems to balance dual-action antihistamine and mast cell effects without the membrane destabilization and the expulsive degranulation characteristic of pure antihistamines.

Given topical steroids' potential for serious side effects, doctors traditionally have reserved these agents to treat only severe ocular allergy. Earlier-generation steroids such as FML (fluoromethalone, Allergan) and Vexol (rimexolone, Alcon Laboratories) are now used less frequently for allergy owing to side effects such as IOP elevation and cataract formation. The new generation topical steroid Alrex (loteprednol etabonate suspension 0.2%, Bausch & Lomb), with a purportedly improved side effect profile, has renewed interest in using steroids to treat allergic conjunctivitis.

Remember, however, that steroids need to be ramped up over several weeks to reach maximal effect. Topical steroids are clinically effective primarily on late phase of the allergic reaction. They do nothing to counteract histamine release or production. Instead, they work intracellularly to inhibit production of pro-inflammatory mediators such as cytokines, leukotrienes and prostaglandins, which subsequently inhibits leukocyte recruitment and activation.

Topical steroids' broad anti-inflammatory effects can help as adjunctive pulse treatment with other faster-acting medications such as emadastine or olopatadine when confronted with prolonged allergic response. Don't forget that IOP may rise sharply even with mild steroids and that other steroid complications may still occur. Patients on topical steroids should be monitored closely. Typical steroid dosing is qid. Given the risks of serious, potentially sight threatening complications, reserve topical steroids for severe allergies unresponsive to other treatment.

Topical NSAIDs are agents that inhibit the production of prosta-glandins and thromboxane by blocking the activity of cyclo-oxygenase. They relieve the itching in allergic conjunctivitis, but are used less frequently now that we have more effective options available. Topical NSAIDs also sting on instillation. Acular (ketorolac tromethamine, Allergan) and Voltaren (diclofenac sodium, Novartis Ophthalmic) are the two commonly used topical NSAIDs.

While no one fully understands their mechanism of action, topical mast cell stabilizers have been a mainstay of allergy therapy for years. Safe and effective with minimal systemic absorption, these medications treat asthma and allergic rhinitis, and are used topically for allergic conjunctivitis. Mast cell stabilizers include Alomide (lodoxamide tromethamine, Alcon Laboratories), Opticrom (cromolyn sodium, Allergan), Crolom (cromolyn sodium, Bausch & Lomb) and Alamast (pemirolast potassium 0.1%, Santen Pharmaceuticals).

Mast cell stabilizers usually take several weeks for their effects to become clinically apparent. However, they can be quite effective in managing chronic allergy. In a recent clinical trial, pemirolast completely eliminated itching in treated patients. Some mast cell stabilizers may have other modulatory effects. For example, lodoxamide tromethamine also inhibits leukotriene release, which may be helpful in managing severe chronic ocular allergy such as VKC and AKC.

Patanol is the first in this class of multi-action allergy medications.^6,7 Its combined antihistamine and mast cell stabilization activity with an additional anti-inflammatory effect make this drug an excellent choice. Besides its antihistamine effects and mast cell stabilization, Patanol is also a cytokine-inhibitor. Notably, olopatadine was the first and remains the only topical medication that has actually been tested for effectiveness on human conjunctival mast cells. Functional and morphological differences between respiratory and conjunctival mast cells make generalized systemic testing clinically irrelevant and interspecies mast cell differences likewise make animal testing of negligible value.

Zaditor (ketotifen, Novartis Ophthalmics) also combines mast cell stabilizing and antihistamine effects along with disrupted eosinophil recruitment--which may be especially beneficial in chronic allergic states such as VKC. Alocril (nedocromil sodium, Allergan) is a new class of ophthalmic mast cell stabilizer with similar multiple actions; however, the risk of headaches limits its use. The bid dosing and superb efficacy of these medications make them ideal for contact lens wearers and cost-effective for any allergy sufferer.