Last month we took a closer look at pollens, the instigators of seasonal allergies. But there are more allergy-causing elements in the world than just trees, weeds and grasses. A host of commonly occurring substances, such as animal dander, dust mites, insect detritus and various indoor molds can elicit allergic reactions that include allergic conjunctivitis. What’s more, these allergens elicit these allergic signs and symptoms year-round. The subsequent one-two punch of seasonal and perennial allergies has a substantial health impact. Annual costs for allergy prescription medications alone exceeded $6 billion as recently as 2002,1 and although that dollar amount may have declined in the past decade as many of the most popular drugs went from prescription to generic to over-the-counter status, disease prevalence continues to rise. An estimated 50 to 60 million Americans suffer from seasonal or perennial rhino-conjunctivitis.2 Of these, between 60 and 90 percent experience ocular symptoms including hyperemia, pruritus or chemosis.2,3
This month we’ll describe the similarities and differences between perennial allergens and seasonal pollens, and explore their critical impact on the growing numbers of patients who suffer from ocular allergy year-round.
The Usual Suspects
Allergens are often classified as either indoor or outdoor varieties.4 Indoor (perennial) allergens, such as those present in the home, can be further classified according to their specific source. Pets and domestic animals bring their dander, while dust mites, cockroaches and molds provide allergens in form of feces, spores and other debris. Among the most common allergies are those to cats, dogs and other domesticated animals. These are the allergies that particularly highlight the higher prevalence of atopic diseases in modern societies.5 Both dogs and cats produce multiple allergenic proteins expressed in the discarded skin fragments that constitute their dander. Cat allergies are particularly common, and show the most significant association with more serious and chronic allergy, including allergic forms of asthma.
Among all categories of perennial allergen sources, the dust mite is king.6,7 These invisible (about 200 µm in length) members of the spider family are found in abundance in virtually every place where humans live. While their name implies that the levels of mite allergens can be controlled by frequent, rigorous cleaning, maintenance of a lower humidity is at least as important as conscientious use of a vacuum. As many as 14 dust mite allergens have been identified,8 with Der p 1 and Der p 2 demonstrating positive skin tests in the highest percentage of allergy sufferers.7 Dust mite allergens, particularly Der p 1, are especially noteworthy in that they exhibit proteolytic activity capable of causing damage to ocular, nasal or alveolar epithelial cells.9
While they are less pervasive than dust mites, cockroaches are also significant contributors to the allergen burden, especially in urban localities. The dominant allergens from members of the genus Blattella and Periplaneta, including Bla g 2, Bla g 5, and Per a 10, exhibit proteolytic activity similar to the enzyme activity reported for Der p 1.8 The urban setting can exacerbate the effects of these allergens when they combine with components of industrial pollutants, as has been shown for seasonal allergens.10
Another major source of perennial allergens is indoor and outdoor molds.11 Many molds, such as Alternaria, Cladosporium and Aspergillus grow indoors and outdoors, but it’s thought that the primary sensitization to mold allergens is due to indoor spore exposure. In some respects molds can be considered seasonal, as the spore production in most temperate regions peaks in the fall. Despite this, molds persist in indoor environments year-round, as do the allergic reactions they initiate. The allergens present in mold spores are quite different from other allergen sources. Mold allergies are among the most common type of allergy, with estimates of 3 to 10 percent incidence worldwide, and skin test reactivity in 10 to 30 percent of patients with allergic rhinoconjunctivitis.11
The attack on the ocular surface that results from prolonged allergen exposure can lead to proteolytic breakdown of key epithelial proteins, especially those involved in maintenance of the cellular tight junctions such as the cadherins, keratins and occludins.14,15 Disruption of the cell-cell contact points increases access of inflammatory cells to the ocular surface and promotes secretion and activity of pro-inflammatory cytokines. This combined assault has been described as “urban eye allergy syndrome,”16 but this descriptor is misleading in that it implies that the disease is limited to large metropolitan areas. A number of studies have suggested that co-morbidity of seasonal and perennial allergy may be enough to tip the scales, overwhelm both natural barriers and traditional antihistamine therapies and lead to a chronic, inflammatory allergic state. In clinical trials, patients with perennial allergy are more likely to experience chronic disease in response to seasonal allergens.17 Other studies have shown that damage to the epithelial barrier function persists even in the absence of allergens, placing these individuals at greater risk for more severe disease in future allergic responses.14 As our knowledge of allergens expands, it’s becoming evident that allergic disease results from both the familiar IgE/mast cell effects and a second, more direct assault on the ocular surface from the combination of environmental toxins and allergen-based degradative enzymes.
It’s clear that therapies developed and tested on patients with seasonal conjunctivitis may not be sufficient to treat more chronic disease that can occur with perennial allergens. As with most inflammatory disorders, the natural tendency is to reach for the corticosteroids, and these drugs, especially topical formulations, are effective in treating inflammation associated with chronic allergy.
Recent studies suggest that some topical antihistamines may also act to reduce ocular surface damage associated with chronic disease.15 Overall, however, it appears that there is a growing need for new treatment approaches to address the needs of patients with chronic ocular allergy. This is particularly true as our patient population matures, adding co-morbidities such as dry eye into the therapeutic equation. At the recent Tear Film & Ocular Surface Society Asia symposium, Paul Gomes of Ora Inc. presented results of a survey showing 60 percent of patients being treated for dry eye also reported signs and symptoms of chronic ocular allergy.
In order to develop new therapies, it’s critical to adopt appropriate clinical protocols that specifically address the treatment of chronic allergy. This can involve adaptations to either traditional allergen challenge methods or modified selection criteria to either CAC or environmental studies. In either case, it’s necessary to carefully, clearly identify patients with significant levels of chronic disease if one hopes to identify effective new therapies.
Several prospective therapies show particular promise as treatments for chronic allergy. As with any allergy therapy, the mast cells are the primary targets for intervention. In mast cells (and basophils) the coupling of antigen binding to the release of histamine and other allergic mediators is critically dependent upon the action of a number of intermediate enzymatic steps. Among these are the protein phosphorylations catalyzed by a tyrosine kinase originally identified in spleen cells (Spleen tyrosine kinase, or Syk).18 Inhibitors of Syk have been shown to provide potent, long-duration attenuation of mast cell degranulation, and so are ideal candidates for treatment of allergy, both acute and chronic. Another promising new class of drugs is the partial glucocorticoid agonists, drugs designed to retain the anti-inflammatory effects of corticosteroids without their dose-limiting adverse effects on intraocular pressure.19 Examples of both of these classes of drugs have been effective in preclinical models of chronic allergy, and they should be moving toward human studies in the near future.
Immunotherapy for allergies has always been a treatment of last resort, but the combination of increased prevalence and severity of disease suggests that it deserves consideration as a therapeutic option, albeit on an individual patient basis. The limitation of IT is that it is allergen specific, as demonstrated by a recent study of patients with grass and mite allergies treated with allergen-specific therapy over a three-year period.20 Results showed a 16- to 30-fold decrease in allergen sensitivity, but that decrease didn’t cross over to the untreated allergen. Since the majority of patients have multiple allergen sensitivities, therapy would necessarily focus on the worst of the offenders, or involve multiple allergen immunizations.
As in any conflict, you arm yourself with both tools of combat and knowledge of your adversary. Therefore, a knowledge of pollens and perennial allergens is vital when developing a battle plan against ocular allergies. REVIEW
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute. Dr. McLaughlin is a medical writer at Ora Inc.
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