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,Stempel DA, Woolf, R. The cost of treating allergic rhinitis. Curr.Allergy Asthma Reps.2002;2:223-230. 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.Van Cauwenberge P, De Belder T, Vermeiren J, Kaplan A. Global resources in allergy (GLORIA): Allergic rhinitis and allergic conjunctivitis. Clin Exper Aller Rev 2003;3:46-50. Of these, between 60 and 90 percent experience ocular symptoms including hyperemia, pruritus or chemosis.,Blaiss M. Allergic rhinoconjunctivitis: Burden of disease. Allergy Asthma Proc 2007;28:393-7.
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.Platts-Mills TA. Indoor allergens. In: E Middleton Jr, ed. Allergy: Principals and Practices, 5th edition. St Louis: Mosby, 1998:393-409. 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.Erwin EA, Woodfolk JA, Custis N, Platts-Mills TA. Animal Danders. Immunol Clin N Am 2003;23:469-481. 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.
On the surface it would seem that perennial allergies would be easy to contain with avoidance measures, particularly when compared to seasonal allergens such as pollens. But it’s not as easy as giving the cat up for adoption. There are more than 80 million pet cats in the United States, and cat allergens are widely distributed even in places such as schools, public buildings and homes without cats. To a lesser extent the same is true for dog allergens, although they don’t appear to be as allergenic as those from the cat, particularly the Fel d 1 allergen. In fact, the high levels of environmental cat allergens are offset, at least to some degree, by the tolerance that develops in many sensitized individuals. Unlike most other perennial allergens, high levels of exposure to Fel d 1 can lead to tolerance, as demonstrated by studies showing that up to half of children who live with cats develop a robust antibody response without exhibiting signs or symptoms of rhino-conjunctivitis. Similar studies with other perennial allergens do not show this tendency.
Among all categories of perennial allergen sources, the dust mite is king.Arlian LG, Morgan MS, Neal JS. Dust mite allergens: Ecology and distribution. Current Allergy Asthma Reports. 2002;2:401-411. ,Bessot JC, Pauli G. Mite allergens: An overview. Eur Ann Allergy Clin Immunol 2011;43:141-156. 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,Http://www.Allergen.org. Accessed 29 March 2012. 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.Chapman MD, Wünschmann S, Pomés A. Proteases as Th2 adjuvants. Curr Allergy Asthma Rep 2007;7:363-7.
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.Riediker M, Monn C, Koller T, Stahel WA, Wüthrich B. Air pollutants enhance rhinoconjunctivitis symptoms in pollen-allergic individuals. Ann Allergy Asthma Immunol 2001;87:311-8.
Another major source of perennial allergens is indoor and outdoor molds.Hamilos DL. Allergic fungal rhinitis and rhinoconjunctivitis. Proc Am Thorac Soc 2010;7:245-252. 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.
Hygiene Hypothesis Revisited
In 1989 a paper in the British Medical Journal described a study showing that the incidence of rhino-conjunctivitis in children who were followed from birth until adulthood was inversely proportional to the number of siblings in their families.Strachan DP. Hay fever, hygiene, and household size. Brit Med J 1989;299:1259-1231. The author, David Strachan, MD, PhD, suggested that this could be due to an increased rate of neonatal infections in children who shared a household with “unhygienic siblings.” What may have seemed like significant conjecture at that time has since become a generally accepted explanation for the disparity in rates of allergic disease between developed and developing countries. Allergies, it seems, are a price we pay for a clean, healthy childhood and the associated increases in longevity. While genetics clearly plays a role in atopy, early exposure to an array of allergenic stimuli somehow acts to dampen subsequent immune system activity. Since Dr. Strachan’s landmark paper, research has focused upon possible mechanisms of such an effect. For a time bacterial and viral infections in early life were thought to shift the balance between Th1 and Th2 immunity (favoring a less atopic Th1) but more recent reports suggest that it may be helmenthic infections that drive the immunological balance away from the tendency for atopy.Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: Revisiting the hygiene hypothesis. Nature Rev Immunol 2001;1:69-75. ,Mekhaiel DN, Daniel-Ribeiro CT, Cooper PJ, Pleass RJ. Do regulatory antibodies offer an alternative mechanism to explain the hygiene hypothesis? Trends in Parasitology 2011;27:523-529. The boom in probiotics may represent the biggest single result of the hypothesis, even though evidence for probiotic effects in therapy of allergic diseases remains equivocal. Recent reports establishing a role for cytokines involved in the Th1-Th2 balance, such as IL-10, may hold promise. Stay tuned.
It’s not surprising that patients with perennial allergies experience more severe allergic symptoms; unlike seasonal disease, they are typically exposed to the offending allergens year-round. But other factors also contribute to the severity of their disease.Wong AH, Barg SS, Leung AK. Seasonal and perennial allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2009;3:118-27. Chronic exposure to allergens is likely to cause damage to the ocular surface, and the subsequent immune response that is established creates a constant state of inflammation.Choi SH, Bielory L. Late-phase reaction in ocular allergy. Curr Opin Allergy Clin Immunol 2008;8:438-444. Atmospheric contaminants such as ozone, nitric oxides and hydrocarbon exhaust have the potential to act directly on the ocular surface, or indirectly on airborne allergens to further enhance this effect. These challenges can eventually lead to compromising the corneal and conjunctival epithelial layer which functions as the barrier to environmental assault.
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.Hughes JL, Lackie PM, Wilson SJ, Church MK, McGill JI. Reduced structural proteins in the conjunctival epithelium in allergic eye disease. Allergy 2006;61:1268-1274.,Ono SJ, Lane KJ. Comparison of effects of alcaftadine and olopatadine on conjunctival epithelium and eosinophil recruitment in a murine model of allergic conjunctivitis. Drug Design, Development and Therapy 2011;5:77–84. 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,”Leonardi A, Lanier B. Urban eye allergy syndrome: A new clinical entity? Curr Med Res Opin 2008;24:2295-2302. 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.Gomes P, Abelson MB, Mandell K. Perennial allergen skin sensitivity as a predictor of seasonal allergic rhinoconjunctivitis severity. Journal of Allergy and Clinical Immunology 2010; 125S:AB172. 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. 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. 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).Riccaboni M, Bianchi I, Petrillo P. Spleen tyrosine kinases: Biology, therapeutic targets and drugs. Drug Discov Today 2010;15:517-30. 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.Baiula M, Spartà A, Bedini A, et al. Eosinophil as a cellular target of the ocular anti-allergic action of mapracorat, a novel selective glucocorticoid receptor agonist. Mol Vis 2011;17:3208-23. 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.S. Dreborg S, Lee TH, Kay AB, Durham SR. Immunotherapy is allergen-specific: A double-blind trial of mite or timothy extract in mite and grass dual-allergic patients. Int Arch Allergy Immunol 2012;158:63-70. 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.
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.