Allergies: The Mark of Industrialization?

New treatments address the challenge of urban environments.

BY GAIL L. TORKILDSEN, M. D., AND PAUL J. GOMES, M. S.

When the association between respiratory disease and airborne soot was first realized in thirteenth century England, King Edward I attempted to eliminate this problem by prohibiting craftsmen from burning coal.¹ Industrialization continued over the centuries, and global warming and increased carbon dioxide levels soon followed. Today, air pollution comes in many forms and irritates many individuals, especially atopic city-dwellers.

As researchers continue to investigate urban and rural environments and the mechanisms of allergic disease, newer and improved treatments have been developed to better serve atopic individuals in these settings. In this article, we will examine their efficacy in meeting the problems posed by industrialized cultures' high-allergen environments.

Urbanization and Allergies

When the Industrial Revolution took place in Great Britain and the United States, an increasing number of affluent white males were suddenly afflicted with seasonal catarrh — nasal and bronchial inflammation, increased mucus production, and itchy, swollen eyes. They soon discovered that traveling to a different region prior to and during the catarrh season prevented its onset. Eventually, as the summer resorts burgeoned, it became apparent that allergy was not solely a mark of affluence.² At the time of the Industrial Revolution, however, the specific factors that contributed to the sudden and increasing prevalence of allergies were unknown.

The higher prevalence of allergy in urban environments is somewhat counter-intuitive, as cities have noticeably fewer open spaces containing trees and fields of flowers and ragweed. The urban allergy phenomenon may be partially explained by the hygiene hypothesis, which postulates that rural exposure to microbes and allergens encourages the maturation of the Th1 response to balance the neonatal Th2-favoring system. Studies have shown that growing up on a farm is correlated with a reduced risk of developing atopy later in life,³ and that children living in cities have higher rates of allergy than their rural counterparts do.^4,5

It has also been suggested that a later-in-life introduction to farm animals might actually increase the risk of atopic sensitization.^6,7 Because animals tend not to utilize antibacterial soaps, it may be that the exposure to high levels of bacterial endotoxins promotes Th1 cell proliferation in a young human's developing immune system.⁸ Similarly, the consumption of unpasteurized milk might also contribute to the decreased prevalence of allergic disease in rural areas, as unpasteurized milk contains more gram-negative bacteria than pasteurized milk does. Ingestion of non-infectious bacteria can lead to changes to gut flora that help us digest food, resulting in a lower chance of developing allergies.^9,10

Cities Alter the Allergenicity of Pollen

Within the city limits, pollen is much more likely to interact with air pollution, a known irritant that enhances its allergenicity. Pollutants damage the cell walls of pollen grains by accumulating on them, causing the release of the grain's proteinaceous contents, thereby exposing atopic individuals to more allergenic material.¹¹ To further exacerbate the ocular allergic response, hydrocarbons from diesel exhaust, sunlight, and nitrogen oxide interact and generate low level ozone, which results in oxidative stress on the conjunctival epithelium, potentially diminishing the protection provided by the tear film barrier. Studies have shown tear film stability to be worse and dry eye to be more prevalent among city-dwellers who were exposed to air pollution than among inhabitants of non-urban areas.^12,13

The elevated carbon dioxide levels and temperatures in cities increase both pollen production and allergenicity.¹⁴ Tall buildings in urban environments also trap in more heat, increasing atmospheric temperatures.¹⁵ Furthermore, 50% of atopic Americans are sensitized to ragweed,¹⁶ which thrives in disturbed soil.^17,18 Air pollutants, carbon dioxide and higher temperatures are all conducive to the enhanced growth and pollen production of plants, including ragweed.

Indeed, rhinoconjunctivitis symptoms among sensitized patients have been shown to be exacerbated by air pollutants. Air pollution elicited rhinoconjunctivitis symptoms in patients with atopy even when ambient pollen counts were moderate and met air quality standards.¹⁹ Ozone pre-treatment before nasal antigen challenge has been shown to significantly increase the presentation of upper and lower respiratory symptoms, as well as elevate levels of nasal lavage neutrophils, eosinophils and mononuclear cells; ozone exposure also resulted in the shedding of epithelial cells.²⁰ Additionally, diesel exhaust particle exposure prior to nasal dust mite allergen challenge caused three times greater histamine release than pre-treatment with placebo did.²¹

Atmospheric Pollen Levels

In addition to pollution, various climatic factors can influence atmospheric pollen levels. Higher temperatures have been shown to increase pollen counts,¹⁹ as has humid weather, which induces pollen grain release. Rain can also elevate pollen levels, since it can bring on osmotic shock to pollen grains, causing them to burst.²² As pollen levels are periodically measured and are reported, sensitized individuals can plan their daily activities and treatment regimens in accordance with environmental changes. Pollen levels of various cities in the United States can be searched online (see "Monitoring Pollen Levels," above); some sites display nationwide maps of levels of various types of pollen.

During peak season, airborne birch and grass pollen concentrations often reach figures in the thousands (per cubic meter), but it only takes concentrations of less than 100 grains/m3 of birch, grass, or ragweed pollen to elicit allergy signs and symptoms.²³ A study showed that the lowest concentration of airborne grass pollen that induced ocular allergic reactions was 22 grass pollen grains/m3, which occurred at the early phase of the grass pollen season. Patients with lower reactivity during a conjunctival provocation test developed conjunctival symptoms later in the grass pollination season, and the mean daily pollen level that led to moderate conjunctival symptoms was 52 pollen grains/m3.²⁴ Therefore, pollen counting and forecasts are all the more valuable for allergic conjunctivitis patients, as this information allows patients to be aware of what days they are more likely to need their allergy medications.

To provide information on a drug's potency, environmental clinical studies can investigate its ability to control the signs and symptoms of ocular allergy at various pollen levels throughout the pollen season. In an environmental study with a confirmatory conjunctival allergen challenge (CAC) comparing the effects of the topical ophthalmic antihistamines epinastine (Elestat, Inspire Pharmaceuticals) and levocabastine (Livostin, CIBA) during two 1-week periods of highest pollen counts, both drugs elicited comparable superiority over placebo in reducing mean itching and redness scores.²⁷

Another environmental study with a confirmatory CAC investigating olopatadine 0.2% conducted from the months of April to August revealed that olopatadine 0.2% (Pataday, Alcon) significantly reduces ocular itching and redness at various pollen levels.²⁸ Furthermore, a hybrid environmental study indicated that olopatadine 0.2% significantly decreased the frequency and severity of pollen effects on sneezing, itchy nose, and runny nose associated with allergic rhinoconjunctivitis.²⁹

Allergy-Fighting Agents

People who are allergic to pollen can treat signs and symptoms of seasonal allergic conjunctivitis (SAC) with a variety of ophthalmic medications available on the market, including antihistamines, mast-cell stabilizers, combination antihistamine/mast-cell stabilizers, non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Because of their dual activity, rapid onset of action, and strong safety and efficacy profiles, combination antihistamine/mast-cell stabilizers currently comprise the mainline treatment for allergic conjunctivitis. The most current generation of combination antihistamine/mast-cell stabilizers includes olopatadine 0.1% (Patanol, Alcon) and 0.2%, ketotifen fumarate 0.025% (Zaditor, Novartis), epinastine 0.05%, and azelastine 0.05% (Optivar, Meda Pharmaceuticals).

Many allergy sufferers treat their disease with systemic antihistamines such as loratadine and cetirizine HCl; however, several studies^30-32 suggest that topical medications provide the best treatment: They provide the greatest sign and symptom relief and also minimize any antimuscarinic drying effects. One study showed that the adjunct therapy of olopatadine 0.1% to the oral administration of loratadine tablets significantly reduced ocular itching in comparison to loratadine alone.^30,31 Another study indicated that loratadine and cetirizine HCl exerted ocular drying effects in a dosedependent manner, while topical ophthalmic solutions ketotifen, epinastine and olopatadine 0.1% did not.³²

In a comparative study of azelastine and mast-cell stabilizer sodium cromoglycate conducted from April to September in the United Kingdom, azelastine yielded the lowest scores of itching, redness and tearing.³³ An environmental study on epinastine, which is indicated for the prevention of itching associated with allergic conjunctivitis, revealed that it effectively diminished ocular itching and redness associated with allergic conjunctivitis during peak pollen periods.²⁷ Environmental studies have also shown that olopatadine 0.1%³⁴ and 0.2% is efficacious in the reduction of ocular itching and redness, as well as sneezing, nasal itching and rhinorrhea.

Olopatadine 0.2%, which is indicated for once-daily dosing regimen, provides continuous daily relief, in my experience. It has a rapid onset of action, and works during times of varying atmospheric pollen concentrations - a therapeutic bonus, as pollen levels can fluctuate throughout the day.^28,29 Ketotifen fumarate, now available OTC, is a readily available medication that is indicated for the relief of itching associated with allergic conjunctivitis.^35-37 It provides rapid relief and is indicated for twice-daily dosing.

Ketorolac tromethamine 0.5% ophthalmic solution is the only NSAID approved for the treatment of itching associated with SAC. Ketorolac dosed q.i.d. as a treatment for SAC has been shown to be safe and effective;^38,39 however, a comparative study employing the conjunctival provocation test revealed that olopatadine 0.1% was more comfortable and effective than ketorolac in reducing ocular itching and redness.⁴⁰ As the mechanism of NSAIDs and corticosteroids is primarily anti-inflammatory, they have minimal mast-cell stabilizing effects and are not considered main-line therapy.

Corticosteroids are seldom used to manage the signs and symptoms of seasonal allergic conjunctivitis, as they are known to bring on side effects such as cataracts, increased IOP, superinfection and delayed wound healing. Loteprednol etabonate 0.2%, the only approved steroid for SAC, has been shown to be well-tolerated and efficacious in the treatment of the disease, particularly when used consistently over the allergy season. No significant changes in IOP were found in these studies.^41-42

The intensified allergenicity of pollen and heightened levels of carbon dioxide and diesel exhaust in cities means that more allergen is available in the environment to irritate atopic individuals. Studies have shown epinastine and olopatadine to perform well during periods of high pollen levels,^{27-29, 34} which inevitably occurs in urban areas. Still, the constant bombardment of allergen can trigger late phase allergic reactions — which can last for hours after allergen exposure — in various regions of the body.^43-45 Longer lasting medications may provide added benefit for busy urbanites.

Conclusion

Understanding the interaction between our living environments and allergy is important for the further investigation of allergens and atopic disease. As international industrialization progresses and continues, pollution, global warming and the incidence of allergic disease will likely continue to increase. It is important to identify the likely allergenic culprit and to help the patient development a management program. Today, most people cannot move to another region of the country to avoid seasonal allergies at home — so efficient management is important to maintaining patients' quality of life. OM

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Gail L. Torkildsen, M.D., is in private practice in Andover, Mass., and has served as a principal investigator for numerous studies. She can be reached at mdlasik@comcast.net. Dr. Torkildsen claims no financial relationship with any of the manufacturers mentioned in this article. Paul J. Gomes, M.S., is the director of allergy at ORA Clinical Research and Development, North Andover, Mass. He can be reached at pgomes@oraclinical.com.