Rising incidence requires more effective treatments.

By Mark B. Abelson, M.D., and Lauren Lilyestrom

Back in the good old days, allergies, including ocular allergies, were considered rare afflictions of the economically privileged. Allergies were actually a somewhat desired sign of status; farm hands seldom, if ever, developed allergies to hay and horses, but those who had never set foot in a stall suffered when suddenly cornered by airborne allergens.

As industrialization progressed, allergy became a disease of the city-dwelling masses. Through pollution, our urbanized world has created an ideal environment for the enhancement and production of allergens. Diesel exhaust makes the effect of over-abundant pollen even worse by degrading the tear film/conjunctival mast cell barrier, opening the eye up to allergen invasion. Even without human interference, Mother Nature does a fine job of keeping weather patterns from being too monotonous � thus local pollen counts change daily. All this has made for lowered allergic thresholds, exaggerated allergic symptoms and an increase in allergic prevalence. Today, about 20% of the general population endures the signs and symptoms of ocular allergies.

This article will discuss how environmental factors are contributing to the rising incidence of ocular allergies. In addition, it will assess the effectiveness of treatments for ocular allergy that are available today.

Figure. The difference between this scene from Beijing, China, on a sunny day after several days of rain (left) and the same scene on a normal sunny day provides a visible example of the effect weather patterns can have on pollution and air quality.

An Overview of Ocular Allergy
The reasons for the increased incidence of ocular allergy are numerous, varied and oftentimes contradictory. Genetics are known to predispose people to an allergic tendency and determine its severity; nevertheless, it is the environment which turns on those genes and sensitizes the individual to a given allergen. Environmental triggers are virtually endless, and tend to prefer surprise and variety over the mundane and predictable. It follows, then, that the degree to which an individual is bothered by allergies varies from day to day.

Allergies and their respective allergens are often divided into two groups according to their typical patterns of action. Perennial allergens are available year-round to harass genetically unlucky people, and include pet dander, dust, mites and mold. Seasonal allergies bombard their victims during the warmer seasons � the culprits being plant pollens. Conveniently, seasonal allergies can be awakened in the colder months, courtesy of complementary growing seasons in other regions and overnight shipping. This constant yet capricious nature of allergens makes an awareness of daily weather and regional climate patterns imperative to controlling one�s allergies.

Pollen counts, collected from stations around the country, serve as warnings to those prone to ocular allergies; however, individual responses to any given pollen count vary with the individual�s degree of sensitization and exposure. In general, warm, dry weather exacerbates allergic reactions, especially if a breeze is present to blow around pollen grains: spring through fall are the notorious allergy seasons. Mediterranean climates, with hot, dry summers and cool, wet winters, are particularly conducive to high pollen production.¹ Allergic reactions to pollen tend to be comparatively low after a rainstorm, when the pollen has been knocked out of the air (Figure). Similarly, pollen counts tend to be at their highest mid-morning, once the morning dew has evaporated. Reactions to mold, on the other hand, peak during warm, moist weather.
Normally, pollen is least bothersome in the winter, when plants are dormant and pollen counts are undetectable; nevertheless, the cold air forces people inside, only to find themselves breathing in dust, dander and mold. New England�s pollen counts, like its weather, tend to be quite erratic. Normal winters involve the ground freezing, snow and plants either dying or entering dormancy. However, during mild winters plants may never enter full dormancy, and therefore come spring, they flower earlier.

Impact of Climate Change
Pollen count fluctuations in response to normal day-to-day weather variations are well-accepted and understood. On the other hand, the worldwide increase in allergies over the last century has been correlated with global climatic change. So-called �tree huggers� have gradually been joined by more methodical scientists in their doomsday warnings about global warming. In northern climates, warming has made the spring come sooner and last longer � an estimated 5 days per decade² � and the projected effects for allergy sufferers are foreboding.

Global warming is now a widely accepted phenomenon, with most countries and scientists acknowledging its existence. Generally, human activity is blamed for the bulk of the warming, but natural climate variation, scientific bias and increased solar activity have also been cited as scapegoats. Massive amounts of research have been performed in attempts to narrow the causes of the increase in average global temperature, with little definitive, quantitative success. Nevertheless, the role of carbon dioxide is irrefutable. While naturally occurring CO2 and methane maintain the earth�s comfortable temperature, human activity � specifically, fossil fuel burning, breeding too many cows and deforestation � has increased the amount of CO2 in the atmosphere.³

This �thickening� of the atmosphere traps more of the sun�s heat, thereby warming the earth. Without the natural greenhouse effect, Earth would be about as lively as Mars. Much debate exists over how much of the increase in global temperature is the fault of humanity�s industrialization and careless ways, but the excess CO2 shows no signs of vacating our atmosphere anytime soon.⁴ Thousands of studies have explored the potential effects of increased average temperatures on everything from sea levels (the tiny atoll country of Tuvalu has been doomed to a rapid Atlantis-fate),⁵ to drowning polar bears,⁶ to the aforementioned earlier arrival of spring.

Warmer Climate; More Pollen
Although not evident every year, on average May flowers have been blooming earlier since early last century. The one plausible estimate (95% confidence interval) for average global surface temperature change, by Folland et al. in 2001, is an increase of 0.6� C between the late 1800s and 1994.7 The Intergovernmental Panel on Climate Change projects a global temperature increase of anywhere from 1.4� - 5.8� C from 1990-2100.8 Plant reproductive development and flowering is highly dependent on temperature,9,10 and several studies have suggested that the corresponding high CO2 concentrations speed along the development of spring plants and increase pollen production.¹¹

A recent study performed by researchers at Harvard School of Public Health simulated the projected levels of CO2 in controlled greenhouses. Ragweed, the cause of late-summer ocular allergies, was shown to have increased pollen production up to 55%.¹² Because ragweed is prevalent all over the continental United States and its pollen can travel several miles on a dry, windy day, we have no chance of escaping or eradicating it. Ragweed grows best on disturbed soil, which provides a possible explanation for higher pollen counts in expanding urban areas. Other studies have confirmed the impact of increased CO2 on late-season plants, including an increased potency of poison ivy.¹³ Because allergies appear to be more severe in New England,¹⁴ elongated and more potent allergy seasons are not eagerly anticipated.

Role of Diesel Exhaust
In addition to the larger and more persistent quantities of airborne pollens, oxidative stress is also an ocular allergy-exacerbating result of our industrialized world. It appears that pollen grains contain oxidases which, when hydrated, produce H2O2, a reactive oxygen species (ROS). ROS degrade cell membranes � including those of mast cells, resulting in histamine release. This suggests a mechanism by which pollen may initiate and augment allergic conjunctivitis¹⁵. Moreover, low-level ozone (O3, another ROS) is formed when sunlight reacts with hydrocarbons and nitrous oxide � primarily produced by diesel exhaust � and causes oxidative stress.

Our own glutathione-S-transferases (GST) enzymes are involved in reactive oxygen species metabolism; however, there are many genetic variants. Variants of GSTMu1, GSTTheta1 and GSTPi1 are common, and have been found to influence allergic susceptibility to pollution. It is thought that 15% to 20% of the population has a high risk of heightened allergic response due to diesel particles.¹⁶ To a limited extent, antioxidants reverse this effect in mice and have been suggested as a remedy for humans.^16,17

To add to the problem, diesel exhaust particles enhance allergic responses by agglomerating on the surface of pollen grains. Their oxidative properties change the grain�s morphology, resulting in the release of their allergenic proteins.¹⁸ Pollen, an allergen on its own, and already becoming overabundant because of rising CO2 levels, is therefore also becoming hyper-allergenic. In response, people�s allergic thresholds are being lowered.^18,19 Previously non-allergic people may indeed develop the pleasures of ocular allergies, and those who had troublesome allergies to begin with might provide a boom for the ophthalmic pharmaceutical industries.

Ocular Allergy Sufferers Increasing
It is estimated that the ocular allergy market has expanded from $6 million to $500 million in sales in the last 30 years. In addition, some studies have suggested that pollution, especially on dry, windy days, irritates and speeds the breakdown of the tear film barrier, resulting in dry eye symptoms and leaving the eye more exposed to allergens.20-22
Adding to the allergenic excitement are seemingly random yet major climatic events. The cause of El Ni�o � temperature fluctuations of the central Pacific Ocean that occur every few years and wreak havoc on climate patterns � remains elusive. Computer models have not yet been developed that can compare both global warming and El Ni�o data. In 1997-1998, El Ni�o was particularly strong. High mold and pollen counts were recorded during the 1998 pollen season, and the suggestion has been made that they, along with increased allergy-related hospitalization rates, were related to el Ni�o.23,24 More research is needed to determine the cause of the El Ni�o phenomenon.
So what can be done? Ocular allergy is estimated to affect over 20% of the U.S. population, and its incidence seems to be rising.25 For much of the population, allergic conjunctivitis is a daily nuisance and avoidance is not a viable option.

Comparing Treatments
Climate variations cannot be controlled, and humanity has only worsened the weather�s effect on allergies through pollution. Ocular allergy sufferers may also want to invest in anti-allergic medications; luckily there is no shortage of choices (Table). Systemic anti-allergic medications have been shown to have reduced efficacy and to induce dry eye symptoms in comparison studies with topical medications.26,27 Antihistamines, mast-cell stabilizers and antihistamine/mast-cell stabilizers have varying efficacies and indications, but the most effective relief comes from the combination antihistamine/mast-cell stabilizers. Their mode of action is twofold: stabilizing conjunctival mast cells to prevent release of histamine and other pro-allergic mediators and blocking histamine from binding to its receptors to prevent the signs and symptoms of allergic conjunctivitis.25 An added benefit is that they do not break down the tear film/mast-cell barrier.28 In severe, chronic forms of allergic conjunctivitis or in patients who present with an enhanced inflammatory component to their condition, steroids and NSAIDs may be prescribed.

Ocular allergies are best treated by a product that has both antihistaminic and mast-cell stabilizing properties that is easily dosed, safe and effective. Currently, the most frequently prescribed treatment is olopatadine 0.1% (Patanol, Alcon). A new formulation, olopatadine 0.2% (Pataday, Alcon), has recently become available. This agent has built on the already-existing superior performance of its 0.1% predecessor, which is currently the most prescribed anti-allergic eye drop with 26 million prescriptions written to date.29
Olopatadine 0.2% has demonstrated enhanced efficacy (in patients with both allergic conjunctivitis and rhinoconjunctivitis),30 long-lasting relief (up to 24 hours), and an added convenience of once-daily dosing.31,32 Of the ocular allergy sufferers, 90% are still self-medicating with less-than-optimal OTC products that do not provide full day coverage. They must be informed that there are more efficacious, longer-lasting and better-tolerated prescription products available.

A Long-Term Problem
The combination of global warming with increased pollen production and air pollution makes for lowered allergic thresholds, exaggerated allergic symptoms and an increase in allergic incidence.
Although worldwide and national efforts are underway to curtail the progress of global warming, its effects will be with us for decades. And regardless of human-induced global temperature changes, normal variations in weather patterns can result in fluctuations in pollen load. Symptom relief is available in multiple medicinal forms, but the complex mechanisms and causes of allergies maintain the cure�s elusive nature. Humanity is only beginning to recognize the severity and permanence of its actions on this planet � and that the consequences can impact our own day-to-day functioning. OM

Mark B. Abelson, M.D., an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. He can be reached at mbabelson@oraclinical.com. Lauren Lilyestrom is a medical writer at ORA Clinical Research & Development in North Andover, Mass.

References
 1. Zanolin M, Pattaro C, Corsico A, et al. The role of climate on the geographic variability of asthma, allergic rhinitis and respiratory symptoms: results from the Italian study of asthma in young adults. Allergy. 2004;59:306-314.
 2. Root T, Price J, Hall K, Schneider S, Rosenzweig C, Pounds J. Fingerprints of global warming on wild animals and plants. Nature. 2003;421:57-60.
 3. Keeling C, Whorf T. Atmospheric carbon dioxide records from sites in the SIO air sampling network. 2005. In Trends: A Compendium of Data on Global Change. Carbon Dioxide Information Analysis Center, Oak Ridge National Laboratory. U.S. Department of Energy, Oak Ridge, Tenn. Accessed Dec. 20, 2006. Available at: http://cdiac.ornl.gov/trends/co2/sio-mlo.htm
 4. Hansen J, Sato M, Ruedy R, Lo K, Lea D, Medina-Elizade M. Global temperature change. Proc Nat Acad Sci. 2006;103:14288-14293.
 5. Berzon A. �Tuvalu is Drowning.� March 31, 2006. At Salon News. Accessed Dec. 20, 2006. Available at: http://www.salon.com/news/feature/2006/03/31/
tuvalu/index.html
 6. Iredale W. Polar bears drown as ice shelf melts. The Sunday Times � Britain. Dec. 18, 2005. Accessed Dec. 19, 2006. Available at: http://www.timesonline.
co.uk/article/0,,2087-1938132,00.html
 7. Folland CK, Karl TR, Christy JR, et al. Observed climate variability and change. In: Houghton JT, Ding Y, Griggs DJ, et al, eds. Climate change 2001: The scientific basis, Contribution of Working Group I to the Third Assessment Report of the Intergovernmental Panel on Climate Change. Cambridge: Cambridge University Press, 2001;99-181. Available at: http://www.grida.no/climate/
ipcc_tar/wg1/048.htm
 8. Easterling D, Karl T. National Oceanic and Atmospheric Administration. Global Warming: Frequently Asked Questions. Accessed Dec. 19, 2006. Available at: http://lwf.ncdc.noaa.gov/oa/climate/globalwarming.html
 9. Clot B. Trends in airborne pollen: an overview of 21 years of data in Neuchatel (Switzerland). Aerobiologia. 2003;19:227-234.
10. van Vliet A, Overeem A, de Groot R, Jacobs A, Spieksma FTM. The influence of temperature and climate change on the timing of pollen release in the Netherlands. Int J Climatol.