Symposium

Terrence P. O’Brien, MD: The prevalence of ocular allergy continues to increase on a global scale. Although ocular allergies cannot be cured, treatment relieves symptoms and helps patients attain an improved quality of life. In this roundtable, physicians from around the world gather here today to discuss the impact of allergy from a global perspective. To set the foundation for this discussion, please describe the mechanism of the allergic response in the conjunctiva including allergen contact, mast cell activation, and the inflammatory response.

Peter K. Smith, FRACP, PhD: When patients with allergic tendencies are exposed to an allergen, an asymptomatic sensitization process occurs in which the dendritic cell picks up the allergen and presents it to the T cell, which then travels to the lymph node to alert the B cell. The B cell produces immunoglobulin E (IgE), which binds to high-affinity receptors on mast cells and basophils in the target area, most commonly the ocular subconjunctiva. A sensitized person has an increased number of mast cells on the ocular surface.

Mast cell degranulation Figure 1: When the B cell is allerted to an allergen, it releases immunoglobulin E (IgE) molecules that adhere to the mast cell. Allergens binding to the IgE causes mast cell degranulation to occur, triggering the release of inflammatory mediators such as histamine, tryptase, and prostaglandins, that produce the symptoms of ocular allergy. Source: Smith P

Marietta P. Karavellas, MD: When IgE molecules adhere to mast cell membranes and bind allergens, mast cell degranulation occurs and inflammatory mediators are released, including histamine, tryptase, eosinophil chemotactic factor-a, platelet-activating factor, and prostaglandins. These mediators cause vasodilation, increased vascular permeability, and itching, producing the signs and symptoms of ocular allergy (Figure 1). The inflammatory mediators attract and activate inflammatory cells, enhancing and perpetuating the inflammatory response. Rubbing the eyes can cause mechanical degranulation, adding to the cycle.

Andrea Leonardi, MD: Mast cells in the eye differ from those in the nasal mucosa and respiratory tract. Mast cells can be categorized as either MC_T (tryptase, also called mucosal mast cell) or MC_TC (tryptase and chymase, also called connective type mast cell) phenotypes. Immunohistochemical phenotyping shows that the MC_TC phenotype is predominant in healthy human conjunctiva and the skin. On the other hand, the MC_T phenotype is typical of the respiratory tract. Mast cell stabilizers developed for the respiratory tract act on a specific mast cell subtype and do not have the same effect on the ocular surface.

Evidence shows that the two types of mast cells have different pharmacologic responses in vitro. Drugs such as cromolyn and nedocromil can stabilize mucosal mast cells, but the in vitro model of conjunctival-derived mast cell cultures shows that these drugs only partially inhibit mast cell degranulation and histamine, confirming the limited efficacy of these drugs in the clinical treatment of ocular allergy. In contrast, olopatadine inhibits histamine release in a concentration-dependent manner and shows up to 100% histamine inhibition for the clinically relevant concentration.¹

Global prevalence of allergy

O’Brien: Approximately how many people in your respective countries suffer from ocular allergies?

Smith: Approximately 20% of the population in Australia has ocular allergies.

Denise de Freitas, MD: The epidemiology of ocular allergy is not studied in Brazil. In our referral service, ocular allergy accounts for 20% to 25% of the cases.

Karavellas: An estimated 10% to 25% of the Greek population has allergic disease, but no data have been collected on the prevalence of ocular allergy specifically. Several researchers report a dramatic increase in allergic disorders during the past 2 decades, and prevalence is significantly higher in the large cities compared with that in rural areas.²

Irina S. Barequet, MD: We do not have statistics on the prevalence of allergy in Israel, but it is a common problem both in primary care clinics and secondary and tertiary centers. Differential diagnosis of seasonal and perennial allergies has also proven difficult, possibly because Israel does not have four completely distinct seasons with regard to pollen and dust.

Ramon Naranjo-Tackman, MD: My understanding is that in referral hospitals, inflammatory disease departments report that 20% of patients have ocular allergies. After February, when seasonal allergies occur, the incidence increases to 35%, most of whom are young. It is possible that in highly polluted areas, chronic conjunctivitis may have combined causes. There is an increase in patients with allergy as well as patients with late-phase allergy.

Victor L. Caparas, MD, MPH: Many countries in Southeast Asia including China, Taiwan, Singapore, Thailand, and the Philippines lack accurate statistics on epidemiology. Clinical statistics are also limited, making it difficult to determine the prevalence of ocular allergy in the region. Patients in Southeast Asia experience nonspecific perennial allergies because they have only two seasons and may not experience the dramatic increases in pollen that patients in temperate climates may experience.

Marino J. Discepola, MD, FRCSC, DABO: Approximately 20% of Canada’s general population experiences allergies,³ and a majority of these patients can be classified in one of two groups: patients who develop allergies in childhood and patients who develop allergies in young adulthood and later.

Leonardi: In Europe, approximately 15% to 25% of the general population experiences some form of allergy, but no studies have focused solely on conjunctivitis. In general, based on patient interviews, 80% to 90% of patients with allergies have had some form of eye symptoms.⁴

Economic and social impact

O’Brien: What impact does allergy impose on patients’ lives and livelihoods?

Smith: Ocular allergies are chronic inflammation syndromes that affect approximately one in five people worldwide.⁵ The eye is one of the most sensory organs in the body and when inflamed, pain and resulting reduced quality of life occur. Therefore, the ability to identify and treat ocular allergies is important.

The eye is one of the most sensory organs in the body and when inflamed, pain and resulting reduced quality of life occur. — Peter K. Smith, FRACP, PhD

Karavellas: Depending on the severity and duration of the allergic symptoms, itching, tearing, and ocular irritation can significantly affect patients’ lives. Symptoms can lead to absence from work and decreased productivity in adults, and absence from school and difficulty studying in children. Sleep is often disrupted, which affects patients’ energy and productivity throughout the day. Patients with allergies must often restrict outdoor activities, including hobbies and sports, to avoid allergen exposure.

de Freitas: My colleagues and I treat patients who experience extreme limitations from allergy. The children do not lead typical lives, which compromises their development and causes psychological trauma. The impact can have lifetime repercussions.^6-8

O’Brien: Conjunctival hyperemia, the stigma of red eye, may cause patients to endure psychological and emotional distress.

Smith: The Asthma and Rhinitis Center reports that worldwide, approximately 70% of patients who have rhinitis will also have allergic conjunctivitis. Almost one-third of European patients with allergic rhinoconjunctivitis are unaware of their condition. A questionnaire asking, “Do you have itchy eyes?” could reveal an uninformed population of patients with ocular allergies.^9,10

O’Brien: Does ocular allergy contribute to a negative economic impact on the workforce?

Naranjo-Tackman: The economic impact of allergy is evident in the working population. Staring at a computer monitor many hours each day can exacerbate allergy symptoms such as dryness and redness of the eye. This in turn impacts the ability to work and may increase economic costs.

Discepola: Sometimes patients take systemic medications such as antihistamines, which can cause drowsiness and lead to decreased productivity. When these costs are added up over time, the economic impact of allergy is significant.

Barequet: Several studies have reported differences in occurrence of atopic diseases between rural and urban areas within the same country.^11,12 Families sometimes move to other areas to help relieve symptoms in children with severe ocular allergies. This can impact both the financial and psychological condition of the family and the development of the child.

Leonardi: There are two primary categories of patients with ocular allergies. Patients with severe diseases such as vernal keratoconjunctivitis (VKC) or atopic keratoconjunctivitis (AKC) represent the minority of cases. The majority of patients are affected by seasonal and perennial allergic conjunctivitis, which causes a greater economic impact even though severe cases cause a greater psychological and physiologic impact on patients and their families.

Common types of allergic conjunctivitis in specific countries

O’Brien: One of the problems also associated with ocular allergies is chronic ocular itching. Habitual rubbing of the eye can lead to topographic changes to the cornea, accelerated astigmatism, and possibly ectasia or keratoconus. Earlier diagnosis and aggressive treatment in the early stages of the disease might avoid late-stage complications that are difficult to manage. I find that dual-action agents have become the standard and are preferred among physicians. From a practicing clinical perspective, what are the most common types of allergic conjunctivitis in your respective countries?

Habitual rubbing of the eye can lead to topographic changes to the cornea, accelerated astigmatism, and possibly ectasia or keratoconus. — Terrence P. O'Brien, MD

Karavellas: Seasonal allergic conjunctivitis is the most common type of allergic conjunctivitis in Greece. The country has a warm, temperate climate that causes long pollinic seasons. Recently, mild winters and low rainfall have led to longer allergy seasons that begin earlier. However, the incidence of perennial conjunctivitis is increasing, especially in large cities such as Athens. VKC is uncommon but is a significant problem in the pediatric population. AKC is rare.

de Freitas: In Brazil, VKC is most common and often severe. Perennial is the second most common allergic conjunctivitis. In Sao Paulo, an urban center, acute allergic conditions are rare.

Barequet: Perennial is the leading type of allergic conjunctivitis in Israel, and VKC is the second most common. VKC, although more rare, is related with significant morbidity.

Naranjo-Tackman: In Mexico, perennial allergies occur most frequently, but we also have high incidences of severe VKC.

Discepola: Seasonal allergic conjunctivitis is the most common form of allergy in Canada. A minority of my patients have perennial allergies, which is the second most prevalent type. VKC is rare because of the cold climate, and AKC is rarer.

Leonardi: Having worked in both allergy and ophthalmology departments, I have treated patients with both simple and severe conjunctivitis. Seasonal is the most common type of allergy, perennial is the second most common, and VKC and AKC account for 5% to 10% of patients with ocular allergy. The majority of patients treated at referral centers have VKC or AKC, but the estimated incidence of this disease is low. In our area, the incidence of VKC is approximately 1/100,000, with a higher rate in males <16 years of age (10/100,000) compared with females (4.2/100,000). In patients older than 16 years of age, the incidence of the disease was extremely rare (0.06/100,000), with no difference between males and females.¹³

O’Brien: VKC and AKC are the most challenging to treat, yet statistically, they occur less frequently. In the United States, an estimated 90% to 95% of all ocular allergies are seasonal. Perennial is second in frequency.

Allergy and the urban environment

O’Brien: Regarding the role of the environment in allergy, are there regional differences in your country with respect to environmental pollutants and the impact on allergy?

Naranjo-Tackman: The conjunctivitis seen in Mexico City differs from that seen in Gulf Coast areas, which is mostly rural and agricultural. In the Gulf Coast, seasonal allergies are more prevalent than other forms of allergy. The type of industry that exists in a city will determine which pollutant causes the greater concern.

Karavellas: Numerous studies from around the world have indicated a significant increase in the prevalence of all allergic disease, including ocular allergy, asthma, allergic rhinitis, and dermatitis. The prevalence is higher in developed countries and urban populations. The rapid, dramatic increase cannot be attributed to genetic factors.^14,15 Changes in environmental factors must be involved. Urbanization has led to increased exposure to air pollutants, which causes more severe allergic reactions. Climatic changes associated with the greenhouse effect have altered plant growth and pollen production, leading to longer and heavier pollinic seasons. Multiple factors appear to be involved in what has been called the “allergy epidemic.”

Patients living in urban centers may experience worsened symptoms because pollutants affect the tear film barrier, exposing the eye to allergens. — Victor L. Caparas, MD, MPH

Caparas: In Southeast Asia, environmental pollution accounts for the increase in allergy. Every year, thousands of hectares of Indonesian rainforest sectors burn, causing smog and haze to blanket the region for weeks. Patients living in urban centers may experience worsened symptoms because pollutants affect the tear film barrier, exposing the eye to allergens.

O’Brien: In large urban centers, levels of pollution, particularly hydrocarbons, appear to be increasing. Is this affecting the prevalence and features of ocular allergies?

Leonardi: Allergen susceptibility might be greater in individuals who live in areas with increased air pollution because the respiratory tract and eye are very sensitive to irritants during ongoing allergic inflammation. Both allergens and pollutants can directly initiate mucosal inflammation through several mechanisms including oxidative stress, proinflammatory cytokine production, cyclooxygenase, and lipoxygenase and protease activation. For example, when diesel emission particles contact respiratory epithelium, proinflammatory compounds form and macrophages engulf the particles, initiating a proinflammatory cascade. Most airborne pollutants function as mucosal adjuvants, interacting with both innate and adaptive immune cells that then skew the immune response to antigens toward a T helper type 2-like phenotype. It can be speculated that synergetic oxidative insult occurs with the copresence of pollens and pollutants. “Urban eye syndrome” may be considered as a transversal, crossover condition that has some common features of allergy, dry eye, and toxic conjunctivitis, related to poor air conditions and an urban environment (A. Leonardi, B. Lanier, manuscript submitted 2008).¹⁶

Karavellas: Urban areas have significantly higher rates of allergic disease than rural areas.¹⁷ This has led to a search for the causes of urban allergies. Pollutants such as sulfur dioxide, nitrogen oxides, and carbon monoxide can compromise the tear film barrier, making the conjunctiva more susceptible to allergenic stimulation. Air pollutants also alter pollen and increase allergenicity. High carbon dioxide levels and temperature increases stimulate the growth of plants and weeds and multiply pollen production. Genetic factors also seem to play a role. Individuals with a genetic deficiency involving glutathione transferases, enzymes that neutralize superoxides, were shown to exhibit enhanced allergic responses to a combination of pollen and diesel exhaust particles.¹⁸

The microenvironment in inner city homes and workplaces is also a factor. Conversely, rural living, especially in agricultural settings, may provide a protective effect. Children raised on farms have lower rates of sensitization and allergic disease. Researchers theorize that exposure to bacteria at an early age may shift the Th1/Th2 balance toward Th1 immune reactions, providing protection from allergic disease.^19,20

Leonardi: Lifestyle and environmental factors in western industrialized cities seem to facilitate allergy onset in immigrants from developing countries. For example, immigrants from North Africa that were healthy at home developed allergy and asthma symptoms after immigration to Milan. Similarly, Albanian immigrants to Italy, in spite of the low prevalence of allergic diseases and sensitization in their country, manifested with time an increasing prevalence of sensitization to local allergens and nasal symptoms after immigration to Italy.^21-23

Smith: It is most likely excitation of the immune system that determines whether patients will experience a Th1- or Th2-mediated response. Certain genetic polymorphisms appear to play a role in determining whether bacterial exposure reduces the risk for allergy. Eder and colleagues reported a gene polymorphism in the Th2 receptor was associated with reduced risk for asthma.²⁴

Caparas: During June and July 2007, I conducted a survey in several polluted areas of Manila. The results showed high incidences of eye redness, itching, and burning in people who worked in or inhabited the area for long periods of time. The mucous adjuvant hypothesis developed by Diaz-Sanchez ¹⁶ suggests that a pollutant such as a diesel exhaust particle lands on the conjunctiva and causes what ophthalmologists identify as urban allergic reaction. When a diesel exhaust particle lands on the cells of the conjunctiva, it can directly cause the release of inflammatory mediators by the production of active oxygen species. It can also cause a direct enhancement of mast cells and basophils, which contain chemicals that cause allergy symptoms. These allergens can also cause T-cell-type inflammation, similar to that in chronic allergy, whereby they influence the T cell, producing IgE antibodies and causing the classic allergic reaction.^16,25,26 Studies by Magitte²⁷ report that the pollutants increase the antigenic potential of pollen by as much as 20 to 50 times. Riediker and colleagues published findings showing that exposure to air pollutants may worsen allergic symptoms during the pollen season.²⁸

Exposure to a combination of air pollutants and pollen can result in more severe allergic responses than exposure to pollen alone. — Marietta P. Karavellas, MD

Naranjo-Tackman: Patients living in urban centers are more susceptible to disease of the conjunctiva because contaminated environments cause tears to evaporate more quickly and contain less water. Therefore, patients do not have the tears necessary to wash out contaminants that can cause allergy.

Karavellas: Exposure to a combination of air pollutants and pollen can result in more severe allergic responses than exposure to pollen alone. The mechanisms by which air pollution affects allergic reactions are not yet entirely clear. Electron microscopy studies have shown that airborne particles accumulate on the surface of pollen grains, altering their shape and characteristics. Pollutants can induce the release of allergen-containing granules from pollen grains. Nitrogen oxides and ozone can cause nitration of pollen proteins, possibly increasing their allergenic potential. Future research will clarify how pollutants affect pollen and contribute to allergic reactions.

Differential diagnosis

O’Brien: How difficult is it for primary care physicians to make a definitive diagnosis of the patient presenting with red eye?

Discepola: I think some primary care physicians feel insecure about the eye, and this can lead to misdiagnosis, such as mistaking blepharitis for allergic conjunctivitis. Itching and burning symptoms are assumed to be allergic. Education needs to be improved so that primary care physicians know what they are treating.

Karavellas: Many ocular conditions can present as red eye, and these vary in clinical significance and potential for ocular morbidity. Often, more than one disease is present, making the diagnosis complicated. A detailed history of the patient’s symptoms can be used to rule out possible causes, but a full ophthalmic examination is necessary for an accurate diagnosis. A specific etiologic diagnosis is the key to effective treatment.

de Freitas: The most important symptom is itching. When children rub their eyes constantly, then the first diagnosis is allergy. Dry eye causes intermittent itching in the inner corners of the eyes that differs from allergic itching. To differentially diagnose the disease, I recommend considering the time of year, the chief complaint of rubbing, and clinical findings of papillae or hypertrophy in the upper and lower tarsal conjunctiva in conjunction with signs and symptoms.

O’Brien: It is important to carefully distinguish between itching, burning, and other similar symptoms to determine the primary cause of ocular discomfort with surface inflammation.

Barequet: Accurate diagnosis is essential. If treatment is directed toward the wrong condition, symptoms may worsen. For example, when blepharitis is treated with shampoos and cleansing solutions, the irritation from the solutions can worsen an allergic condition.

O’Brien: What are the specific biomicroscopic signs that suggest allergy?

Naranjo-Tackman: The presence of papillae and engorged vessels is a sign of allergy in younger patients. Patient history and symptoms should be used instead of clinical data when diagnosing an adult patient because the results will not be as reliable as in the younger patient. An older patient could have pre-existing pterygium or tortuous vessels.

O’Brien: Papillae and mucoid discharge may be associated with allergy or chronic bacterial infection. However, mucoid discharge is also a symptom of dysfunctional tear states with aqueous deficiency.

Allergic Conjunctivitis Figure 2: When differentially diagnosing allergic conjunctivitis, clinicians should consider itching, ocular discharge, and presence of giant papillae or follicles. Source: Smith P

Naranjo-Tackman: Secretion is one symptom that can be useful to primary care physicians. They should consider itching, the characteristics of the secretion, the age of the patient, and patient history. The significance of symptoms depends on the age of the patient. If the patient is 65 years old, discharge could be a result of lack of secretion in the lacrimal glands. In a young patient, white mucoid secretion with rubbing or itching suggests a diagnosis of allergy.

Smith: Patients with ocular allergy will have other allergy symptoms, such as allergic pleats, allergic shiners, transverse creases, and dry lips because of mouth breathing. These signs, when combined with clinical data and patient history, can be helpful in diagnosing allergy.

O’Brien: Do you follow a set of guidelines to help differentially diagnose red eye? Are there any pearls that you can offer to your colleagues in the medical community?

Discepola: Palpating the preauricular node can be useful to rule out adenovirus. A slit-lamp investigation can be used to look for follicles, papillae, chemosis, and lid swelling. The cornea should also be examined for signs of keratitis.

O’Brien: What is your approach or how do you train your community physicians to recognize allergy over other similar conditions?

Karavellas: A patient’s description of symptoms offers valuable insight regarding both the disease and the individual patient. Itching is the classic symptom of allergy and is necessary to make the diagnosis. Ocular discharge is also important and often better described by the patient than that seen on examination. A significant point in the examination is the conjunctival reaction, particularly the presence of giant papillae or follicles (Figure 2). Basic staining and tear film tests are also necessary. It is important to keep in mind that more than one disease may be present in the eye. Some ocular conditions predispose patients to develop others.

Leonardi: I suggest talking extensively with the patient before proceeding to a clinical examination to develop an idea of the patient’s history, onset of symptoms, behavior, work setting, environment, and lifestyle. Patients with seasonal allergies may present with no symptoms. Perennial ocular allergy is the most challenging disease to diagnose because the signs and symptoms can be similar to those of blepharitis, infections, and dry eye. Many patients have dry eye or tear film instability. If a patient is in an active clinical phase and has red eye, tear cytology can be used to identify inflammatory cells and help to support a clinical hypothesis. Tear cytology is a rapid, easy test to perform, and the presence of even one eosinophil is highly indicative of allergic pathology, whereas the absence of eosinophils does not exclude an allergic diagnosis.

Coexistence of dry eye and ocular allergy

O’Brien: Do the conditions of dry eye and ocular allergy coexist? If so, how frequently does this occur?

Karavellas: It is common for allergic conjunctivitis and dry eye to occur concomitantly. Therefore, it is essential to assess tear production and stability in every patient with ocular allergy. Patients with dry eye may be prone to allergic conjunctivitis and/or present with more severe symptoms because of a deficient tear film barrier and the relative inability to wash away allergens. On the other hand, ocular allergies predispose patients to dry eye through various mechanisms (Figure 3). Systemic antihistamines reduce aqueous tear production through their antimuscarinic effects. In AKC, meibomian gland dysfunction, goblet cell loss, and conjunctival fibrosis may cause severe tear film deficiency.

Allergy and ocular epithelium Figure 3: Allergic damage to the eye will cause disruption to the conjunctiva and also to the mucin layer on the sclera. As a consequence there is an altered tissue surface and drainage. With reduced drainage, there is less clearance of allergen and mediators that can result in more inflammatory damage. With disrupted epithelial surfaces a dry eye can evolve, and non-specific mast cell degranulation is more likely to occur. Source: Smith P

de Freitas: Dry eye occurs more frequently in patients with chronic ocular allergy, which causes changes in the ocular surface and mucus secretion. Treatment consists of nonpreserved artificial tears. Use of systemic antihistamines can increase ocular dry eye condition and surface damage.

Barequet: These conditions may be interrelated because both dry eye and allergic conjunctivitis can be mediated by CD4+ T cells. Dry eye can also contribute to allergy. An insufficient amount of tearing can impact the ability to wash out the allergen, which may aggravate a predisposition to allergy. Seasonal allergic conjunctivitis can be associated with advanced tear instability and thickening of the tear film lipid layer. Dry eye syndrome or rosacea may be similar to chronic allergic diseases.

Discepola: In addition, inflammatory mediators that are released are not flushed out as well. New antihistamines are nonsedating, but not nondrying. Patients taking new-generation antihistamines experience a significant reduction in tear production, which worsens the eye condition.

Caparas: Some patients develop allergies from contact lens use because contact lenses naturally cause dry eyes. Many patients with allergies also use vasoconstrictors to whiten eyes and temporarily relieve itch, but chronic use can cause rebound dryness and red eyes. In addition, tear supplements can alleviate symptoms of allergies because they dilute and wash away the amount of allergen in the eye, not because the eyes are moistened. The intact tear film also acts as a barrier against the attachment of antigens, such as diesel exhaust particles, on the conjunctival surface. In fact, Suzuki and colleagues found a correlation between the tear film lipid layer thickness and SAC.²⁹

O’Brien: Some patients with dysfunctional tear syndrome are treated with adjunctive measures, such as punctal occlusion using either temporary or permanent plugs, which create a stasis of tear film turnover and stagnation of proinflammatory cytokines in the tear film that can propagate allergic response. In addition to cytopathologic examination, are other tests available to help primary care physicians quickly and accurately diagnose ocular allergy in patients with more challenging cases?

Caparas: Allergy specialists suggest testing the amount of IgE antibody in tears to differentiate between dry eye and allergy; however, IgE is difficult to isolate. Researchers in Japan and elsewhere have studied IgE levels in the blood and attempted to find a correlation between high serum IgE and allergy.^30-32 These results would then have to correlate with the Schirmer’s test and tear clearance test for confirmation. Even with the use of these tests, the line between dry eye and allergy continues to be blurred. Allergy will present with characteristic findings in the conjunctiva, and dry eye will present with low scores on tests such as the Schirmer’s test, break-up times, and corneal and conjunctival staining. Infections will have a more severe presentation including redder eyes, purulent or mucoid discharge, and a history different from that for dry eye or allergy, which is recurrent or chronic.

Treatment Pearls Goals for Treatment: Alleviate symptoms Prevent ocular damage and vision loss Use treatment regimen with minimal drug-induced side-effects Treating Patients with Seasonal Allergic Conjunctivitis: Collaborate with an allergy specialist Identify possible allergens Instruct the patient in allergen avoidance measures Prescribe a dual-action eye drop to prevent mast cell degranulation and block histamine binding Initiate treatment before expected onset of symptoms and continue throughout allergy season Instruct the patient to avoid warm environments Use artificial tears as an adjunctive measure Prescribe a bioavailable agent that can be administered twice or once a day to improve patient compliance

Leonardi: Total tear IgE analysis, used to differentially diagnose IgE-mediated diseases, has become popular as a simple and rapid diagnostic test for the semiquantitative determination of total IgE in tears. The test utilizes paper strips that are applied directly to the lower fornix of the conjunctiva in a manner similar to that used for the Schirmer’s test. This immunologic assay has potential applications as a local “marker” of ocular allergy that does not exist presently; however, its reproducibility is poor, and it is relatively expensive. New technologies, such as microchip tests for osmolarity, may be used in the future to identify mediators specific to ocular allergy. Stationary phase protein array technology for tear analysis can be used to characterize the distribution of multiple inflammatory mediators in normal, dry eye, and allergic tears.³³

Treating different types of ocular allergy

O’Brien: How do you treat patients with different types of ocular allergy?

Karavellas: The goal for treating all types of allergic conjunctivitis is to alleviate symptoms and prevent ocular damage and vision loss, with a minimum of drug-induced side effects. Treatment should be tailored to the type of disease, severity of symptoms, and the needs of each patient (Figure 4). Educating the patient and the family on the nature of the disease and ways to avoid allergen exposure is also crucial.

Chronic ocular allergy Figure 4: a) Vernal keratoconjunctivitis b) Atopic keratoconjunctivitis. Vernal and atopic keratoconjunctivitis are chronic, sight-threatening diseases that prove more challenging to treat. For patients with chronic allergy, it is beneficial to consult an allergy specialist. Treatment options include cyclosporin A, systemic antihistamines, and topical and systemic steroids. Source: Smith P

O’Brien: What is your routine approach to treating seasonal allergic conjunctivitis, and what do you do when patients do not respond to initial treatment efforts?

Karavellas: For patients with seasonal allergic conjunctivitis, I collaborate with an allergy specialist to identify possible allergens and instruct the patient in allergen-avoidance measures such as taking showers and changing clothes when the patient comes indoors and using protective eyewear. Cold compresses and cold tear substitutes can help to alleviate symptoms in mild cases. Medical treatment using dual-action eye drops such as olopatadine prevents mast cell degranulation and blocks histamine binding. Ideally, this treatment is initiated before the expected onset of symptoms and continues throughout the allergy season.

For patients with perennial allergic conjunctivitis, allergen identification and avoidance are more difficult. Protection against common indoor allergens includes cleaning mattresses and pillows regularly and reducing dust reservoirs such as carpets and furniture upholstery. Dual-action drugs are effective for perennial ocular allergy, alleviating symptoms long term. In my experience, drugs such as olopatadine effectively relieve itching, tearing, and irritation in patients with seasonal and perennial ocular allergies. Patients experience no discomfort or significant side effects.

A dual-action drug, one that is both a potent antihistamine and a mast cell stabilizer, works instantly and interrupts the allergic cascade. — Marino J. Discepola, MD, FRCSC, DABO

Barequet: I encourage patients to avoid warm environments and to use artificial tears as an adjunctive measure. I primarily prescribe a dual-action drug to relieve symptoms in a fast, stable way. Compliance can be a concern when prescribing drops that must be applied three times a day. Twice-a-day drops such as olopatadine can improve patient compliance. Once-a-day olopatadine is not yet available in Israel.

Discepola: A dual-action drug, one that is both a potent antihistamine and a mast cell stabilizer, works instantly and interrupts the allergic cascade. The next time the patient is exposed to the allergen, the mast cells will not degranulate. This treats the fundamental problem rather than masks the symptoms with an antihistamine. Dual-action drugs are also safe.³⁴ In my practice, I prescribe only dual-action drugs.

Smith: Dual-action drugs have revolutionized the treatment of ocular allergies. I find that they are fast acting, easy to use, and preventative as well as instantly therapeutic. The economic basis of a once- or twice-a-day dosing drug is also important. The symptom reduction per dose is important. The efficacy is likely to be greater with compliance, which is improved with less frequent dosage regimes.

Caparas: I also use a combination of antihistamine and mast cell stabilizer, such as olopatadine, to treat ocular allergy. Olopatadine acts directly and prophylactically toward histamine, the chemical that causes allergic symptoms and the cell that produces histamine. Treatment and prevention occur at the same time. Previously, pure mast cell stabilizers such as cromolyn sodium ophthalmic solution were used. When used alone, mast cell stabilizers prevent further release of histamine, but immediate relief from symptoms does not occur. Previously, we also used a vasoconstrictor and antihistamine combination, but this caused rebound redness, which worsens dry eye.

Leonardi: I use dual-action drugs for patients with seasonal allergic conjunctivitis. These drugs are safe and can be used twice a day or once a day. Some components of the same class of drugs can cause a slight burning sensation in the eye or leave a bad taste in the mouth. Olopatadine, on the other hand, has been well tolerated, and no side effects have been reported. Some patients do not respond to dual-action drugs, which is normal because a small percentage of patients in a general population do not respond to any kind of drugs. When this is the case, I recommend switching to an older drug or a simple topical antihistamine.

Treating vernal keratoconjunctivitis

O’Brien: Please discuss the clinical approach for management of VKC.

Karavellas: VKC and AKC are chronic, potentially sight-threatening diseases. Close patient follow-up and consultation with an allergy specialist are essential to prevent permanent ocular damage. Topical immunomodulatory medications, such as cyclosporin, are also very effective in inhibiting ocular surface inflammation associated with atopic disease and can reduce the need for steroid use.

de Freitas: I prescribe corticosteroids if the patient has significant punctuate keratitis, a shield ulcer, or a compromised limbal area. Surgery is sometimes necessary for children when compliance is a concern and the disease cannot be medically controlled. During surgery the upper tarsal papilla are excised, and an autologous healthy oral mucosa is transplanted to the cruent area.

Barequet: Some children with severe VKC do not respond to topical steroid treatment, and systemic steroids must be used to suppress severe exacerbation. Topical cyclosporin A, a steroid-sparing agent, can be used to alleviate symptoms of severe allergic conjunctivitis.

Leonardi: Patients with VKC and AKC can experience symptoms for at least 6 months of the year. These diseases have different phases, and the patient must be prepared for the acute recurrences. I try to avoid steroids because the patients are usually children and must be treated for years. I use a combination of two drugs, lodoxamide and olopatadine. VKC and AKC are related to eosinophil, lymphocyte, and mast cell activation. Lodoxamide is effective on activated eosinophils, and olopatadine acts as a mast cell stabilizer and antihistamine. VKC and AKC are associated with increased levels of IgE ECP, a protein released by activated eosinophils, and many other proinflammatory mediators and inflammatory markers. These forms should be considered systemic diseases with organ localization; therefore, I treat these patients with systemic antihistamines as a basic approach. If the combination of lodoxamide and olopatadine is not successful, I add a topical steroid, such as prednisolone 1% or soft steroids, as a pulse therapy in addition to the other drugs. Strong steroids are not necessary to treat limbal diseases. If the pulse therapy is too frequent, the disease is too severe, or the patient does not respond to steroids, cyclosporin topical treatment can be used. In these cases, inflammation can be reduced with the use of a short, intense pulse of topical steroids and topical cyclosporin for long-term treatment.

O’Brien: When treating patients with more challenging conditions such as VKC and AKC, a multifaceted treatment approach involving several medications, adjunctive therapies, cyclosporin A, and corticosteroids can be helpful in controlling the disease (Figure 5).

Treating AC Figure 5: In the treatment of ocular allergies there are a range of strategies. The most recognized therapies (shown in white) include allergen reduction measures, mast cell stabilizers, antihistamines, combination mast cell stabilizer and antihistamines, steroids, immunotherapy, and cyclosporin A. Potential therapies (shown in yellow) include T cell vaccines, anti-cytokine agents such as IL5 or 13, monoclonal anti-IgE, non-steroidal anti-inflammatory agents and specific protease inhibitors. Source: Smith P

O’Brien: Do eosinophils have a significant role in seasonal ocular allergy or are they associated with VKC or AKC?

Caparas: Eosinophils are more often found in chronic types of allergy such as VKC and AKC. An article by Montan reported that in cases of VKC and AKC, more early-phase patients had eosinophilia in their conjunctiva compared with patients with seasonal allergies. The mast cells and eosinophils mutually influence each other. In eosinophilia, increased adhesion to the epithelium can occur, which is believed by some to be the basis for its association to chronic types of allergy.³⁵

Barequet: Eosinophils signal late-phase reactions in allergic conjunctivitis. Studies show tears collected from patients with allergies contain bioactivity capable of upregulating eosinophil adhesion to human conjunctival epithelial cells in vitro. Treating patients with olopatadine inhibits this process, suggesting that some cellular targets of the drug may help promote eosinophil adhesion. ³⁶

Karavellas: Eosinophils play a significant role in the pathogenesis of VKC. Eosinophilic infiltration of the conjunctiva is a characteristic finding, and eosinophil-derived mediators may be detected in VKC, AKC, and giant papillary conjunctivitis. In seasonal allergic disease, ocular inflammation is primarily the result of mast cell degranulation and the effects of the chemical mediators that are released.

Looking to the future

O’Brien: Describe what you consider the ideal treatment for allergic conjunctivitis. What characteristics would it have?

Karavellas: Future therapeutic strategies will be aimed at preventing the allergic response. One approach is to minimize the likelihood of developing atopic disease by modulating the Th1/Th2 balance toward nonallergenic reactions during early childhood. New research focuses on the development of novel anti-inflammatory agents to inhibit the production of proinflammatory cytokines at the transcriptional level. Safety, efficacy, extended duration of action, and convenient dosing are the characteristics of an ideal therapeutic agent.

Smith: I think T-cell vaccines will be available in the future. For allergen-mediated disease, administering peptide immunotherapy may turn off T-cell activity. The efficacy of T-cell vaccines has been tested on cat allergies. With a single injection, researchers have been able to stimulate tolerance with a T-cell epitype. Monoclonal anti-IL-5 is a potential specific therapeutic modality that has been used to treat eosinophilic esophagitis.

Caparas: As we learn more about the mechanisms of allergies, we are better able to identify the particular cells or chemicals that are released to cause allergy. In the future, I think genetic modification will be introduced that will reduce or reverse the sensitization that occurs in the allergy process.

Patients with allergies need medications that interfere with the initial mechanisms causing allergic sensitization. — Andrea Leonardi, MD

Leonardi: It will be difficult to target a single molecule or mechanism and down-regulate a complex cascade of events. Patients with allergies need medications that interfere with the initial mechanisms causing allergic sensitization. The development of more effective topical immune-modulating agents that control multiple aspects of the disease without side effects, or treatments that target key mechanisms that induce allergy, may further improve the treatment of severe ocular allergies. New drug-delivery systems such as subconjunctival implants, liposomes, or nanoparticles that increase bioavailability and extended contact of compounds with the ocular surface may also improve patient compliance.

O’Brien: We do not have a cure for ocular allergies, but new drugs and strategies have been developed that help patients manage the symptoms to reduce suffering. The prevalence and type of ocular allergy differ from country to country, depending on the climate and environmental factors. However, the impact of ocular allergy on quality of life seems to be consistent throughout the world. Our discussion has shown that accurate diagnosis, a reduction in environmental pollutants, and innovative therapies, such as once-a-day dosing, can help curb the social and economic impact on patients with ocular allergies.

I thank Ocular Surgery News Europe/Asia-Pacific Edition for organizing this panel and Alcon Laboratories, Inc., for its sponsorship. I especially thank the distinguished international faculty for participating in our stimulating discussion.

References

1. Yanni JM, Miller ST, Gamache DA, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol. 1997;79:541-545.
2. Barnes M, Cullinan P, Athanasaki P, et al. Crete: does farming explain urban and rural differences in atopy? Clin Exp Allergy. 2001 ;31:1822-1828.
3. Doughty MJ, Fonn D, Richter D, et al. A patient questionnaire approach to estimating the prevalence of dry eye symptoms in patients presenting to optometric practices across Canada. Optom Vis Sci. 1997;74:624-631.
4. Berger W, Abelson MB, Gomes PJ, et al. Effects of adjuvant therapy with 0.1% olopatadine hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using systemic or nasal therapy. Ann Allergy Asthma Immunol. 2005;95:361-371.
5. Merck Manual Home Edition. http://www.merck.com/mmhe/sec20/ch229/ch229d.html. Accessed November 22, 2007.
6. Sacchetti M, Baiardini I, Lambiase A, et al. Development and testing of the quality of life in children with vernal keratoconjunctivitis questionnaire. Am J Ophthalmol. 2007;144:557-563.
7. Roberts G, Mylonopoulou M, Hurley C, et al. Impairment in quality of life is directly related to the level of allergen exposure and allergic airway inflammation. Clin Exp Allergy. 2005;35:1295-1300.
8. Smith AF, Pitt AD, Rodruiguez AE, et al. The economic and quality of life impact of seasonal allergic conjunctivitis in a Spanish setting. Ophthalmic Epidemiol. 2005;12:233-242.
9. Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J. 2004;24:758-764.
10. Gradman J, Wolthers OD. Allergic conjunctivitis in children with asthma, rhinitis and eczema in a secondary outpatient clinic. Pediatr Allergy Immunol. 2006;17:524-526.
11. Hijazi N, Ablkhail B, Seaton A. Asthma and respiratory symptoms in urban and rural Saudi Arabia. Eur Respir J. 1998;12:41-44.
12. von Mutius E, Fritzsch C, Weiland SK, et al. Prevalence of asthma and allergic disorders among children in united Germany: a descriptive comparison. BMJ. 1992;305:1395-1399.
13. Leonardi A, Busca F, Motterle L, et al. Case series of 406 vernal keratoconjunctivitis patients: a demographic and epidemiological study. Acta Ophthalmol Scand. 2006;84:406-410.
14. Woolcock AJ, Peat JK. Evidence for the increase in asthma worldwide. Ciba Foundation Symp. 1997;206:122-139.
15. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351:1225-1232.
16. Saxon A, Diaz-Sanchez D. Air pollution and allergy: you are what you breathe. Nat Immunol. 2005;6:223-226.
17. Nikolaou N, Siddique N, Custovic A. Allergic disease in urban and rural populations: increasing prevalence with increasing urbanization. Allergy. 2005;60:1357-1360.
18. Gilliland F, Li Y, Saxon A, Diaz-Sanchez D. Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet. 2004;363:119-125.
19. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259-1260.
20. Sublett JL. The environment and risk factors for atopy. Curr Allergy Asthma Rep. 2005;5:445-450.
21. Tedeschi A, Barcella M, Bo GA, et al. Onset of allergy and asthma symptoms in extra-European immigrants to Milan, Italy: possible role of environmental factors. Clin Exp Allergy. 2003;33:449-454.
22. Ventura MT, Munno G, Giannoccaro F, et al. Allergy, asthma and markers of infections among Albanian migrants to Southern Italy. Allergy. 2004;59:632-636.
23. Davies RJ, Rusznak C, Devalia JL. Why is allergy increasing? Environmental factors. Clin Exp Allergy. 1998; 28 (suppl 6):8-14.
24. Eder W, Klimecki W, Yu L, et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol. 2004;113:482-488.
25. Takizawa H. Diesel exhaust particles and their effect on induced cytokine expression in human bronchial epithelial cells. Curr Opin Allergy Clin Immunol. 2004;4:355-359.
26. Matsuura N, Uchio E, Nakazawa M, et al. Predominance of infiltrating IL-4-producing T cells in conjunctiva of patients with allergic conjunctival disease. Curr Eye Res. 2004;29:235-243.
27. Majd A, Chehregani A, Moin M, et al. The effects of air pollution on structures, proteins, and allergenicity of pollen grains. Aerobiologia. 2004;20:111-118.
28. Robertson CF, Roberts MF, Kappers JH. Asthma prevalence in Melbourne schoolchildren: have we reached the peak? Med J Aust. 2004;180: 273-276.
29. Suzuki S, Goto E, Dogru M, et al. Tear film lipid layer alterations in allergic conjunctivitis. Cornea. 2006;25:277-280.
30. Mimura T, Amano S, Funatsu H, et al. Correlations between allergen-specific IgE serum levels in patients with allergic conjunctivitis in spring. Ocul Immunol Inflamm. 2004;12:45-51.
31. Rolinck-Werninghaus C, Kopp M, Liebke C, et al. Lack of detectable alterations in immune responses during sublingual immunotherapy in children with seasonal allergic rhinoconjunctivitis to grass pollen. Int Arch Allergy Immunol. 2005;136:134-141.
32. Dehlink E, Eiwegger T, Gerstmayr M, et al. Absence of systemic immunologic changes during dose build-up phase and early maintenance period in effective specific sublingual immunotherapy in children. Clin Exp Allergy. 2006;36:32-39.
33. Sack R, Conradi L, Beaton A, et al. Antibody array characterization of inflammatory mediators in allergic and normal tears in the open and closed eye environments. Exp Eye Res. 2007;85:528-538.
34. Abelson MB, Turner D. A randomized, double-blind, parallel-group comparison of olopatadine 0.1% ophthalmic solution versus placebo for controlling the signs and symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Clin Ther. 2003;25:931-947.
35. Montan PG, van Hage-Hamsten M. Eosinophil cationic protein in tears in allergic conjunctivitis. Br J Ophthalmol. 1996;80:556-560.
36. Cook EB, Stahl JL, Brooks AM, et al. Allergic tears promote upregulation of eosinophil adhesion to conjunctival epithelial cells in an ex vivo model: inhibition with olopatadine treatment. Invest Ophthalmol Vis Sci. 2006;47:3423-3429.