Ocular allergy: A growing global problem

Ocular allergy: A growing global problem

Francis S. Mah, MD: Millions of people are affected by ocular allergy, with the majority experiencing seasonal or perennial allergic conjunctivitis. Persistent symptoms of seasonal or perennial ocular allergy, such as itching, redness, lid swelling, tearing, and swollen eyes, can significantly impact quality of life.

What is the mechanism of the allergic response in the conjunctiva?

Murat Irkec, MD: Allergy generally can be divided into two groups, with the first group comprising the seasonal and perennial types and the second group the vernal, atopic, and perhaps debatably, giant papillary conjunctivitis. The seasonal and perennial allergic conjunctivitis group is an IgE-dependent mast cell disease, which means it is a class I allergic condition. Patients in this group initially will have mast cells sensitized to certain antigens. There are receptors for IgE on the mast cells, and when there is cross-linking between two IgE molecules with the help of the antigen, degranulation will occur. Because of the degranulation, preformed mediators – basically histamines – flood the ocular surface.

Thus, seasonal and perennial allergic conjunctivitis is basically an IgE-mediated mast cell degranulation disease. It is hypocellular, and the role of eosinophils is not outstanding. A few eosinophils may be seen in late phases of the allergic reaction in this type of allergy. The second group, which includes vernal and atopic disease, is more destructive to the ocular surface and has a more complex pathogenesis.

Global perspectives on ocular allergy

Mah: What is the prevalence of ocular allergy among general populations in different countries?

Anna Groblewska, MD: Although data are inconclusive, approximately 20% of the population in Poland has ocular allergies. Most patients experience seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC). Occasionally, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC) occur.

Juan Stoppel, MD: In Chile, approximately 20% to 25% of the population has some type of ocular allergy, primarily SAC, PAC and VKC. AKC in Chile is rare.

Michael B. Raizman, MD: In the US, many patients with allergies experience ocular involvement. VKC tends to be uncommon, perhaps because of the relatively cool climate, but in some southern states VKC is prevalent. AKC is uncommon compared with SAC and PAC, but the prevalence seems to be increasing. There are several theories about why the incidence of allergy in general is increasing in the United States and worldwide. Some clinicians attribute the growth to improved diagnosis and better recognition of the allergic phenomenon, whereas others propose that increased pollution and environmental factors play a role. A hygiene theory is emerging that suggests that decreased exposure to bacteria and allergens in childhood may increase susceptibility to allergy later in life.

Victor L. Caparas, MD, MPH: In many areas of Southeast Asia and in Asia in general, epidemiologic data on ocular allergy are limited compared with data on other ocular diseases. In the Philippines, it is estimated that approximately 10% to 15% of the population experiences some form of ocular allergy, primarily the perennial type. As in many countries on or near the equator, the Philippines generally has just two seasons, wet and dry, and the types of allergy there generally occur throughout the year and are often aggravated by dust, mites or environmental factors such as pollution.

Irkec: Nearly 15% of the Turkish population experiences ocular allergy. SAC is the most prevalent type of allergy in Turkey, with PAC the second most common. The estimated prevalence of VKC is approximately 5% of the population with allergy. Although AKC is rare in Turkey, atopic dermatitis is not. There are also regional differences in the distribution of allergic conjunctivitis. For example, in the northern part of Turkey, SAC occurs more often, but in the southern and southeastern areas, VKC is more common. VKC is more threatening to the quality of life because it can lead to blindness and has been associated with keratoconus.

Andrea Leonardi, MD: The epidemiologic data on ocular allergy in Europe are not clear. It is estimated that approximately 15% to 25% of the population in Europe has ocular allergy. Data extrapolated from larger general studies indicate that the incidence of rhinoconjunctivitis has increased over the past 15 to 20 years, but that the incidence of asthma has remained constant or decreased over the past 5 to 10 years.¹ The increase in rhinitis and allergic conjunctivitis may be related to patient and physician education or environmental changes.

AKC is rare in Italy and Europe. It is probably more common in the United Kingdom than in Italy and other countries in southern Europe. VKC is relatively common, with between 7 and 10 new cases per year per every 100,000 children. Further, it is not as rare as we had believed because we needed to consider not only the severe cases, but the mild cases that ophthalmologists do not see often.

Another factor that has not been cited regularly, but that is becoming more common, is contact sensitization to cosmetics, drugs and other substances that come into contact with the ocular surface or eyelid. This type of non-IgE- mediated sensitization has a different pathogenesis, a T-cell–mediated delayed hypersensitivity reaction to haptens, which causes eyelid eczema, itching and mast cell activation.²

Jesús Merayo, MD, PhD, MBA: In Spain, the prevalence of all allergies increased during the past 30 years from 15% to approximately 25% to 30% of the population. Most of these people experience clinical symptoms in the eye. The most common types of allergy seen by pediatricians, general physicians and allergists are SAC and PAC. VKC tends to be more prevalent in central and southern Spain with no change in prevalence in the past years. AKC is rare, and if ophthalmologists learned more about this condition, diagnosis and treatment could be established earlier and result in improved patient outcomes. The number of patients with GPC seems to have decreased in the past decade most likely because contactologists have improved education in contact lens care, and new materials have been used in contact lenses. New disposable contact lenses may prevent biofilm, proteins and other mediators that trigger the inflammatory response of the ocular surface from building up on the surface.

Also, there is a connection between the increase in dry eye and environmental influences such as air conditioning or heating. Tear film damage allows allergens and toxic compounds to reach the conjunctival epithelium and begins the inflammatory response.

Hiroshi Fujishima, MD: In Japan, more than 40% of the population experiences allergies. In northern Japan, a smaller percentage of patients have ocular allergies. A major problem is SAC, particularly because of cedar pollen and the weather in Japan getting warmer and more humid due to pollution. Although the air is clearer now, a significant portion of the population still experiences an increase in pollen allergy. The cedar pollen count might be high one day, drop suddenly, and then reach high levels again. It appears temperature warming might also affect the cedar pollen count in Japan. The other problem in Japan is an increase in AKC. AKC is not only an ocular surface problem, but also causes cataracts, retinal detachments, and keratoconus. One final point is that, as in other countries, the combination of allergy and dry eye in Japan is increasing, especially in older people. We need to treat both the allergic response and dry eye syndrome in these patients.

Mah: It seems that the prevalence of ocular allergy is rising in many countries. Clearly, Japan is on the high end, with approximately half its population experiencing allergies. Do you think that increased recognition of symptoms accounts for the increased prevalence in the Philippines?

Caparas: It is possible that physicians are giving more attention to these symptoms, whereas previously they might have been prioritized lower because of economic constraints. There may not have been a problem recognizing allergy symptoms, but perhaps it is more an issue of assigning them more importance and understanding how they impact patients’ lives.

Mah: Beside cedar pollen in Japan, what are some other common allergens?

Merayo: In Spain, the classic allergy season occurs in spring. Over the past decade, allergy season seems to begin earlier, with the increase in pollen counts from olive trees and other airborne allergens appearing as early as January. As the rest of the plants begin pollination, patients experience allergies during the first 6 months of the year and some grass pollen allergies from September through October.

Leonardi: Careful review of pollen counts in southern Europe and elsewhere, show that pollen counts are high in months not usually associated with pollen-related allergy. Seasons are becoming longer and conditions more severe because of global warming and other environmental factors, such as air pollution. Indoor allergens and indoor-related allergies have increased as well because of poor ventilation systems in modern buildings. Exposure to indoor pollutants, such as second-hand smoke and cooking combustion products have been linked to respiratory tract and skin illnesses.³

Irkec: Conditions are similar in Turkey in that the allergy season begins at the end of April and lasts through September. In the case of seasonal allergy, the most common allergy is grass pollen followed by acacia tree pollen, which is common in Mediterranean countries, and grain and wheat pollen. Mites are the most common cause of indoor allergy, and mold is becoming more problematic as well as cockroach allergen. Feline antigens are also increasing, especially as cats become more popular as pets.

Caparas: The Philippines have a different pattern altogether. There are more perennial allergies, overwhelmingly caused by dust mites and cockroach droppings. The prevalence of seasonal allergies depends primarily on the weather. When it is dry, people experience more seasonal allergy, but when it rains and there is no pollen circulating, seasonal allergy subsides. There is, however, an upsurge in perennial allergy during wet weather because of mold.

Raizman: In the United States, seasonal allergens are produced primarily by trees in spring, grass in summer, and weeds in late summer. There are many different climates in the United States, and in the south, where trees are prominent throughout the winter months, year-round seasonal allergies are common. Perennial antigens are similar to what has been noted above, namely, dust mites, molds and animal dander.

Groblewska: In Poland, seasonal allergies begin in early February and last until October. In spring, the primary causes of allergy are trees, some types of grass and weeds. Perennial allergens in Poland are associated with mites, mold and animal dander.

Stoppel: In Chile, seasonal allergies begin in September and tend to end in March. The main causes are trees, grass and weeds in summer. For perennial allergies, the primary causes are dust mites and animal dander. Environmental conditions are causative in all countries. It seems that pollution may affect the incidence and severity of allergy.

Impact on quality of life

Mah: What type of impact can ocular allergy have on the patient’s quality of life?

Raizman: In the past, physicians may have underestimated the importance of allergies, considering them a nuisance and minor inconvenience to patients. However, seasonal allergies may affect patients’ ability to work. Physicians also should not trivialize the effects of allergy on patients’ recreational activities and ability to enjoy being outdoors.

Mah: How do patients typically describe the severity of their symptoms?

Caparas: Typically, when patients see an ophthalmologist, their symptoms are already severe. Their eyes are itchy, red and teary. Yet physicians are beginning to see another population of patients whose symptoms may be less severe, but more persistent, occurring every day for several hours a day. This can be disturbing for them, and it is probably the factor that affects work and quality of life most.

Leonardi: The severity of symptoms in patients with SAC or PAC is extremely subjective. You may see patients describing themselves as having miserable lives because of their disease and find, objectively, a relatively mild form of allergy, or the opposite. Children affected by VKC, and especially their parents, experience reduced quality of life for the entire family (Figures 1 and 2). Children have a strong body language and although they do not describe their symptoms entirely, it is possible to understand that this disease impacts their day-to-day life. Their parents, too, are impacted psychologically because they see their children suffering and have a forced change in their daily schedule. Adult patients with AKC or eyelid dermatitis might also experience a psychological effect as a consequence of the cosmetic appearance of the skin in addition to their persistent inflammatory symptoms.

Fujishima: Another problem is that sometimes antihistamine pills and other allergy drugs taken systemically can cause drowsiness and decreased concentration. Also, contact lens wearers might have to stop wearing their lenses for a while, and this can be an inconvenience.

Irkec: Because the beginning of allergy season coincides with the end of the school year, many children are affected, and their success in school decreases because of itching and tearing that can be distracting.

Leonardi: The economic impact is particularly important for patients with severe chronic disease. They usually have to see several doctors and try several drugs before they get an accurate diagnosis and the appropriate medication. This emphasizes the importance of making the correct diagnosis as soon as possible.

Differential diagnosis

Mah: How difficult is it for the primary care physician to differentially diagnose red eye as dry eye, ocular allergy or ocular infection?

Merayo: For nonophthalmologists, such as general physicians or pediatricians, it can be difficult because they do not have the tools to make an accurate diagnosis. They usually treat patients based on symptoms. If there is itching but no loss of visual acuity or discharge or pain, a general physician may treat the allergy after identifying the primary symptom of itching. They should treat the patient for 48 hours and, if improvement occurs, continue the treatment. If the patient does not improve or experiences a decline in visual acuity or any pain, the physician should refer the patient to an ophthalmologist. General physicians should also refer if there is concern about side effects or ocular complications from the medication.

In some countries physicians might need to make the differential diagnosis of itching with parasitic infections when these diseases are prevalent. In Spain, these types of infections are rare but can occur.

Fujishima: General practitioners and pediatricians need to understand the difference between infection and allergy. A delay in treatment of allergy is not critical, but a delay in treatment of infection can be serious. Thus, if we understand which is which, the patient can receive the appropriate treatment immediately.

Mah: That is a very important rule. If there is any question at all for the pediatrician or general practitioner, he or she should not delay the referral. If there is definitely no infection, then 24 to 48 hours is a good time frame to try different therapies.

How are patients with ocular allergy diagnosed in your practice?

Groblewska: I usually start by talking to parents because we treat a lot of children. I ask about allergy signs and symptoms. I also try to carry out tests that can be done at outpatient clinics such as a test for IgE in tears, tear break-up time, Schirmer’s test or staining. In my outpatient clinic, I can observe the patient every day if necessary. If they require surgery or a complicated treatment, I can refer the patient to the clinic.

Stoppel: I think the diagnosis is primarily a clinical diagnosis. As we have indicated previously, itching is the main part of the diagnosis. If there is no itching, then it is not allergy. Many of my patients are referred from general practitioners or from other ophthalmologists. The patients referred from general practitioners have been diagnosed with allergy, but in many cases have been taking only oral antihistamines and no topical drops. Patients referred by other ophthalmologists often do not actually have allergy. The three primary differential diagnoses involved are dry eyes, chronic meibomitis and blepharitis.

Mah: How would you try to distinguish these three differential diagnoses? Are these three separable?

Raizman: It is common for them to present simultaneously. The main reason I will see patients in consultation or patients who have failed good anti-allergy therapy is that they have concomitant blepharitis or dry eye. I agree that the diagnosis of allergy is primarily clinical, so I do not perform specific tests in the office. Of course, the symptom of itching is critical, but we have to look for blepharitis and dry eye as well and treat all of the conditions.

Caparas: One of the major problems general physicians have is differentiating viral conjunctivitis from allergy. Several epidemics of mostly adenoviral conjunctivitis occur in the Philippines every year. Typically, these patients are referred with a combination of antibiotics and steroids to treat symptoms of what was thought to be viral conjunctivitis without taking a proper history or performing a thorough clinical exam. We try to educate general practitioners to review patient history carefully and to examine the differential symptoms that help determine whether the condition is viral conjunctivitis or allergy.

Dry eye and ocular allergies

Mah: Do dry eye and ocular allergy coexist? Does either condition make the patient more susceptible to the other?

Leonardi: I always believe the diagnosis starts in the waiting room. It can be crucial to observe patient behavior when they are not in front of the ophthalmologist and perhaps may not report all of his or her symptoms, the facts that may cause them, underlying diseases or drug use. Ophthalmologists should talk to patients in detail. Usually when patients report that they are allergic to “everything,” and they believe that they are, this turns out not to be the case. Patients may have a different opinion on to what they are allergic. Thus, it is important to perform the appropriate tests, even if only to show patients what their condition actually is and whether they are actually allergic to a potential allergen. Showing the results of the Schirmer’s test strips, the prick test, or provocation tests may be useful in convincing patients and determining a proper diagnosis.⁴

If a patient presents with a red eye that I cannot identify, a useful test is a tear or conjunctival cytology to identify what type of cells are involved in the inflammation.

Raizman: Occasionally I will see patients who come into the office after sitting in the air- conditioned waiting room. Their eyes look perfect, and all test results would be negative. Thus, physicians must listen carefully to the patient’s history to make an appropriate diagnosis.

Fujishima: In my experience, patients with dry eye typically report that symptoms are worse after work or in the evening, whereas patients with allergy complain of discomfort in the morning.

Leonardi: I agree that the diagnosis is mostly clinical, but it has to be combined with objective tests that can explain the cause and the course of symptoms. In middle-aged patients who work in offices all day, the study of tear film will reveal a dry eye condition or blepharitis, but if allergy is suspected, then allergy tests must be performed to confirm it. If patients have both conditions concomitantly, treating dry eye or allergy individually might not be sufficient. The two conditions might also coexist because systemic or oral allergy drugs can have a drying effect.

Irkec: I agree with my colleagues here that the diagnosis is basically clinical, but taking a careful history is critical. Most patients experience rhinitis and other similar problems. More than 10% may suffer from asthma, gastrointestinal problems or food allergies.

We have a good allergy clinic in my university hospital. For mild to moderate cases, we diagnose and treat patients, but in severe or more complicated cases, we collaborate with the allergists.

Mah: Are there any other comments or tips on how to make an accurate diagnosis for allergy or how to educate nonophthalmologists who refer patients to us?

Leonardi: One tip is that if there are too many follicles in the conjunctiva, usually this is not allergy but toxicity to drugs. Thus, the clinician must once again, go back to the history to determine how patients are treating themselves. Sometimes patients carry a vasoconstrictor with them but they do not think to show it to the clinician because they think of it as just an “eye drop” and not as a medication. Yet this is a very common cause of chronic red eye and inflammation.

Mah: That is an excellent point. It can be confusing when you see red eye and follicles in the conjunctiva.

Raizman: In terms of the examination of papillae and follicles, I teach residents that young patients generally have papillae and may have follicles without disease. Thus, you should not make too much of papillae or follicles in young patients; it does not mean they have allergies. Also, many people with allergies do not have any papillae at all, so you cannot necessarily rely on that finding.

Mah: How are allergies impacted by toxins that may be on the rise due to increased urbanization in various parts of the world?

Caparas: Urban allergy is a term that some clinicians use to describe nonspecific, chronic low-grade itching, redness, and burning – a nonspecific conjunctivitis. Urban allergy is not actually a specific allergic condition, but a combination of several factors triggered by increasing pollution. Some clinicians believe pollution increases the allergic potential of any allergen. Some have called this the mucosal adjuvant hypothesis.

Leonardi: Allergen susceptibility might be increased in areas with increased air pollutants. Both allergens and pollutants can initiate specific and nonspecific mucosal inflammation directly through several interweaving mechanisms including oxidative stress, pro-inflammatory cytokine production, and cyclo-oxygenase, lipoxygenase, and/or protease activation.⁵

Treatment options

Mah: I have found that avoidance and immunotherapy can be important tools. What are your pearls for treating different types of ocular allergy, including seasonal, perennial, vernal and atopic forms?

Groblewska: I think that we should differentiate seasonal and perennial allergies from vernal and atopic allergies because they are not the same phenomena. Of course, avoidance is important, but we should remind patients with perennial allergies to use artificial tears to wash allergens from the tear film. I believe we should use dual-action medications in this patient group.

With vernal or atopic allergies, it is more complicated, and the clinician must consider how the cornea is involved in these diseases. I would like to emphasize that these diseases should be treated by ophthalmologists rather than by allergists, pediatricians or general practitioners. If there is something wrong with the cornea, I often will use atropine and antibiotics. In these cases, patients generally have allergies that go beyond the eye, and they should also be treated by an allergist. However, the ophthalmologist should be the primary caregiver.

Stoppel: Because many patients with allergies test positive for many allergens, it is difficult to avoid the specific antigen or allergen that causes the reaction. It is useful to remember that sunglasses can work as a shield and prevent a large quantity of allergens from coming into contact with the ocular surface. For seasonal allergies, I typically use drugs such as Patanol (olopatadine HCl 0.1% ophthalmic solution, Alcon Laboratories, Inc.) because of the dual mechanism of action and also sometimes artificial tears. VKC and AKC are different entities in that they can produce severe corneal disease and should be treated only by an ophthalmologist. I find Alomide (lodoxamide ophthalmic solution, Alcon Laboratories, Inc.) to be useful as well as cyclosporine for immunomodulation in some patients.

Raizman: One of the most common reasons for treatment failure is that patients have not been educated about some simple avoidance measures. It is impossible for patients to avoid all allergens, and some people have to be outside on high pollen count days. However, we can recommend that patients change clothes, brush their hair and wash their hands and face when they come in from outside. We should at least emphasize that they should try to reduce the pollen before they go to bed so they do not have pollen in their pillow. These are simple measures that patients understand. They just may not think about them. Similarly, we can tell patients to keep their hands away from the face, even when pollen counts are high. Although it is a relatively small amount of pollen that lands on the conjunctiva or in the nose, when patients touch the face, they introduce an enormous inoculation of pollen into the eyes and nose. Reminding them to avoid rubbing the eyes, which brings pollen into the eyes and also mechanically degranulates mast cells, is an important part of education, and many patients have told me that this advice has helped them quite a bit. Of course, we need to rely on the effective drugs, but without that little bit of education, even our most effective drugs will not always work.

Irkec: I agree that avoidance is important with seasonal allergies as well as with perennial allergies to some degree. For example, a shower just before bed can be effective. Also, ocular lubricants work well in most patients and are comfortable. Of course, dual-acting medications such as Patanol solution have been the mainstay in our treatment of SAC for many years. For vernal disease, I usually begin by prescribing steroids for 2 to 3 weeks. We have the commercial preparation of topical cyclosporine A, but in vernal cases the clinician should prescribe these drops at least four times a day and only in combination with steroids at the onset. For severe cases of VKC, clinicians should use higher concentrations of cyclosporine A. Some surgical interventions, including excision of the giant papillae, can be effective in decreasing the number of cytokines and inflammatory mediators.

Leonardi: I also tell the patient not to use any kind of homeotherapy or plant extracts to treat allergies. In Italy, some patients use chamomilla eye drops because it is a mild, natural decongestant, but the pollens in this flower are highly allergenic because it is in the Compositae family. For seasonal and perennial cases, I believe dual-action drugs are the first choice. Patanol solution has been shown to be the most effective drug in the category compared with other anti-allergic topical drugs. Of course, the patient might be satisfied using vasoconstrictors or the over-the-counter combination of vasoconstrictors and antihistamines. This is when clinicians need to educate patients on the difference between various compounds and their action and potential side effects. We may see patients with chronic vasodilation because they have been using vasoconstrictors for years. Thus, it is better to spend a little more time to teach every patient which drug is best for him or her. I would like to go back to the importance of allergy tests because I think it is necessary to correlate symptoms to the offending allergen or allergens. Thus, it is useful to determine to what they are allergic in order to conclusively plan a long-term therapeutic strategy.

In severe conditions like VKC, it is critical to educate patients and parents and to begin early in the season to treat children with anti-allergic drugs such as lodoxamide, which is effective on eosinophil activation. We begin treating patients in late February or early March, depending on how early the warm season begins, combining Alomide solution four times a day with Patanol solution twice a day. This will not prevent the need for steroids entirely, but it will definitely reduce steroid use. When I prescribe steroids, I prefer high doses as “pulse therapy” for 3 or 4 days in addition to the basal treatment with the other two drugs. I ask the patients or the parents to report how often steroids were required as pulse therapy over a 3-month period. If the use of corticosteroids is too frequent or not effective, I might propose using cyclosporine as another option for long-term therapy.

Merayo: To reduce the exposure to allergens, children should take a shower immediately after school and wear different clothes indoors and outdoors. For acute cases, physical therapies such as a cold compress are recommended. When topical medications are necessary, the best medical approach is a dual-action medication with both an antihistamine and a mast cell stabilizer such as Patanol solution. As we encounter more complicated cases such as vernal allergy, I generally invite the patient’s family to my office to come to an agreement over education for both the family and patient. An agreement is mandatory to recognize the role of each person in the treatment of chronic and eventually destructive disease of the ocular surface.

Regarding steroids, there is a high risk of complications from steroid abuse, especially in children who undergo long-term treatment. For this reason, physicians must educate patients and family members of the potential steroid abuse. If steroids are recommended, they should be administered every 2 hours at the beginning of treatment and reduced in frequency progressively and rapidly until discontinuation.

AKC is a difficult chronic disease and ophthalmologists may require assistance from other colleagues, such as allergists and experts in managing immunosuppressive therapy.

Finally, I favor a medical approach over a surgical one. I see older patients who have considerable scarring of the conjunctiva, secondary to surgical treatment of giant papillae for VKC (Figure 3). There is a role of reconstruction of the ocular surface in cases of advanced chronic cicatrizing conjunctivitis secondary to ocular allergy disorders such as AKC.

Fujishima: For seasonal and perennial cases, I usually begin treating patients at the end of January, when cedar pollen season begins. Treatment depends on the patient’s symptoms. When the primary symptom is itching, I choose antihistamine eye drops as the first line of treatment. When the primary symptom is foreign body sensation, I prescribe a mast cell stabilizer eye drop. When both symptoms are present, I often use a dual-action eye drop.

Recently, olopatadine is my first choice for treating patients with allergy. For children, Patanol solution is favorable; they like it because it does not cause pain.

When treating patients with more severe allergies, such as AKC or VKC, I add a cyclosporine A eye drop or Bromfenac (NSAID) to decrease inflammation without increasing IOP.

I do not like using steroids, especially in younger patients. However, in some cases, I will prescribe steroids for a short period. I do not use steroids because in Japan, many patients have glaucoma, including steroid-induced glaucoma.

When there is a cobblestone appearance, surgery may be necessary. Each cobblestone contains inflammatory cells. Nonsurgical removal of the inflammatory cells followed by immunosuppressive treatment can be effective. However, about 1 month into treatment, patients may become exhausted from the pain and blurred vision. If inflammation remains after 1 month of nonsurgical treatment, we try a surgical option.

Mah: Avoidance and education are critical for management of seasonal and perennial allergies. Immunotherapy is another important tool to pinpoint the sources of the allergies. Early therapeutic options include artificial tears or lubricating eye drops to dilute the allergens, followed by a dual-action medication such as Patanol solution. For more severe cases, such as atopic and vernal cases, clinicians may consider other systemic or topical therapies such as cyclosporine and oral systemic medications. In the United States, we have some reservations about using NSAIDs topically, especially for severe ocular surface disease.

Raizman: I believe that some of these patients need oral antihistamines because of the severity of the systemic disease. But, as ophthalmologists, we often see the drying effect of even the newest oral antihistamines. All oral antihistamines dry the eye to some extent. Again, I do not feel our allergist colleagues always realize that eye drops can be used in conjunction with oral treatments. Some of my patients who take oral medications only for nasal symptoms experience relief of dry eye symptoms if they switch from the oral drug to a nasal spray. This eliminates the drying effect, and their eyes feel better. I commonly switch my patients from a systemic antihistamine to a nasal steroid.

Leonardi: Regarding the use of immunosuppressants, clinicians must be very careful in choosing them because they are not approved for topical use.

Applying clinical experience to drug choice

Mah: When discussing seasonal and perennial disease specifically, it is important to differentiate vasoconstrictors from topical antihistamines and mast cell stabilizers. Also to differentiate all these drugs from the dual-action medications. We need to make these distinctions to determine which are preferred for seasonal and perennial allergies. Is there any role for over-the-counter vasoconstrictors in today’s treatment regimen? What effects do they have?

Groblewska: Many patients use vasoconstrictors because they can purchase them easily over the counter. It is probably okay when used for a short time. However, looking at long-term results, allergists and ophthalmologists in Poland have suggested that over-the-counter vasoconstrictors should no longer be used for ocular allergy.⁶

Mah: How can we differentiate between mast cell stabilizers, antihistamines and dual-action drugs? Is there a role for a mast cell stabilizer only or for an antihistamine only?

Stoppel: If patients must use both a mast cell stabilizer and an antihistamine, they have two bottles instead of one, and treatment compliance can be poor. So I prefer to prescribe only one drug with both mechanisms of action.

Caparas: I believe the biphasic effect of antihistamines is well known among allergists but probably not as well known among ophthalmologists and general practitioners. The concept is that the molecules of many antihistamines penetrate the mast cell membrane up to a given concentration and inhibit the release of histamine. At a certain concentration, however, the mast cell membrane is disrupted, producing the paradoxical release of histamine. Therefore, the clinician can actually defeat the purpose of using an antihistamine. This does not happen with Patanol solution, which has anti-allergy effects beside its mast cell stabilization properties, including the inhibition of TNF-alpha, other cytokines and other chemical mediators.

Selecting the optimal dual-action medication

Mah: If we agree that we should use the dual-action medications, how can we differentiate among them for patients with seasonal and perennial conjunctivitis?

Leonardi: Several studies have shown that Patanol solution is more effective than other drugs in the same category, such as ketitofen, azelastine, and epinastine. Patanol solution is also more comfortable than other drugs because it does not burn, sting, or leave an unpleasant taste. I have had some negative experiences with children who developed unpleasant taste after receiving an eye drop. The data reported in the literature over the past 8 years show that Patanol solution is better than the competing drugs in terms of comfort and efficacy.^7-13

Mah: Typically, the pH, the vehicle or the osmolarity can affect whether a drug is comfortable for patients. It could be a combination of several factors. It is important to remember that antihistamines have to be used 4 times a day, whereas Patanol solution, for example, and the other dual-acting medications are twice-a-day drugs. Compliance will be better, particularly for pediatric patients. Also, parents will appreciate that their child is prescribed a drug that does not sting, burn, taste unpleasant, or have to be administered four times a day.

Merayo: From my point of view, we must avoid vasoconstrictors.

Raizman: I also never recommend vasoconstrictors – I do not see any role for them in treatment. Patients like vasoconstrictors because they make their eyes white, but we have shown in laboratory tests that redness from conjunctivitis lasts very briefly and is only a problem if patients rub their eyes. If we educate patients to not rub their eyes, redness should not occur and thus no need to use a vasoconstrictor. In addition, the efficacy of antihistamines in the vasoconstrictor-antihistamine combinations is a few log units less than that of the newer products, such as Patanol solution.

Mah: Do eosinophils play a significant role in the treatment of seasonal allergies?

Irkec: Actually, there is no confirmed place for eosinophils in treating seasonal ocular allergy. In experimental models, there is a small increase in neutrophils and eosinophils in late phases, but this is not a critical issue in real-life cases.² However, in atopic and vernal cases, which are similar to asthma with respect to the remodeling of the ocular surface, there is a confirmed role of eosinophils from the outset. We have done significant research on tear levels of eotaxin in seasonal allergic conjunctivitis and have found an increase in eotaxin. In contrast, there is no increase in the number of eosinophils that are chemotactic by eotaxin. Also, the dual-acting agents such as Patanol solution decrease the level of eotaxin in tears and may be related to mast cell-stabilizing effects.¹⁴

Once-a-day formulation

Mah: I think we are in agreement that Patanol solution has excellent specificity and potency and is the leading dual-acting medication available. I know we do not all have access to Pataday solution, the once-a-day formulation, but are there any comments on it?

Stoppel: The once-a-day formulation improves my patients’ compliance. It is easy to use – just once a day in the morning – and it is comfortable. Patients do appreciate that because they can simply instill the drop once before leaving the home.

Mah: What are the specific differences between Patanol and Pataday solutions?

Raizman: I have had experience with the once-a-day formulation for 2 years. Pataday solution has twice the concentration of Patanol solution, but without any change in comfort and safety profiles. Thus, it gives enhanced efficacy with no downside. My patients have found it to be efficacious and equally comfortable, so they prefer the Pataday solution. I advise these patients to use Pataday solution once in the morning and to use an artificial tear later in the day.

Mah: I have had the same experience. Have you noticed drying or other issues?

Raizman: Never. Drying is not an issue with Patanol solution, Pataday solution or any other topical antihistamine products.

Stoppel: I think this is a major improvement because not long ago, we prescribed mast cell stabilizers and antihistamines—each of them 1 drop three or four times a day. Now we have just one drug requiring one drop a day that will produce the same effect.

Mah: It is a significant improvement, especially for patient groups such as children. Even with Patanol solution’s success, we have seen data indicating that patients are even more satisfied with Pataday solution.¹⁵ The once-a-day formulation has been a major benefit to our patients, and clinicians who practice where Pataday solution is not yet approved can look forward to this medication.

Future treatment pathways

Mah: We have discussed numerous approaches to and theories about the treatment of seasonal, perennial, atopic and vernal allergic disease. Although there are many differences among the faculty in terms of country, climate, experiences, research and background, I think we are in general agreement on what we should do in the management of ocular allergy. What are some thoughts on the directions treatments might take in the future?

Merayo: Perhaps advances will come from biomarkers of the allergic response found in tears that will help clinicians determine the type of allergen that affects each patient and which pathway of the inflammatory response is responsible for the reaction.

Raizman: We may soon have in-office rapid diagnostic techniques available at a reasonable cost to detect IgE or histamine. This might help with some cases, although as we have already discussed, diagnosis is not the most challenging aspect of allergy management.

Irkec: I think we need more information on the genetic causes of vernal and atopic allergy. We do not know which genes are responsible for this type of complex pathology. We can look to asthma patients for examples, but we also have to rely on better immunotherapeutic approaches in the future. I hope we will also have more information on patient lifestyle, including nutrition and probiotics, and what this role might be in the evolution of allergy. All of these directions make it an exciting time in allergy research

. Leonardi: It may be difficult to target a single molecule or mechanism and downregulate a complex cascade of events. However, in the near future we expect to have monoclonal antibodies or antibody fragments that target key molecules involved in the development of allergic inflammation. New delivery systems such as subconjunctival implants, liposomes or nanoparticles that increase bioavailability and prolong the time that compounds remain on the ocular surface may be another future opportunity for improving patient compliance and drug efficacy.

Mah: I thank the faculty for participating in this excellent discussion. Allergy is a condition that affects between 15% and 40% of the population and, as discussed, there are excellent therapies in place today to treat these patients. We also have had a brief discussion of what therapies might become available in the future. I thank Ocular Surgery News Europe/Asia-Pacific Edition for organizing this panel and Alcon Laboratories, Inc., for its sponsorship. I thank the world- renowned, international faculty for an informative and comprehensive discussion on the diagnostic, management, and treatment strategies for ocular allergies.

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