During a symposium at the 2000 American College Allergy, Asthma, and Immunology's Annual Meeting, a panel of three leaders in allergy, immunology, and ophthalmology presented the latest data on the pathophysiology, differential diagnosis, and management of allergic conjunctivitis and other ocular disease.
This program was supported by an unrestricted educational grant from Alcon Laboratories.
Pathophysiologic Mechanisms of Allergic Conjunctivitis
As many as 40% of persons with allergic disease may also suffer from allergic conjunctivitis. However, allergic conjunctivitis may be undertreated in persons who have concomitant lung or nasal symptoms, said Sergio Bonini, MD, Professor of Allergy, University of Naples, Italy, and President, European Academy of Allergology and Clinical Immunology. In a symposium moderated by Robert Q. Lanier, MD, Dr. Bonini emphasized that understanding the pathophysiologic mechanisms underlying the signs and symptoms of allergic conjunctivitis (AC) is essential in managing this disease effectively.
There are several types of AC, each of which has unique clinical manifestations. It is believed that a main pathophysiologic mechanism-the immunoglobulin (Ig) E interaction at the mast cell-is shared among AC types. However, there are also major differences in pathophysiology between the AC types.
Seasonal and Perennial Allergic Conjunctivitis
Seasonal AC involves vasodilation, edema of the eyelid, and tearing and itching of the eye, and often a positive skin test. The signs and symptoms of perennial AC are more mild, but persist year round. Both types are often associated with allergic rhinitis. Upon allergen challenge, persons with seasonal or perennial AC exhibit the typical early-phase reaction, with the intensity dependent on the amount of allergen and sensitization of the patient. Studies show that the early-phase reaction is marked by an accumulation of neutrophils and increase of tryptase in tears. A late-phase reaction, described by Bonini and colleagues, is characterized by an accumulation of eosinophils and lymphocytes and an increase in histamine, but not tryptase. While some cases can be quite mild and transient, others involve recruitment of inflammatory cells and the persistence of inflammation.
Vernal and Atopic Keratoconjunctivitis
Vernal keratoconjunctivitis, a disease occurring mainly in boys, is characterized by the presence of giant papillae, with excess mucous between the papillae, and intense photophobia. In atopic keratoconjunctivitis, atopic eczema is present around the eye, and inflammation can be severe. Vernal conjunctivitis is often associated with asthma, atopic keratoconjunctivitis with eczema and other inflammatory diseases. In both types of keratoconjunctivitis, the cornea may be involved and vision may be severely impaired. The prevalence of positive skin tests in vernal conjunctivitis is 50%; however, total IgE and eosinophils are increased in both skin-positive and negative patients.
Vernal keratoconjunctivitis involves a higher number of inflammatory cells, including mast cells, eosinophils, and lymphocytes, than seasonal and perennial AC. Antibody stains show mast cells in biopsies (often degranulated), paralleled by a high level of tryptase found in tears. Tests show activated eosinophils not only in the conjunctiva, but also at the peripheral level. Adhesion molecules and EG-2 are overexpressed in the peripheral cell. "This shows that keratoconjunctivitis is not confined to the conjunctiva, but is a severe inflammatory and systemic disease," said Dr. Bonini. Non-inflammatory factors, such as sex hormone levels, may also play a role in vernal keratoconjunctivitis. Both vernal and atopic keratoconjunctivitis appear to be Th-2- related diseases, involving inflammation and hyperreactivity.
From the data thus far, three phases of AC disease can be distinguished: 1) the formation of IgE antibodies; 2) presence of Th-2 cells and inflammation; and 3) hyperreactivity of the target organ. Most cases of seasonal AC are likely associated with IgE antibodies, without much inflammation or hyperreactivity out of season. Perennial and some seasonal AC diseases correlate with the pathophysiologic changes of late-phase reaction, progressing from type I/IgE-mediated mechanisms to allergic inflammation. Vernal and atopic keratoconjunctivitis may be related to aTh-2 profile including polyclonal IgE activation, as well mast cell and eosinophil activation. Finally, more severe cases of vernal and atopic keratoconjunctivitis as well as contact lens conjunctivitis may be associated with hyperreactivity of the conjunctiva.
Conclusion
In closing, Dr. Bonini emphasized the importance of addressing the unique symptoms of allergic disease of the eye, but also of viewing these symptoms in the context of the whole patient. "A collaborated and unified approach to treatment of allergic disease on the part of allergists, ophthalmologists, and primary care providers is essential to ensuring optimal patient care and quality of life," the speaker concluded.
Management of Allergic Conjunctivitis
The development of new therapeutic agents in recent years has led to increased relief and reduced treatment-related side effects for persons with allergic conjunctivitis, said Dennis L. Spangler, MD, Assistant Professor, Medical College of Georgia and Chief Medical Officer, Atlanta Allergy and Asthma Clinic. According to Dr. Spangler, it is important for allergists to question patients with allergic rhinitis carefully about potential ocular symptoms. While many of the older therapies for AC are now available over the counter, Dr. Spangler stressed that the newer prescription medications provide more effective relief with fewer side effects.
Over-the-Counter Eye Drops
Many non-prescription topical agents can provide temporary AC symptom relief, but patients often are not aware of their potential to cause further irritation and increase ocular sensitivity. Non-prescription topical vasoconstictor agents-such as oxymetazoline, naphazoline, and tetrahydrozoline-operate by shrinking the vessels in the eye, to reduce redness. However, vasoconstrictors may cause irritation, decreased tear production, dilatation of the pupil, visual disturbance, aggravation of narrow glaucoma, and rebound disease, and should not be used on a long-term basis.
Over-the-counter topical vasoconstrictor/antihistamine combination products, such as pheniramine maleate-naphazoline and antazoline phosphate-naphazoline, can be more effective than antihistamines alone in temporarily relieving mild symptoms of AC when applied four times/daily. However, patients should be advised that extended use can be associated with persistent rebound swelling and redness.
Oral & Topical Antihistamines
Oral antihistamines-such as loratadine, fexofenadine, and cetirizine-can be used to relieve itchy eyes, but can also exacerbate ocular symptoms by decreasing tear production, said Dr. Spangler. One study of loratadine alone versus loratadine with the mast cell stabilizer/antihistamine olopatadine showed a superior effect with the combination approach. Dr. Spangler noted, "Topical agents are much more appropriate for the treatment of AC, providing rapid onset of action, better duration and efficacy, and less potential for irritation and drying."
Indeed, the topical H1 receptor antagonists-levocabastine, emedastine, and azelastine-are potent agents that can be effective in relieving the itching associated with AC. Potential disadvantages include four times/daily dosing for levocabastine and emedastine, as well as some stinging and burning and only limited pediatric use for levocabastine. Azelastine is delivered via twice/daily dosing, but may cause significant ocular burning and stinging, headache, and bitter aftertaste.
NSAIDs
Only one nonsteroidal anti-inflammatory drug (NSAID) ophthalmic drop product, ketorolac, is currently available. This drug is indicated for persons 12 years and older, and can reduce the itching associated with AC. However, ketorolac has little effect on eye redness, requires four times/daily dosing, and is associated with a significant amount of burning and stinging. "This product may be most effective as an anti-inflammatory agent in the postsurgical setting," Dr. Spangler noted. He pointed out that a distinct advantage with ketorolac is the ability to combine it with an antihistamine/mast cell stabilizer for patients who do not respond sufficiently to a single agent.
Topical Corticosteroids
Topical corticosteroids-such as loteprednol, dexamethasone, rimexolone, and fluorometholone-are potent medications, working quickly to relieve all symptoms of AC. However, topical corticosteroids are associated with significant and serious side effects, including increased intraocular pressure, secondary infection, and the potential to cause melting of the cornea and glaucoma. "I would recommend an ophthalmic evaluation to rule out increased intraocular pressure before prescribing a corticosteroid. When a corticosteroid is needed, I would not prescribe refills and would recommend the mildest form given for the shortest period possible," Dr. Spangler explained.
Mast Cell Stabilizers
Mast cell stabilizers-cromolyn sodium, lodoxamide, pemirolast, and nedocromil-inhibit the release of mast cell mediators to prevent the symptoms of AC. "Clinicians should note that these agents are essentially for the prevention of allergic reaction; therefore, regular use on anticipation of the allergen is needed," Dr. Spangler explained.
Cromolyn and lodoxamide are effective agents with good safety profiles, with lodoxamide being the more potent. Both are indicated for the treatment of vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis; both can cause transient burning and stinging upon administration. Pemirolast, which is indicated for the prevention of AC-related itching, is also effective but is associated with a relatively high incidence of headache. Cromolyn, lodoxamide, and pemirolast require four times/daily dosing. Nedocromil is indicated for the treatment of AC-related itching and is admininstered twice daily. However, this drug is associated with a high incidence of headache and some occurrence of ocular burning and nasal congestion.
Mast Cell Stabilizer/Antihistamines
The ideal agent for treatment of AC would address both the acute and chronic phases of the allergic inflammatory process in the eye, have few side effects, be safe for use in children, be safe and effective for long-term use, be safe to combine with other medications, and enhance patient compliance. Indeed, mast cell stabilizer/ antihistamine combination products best meet this profile. The antihistamine blocks the acute reaction, while the mast cell stabilizer lessens delayed hypersensitivity response.
Ketotifen. This drug is indicated for the prevention of AC-related ocular itching in individuals 3 years and older, with twice daily administration. Studies on ketotifen also show a mast cell stabilizing effect, but much of these data were derived using mast cells of the respiratory tract, rather than mast cells of the eye and skin. "Further data are needed to verify that this effect will also occur in the eye cells," said Dr. Spangler. Some studies also show that eye redness and irritation may occur upon administration.
Olopatadine. Olopatadine is indicated for persons 3 years and older and offers convenient twice daily dosing. Olopatadine is the only drug approved by the U.S. Food and Drug Administration for the treatment of all signs and symptoms of AC, effectively relieving eye itching, redness, swelling, tearing, and chemosis. In addition to its antihistamine effects, olopatadine exerts many anti-inflammatory effects, including reducing tumor necrosis factor-alpha levels and inhibiting leukotriene release. Yanni and colleagues recently conducted an in vitro study of olopatadine and ketotifen in ocular mast cells. As olopatadine concentrations increased, inhibition of mast cell mediator release also increased. However, as ketotifen concentrations increased, stimulation of these mediators began to occur. Moreover, Berdy and colleagues recently used a conjunctival antigen challenge model to compare the effects of olopatadine versus ketotifen. In a randomized, double-masked, contralaterally controlled study, patients were pretreated with either ketotifen and olopatadine, one drug in each eye. They were then stimulated with antigen and assessed for itchiness and discomfort. Both drugs resulted in improvement, but olopatadine produced less ocular discomfort and was more effective in reducing itching.
In closing, Dr. Spangler stressed the importance of allergists and primary care physicians in 1) discussing potential ocular symptoms with all patients who present with allergic rhinitis and 2) making patients with AC aware of the newer and most effective, safe, and convenient treatment options available to them.
Differential Diagnosis of Chronic Conjunctivitis and Red Eye Disease
It is imperative that primary care physicians, allergists, and ophthalmologists collaborate to provide prompt and optimal care to persons with serious ocular disease, said C. Stephen Foster, MD, Director, Ocular Immunology and Uveitis Service, Massachusetts Eye and Ear Infirmary, and Professor of Ophthalmology, Harvard Medical School, Boston. In determining whether a patient requires an immediate referral to an ophthalmologist, an accurate differential diagnosis is needed between vision- and non-vision-threatening conjunctivitis and red eye disease.
Select Non-Vision-Threatening Conjunctivitis & Red Eye Disease
Sty or chalazion. A sty or chalazion may produce red eye, and may result in chronic conjunctivitis. The diagnosis is straightforward, and requires treatment with hot compresses four times daily. In chronic cases, fibrosis may require surgical excision.
Blepharitis. This condition involves inflammation of the eyelid, with a toothpaste-quality to the meibomian glands of the lid. Blepharitis requires treatment with warm compresses, lid hygiene measures, and an antibiotic ointment at bedtime.
Dry eye. Dry eye occurs commonly in elderly persons, and is characterized by ocular irritation, sometimes with itching, burning, or a dry sensation. This condition requires the use of warm compresses, lid massage, and tear plugs to address deficient lipid contribution and to conserve tears. Tear stimulants, humidifiers, and, in the future, topical androgens might also be helpful.
Conjunctivitis. In addition to allergic conjunctivitis, allergists or primary care physicians may see patients with bacterial or viral conjunctivitis. The clinical features of bacterial conjunctivitis include a thick, mucopurulent discharge that sticks to lashes and lids. Exudate should be cultured, and empiric broad-spectrum bacteriocidal antibiotic therapy initiated. Viral conjunctivitis is a highly infectious condition, characterized by a watery discharge and often a history of recent upper respiratory symptoms. Treatment is not needed, but patients should return in the case of photophobia or purulent discharge.
Select Vision-Threatening Conjunctivitis & Red Eye Disease
Atopic and vernal keratoconjunctivitis. Both of these are potentially blinding allergic diseases. Inflammatory infiltrates cause trophic defects that eventuate into stromal loss, sometimes with ulceration and perforation, always with corneal scarring. "Sadly, about one third of our patients with vernal keratoconjunctivitis are legally blind upon their first consultation," Dr. Foster said. The most important course of treatment of keratoconjunctivitis is attention to history and avoidance of allergens. Preservative-free topical medications should be used, and systemic agents (particularly cyclosporine) optimized. For local ocular care, Dr. Foster recommended olopatadine twice daily. "Studies show that olopatadine is more effective than nedocromil, cromolyn, or ketotifen, and is less costly as well," he said. Short-burst interventional corticosteroid therapy may be needed for atopic keratoconjunctivitis, but should be discontinued as quickly as possible.
Gonococcal and herpes conjunctivitis. Gonococcal conjunctivitis can quickly lead to corneal melting and perforation, with herniation of the iris. Herpes simplex keratitis-related conjunctivitis, the most common cause of corneal blindness in the United States, is characterized by dermatitis, dendritic disease, ulcer, and risk of corneal scarring and loss of vision. "This is one reason for caution with the chronic use of corticosteroids in patients with serious ocular disease," Dr. Foster noted.
Chronic conjunctivitis. Chronic conjunctivitis in the elderly can develop as the result of a number of autoimmune processes, ranging from lichen planus to ocular cicatricial pemphigoid disease. A biopsy is essential in making an accurate diagnosis and initiating treatment, said Dr. Foster. Ocular rosacea, a common condition, can also cause chronic conjunctivitis and can involve the cornea, producing irregular scarring and neovascularization. Finally, malignant mas- querade conjunctivitis can result in chronic conjunctivitis. Culprits can be squamous or sebaceous cell carcinoma, lymphoma, or amelanotic melanoma.
Uveitis and scleritis. Patients with uveitis have red eye, discomfort or pain, exquisite photophobia, and disturbance in vision. The hallmark feature of scleritis is pain, with exquisite tenderness upon gentle palpation of the globe. If not treated properly, this disease results in loss of sclera, necrotization, and herniation of the uvea. Glaucoma is also highly prevalent among patients with scleritis.
Conclusion
In closing, Dr. Foster pointed out that many conjunctivitis and red eye syndromes are reflections of allergic processes that can be effectively managed by an allergist or primary care physician. "In the case of uncertain diagnosis or serious ocular disease, co-management by the primary care physician, allergist, and ophthalmologist results in optimal patient care and preservation of vision," he concluded.
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