Subject Review Medical Therapy for Ocular Allergy
STEFAN D. TROCME, M.D.,* Department of Ophthalmology; MICHAEL B. RAIZMAN, M.D., Department of Ophthalmology, New England Medical Center, Tufts University School ofMedicine, and the Department ofRheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; GEORGE B. BARTLEY, M.D., Department ofOphthalmology
The ocular manifestations of allergy have traditionally been classified into four categories-namely, hay fever conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and contact lensassociated giant papillary conjunctivitis. Typically, hay fever conjunctivitis is characterized by mild conjunctival inflammation, whereas the other disorders may have severe inflammation and clinical manifestations. Potentially blinding corneal complications may result from vernal keratoconjunctivitis and atopic keratoconjunctivitis. Although hay fever conjunctivitis is clearly an immediate hypersensitivity reaction, the immunologic mechanisms that cause vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis are primarily unknown and speculative. Treatment of patients with ocular allergies is often challenging and may necessitate collaborative efforts of an ophthalmologist and an allergist. Herein we discuss conventional therapy and new, promising antiallergy drugs. Prausnitz and Kustner' first described a wheal and flare reaction to an intracutaneous injection of fish extract in a person sensitive to the antigen. They found that the reactivity could be transferred to the skin of a nonsensitive person by injecting the serum of a sensitive person; the seruminjected sites would exhibit a wheal and flare reaction on subsequent antigen challenge (the Prausnitz-Kustner reaction). The transferable serum component was labeled "reagin." Later, the term "atopy" was coined by Coca and Cooke- to denote a strange skin reaction (wheal and flare) to antigen challenge in persons with a history of allergy. Subsequently, research disclosed that the component present in serum (reagin) was a new class of immunoglobulin called immunoglobulin E (lgE) by the World Health Organization. IgE is characterized by an extremely high reactivity of the skin,' and studies have demonstrated the positive correlation between IgE titers and reaginic activity by the PrausnitzKiistner reaction."
*Current address: University of Texas Medical Branch, Galveston, Texas. Individual reprints of this article are not available. Mayo Clin Proc 67:557-565, 1992
Immunoglobulins that adhere to the mast cell membrane and are responsible for the immediate hypersensitivity reaction (type I hypersensitivity) are referred to as cytotropic antibodies. Although IgE is considered the principal cytotropic antibody in humans, IgG-type antibody with cytotropic properties has been reported.' In experimental animals, both IgE and IgG homocytotropic immunoglobulins may be present; the predominant antibody may depend on the species and the immunization protocol. The two types of cytotropic antibody exhibit different abilities to sensitize tissue (mast cells) for immediate hypersensitivity. Passive sensitization with serum that contains homocytotropic IgG occurs in 3 to 6 hours; however, it is short-lived and lasts only 12 to 24 hours, after which time antigenic challenge causes no reaction. Conversely, passive sensitization with IgE occurs in 6 hours but increases by 24 to 72 hours and may remain for 3 to 6 weeks. -Investigators have long recognized that mast cells may differ morphologically, biochemically, and functionally, depending on anatomic site. Enerback" described the fixation and the histochemical staining that separated the atypicalor mucosal mast cells from the connective tissue-type mast cells of the skin and peritoneal cavity of the rat. Befus and colleagues? found similar heterogeneity of mast cells in 557
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humans. Distinguishing the particular subset of mast cells in a specific anatomic site such as the eye may be of therapeutic interest because certain antiallergy drugs may influence only one type of mast cell. Eosinophils, which may have an important pathogenetic role in atopy, are commonly present in patients with various types of ocular allergy.8 Degranulating eosinophils release eosinophil granule major basic protein, which may have profound cytotoxic effects? and may enhance degranulation of mast cells." Extracellular major basic protein has been identified at sites of tissue injury in patients with asthma" and atopic dermatitis. 12 Approximately 10% of the US population has hereditary allergic disorders. Immediate hypersensitivity is characteristic of atopy. Levels of suppressor T cells are decreased, and B-cell activity is enhanced; this decrease results in the production of high concentrations of IgE. The risk of atopic disease developing is at least 10 times higher when the initial IgE concentration is more than 1 standard deviation above the normal range than when it is below that level. 13 Traditionally, the ocular manifestations of allergy include hay fever conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. Hay fever conjunctivitis, which is the most common ocular allergy, probably represents an immediate hypersensitivity reaction. After transfer of serum from an allergic patient to a normal subject, a hay fever conjunctivitis-like reaction can be produced in the normal person by challenge with the appropriate antigen." In contrast, the clinical and histopathologic characteristics of vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis are more complex, and the pathogenetic mechanisms are primarily unknown.
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lowed by a late recurrence of signs and symptoms, a latephase reaction that peaks at 6 to 8 hours and may last up to 12 hours. 15 Histologically, the late-phase reaction in human skin is characterized by a lO-fold increase in the number of infiltrating cells. The late-phase reaction may be defined as a sequence of changes that may be clinical, histologic, or chemical and occur or reach peak intensity after the subsidence of the immediate phase. A conjunctival late-phase reaction has been described in an experimental animal model of ocular type I hypersensitivity" and in hay fever conjunctivitis in humans. I? The clinical importance of the conjunctivallate-phase reaction is only speculative; cellular infiltration of the conjunctiva may contribute to some of the signs and symptoms in patients with ocular allergy. Recent studies suggest that eosinophils and neutrophils have a role in the late-phase reaction in human skin." Immunotherapy has been widely used in patients with atopic disease in which the offending antigen is well established. A series of inoculations with minute doses of the specific antigen that causes the allergy is administered in gradually increasing doses over time, as tolerated by the patient. The development of noncytotropic (lgG) antibody as a consequence of desensitization was first noted by Cooke and associates;" the generated IgG antibodies can neutralize an antigen and prevent degranulation of mast cells." The efficacy of immunotherapy is well substantiated," although nasal hay fever seems to respond better to treatment than do ocular symptoms. Acute symptoms of hay fever can be alleviated by vasoconstriction induced either by cold compresses or by treatment with topically applied epinephrine." Other vasoconstricting agents for topical use such as naphazoline hydrochloride may be helpful in mild cases of hay fever conjunctivitis. Topically applied antihistamines also have favorable effects on hay fever conjunctivitis, although a topical combination therapy with a vasoconstricHAY FEVER CONJUNCTIVITIS Hay fever conjunctivitis is characterized by bilateral symp- tor and an antihistamine is more effective than either toms of itching and tearing; concurrent hay fever rhinitis is drug alone." Systemic antihistamines are rarely indicated common. Signs may be virtually absent or consist of mild for hay fever conjunctivitis, but they can be used for severe conjunctival injection and edema. Symptoms may be sea- cases. sonal or perennial, depending on the nature of the offending Cromolyn sodium acts as an antiallergy agent by stabilizallergen. The most common allergens that cause hay fever ing the mast ce1F4 and inhibiting activation of eosinophils are pollens or ragweed, grass, trees, animal danders, and and neutrophile." Treatment with 4% cromolyn sodium house dust. Airborne allergens presumably dissolve in the drops four times a day substantially decreases symptoms in tear film and traverse the conjunctival epithelium to contact patients with mild hay fever conjunctivitis." IgE-primed mast cells; degranulation of mast cells and reTopically applied corticosteroids are seldom used for the treatment of hay fever conjunctivitis, but they may be conlease of inflammatory mediators result. Traditionally, hay fever conjunctivitis has been portrayed sidered if the symptoms are severe and if conservative theras an immediate hypersensitivity reaction with short-lived apy has failed. A regimen of low-dose corticosteroids, such signs and symptoms that emerge within minutes after expo- as 0.12% prednisolone twice a day, may be effective without sure to the antigen. Immediate hypersensitivity, however, causing severe ocular side effects. Treatment with fluoromay not always be short-lived. In human skin, the wheal and metholone may also be considered because it is associated flare of the antigen-induced immediate reaction may be fol- with fewer ocular side effects than many other topically
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Fig. 1. Vernalkeratoconjunctivitis withcobblestone appearance of numerous large, inflammatory papillae on undersurface of upper eyelid.
Fig. 2. Homer's points or Trantas' dots. These inflammatory nodules are composed of eosinophils and are found near corneosclerallimbus in vernal keratoconjunctivitis; they are virtually pathognomonic for the disorder.
applied corticosteroids. Experimental" and clinical" studies suggest that corticosteroids influence type I hypersensitivity by predominantly suppressing the late-phase reaction and, to a lesser extent, the immediate-phase reaction.
other. The papillae may be so severe that their weight causes mechanical ptosis. The white dots (Homer's points or Trantas' dots) usually occur in the limbal area and persist from 2 days to a week (Fig. 2). Limbal papillae may extend onto the cornea and form a pannus. Punctate epithelial keratopathy may be present; in severe cases, the epithelium may break down and a shieldlike ulcer may develop (Fig. 3). Corneal ulceration is common in children and may damage sight in severe cases. The most common corneal degenerative change in vernal keratoconjunctivitis is pseudogerontoxon that resembles corneal arcus. Changes in corneal curvature may occur, and keratoconus may develop later in the course of the disease.
VERNAL KERATOCONJUNCTIVITIS Arlt first described vernal keratoconjunctivitis in 1846, and the term "vernal catarrh" or "spring catarrh" was later coined by Seamish in 1872 after seasonal flares of the disease were observed. In 1880, Homer described white points (Homer's points) located on the limbus, an observation later confirmed by Trantas (Trantas' dots). Emmert, in 1888, described three types of vernal keratoconjunctivitis: (1) palpebral, with papillae mainly involving the superior tarsal conjunctiva; (2) limbal, with papillae located on parts or all of the limbus; and (3) mixed, with components of both palpebral and limbal types. Vernal keratoconjunctivitis is a disease of childhood and youth, and the frequency is higher in boys than in girls. It occurs most frequently in warm climates, and patients often have a family history of atopy. Childhood vernal keratoconjunctivitis usually "bums out" after 4 to 10 years. In middleaged patients, however, the disease may not resolve, and the course is severe and protracted. Patients invariably complain of itching, which may be severe. Ocular discharge is common; accumulations of ropy mucus may be found in the conjunctival fornix. Tearing, photophobia, and conjunctival injection may be prominent features. Giant papillae (Fig. 1) form on the superior tarsal or limbal conjunctiva (as previously mentioned), depending on the type of vernal keratoconjunctivitis. Although this is a bilateral disease, one eye may be more affected than the
Fig. 3. A shield ulcer of the cornea in a patient with vernal keratoconjunctivitis.
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Fig.4. Photomicrographs demonstrating deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis. A, Section of conjunctiva. Note papilla formation and subepithelial inflammatory infiltrate. (Hematoxylin-eosin; original magnification, xl60.) B, Serial section stained for immunofluorescence, showing extensive staining for major basic protein. (Original magnification, x160.) (From Trocme and associates." Published with permission from The American Journal of Ophthalmology. Coypright by the Ophthalmic Publishing Company.)
The conjunctival histopathologic features are characterized by lymphocyte, plasma cell, eosinophil, and, to some extent, basophil infiltration. As the disease progresses, fibrous tissue proliferates to form giant papillae. Mast cells and eosinophils are routinely detected in the conjunctival epithelium. A recent report indicated that the population of mucosal-type mast cells is increased in the conjunctiva of patients with vernal keratoconjunctivitis." The total number of mast cells is also increased sevenfold" in association with increased levels of histamine in the tears." Massive degranulation of conjunctival eosinophils has also been demonstrated, and large amounts of major basic protein have been found in the conjunctiva's (Fig. 4) and tears." Major basic protein has been implicated as a pathogenetic factor in the formation of corneal shield ulcers, and this theory is supported by identification of major basic protein in vernal shield ulcers in humans (unpublished observations) and by recent in vitro experiments that demonstrated inhibition of healing of corneal epithelial wounds and epithelial metabolism by major basic protein in the rat. 34 The treatment of vernal keratoconjunctivitis is frequently challenging and may necessitate a multidisciplinary approach. Attempts to avoid the allergen by moving to a cool climate can sometimes be of benefit to the patient. If the allergen is well defined, immunotherapy (as described previously) may be considered. Topically applied 4% cromolyn sodium four times a day may be beneficial," particularly in patients with seasonal symptoms. Topically applied corticosteroids such as 1% methylprednisolone may be used temporarily to treat inflammatory flares, but long-term use
should be avoided to minimize the potential untoward side effects of glaucoma or cataract. Ocular inflammation can also be decreased by systemically administered antihistamines, such as terfenadine (Seldane, 60 to 120 mg twice a day), astemizole (Hismanal, 10 mg once a day), and hydroxyzine hydrochloride (Atarax, 50 mg at bedtime and increased to as much as 400 mg daily). In severe cases, topically applied 2% cyclosporine may be effective." Corneal shield ulcers may necessitate application of a therapeutic contact lens, patching, and tarsorrhaphy in addition to the measures outlined. ATOPIC KERATOCONJUNCTIVITIS Hogan" first described five patients with a condition he labeled "atopic keratoconjunctivitis." He defined the disease as bilateral keratoconjunctivitis associated with atopic dermatitis. The onset of the disease is often in the late teen years, and the condition may persist for many years. It is always bilateral, and the seasonal variation and association with hot weather are less pronounced than with vernal keratoconjunctivitis. Symptoms include itching, burning, tearing, and mucopurulent discharge. Signs, which may be similar to those of vernal keratoconjunctivitis, include Homer's points, corneal vascularization and ulceration, keratoconus, blepharoconjunctivitis, and pseudogerontoxon. 38•39 Patients may also have severe lid edema, blepharitis, and secondary skin infections (Fig. 5). Conjunctival involvement affects predominantly the inferior forniceal and palpebral conjunctivae. In a recently reported series of atopic keratoconjunctivitis, subepithelial fibrosis, forniceal
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IgE anti-Staphylococcus aureus antibodies are present in serum, plasmapheresis may be considered.
CONTACT LENS-ASSOCIATED GIANT
Fig. 5. Severe blepharitis and perioral lesions with probable bacterial superinfection in a patient with atopic keratoconjunctivitis.
foreshortening, and symblepharon formation were found in 58%, 29%, and 27% of cases, respectively; thus, atopic .keratoco~junctivitis is an important consideration in the differential diagnosis of chronic cicatrizing conjunctivitis." The conjunctival histopathologic characteristics include infiltration with mast cells, basophils, lymphocytes, and eosinophils. Furthermore, pronounced degranulation of eosinophils and neutrophils can be demonstrated by use of immunofluorescence (unpublished observations). Tears contain major basic protein, similar to the findings invernal keratoconjunctivitis. Corneal and conjunctival complications of atopic keratoconjunctivitis are potentially blinding. Patients with atopic dermatitis and keratoconjunctivitis are also susceptible to herpes simplex and staphylococcal infections. Cataracts develop in 10% of patients with atopic dermatitis and keratoconjunctivitis." The cataract may be anterior subcapsular (Fig. 6) or of the posterior polar type and is almost always bilateral. The treatment of atopic keratoconjunctivitis is similar to that outlined for the vernal type. Therapy with antiviral agents for herpes simplex infections and with antibiotics for staphylococcal infections maybe used as indicated. Relatively lengthy regimens of corticosteroid treatment may also be needed to control inflammation.. If high concentrations of
PAPILLARY CONJUNCTIVITIS Loss of tolerance of contact lenses because of giant papillary conjunctivitis of the upper tarsal conjunctiva has been described.? Giant papillary conjunctivitis occurs in 5 to 10% of persons who wear soft contact lenses and in 4% of those who wear hard contact lenses; giant papillary hypertrophy can also be produced by suture material after cataract operation and by an ocular prosthesis. The association between giant papillary conjunctivitis and atopy is unclear, although it has been suggested by one study." The earliest symptoms are mild itching and watering while contact lenses are worn. As the disease progresses, the patient may complain of a foreign body sensation and upper lid "grabbing" of the contact lens, which may be pulled off the cornea and remain under the upper lid. Signs consist of giant papillae that form on the tarsal conjunctiva of the upper lid (Fig. 7); during active stages, the surface of the papillae may stain with fluorescein and resemble vernal keratoconjunctivitis. The bulbar conjunctiva may become hyperemic and sometimes edematous. Occasionally, Trantas' dots and limbal inflammation may occur. Histopathologically, the conjunctiva is characterized by infiltration with eosinophils, lymphocytes, plasma cells, mast cells, and basophils; eosinophils, mast cells, and basophils may also be noted in the conjunctival epithelium." Mast cells are increased and are extensively degranulated, although not to the extent found in vernal keratoconjunctivitis. Eosinophils are present in conjunctival smears in 25% of affected patients; the concentration of major basic protein in
Fig. 6. An anterior lenticular opacity (cataract) associated with atopic keratoconjunctivitis.
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conjunctivitis. Topically applied cromolyn sodium can also be used while the patient wears contact lenses, to increase
tolerance. When the conjunctiva cannot tolerate soft contact lenses despite these measures, rigid gas-permeable lenses can often be worn. With complete compliance, 85% of patients can continue to wear contact lenses.
DEVELOPMENTS IN DRUG THERAPY FOR OCULAR ALLERGY Corticosteroids.-When topically applied medications such
Fig. 7. Giant papillary conjunctivitis, an allergicresponse associated primarily withwearingof contactlenses. tears does not seem to be increased," although major basic protein is present in the affected conjunctiva (Fig. 8)32 and in coatings of contact lenses from patients with concurrent atopy and giant papillary conjunctivitis (Fig. 9).44 Treatment consists of a temporary discontinuation of the wearing of contact lenses, at which time 4% cromolyn sodium ophthalmic solution can be administered four times a day. Topically applied corticosteroids are seldom indicated. Often, old contact lenses must be discarded, and the patient must wear new uncoated contact lenses. Meticulous cleaning with enzymes and surfactants is critical for successful wearing of contact lenses in the patient with giant papillary
as antihistamines, vasoconstricting agents, or cromolyn sodium are ineffective, topically applied corticosteroids are a consideration for the short-term management of ocular allergy. Corticosteroids diminish the signs and symptoms of ocular allergy by decreasing capillary permeability and by blocking the influx of inflammatory cells to the site of disease. They are particularly helpful in the treatment of vernal and atopic keratoconjunctivitis, but they are seldom used for giant papillary keratoconjunctivitis or hay fever conjunctivitis. Long-term use of corticosteroids is fraught with complications, including glaucoma, formation of cataracts, and infection. Allansmith" found "pulse" therapy with topically applied dexamethasone (1% every 2 hours eight times daily and gradually tapered over days to weeks) to be effective.
Nonsteroidal Anti-inflammatory Agents.-Inflammatory cells contain two major enzymes: cyclooxygenase and 5-lipoxygenase. They are able to convert arachidonic acid into products (prostaglandins and leukotrienes) that have an important role in inflammation. Commonly used nonsteroidal anti-inflammatory agents such as aspirin and in-
Fig. 8. Photomicrographs of deposition of eosinophil granule major basic protein in giant papillary conjunctivitis. A, Section of conjunctiva. Noteaccumulation of inflammatory cells in substantiapropria. (Hematoxylin-eosin; original magnification, xI60.) B, Serial sectionstainedfor immunofluorescence,showing focal stainingfor majorbasic protein. (Original magnification, xI60.) (FromTrocme and associates." Published with permission from The American Journal of Ophthalmology. Copyright by the Ophthalmic Publishing Company.)
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Fig. 9. Contact lens from patient with atopy. A, Staining with hematoxylin-eosin shows some surface deposits. B, Staining for immunofluorescence shows prominent eosinophil granule major basic protein, primarily on anterior surface. (From Trocme and associates." By permission of Contact Lens Association of Ophthalmologists.)
domethacin are categorized as inhibitors of cyclooxygenase. Vernal keratoconjunctivitis has been alleviated after treatment with orally administered aspirin, although the necessary high doses could produce serious side effects." Topically applied inhibitors of cyclooxygenase (l % suprofen and 0.03% flurbiprofen) have also had beneficial effects on vernal keratoconjunctivitis" and allergic conjunctivitis," respectively. Currently, inhibitors of lipoxygenase are purely investigational, but they may hold promise as future antiallergy drugs. Inhibitors of lipoxygenase such as REV5901, MK-57l, and MK-886 seem effective for decreasing inflammation in experimental model systems (Ford-Hutchinson AW: Personal communication). Stabilizers ofMast Cells.-Traditionally, the mechanism of action of stabilizers of mast cells (cromolyn sodium, lodoxamide tromethamine, and nedocromil) has been thought to be the prevention of the flux of calcium across the cell membrane. Recent studies with disodium cromoglycate, however, indicated that stabilizers of mast cells may act through other mechanisms, such as inhibition of activation of neutrophils, eosinophils, and monocytes." A recent clinical study" showed that a new stabilizer of mast cells, lodoxamide (0.1% ophthalmic solution), may be more effective than topically applied cromolyn sodium for alleviating the signs and symptoms in various types of ocular allergy. Another new agent, nedocromil, also has beneficial effects on ocular allergy and may offer the advantage of being more effective for stabilizing the mucosal mast cell." Vasoconstricting Agents and Antihistamines.-Antihistamines can decrease the symptoms of allergy by blocking histamine receptors (HI or H2) ; the activation of HI receptors seems to be most responsible for the symptoms of ocular allergy. The five classes of HI-blocking antihistamines are
alkylamines, ethanolamines, ethylenediamines, phenothiazines, and piperazines. Preparations of these antihistamines for ophthalmic use include an alkylamine (pheniramine maleate) and two ethylenediamines (antazoline phosphate and pyrilamine maleate)." A new potent HI-blocking antihistamine, levocabastine, was recently reported to be effective for decreasing the clinical signs and symptoms of ocular allergy. 52 Although topically applied antihistamines can be used alone for treating ocular allergy, a recent study indicated that combined use of an antihistamine (antazoline phosphate) and a vasoconstrictor (naphazoline hydrochloride) is more effective than using each agent separately." IgE Pentapeptide.-IgE pentapeptide is a synthetic peptide that has been hypothesized to act as an antiallergy agent by competitively blocking the binding of intact IgE to specific cell receptors. A 0.5% ophthalmic solution has been reported to be effective for decreasing the signs and symptoms of ocular allergy. 53 Cyclosporine.-Cyclosporine is a cyclic peptide that has immunosuppressive effects that inhibit the actions of interleukin 2 on T lymphocytes. In a double-masked clinical trial, investigators demonstrated that 2% cyclosporine in castor oil decreases the clinical signs and symptoms in vernal keratoconjunctivitis."
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Garrity JA, Liesegang TJ: Ocular complications of atopic dennatitis. Can J Ophthalmol 19:21-24,1984 39. Tuft SJ, Kemeny DM, Dart JKG, Buckley RJ: Clinical features of atopic keratoconjunctivitis. Ophthalmology 98:150-158,1991 40. Foster CS, Calonge M: Atopic keratoconjunctivitis. Ophthalmology 97:992-1000,1990 41. Beetham WP: Atopic cataracts. Arch Ophthalmol 24:21-37, 1940 42. Allansmith MR, Korb DR, Greiner JV, Henriquez AS, Simon MA, Finnemore VM: Giant papillary conjunctivitis in contact lens wearers. AmJ Ophthalmol 83:697-708,1917 43. Buckley RJ: Pathology and treatment of giant papillary conjunctivitis. II. The British perspective. Clin Ther 9:451-457, 1987 44. Trocme SD, Kephart GM, Bourne WM, Maguire D, Gleich GJ: Eosinophil granule major basic protein in contact lenses of patients with giant papillary conjunctivitis. CLAO J 16:219-222, 1990 45. Allansmith MR: Vernal conjunctivitis. In Duane's Clinical Ophthalmology. Vol 4, Chapter 9. Edited by W Tasman, EA Jaeger. Philadelphia, JB Lippincott Company, 1986, pp 1-8 46. Abelson MB, Butrus SI, Weston JH: Aspirin therapy in vernal conjunctivitis. Am J Ophthalmol 95:502-505, 1983 47. Buckley DC, Caldwell DR, Reaves TA Jr: Treatment of vernal conjunctivitis with suprofen, a topical nonsteroidal anti-inflammatory agent (abstract). Invest Ophthalmol Vis Sci 27 (Supp1):29, 1986
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Bishop K, Abelson M, Cheetham J, Harper D: Evaluation of flurbiprofen in the treatment of antigen-induced allergic conjunctivitis (abstract). Invest Ophthalmol Vis Sci 31 (Suppl):487,1990 Fahy G, Easty DL, Collum L, Lumbroso P, Ober M, Verin P, Mackie I, Verstappen A: Double masked efficacy and safety evaluation of Lodoxamide 0.1% ophthalmic solution versus Opticrom 2%-a multicentre study. Excerpta Medica International Congress Series No. 803, 1988, pp 341342 Stockwell A, Easty D: Double blind group comparative trial of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis (abstract). Invest Ophthalmol Vis Sci 29 (Suppl):229, 1988 Weston JH, Abelson MB: Antihistamines. In Clinical Ophthalmic Pharmacology. Edited by DW Lamberts, DE Potter. Boston, Little, Brown and Company, 1987, pp 417-424 Smith LM, Southwick PC, DeRosia DR, Abelson MB: The effects of levocabastine, a new highly potent and specific histamine HI receptor antagonist, in the ocular allergen challenge model of allergic conjunctivitis (abstract). Invest Ophthalmol Vis Sci 30 (Suppl):502, 1989 Floyd R, Kalpaxis J, Thayer T, Rangus K: Double-blind comparison of HEPP'" (IgE pentapeptide) 0.5% ophthalmic solution (H) and sodium cromolyn ophthalmic solution, USP 4% (0) in patients having allergic conjunctivitis (abstract). Invest Ophthalmol Vis Sci 29 (Suppl):45, 1988
STEFAN D. TROCME, M.D.,* Department of Ophthalmology; MICHAEL B. RAIZMAN, M.D., Department of Ophthalmology, New England Medical Center, Tufts University School ofMedicine, and the Department ofRheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; GEORGE B. BARTLEY, M.D., Department ofOphthalmology
The ocular manifestations of allergy have traditionally been classified into four categories-namely, hay fever conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and contact lensassociated giant papillary conjunctivitis. Typically, hay fever conjunctivitis is characterized by mild conjunctival inflammation, whereas the other disorders may have severe inflammation and clinical manifestations. Potentially blinding corneal complications may result from vernal keratoconjunctivitis and atopic keratoconjunctivitis. Although hay fever conjunctivitis is clearly an immediate hypersensitivity reaction, the immunologic mechanisms that cause vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis are primarily unknown and speculative. Treatment of patients with ocular allergies is often challenging and may necessitate collaborative efforts of an ophthalmologist and an allergist. Herein we discuss conventional therapy and new, promising antiallergy drugs. Prausnitz and Kustner' first described a wheal and flare reaction to an intracutaneous injection of fish extract in a person sensitive to the antigen. They found that the reactivity could be transferred to the skin of a nonsensitive person by injecting the serum of a sensitive person; the seruminjected sites would exhibit a wheal and flare reaction on subsequent antigen challenge (the Prausnitz-Kustner reaction). The transferable serum component was labeled "reagin." Later, the term "atopy" was coined by Coca and Cooke- to denote a strange skin reaction (wheal and flare) to antigen challenge in persons with a history of allergy. Subsequently, research disclosed that the component present in serum (reagin) was a new class of immunoglobulin called immunoglobulin E (lgE) by the World Health Organization. IgE is characterized by an extremely high reactivity of the skin,' and studies have demonstrated the positive correlation between IgE titers and reaginic activity by the PrausnitzKiistner reaction."
*Current address: University of Texas Medical Branch, Galveston, Texas. Individual reprints of this article are not available. Mayo Clin Proc 67:557-565, 1992
Immunoglobulins that adhere to the mast cell membrane and are responsible for the immediate hypersensitivity reaction (type I hypersensitivity) are referred to as cytotropic antibodies. Although IgE is considered the principal cytotropic antibody in humans, IgG-type antibody with cytotropic properties has been reported.' In experimental animals, both IgE and IgG homocytotropic immunoglobulins may be present; the predominant antibody may depend on the species and the immunization protocol. The two types of cytotropic antibody exhibit different abilities to sensitize tissue (mast cells) for immediate hypersensitivity. Passive sensitization with serum that contains homocytotropic IgG occurs in 3 to 6 hours; however, it is short-lived and lasts only 12 to 24 hours, after which time antigenic challenge causes no reaction. Conversely, passive sensitization with IgE occurs in 6 hours but increases by 24 to 72 hours and may remain for 3 to 6 weeks. -Investigators have long recognized that mast cells may differ morphologically, biochemically, and functionally, depending on anatomic site. Enerback" described the fixation and the histochemical staining that separated the atypicalor mucosal mast cells from the connective tissue-type mast cells of the skin and peritoneal cavity of the rat. Befus and colleagues? found similar heterogeneity of mast cells in 557
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humans. Distinguishing the particular subset of mast cells in a specific anatomic site such as the eye may be of therapeutic interest because certain antiallergy drugs may influence only one type of mast cell. Eosinophils, which may have an important pathogenetic role in atopy, are commonly present in patients with various types of ocular allergy.8 Degranulating eosinophils release eosinophil granule major basic protein, which may have profound cytotoxic effects? and may enhance degranulation of mast cells." Extracellular major basic protein has been identified at sites of tissue injury in patients with asthma" and atopic dermatitis. 12 Approximately 10% of the US population has hereditary allergic disorders. Immediate hypersensitivity is characteristic of atopy. Levels of suppressor T cells are decreased, and B-cell activity is enhanced; this decrease results in the production of high concentrations of IgE. The risk of atopic disease developing is at least 10 times higher when the initial IgE concentration is more than 1 standard deviation above the normal range than when it is below that level. 13 Traditionally, the ocular manifestations of allergy include hay fever conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. Hay fever conjunctivitis, which is the most common ocular allergy, probably represents an immediate hypersensitivity reaction. After transfer of serum from an allergic patient to a normal subject, a hay fever conjunctivitis-like reaction can be produced in the normal person by challenge with the appropriate antigen." In contrast, the clinical and histopathologic characteristics of vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis are more complex, and the pathogenetic mechanisms are primarily unknown.
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lowed by a late recurrence of signs and symptoms, a latephase reaction that peaks at 6 to 8 hours and may last up to 12 hours. 15 Histologically, the late-phase reaction in human skin is characterized by a lO-fold increase in the number of infiltrating cells. The late-phase reaction may be defined as a sequence of changes that may be clinical, histologic, or chemical and occur or reach peak intensity after the subsidence of the immediate phase. A conjunctival late-phase reaction has been described in an experimental animal model of ocular type I hypersensitivity" and in hay fever conjunctivitis in humans. I? The clinical importance of the conjunctivallate-phase reaction is only speculative; cellular infiltration of the conjunctiva may contribute to some of the signs and symptoms in patients with ocular allergy. Recent studies suggest that eosinophils and neutrophils have a role in the late-phase reaction in human skin." Immunotherapy has been widely used in patients with atopic disease in which the offending antigen is well established. A series of inoculations with minute doses of the specific antigen that causes the allergy is administered in gradually increasing doses over time, as tolerated by the patient. The development of noncytotropic (lgG) antibody as a consequence of desensitization was first noted by Cooke and associates;" the generated IgG antibodies can neutralize an antigen and prevent degranulation of mast cells." The efficacy of immunotherapy is well substantiated," although nasal hay fever seems to respond better to treatment than do ocular symptoms. Acute symptoms of hay fever can be alleviated by vasoconstriction induced either by cold compresses or by treatment with topically applied epinephrine." Other vasoconstricting agents for topical use such as naphazoline hydrochloride may be helpful in mild cases of hay fever conjunctivitis. Topically applied antihistamines also have favorable effects on hay fever conjunctivitis, although a topical combination therapy with a vasoconstricHAY FEVER CONJUNCTIVITIS Hay fever conjunctivitis is characterized by bilateral symp- tor and an antihistamine is more effective than either toms of itching and tearing; concurrent hay fever rhinitis is drug alone." Systemic antihistamines are rarely indicated common. Signs may be virtually absent or consist of mild for hay fever conjunctivitis, but they can be used for severe conjunctival injection and edema. Symptoms may be sea- cases. sonal or perennial, depending on the nature of the offending Cromolyn sodium acts as an antiallergy agent by stabilizallergen. The most common allergens that cause hay fever ing the mast ce1F4 and inhibiting activation of eosinophils are pollens or ragweed, grass, trees, animal danders, and and neutrophile." Treatment with 4% cromolyn sodium house dust. Airborne allergens presumably dissolve in the drops four times a day substantially decreases symptoms in tear film and traverse the conjunctival epithelium to contact patients with mild hay fever conjunctivitis." IgE-primed mast cells; degranulation of mast cells and reTopically applied corticosteroids are seldom used for the treatment of hay fever conjunctivitis, but they may be conlease of inflammatory mediators result. Traditionally, hay fever conjunctivitis has been portrayed sidered if the symptoms are severe and if conservative theras an immediate hypersensitivity reaction with short-lived apy has failed. A regimen of low-dose corticosteroids, such signs and symptoms that emerge within minutes after expo- as 0.12% prednisolone twice a day, may be effective without sure to the antigen. Immediate hypersensitivity, however, causing severe ocular side effects. Treatment with fluoromay not always be short-lived. In human skin, the wheal and metholone may also be considered because it is associated flare of the antigen-induced immediate reaction may be fol- with fewer ocular side effects than many other topically
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Fig. 1. Vernalkeratoconjunctivitis withcobblestone appearance of numerous large, inflammatory papillae on undersurface of upper eyelid.
Fig. 2. Homer's points or Trantas' dots. These inflammatory nodules are composed of eosinophils and are found near corneosclerallimbus in vernal keratoconjunctivitis; they are virtually pathognomonic for the disorder.
applied corticosteroids. Experimental" and clinical" studies suggest that corticosteroids influence type I hypersensitivity by predominantly suppressing the late-phase reaction and, to a lesser extent, the immediate-phase reaction.
other. The papillae may be so severe that their weight causes mechanical ptosis. The white dots (Homer's points or Trantas' dots) usually occur in the limbal area and persist from 2 days to a week (Fig. 2). Limbal papillae may extend onto the cornea and form a pannus. Punctate epithelial keratopathy may be present; in severe cases, the epithelium may break down and a shieldlike ulcer may develop (Fig. 3). Corneal ulceration is common in children and may damage sight in severe cases. The most common corneal degenerative change in vernal keratoconjunctivitis is pseudogerontoxon that resembles corneal arcus. Changes in corneal curvature may occur, and keratoconus may develop later in the course of the disease.
VERNAL KERATOCONJUNCTIVITIS Arlt first described vernal keratoconjunctivitis in 1846, and the term "vernal catarrh" or "spring catarrh" was later coined by Seamish in 1872 after seasonal flares of the disease were observed. In 1880, Homer described white points (Homer's points) located on the limbus, an observation later confirmed by Trantas (Trantas' dots). Emmert, in 1888, described three types of vernal keratoconjunctivitis: (1) palpebral, with papillae mainly involving the superior tarsal conjunctiva; (2) limbal, with papillae located on parts or all of the limbus; and (3) mixed, with components of both palpebral and limbal types. Vernal keratoconjunctivitis is a disease of childhood and youth, and the frequency is higher in boys than in girls. It occurs most frequently in warm climates, and patients often have a family history of atopy. Childhood vernal keratoconjunctivitis usually "bums out" after 4 to 10 years. In middleaged patients, however, the disease may not resolve, and the course is severe and protracted. Patients invariably complain of itching, which may be severe. Ocular discharge is common; accumulations of ropy mucus may be found in the conjunctival fornix. Tearing, photophobia, and conjunctival injection may be prominent features. Giant papillae (Fig. 1) form on the superior tarsal or limbal conjunctiva (as previously mentioned), depending on the type of vernal keratoconjunctivitis. Although this is a bilateral disease, one eye may be more affected than the
Fig. 3. A shield ulcer of the cornea in a patient with vernal keratoconjunctivitis.
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Fig.4. Photomicrographs demonstrating deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis. A, Section of conjunctiva. Note papilla formation and subepithelial inflammatory infiltrate. (Hematoxylin-eosin; original magnification, xl60.) B, Serial section stained for immunofluorescence, showing extensive staining for major basic protein. (Original magnification, x160.) (From Trocme and associates." Published with permission from The American Journal of Ophthalmology. Coypright by the Ophthalmic Publishing Company.)
The conjunctival histopathologic features are characterized by lymphocyte, plasma cell, eosinophil, and, to some extent, basophil infiltration. As the disease progresses, fibrous tissue proliferates to form giant papillae. Mast cells and eosinophils are routinely detected in the conjunctival epithelium. A recent report indicated that the population of mucosal-type mast cells is increased in the conjunctiva of patients with vernal keratoconjunctivitis." The total number of mast cells is also increased sevenfold" in association with increased levels of histamine in the tears." Massive degranulation of conjunctival eosinophils has also been demonstrated, and large amounts of major basic protein have been found in the conjunctiva's (Fig. 4) and tears." Major basic protein has been implicated as a pathogenetic factor in the formation of corneal shield ulcers, and this theory is supported by identification of major basic protein in vernal shield ulcers in humans (unpublished observations) and by recent in vitro experiments that demonstrated inhibition of healing of corneal epithelial wounds and epithelial metabolism by major basic protein in the rat. 34 The treatment of vernal keratoconjunctivitis is frequently challenging and may necessitate a multidisciplinary approach. Attempts to avoid the allergen by moving to a cool climate can sometimes be of benefit to the patient. If the allergen is well defined, immunotherapy (as described previously) may be considered. Topically applied 4% cromolyn sodium four times a day may be beneficial," particularly in patients with seasonal symptoms. Topically applied corticosteroids such as 1% methylprednisolone may be used temporarily to treat inflammatory flares, but long-term use
should be avoided to minimize the potential untoward side effects of glaucoma or cataract. Ocular inflammation can also be decreased by systemically administered antihistamines, such as terfenadine (Seldane, 60 to 120 mg twice a day), astemizole (Hismanal, 10 mg once a day), and hydroxyzine hydrochloride (Atarax, 50 mg at bedtime and increased to as much as 400 mg daily). In severe cases, topically applied 2% cyclosporine may be effective." Corneal shield ulcers may necessitate application of a therapeutic contact lens, patching, and tarsorrhaphy in addition to the measures outlined. ATOPIC KERATOCONJUNCTIVITIS Hogan" first described five patients with a condition he labeled "atopic keratoconjunctivitis." He defined the disease as bilateral keratoconjunctivitis associated with atopic dermatitis. The onset of the disease is often in the late teen years, and the condition may persist for many years. It is always bilateral, and the seasonal variation and association with hot weather are less pronounced than with vernal keratoconjunctivitis. Symptoms include itching, burning, tearing, and mucopurulent discharge. Signs, which may be similar to those of vernal keratoconjunctivitis, include Homer's points, corneal vascularization and ulceration, keratoconus, blepharoconjunctivitis, and pseudogerontoxon. 38•39 Patients may also have severe lid edema, blepharitis, and secondary skin infections (Fig. 5). Conjunctival involvement affects predominantly the inferior forniceal and palpebral conjunctivae. In a recently reported series of atopic keratoconjunctivitis, subepithelial fibrosis, forniceal
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IgE anti-Staphylococcus aureus antibodies are present in serum, plasmapheresis may be considered.
CONTACT LENS-ASSOCIATED GIANT
Fig. 5. Severe blepharitis and perioral lesions with probable bacterial superinfection in a patient with atopic keratoconjunctivitis.
foreshortening, and symblepharon formation were found in 58%, 29%, and 27% of cases, respectively; thus, atopic .keratoco~junctivitis is an important consideration in the differential diagnosis of chronic cicatrizing conjunctivitis." The conjunctival histopathologic characteristics include infiltration with mast cells, basophils, lymphocytes, and eosinophils. Furthermore, pronounced degranulation of eosinophils and neutrophils can be demonstrated by use of immunofluorescence (unpublished observations). Tears contain major basic protein, similar to the findings invernal keratoconjunctivitis. Corneal and conjunctival complications of atopic keratoconjunctivitis are potentially blinding. Patients with atopic dermatitis and keratoconjunctivitis are also susceptible to herpes simplex and staphylococcal infections. Cataracts develop in 10% of patients with atopic dermatitis and keratoconjunctivitis." The cataract may be anterior subcapsular (Fig. 6) or of the posterior polar type and is almost always bilateral. The treatment of atopic keratoconjunctivitis is similar to that outlined for the vernal type. Therapy with antiviral agents for herpes simplex infections and with antibiotics for staphylococcal infections maybe used as indicated. Relatively lengthy regimens of corticosteroid treatment may also be needed to control inflammation.. If high concentrations of
PAPILLARY CONJUNCTIVITIS Loss of tolerance of contact lenses because of giant papillary conjunctivitis of the upper tarsal conjunctiva has been described.? Giant papillary conjunctivitis occurs in 5 to 10% of persons who wear soft contact lenses and in 4% of those who wear hard contact lenses; giant papillary hypertrophy can also be produced by suture material after cataract operation and by an ocular prosthesis. The association between giant papillary conjunctivitis and atopy is unclear, although it has been suggested by one study." The earliest symptoms are mild itching and watering while contact lenses are worn. As the disease progresses, the patient may complain of a foreign body sensation and upper lid "grabbing" of the contact lens, which may be pulled off the cornea and remain under the upper lid. Signs consist of giant papillae that form on the tarsal conjunctiva of the upper lid (Fig. 7); during active stages, the surface of the papillae may stain with fluorescein and resemble vernal keratoconjunctivitis. The bulbar conjunctiva may become hyperemic and sometimes edematous. Occasionally, Trantas' dots and limbal inflammation may occur. Histopathologically, the conjunctiva is characterized by infiltration with eosinophils, lymphocytes, plasma cells, mast cells, and basophils; eosinophils, mast cells, and basophils may also be noted in the conjunctival epithelium." Mast cells are increased and are extensively degranulated, although not to the extent found in vernal keratoconjunctivitis. Eosinophils are present in conjunctival smears in 25% of affected patients; the concentration of major basic protein in
Fig. 6. An anterior lenticular opacity (cataract) associated with atopic keratoconjunctivitis.
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conjunctivitis. Topically applied cromolyn sodium can also be used while the patient wears contact lenses, to increase
tolerance. When the conjunctiva cannot tolerate soft contact lenses despite these measures, rigid gas-permeable lenses can often be worn. With complete compliance, 85% of patients can continue to wear contact lenses.
DEVELOPMENTS IN DRUG THERAPY FOR OCULAR ALLERGY Corticosteroids.-When topically applied medications such
Fig. 7. Giant papillary conjunctivitis, an allergicresponse associated primarily withwearingof contactlenses. tears does not seem to be increased," although major basic protein is present in the affected conjunctiva (Fig. 8)32 and in coatings of contact lenses from patients with concurrent atopy and giant papillary conjunctivitis (Fig. 9).44 Treatment consists of a temporary discontinuation of the wearing of contact lenses, at which time 4% cromolyn sodium ophthalmic solution can be administered four times a day. Topically applied corticosteroids are seldom indicated. Often, old contact lenses must be discarded, and the patient must wear new uncoated contact lenses. Meticulous cleaning with enzymes and surfactants is critical for successful wearing of contact lenses in the patient with giant papillary
as antihistamines, vasoconstricting agents, or cromolyn sodium are ineffective, topically applied corticosteroids are a consideration for the short-term management of ocular allergy. Corticosteroids diminish the signs and symptoms of ocular allergy by decreasing capillary permeability and by blocking the influx of inflammatory cells to the site of disease. They are particularly helpful in the treatment of vernal and atopic keratoconjunctivitis, but they are seldom used for giant papillary keratoconjunctivitis or hay fever conjunctivitis. Long-term use of corticosteroids is fraught with complications, including glaucoma, formation of cataracts, and infection. Allansmith" found "pulse" therapy with topically applied dexamethasone (1% every 2 hours eight times daily and gradually tapered over days to weeks) to be effective.
Nonsteroidal Anti-inflammatory Agents.-Inflammatory cells contain two major enzymes: cyclooxygenase and 5-lipoxygenase. They are able to convert arachidonic acid into products (prostaglandins and leukotrienes) that have an important role in inflammation. Commonly used nonsteroidal anti-inflammatory agents such as aspirin and in-
Fig. 8. Photomicrographs of deposition of eosinophil granule major basic protein in giant papillary conjunctivitis. A, Section of conjunctiva. Noteaccumulation of inflammatory cells in substantiapropria. (Hematoxylin-eosin; original magnification, xI60.) B, Serial sectionstainedfor immunofluorescence,showing focal stainingfor majorbasic protein. (Original magnification, xI60.) (FromTrocme and associates." Published with permission from The American Journal of Ophthalmology. Copyright by the Ophthalmic Publishing Company.)
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Fig. 9. Contact lens from patient with atopy. A, Staining with hematoxylin-eosin shows some surface deposits. B, Staining for immunofluorescence shows prominent eosinophil granule major basic protein, primarily on anterior surface. (From Trocme and associates." By permission of Contact Lens Association of Ophthalmologists.)
domethacin are categorized as inhibitors of cyclooxygenase. Vernal keratoconjunctivitis has been alleviated after treatment with orally administered aspirin, although the necessary high doses could produce serious side effects." Topically applied inhibitors of cyclooxygenase (l % suprofen and 0.03% flurbiprofen) have also had beneficial effects on vernal keratoconjunctivitis" and allergic conjunctivitis," respectively. Currently, inhibitors of lipoxygenase are purely investigational, but they may hold promise as future antiallergy drugs. Inhibitors of lipoxygenase such as REV5901, MK-57l, and MK-886 seem effective for decreasing inflammation in experimental model systems (Ford-Hutchinson AW: Personal communication). Stabilizers ofMast Cells.-Traditionally, the mechanism of action of stabilizers of mast cells (cromolyn sodium, lodoxamide tromethamine, and nedocromil) has been thought to be the prevention of the flux of calcium across the cell membrane. Recent studies with disodium cromoglycate, however, indicated that stabilizers of mast cells may act through other mechanisms, such as inhibition of activation of neutrophils, eosinophils, and monocytes." A recent clinical study" showed that a new stabilizer of mast cells, lodoxamide (0.1% ophthalmic solution), may be more effective than topically applied cromolyn sodium for alleviating the signs and symptoms in various types of ocular allergy. Another new agent, nedocromil, also has beneficial effects on ocular allergy and may offer the advantage of being more effective for stabilizing the mucosal mast cell." Vasoconstricting Agents and Antihistamines.-Antihistamines can decrease the symptoms of allergy by blocking histamine receptors (HI or H2) ; the activation of HI receptors seems to be most responsible for the symptoms of ocular allergy. The five classes of HI-blocking antihistamines are
alkylamines, ethanolamines, ethylenediamines, phenothiazines, and piperazines. Preparations of these antihistamines for ophthalmic use include an alkylamine (pheniramine maleate) and two ethylenediamines (antazoline phosphate and pyrilamine maleate)." A new potent HI-blocking antihistamine, levocabastine, was recently reported to be effective for decreasing the clinical signs and symptoms of ocular allergy. 52 Although topically applied antihistamines can be used alone for treating ocular allergy, a recent study indicated that combined use of an antihistamine (antazoline phosphate) and a vasoconstrictor (naphazoline hydrochloride) is more effective than using each agent separately." IgE Pentapeptide.-IgE pentapeptide is a synthetic peptide that has been hypothesized to act as an antiallergy agent by competitively blocking the binding of intact IgE to specific cell receptors. A 0.5% ophthalmic solution has been reported to be effective for decreasing the signs and symptoms of ocular allergy. 53 Cyclosporine.-Cyclosporine is a cyclic peptide that has immunosuppressive effects that inhibit the actions of interleukin 2 on T lymphocytes. In a double-masked clinical trial, investigators demonstrated that 2% cyclosporine in castor oil decreases the clinical signs and symptoms in vernal keratoconjunctivitis."
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