MASTERING THE MECHANICS OF OCULAR ALLERGY
An expert reveals the complex inner workings of this seemingly simple condition, to help you deliver appropriately targeted therapy.
This course reviews the pathophysiology and cellular mechanisms of several common forms of ocular allergy. Various immune processes and pharmacologic interventions are discussed to help clinicians improve their ability to diagnose and manage these conditions more effectively.
William Townsend, OD, practices in a multilocation setting in Texas. He is an adjunct professor at the University of Houston College of Optometry and preceptor for senior externs who rotate through his practice. He conducts research in pharmaceutical agents, contact lens materials and solutions, and ocular surface disease. Dr. Townsend is a fellow of the American Academy of Optometry and president of the Ocular Surface Society of Optometry.
This course is COPE approved for 1 hour of CE credit. COPE ID 45118-AS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Joint Sponsorship Statement:
This continuing education course is jointsponsored by the Pennsylvania College of Optometry.
Dr. Townsend has no financial disclosures relevant to the content of this course.
Fifty years ago, a pair of Japanese immunologists, Drs. Teruko and Kimishige Ishizaka, discovered an antibody isotype in serum γ globulin while in residence at the University of Colorado Medical School.1 This fraction, which they called "erythemainducing γ globulin," was present under normal conditions; however, under certain conditions it was associated with increased inflammation, such as in the presence of allergy.
These findings, published in 1966, have since provided the foundation for further understanding of the role of erythemainducing γ globulin—later known as immunoglobulin E (IgE)—in allergy.2 Subsequent research has identified hundreds of immunologically active molecules, including histamine, bradykinin, serotonin, leukotrienes, prostaglandins, major histocompatibility complex (MHC1), interferons, chemotactic factors and the complement system.1
Even now, five decades later, we continue to hone our understanding of the immune system; thus, to properly diagnose and manage the conditions that fall under the term, "ocular allergy," we must recognize there are several disparate underlying processes at work in these conditions, and understand the respective pathophysiology of each.
WHAT’S IN A NAME?
The term allergy is defined by the American Academy of Asthma, Allergy, and Immunology as "a chronic condition involving an abnormal reaction to an ordinarily harmless substance called an allergen."3 Interestingly, this term has only existed for slightly more than a century: it was coined in 1906 by Austrian pediatrician Clemens E. von Pirquet from the Greek words allos, meaning "other, different or strange," and ergon, meaning "activity."4
Allergy is a form of hypersensitivity—an inappropriate expression of a typical immune response that can cause tissue damage or alteration—that may involve almost any part of the body.5 Four types of hypersensitivity reactions exist: Types I, II and III hypersensitivity are antibodymediated, while Type IV is mediated by Tcells and macrophages.5 Type I hypersensitivity can vary in severity from a localized reaction such as allergic rhinitis to serious systemic conditions like anaphylactic shock.5 Most ocular allergies result from either Type I or Type IV hypersensitivity, or a combination of both.
Roughly 20% of Americans (i.e., 50 million people) are affected by some form of allergy, and the incidence is steadily increasing.6 Atopy, or the propensity to become allergic, is highly inheritable; the risk for developing asthma, allergic rhinitis or atopic dermatitis is three times greater in individuals who have more than one firstdegree relative with allergic disease.7 But, nonhereditary factors also play a crucial role in developing allergy; in monozygotic twins, concordance rates for asthma and allergies are approximately 50%. This suggests that other factors such as environment may influence whether or not an individual develops allergy.7
TYPE I (IMMEDIATE)
Multiple immune system components are involved in an allergic reaction, but the act of IgE binding to and enabling the degranulation of mast cells is ultimately what mediates allergy. Tlymphocytes and Blymphocytes do participate in the process, however.8
Mast cells respond to danger signals of innate and acquired immunity by releasing inflammatory mediators into the surrounding environment and recruiting other inflammatory cells into the region.8 Thus, the allergic response begins with sensitization of mast cells to a specific allergen (see "Type I Response: Sensitization and Activation,"). Mast cells are most abundant in tissues with the highest risk for invasion (e.g., skin, lymphoid, lung, nasal and gastric mucosal, conjunctival, urinary bladder, perivascular and uterine tissue).
Type I Response: Sensitization and Activation
The following is a simplified description of the mechanism of Type I hypersensitivity, which typically has a rapid onset, is not directed at any specific target and in many cases is self-limiting.
Type IV Response: Mechanisms
Type IV Hypersensitivity:
Interestingly, while mast cells and basophils are functionally and histologically similar, the latter resides in the circulatory system.8 Together with eosinophils and neutrophils, these cells form a category known as granulocytes, multilobed leukocytes characterized by the presence of granules in their cytoplasm. The unique content in the cytoplasm in each of these cells, especially granule content, determines their staining characteristics and the manner in which they affect tissues after they degranulate.9
Mast cells are grouped according to the presence or absence of two proteases—tryptase and chymase— in their cytoplasm. All mast cells contain tryptase (Tt mast cells), but mast cells containing both tryptase and chymase (Ttc mast cells) reside in a limited number of tissues. The two subtypes are believed to have different functions and have been shown to respond in unique ways to some pharmaceutical agents.10
TYPE IV (DELAYED)
This is a specific, cellmediated response that focuses on one target molecule—in other words, an alteration in cellbased or cellular immunity—that develops more slowly than Type I (i.e., more than 12 hours after exposure at minimum, and more commonly over a period of days to weeks.)5,11
Cellular immunity serves as a powerful defense against intracellular pathogens, including mycobacteria, fungi, certain parasites and tumor cells, through use of CD4+ Tcells.11 Loss or reduction of these cells can impair the host response against intracellular pathogens such as Mycobacterium tuberculosis—in effect, macrophages engulf the bacteria but are unable to kill them.11 As such, loss of this form of immunity can be devastating. The best illustration of the results that occur when cellular immunity fails is acquired immunodeficiency syndrome (AIDS).
BREAKING IT DOWN
Allergic eye diseases fall into one of two categories: IgEmediated conditions and cellmediated conditions. They range in severity from mildly irritating to potentially sightthreatening (Table 1).
|Table 1. Features of Several Common Types of Allergic Eye Disease (AED)|
|• 25–50% of population with AED
• 10-15% of general population
||Small tarsal papillae||Yes|
|0.03% of general population||Mild
||Similar; less severe||Presents year-round with
|1.5% of general population||• Sight-threatening
• Ranges from
|• Conjunctival scarring
• Papillae formation
• Severe corneal opacifi cation
• Cataract and keratoconus association
|Unknown||• Not sightthreatening
• Similar to AKC
• Similar to AKC but without keratopathy
• Cataract and keratoconus association
|• 0.5% of population with AED
• Higher prevalence in males under
14 years old vs. females
• Typically resolves by puberty
• After puberty, prevalence is
equal between males and females
||• Florid, giant papillae in tarsus or limbus
• Conjunctival scarring
• Cornea PEE develop into ulcer with plaque
• Sight threatening
• Trantas' dots (eosinophils) and
||• Reaction to presence of contact lens,
stitches or prosthesis
• Florid, giant papillae
|Contact dermatitis||Unknown||Moderate||• Affects skin, not cornea
• Reaction to particular allergen
• Skin erythema
Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are the two most common forms of ocular allergy, affecting up to 20% of the population. SAC constitutes 90% of all cases of allergic eye disease 5% of allergic eye disease is caused by PAC.12 Both are uncomplicated forms of Type I hypersensitivity that differ in the seasons in which they occur, and the allergens involved.13
Allergic conjunctivitis is strongly associated with systemic allergy, and occurs in 50% to 75% of individuals who suffer from allergic rhinitis, the most common allergic disorder. Signs and symptoms include itching, tearing, chemosis and conjunctival injection, eyelid edema and papillary hypertrophy.12
Prevalence of seasonal allergic conjunctivitis is tied to the pollination of plants and so tends to peak in spring, late summer and early fall. However, there can be slight variations in timing depending on climate. Signs and symptoms include itching, chemosis, injection and epiphoria.14 Perennial allergic conjunctivitis is triggered by allergens commonly found in the home or office environment, including animal dander, mold spores and dust mites. Interestingly, roughly 36% of individuals with confirmed dust mite allergy also had accompanying conjunctivitis.15 Individuals with PAC often have seasonal exacerbations that occur in conjunction with the peak seasons of SAC, and so may require more intensive therapy during those periods when pollen levels are elevated.
KEEPING ALLERGENS AT BAY
One obvious means of reducing the effects of pollen is avoidance. Individuals with SAC can achieve this, at least to some extent, by lifestyle changes during peak pollen release. Examples include keeping windows closed and avoiding outside activities when pollen levels are high as much as possible. If it’s necessary to venture outside, wearing close fitting, wraparound glasses and washing hands once inside again can help prevent exposure. Allergens can also become attached to hair, so washing hair prior to sleeping and changing pillowcases on a daily basis is also beneficial.12
Many pharmacologic options for the management of noncomplicated allergy also exist. Conjunctival decongestants are synthetic adrenergic agents that cause vasoconstriction and therefore improve the appearance of individuals with allergic conjunctivitis. Their effects are shortlived with little effect on itching, however, and longterm use may lead to rebound hyperemia.14
Parenteral firstgeneration antihistamines are commonly used in systemic allergy, but may be counterproductive in managing ocular allergic disease. They may bind histamine receptors in the central nervous system, leading to sedation and an exertion of anticholinergic effects including dry mouth, dry eye and tachycardia. The overall effect is an increase in the concentration of allergens in the tears.12
Mast cell degranulation releases histamine into surrounding tissues. The binding of histamine to H1 and H2 receptors on conjunctival nerves and small blood vessels produces itching, vascular dilation and extravasation of fluid into conjunctival tissue.26 Topical singleacting mast cell stabilizers exert their therapeutic effects by preventing degranulation of mast cells. A num ber of these compounds have been evaluated for pulmonary allergy, where Tt mast cells predominate. Their efficacy in the Ttc mast cells found in conjunctival tissues has thus far not been established.
Histamine is only one of several preformed mediators that are released when a mast cell degranulates; that event also initiates the production and release of newly formed mediators. Antihistamines are beneficial but do not block the effects of nonhistamine mediators. Dualacting mast cell stabilizers/ antihistamines are the most recent class of medications to be approved for ocular allergy. These agents effectively reduce itching associated with allergic conjunctivitis, and their effects are better tolerated and last longer than singleaction antihistamines.12,14 Because of these benefits, dualacting agents have become the principle therapy for the treatment of allergic conjunctivitis.
Given the high incidence of allergic conjunctivitis and the emergence of dualaction agents as the preeminent therapy for these conditions, it is important for the clinician to appreciate that mast cell heterogeneity is a crucial point to consider when researchers design mast cell stabilizers for a specific type of tissue.
Cromolyn sodium and nedocromil—mast cell stabilizers originally developed for asthma, and introduced as inhalers—were eventually formulated as therapeutic agents for allergic conjunctivitis.2729 In human conjunctiva, Ttc mast cells are more prevalent than Tt mast cells. In tissues such as bronchial epithelium, alveoli, epithelium of the nasal mucosa and small intestine mucosa, Tt type mast cells predominate. Yanni et al. evaluated the efficacy of various topical mast cell stabilizers in human conjunctival tissue. Their study concluded that olopatadine, a mast cell stabilizer/antihistamine, was more efficacious in stabilizing human conjunctival mast cells.30
Topical corticosteroids reduce inflammation in a number of ways. They suppress mast cell proliferation; reduce inflammatory cell incursion and block the production of inflammatory mediators; inhibit cellmediated immune responses; and block the production of prostaglandins, leukotrienes and platelet activating factors.12 Unfortunately, they also exhibit side effects that include increased intraocular pressure, delayed wound healing, secondary infection and cataract formation.
The introduction of steroid preparations with a reduced IOPelevating profile has made steroid use in ocular allergy more feasible, but the other risk factors make longterm use for noncomplicated allergy questionable.16 Noncomplicated allergic eye disease comprises 95% of all ocular allergies. The nonthreatening nature of these conditions and the efficacy and safety profile of combination mast cell stabilizers/antihistamines suggests that the combination medications be firstline agents for management of these conditions
THE RITE OF SPRING
Vernal keratoconjunctivitis (VKC) is an inflammatory condition of the ocular surface mediated primarily by Th2 lymphocytes; it is more prevalent in younger males who reside in hot, humid climates.16
VKC typically presents before 10 years of age and usually resolves some time after puberty, typically four to 10 years after the initial onset. VKC is fairly uncommon, with roughly 1.2 to 10.6 cases per 10,000 people. Corneal complications are even lower: 0.3 to 2.2 per 10,000 people.16
As the name "vernal" suggests, the condition occurs primarily in the spring months. It presents in several forms: the tarsal or palpebral form primarily affects the upper eyelid while the limbal form targets the cornea and conjunctiva, or a combination of both. The disease is more common in males, with a male to female ratio varrying from 4:1 to 2:1 in young individuals. But, after 20 years, the male to female ratio becomes almost equal.17,18
Fig. 1. The presence of giant papillae is a hallmark of palpebral VKC.
The pathogenesis of VKC is complex and involves overexpression of mast cells, eosinophils, neutrophils, Th2derived cytokines, chemokines, adhesion molecules, growth factors, fibroblast and lymphocytes.16 One hallmark feature of palpebral VKC is the presence of giant papillae on the tarsal surface of the eyelid, which are typically several millimeters in diameter and composed of extracellular matrix and fibroblasts in response to IL4 and IL13 (Figure 1). These giant papillae are populated with neutrophils, plasma cells, mononuclear cells and eosinophils. Analysis of tears from VKC patients reveals increased levels of IgE, histamine, leukotrienes, prostaglandins and kinase. With so many inflammatory mediators in tears, it should come as no surprise that there is often corneal involvement in individuals suffering from VKC.
Limbal VKC presents as white or yellow deposits of degenerating eosinophils located at the limbus or perilimbal are of the conjunctiva. These lesions, known as Horner–Trantas dots, are more prevalent in VKC patients from warm climates.
In a Thailand study of 48 subjects, 58% had the limbal form, 33% had the palpebral form and the remainder had both forms. Cyclosporine therapy was more successful in the palpebral group.19
Eosinophils, like mast cells, are granulocytes; both are prevalent in VKC.8 They differ from mast cells in the contents of their granules, which include major basic protein (MBP), a substance that accounts for over 50% of granule protein weight, and eosinophilderived neurotoxin (EDN), a compound that is toxic to myelinated neurons.8 The vast majority of eosinophils are located in the gut and lungs, where they actively protect against invading organisms.20 Cationic proteins (pH 911) such as MBP are very effective in reducing GI parasites, including helminths and schistosomula, but unfortunately cause tissue damage in eosinophilbased diseases such as asthma and VKC.8
During the active phase of VKC, approximately 50% to 90% of cells in tears are eosinophils; mast cell concentration in conjunctival tissue is also elevated.18
Fig. 2. Some individuals with VKC can develop corneal lesions known as shield ulcers.
Degranulation of mast cells and the accompanying release of histamine produces intense itching and chemosis characteristic of VKC. A small percentage of individuals with VKC develop reduced vision, due to sterile corneal ulceration and scarring. The corneal lesions, which are often referred to as "shield ulcers," appear in the superior cornea and may involve the visual axis (Figure 2). The development of these lesions is multifactorial. The release of cationic proteins and fibroblast damage.21 Eosinophil adhesion to fibroblasts is thought to also contribute to the pathogenesis of severe, persistent allergic corneal ulcers.18
Systemic and topical antihistamines, as well as dualacting antihistamine/mast cell stabilizers, are beneficial in managing VKC, but the more severe effects of this condition result from uncontrolled cellularbased immunity.18
Topical corticosteroids have long been a mainstay therapy for more severe manifestations of VKC. Ocular complications of longterm corticosteroid use are well documented, and include increased intraocular pressure, glaucoma and corneal mechanical eye rubbing traumatize the cornea and contribute to shield ulcers. Fibroblasts are also thought to be important in the development of shield ulcers. Eosinophils can adhere to the activated corneal fibroblasts and induce subsequent opacification, and conjunctival necrosis.22,23 Immunosuppressive agents that do not cause IOP elevation have been successfully used in the management of VKC and other inflammatory conditions of the ocular surface.24
Vichyanond and Kosrirukvongs reported the use of cyclosporine A (CsA) and tacrolimus in the management of VKC. CsA inhibits calcineurin, an intracellular signaling protein, by binding to its receptor. This reduces Th2 production of cytokines, chemokines and IL4 and IL5. The original preparation, a 2% concentration of CsA in oil, was effective in reducing signs and symptoms associated with VKC, but led to frequent complaints of discomfort and low tissue concen trations of the medication. Researchers were able to achieve higher tissue concentrations with reduced side effects by reformulating CsA in an aqueous base at a lower concentration (0.1%).24
Tacrolimus is a naturally occurring compound that inhibits the effects of calcineurin via a pathway that is entirely different from cyclosporine’s. Tacrolimus prevents the release of histamine and production of inflammatory mediators such as leukotriene C4; it has an up to 50fold greater rate of inhibition when compared to CsA. It has been successfully used to treat atopic dermatitis, a relapsing skin disorder in children caused by overproduction cytokines by Th1 and Th2 cells.24
Despite advances in treating VKC with topical therapy that do not include steroids, during periods of high allergen release, it may become necessary to prescribe topical steroids to successfully treat episodic exacerbation of the condition.
Interestingly, detecting elevated levels of a cytokine may allow more definitive diagnosis of VKC. Inada et al. found similar levels of CCL20—a cytokine involved in regulating immune responses, homeostasis and inflammation in mucosal tissues—in controls and individuals with mild VKC, but elevated levels in subjects with severe VKC.25
Regardless, it’s important to remember VKC can closely mimic the signs and symptoms of SAC, but with the potential for permanent vision loss. So, always test any patient, especially a young male, who presents with severe itching, stringy discharge and other signs and symptoms suggestive of VKC.
- Campbell DE, Mehr S. Fifty years of allergy: 19652015. J Paediatr Child Health. 2015 Jan;51(1)913.
- Takai T, Karasuyama H. The study of allergy by Japanese researchers: a historical perspective. Int. Immunol. 2009;21(12):131116
- American Academy of Allergy, Asthma and Immunology. Allergy. Available at: www.aaaai. org/conditionsandtreatments/conditionsdictionary/allergy.aspx. Accessed January 8, 2015.
- Online Etymology Dictionary. Allergy. Available at: www.etymonline.com/index. php?term=allergy. Accessed January 8, 2015.
- Roitt I, BrostoffJ, Male D. Immunology Chicago Mosby 1993 19.12
- Asthma & Allergy Foundation of America. Allergy Facts and Figures. Available at: www.aafa. org/display.cfm?id=9&sub=30. Accessed Jan. 8, 2015.
- Ortiz RA, Barnes KC. Genetics of allergic diseases. Immunol Allergy Clin North Am. 2015 Feb;35(1):1944.
- Stone KD, Calman P, Metcalfe DD. IgE, Mast Cells, Basophils, and Eosinophils. J Allergy Clin Immunol. 2010 Feb; 125(2Suppl 2):S73S80.
- Wikipedia. Granulocyte. Available at: http:// en.wikipedia.org/wiki/Granulocyte. Accessed January 8, 2015.
- Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev. 2007 Jun;217:14154.
- Medscape. Delayed Hypersensitivity Reactions. Available at: emedicine.medscape.com/ article/136118overview. Accessed Feb. 10, 2015.
- Bilkhu PS, Wolffsohn JS, Naroo SA. A review of nonpharmacological and pharmacological management of seasonal and perennial allergic conjunctivitis. Cont Lens Anterior Eye. 2012 Feb;35(1):916.
- Freidlaender MH. Ocular allergy. Curr Opin Allergy Clin Immunol. 2011 Oct;11(5):47782.
- Bielory L, Meltzer EO, Nichols KK, et al. An algorithm for the management of allergic conjunctivitis. Allergy Asthma Proc. 2013 SepOct;34(5):40820.
- Frati F, Scurati S, et al. Evaluation of house dust mite allergy in real life: patients' characteristics and satisfaction with treatment. Eur Ann Allergy Clin Immunol. 2014 Jan;46(1):1721.
- La Rosa M, Lioneti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr. 2013 Mar 14;39:18.
- Bielory L. Allergic and immunologic disorders of the eye. Part II: Ocular allergy. J Allergy Clin Immunol. 2000 Dec;106(6):101932.
- Kumar S. Vernal keratoconjunctivitis: a major review. Acta Ophthalmol. 2009 Mar;87(2):13347.
- Kosrirukvongs P, Vichyanond P, Wongsawad W. Vernal keratoconjunctivitis in Thailand. Asian Pac J Allergy Immunol. 2003 Mar;21(1):2530.
- Merck Manuals. Eosinophil Production and Function. Available at: www.merckmanuals. com/professional/hematology_and_oncology/ eosinophilic_disorders/eosinophil_production_ and_function.html. Accessed February 10, 2015.
- Trocme SD, Leiferman KM, George T, et al. Neutrophil and eosinophil participation in atopic and vernal keratoconjunctivitis. Curr Eye Res. 2003;26:319–25.
- Pleyer U, Ursell P, Rama P. Intraocular Pressure Effects of Common Topical Steroids for PostCataract Inflammation: Are They All the Same? Ophthalmol Ther. 2013 Dec; 2(2):55–72.
- Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000 Dec;11(6):478–83.
- Vichyanond P, Kosrirukvongs P. Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis. Curr Allergy Asthma Rep. 2013 Jun;13(3):30814.
- Inada N, Ishimori A, Shoji J. CCL20/MIP3 alpha mRNA expression in the conjunctival epithelium of normal individuals and patients with vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol. 2014 Dec; 252(12):1977–84.
- Bielory L Ghafoor S. Histamine receptors and the conjunctiva. Curr Opin in Allergy Clin Immunol. 2005 Oct;5(5):43740.
- Storms W, Kaliner MA. Cromolyn sodium: fitting an old friend into current asthma treatment. J Asthma. 2005 Mar;42(2):7989.
- Cox JS, Altounyan RE. Nature and modes of action of disodium cromoglycate (Lomudal). Respiration. 1970;27:Suppl:292309.
- Lal S, Malhotra S, Gribben D, et al. Nedocromil sodium: a new drug for the management of bronchial asthma. Thorax. 1984;39(11):80912.
- Yanni JM, Sharif NA, Gamache DA, et al. A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs. Acta Ophthalmol Scand Suppl. 1999;(228):337.
- McGill J, Holgate S, Church M, et al. Allergic eye disease mechanisms. Br J Ophthalmol. 1998 Ot; 82(10);120314.
- Dachman WD, Bedarida G, Blaschke TF, et al. Histamineinduced venodilation in human beings involves both H1 and H2 receptor subtypes. J Allergy Clin Immunol. 1994 Mar;93(3):60614.