Allergic Conjunctivitis 

Updated: Oct 08, 2019
Author: Mark Ventocilla, OD, FAAO; Chief Editor: Andrew A Dahl, MD, FACS 

Overview

Background

The ocular surface may exhibit a wide variety of immunologic responses resulting in inflammation of the conjunctiva and cornea. In the Gell and Coombs classification system for various immunologic hypersensitivity reactions, 5 types of reactions are recognized. The major type I hypersensitivity reactions involving the conjunctiva are commonly referred to as allergic conjunctivitis and are further subclassified into seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC). Far less common are the more severe forms of allergic conjunctivitis, including atopic keratoconjunctivitis (AKC), giant papillary conjunctivitis (GPC), and limbal and tarsal vernal keratoconjunctivitis (VKC).

Diagnosis of allergic conjunctivitis is generally made by thorough history and careful clinical observation (see Clinical). The presence of an antigen triggers the allergic cascade, and, thus, avoidance of the offending antigen is the primary behavioral modification for all types of allergic conjunctivitis. In other respects, management of allergic conjunctivitis varies somewhat according to the specific subtype. Allergic conjunctivitis can be treated with a variety of drugs, including topical antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs, and corticosteroids (see Treatment).

See the following for more information:

  • Acute Hemorrhagic Conjunctivitis

  • Atopic Keratoconjunctivitis

  • Bacterial Conjunctivitis

  • Emergent Treatment of Acute Conjunctivitis

  • Epidemic Keratoconjunctivitis

  • Giant Papillary Conjunctivitis

  • Keratoconjunctivitis Sicca

  • Neonatal Conjunctivitis

  • Superior Limbic Keratoconjunctivitis

  • Viral Conjunctivitis

Immunologic reactions of conjunctiva and cornea

Type I (immediate) hypersensitivity reactions occur when a sensitized individual comes in contact with a specific antigen. Immunoglobulin E (IgE) has a strong affinity for mast cells, and the cross-linking of 2 adjacent IgE molecules by the antigen triggers mast cell degranulation.

The mast cell’s degranulation releases various preformed and newly formed mediators of the inflammatory cascade. Most notable of these inflammatory mediators are histamine, tryptase, chymase, heparin, chondroitin sulfate, prostaglandins, thromboxanes, and leukotrienes. These various inflammatory mediators, together with various chemotactic factors, result in an increase in vascular permeability and migration of eosinophils and neutrophils. This type I hypersensitivity reaction is the most common allergic response of the eye. These immune-derived reactions may also be the underlying cause of more rare and serious ocular conditions, such as ocular cicatricial pemphigoid (OCP) and Mooren ulcer.

Type III hypersensitivity reactions result in antigen-antibody immune complexes, which deposit in tissues and cause inflammation. A classic systemic type III reaction is the Arthus reaction, and ocular type III hypersensitivity reactions include Stevens-Johnson syndrome and marginal infiltrates of the cornea. These type III reactions can often induce a corneal immune (Wessely) ring that disintegrates as the inflammatory reaction subsides.

Type IV hypersensitivity reactions, also known as cell-mediated immunity, are facilitated by T lymphocytes, rather than merely antibodies. This inflammatory cell-driven reaction is also referred to as delayed-type hypersensitivity, since its onset is generally after 48 hours, in contrast to the type I reaction, which is an immediate hypersensitivity.

Type IV hypersensitivity reactions imply immunocompetence on the part of the individual since an intact immune system is required to mount the cell-mediated response. Ocular examples of type IV hypersensitivity include phlyctenular keratoconjunctivitis, corneal allograft rejection, contact dermatitis, and drug allergies, although drug sensitivities can lead to all four types of hypersensitivity reaction.

Allergic conjunctivitis subtypes

Allergic conjunctivitis may be divided into 5 major subcategories.

Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are commonly grouped together.

Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC) constitute the remaining subtypes of allergic conjunctivitis.

Early diagnosis and treatment will help prevent the rare complications that can occur with this disease.

Prognosis

Since allergic conjunctivitis generally clears up readily, the prognosis is favorable. Complications are very rare, with secondary corneal ulcers or keratoconus occurring rarely. Although SAC, PAC, and GPC commonly reoccur, they rarely cause any visual loss. Conversely, VKC and AKC are frequently associated with significant risk of progressive corneal damage and resultant visual loss.

Patient education

Patients should make every attempt to identify the allergen causing the problem and to avoid the offending antigen. For patient education information, see the Eye and Vision Center, as well as Pinkeye, Eye Allergies, and How to Instill Your Eyedrops.

Pathophysiology

Seasonal and perennial allergic conjunctivitis

Since the conjunctiva is a mucosal surface similar to the nasal mucosa, the same allergens that trigger allergic rhinitis may be involved in the pathogenesis of allergic conjunctivitis. Common airborne antigens, including dust, molds, pollen, grass, and weeds, may provoke the symptoms of acute allergic conjunctivitis, such as ocular itching, redness, burning, and tearing. The main distinction between SAC and PAC, as implied by the names, is the timing of symptoms.

Individuals with SAC typically have symptoms of acute allergic conjunctivitis for a defined period of time, that is, in spring, when the predominant airborne allergen is tree pollen; in summer, when the predominant allergen is grass pollen; or in fall, when the predominant allergen is weed pollen. Typically, persons with SAC are symptom-free during the winter months in cooler climates because of the decreased airborne transmission of these allergens. Seasonal allergic conjunctivitis can manifest itself through tear film instability and symptoms of eye discomfort during the pollen season. One study found that outside the pollen season, allergic inflammation did not cause permanent tear film instability.[1]

In contrast, individuals with PAC may have symptoms that last the year round; thus, PAC may not be caused exclusively by seasonal allergens, although they may play a role. Other common household allergens, such as dust mite, cockroach dust, cigarette smoke, airborne allergens, molds, and pet dander, may be responsible for the symptoms of PAC.

Vernal keratoconjunctivitis

VKC is a chronic bilateral inflammation of the conjunctiva, commonly associated with a personal and/or family history of atopy. More than 90% of patients with VKC exhibit one or more atopic conditions, such as asthma, eczema, or seasonal allergic rhinitis. Corneal complications and conjunctival scarring frequently occur, particularly in more severe cases and in patients whose VKC onsets at a very young age.

Atopic keratoconjunctivitis

AKC is a bilateral inflammation of conjunctiva and eyelids, which has a strong association with atopic dermatitis. It is also a type I hypersensitivity disorder with many similarities to VKC, yet AKC is distinct in a number of ways.

In 1953, Hogan first described the association between atopic dermatitis and conjunctival inflammation.[2] He reported 5 cases of conjunctival inflammation in male patients with atopic dermatitis.[2] Atopic dermatitis is a common hereditary disorder that usually first appears childhood; symptoms may regress with advancing age. Approximately 3% of the population is afflicted with atopic dermatitis, and, of these, approximately 25% have ocular involvement. Again, more advanced cases may result in significant conjunctival cicatrization, severe dry eye, and loss of corneal clarity through chronic or acute keratitis.

Giant papillary conjunctivitis

GPC is an immune-mediated inflammatory disorder of the superior tarsal conjunctiva. As the name implies, the primary finding is the presence of "giant" tarsal papillae, which are typically greater than 0.3 mm in diameter.

A combination of type I and type IV hypersensitivity reactions may be responsible for the pathogenesis of GPC. It is believed that an antigen is present, in predisposed individuals, which stimulates the immunological reaction and the development of GPC.

Prolonged mechanical irritation to the superior tarsal conjunctiva, of the upper lid, from any of a variety of foreign bodies may also be a contributing factor in GPC. Although contact lenses (hard and soft) are the most common irritant, ocular prostheses, extruded scleral buckles, elevated glaucoma shunts or filtering blebs, scleral shells, and exposed sutures following previous surgical intervention may also precipitate GPC.

Epidemiology

Allergic conjunctivitis occurs very frequently and is seen most commonly in areas with high seasonal allergen and pollen counts. VKC occurs predominantly in areas with tropical and temperate climates, such as the Mediterranean, the Middle East, and Africa. The limbal form of VKC commonly occurs in dark-skinned individuals from Africa and India.

Sexual and age-related differences in incidence

VKC has a significant male preponderance, typically affecting young males. The onset of VKC generally occurs in the first decade and persists throughout the first 2 decades. Symptoms usually peak prior to the onset of puberty and then subside.

Prognosis

In general, the prognosis of SAC and PAC is good despite significant discomfort and undesirable cosmetic consequences. Occasionally, individuals with chronic recurrences develop significant conjunctivochalasis or, less commonly, a corneal Dellen secondary to persistent limbal conjunctival chemosis. Conversely, AKC and VKC may lead to significant corneal complications such as ulceration and opacification, leading to permanent visual loss. Furthermore, significant chronic ocular surface disease places these patients at high risk for corneal transplantation complications and rejection. Lid involvement from any type of allergic conjunctivitis, particularly GPC, can significantly compromise contact lens tolerance. Medications used for allergic disease may lead to complications such as preservative toxicity and steroid-induced intraocular pressure (IOP) elevations or steroid-related cataract.

 

Presentation

History

Diagnosis of allergic conjunctivitis generally is made by taking a thorough history and by careful clinical observation. In seasonal and perennial allergic conjunctivitis, important features of the history include a personal or family history of atopic disease, such as allergic rhinitis, bronchial asthma, and/or atopic dermatitis. Perhaps the most important feature in the clinical history is the symptom of itching. Without itching, the diagnosis of allergic conjunctivitis becomes suspect.

Vernal keratoconjunctivitis

With vernal keratoconjunctivitis (VKC), as with other allergic or type I hypersensitivity disorders, itching is the most important and most common symptom. Other commonly reported symptoms are photophobia, foreign body sensation, tearing, and blepharospasm. Photophobia due to chronic keratitis is also common.

Ocular signs of VKC commonly are seen in the cornea and conjunctiva. In contrast to atopic keratoconjunctivitis (AKC), the eyelid skin usually is not as significantly involved.

Atopic keratoconjunctivitis

In AKC, unlike VKC, the symptoms are perennial. There may be seasonal variation, however, with worsening symptoms during winter months. The single most common symptom is bilateral itching of the eyelids, but watery discharge, redness, photophobia, and pain may be associated.

Giant papillary conjunctivitis

Primary symptoms in giant papillary conjunctivitis (GPC) are ocular itching with a mucoid or ropy discharge, very similar to that seen in VKC. Another symptom of GPC may be persistent foreign body sensations when using contact lenses, resulting in a decrease wear time and potential reduction in the visual acuity. Contact lens intolerance is especially problematic in patients with keratoconus who are highly dependent on contact lenses for optimal visual function.

Physical Examination

Seasonal and perennial allergic conjunctivitis

Classic signs of allergic conjunctivitis include injection of the conjunctival vessels as well as varying degrees of chemosis (conjunctival edema) and eyelid edema. The conjunctiva often has a milky appearance due to obscuration of superficial blood vessels by edema within the substantia propria of the conjunctiva. Edema is generally believed to be the direct result of increased vascular permeability caused by release of histamine from conjunctival mast cells.

Vernal keratoconjunctivitis

VKC may be subdivided into 2 varieties, as follows: palpebral and limbal. The classic conjunctival sign in palpebral VKC is the presence of giant papillae. The papillae most commonly occur on the superior tarsal conjunctiva; usually, the inferior tarsal conjunctiva is unaffected. Giant papillae assume a flattop appearance, which often is described as "cobblestone papillae." In severe cases, large papillae may cause mechanical ptosis (drooping eyelid). The astute clinician's attention is always drawn to the everted upper tarsus, which reveals key telltale signs, including papillae, vascular abnormalities, conjunctival inclusion cysts, follicles, subconjunctival scarring, and entropion.

A ropy mucous discharge may be present, which commonly is associated with tarsal papillae. Large numbers of eosinophils, indicating the presence of extended periods of inflammation, are present in the discharge.

The limbal form of VKC commonly occurs in dark-skinned individuals, such as those from Africa or India. As the name implies, papillae tend to occur at the limbus, the junction between the cornea and the conjunctiva, and have a thick gelatinous appearance. They commonly are associated with multiple white spots (Horner-Trantas dots), which are collections of degenerated epithelial cells and eosinophils. Horner-Trantas dots rarely last longer than a week from their initial presentation and generally resolve rapidly with the initiation of topical corticosteroid therapy.

While corneal vascularization is rare, the cornea may be affected in a variety of ways. Punctate epithelial keratopathy (PEK) may result from the toxic effect of inflammatory mediators released from the conjunctiva. The appearance of PEK may be a precursor for the characteristic shield ulcer, which is pathognomonic of VKC. A "shield" ulcer is typically superficial, located superiorly in the cornea, and oval or pentagonal in shape. Its margins may be slightly elevated. PEK can coalesce, resulting in frank epithelial erosion and forming into a shield ulcer, which is typically shallow with white irregular epithelial borders.

Although the pathogenesis of a shield ulcer is not well understood, the major factor in promoting development may be chronic mechanical irritation from the giant tarsal papillae. Some evidence suggests that the major basic protein released from eosinophils may also promote ulceration.

Another type of corneal involvement is vernal pseudogerontoxon, which is a degenerative lesion in the peripheral cornea resembling corneal arcus. Keratoconus may be seen in chronic cases, which may be associated with chronic eye rubbing in predisposed individuals.

Atopic keratoconjunctivitis

AKC may affect eyelid skin and lid margin, conjunctiva, cornea, and lens. Skin of the eyelids may exhibit eczematoid dermatitis with dry, scaly, and inflamed skin and the lid margins may show meibomian gland dysfunction and keratinization. Moreover, staphylococcal colonization of eyelid margins is very common in AKC and may result in blepharitis. Conjunctiva may show chemosis and typically a papillary reaction, which is more prominent in the inferior tarsal conjunctiva, in contrast to that seen in vernal keratoconjunctivitis.

Hyperplasia of limbal regions may result in a gelatinous thickening, similar to the limbal variant of VKC, and, although rare, Horner-Trantas dots also may be present. Fibrosis or scarring of the conjunctiva may result in a shortened fornix or symblepharon formation with chronic inflammation. Corneal involvement ranges from PEK early in the course of the disease, to neovascularization, stromal scarring, and possibly ulceration. There is also a strong association between AKC and herpes simplex labialis and herpes simplex viral keratitis.

As seen in VKC patients, the chronic eye rubbing of the cornea may contribute to the development of keratoconus. Characteristic lenticular changes in AKC include anterior or posterior subcapsular cataract formation. These slow progressing lens opacities are usually bilateral and present in the second decade of life. There is some reasonable speculation that the long-term use of topical corticosteroids can also induce the lenticular changes later in life.

Giant papillary conjunctivitis

Examination of superior tarsal conjunctiva reveals the presence of large cobblestone papillae, which are generally 0.3 mm or greater in diameter.

In her original description of GPC in 1977, Allansmith described 3 zones of superior tarsal conjunctiva.[3] Zone 1 is located closest to the fornix and is the most inferior portion of the tarsal conjunctiva seen when the upper eyelid is everted. Zone 3 is located closest to the eyelid margin. Zone 2 is located between zone 1 and zone 3.

Papillae typically associated with soft contact lenses initially appear in zone 1 and progress toward zone 3, while those associated with rigid gas permeable contact lenses exhibit a reverse pattern, with zone 3 affected first. GPC associated with a localized irritant, such as an exposed suture or a filtering bleb, is typically localized to the area overlying these inciting lesions.

Another clinical sign of GPC may be chronic bulbar conjunctival injection and inflammation due to prolonged and persistent use of contact lenses.

 

DDx

Diagnostic Considerations

Allergic conjunctivitis must be differentiated from viral and bacterial conjunctivitis or other infectious external diseases of the eye. Clinical features (eg, recent exposure to an individual with infective conjunctivitis) may be helpful in this regard.

The main distinction between seasonal and perennial allergic conjunctivitis, as implied by the names, is the timing of symptoms (see Pathophysiology). Major differentiating factors between vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are shown in the table below.

Table. Major Differentiating Factors Between VKC and AKC (Open Table in a new window)

Characteristics

VKC

AKC

Age at onset

Generally presents at a younger age than AKC' first decade

Second to third decade

Sex

Males are affected preferentially.

No sex predilection

Seasonal variation

Typically occurs during spring months

Generally perennial

Discharge

Thick mucoid discharge

Watery and clear discharge

Conjunctival scarring

Moderate incidence of conjunctival scarring

Higher incidence of conjunctival scarring

Horner-Trantas dots

Horner-Trantas dots and shield ulcers are commonly seen.

Presence of Horner-Trantas dots is rare.

Corneal neovascularization

Not present, unless secondary to infectious keratitis

Deep corneal neovascularization tends to develop

Presence of eosinophils in conjunctival scraping

Conjunctival scraping reveals eosinophils to a greater degree in VKC than in AKC

Presence of eosinophils is less likely

Differential Diagnoses

 

Workup

Approach Considerations

Allergy-specific tear and conjunctival scraping laboratory tests are not currently available except in academic or commercial research settings. Similarly, impression cytology techniques are potentially enlightening yet available to only a few dedicated research centers and ophthalmology-specific diagnostic laboratories. Conjunctival scrapings can be sent to hospital cytology laboratories and may be useful if a pathologist with a particular interest in ocular diseases is readily available.

In seasonal and perennial allergic conjunctivitis, superficial conjunctival scrapings may help to establish the diagnosis by revealing eosinophils, but only in the most severe cases, since eosinophils are typically present in the deeper layers of the substantia propria of the conjunctiva. Therefore, the absence of eosinophils on conjunctival scraping does not rule out the diagnosis of allergic conjunctivitis.

Many investigators have described measurement of tear levels of various inflammatory mediators, such as IgE, histamine, and tryptase, as indicators of allergic activity. Additionally, skin testing by an allergist may provide definitive diagnosis and pinpoint the offending allergen(s). Skin testing is now highly practical and readily available to all practicing ophthalmologists, as well as to optometrists in some states.

In vernal keratoconjunctivitis (VKC), conjunctival scrapings of the superior tarsal conjunctiva and of Horner-Trantas dots show an abundance of eosinophils. Conjunctival scrapings of patients with atopic keratoconjunctivitis (AKC) may demonstrate the presence of eosinophils, although the number is not as significant as that seen in VKC. Additionally, free eosinophilic granules, which are seen in VKC, are not seen in AKC.

Advanced point-of-service testing may soon become available through several diagnostic technology companies. Biomarkers such IgE, matrix metalloprotease-9 (MMP-9), or eosinophilic basic protein (EBP) may prove to be clinically useful surrogates for disease activity level and therapeutic response monitoring. Specimens can be obtained by tear sampling or conjunctival scraping techniques.

Histologic Findings

Vernal keratoconjunctivitis

Conjunctival scrapings of the superior tarsal conjunctiva show an abundance of eosinophils. Conjunctival biopsy reveals that there are a large number of mast cells within the substantia propria. Histochemical analysis of mast cells, present in VKC, reveals neutral proteases tryptase and chymase. There is enhanced fibroblast proliferation, which leads to the deposition of collagen within the substantia propria and, as result, induces conjunctival thickening.

B-cell and T-cell lymphocytes are present locally, which combine to produce IgE. Specific IgE and IgG as well as the inflammatory mediators histamine and tryptase have been isolated from tears of patients with VKC. Although VKC is typically recognized as a type I hypersensitivity reaction, evidence has been found that supports some involvement of type IV hypersensitivity reaction.

Atopic keratoconjunctivitis

Conjunctival scrapings of patients with AKC may demonstrate the presence of eosinophils, although the number is not as significant as that seen in VKC. Additionally, free eosinophilic granules, which are seen in VKC, are not seen in AKC. Mast cells also may be found within the substantia propria of the conjunctiva in greater numbers.

There is an increased amount of IgE in the tears of patients with AKC. Although AKC is typically recognized as a type I hypersensitivity reaction, evidence has been found that supports some involvement of type IV hypersensitivity reaction, as is the case in VKC.

Giant papillary conjunctivitis

Histologic findings in GPC consist of cellular infiltration of the conjunctiva by a number of cell types. Plasma cells, lymphocytes, mast cells, eosinophils, and basophils have been identified within the substantia propria. Mast cells also may be found in the epithelium. There is also elevated tear levels of immunoglobulin, especially IgE and tryptase also are elevated, as in AKC and VKC.

 

Treatment

Approach Considerations

Avoidance of the offending antigen is the primary behavioral modification for all types of allergic conjunctivitis. In other respects, management of allergic conjunctivitis varies somewhat according to the specific subtype (SAC, PAC, GPC, VKC, AKC).

Allergic conjunctivitis can be treated with a variety of medications, including topical antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. Surgical intervention may be indicated in severe cases of VKC or AKC.

See the following for more information:

  • Acute Hemorrhagic Conjunctivitis

  • Atopic Keratoconjunctivitis

  • Bacterial Conjunctivitis

  • Emergent Treatment of Acute Conjunctivitis

  • Epidemic Keratoconjunctivitis

  • Giant Papillary Conjunctivitis

  • Keratoconjunctivitis Sicca

  • Neonatal Conjunctivitis

  • Superior Limbic Keratoconjunctivitis

  • Viral Conjunctivitis

Management of Seasonal and Perennial Allergic Conjunctivitis

Pharmacologic intervention may be necessary to help alleviate the symptoms of acute allergic conjunctivitis. Various classes of medication may be effective against the symptoms of acute allergic conjunctivitis; each is directed at a specific point in the inflammatory and allergic cascade.

Artificial tears

Artificial tear substitutes provide a barrier function and help to improve the first-line defense at the level of conjunctival mucosa. These agents help to dilute various allergens and inflammatory mediators that may be present on the ocular surface, and they help flush the ocular surface of these agents. Chilled tears, as well as any topical medication, provide an added degree of relief, as well as homeopathic vasoconstriction. Similarly, cold compresses can be extremely useful to avoid the customary irrational rubbing response to chronic or paroxysmal pruritus.

Antihistamines

Systemic and/or topical antihistamines may be prescribed to relieve acute symptoms due to interaction of histamine at ocular H1 and H2 receptors. While systemic antihistamines often relieve ocular allergic symptoms, patients may experience systemic adverse effects, such as drowsiness and dry mouth.

Topical antihistamines competitively and reversibly block histamine receptors and relieve itching and redness but only for a short time. These medications do not affect other proinflammatory mediators, such as prostaglandins and leukotrienes, which remain uninhibited. A number of topical antihistamines are available, including epinastine (Elestat) and azelastine (Optivar). Both are potent antihistamines that have a rapid onset and are effective in relieving the signs and symptoms of allergic conjunctivitis.

Vasoconstrictors

Vasoconstrictors are available either alone or in conjunction with antihistamines to provide short-term relief of vascular injection and redness. Common vasoconstrictors include naphazoline, phenylephrine, oxymetazoline, and tetrahydrozoline. Generally, the common problem with vasoconstrictors is that they may cause dependency with resultant rebound conjunctival injection and inflammation. These pharmacologic agents are ineffective against severe ocular allergies and against other more severe forms of allergic conjunctivitis, such as atopic and vernal disease. They induce chemical tolerance and progressive tachyphylaxis, thereby adding continuously increasing medication and preservative toxicity to the clinical picture.

Mast cell stabilizers

Mast cell stabilizers have a mechanism of action that is unclear. They may aid in the phosphorylation of a 78,000-d protein that terminates secretion of mast cell granules; they may increase calcium influx into the cell preventing membrane changes; and/or they may reduce membrane fluidity prior to mast cell degranulation. The end result is a decrease in degranulation of mast cells, which prevents release of histamine and other chemotactic factors that are present in the preformed and newly formed state.

Note that mast cell stabilizers generally do not relieve existing symptoms and are to be used on a prophylactic basis to prevent mast cell degranulation with subsequent exposure to the allergen. Therefore, they need to be used long term in conjunction with various other classes of medications. Common mast cell stabilizers include cromolyn sodium and lodoxamide (Alomide). Alcaftadine (Lastacaft), bepotastine (Bepreve), olopatadine (Patanol), nedocromil (Alocril), and ketotifen (Zaditor) are also mast cell stabilizers with additional antihistamine properties and proactively inhibit histamine release while blocking subsequent distal pathway histamine receptors.

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) act on the cyclooxygenase metabolic pathway and inhibit production of prostaglandins and thromboxanes. They have no role in blocking mediators formed by the lipoxygenase pathway, such as leukotrienes. Common NSAIDs that are approved for allergic indications include ketorolac tromethamine (Acular).

Corticosteroids

Corticosteroids remain among the most potent pharmacologic agents used in the treatment of chronic ocular allergy. They act at the first step of the arachidonic acid pathway by inhibiting phospholipase, which is responsible for converting membrane phospholipid into arachidonic acid. By preventing the formation of arachidonic acid, corticosteroids effectively block both cyclooxygenase and lipoxygenase pathways, in contrast to NSAIDs, which act only on the cyclooxygenase pathway.

Corticosteroids do have limitations, including ocular adverse effects, such as delayed wound healing, secondary infection, elevated intraocular pressure, and formation of cataract. In addition, the anti-inflammatory and immunosuppressive affects are nonspecific. As a rule, topical steroids should be prescribed only for a short period of time and for severe cases that do not respond to conventional therapy. Severe forms of ocular allergy may require chronic steroid maintenance therapy to avoid permanent structural damage to the ocular surface and central corneal stroma.

Corticosteroids exist in various forms and potencies. Relatively weak steroids, such as rimexolone, medrysone, and fluorometholone, tend to have less potency in the eye, with fewer ocular adverse effects. In contrast, agents such as prednisolone acetate and difluprednate are more potent and have a higher incidence of adverse effects.

Loteprednol etabonate (Lotemax 0.05% and Alrex 0.02%), is an ester steroid, which is rapidly metabolized once it enters the anterior chamber of the eye. Therefore, it is extremely useful in treating ocular surface and superficial corneal inflammations owing to its favorable safety profile and therapeutic index. Alrex has a specific indication for ocular allergy and has been shown in clinical studies to have fewer ocular adverse effects. Lotemax is indicated and FDA approved for SAC and for GPC with concomitant contact lens use.

Immunotherapy

Immunotherapy is a mainstay in the systemic management of allergies. Traditionally, immunotherapy is delivered via subcutaneous injection. However, sublingual (oral) immunotherapy (SLIT) is gaining momentum among allergists. Numerous articles have analyzed the effects of SLIT on allergic conjunctivitis. Preliminary indications are that SLIT may have a moderate effect on the signs and symptoms of allergic conjunctivitis, but further analysis is necessary.[4] A 2012 study confirmed that SLIT may significantly reduce symptoms in children with grass pollen–allergic rhinoconjunctivitis. The preparation studied had significant effects on allergen-specific antibodies and was well tolerated.[5]

Management of Vernal Keratoconjunctivitis

Multiple pharmacologic agents may be used to provide varying degrees of relief. Mucolytic agents, such as acetylcysteine, may help minimize the discharge and provide temporary relief. Vasoconstrictors may reduce hyperemia but are not effective in severe cases on a long-term basis. Moreover, the long-term use of vasoconstrictors may have a rebound effect, leaving the eye untreatably injected. Similarly, topical antihistamines have no significant long-term benefit.

Mast cell stabilizers, with antihistamine effects, are perhaps the mainstay of treatment of VKC and are safe for long-term use. However, topical corticosteroids generally become necessary for most patients with significant symptoms. Because of their potential adverse effects, topical steroids should be prescribed at the lowest effective concentration and for the shortest duration possible.

A pulsed-therapy steroid regimen is generally recommended every 2 hours for the first week followed by a rapid taper; this may be repeated if symptoms recur. Systemic steroids may be used but generally are not necessary for moderate cases of VKC.

Several reports have shown that topical cyclosporine (Restasis), indicated for use in keratoconjunctivitis sicca, may be effective in reducing some of the signs and symptoms of VKC without adverse effects. Oral aspirin has been shown to be effective in relieving some of the inflammation associated with allergy. Treatment of corneal shield ulcers may require antibiotic-steroid ointments, bandage soft contact lens therapy, corneal culture, antibiotic coverage, and amniotic membrane therapy (ProKera, BioTissue, Miami, FL).

A wide variety of steroid-sparing regimens have been used in the treatment of more severe ocular allergies such as AKC and VKC. These include substitution of ester steroids for the traditionally more side-effect–prone ketone steroids, as well as systemic medications including montelukast or methotrexate, or the numerous available oral antihistamines such as loratadine, fexofenadine, and cetirizine.

Surgical treatment

Severe cases of corneal shield ulcer may require superficial keratectomy to promote epithelial regeneration. This debridement also serves to obtain a direct culture specimen in the event that secondary infection ensues and helps guide prophylactic topical antimicrobial therapy. Generally, shield ulcers are chronic conditions that are often refractory to conventional therapy. There have been reports of excimer laser phototherapeutic keratectomy (PTK) being used to remove fibrin deposits on the Bowman layer and theoretically facilitate epithelial healing.

Other surgical procedures, such as cryoablation of giant papillae or surgical removal of papillae with mucosal grafting, generally are not required, but they may be helpful in extremely advanced cases. Remember that since VKC is a self-limited disease, extensive reconstructive surgery may not have an acceptable risk-benefit ratio.

Management of Atopic Keratoconjunctivitis

Treatment of patients with AKC, similar to that for VKC, consists of controlling the environment and avoiding allergens. These patients may require aggressive topical and systemic medications to ultimately provide real symptomatic relief. As with VKC, topical vasoconstrictors and antihistamines may provide very limited, short-term relief, so they are not the mainstay of treatment.

The use of topical mast cell stabilizers and topical corticosteroids provide significant relief of symptoms. Mast cell stabilizers have to be used for several weeks before taking effect; in the interim, topical steroids used in a pulsed fashion may help to control symptoms. Systemic antihistamines that are specific for H1 histamine receptors have been found to be helpful. Systemic steroids are occasionally required, except in cases of vision-threatening complications.

Systemic cyclosporine, which has been shown to be effective in the treatment of atopic dermatitis, has also shown promise in controlling ocular inflammation in AKC. Postulated mechanism of action is inhibition of the ability of T lymphocytes to produce interleukin 2 (IL-2), which is responsible for recruiting and activating new T cells. However, as with any systemic therapy, adverse effects may be significant; therefore, monitoring of therapeutic serum levels and renal function is essential.

Concomitant herpes simplex virus infection should be treated with either topical (ganciclovir [Zirgan], Bausch & Lomb, Rochester, NY) or oral antiviral agents (valacyclovir, acyclovir, famciclovir), as needed. Topical trifluridine (Viroptic) requires 9-times-per-day dosing and contains a thimerosal-based preservative, thereby exposing the already compromised ocular surface to unnecessary toxicity. A subset of patients with recalcitrant and debilitating AKC may benefit from plasmapheresis, as was described by Aswad in 2 patients, one of whom had hyperimmunoglobulinemia E.[6]

Penetrating keratoplasty may be undertaken in cases of severe corneal scarring or thinning. However, great attention to control ocular surface inflammation is required.

Management of Giant Papillary Conjunctivitis

Resolution of symptoms and restoration of functional use of contacts lenses or ocular prosthetics are the main goals of treatment for GPC. Although removal of the responsible foreign body is the definitive treatment, and that may be appropriate for exposed sutures or scleral buckles, complete discontinuation of contact lenses or ocular prosthetics may be met with some degree of resistance from patients. Fortunately, contact lens wear does not need to be completely discontinued to minimize the symptoms of GPC.

Significant reduction in the signs and symptoms may be achieved by changing the contact lens care routine. Disinfecting solutions that contain chemical preservatives should be totally discontinued. Converting from soft daily-wear contact lenses to disposable or daily-disposable soft contact lenses may prevent the accumulation of proteinaceous deposits, which may be the antigenic stimulus for GPC. Advanced-design hybrid contact lenses (SynergEyes) or scleral contact lenses may also provide significant relief with extended comfortable wearing time.

Rigid gas-permeable contact lenses may provide further relief from symptoms if disposable lenses do not provide adequate response. This relief is due to the decreased proclivity of the rigid gas-permeable contact lenses to develop adherent deposits and coatings.

Pharmacologic treatment of GPC includes the use of mast cell stabilizers, topical corticosteroids, and antihistamines, in a manner similar to that in the other immunologic conjunctival disorders discussed previously. As always, care must be taken when using topical corticosteroids; a pulsed regimen is recommended to minimize adverse reactions. Loteprednol is ideally suited when long-term topical steroid therapy is indicated.

Prevention of Allergic Conjunctivitis

Seasonal and perennial allergic conjunctivitis

Avoidance of the offending antigen is the primary behavioral modification; specific testing by an allergist, otolaryngologist, or eye care provider will identify the responsible allergen(s) and help the individual to establish a viable long-term strategy to avoid the allergen. Point-of-service 60-antigen regionally specific noninvasive fully reimbursable skin testing can readily be performed in the ophthalmologist’s office, as well as the optometrist’s office (in some states), with the Doctors Allergy Formula test kit (Bausch & Lomb), facilitating patient access and enhancing convenience. Contact reactions caused by medications or cosmetics are also treated best by avoidance.

Vernal keratoconjunctivitis

As with most type I hypersensitivity disorders, allergen avoidance should be emphasized as the first-line treatment. Although permanent relocation to a cooler climate is not feasible in many cases, it remains a very effective therapy for VKC.

Maintenance of an air-conditioned environment and control of dust particles at home and work may also be beneficial. Local measures, such as cold compresses and periodic instillation of artificial tears, have also been shown to provide temporary relief.

As with all allergic conditions, rubbing should be minimized through counseling, family engagement, cool compresses, chilled eye drops, and frequent handwashing to remove adherent pollen and bioadhesive allergens.

 

Medication

Medication Summary

Allergic conjunctivitis can be treated with a variety of drugs. These include topical antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. As always, care must be taken when using topical corticosteroids; pulsed regimen is recommended to minimize adverse reactions.

Antihistamines, Ophthalmic

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. They block the effects of endogenously released histamine.

Emedastine difumarate (Emadine)

This agent is a relatively selective H1 receptor antagonist for topical administration. The 0.05% ophthalmic solution contains 0.884 mg/mL of emedastine difumarate. 

Epinastine (Elestat)

A direct histamine-1 receptor antagonist, epinastine does not penetrate the blood-brain barrier and therefore should not induce adverse CNS effects. It is indicated for symptoms due to allergic conjunctivitis.

Azelastine ophthalmic

Azelastine, now available as a generic, competes with H1-receptor sites on effector cells and inhibits release of histamine and other mediators involved in the allergic response.

Bepotastine besilate ophthalmic solution (Bepreve)

Bepotastine besilate is a topically active antihistamine that directly antagonizes H1-receptors and inhibits release of histamine from mast cells. It is indicated for itching associated with allergic conjunctivitis.

Alcaftadine ophthalmic (Lastacaft)

An H1-receptor antagonist indicated for prevention of itching associated with allergic conjunctivitis, alcaftadine inhibits histamine release from mast cells, decreases chemotaxis, and inhibits eosinophil activation. It is available as a 0.25% ophthalmic solution.

Cetirizine ophthalmic (Zerviate)

Histamine-1 receptor antagonist; inhibits histamine release from mast cells, decreases chemotaxis, and inhibits eosinophil activation. Indicated for ocular itching associated with allergic conjunctivitis. It is administered twice daily.

Mast Cell Stabilizers

Class Summary

Mast cell stabilizers inhibit the degeneration of sensitized mast cells when exposed to specific antigens by inhibiting the release of mediators from the mast cells. These agents block calcium ions from entering the mast cell. Olopatadine is a relatively selective H1 receptor antagonist and inhibitor of histamine release from mast cells.[7, 8]

Lodoxamide tromethamine (Alomide)

Lodoxamide is a mast cell stabilizer. The active ingredient in this product is 1.78 mg lodoxamide tromethamine.

Olopatadine (Patanol, Pataday, Pazeo)

Olopatadine is a relatively selective H1 receptor antagonist and inhibitor of histamine release from mast cells. The active ingredient of Patanol is 1.11 mg olopatadine hydrochloride; Pataday is 2.22 mg olopatadine hydrochloride.

Ketotifen (Zaditor, Alaway, Thera Tears Allergy, Claritin Eye, Zyrtec Itchy Eye)

Ketotifen is an over-the-counter (OTC) antihistamine eye drop. It is a noncompetitive H1-receptor antagonist and mast cell stabilizer. This agent inhibits release of mediators from cells involved in hypersensitivity reactions.

Nedocromil ophthalmic (Alocril)

Nedocromil interferes with mast cell degranulation, specifically with release of leukotrienes and platelet activating factor.

Corticosteroids

Class Summary

Corticosteroids have both anti-inflammatory (glucocorticoid) and salt retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Loteprednol etabonate (Lotemax, Alrex)

This agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. It is a topical ester steroid eye drop that poses a decreased risk of glaucoma when compared with prednisolone acetate. It is available in 0.2% and 0.5% concentrations, as well as a gel formulation, a preservative-free ointment preparation, and in combination with tobramycin (Zylet, Bausch & Lomb).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Class Summary

The mechanism of action of NSAIDs is believed to be through inhibition of the cyclooxygenase enzyme that is essential in the biosynthesis of prostaglandins, which results in vasoconstriction, decrease in vascular permeability and leukocytosis, and a decrease on intraocular pressure.

Ketorolac tromethamine (Acular, Acuvail)

A member of the pyrrolo-pyrrole group of NSAIDs, ketorolac inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors; in turn, this results in reduced inflammation. The active ingredient is 0.5% ketorolac tromethamine.

Monoclonal Antibodies

Class Summary

Recombinant DNA-derived humanized immunoglobulin G monoclonal antibodies that bind selectively to human immunoglobulin E on the surface of mast cells and basophils may improve symptoms. Therapy reduces mediator release, responsible for promoting an allergic response.

Omalizumab (Xolair)

This biologic is a monoclonal antibody that is highly specific for the IgE receptor, thus blocking binding of high serum levels of IgE in atopic and asthmatic individuals. Also known as Xolair, it is an antibody that helps decrease allergic responses. Xolair is used to treat moderate to severe asthma that is caused by allergies in adults and children who are aged at least 12 years. It is not a rescue medicine for treating an asthma attack. It has been shown to be effective in patients with atopic keratoconjunctivitis.

Decongestants, Ophthalmic

Class Summary

Stimulates alpha-adrenergic receptor in the arterioles of the conjunctiva, thereby decreasing redness in the eye.

Tetrahydrozoline, ophthalmic (Rohto Arctic, Visine Advanced Relief, Visine Maximum Redness Relief)

The alpha-adrenergic effects of tetrahydrozoline in the arterioles of the conjunctiva may produce vasoconstriction.

Ophthalmic Lubricants

Class Summary

Lubricants act as humectants in the eye. The ideal artificial lubricant should be preservative-free; contain potassium, bicarbonate, and other electrolytes; and have a polymeric system to increase its retention time. Lubricating drops are used to reduce morbidity and to prevent complications. Lubricating ointments prevent complications from dry eyes. Ocular inserts reduce symptoms resulting from moderate to severe dry eye syndromes.

Artificial tears (Altalube, Bion Tears, HypoTears, LiquiTears, Soothe, Systane, Tears Again, Viva-Drops)

Artificial tears are used to increase lubrication of the eye. Nonpreserved artificial tears are recommended for use. Tears should be applied liberally throughout the day, and, if necessary, a lubricating ointment may be used at night.

 

Questions & Answers

Overview

What is allergic conjunctivitis?

How is allergic conjunctivitis diagnosed?

Where can more information be found on allergic conjunctivitis?

What are type I hypersensitivity reactions in allergic conjunctivitis?

What are type III hypersensitivity reactions in allergic conjunctivitis?

What are type IV hypersensitivity reactions in allergic conjunctivitis?

What are the subcategories of allergic conjunctivitis?

How are complications of allergic conjunctivitis prevented?

What is the prognosis of allergic conjunctivitis?

What is included in the patient education information for allergic conjunctivitis?

Which antigens may trigger allergic conjunctivitis?

What are the symptoms of seasonal allergic conjunctivitis (SAC)?

What are the symptoms of perennial allergic conjunctivitis (PAC)?

What is the pathogenesis of vernal keratoconjunctivitis (VKC)?

What is the pathogenesis of atopic keratoconjunctivitis (AKC)?

What is the pathogenesis of giant papillary conjunctivitis (GPC)?

What is the prevalence of allergic conjunctivitis?

How does the prevalence of allergic conjunctivitis vary by sex?

What is the prognosis of allergic conjunctivitis?

Presentation

How is allergic conjunctivitis diagnosed?

What are the signs and symptoms of vernal keratoconjunctivitis (VKC)?

What are the signs and symptoms of atopic keratoconjunctivitis (AKC)?

What are the signs and symptoms of giant papillary conjunctivitis (GPC)?

What are the classic physical findings of allergic conjunctivitis?

What are the physical findings characteristic of vernal keratoconjunctivitis (VKC)?

What are the physical findings characteristic of the limbal form of vernal keratoconjunctivitis (VKC)?

Which physical findings of the cornea are characteristic of vernal keratoconjunctivitis (VKC)?

What is vernal pseudogerontoxon in allergic conjunctivitis?

Which physical findings are characteristic of atopic keratoconjunctivitis (AKC)?

Which physical findings are characteristic of giant papillary conjunctivitis (GPC)?

DDX

How is allergic conjunctivitis differentiated from viral and bacterial conjunctivitis?

How are the subtypes of allergic conjunctivitis differentiated?

What are the differential diagnoses for Allergic Conjunctivitis?

Workup

What is the role of conjunctival scrapings in the diagnosis of allergic conjunctivitis?

What does the absence of eosinophils in superficial conjunctival scrapings suggest in the workup of allergic conjunctivitis?

What is the importance of tear level measurement in the diagnosis of allergic conjunctivitis?

How are conjunctival scrapings used to differentiate subtypes of allergic conjunctivitis?

What is the role of advanced point-of-service testing in the diagnosis of allergic conjunctivitis?

Which histologic findings are characteristic of vernal keratoconjunctivitis (VKC)?

Which histologic findings are characteristic of atopic keratoconjunctivitis (AKC)?

Which histologic findings are characteristic of giant papillary conjunctivitis (GPC)?

Treatment

What is the primary behavioral modification used in the treatment of all types of allergic conjunctivitis?

Which medications are used in the treatment of allergic conjunctivitis?

Where can more information be found regarding the treatment approaches for allergic conjunctivitis?

What is the role of medications in the treatment of allergic conjunctivitis?

What is the role of artificial tears in the treatment of allergic conjunctivitis?

What is the role of antihistamines in the treatment of allergic conjunctivitis?

What is the role of vasoconstrictors in the treatment of allergic conjunctivitis?

What is the role of mast cell stabilizers used in the treatment of allergic conjunctivitis?

What is the role of NSAIDs in the treatment of allergic conjunctivitis?

What is the role of corticosteroids in the treatment of allergic conjunctivitis?

What are the possible adverse effects of corticosteroids in the treatment of allergic conjunctivitis?

What are the different forms of corticosteroids used in the treatment of allergic conjunctivitis?

What is the role of loteprednol etabonate in the treatment of allergic conjunctivitis?

What is the role of immunotherapy in the treatment of allergic conjunctivitis?

Which medications are used in the treatment of vernal keratoconjunctivitis (VKC)?

What are the treatment options for vernal keratoconjunctivitis (VKC)?

When is a pulsed-therapy steroid regimen indicated in the treatment of allergic conjunctivitis?

What is the role of topical cyclosporine in the treatment of allergic conjunctivitis?

Which steroid-sparing regimens are used in the treatment of allergic conjunctivitis?

When is surgery indicated in the treatment of allergic conjunctivitis?

What are the treatment options for atopic keratoconjunctivitis (AKC)?

Which medications are used in the treatment of atopic keratoconjunctivitis (AKC)?

What is the role of systemic cyclosporine in the treatment of atopic keratoconjunctivitis (AKC)?

How is herpes simplex virus (HSV) infection managed in patients with atopic keratoconjunctivitis (AKC)?

What is the role of penetrating keratoplasty in the treatment of atopic keratoconjunctivitis (AKC)?

What are treatment goals for giant papillary conjunctivitis (GPC)?

What is the role of contact lens care in the management of giant papillary conjunctivitis (GPC)?

What is the role of rigid gas-permeable lenses in the treatment of giant papillary conjunctivitis (GPC)?

Which medications are used in the treatment of giant papillary conjunctivitis (GPC)?

How is allergic conjunctivitis prevented?

What is the first-line of treatment for allergic conjunctivitis?

Which environmental modifications are used in the prevention of allergic conjunctivitis?

Which precautions should be taken against eye rubbing for the prevention of allergic conjunctivitis?

Medications

Which medications are used in the treatment of allergic conjunctivitis?

Which medications in the drug class Ophthalmic Lubricants are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Decongestants, Ophthalmic are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Corticosteroids are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Mast Cell Stabilizers are used in the treatment of Allergic Conjunctivitis?

Which medications in the drug class Antihistamines, Ophthalmic are used in the treatment of Allergic Conjunctivitis?