Vernal keratoconjunctivitis

INTRODUCTION — There are five main types of ocular allergy: seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC). VKC and AKC are chronic, bilateral, and severe forms of allergic inflammation affecting the ocular surface. These two relatively uncommon types of allergic eye disease can cause severe damage to the ocular surface, leading to corneal scarring and vision loss if not treated properly (this occurs more commonly with AKC than VKC). Type I hypersensitivity reactions are important in these diseases, although they are not the only pathophysiologic mechanism. VKC is reviewed in this topic. AKC is discussed separately. (See "Atopic keratoconjunctivitis".)

GPC is an inflammatory disorder that represents a reaction to lid movement over a foreign substance, such as hard contact lenses. Toxic conjunctivitis is not allergic in nature, but it is frequently confused with allergic ocular disease. It develops with protracted use of topical medications, mostly due to preservatives. GPC and toxic conjunctivitis are discussed in detail separately. (See "Giant papillary conjunctivitis" and "Toxic conjunctivitis".)

Seasonal and perennial allergic conjunctivitis, the most common forms of ocular allergy, are also discussed separately. (See "Allergic conjunctivitis: Clinical manifestations and diagnosis".)

EPIDEMIOLOGY — VKC most commonly occurs in boys living in warm, dry, subtropical climates, such as the Mediterranean, the Middle East, Central and West Africa, South America, and Asian countries, such as Japan, Thailand, and India [1]. The limbal form of VKC is seen most often in dark-skinned individuals from Africa and India. VKC is generally rare in cooler climates, such as Northern Europe and the temperate areas of North America. In the past, prevalence in these regions has been approximately 0.03 percent of the population. As an example, prevalence for Western Europe was 3.2 in 10,000, whereas a higher prevalence ranging from 2.4 to 27.8 in 10,000 was seen in Italy, a country with a Mediterranean climate [2]. However, the prevalence in cooler regions has increased, probably due to immigration of individuals from susceptible populations [3].

Males are more commonly affected than females. In one series, the male-to-female ratio was 3.2:1 in patients <20 years of age but was nearly equal in older patients [4]. Age at onset is generally before 10 years, with the earliest reported onset at five months of age [5], although VKC can infrequently occur in adults. Patients usually "outgrow" the disease with the onset of puberty.

VKC is associated with other atopic manifestations in approximately one-half of patients; however, atopy is not necessarily related to the underlying pathogenesis of this condition [4,6]. The most common concomitant atopic diseases are asthma and allergic rhinitis. Aeroallergen sensitization by skin prick testing or allergen-specific immunoassay was reported in over 50 percent of patients in one study [4]. A family history of atopy was also reported in approximately one-half of patients in two studies [4,7]. In another study, atopy was more common in patients with the palpebral or tarsal form of the disease compared with the limbal form [8]. VKC was associated with a family history of other inflammatory diseases, such as psoriasis and thyroiditis, in one series [7].

PATHOGENESIS — The exact pathogenic mechanisms of VKC are not fully elucidated. Classic immunoglobulin E (IgE) mediated hypersensitivity and T helper cell type 2 (Th2) mediated responses are thought to play a major role [6,9-11], but other mechanisms may be involved, including immunoglobulin G (IgG) mediated responses, basophil hypersensitivity, and cellular delayed-type hypersensitivity.

Evidence supporting an atopic origin for VKC includes the following:

●Seasonal incidence

●Increased number of eosinophils and mast cells in conjunctival specimens

●High levels of IgE in serum and tears

●Increased levels of mediators derived from mast cells and eosinophils, including histamine and tryptase, in tears

●Therapeutic response to mast cell stabilizers

Conjunctival accumulation of Th2 CD4+ cells may give rise to hyperreactivity against substances that commonly contact the conjunctiva. Offending allergens include pollens, dust mites, molds, and animal epithelium [8,12,13]. Nonspecific stimuli, such as wind, sunlight, and heat, also probably play a role [14,15].

Mast cells play a key role in the development of IgE-mediated reactions. In addition, they release inflammatory mediators (eg, histamine, interleukins) [16-18] that stimulate fibroblast activity and production of collagens I and III, resulting in the typical formation of giant papillae in VKC [19]. Furthermore, there is increased expression of histamine receptors (H₁, H₂, and H₄ receptors) in conjunctival tissue [20]. The necessary vascular supply of the forming giant papillae is provided by capillary proliferation. Chronic conjunctival inflammation in VKC is associated with increased staining via immunohistochemistry for mediators that may stimulate vascular proliferation [21].

Histologic analysis of ocular tissue reveals proliferative changes in the epithelium, hyperplasia of connective tissue, and cellular infiltration of the substantia propria [4,19]. The inflammatory infiltrate includes eosinophils, neutrophils, basophils, lymphocytes, plasma cells, mast cells, and fibroblasts. Conjunctival scrapings of VKC patients show a predominance of eosinophils, while basophils, neutrophils, and lymphocytes are rare. Increased numbers of mast cells, eosinophils, and lymphocytes are seen in conjunctival biopsies. Cytologic examination of mucus secretions reveals a predominance of eosinophils [22-24].

CLINICAL MANIFESTATIONS

Symptoms — Almost all patients with VKC note ocular pruritus [1,4].

Other symptoms of VKC include (in approximate order of frequency from high to low, although the frequency of each is highly variable):

●Photophobia

●Thick mucus discharge

●Tearing

●Burning

●Foreign body sensation

●Pain

●Blurred vision

VKC is named as such because severe symptoms most commonly occur in the spring (hence "vernal"), at least in the first few years of the disease. In one series of 195 patients in Italy, over three-quarters of patients had seasonal symptoms that began in March/April and resolved in September [4]. However, over one-fifth had chronic symptoms since disease onset, and an additional 16 percent of patients went on to have chronic symptoms after a seasonal presentation.

Signs — Bilateral eye involvement and presence of giant cobblestone-like papillae on the upper tarsal conjunctiva (conjunctiva lining the upper eyelid) are nearly universal findings in patients with VKC (picture 1) [1,4].

Other signs of VKC include (in approximate order of frequency from high to low, although the frequency of each is highly variable):

●Conjunctival and episcleral hyperemia

●Superficial keratopathy

●Sticky, nonpurulent mucus discharge

●Horner-Trantas dots (picture 2)

●Corneal shield ulcers

●Ptosis

●Blepharospasm

Examination of VKC patients may reveal a predominance of upper tarsal signs (palpebral VKC), limbal signs (limbal VKC), or a combination thereof:

●The tarsal or palpebral form involves the part of the conjunctiva that covers the inside of the eyelid (tarsus). Upper tarsal papillae are discrete, enlarged (>1 mm), and give rise to a classic "cobblestone" appearance with flattened tops (picture 3). Subepithelial fibrosis resulting from papillae hypertrophy can cause increased eyelid thickening and ptosis. Thick, ropy mucus secretions are usually present and associated with tarsal papillae. The skin or lid margins are rarely involved, and the cornea is also typically not involved.

●The limbal form involves the limbus of the eye, the thin border between the cornea and the sclera. Gelatinous, confluent, yellow-gray infiltrates (Horner-Trantas dots) are pathognomonic of the limbal form of the disease (picture 4). Punctate collections of epithelial cells, eosinophils, and calcified corneal concretions may also be observed. Other corneal signs, which may also be sight threatening, include superficial peripheral neovascularization, punctate corneal epitheliopathy, shield ulcers, subepithelial scarring, and plaque formation secondary to accumulation of inflammatory debris. Shield ulcers are usually found in the upper half of the visual axis (picture 5). After resolution, the ulcerated area leaves a ring-like scar.

DIAGNOSIS — There are no established diagnostic criteria for VKC. The diagnosis of VKC is based upon the typical epidemiology and clinical features of VKC (eg, young boys living in warm climates who present with ocular pruritus and giant papillae on the conjunctival lining of the upper eyelid). A clinical grading system was proposed to aid in the diagnosis and management of VKC (table 1) [25,26]. (See 'Epidemiology' above and 'Clinical manifestations' above and 'Signs' above.)

DIFFERENTIAL DIAGNOSIS — The main disease to consider in the differential diagnosis is atopic keratoconjunctivitis (AKC). However, in contrast to VKC, AKC is perennial from the outset, affects predominantly the lower tarsus (eyelid), and commonly presents with vision-threatening corneal scars and neovascularization.

TREATMENT

Overview — Therapy for VKC is long term and requires frequent follow-up. The management approach includes both pharmacologic and nonpharmacologic therapies (algorithm 1) [27].

Topical antihistamines and mast cell stabilizers are first-line pharmacologic therapies. Treatment with topical corticosteroids is best undertaken by an ophthalmologist. Patients who do not respond to these therapies may benefit from an allergy evaluation and possibly allergen immunotherapy. Additional medications that may be effective in some patients include calcineurin inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), and oral antihistamines.

A proposed grading system may aid in choice of treatment (table 1) [26].

Treatment of underlying conditions, such as blepharitis, is also necessary for successful management of VKC. (See "Blepharitis".)

Basic eye care and avoidance of triggers — All patients should be counseled in basic eye care and trigger avoidance (algorithm 1). These include:

●Avoidance of nonspecific triggers, such as wind, heat, salt water, and sunlight whenever possible

●Avoidance of exposure to known aeroallergens in patients with IgE-mediated disease (this can be challenging as patients with VKC can react to multiple aeroallergens)

●Avoidance of eye rubbing as it leads to a mechanical mast-cell degranulation, as well as exacerbation of the allergic process

●Artificial tears, especially in patients who develop tear film insufficiency due to the anticholinergic effect of systemic antihistamines

●Cool compresses

Initial topical therapy — We suggest a topical dual-acting mast cell stabilizer and antihistamine as first-line therapy (algorithm 1). Alternatives are a combination of a separate topical mast cell stabilizer and a topical antihistamine or a mast cell stabilizer alone. These agents should be used on a daily basis throughout the affected season (usually just the spring, but symptoms may extend into other seasons depending upon levels of pollen allergens and may occur nearly year round). If a dual-acting agent is not an option, alternatives are a combination of a separate topical mast cell stabilizer and a topical antihistamine or a mast cell stabilizer alone. However, the dual agents were more effective than mast cell stabilizers alone in studies using a conjunctival allergen challenge model [28-33]. Topical antihistamines alone are minimally effective for VKC and are not used as monotherapy.

Dual-acting agents have two main actions. As mast cell stabilizers, they inhibit mast cell degranulation, which is the first step in the allergic cascade. They also inhibit leukocyte activity and dampen mediator release from mast cells, basophils, eosinophils, and neutrophils. As antihistamines, they competitively and reversibly block histamine receptors in the conjunctiva and eyelids, thereby blocking the actions of the primary mast cell-derived mediator [34]. This also helps reduce the late phase of the allergic response.

Dual-acting agents include olopatadine, azelastine hydrochloride, epinastine, pemirolast potassium, and ketotifen fumarate (this last option is available in a generic formulation and is over the counter in the United States). These drugs have been studied extensively in seasonal and perennial allergic conjunctivitis [35-37]. However, there are only a few nonrandomized studies on use of these drugs, specifically olopatadine and ketotifen, in patients with VKC [33,38]. Common side effects of these medications include stinging upon instillation and headache. (See "Allergic conjunctivitis: Management".)

In one observational study, topical olopatadine hydrochloride 0.1% significantly decreased most signs and symptoms of VKC, including itching, tearing, burning, mucus discharge, conjunctival hyperemia, and corneal involvement after two months of therapy [33]. However, photophobia and limbal papillae did not improve significantly. In another observational study, patients treated with ketotifen had greater improvement in itching, tearing, conjunctival hyperemia, mucus discharge, and photophobia after three weeks of therapy than patients treated with olopatadine [38].

Topical mast cell stabilizers include cromolyn sodium [39], nedocromil sodium [40,41], and lodoxamide [42,43]. Mast cell stabilizers have repeatedly been shown to be effective in patients with VKC [39-43]. A systematic review and meta-analysis of these agents showed that all resulted in significant improvement in signs and symptoms of VKC, with the exception of photophobia [44]. Comparison of the efficacy of the different drugs was not possible due to variability in the study designs. Mast cell stabilizers have no effect on mediators once they are released but are effective in preventing mast cell degranulation. The onset of action of these drugs is 5 to 14 days after initiation of therapy. Thus, these drugs are not useful for acute symptoms. In addition, dosing of mast cell stabilizers is three to four times daily compared with twice daily for most agents with combined actions. These features may limit patient compliance.

Add-on initial therapy for moderate-to-severe disease — There is no widely accepted grading scheme for VKC. In general, the condition is considered severe when it affects vision or leads to symptoms of itch and irritation most of the time. Patients with mild-to-moderate disease have intermittent symptoms (more frequent in the moderate group but not nearly continuous as with severe disease) and no visual deficits. We suggest adding a second- or third-generation oral antihistamine in patients with moderate-to-severe disease. Oral antihistamines, including fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine, have demonstrated efficacy in the treatment of allergic conjunctivitis but have not been well studied in patients with VKC [45]. These agents have a slower onset of action compared with topical agents (one-half to two hours rather than a few minutes). Maximizing the dose of nonsedating antihistamine will often improve efficacy. (See "Allergic conjunctivitis: Management".)

Oral antihistamine use may be associated with drying of mucosal membranes and decreased tear production in some patients, especially those with concomitant dry eye. This side effect can usually be countered with the liberal application of artificial tears. Cetirizine causes sedation in a subset of patients, despite its categorization as nonsedating.

Treatment of refractory disease — For patients with VKC who fail to respond to two to three weeks of a dual-acting antihistamine/mast cell stabilizer (first confirming consistent use), we suggest a short-term, high-dose pulse regimen of topical corticosteroids, with referral to an ophthalmologist for management of this therapy (algorithm 1). If control is not obtained after two to three weeks of topical corticosteroid therapy, we refer to an allergy specialist for possible allergen immunotherapy (VKC is unlikely if testing to aeroallergens is negative, and the patient should be evaluated for other causes of conjunctivitis). For patients with moderate-to-severe disease who require frequent or prolonged courses of topical corticosteroids and have trouble controlling symptoms when topical corticosteroids are reduced, we suggest using topical cyclosporine 0.1% one drop each eye four times daily (can be increased to 2% one drop each eye two times daily in severe or unresponsive cases) as a corticosteroid-sparing agent. An alternative is topical tacrolimus. A topical calcineurin inhibitor such as cyclosporine is used rather than topical corticosteroids if the corneal epithelium is compromised, particularly in the presence of shield ulcers (see 'Treatment of corneal shield ulcers' below). Several classes of medications may need to be used concurrently. Starting one does not mean others have to be terminated. In general, we recommend starting, stopping, and tapering medication based upon the patient's symptoms. Most patients have adequate control with these measures over time, but a small percentage require systemic immunosuppressive therapy (eg, cyclosporine). Systemic glucocorticoids are not used for VKC.

Topical corticosteroids — A short-term, high-dose pulse regimen of topical corticosteroids is often necessary in patients with VKC who fail to respond to two to three weeks of a dual-acting antihistamine/mast cell stabilizer, particularly those with significant seasonal exacerbations. Close follow-up with an ophthalmologist is required due to vision-threatening side effects of topical corticosteroids, such as glaucoma, cataracts, and secondary infections. Patients should know that blindness is a risk of unsupervised topical corticosteroid therapy. Topical corticosteroids are not used if the corneal epithelium is compromised. (See 'Treatment of corneal shield ulcers' below.)

In severe cases of VKC, prednisolone acetate 1% eight times daily for one week leads to significant symptom relief and thereafter should be tapered rapidly once control is gained [46]. In less severe cases, pulse therapy with topical "soft" steroids on a two to four times per day basis for approximately two weeks is effective in gaining control of the allergic response so that mast cell stabilizers, antihistamines, and artificial tears have a greater chance to work [40,47]. Use of topical "soft" corticosteroids for greater than six weeks is associated with a significantly increased risk of complications.

Prednisolone acetate 1% and dexamethasone 0.1% have the greatest efficacy/potency but also the greatest risk of raising intraocular pressure (IOP) among all topical corticosteroids. By comparison, "soft" steroids are a group of topical corticosteroids that have a greatly reduced risk of causing increased IOP because they bind with high affinity to the glucocorticoid receptor and the unbound drug undergoes rapid inactivation upon penetration of the cornea. Topical "soft" corticosteroids include prednisolone acetate 0.12%, fluorometholone, medrysone, loteprednol etabonate 0.5 or 0.2%, and rimexolone 1%.

Observational studies and one randomized trial have shown that topical corticosteroids are effective in treating VKC [4,40,47]. In the small, randomized trial, a two-week course of fluorometholone 0.1% was more effective than nedocromil 2% in decreasing signs and symptoms of VKC, including papillary hypertrophy, Horner-Trantas dots, mucus discharge, conjunctival hyperemia, and tearing [40].

Corticosteroids suppress the late-phase reaction in both experimental and clinical settings. These drugs, in part, limit the inflammatory cascade by inhibiting phospholipase A2. Consequently, they reduce the formation of lipid-derived mediators from arachidonic acid, which prevents leukocyte migration, hydrolytic enzyme release, fibroblast growth, and changes in vascular permeability.

Allergen immunotherapy — Patients should be referred to an allergy specialist for consideration of allergen immunotherapy if control is not obtained with topical corticosteroids after two to three weeks of therapy [48]. The indications for and efficacy of allergen immunotherapy are reviewed in greater detail separately. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)

Calcineurin inhibitors — The calcineurin inhibitors that are most commonly used in ocular allergy include topical cyclosporine and tacrolimus and systemic cyclosporine. An important advantage of the topical calcineurin inhibitors is that they do not cause the same side effects typically seen with topical corticosteroids, such as an increase in IOP. Thus, long-term use of these agents is considered safe when used topically, unlike chronic use of topical corticosteroids, and only minimal amounts can be traced systemically. However, topical cyclosporine and tacrolimus are generally not chosen over topical corticosteroids for acute exacerbations, because of their much slower onset of action (weeks to a couple of months rather than hours to days). Systemic cyclosporine is reserved for corticosteroid-dependent patients who do not respond to other therapies.

Cyclosporine diminishes the effect of interleukin (IL) 2 on T cells and leads to decreased expansion of T helper cells. It may also inhibit mast cell proliferation and survival. Cyclosporine reduces collagen production and induces apoptosis of conjunctival fibroblasts from VKC patients. Tacrolimus has similar mechanisms of action [49,50]. Efficacy of topical cyclosporine and topical tacrolimus was similar (symptom and sign score -2.06 and -2.39, respectively) in a meta-analysis of VKC therapies [51].

Topical cyclosporine — Topical cyclosporine 2% emulsion improved signs and symptoms of VKC in several small, randomized trials [52,53] and observational studies [54-57]. Both randomized trials demonstrated a significant improvement in symptoms (eg, itching, tearing, mucus discharge) and signs (papillary hypertrophy, conjunctival hyperemia, Horner-Trantas dots) compared with placebo [52,53]. However, 4 of 24 patients in one of the trials required a brief course of topical corticosteroids during the four-month study period [53]. In one study, topical cyclosporine 0.1% was less effective than topical dexamethasone 0.15% for acute flare ups, with less improvement in symptoms and signs and a greater number of patients requiring rescue therapy with topical dexamethasone [58]. In two subsequent randomized trials, topical cyclosporine emulsion 0.1% four times daily was more effective than cyclosporine emulsion 0.1% twice daily, cyclosporine emulsion 0.05% four times daily, and placebo for both corneal fluorescein staining and itching [59,60].

Topical tacrolimus — Efficacy of topical tacrolimus in patients with VKC was demonstrated in small, observational studies [49,50] and randomized trials [61-66]. While topical tacrolimus and topical cyclosporine have similar efficacy, topical tacrolimus is more likely to cause a burning sensation, which impacts adherence and limits use [51]. Several randomized trials demonstrated a significant improvement in symptoms and signs with tacrolimus treatment. In two randomized trials comparing cyclosporine with 0.1% tacrolimus, patients achieved similar statistically significant improvement in both signs and symptoms [61,62]. In another trial, tacrolimus 0.03% resulted in similar improvement in signs and symptoms as compared with tacrolimus with 1% olopatadine [63]. In yet another trial comparing 0.03% tacrolimus with 0.05% cyclosporine, patients in both groups demonstrated equal efficacy to both drugs [64]. However, tacrolimus 0.03% was more effective than sodium cromoglycate 4% in one trial [65]. In a subsequent trial, a lower concentration of 0.005% tacrolimus was as effective as interferon alpha-2b in improving both signs and symptoms [66]. Topical tacrolimus 0.1% was also shown to be effective in a double-blind crossover trial of 30 patients with severe VKC who failed to respond to topical cyclosporine [61].

Systemic cyclosporine — In the authors' clinical experience, systemic cyclosporine can be helpful in controlling severe, corticosteroid-dependent cases of allergic ocular disease that have not responded to other therapy, thereby reducing the need for long-term corticosteroid use. However, no randomized trial has been performed evaluating the utility of systemic cyclosporine in the treatment of ocular allergy [67]. Systemic cyclosporine is generally limited to patients with severe atopic keratoconjunctivitis (AKC) who do not respond adequately to topical therapy; it would be extremely rare to use this therapeutic approach in VKC. If administered, oral dosing is 2.5 to 5 mg/kg per day during the affected season. The patient must be closely monitored for any adverse effects including kidney dysfunction, bone marrow suppression, hypertension, tremor, hirsutism, and gingival hyperplasia. Systemic cyclosporine is rarely, if ever, needed in VKC.

Treatment for subsequent seasons — In patients with known disease, a dual-acting agent should be started approximately a month before the usual onset of their seasonal symptoms and continued for the duration of the season. Dual-acting agents have a quick onset of action, but the start of the season can vary from year to year, and allergic responses, once activated, can last up to two months. Thus, it is better to start treatment a bit early to ensure that the mast cells are stabilized before the onset of the season. While mast cell stabilizers have a slower onset of action than dual-acting agents, starting one of these drugs a month before the usual onset of symptoms is usually sufficient. Topical cyclosporine, while effective, is typically not used as initial therapy for subsequent seasons, because it would need to be started even further in advance of the season due to its very slow onset of action [58,68]. The approach for patients who fail to respond to initial therapy in subsequent seasons is similar to that outlined above. Patients who are asymptomatic on just a dual-acting agent or mast cell stabilizer for a season can do a trial without therapy the following season to determine if the disease has resolved. (See 'Add-on initial therapy for moderate-to-severe disease' above and 'Treatment of refractory disease' above and 'Prognosis' below.)

Treatment of corneal shield ulcers — Corneal shield ulcers are a vision-threatening complication of VKC. Topical cyclosporine is used rather than topical corticosteroids if the corneal epithelium is compromised, particularly in the presence of shield ulcers, because topical corticosteroids have been shown to interfere with re-epithelialization. Additional therapy for sterile corneal ulcers includes debridement of inflammatory debris and the use of wide-spectrum antibiotics, such as moxifloxacin or gatifloxacin four times per day [69-72]. Patching, bandage contact lenses, and temporary tarsorrhaphy (upper and lower eyelids are partially sewn together) may be required to help the epithelial defects heal. Infectious ulcers should be referred promptly to the appropriate specialist due to the high likelihood of vision loss and the complexity of treatment.

Additional agents — Nonsteroidal antiinflammatory drugs (NSAIDs) have been studied in the treatment of VKC but are used rarely due to the availability of agents with greater efficacy. NSAIDs block the action of cyclooxygenase and thus inhibit the conversion of arachidonic acid to prostaglandins and thromboxanes. Topical NSAID preparations include ketorolac [73,74], bromfenac [75], diclofenac [76], flurbiprofen [77], and indomethacin [78]. Ketorolac was shown to be more effective in treating symptoms of VKC than placebo in one small, randomized trial [73] and had greater efficacy in treating symptoms, but not signs of VKC, than cyclosporine 0.5% by day 7 in another randomized trial [74]. Flurbiprofen demonstrated lower efficacy compared with topical betamethasone [77]. Indomethacin treatment showed mixed results for VKC [78].

Omalizumab, an anti-IgE monoclonal antibody, was shown to resolve ocular signs and symptoms of VKC in a series of four children despite negative blood and skin testing for environmental allergies [79]. Dosing was based upon weight and total IgE level using the same dosing schedule used for patients with asthma. Improvement was noted within the first few weeks of treatment, and none of the patients relapsed after treatment was discontinued after six months of therapy. These results are consistent with other case reports [80-83]. The exact mechanism that leads to clinical improvement in these patients is unclear, and further study is needed. (See "Anti-IgE therapy", section on 'Administration'.)

PROGNOSIS — Overall, most patients do well with treatment and only require seasonal therapy. Patients typically outgrow VKC, but it can take a number of years. Vision loss in VKC is rare but can occur due to corneal scarring, neovascularization, and amblyopia. A more severe baseline grade, a younger age of onset, and a higher rate of recurrences of ocular inflammation were all associated with a worse visual outcome in a series of 110 patients, suggesting that more aggressive treatment may be appropriate in these higher-risk patients [26].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergic eye disease".)

SUMMARY AND RECOMMENDATIONS

●Vernal keratoconjunctivitis (VKC) is a seasonally recurring, bilateral, and severe form of allergic inflammation affecting the ocular surface. This relatively uncommon type of allergic eye disease can cause severe damage to the ocular surface, leading to corneal scarring and vision loss if not treated properly. (See 'Introduction' above.)

●VKC most commonly occurs in boys living in warm, dry, subtropical climates. (See 'Epidemiology' above.)

●The most common manifestations of VKC are ocular pruritus and giant cobblestone-like papillae on the upper tarsal conjunctiva (picture 3). (See 'Clinical manifestations' above and 'Signs' above.)

●The diagnosis of VKC is based upon the typical epidemiology and clinical features of VKC (eg, young boys living in warm climates who present with ocular pruritus and giant papillae on the conjunctival lining of the upper eyelid). (See 'Diagnosis' above.)

●The management approach includes both nonpharmacologic measures (ie, basic eye care and trigger avoidance) and pharmacologic therapies (algorithm 1). (See 'Treatment' above.)

●We suggest a topical dual-acting mast cell stabilizer and antihistamine as first-line therapy (Grade 2C). Alternatives are a combination of a separate topical mast cell stabilizer and a topical antihistamine or a mast cell stabilizer alone. We suggest adding a second- or third-generation oral antihistamine in patients with moderate-to-severe disease (Grade 2C). (See 'Initial topical therapy' above and 'Add-on initial therapy for moderate-to-severe disease' above.)

●We suggest a short-term, high-dose pulse regimen of topical corticosteroids in patients with VKC who fail to respond to two to three weeks of a dual-acting antihistamine/mast cell stabilizer (Grade 2C). Close follow-up with an ophthalmologist is required due to vision-threatening side effects of topical corticosteroids, such as glaucoma, cataracts, and secondary infections. (See 'Topical corticosteroids' above.)

●We suggest using topical cyclosporine 0.1% one drop each eye four times daily as a corticosteroid-sparing agent in patients with moderate-to-severe disease who require frequent or prolonged courses of topical corticosteroids (Grade 2C). The dose may be increased to 2% one drop each eye two times daily in severe or unresponsive cases. Topical tacrolimus is an alternative to topic cyclosporine but is more likely to cause a burning sensation, which can impact adherence to treatment. (See 'Calcineurin inhibitors' above.)

●Corneal shield ulcers are a vision-threatening complication of VKC. Topical cyclosporine is used rather than topical corticosteroids if the corneal epithelium is compromised, particularly in the presence of shield ulcers. Additional therapy is also required. (See 'Treatment of corneal shield ulcers' above.)

●Vision loss in VKC is uncommon but can occur due to corneal scarring, neovascularization, and amblyopia. (See 'Prognosis' above.)