Vernal keratoconjunctivitis

Vernal conjunctivitis also called vernal keratoconjunctivitis is a severe type of seasonal allergic conjunctivitis that results in small, raised lumps on the inside of the upper eyelid called Horner Tranta dots and a stringy (ropey), mucus discharge (Figures 3, 4 and 5) ¹, ², ³. Large bumps or papillae on the conjunctiva are a classic sign of vernal conjunctivitis. Histopathology shows eosinophils in the conjunctival secretions. Vernal conjunctivitis is frequently associated with allergic rhinitis, atopic dermatitis, or asthma. Vernal conjunctivitis may be associated with a single allergen but more usually with multiple sensitivities. Vernal conjunctivitis is often seen in areas of the world where the weather is hot and dry than in cold climates, most commonly in Asia, Central and West Africa and South America ⁴, ⁵, ⁶, ⁷, ⁸, ³. Vernal conjunctivitis is also seen commonly in the Middle East, Japan, India, the Mediterranean area, North America, and Australia ⁹, ¹⁰. At least one study showed prevalence ranges from 4.0 to 11.1% prevalence of vernal keratoconjunctivitis in African countries schoolchildren ⁶, ¹¹. Vernal conjunctivitis is thought to be relatively unusual in North America and Western Europe ¹², ⁹. One European study demonstrated the prevalence of vernal conjunctivitis was between 1.2 to 10.6 per 10,000 and 0.8/10,000 with corneal complications has been reported ⁷. The increased incidence in hot regions is speculated to be secondary to a higher level of pollution by pollens and various other allergens ³.

Vernal conjunctivitis is a T-helper-2 (Th2) lymphocyte-driven disease characterized by infiltration of the conjunctiva by a number of inflammatory cell types, including eosinophils, mast cells, and T lymphocytes ¹³, ¹⁴. This differs from atopic keratoconjunctivitis, which has been shown to involve both Th1 and Th2 inflammatory cascades ¹⁵. Increased levels of tumor necrosis factor (TNF) alpha, histamine, tryptase, IgE, and IgG antibodies are observed on pathologic examination of tears ¹⁶. It is believed that the exaggerated immunoglobulin E (IgE) response observed with vernal conjunctivitis in response to common allergens may be a secondary event ¹⁴. Mast cells and basophils cause the immediate reaction through the release of histamine and the recruitment of inflammatory cells lymphocytes and eosinophils ¹. This results in the release of a number of pro-inflammatory cytokines, including but not limited to interleukin (IL)-4, IL-5, and IL-13, as well as other toxic cell mediators such as eosinophil cationic protein, eosinophil-derived neurotoxin/eosinophil protein X (EDN/EPX) that result in corneal damage ¹⁴, ¹⁷. Release of these factors mediates the remodeling, eye inflammation, and itch that are commonly associated with vernal conjunctivitis.

Diagnosis and treatment of vernal conjunctivitis is a challenge for many ophthalmologists, since no precise diagnostic criteria have been established, the pathogenesis of the disease is unclear, and anti-allergic treatments are often ineffective in patients with moderate or severe disease ¹.

Vernal conjunctivitis usually affects both eyes and is severe, occurring seasonally and mainly in children and more common in young boys than girls, but this difference becomes smaller as age increases ¹⁸. Often, patients with vernal conjunctivitis also have asthma or eczema. The majority of vernal conjunctivitis occurs in patients between the ages of 5 to 25 years of age with an age of onset between 10 to 12 years old; however there are reports of patients as young as 5-months-old ¹⁰, ¹⁹. Symptoms typically occur throughout the year, but are worse in spring (vernal means springtime in Latin) and summer time. 23% of patients may have a perennial (all year round) form of them disease and many may have recurrences outside of the springtime ¹⁰, ¹⁸. Symptoms can be so bad that children need to be treated with topical (eye drops) or systemic (oral tablets) steroids in addition to allergy eye drops such as topical cromolyn or antihistamine preparations. However, vernal conjunctivitis is more difficult to treat than other types of allergic conjunctivitis, and may need special immune based medications such as cyclosporine drops to control the eye inflammation and prevent other eye problems. Sleeping in an air-conditioned room, ice packs and cold compresses can help with symptom relief. Furthermore, without adequate treatment, the seasonal vernal conjunctivitis can evolve into a chronic perennial vernal conjunctivitis after a mean of 3 years from disease onset ¹⁴.

Most vernal conjunctivitis patients eventually do grow out of vernal conjunctivitis usually lasts between five to ten years and usually resolves after puberty or adolescence and is rarely seen after the age of thirty. In contrast, children diagnosed with atopic keratoconjunctivitis will suffer from signs and symptoms throughout their life, and may develop more severe complications, as the atopic keratoconjunctivitis is progressive ²⁰.

Figure 1. Human eye

Figure 2. Eye anatomy

Figure 3. Vernal conjunctivitis

Figure 4.  Vernal keratoconjunctivitis

Footnote: Large cobblestone papillae. Upper tarsal giant papillae are typical of vernal conjunctivitis. These have characteristically flattened tops which sometimes demonstrate stain with fluorescein. Giant papillae can sometimes be seen near the limbus and, while relatively uncommon, symblepharon formation (an eye condition that causes the conjunctiva of the eye to stick to itself or the cornea) and conjunctival fibrosis (scar) can occur.

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Figure 5. Horner–Trantas dots

Footnote: Peri-limbal Horner–Trantas dots are focal white dots consisting of degenerated epithelial cells and eosinophils and are indicative of vernal keratoconjunctivitis.

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Figure 6. Vernal conjunctivitis treatment options

Footnotes: Treating vernal keratoconjunctivitis should entail a stepwise approach, identifying triggers, educating patients/caregivers on good ocular health, and addressing symptoms. In a new paradigm of management, the use of immunomodulators (e.g., topical cyclosporine A) should be considered early to tackle the inflammatory and chronic nature of vernal keratoconjunctivitis, with topical corticosteroids reserved as an add-on, short-pulse therapy for persistent disease, during acute exacerbations, or in patients with corneal involvement. Any use of corticosteroids requires tapering once symptoms have been controlled to avoid adverse events. For patients with an identified allergy, referral to an allergist is recommended for additional systemic treatment. In the rare patients who do not respond to medical treatment, surgery may be required.

*In the case of associated rhinitis, consider treatment according to Allergic Rhinitis and its Impact on Asthma (ARIA) protocol;

†No improvement is defined as no improvement in symptoms or changes in conjunctival, papillary or ocular surface clinical signs.

Abbreviations: CE = cationic emulsion; CsA = cyclosporine A; IgE = immunoglobulin E.

[Source ¹. Adapted from Leonardi et al. ²¹]

Vernal conjunctivitis causes

Vernal conjunctivitis is a severe type of seasonal allergic conjunctivitis that results in small, raised lumps on the inside of the upper eyelid called Horner Tranta dots and a stringy, mucus discharge ²², ²³. A personal or family history of atopy is seen in a large proportion of vernal conjunctivitis patients ²⁴. Atopy is a genetic tendency to develop allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis (eczema). Vernal conjunctivitis was originally thought to be due to a solely immunoglobulin E (IgE) mediate reaction via mast cell release and cell-mediated immune mechanisms ²⁵. It has now been shown that IgE is not enough to cause the varied inflammatory response that is seen with vernal conjunctivitis ¹². Activated eosinophils have also been implicated to play a significant role in the pathophysiology of vernal conjunctivitis and these can be shown consistently in conjunctival scrapings of vernal conjunctivitis patients; however mononuclear cells and neutrophils are also seen ²⁵, ¹². Additionally, the role of type 4 hypersensitivity mediated by CD4 T-helper-2 (Th2) lymphocytes with immunomodulators such as IL-4, IL-5, and bFGF has also been highlighted through a few studies ¹³, ¹⁴, ¹⁰, ¹². This differs from atopic keratoconjunctivitis, which has been shown to involve both Th1 and Th2 inflammatory cascades ¹⁵. Immunomodulators like interleukins 4 (IL-4), IL-5, IL-13, and fibroblast growth factors have also been implicated. Increased levels of tumor necrosis factor (TNF) alpha, histamine, tryptase, IgE, and IgG antibodies are observed on pathologic examination of tears ¹⁶. There is also reported over-expression of cytokines and chemokines in the conjunctiva of these patients ²⁶. Thought has been given to a possible endocrine predisposing factor as well as there is a decrease in symptoms and prevalence after puberty ²⁵, ¹⁰.

Apart from personal allergy history, other predisposing factors include male gender, close contact with animals, and increased exposure to dust and sunlight ²⁷.

A hereditary association or genetic link has been suggested, but no direct genetic associations have been made. Vernal conjunctivitis is seen more often in patients who have family history of atopy and might be positive in close to 49% of these cases. But no clear correlation with specific genetic loci has been identified ¹⁰.

Vernal conjunctivitis types

Vernal conjunctivitis or vernal keratoconjunctivitis is a subtype of allergic conjunctivitis ²². The episodes are often periodic and have seasonal recurrences. Seasonal exacerbations characterize vernal keratoconjunctivitis in the initial stages with a peak incidence during spring and summer. Over time, vernal conjunctivitis tends to become perennial (all year round).

Additional types of vernal conjunctivitis include perennial and seasonal rhinoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis ².

Vernal conjunctivitis is classified into three clinical subtypes based on the location of the papillae into palpebral (tarsal), limbal (bulbar), and mixed forms ¹³, ²⁸, ¹:

• Palpebral vernal conjunctivitis (tarsal vernal conjunctivitis). Palpebral vernal conjunctivitis is characterized by large, cobblestone-like papillae on the upper tarsal conjunctiva. These can differ in shape and size, but are usually defined as >1.0 mm in diameter ²⁹, ¹³. There is a close association between the inflamed conjunctiva and the corneal epithelium, often leading to significant corneal disease.
• Limbal vernal conjunctivitis (bulbar vernal conjunctivitis). Limbal vernal conjunctivitis typically involves Horner–Trantas dots indicating lymphocytic and eosinophilic infiltration of the limbal conjunctiva ²⁹, ¹³. Limbal vernal conjunctivitis typically affects the Black and Asian populations.
• Mixed vernal conjunctivitis. Mixed vernal conjunctivitis has features of both the palpebral (tarsal) and limbal (bulbar) subtypes in only one eye (as signs are often heterogeneous between eyes) ²⁹.

According to the Management of Vernal Keratoconjunctivitis in Asia (MOVIA) Expert Working Group, the most common form of vernal conjunctivitis seen in clinics across Asia is the tarsal form; however, up to one-third of patients are assumed to have the mixed form ¹. The limbal form of vernal conjunctivitis is considered less common in Asia (based on clinical experience) ¹.

Figure 7. Palpebral vernal conjunctivitis

Footnote: Palpebral vernal conjunctivitis also called tarsal vernal conjunctivitis is characterized by large, cobblestone-like papillae on the upper tarsal conjunctiva.

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Figure 8. Limbal vernal conjunctivitis

Footnote: Limbal vernal conjunctivitis typically involves Horner–Trantas dots, indicating lymphocytic and eosinophilic infiltration of the limbal (bulbar) conjunctiva. The mixed form is characterized by the presence of both tarsal and limbal subtypes in only one eye.

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Figure 9. Shield ulcer

Footnote: Shield ulcer formation. Shield ulcers usually form on the upper third of the cornea. Plaques can also form when inflammatory debris accumulates at the base of a shield ulcer.

[Source ¹ ]

Vernal conjunctivitis signs and symptoms

The most common eye symptoms of vernal conjunctivitis are initially severe itching, redness, and tearing. Other common symptoms include blurred vision, photophobia, foreign body sensation, burning, blinking or eye twitching (blepharospasm) and a characteristic ropey, stringy mucus, and/or serous discharge ²⁹, ³⁰, ²⁵, ¹⁰. Other typical signs and symptoms include moderate-to-intense conjunctival hyperemia, mild-to-moderate chemosis, foreign-body sensation, and pain, all of which can be very intense upon awakening, causing what is called “the morning misery” ²⁹. Vernal conjunctivitis typically affect both eyes but may also affect one eye only.

Clinical signs of vernal conjunctivitis include a papillary reaction of the upper tarsal conjunctiva and throughout the limbus. The signs of vernal conjunctivitis can be divided into conjunctival, limbal and corneal signs ³. Moreover, the clinical examination findings also vary dependent on the geographical location ³¹.

• Conjunctival signs include diffuse conjunctival injection and upper tarsal giant papillae. These are discrete >1mm in diameter that characteristically have flattened tops which sometimes demonstrate stain with fluorescein ²⁵, ³². Additionally, these giant papillae can sometimes be seen near the limbus and, while relatively uncommon, symblepharon formation (an eye condition that causes the conjunctiva of the eye to stick to itself or the cornea) and conjunctival fibrosis can occur ³³.
  • Palpebral disease: In the early stages, there is conjunctival hyperemia and velvety papillary hypertrophy of the superior tarsal plate. In the intense disease, flat polygonal macropapillae, which are <1mm in size, are seen along with the whitish inflammatory disease. With further disease progression, these can form giant papillae that are>1mm in size and result from rupture of the dividing septa. Mucoid deposits can occur between giant papillae. The milder form of the pathology is characterized by minimal conjunctival congestion and decreased mucus production ³⁴.
  • Bulbar disease: The bulbar disease is also called limbal disease and is particularly more common and severe in tropical regions. This is characterized by congestion of the bulbar conjunctiva in the interpalpebral area. Gelatinous thickened papillae can form around the limbus and are associated with apically located whitish cellular collections known as Horner Tranta Spots ³⁵.
• Limbal signs include thickening and opacification of the limbal conjunctiva as well as gelatinous appearing and sometime confluent limbal papillae. Peri-limbal Horner-Trantas dots are focal white limbal dots consisting of degenerated epithelial cells and eosinophils ²⁵. Limbal disease can result in a limbal stem cell deficiency which can lead to pannus formation with corneal neovascularization ³³.
• Corneal signs vary according to the severity of the disease process ²⁵. Punctate epithelial erosions or keratitis can coalesce into macro-erosions of the epithelium ¹².
  • Plaques containing fibrin and mucous can accumulate into macro-erosions forming Shield ulcers (see Figure 9). Corneal neovascularization can ensue and resolution can leave a characteristic ring-like scar ³², ⁹.
  • A waxing and waning gray-white lipid depositing in the peripheral, superficial stroma can occur and is known as pseudogerontoxon ²⁵. Pseudogerontoxon is characterized by a paralimbal band of superficial scarring adjacent to the inflamed limbus resulting from recurrent limbal disease. It usually mimics arcus senalis.
  • Vernal keratoconjunctivitis is also associated with corneal ectasias, particularly keratoconus, which results from persistent eye rubbing and occasionally superficial vascularization. Keratoconus has been shown to be more prominent in vernal conjunctivitis patients as well; possibly due to increased eye rubbing of chronically irritated patients ³⁶.
  • Associated bilateral herpes simplex keratitis has also been reported ³⁷
• Lid signs. Blepharitis is often associated with patients with vernal keratoconjunctivitis. Some cases might be seen with eczema or maceration of the lid. Subconjunctival fibrosis and symblepharon can rarely develop due to the inflammatory complications ³⁸.

Severe vernal conjunctivitis can result in sight-threatening complications ¹. Eye surface damage as a result of repetitive eyelid trauma and vernal conjunctivitis-associated inflammatory activity can lead to corneal complications such as superficial punctate keratopathy, shield ulcers, corneal scarring, keratoconus, dry eyes, limbal stem-cell deficiency, and secondary infections ²⁹, ⁴, ³⁹, ⁴⁰. Shield ulcers, which can be self-limiting or associated with bacterial keratitis, usually form on the upper third of the cornea, and can lead to loss of vision (see Figure 9) ¹³. Plaques can also form when inflammatory debris accumulates at the base of a shield ulcer ³⁹ and can be particularly resistant to topical therapy or require surgical intervention ¹³. Limbal stem-cell deficiency can occur with longstanding inflammation ¹³. Keratoconus and irregular astigmatism can result from frequent eye rubbing in the pediatric population ⁴¹, ⁴², ⁴³. In these patients, there is a fine balance between the benefits of corticosteroids and the risk for vision loss as a result of overtreatment. Patients with severe vernal conjunctivitis may also develop lid complications and acquire ptosis often with atopic dermatitis ¹. The variable severity of these complications in each patient presents a challenge to ophthalmologists to not only manage acute episodes, but also to prevent reappearances.

Vernal conjunctivitis complications

The ocular complications reported among vernal keratoconjunctivitis patients include steroid-induced cataract, steroid-induced glaucoma, irregular astigmatism, keratoconus, acute hydrops, shield ulcer, central corneal scars, and limbal tissue hyperplasia ².

Vernal conjunctivitis differential diagnosis

The close differentials of vernal keratoconjunctivitis include all types of allergic conjunctivitis, including seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis ². Most of these are IgE mediated responses except giant papillary conjunctivitis. None have gender predilection, except atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis, which are more prevalent among males. History and physical examination often help in distinguishing between these clinical entities.

Atopic keratoconjunctivitis (AKC) typically has an older age of onset in 20-50 years of age, as opposed to onset prior to age 10 years with vernal conjunctivitis ². Conjunctival involvement is classically on the upper tarsus in vernal conjunctivitis and on the lower tarsus in atopic keratoconjunctivitis. Additionally, atopic keratoconjunctivitis is typically more chronic in nature and more commonly results in scarring of the cornea and conjunctival cicatrization, whereas vernal conjunctivitis is typically more self-limiting and do not result in severe vision-threatening complications ⁴⁴, ³². Atopic keratoconjunctivitis (AKC) is more commonly associated with asthma, rhinitis, dermatitis. Vernal keratoconjunctivitis is associated with increased goblet cells compared to decrease goblet cells in atopic keratoconjunctivitis.

Vernal conjunctivitis treatment

Management should follow a stepwise approach with active patient education ¹:

1. Address triggers and aggravating factors (e.g., environment and allergens).
2. Maintain eye health, including frequent hand, face, and hair washing.
3. Use of eye lubricants and cold compresses should always be considered.
4. For the use of any eye drops on the eye surface, it is recommended to use preservative-free compounds, where possible, to minimize eye surface toxicity.

• Conventional topical anti-allergic drugs
  • Dual-acting agents, antihistamines, and mast cell stabilizers are all effective for reducing signs and symptoms of mild or moderate vernal conjunctivitis.
  • Dual-acting agents should be considered ahead of monotherapy with antihistamines or mast cell stabilizers.
• Cyclosporine A 0.1% cationic emulsion
  • Topical cyclosporine A 0.1% cationic emulsion should be considered for patients with in moderate-to-severe or persistent vernal conjunctivitis.
  • Patients should be instructed on how to apply cyclosporine A eye drops to minimize stinging or burning on instillation, such as using artificial tears prior to instillation.
• Topical corticosteroid eye drops
  • In patients with only conjunctival involvement, topical corticosteroids should be reserved for use after loss of control or persistence of symptoms with immunomodulators such as cyclosporine A.
  • Topical corticosteroids are effective for the management of acute exacerbations, or when the cornea is involved, and preferably only introduced in patients with more severe disease. In these individuals, corticosteroids should be used in combination with cyclosporine A to account for the fact that cyclosporine A may require ≥1 week to act.
  • Because of an increased risk of adverse events/or vision loss with chronic use, topical corticosteroid eye drops should be used in short pulses alone or in combination with cyclosporine A under the supervision of an ophthalmologist and tapered rapidly.
• Tacrolimus
  • In regions where available, tacrolimus should be reserved for patients with severe vernal conjunctivitis that is refractory to cyclosporine A.
  • Tacrolimus can be considered as a treatment for moderate-to-severe vernal conjunctivitis in patients with allergy of the eyelid, but note this may be off-label.
• Vasoconstrictors
  • Vasoconstrictors are not recommended for the treatment of vernal conjunctivitis. Topical vasoconstrictors can be effective at alleviating hyperemia but offer little to no relief from itchiness and have a short duration of action. If used to address hyperemia, vasoconstrictors should be used with caution and only for a short period (no longer than 5–7 days) due to adverse events and tachyphylaxis ⁴⁵.
  • Vasoconstrictors may cause several side effects including rebound redness, chronic follicular conjunctivitis, and tachyphylaxis. Vasoconstrictors are rarely used in the pediatric population. It is recommended that these agents should be avoided.
  • Topical decongestants do not reduce the allergic response because they do not antagonize any of the mediators of allergic inflammation. Burning or stinging on instillation is a common adverse event, and prolonged use and/or discontinuation following longer-term use can lead to rebound hyperemia and conjunctivitis medicamentosa ⁴⁶. These events are usually associated with topical combinations of vasoconstrictors and first-generation antihistamines, such as pheniramine and antazoline, which are available as over-the-counter products.
• Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended as they do not target the specific inflammatory mechanism associated with vernal conjunctivitis.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) used in the treatment of eye allergy typically inhibit cyclooxygenase (COX)-1 and COX-2 enzymes ²⁹. Some have demonstrated a slight effect in the treatment of ocular allergy, by targeting itching, intercellular adhesion molecule-1 expression, and tear tryptase levels ²⁹, ⁴⁵. However, use of NSAIDs is not encouraged in vernal keratoconjunctivitis because of their local side effects, such as burning or stinging after application, increased risk of inducing keratitis on the ocular surface, and because they do not target the specific inflammatory mechanism associated with vernal keratoconjunctivitis.
• Oral antihistamines
  • Second-generation systemic non-sedative antihistamines are preferred over older first-generation antihistamines.
• Allergen-specific immunotherapy
  • Allergen-specific immunotherapy is only recommended when clearly defined systemic hypersensitivity to an identified allergen exists.
  • Patients requiring allergen-specific immunotherapy should be referred to an allergist or specialist ophthalmologist.
• In selected patients with ocular complications or persisting symptoms following prior treatments
  • Surgery, oral corticosteroids (short pulses) or corticosteroid lid injection, or systemic treatment with immunomodulators or biologics may be appropriate options for use by corneal specialists.

In patients with a history of vernal conjunctivitis, drug treatment should be planned early and started at the beginning of spring or continued all year, depending on allergen exposure and duration of symptoms ²⁹.

Table 1. Overview of medications currently available for the management of vernal conjunctivitis

Class	Drug	Standard dosing	Indication	Considerations
Topical antihistamines (second generation)	Antazoline Emedastine Levocabastine	QID	Relief of itching Relief of signs and symptoms	• Short duration of action • Frequently not enough alone to treat the entire disease
Mast cell stabilizers	DSCG Lodoxamide NAAGA Pemirolast potassium	BID to QID	Relief of signs and symptoms	• Long-term use • Slow onset of action • Prophylactic dosing • Frequently not enough alone to treat the entire disease
Dual-acting agents (antihistamine + mast cell stabilizers)	Alcaftadine Azelastine Bepotastine Epinastine Ketotifen Olopatadine	QD QD to BID BID BID BID to QID BID	Relief of itching Relief of signs and symptoms	• Side effects • Bitter taste (azelastine) • Frequently not enough alone to treat the entire disease
Immunomodulators (calcineurin inhibitors)	Cyclosporine A Tacrolimus	QD to QID QD	Treatment of severe vernal keratoconjunctivitis and AKC not responding to anti-allergic drugs	• Pharmacy-compounded preparations vary from center to center • Quality control and availability of pharmacy-compounded preparations are poor • Tacrolimus is largely used off-label in ocular allergy (tacrolimus is approved for vernal keratoconjunctivitis only in Japan)
Corticosteroids	Betamethasone Desonide Dexamethasone Fluorometholone Hydrocortisone Loteprednol Prednisolone Rimexolone	As required (up to 7 days)	Treatment of allergic inflammation Use in moderate-to-severe forms	• Risk for long-term adverse events • No mast cell stabilization • Potential for inappropriate patient use • Requires close monitoring
Vasoconstrictors (vasoconstrictor–antihistamine combinations)	Naphazoline/ pheniramine	BID to QID	Episodic itching and redness	• Rapid onset but short duration of action • Only addresses hyperemia • Associated with a range of side effects • Potential for inappropriate patient use

Footnotes: * Availability and access to treatments may vary across clinics, hospitals, regions, and countries. Each treatment option should be considered in accordance with the level of evidence available at the time.

Abbreviations: AKC = atopic keratoconjunctivitis; BID = twice daily; DSCG = disodium cromoglycate; NAAGA = N-acetyl-aspartyl glutamic acid; QD = once daily; QID = four times daily; VKC = vernal keratoconjunctivitis.

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Vernal conjunctivitis treatment options

Removal of any and all possible allergens as well as conservative management such as cool compresses and lid scrubs make up the first line of therapy ⁴⁷. A topical antihistamine only may work in mild cases ⁴⁷. Topical mast cell stabilizers (cromolyn sodium, nedocromil sodium, and lodoxamide) are typically used with topical antihistamines and have been shown to be effective in moderate presentations of vernal conjunctivitis ⁴⁷. Mast-cell stabilizers have a loading period to reach their full therapeutic effect ¹². Overall, topical antihistamines (instilled four times daily) appear to be safe and well tolerated in patients with vernal conjunctivitis ¹. Alongside mast cell stabilizers and dual-acting agents, they are often the first-choice treatment and are effective in reducing the signs and symptoms of vernal conjunctivitis ⁴⁵. Antihistamine drugs with eye activity are a good therapeutic option for patients with allergic conjunctivitis, including vernal conjunctivitis, since they can inhibit proinflammatory cytokine secretion from conjunctival epithelial cells ⁴⁸.

Antihistamines

When you have an allergic reaction your body releases histamine from mast cells, which leads to hay fever. Antihistamines block this reaction. Antihistamines act via histamine receptor antagonism to block the inflammatory effects of histamine and relieve any associated signs and symptoms. Most antihistamines used in the treatment of eye allergy are histamine-1 (H1) receptor antagonists, although some agents have affinity for other subtypes. Histamine-2 (H2) antagonists have been shown to modulate both cell growth and migration. Animal model studies have shown that antihistamines may even reduce infiltration of eosinophils and thus reduce the clinical aspects of the late-phase reaction ²⁹.

First-generation antihistamines are well tolerated and associated with a favorable long-term safety record, but are associated with instillation pain, short duration of action, and limited potency ⁴⁹. First-generation antihistamines remain available in over-the-counter products, particularly in combination with vasoconstrictors (substances that cause the walls of blood vessels to narrow, or constrict). While newer antihistamines are also H1 antagonists, they have a longer duration of action (4–6 hours) and are better tolerated than their predecessors ²⁹.

Topical antihistamines are widely available without a prescription. Antihistamines competitively block histamine receptors (e.g., H1 or H4) on nerve endings and blood vessels of the mucosal surface, thereby reducing itchiness and conjunctival redness ⁵⁰. First-generation antihistamines were associated with a range of systemic side effects (e.g., sedation, dizziness, cognitive impairment, blurred vision) caused by anticholinergic actions and nonspecific binding to histamine H2 receptors in addition to drying of the ocular surface. Newer oral, intranasal, and topical ocular antihistamines demonstrate improved H1 receptor selectivity, with fewer adverse effects; however, eye side effects, such as burning and dryness, remain a concern. Topical antihistamines (e.g., levocabastine, emedastine difumarate) are useful for providing rapid relief of allergic conjunctivitis symptoms, but their duration of action is limited; most topical antihistamines require dosing four times.

Mast cell stabilizers

Alongside antihistamines and dual-acting agents, mast cell stabilizers (instilled two to four times daily) form the first line of treatment and are effective in reducing the signs and symptoms of vernal keratoconjunctivitis. Mast cell stabilizers have been shown to act on multiple cells involved in allergic inflammation, including eosinophils, neutrophils, macrophages, mast cells, and monocytes. For example, lodoxamide is known to have an effect on eosinophil activation (shown in studies by measuring tear eosinophil cationic protein before and after therapy), while N-acetyl-aspartyl glutamic acid (NAAGA) is known to inhibit leukotriene synthesis and release of histamine by mast cells ²⁹. Overall, mast cell stabilizers are generally well tolerated especially preservative-free options; however, there are tolerability concerns with some agents, including burning and stinging sensations upon instillation, blurred vision, and an undesirable aftertaste. Data on long-term efficacy and safety of mast cell stabilizersare lacking ⁴⁵.

Dual-Acting Antihistamine–Mast Cell Stabilizing Agents

Dual-acting agents are the combination of mast cell stabilizing properties and histamine receptor antagonism (instilled twice daily) has shown clear benefits in treating forms of eye allergy ¹. This dual action rapidly alleviates multiple signs and symptoms of allergic conjunctivitis in the short term and blocks the feed-forward cycle of persistent inflammation caused by continuous mast cell activation in the long term to promote regression of allergic conjunctivitis. Antihistamine–mast cell stabilizing agents (e.g., olopatadine, alcaftadine, epinastine, bepotastine besilate) are currently considered first-line therapeutics for allergic conjunctivitis because they offer acute symptomatic relief and control inflammation, and can be used chronically without long-term safety concerns. Most dual-acting agents require twice-daily dosing. Olopatadine 0.2% and alcaftadine are indicated for once-daily dosing and maintain effectiveness through 16 hours after administration in conjunctival allergen challenge studies ⁵¹, ⁵², ⁵³.

Dual-acting agents are well tolerated and are not associated with significant ocular drying effects ²⁹, and should be preferred over monotherapy with antihistamines or mast cell stabilizers alone. A key benefit of dual-acting agents is the provision of rapid symptomatic relief by alleviating itching and redness ²⁹. Olopatadine and ketotifen, for example, have shown to be effective in relieving itching, tearing, conjunctival hyperemia, mucus discharge, and photophobia ⁵⁴.

If seasonal recurrence is known, it is suggested that mast-cell stabilization therapy be initiated prior to the season in which symptoms are encountered and continued throughout the season ¹². Dual-action agents with both histamine-1 (H1) blocking mechanism and mast-cell stabilization have the benefits of working immediately and having long-term disease modifying effects. Topical corticosteroids are typically the most effective. High pulse dose with quick tapering and use of low-absorptions corticosteroids (fluoromethelone, loteprednol, remexolone, etc.) is preferred when using topical corticosteroid therapy  ⁴⁷. Oral corticosteroids can be considered in sight threatening conditions ²⁵, ⁹. Supratarsal injection of local corticosteroid (triamcinolone or dexamethasone) into the upper tarsal papillae can sometimes offer short term relief as well ⁵⁵.

Cyclosporine A

Long term immunomodulation (a process in which the immune system is modified or modulated in a beneficial way) with steroid sparing agents such as cyclosporine and tacrolimus is often needed. Topical calcineurin inhibitors (topical immunomodulators) are frequently prescribed for patients with vernal conjunctivitis ⁴⁵. Topical calcineurin inhibitors are recommended in patients with acute-phase or persistent, moderate or severe vernal conjunctivitis that is not responding to anti-allergic drugs ⁴⁵. Topical Cyclosporine A is effective in controlling ocular surface inflammation in vernal conjunctivitis and is thought to work by inhibiting Th2 proliferation and IL-2 production, and by reducing levels of immune cells and mediators acting on the ocular surface and conjunctiva ⁵⁶. Different concentrations of cyclosporine A, ranging from 0.05 to 2.0%, are currently available in different countries with different clinical indications ⁵⁷, ⁵⁸. The 0.1% cationic emulsion (CE) formulation increases the bioavailability of cyclosporine A in the tear film compared with available oil-based (often used when cyclosporine A is pharmacy-compounded) or anionic emulsion cyclosporine A formulations ⁵⁹. Clinical studies on the efficacy of topical cyclosporine A 0.1% cationic emulsion (CE) for treating vernal conjunctivitis have consistently shown a beneficial effect of cyclosporine A, with safety and efficacy demonstrated for up to 7 years and comparable with those seen in patients with dry eye disease ⁵⁶, ⁶⁰, ⁶¹, ⁶².

There is no consensus on the minimum effective concentration of cyclosporine A to treat vernal conjunctivitis, as this can depend on the emulsion vehicle ¹. Topical cyclosporine A in concentrations of 0.05% to 2% has been shown to decrease inflammatory cytokines and the signs and symptoms of treated vernal conjunctivitis patients ⁶³, ⁶⁴. Currently, cyclosporine A 0.1% cationic emulsion (CE) is approved based on significant improvements in signs, symptoms, and quality of life in patients with severe vernal conjunctivitis, and is commercially available across Asia. It is recommended that cyclosporine A 0.1% CE should be initiated twice daily for patients with mild-to-moderate disease and four times daily for those with moderate-to-severe disease for up to 6 months. Other commercially available cyclosporine A formulations exist but are not approved for use in vernal conjunctivitis (as of December 2020) ¹. In addition, cyclosporine A may be compounded in hospital-based pharmacies to provide variable concentrations and formulations; however, its quality may be compromised, and availability is limited to specialist centers ¹.

The most commonly associated side effects with cyclosporine A is a stinging or burning sensation on instillation, and no new safety issues were identified in long-term follow-ups ¹. Instillation pain can be minimized by following a standard technique for eye drop instillation, which includes using artificial tears prior to instillation (avoiding any potential washout effect of the subsequently administered cyclosporine A, by waiting at least 10 minutes between administrations), followed by one drop into the lower conjunctival sac of each eye in the morning, at noon, in the afternoon, and in the evening, approximately 4 hours apart ⁶². Patients should also be counseled to expect stinging and burning when the drops are applied, but that the sensation should taper off with regular use as prescribed.

After long cycles of treatment, cyclosporine A can allow control of symptoms without corticosteroids ¹. There is a trend in the Asia-Pacific region, in using cyclosporine A as a first-line treatment for patients who present with moderate-to-severe or persistent vernal conjunctivitis ¹. In patients presenting with conjunctival involvement only, cyclosporine A alone is recommended for treatment, while corticosteroids should only be prescribed (as short pulses) if there is an inadequate response to cyclosporine A ¹. Otherwise, cyclosporine A can be used in combination with corticosteroids in patients with corneal complications (or limbitis) or acute exacerbations, in the understanding that cyclosporine A may take over a week to act due to its immunosuppressive mechanism of action ¹.

Tacrolimus

Tacrolimus is a strong, non-steroidal immunosuppressant that binds to FK506-binding proteins in T lymphocytes and inhibits calcineurin activity ⁶⁵. Tacrolimus has been investigated in a small randomized controlled trial in vernal keratoconjunctivitis, where it demonstrated improvements in symptoms of itching, foreign-body sensation, and photophobia, as well as in signs of limbal inflammatory activity and keratitis, with maintenance of disease control ⁶⁶, ⁶⁷. Tacrolimus may be administered as eye drops or an ointment. The use of tacrolimus (0.03%) ointment in ophthalmic and dermatologic form is currently off-label in Asia for patients with vernal keratoconjunctivitis. However, there are findings in published studies of small population sizes demonstrating effectiveness and tolerability ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹.

Tacrolimus 0.1% topically has also shown to improved signs and symptoms of vernal conjunctivitis, with one study showing improvement even in patients unresponsive to 0.1% topical cyclosporine A ⁷², ⁷³. A study comparing the use of 0.1% tacrolimus ophthalmic ointment dosed twice a day versus 2% cyclosporine A eye drops four times a day for the treatment of vernal conjunctivitis, did not find a statistically significant difference in signs or symptoms or side effects between the two groups ⁷⁴. Additionally, adult patients with vernal conjunctivitis may respond more favorably to topical cyclosporine A therapy ⁷⁵. Oral anti-histamines are sometimes used, but there is no real evidence in their support ³.

Similar to cyclosporine A, tacrolimus may be associated with instillation pain ⁶⁵. As a strong immunosuppressant, topical tacrolimus may be associated with an increased risk for corneal infections with prolonged use, and close monitoring of patients on long-term therapy is necessary ⁷¹. Topical tacrolimus (0.02–0.1%) should be reserved for patients with severe vernal keratoconjunctivitis involving allergy of the eyelid or whose disease is refractory to cyclosporine A ⁴⁵.

Topical corticosteroid

Topical corticosteroid eye drops should be used as short, pulsed therapy to provide symptomatic relief in patients with more persistent vernal keratoconjunctivitis or acute exacerbations, or when the cornea is involved (e.g., patients with shield ulcers or hyperplasia in limbal vernal keratoconjunctivitis), and under an ophthalmologist’s supervision ⁴⁵. Topical corticosteroids can be administered at a low or high dose, depending on the severity of vernal keratoconjunctivitis, and can be given up to four times daily with or without cyclosporine A. Corticosteroids act by suppressing the late-phase reaction in both experimental and clinical settings. Corticosteroids, in part, limit the inflammatory cascade by inhibiting phospholipase A2, and consequently act to prevent migration of leukocytes, release of hydrolytic enzymes, growth of fibroblasts, and lead to changes in vascular permeability ⁷⁶.

Corticosteroids with low intraocular absorption (“soft steroids”), such as hydrocortisone, fluorometholone and loteprednol, may be preferred ²⁹. Dosages are chosen based on the inflammatory state of the eye, with therapy prescribed in pulses of 3–5 days (1). Loteprednol is usually indicated for 7–8 days in the treatment of the acute phase ²⁹. Prednisolone, dexamethasone, and betamethasone are sometimes considered only as second-line options, or as first-line treatment in more severe cases, due to their potential effect on intraocular pressure ²⁹. Steroid–antibiotic combination eye drops are not recommended, since vernal keratoconjunctivitis is an allergic inflammation and not an infection ²⁹.

Moderate-to-severe vernal keratoconjunctivitis may require repeated topical corticosteroid treatment to downregulate conjunctival inflammation ²⁹. Persistent and severe symptoms, thick mucus discharge with moderate-to-severe corneal involvement, numerous and inflamed limbal infiltrates, and/or giant papillae may indicate a need for corticosteroids in addition to cyclosporine A use ²⁹. However, use of corticosteroids as first-line therapy is not recommended in those with only conjunctival involvement ²⁹.

Corticosteroids are not recommended for long-term use because of the increased risk for ocular adverse events, including increased intraocular pressure (IOP), glaucoma, cataracts, and susceptibility to infection ²⁹. These adverse events depend, in part, on the structure of the steroid, the dose, and duration of treatment ⁷⁷. Treatment with corticosteroids requires careful monitoring for the development of intraocular pressure (IOP), which should be promptly brought under control to prevent deterioration or loss of vision ⁷⁸.

Supratarsal corticosteroid injections have demonstrated some value in treating adults with vernal keratoconjunctivitis but may not be an appropriate approach for children or for application by general ophthalmologists ⁷⁸, ⁷⁹. For more specialist ophthalmologists, this may be an option in children with refractory, severe, or challenging vernal keratoconjunctivitis.

Oral antihistamines or antileukotrienes

Systemic treatment with oral antihistamines or antileukotrienes can reduce the severity of flare-ups and generalized hyperreactivity ²⁹. Oral antihistamines are good for treating hay fever symptoms, especially if you have a lot of different symptoms. You can also take oral antihistamines in advance if you know you are going to be exposed to allergens or triggers. Newer second-generation antihistamines are preferred over older first-generation antihistamines, in order to avoid the sedative and anticholinergic effects that are associated with first-generation agents ⁸⁰.

Newer, less-sedating antihistamines

Newer antihistamines may rarely cause drowsiness; do not drive or operate machinery if you are affected e.g. cetirizine (Zilarex, Zyrtec), desloratadine (Aerius), fexofenadine (Fexotabs, Telfast), loratadine (Claratyne, Lorano).

Cetirizine and loratadine are available as syrups for children; check correct doses for different age groups. Cetirizine is more likely to cause drowsiness than other less sedating antihistamines.

Older, sedating antihistamines

Older sedating antihistamines can cause drowsiness, sometimes the next day; it is important you do not drive or operate machinery e.g. chlorpheniramine + pseudoephedrine (Demazin 6 Hour Relief Tablets), dexchlorpheniramine (Polaramine), loratadine + pseudoephedrine (Claratyne-D with Decongestant Repetabs), promethazine (Phenergan, Sandoz Fenezal)

Older antihistamines are not available without a prescription for children under 2 years old. Do not drink alcohol with antihistamines that make you drowsy.

If you have other medical conditions, such as glaucoma, epilepsy or prostate problems, or you take antidepressants, check with your doctor before taking these medicines.

Systemic immunotherapy

Systemic immunotherapy is also an option, especially for those patients with underlying systemic atopic disease such as atopic dermatitis and asthma. There are case reports of the successful use of omalizumab, an anti-IgE monoclonal antibody, in patients with vernal conjunctivitis recalcitrant to other treatment modalities, but this remains an off-label use ⁸¹, ⁸². Dupilumab is a human monoclonal antibody against interleukin-4 receptor alpha used in the treatment of atopic dermatitis. There is currently a multi-center, double-masked, randomized, and placebo-controlled, parallel-group study that is evaluating the safety and efficacy of dupilumab in the treatment of signs and symptoms of individuals with atopic keratoconjunctivitis (NCT04296864), and may also play a role in treating vernal disease in those patients older than 12 years ⁸³. However, dupilumab has been found to itself induce atopic keratoconjunctivitis compared to placebo in treated patients, so its role as a primary treatment is debatable ³.

Allergen-specific immunotherapy

Allergen-specific immunotherapy is indicated only when a clearly defined systemic hypersensitivity to an identified allergen exists ⁴⁵ and should be managed by an allergist or specialist ophthalmologist. The combination of clinical history with the results of a skin-prick test and specific serum IgE should be taken into consideration when the choice of immunotherapy is made ⁴⁵. There are currently no robust studies of allergen-specific immunotherapy in vernal keratoconjunctivitis ⁴⁵. A meta-analysis of several double-blind, randomized, placebo-controlled trials investigating sublingual immunotherapy for allergic conjunctivitis, reported a significant reduction in total ocular symptom scores and ocular signs (redness, itchiness, and tearing) vs. placebo in pollen-induced allergic conjunctivitis, but not in allergic conjunctivitis associated with house dust mites, in the pediatric population ⁸⁴.

Surgical management

Case reports and ongoing clinical practice have indicated that, in rare instances, specialist surgical management may be beneficial in patients with vernal keratoconjunctivitis ¹. Surgical approaches that focus on conjunctival cobblestone papillae, shield ulcers, corneal plaques, limbal insufficiency, and other ocular surface presentations that do not respond to medical treatment can be beneficial ⁸⁵, ⁸⁶, ⁸⁷.

Surgical approaches can include excision of giant papillae, debridement of the corneal plaque to remove cytotoxic cells, and amniotic membrane transplantation ⁸⁸. Surgical treatment, especially corneal plaque removal, may be appropriate for patients with ulcers of moderate-to-severe severity, because short-term re-epithelialization rates are higher and the number of complications is lower than that associated with medical therapy ⁸⁸. Other reports suggest surgical treatment, such as giant papillae excision, may be appropriate in cases of corneal involvement and in the presence of coarse giant tarsal papillae resulting in ptosis (or mechanical pseudoptosis) ²⁹, ⁸⁹. Amniotic membrane transplantation following keratectomy has been described as a successful treatment for deep ulcers, in severe allergic patients with slight stromal thinning ⁹⁰.

Patients with vernal keratoconjunctivitis who may benefit from surgical intervention should be referred to a corneal specialist first. Leonardi et al. ²⁹ have suggested that cryotherapy and/or giant papillae excision papillae should otherwise be avoided because they only treat the complications of vernal keratoconjunctivitis and not the underlying disease, and may induce unnecessary scarring.

Vernal conjunctivitis prognosis

Generally vernal conjunctivitis is a rather benign and self-limiting disease that may resolve with age or spontaneously at puberty ²⁵, ⁹¹, ⁹². Sometimes the debilitating nature of vernal conjunctivitis when it is active necessitates therapy to control symptoms. Complications typically arise from occasional corneal scarring and the unsupervised used of topical corticosteroids can result in cataracts, or glaucoma can lead to permanent visual impairment ²⁵, ⁹¹. Rarely, complications in the form of keratoconus, shield ulcers, corneal scarring, and vascularisation may significantly affect visual acuity. Corneal ulcers are reported in close to 9.7% of patients ⁹³, ⁹⁴. In some patients (as many as 12% of cases) symptoms may persist beyond childhood, which in some cases may represent a conversion to an adult form of atopic keratoconjunctivitis ²⁵. This persistence into adulthood has been shown to be as high as 12% ⁹⁵.

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