Vernal keratoconjunctivitis (VKC) is an allergic conjunctival disease primarily involving a type I allergic reaction, with proliferative changes in the conjunctiva (giant conjunctival papillae, limbal proliferation)6). In the Japanese Guideline for Allergic Conjunctival Disease, 3rd edition, allergic conjunctival disease (ACD) is defined as “an inflammatory disease of the conjunctiva primarily involving a type I allergic reaction, accompanied by subjective symptoms and objective findings triggered by antigens,” and VKC is classified as a severe type with conjunctival proliferative changes and corneal involvement6).
The term “vernal” means spring, and it was named because it tends to worsen in spring. However, many cases actually follow a perennial course, and the pathophysiology involves not only type I allergy but also a type IV hypersensitivity reaction driven by CD4-positive type 2 helper T cells (Th2 cells).
Allergic conjunctival diseases are classified into the following four types6).
In a 2017 web survey conducted by the Japanese Society of Ophthalmic Allergy targeting members of the Japan Ophthalmologists Association and their families, the prevalence of allergic conjunctival diseases among respondents was 48.7%6). The breakdown by disease type is as follows6). This was a web survey of a specific population including healthcare professionals, so these figures cannot be directly extrapolated to the prevalence in the general Japanese population.
| Disease type | Prevalence |
|---|---|
| Seasonal allergic conjunctivitis (SAC) due to Japanese cedar and cypress | 37.4% |
| Perennial allergic conjunctivitis (PAC) | 14.0% |
| Seasonal allergic conjunctivitis due to allergens other than Japanese cedar and cypress | 8.0% |
| Atopic keratoconjunctivitis (AKC) | 5.3% |
| Vernal keratoconjunctivitis (VKC) | 1.2% |
| Giant papillary conjunctivitis (GPC) | 0.6% |
A 2017 web survey of members of the Japan Ophthalmologists Association and their families found that the prevalence of VKC was highest in people in their 20s6). This cross-sectional survey of a specific population cannot be used to estimate the age of onset, peak age, or proportion of cases persisting into adulthood in the general population.
In Japan, symptoms tend to worsen during the hot, humid summer and in spring when cedar and cypress pollen are dispersed. However, because house dust and mites are common causative allergens, many cases follow a perennial course. The same 2017 web survey found that allergic conjunctival diseases overall were most common in people in their 40s, with a small peak in the teens6). Simple comparisons with past surveys using different populations and methods cannot be used to draw conclusions about changes in the general population or their causes.
VKC is classified based on the site of lesions into the palpebral type, characterized mainly by cobblestone giant papillae on the upper tarsal conjunctiva, the bulbar (limbal) type, characterized mainly by limbal gelatinous elevations and Horner-Trantas dots, and the mixed type, which exhibits features of both. It is reported that the predominant type varies by region and ethnicity. These findings may appear alone or in combination, and treatment is selected according to the disease type and severity6).
Many patients have a personal or family history of atopy. A case report of one family involving monozygotic twins and their father analyzed HLA types, but this is not a study of disease susceptibility or causative genes in the general population2).
VKC is a disease that tends to develop in childhood and is accompanied by conjunctival proliferative changes and corneal lesions. In contrast, atopic keratoconjunctivitis is a chronic severe type that may be associated with atopic dermatitis. Because the findings of the two conditions can overlap, diagnosis is made by combining skin and ocular surface findings, not by age alone6).
According to guidelines, the main subjective symptoms of VKC include intense itching, foreign body sensation, eye pain, photophobia, and tearing. Corneal lesions may cause eye pain and visual impairment6). There is no confirmed evidence to uniformly conclude that eye pain is stronger or more frequent than itching in VKC compared with other allergic conjunctival diseases.
In highly active states, patients may be unable to move upon waking due to severe blepharospasm and mucoid discharge, a condition called “morning misery.” It significantly impacts school performance and daily life, and can lead to school refusal.
Giant papillae, limbal proliferation, and shield ulcer are highly specific objective findings that are central to the diagnosis of VKC6).
Findings of the Upper Tarsal Conjunctiva
Cobblestone giant papillae: Flat papillae with a diameter of 1 mm or more are densely packed on the upper tarsal conjunctiva, giving a cobblestone appearance.
Activity indicators: The degree of hyperemia, mucoid discharge between papillae, and fluorescein staining at the tips of papillae serve as indicators of disease activity.
Observation method: Eversion of the upper eyelid is essential, and evaluation is performed using a slit-lamp microscope.
Findings of the Corneal Limbus
Horner-Trantas spots: White spots seen at the corneal limbus, consisting of degenerated epithelial cells and eosinophil aggregates. They are classified as mild, moderate, or severe based on the number of spots around the entire limbus.
Dike-like elevation: The limbus becomes gelatinously swollen. Limbal papillae may coalesce.
Pseudogerontoxon: In cases with severe limbal inflammation, an arcus senilis-like opacity remains in the peripheral superficial stroma6).
Corneal complications progress in stages according to disease severity. Severity increases in the order of punctate superficial keratitis, desquamative punctate superficial keratitis, epithelial erosion, and shield ulcer6).
In a corneal histologic study of 3 cases (4 eyes) that underwent vision-restoring surgery during the cicatricial phase of VKC, epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization were confirmed3). Immunohistochemically, ABCG2 (a limbal stem cell marker) was negative in all specimens, while p63α was expressed with varying intensity, suggesting that limbal stem cell dysfunction may be partial in this limited group of cicatricial phase cases3).
A rare complication is tarsal conjunctival keratinization. Tarsal conjunctival keratinization was reported in both eyes of one patient with long-standing VKC; after lesion excision and conjunctival autografting, the patient remained recurrence-free for 4 years4).
MBP (major basic protein) and ECP (eosinophil cationic protein) released from eosinophils cause direct cellular damage to the corneal epithelium. Combined with mechanical friction from giant papillae, this leads to the formation of an oval shallow ulcer (shield ulcer) in the superior cornea. When fibrin and mucus deposit on the ulcer base, a corneal plaque forms, hindering epithelial regeneration.
In VKC, in addition to type I allergic reactions, chronic inflammation centered on CD4-positive type 2 helper T cells (Th2 cells) contributes to the formation of the clinical picture 6).
Histopathology of giant conjunctival papillae shows eosinophil infiltration, fibroblast proliferation, extracellular matrix deposition, and numerous T-cell infiltrates. Thus, the formation of giant papillae involves not only type I allergic reactions but also T-cell-dependent chronic inflammation.
The most common causative antigens of VKC are house dust and mites, and it is not uncommon for patients to react to multiple types of antigens such as pollen and animal dander 6). Therefore, symptoms may persist perennially rather than only seasonally.
The exact mechanism has not been elucidated. Although the involvement of endocrine factors such as sex hormones has been discussed, there is no established evidence to explain the higher prevalence in boys based on specific lifestyle behaviors or antigen exposure levels.
Diagnosis is performed in the following three steps using three elements: clinical symptoms (A), type I allergic predisposition (B: systemic + local), and type I allergic reaction in the conjunctiva (C) 6).
| Diagnostic Category | Requirements |
|---|---|
| Clinical Diagnosis | A only (presence of clinical symptoms characteristic of ACD) |
| Clinically Confirmed Diagnosis | A + B (clinical symptoms + positive total IgE in tears, positive serum antigen-specific IgE, or positive skin reaction) |
| Definitive Diagnosis | A + B + C or A + C (in addition to the above, positive eosinophils in conjunctival scrapings) |
Important diagnostic evidence for VKC includes giant papillae, limbal proliferation, corneal lesions (shield ulcer, corneal plaque), eye pain, eye discharge, and hyperemia 6). Clinical diagnosis is made based on characteristic clinical findings (cobblestone-like giant papillae, Horner-Trantas spots, shield ulcer) and inquiries about itching and eye pain, leading to a definitive diagnosis with laboratory findings.
The following tests are combined according to the type and severity of the disease 6).
The tear total IgE test is an auxiliary test to assess local type I allergic predisposition in allergic conjunctival diseases including VKC6). A positive result supports the diagnosis, but a negative result does not rule out VKC. Since the sensitivity, specificity, and positivity rates by disease subtype from the original studies could not be directly verified for the target population and diagnostic criteria, these values are not generalized here.
Treatment of VKC is based on the Japanese Guidelines for the Diagnosis and Treatment of Allergic Conjunctival Diseases, 3rd Edition (2021)6). Since Th2 cells play a central role in the pathogenesis of VKC, anti-allergic eye drops that lack T-cell suppressive activity alone cannot control the disease. Concomitant use of immunosuppressive eye drops or steroid eye drops, which regulate T-cell function, is necessary.
In vernal keratoconjunctivitis, the following drugs are combined according to severity and the presence or absence of corneal lesions6). The strength of recommendation and level of evidence vary by intervention in the guidelines.
| Treatment Intervention | Strength of Recommendation | Level of Evidence | Clinical Role |
|---|---|---|---|
| Tacrolimus eye drops | Strong | A | Main option for severe cases |
| Cyclosporine eye drops | Weak | B | Consider based on disease condition |
| Steroid eye drops | Strong | B | Consider for severe inflammation or corneal lesions; monitor intraocular pressure, etc. |
| Combination of immunosuppressive eye drops and steroid eye drops | Weak | C | Consider based on disease condition |
In a meta-analysis of tacrolimus eye drops, the standardized mean difference in corneal epithelial damage score was -0.89 (95% confidence interval -1.32 to -0.46). Meanwhile, the eyelid papillary score was -0.83 (95% confidence interval -1.68 to 0.03), and since the confidence interval crossed zero, the result only suggests a possible improvement in papillary findings6).
Anti-allergic eye drops
Mediator release inhibitors: Stabilize mast cell membranes and inhibit histamine release. Examples include sodium cromoglicate.
H1 receptor antagonists: Competitively inhibit histamine binding to receptors. Examples include olopatadine and epinastine. Selected when itching is severe. Administered prophylactically as initial treatment before the season.
Immunosuppressive eye drops
Cyclosporine eye drops and tacrolimus eye drops are considered for VKC with proliferative changes that cannot be adequately controlled with anti-allergic eye drops alone. The choice between them is made by the ophthalmologist based on the above differences in recommendation strength, as well as severity, corneal lesions, previous treatment, and adverse events 6). No superiority by disease type or uniform switching order has been established for these two drugs.
Anti-allergic eye drops form the foundation, and immunosuppressive eye drops or steroid eye drops are added depending on severity and corneal lesions 6). After improvement, dose reduction or discontinuation, and resumption upon relapse, are individually adjusted by the ophthalmologist while checking intraocular pressure, corneal findings, and adverse events. Fixed switching orders based on product numbers or changes in instillation frequency by the patient themselves are not performed.
VKC is a disease common in young people, and it is important to note that the proportion of steroid responders (steroid-induced glaucoma) is higher in younger individuals. Regular visits and intraocular pressure measurements are essential. High-potency steroids (Rinderon®) provide rapid effects but carry the risk of a vicious cycle of self-discontinuation upon improvement and subsequent worsening. Particularly after age 10, when medication management shifts from guardians to the patient themselves, attention should be paid to decreased self-management ability.
During use of steroid eye drops, attention should be paid to adverse events such as increased intraocular pressure, cataracts, and infections, and regular ophthalmologic evaluation is required 6).
Prevention and self-care emphasize the following 6).
Both are immunosuppressive eye drops considered for VKC that cannot be adequately controlled with anti-allergic eye drops alone6). The guideline recommends tacrolimus as “strong/A” and cyclosporine as “weak/B”. It has not been established that one is superior depending on the disease type, so the ophthalmologist selects based on severity, corneal lesions, previous treatment response, and adverse events. Do not change the number of instillations or switch medications on your own.
The pathophysiology of VKC is a complex immune reaction involving both type I allergy (immediate type) and type IV hypersensitivity (delayed type).
In type I allergy, antigens that enter the tear fluid cause mast cell degranulation via IgE. In the immediate phase, histamine is released, causing congestion and itching, and in the late phase, newly synthesized mediators such as leukotrienes amplify inflammation.
Th2 cells produce IL-4, IL-5, IL-13, etc., promoting eosinophil recruitment and activation. Activated eosinophils release cytotoxic proteins such as MBP and ECP, contributing to corneal epithelial damage6).
In recent years, the JAK/STAT pathway has been noted to play an important role in Th2 cytokine signaling. JAK1 mediates signaling of IL-4, IL-5, IL-13, IL-31, and TSLP (thymic stromal lymphopoietin), serving as a central pathway in allergic inflammation1). Therefore, JAK inhibitors are attracting attention as a new treatment option for refractory VKC.
Histopathology of conjunctival giant papillae shows eosinophil infiltration, fibroblast proliferation, extracellular matrix deposition, and numerous T-cell infiltrates. The basic pathology of papillae is an angiogenic response, accompanied by conjunctival epithelial thickening and subepithelial inflammatory cell proliferation, with fibrous tissue protruding in a papillary shape. A central blood vessel is surrounded by cellular infiltrates mainly composed of lymphocytes and plasma cells. Giant papillae occur preferentially in the upper tarsal conjunctiva because they develop on the hard tarsal plate.
In corneal tissue from 3 cases (4 eyes) that underwent vision-restoring surgery during the cicatricial phase of VKC, epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization were confirmed3). ABCG2 was negative in all specimens, while p63α was expressed with varying degrees, suggesting that limbal stem cell dysfunction may be partial in this limited group of cicatricial cases3).
In one case of an 18-year-old female with severe VKC and atopic dermatitis, giant papillae and peripheral corneal neovascularization began to flatten within 2 months after starting upadacitinib for atopic dermatitis1). Since the patient had a history of treatment with cyclosporine and tacrolimus eye drops before initiation and this is an uncontrolled single case, the improvement cannot be definitively attributed to upadacitinib alone or a specific combination effect.
JAK1 is involved in signaling of Th2 cytokines (IL-4, IL-5, IL-13, IL-31) and TSLP1). This report represents a stage of proposing a therapeutic hypothesis; accumulation of cases and comparative studies are needed to establish efficacy and safety for VKC1).
HLA typing was analyzed in a case report of one family including monozygotic twins and their father2). The authors position this as the first report of monozygotic twins with VKC, but no conclusion can be drawn about an association between specific HLA types and general VKC susceptibility from observation of a single family2).
A study examining corneal tissue from 3 cases (4 eyes) that underwent vision-restoring surgery during the cicatricial phase of VKC confirmed epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization 3). Based on ABCG2 negativity and p63α expression, the authors suggested the possibility of partial limbal stem cell dysfunction in this group of cicatricial phase cases 3).
Bilateral tarsal conjunctival keratinization was observed in one patient with long-standing VKC. After lesion excision and conjunctival autografting, no recurrence occurred over 4 years 4). The authors consider this the first report of tarsal conjunctival keratinization associated with VKC 4).
In one case of an 11-year-old boy with comorbid growth hormone deficiency, VKC findings improved 6 weeks after switching to tacrolimus eye drops and fluorometholone eye drops 5). The same report identified 6 previous cases in the literature, but this does not indicate an increased prevalence or causal relationship with growth hormone deficiency. The decrease in IL-6 and CRP after growth hormone therapy was also not statistically significant in another population, and its impact on VKC remains unclear 5).
There is insufficient evidence regarding the long-term duration of use of tacrolimus eye drops, and further investigation is needed 6).
There is one case report in which VKC findings improved after starting upadacitinib 1). However, this is a single uncontrolled case, and the effects of conventional ophthalmic treatment cannot be separated, so efficacy has not been established. There is no approved indication for VKC, and it does not replace standard treatment. At present, guideline-based eye drop therapy remains the mainstay 6).
