Allergic conjunctival disease (ACD) is defined as “an inflammatory disease of the conjunctiva primarily involving type I allergic reactions, accompanied by subjective symptoms and objective findings triggered by antigens” 1). Diagnosis requires not only an allergic predisposition but also ocular symptoms and conjunctival inflammatory findings.
According to the clinical practice guidelines of the Japanese Society of Ophthalmic Allergy, ACD is classified into the following subtypes based on the presence of conjunctival proliferative changes, association with atopic dermatitis, and mechanical irritation from contact lenses, etc. 1).
Allergic Conjunctivitis
This subtype does not involve conjunctival proliferative changes. It includes seasonal allergic conjunctivitis, with symptoms appearing during certain seasons due to pollen, and perennial allergic conjunctivitis, with symptoms year-round due to mites or house dust.
Atopic Keratoconjunctivitis
This is a chronic keratoconjunctivitis associated with facial atopic dermatitis. Chronic cases may involve conjunctival fibrosis, corneal neovascularization, and opacification.
Vernal Keratoconjunctivitis
This is a severe type characterized by giant papillae on the upper tarsal conjunctiva and proliferative changes at the corneal limbus. It can cause corneal erosion, persistent corneal epithelial defects, shield ulcers, and corneal plaques.
Giant Papillary Conjunctivitis
This is a disease type associated with repeated mechanical irritation and inflammation from contact lenses, ocular prostheses, exposed sutures, etc., resulting in giant papillae of 1 mm or more in diameter on the upper tarsal conjunctiva.
A 2017 web-based cross-sectional survey of 3,004 members of the Japan Ophthalmologists Association and their families, adjusted for age and region, estimated the prevalence of allergic conjunctival diseases at 48.7%. The same survey reported seasonal allergic conjunctivitis due to cedar and cypress at 37.4%, other seasonal types at 8.0%, perennial at 14.0%, atopic keratoconjunctivitis at 5.3%, and vernal keratoconjunctivitis at 1.2%. The guidelines also list giant papillary conjunctivitis at 0.6%. Because disease types overlap, the total does not add up to 100% 1, 3).
In the same web survey, the overall prevalence was highest in the 40s, with a small peak in the teens. Additionally, a cross-sectional association was observed between regional prevalence of severe disease types and certain air pollutant concentrations, but this single study cannot determine that air pollution is a cause of the disease 3).
Seasonal allergic conjunctivitis occurs during the pollen season of cedar, cypress, grasses, etc. Perennial allergic conjunctivitis occurs year-round due to mites, house dust, animal-derived antigens, etc. Since symptoms alone cannot identify the causative antigen, a combination of history taking and allergy testing is used as needed.
Typical subjective symptoms include eye itching, foreign body sensation, discharge, and tearing 1, 4). Severe eye itching is a highly specific diagnostic clue, but mild itching can also occur in other ocular surface diseases. In children and the elderly, they may complain of a “gritty” or “uncomfortable” feeling rather than itching 1).
In ophthalmology, the palpebral conjunctiva, bulbar conjunctiva, limbus, and cornea are examined separately. Giant papillae, proliferative changes at the limbus, and shield ulcers are important findings indicating severe disease1).
| Site/Finding | None | Mild | Moderate | Severe |
|---|---|---|---|---|
| Palpebral conjunctival injection | None | A few dilated vessels | Many dilated vessels | Individual vessels indistinguishable |
| Palpebral conjunctival papillae | None | 0.1–0.2 mm | 0.3–0.5 mm | ≥0.6 mm |
| Giant papillae | None | Papillae flattened | Less than 1/2 of upper tarsal conjunctiva | 1/2 or more of upper tarsal conjunctiva |
| Bulbar conjunctival edema | None | Partial | Diffuse | Bullous |
| Trantas dots | None | 1 to 4 | 5 to 8 | 9 or more |
| Corneal epithelial disorder | None | Punctate keratitis | Desquamative punctate superficial keratitis | Shield ulcer or corneal erosion |
Giant papillae refer to those with a diameter of 1 mm or more. This table is not for patients to determine severity themselves, but is a standard for standardizing findings in ophthalmology 1).
| Disease type | Main causes and related factors |
|---|---|
| Seasonal allergic conjunctivitis | Pollen from Japanese cedar, cypress, grasses, ragweed, mugwort, etc. |
| Perennial allergic conjunctivitis | Mites, house dust, animal-derived antigens, etc. |
| Vernal keratoconjunctivitis / Atopic keratoconjunctivitis | May involve multiple sensitizations such as mites, house dust, pollen, and animal-derived antigens |
| Giant papillary conjunctivitis | Repeated mechanical irritation from contact lenses, ocular prostheses, exposed sutures, etc. |
A personal or family history of asthma, allergic rhinitis, or atopic dermatitis provides clues for an allergic predisposition. Strong eye rubbing is associated with progression of atopic cataract and acute hydrops in eyes with keratoconus, so it is important to treat itching and avoid rubbing the eyes1, 2).
A meta-analysis of 8 randomized controlled trials in adults with moderate to severe atopic dermatitis showed that the risk of conjunctivitis in the dupilumab group was higher than in the placebo group, with a risk ratio of 2.64. This does not represent the overall risk of developing atopic keratoconjunctivitis. If new eye symptoms occur during treatment, do not discontinue on your own; consult your prescribing physician and an ophthalmologist13).
Diagnosis involves combining the following three elements1).
When only symptoms and findings are present, it is a clinical diagnosis; when tests for allergic predisposition are added, it is a clinically confirmed diagnosis; and when eosinophils in the conjunctival tissue are confirmed, it is a definitive diagnosis1).
Severe ocular itching, giant papillae, limbal proliferative changes, and shield ulcers are findings with high diagnostic specificity. In the absence of proliferative changes, consider seasonal or perennial allergic conjunctivitis based on symptom seasonality; if proliferative changes are present, consider giant papillary conjunctivitis, atopic keratoconjunctivitis, or vernal keratoconjunctivitis based on mechanical irritation and the presence of atopic dermatitis. However, exceptions exist, so the final diagnosis should be made by combining ophthalmic findings and tests 1).
| Examination | What can be determined | Limitations |
|---|---|---|
| Total IgE in tear fluid | Semi-quantifies local ocular IgE levels to aid diagnosis | The causative antigen is unknown, and a negative result cannot rule out the disease. |
| Eosinophils in conjunctival scrapings and ocular discharge | Supports local type I allergic reaction of the conjunctiva | Since the positivity rate is not high, a negative result does not rule it out. |
| Serum antigen-specific IgE | Sensitization to pollen, mites, house dust, fungi, dog/cat-derived antigens, etc. | A positive result alone does not confirm that the antigen is the cause of ocular symptoms. |
| Skin prick test | Immediate reaction to suspected antigens | The result alone does not confirm that the antigen is the cause of ocular symptoms. |
In a study by Shoji et al. examining 223 cases of allergic conjunctival disease, total tear IgE was positive in 72.2% of all cases. By disease type, it was positive in 61.9% of seasonal, 65.4% of perennial, 80.5% of atopic keratoconjunctivitis, 94.7% of vernal keratoconjunctivitis, and 75.0% of giant papillary conjunctivitis, although only 8 cases of giant papillary conjunctivitis were included. In the same study, conjunctival scraping eosinophil testing was performed in 87 cases, with 42.5% (37 eyes) positive. For both tests, a negative result cannot rule out the disease 4).
In an initial product evaluation of a total tear IgE test kit involving 153 individuals (125 with allergic conjunctival disease and 28 controls), the positive agreement rate with clinical diagnosis was 73.6% and the negative agreement rate was 100% 1, 23). This should be interpreted as an agreement rate under study conditions evaluating a specific product, rather than generalized as “sensitivity 73.6%, specificity 100%.”
For allergic conjunctival diseases, including seasonal and perennial types, the first-line treatment is anti-allergic eye drops 1). Drugs with histamine H₁ receptor antagonism or mediator release inhibition are mainly used.
In seasonal allergic conjunctivitis, initial therapy starting about 2 weeks before the predicted pollen dispersal date or as soon as any symptoms appear may reduce symptoms during the peak pollen season 1).
When accompanied by allergic rhinitis, oral antihistamines may also help eye symptoms. Since oral medication solely for eye symptoms may not be covered by insurance, confirm with the prescribing physician 1).
If anti-allergic eye drops alone are insufficient, an ophthalmologist may add steroid eye drops 1). Due to risks such as increased intraocular pressure, cataracts, and infection induction, they should not be used indiscriminately; intraocular pressure and ocular surface condition should be monitored during use. In children, special attention to increased intraocular pressure is necessary.
For vernal keratoconjunctivitis, immunosuppressive eye drops containing cyclosporine or tacrolimus are used 1, 2). A randomized controlled trial of tacrolimus 0.1% ophthalmic solution showed improvement in objective findings, including giant papillae and corneal lesions, in severe allergic conjunctival diseases that did not respond adequately to conventional treatment 6). A nationwide survey of cyclosporine 0.1% ophthalmic solution reported improvement in symptoms and findings in patients with vernal keratoconjunctivitis, as well as cases where steroid eye drops could be reduced or discontinued 7).
| Generic Name/Concentration | Approved Indication in Japan | Approved Dosage |
|---|---|---|
| Cyclosporine 0.1% Ophthalmic Solution | Vernal keratoconjunctivitis with giant papillary proliferation inadequately controlled by anti-allergic drugs | 1 drop, 3 times daily |
| Tacrolimus 0.1% Ophthalmic Solution | Vernal keratoconjunctivitis with giant papillary proliferation inadequately controlled by anti-allergic drugs | 1 drop, 2 times daily |
The above table is based on the PMDA package insert confirmed in July 2026 8, 9). The guidelines recommend the use of steroid eye drops (strength of recommendation: strongly recommended to use, strength of evidence B) and tacrolimus eye drops (same: strongly recommended, strength of evidence A) for atopic keratoconjunctivitis 1). However, in Japan, the use of tacrolimus eye drops for atopic keratoconjunctivitis is off-label, and the guidelines explicitly state this point 1, 2). Immunosuppressive eye drops may cause irritation 1, 6), and attention should also be paid to infectious keratitis 1, 7-9). The medication is selected by an ophthalmologist based on the disease type, severity, and medical history.
In atopic keratoconjunctivitis, if treatment-resistant corneal epithelial defects, corneal ulcers, corneal thinning, or perforation occur, corneal surgery such as amniotic membrane transplantation may be necessary. This is not a treatment for ordinary allergic conjunctivitis but a specialized treatment for severe corneal complications 22).
Steroid eye drops can cause side effects such as increased intraocular pressure, cataracts, and infections. Even if symptoms improve, do not continue or discontinue on your own; use them while having your intraocular pressure and ocular surface condition checked by an ophthalmologist.
When allergens react with IgE antibodies on the surface of mast cells in the conjunctiva, histamine, tryptase, leukotrienes, and prostaglandins are released. This immediate reaction causes itching, redness, conjunctival edema, and tearing 5, 12, 14). In human conjunctival allergen challenge tests, the immediate reaction peaked at about 20 minutes, but the onset time with natural exposure varies 14).
In some patients, inflammation continues for several hours. In experimental challenge tests, infiltration of eosinophils, elevation of eosinophil cationic protein (ECP), and increased expression of adhesion molecules were confirmed about 6 hours later 14). In vernal keratoconjunctivitis, not only type I allergy but also Th2 cells, IL-4, IL-5, IL-13, eosinophils, and conjunctival tissue remodeling are involved in the pathology 10, 15).
In corneal ulcers of two patients with vernal keratoconjunctivitis, eosinophil-derived major basic protein (MBP) was detected in inflammatory debris on the cornea, suggesting involvement of eosinophil granule proteins 16). In atopic keratoconjunctivitis, a correlation between tear ECP levels and the severity of corneal epithelial damage and conjunctival findings has been reported, but ECP alone does not determine diagnosis or treatment strategy 11).
Conjunctival biopsy in atopic keratoconjunctivitis shows goblet cell proliferation, intraepithelial eosinophils and mast cells, and activated T cells, macrophages, and dendritic cells in the substantia propria. This indicates involvement of not only immediate IgE- and mast cell-mediated reactions but also chronic cellular inflammation 17).
Preservative-free artificial tears are not drugs that suppress specific molecular mechanisms; they are used to physically wash away antigens adhering to the ocular surface 1).
The exact pathogenesis of giant papillary conjunctivitis is unknown, but it is thought to involve a combination of repeated mechanical irritation to the upper tarsal conjunctiva and a local immune response to deposits on the contact lens surface 2, 5).
According to guidelines, the following situations require differentiation from corneal lesions or infectious conjunctivitis, or monitoring during treatment 1).
