Nonallergic eosinophilic conjunctivitis

The revised nomenclature, proposed by the Nomenclature Review Committee of the World Allergy Organization, defined allergy as a hypersensitivity reaction initiated by specific immunological mechanisms, whereas nonallergic hypersensitivity should be used for other mechanisms [1]. The committee differentiated asthma as allergic asthma and nonallergic asthma, hypersensitivity symptoms from the nose as allergic rhinitis and nonallergic rhinitis, and conjunctivitis as allergic conjunctivitis and nonallergic conjunctivitis.

Eosinophils are common inflammatory cells both in allergic and nonallergic external eye diseases. They migrate from the bone marrow to the peripheral blood and then through the vessels to sites of inflammation, where cell surface adhesion molecules of the vascular endothelial cells are activated [2]. Eosinophils are stimulated by lymphocyte- and especially mast cell-derived mediators, and remain in the tissue mainly as perivascular cells.

Mast cells can activate eosinophils and vice versa. They are a source of neutrophin and secrete nerve growth factor on immunological stimuli [3]. Nerve growth factor can also activate mast cells further and prolong their survival, as well as act on eosinophils in an autocrine manner [3]. The active cross-talk of eosinophils and mast cells appears to be the basis of persistent inflammation in the conjunctiva.

Asthma and other allergic disorders are characterized by the activation of T cells, which produce eosinophil survival factors, such as interleukin (IL)-5. Eosinophilia and high IL-5 expression are not only associated with chronic asthma, rhinitis and atopic dermatitis, but also elevated IL-5 levels are found in vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis. The physiological cell death, apoptosis, appears to be delayed in persistent eosinophilia.

Eosinophils occur in many external eye diseases as effector cells and markers of disease activity. In patients with conjunctivitis, 55% had eosinophils without signs of atopy and, in the asymptomatic normal population, 6% presented with low-grade conjunctival eosinophilia [4]. Eosinophils were found in conjunctival cytology in 43% of patients with perennial allergic conjunctivitis and in 25% of patients with seasonal allergic conjunctivitis. Eosinophils may also occur in conjunctiva in cell-mediated (type IV) reactions.

It seems that nonallergic eosinophilic conjunctivitis (NAEC) comprises a separate entity, which is poorly described in the literature. Even in a recent review, it is still not mentioned [5]. NAEC may be compared with common conditions including nonallergic eosinophilic rhinitis [6] and nonallergic eosinophilic asthma [7].

We define NAEC as persistent nonallergic (i.e., negative skin-prick tests and no allergen-specific serum immunoglobulin-E antibodies to common environmental allergens) and non-infectious conjunctivitis with at least 1+ eosinophilia (semiquantitative scale from + to ++++) [8] in conjunctival brush cytology.

NAEC may be a rather common clinical condition but no epidemiological data are available. It affects mostly middle-aged and older people, with a predominance of women. The symptoms of NAEC are largely similar to those seen in atopic conjunctivitis and include itching, tearing, redness, foreign body sensation and mild discharge. Mild-to-moderate eosinophilia in conjunctival brush cytology is characteristic. The serum and secretory allergen specific immunoglobulin E antibodies in conjunctival fluid are in reference range and the patients do not have a history of atopic eczema, allergic rhinitis or allergic asthma. Some patients with NAEC also show symptoms of nonallergic eosinophilic rhinitis, asthma or both.

In the differential diagnosis of NAEC, other causes of chronic eye irritation, such as seborrhoic blepharitis, secondary meibomianitis, ocular rosacea and chronic staphylococcal blepharoconjunctivitis, should be excluded but these are uncommon confounders of the diagnosis of NAEC. Significant inflammation of the lid margins and cornea are not typical of NAEC.

Eosinophilic conjunctivitis is usually a mild disorder but may also be severe and tissue destructive, and come close to severe atopic keratoconjunctivitis and vernal conjunctivitis [9]. Even mild NAEC may be a significant nuisance to the patient, often mimicking dry eyes and significantly reducing quality of life.

In the treatment of NAEC, suppressing the eosinophilic inflammation is the main target. Glucocorticosteroids are most effective and induce eosinophilic apoptosis or reduce expression of eosinophil survival factors. Glucocorticoids, ciclosporin A, rapamycin, tacrolimus [10] and the anti-CD4 monoclonal antibody decrease eosinophil numbers by reducing IL-5-producing T cells.

In practice, we have successfully used hydrocortisone-containing eye drops for 1–2 weeks and continued with topical mast cell stabilizers (e.g., chromoglycate, nedochromil or lodoxamide), nonsteroidal anti-inflammatory drugs (e.g., topical diclofenac) or topical antihistamines. However, NAEC treatment with antihistamine eye drops is often insufficient. This may be due to the often-accompanying dry eye. Exacerbations should be treated with a short course (1–2 weeks) of corticosteroid eyedrops (intermittent therapy). Nonsteroidal immunomodulators can also be tried. In a few severe cases, we have used ciclosporin A drops, which are also effective in conjunctival eosinophilia of type IV allergic reactions [11].

Interestingly, a strong reduction in eosinophil cell count in conjunctival cytology was observed after locally administered tacrolimus ointment on the lid skin [12]. Occasionally, a bacterial infection caused by Staphylococci or Chlamydia trachomatis triggers the condition and Chlamydia infection can provoke a long-term eosinophilic conjunctitivitis. After successful treatment with topical antibiotics, eosinophils may disappear. Altogether, patients with NAEC require treatment for months or years.

The origin of NAEC is unknown, as is the origin of nonallergic eosinophilic rhinitis or asthma. In all of these conditions, suppressing the inflammation with topical corticosteroids is the most effective therapy and should be introduced at an early stage. The aim of therapy is not only to prevent symptoms but also the possible cicatrizing inflammatory process in the conjunctiva [13], which may lead to irreversible tissue damage and to persistent dry eye, characterized by degenerative changes in the epithelium and increase of goblet cells.