Description of the condition
The phrase allergic conjunctivitis describes a group of clinically distinct inflammatory conditions of the ocular surfaces including seasonal allergic conjunctivitis ('hayfever'), perennial allergic conjunctivitis, atopic keratoconjunctivitis and vernal keratoconjunctivitis. Atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) are the most serious forms of allergic conjunctivitis. These conditions are usually easy to distinguish, having characteristic epidemiology (AKC has an older age of onset and is seen almost exclusively in patients with atopic dermatitis) and clinical signs (giant papillae seen in VKC). A key distinction is that VKC will usually become quiescent in the third decade whereas AKC will not.
Vernal keratoconjunctivitis (VKC) is a severe form of allergic eye disease that predominantly affects male children (Bonini 2000; Leonardi 2002). The disease is rare in Europe, with an estimated prevalence of 3.2 per 10,000 (Bremond-Gignac 2008). It is more common in warmer climates such as the Mediterranean, Africa, Asia and the Southern United States (Leonardi 2002; Resnikoff 1988). In central Africa the prevalence of VKC in children has been estimated at 4% (Smedt 2011). Onset of disease is typically in the first decade. VKC is characterised by symptoms of itch, photophobia, reduced vision and mucoid discharge. It is usually seasonal, with acute exacerbations in spring and summer, and relative quiescence between acute attacks, but a significant proportion of patients develop year-round disease activity and hence a more chronic disease course.
VKC primarily affects the conjunctiva, the thin smooth layer of tissue covering the white of the eyeball and the inside of the eyelids. It is characterised by conjunctival inflammation with formation of large or giant papillae. It is usually bilateral, although the disease severity may be asymmetric. VKC is classified according to which area of the conjunctiva is most affected. It may affect the palpebral conjunctiva, which is the lining of the inside of the eyelids, or the limbal conjunctiva, which is the covering of the eyeball near the cornea (the clear window at the front of the eyeball). The pattern may also be a mix of limbal and palpebral VKC.
Severe or protracted activity of limbal VKC may cause peripheral corneal scarring. Severe or protracted activity of palpebral VKC may cause central corneal scarring and significantly reduced vision.
VKC is considered a type of atopic disease and patients often have features typical of allergy such as raised serum IgE (antibodies against allergen), the presence of eosinophils (a subtype of white blood cell which is commonly seen in tissues affected by allergic inflammation) in conjunctival biopsy specimens and a personal or family history of other allergic diseases such as asthma or eczema. However, the pathogenesis is incompletely understood. The cellular mechanisms appear to be more complex than just the typical IgE-mediated Type-1 hypersensitivity reaction seen in seasonal allergic conjunctivitis (hayfever) with increased recognition, in recent years, of a role for T lymphocytes in the process (Bonini 2004; Leonardi 1999; Leonardi 2002; Metz 1997).
The condition tends to improve after puberty and to regress as patients enter their twenties (Bonini 2000; Leonardi 2002). If it is not treated appropriately when it is active, VKC has the potential to cause morbidity ranging from chronic ocular discomfort and photophobia, loss of schooling to permanent visual loss from corneal scarring.
Description of the intervention
The spectrum of disease severity is wide. The factors to consider in deciding the treatment strategy for each patient include the severity of the disease at its most active, the severity of the disease at its least active and the frequency of exacerbations. The therapeutic regimen should be tailored for each patient (Sacchetti 2010). A number of topical treatment are used in VKC to try to control disease activity. These include:
topical mast cell stabilisers;
topical dual-acting agents (drugs with both a mast cell stabilising and an antihistamine effect);
topical immunomodulatory agents (e.g., ciclosporin).
Topical steroid has potential side effects including cataract, glaucoma, and enhanced secondary infection, whereas the other treatments listed above have few serious side effects. Therefore the broad therapeutic aim is to control signs and symptoms of VKC while using as little topical steroid as possible (Sacchetti 2010). However, the control of severe exacerbations may require intensive application of steroid drops which, apart from the risk of side effects, may cause practical difficulties for young children and their parents.
Patients whose VKC is quiescent or minimally active between acute exacerbations are often treated with maintenance therapy using a topical mast cell stabiliser or a dual acting agent. Topical mast cell stabilisers are the most commonly used maintenance therapy. They increase the threshold stimulus for mast cell degranulation in the conjunctiva. Their mechanism of action is not well-understood. Some patients with a more severe or chronic course are treated with low-dose maintenance topical steroid or topical ciclosporin.
How the intervention might work
The symptoms and signs of VKC, like all inflammatory conditions, are caused by release of mediators from resident white blood cells in the tissues or the interaction with the tissue by infiltrating activated white blood cells from the blood, or both. The interventions to be studied in this review all interfere with or inhibit some action of white blood cell function. The types of white blood cell seen in the conjunctiva during active VKC include mast cells, neutrophils, eosinophils, macrophages and monocytes, T lymphocytes and dendritic cells. Some of the interventions are more specific for white blood cell subtypes than others. For example, topical steroids are known to have effects on neutrophils, monocytes, dendritic cells and T lymphocytes whereas mast cell stabilisers specifically inhibit mast cell degranulation in response to allergen (by mechanisms that are, as yet, poorly understood).
Why it is important to do this review
VKC causes significant morbidity, loss of schooling and loss of vision in children. A wide variety of treatments are used to treat exacerbations and prevent recurrences of disease. A systematic review of topical treatments for people with VKC, published in 2007, showed that a variety of available topical treatments were effective in treating acute phases of VKC (Mantelli 2007). This review, which included studies published before 2004, revealed a lack of head to head comparisons between treatments for VKC. The aim of the present review is to assess the most up-to-date available evidence on the use of topical interventions for the treatment of VKC. It is hoped that the results of this review, in conjunction with those of concurrent reviews of systemic treatments and systemic versus topical treatments for VKC respectively, will help to identify areas where there is a particular deficiency of data or which might be rewarding targets for further research.