Vernal keratoconjunctivitis (VKC) is an allergic eye disease that especially affects young boys. The most common symptoms are itching, photophobia, burning, and tearing. The most common signs are giant papillae, superficial keratitis, and conjunctival hyperaemia.
Patients with VKC frequently have a family or medical history of atopic diseases, such as asthma, rhinitis, and eczema. However, VKC is not associated with a positive skin test or RAST in 42–47% of patients, confirming that it is not solely an IgE-mediated disease. On the basis of challenge studies as well as immunohistochemical and mediator studies, a Th2-driven mechanism with the involvement of mast cells, eosinophils, and lymphocytes has been suggested. Th2 lymphocytes are responsible for both hyperproduction of IgE (interleukin 4, IL-4) and for differentiation and activation of mast cells (IL-3) and eosinophils (IL-5). Other studies have demonstrated the involvement of neural factors such as substance P and NGF in the pathogenesis of VKC, and the overexpression of oestrogen and progesterone receptors in the conjunctiva of VKC patients has introduced the possible involvement of sex hormones. Thus, the pathogenesis of VKC is probably multifactorial, with the interaction of the immune, nervous, and endocrine systems.
The clinical management of VKC requires a swift diagnosis, correct therapy, and evaluation of the prognosis. The diagnosis is generally based on the signs and symptoms of the disease, but in difficult cases can be aided by conjunctival scraping, demonstrating the presence of infiltrating eosinophils. Therapeutic options are many, in most cases topical, and should be chosen on the basis of the severity of the disease. The most effective drugs, steroids, should however be carefully administered, and only for brief periods, to avoid secondary development of glaucoma.
A 2% solution of cyclosporine in olive oil or in castor oil should be considered as an alternative. The long-term prognosis of patients is generally good; however 6% of patients develop corneal damage, cataract, or glaucoma.
Vernal keratoconjunctivitis (VKC) is a member of a group of diseases classified as allergic conjunctivites including perennial and seasonal rhinoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis.1,2,3 For many years, all allergic conjunctivites were considered (as suggested by Coombs and Gell4) the expression of a classical type I IgE-mediated hypersensitivity reaction at the conjunctival level. More recent clinical observations, however, suggest that other tissues of the eye are also involved in the ocular allergic reaction: the lids, with their high content of mast cells, the tear film, with its immunoglobulins, and the cornea, so important for visual function. New discoveries regarding the pathogenesis of ocular allergies have clearly indicated that the participation of the entire ocular surface in allergic diseases is not only the consequence of tissue contiguity but derives from a complex exchange of information between these tissues through cell-to-cell communications, chemical mediators, cytokines, and adhesion molecules. It is also possible that the neural and endocrine systems may influence the ocular allergic response.
The purpose of this paper is to describe the clinical expression of VKC, to discuss its pathogenetic mechanisms, and to suggest novel therapeutic strategies.
VKC is a chronic bilateral inflammation of the conjunctiva characterized by hyperaemia, chemosis, photophobia, and filamentous and sticky mucous discharge. The hallmark of the disease is the presence of giant papillae (cobblestone appearance) at the upper tarsal conjunctiva (tarsal form) or at limbus (bulbar form).1,2,3 Although there are some differences between the two forms, probably related to geographical variations, it seems likely that both represent different clinical manifestations of the same disease.1 (Figures 1, 2 and 3).
VKC mainly affects boys in their first decade of life and the sequelae of the disease may be responsible for permanent visual impairment. Despite its name, the disease can be frequently present all year round. Approximately 23% of patients have a perennial form of VKC from disease onset and more than 60% have additional recurrences during the winter.5 Furthermore, in almost 16% of the cases, the seasonal (vernal) form evolves into a chronic, perennial inflammation after a mean of 3 years from disease onset, suggesting that the longer patients suffer from VKC, the more apt they are to develop a persistent form of the disease.5
Itching, photophobia, burning, and tearing are the major ocular symptoms. Patients also complained of frequent conjunctival redness after exposure to nonspecific stimuli. This finding supports previous reports suggesting the presence of a conjunctival hyper-reactivity when sun, dust, wind, and other general climactic factors or nonspecific stimuli come in contact with the conjunctival mucosa.6 This hyper-reactivity, which is also known to be frequently associated with asthma and other allergic diseases, may actually be a distinct clinical entity. At present, the exact mechanism for nonspecific hyper-reactivity is not understood, but it is possible that the release of vasoactive mediators could be involved.7
Signs include the presence of giant papillae on the upper tarsal conjunctiva or at the limbus, the presence of aggregates of epithelial cells and eosinophils at the limbus (Trantas’ dots), and marked conjunctival hyperaemia. Subconjunctival fibrosis, symblepharon, and conjunctival keratinization can develop. The cornea is almost always damaged with a superficial keratopathy, or the presence of corneal shield ulcers (occurring in approximately 3–11%) and neovascularization.5,8,9 A blepharitis is frequently associated and eczema or maceration of the lid can be observed. Cataract and steroid-induced glaucoma are the major ocular complications.5,9
Patients with VKC have a family history of atopic diseases in 49% of cases. These patients may also have a medical history of other atopic conditions including asthma (26.7%), rhinitis (20%), and eczema (9.7%).5 Data regarding the frequency of sensitisation are conflicting: Ballow and Mendelson10 reported 19% of positive sensitisation, Easty et al11 reported 80%. In a large series of 195 patients, we found a positive response to skin tests and RAST in 57 and 52%, respectively.5 Total IgE has been shown to be elevated in the serum, and local production of IgE in tears has been postulated.10,11,12,13,14 However, levels of tear IgE were low, at 18.5±19.2 U/ml, in our patients and we never observed a positive RAST in tears in the presence of negative results in the serum.15
Recent studies suggest a more complex non-IgE-dependent pathogenic mechanism. A multitude of cells and mediators have been detected in the serum, conjunctiva, and tears of patients with VKC, which may have a relevant role in the pathogenesis of the disease.13,16,17,18,19 Although many features of VKC suggest an allergic pathogenesis,3,12,20 this eye disease can no longer be considered a classical type I IgE-mediated disease, as included in the classification by Gell and Coombs.16,21 In fact, skin tests and RAST are often negative in VKC and several patients do not have a personal or family history of atopy.5 On the basis of challenge studies as well as immunohistochemical and mediator studies, we recently suggested a Th2-driven mechanism and a definition, similar to that of asthma, of ‘an allergic inflammatory disease of the conjunctiva with mast cells, eosinophils, and lymphocytes’.21 Supporting this definition are the findings that T-cell clones derived from VKC tissues are mainly of the Th2- type and that in the CD4 areas of VKC biopsies, there is an increased in situ hybridization signal for IL-5 associated with increased IL-5, but not IL-2, levels in tears, suggesting Th2 rather than Th1 activity.18,22,23,24,25 It is possible that the pathogenesis of VKC is characterized by a Th2 lymphocyte alteration, while the exaggerated IgE response to common allergens is an inconsistent and, perhaps, secondary event. Th2 lymphocytes are responsible both for hyperproduction of IgE (interleukin 4, IL-4) and for differentiation and activation of mast cells (IL-3) and eosinophils (IL-5). Mast cells and basophils cause the immediate reaction (through the release of histamine) and the recruitment of inflammatory cells (lymphocytes and eosinophils). This cell recruitment (favoured by an overexpression of adhesion molecules) results in the release of other toxic cell mediators (such as eosinophil cationic protein, EDN/EPX) with corneal epithelial damage.18,26,27,28 Indeed, several inflammatory and epithelial cells may induce fibroblast proliferation and collagen production leading to the characteristic conjunctival findings.
While histamine is the main mediator in allergic reactions with a prevalent Type I hypersensitivity mechanism (such as perennial or seasonal allergic conjunctivitis), and in the early phase of allergic reactions (antihistamines are thus effective in these conditions), other mediators are involved in VKC, such as eosinophilic mediators and substances derived from the metabolism of arachidonic acid (prostaglandins and leukotrienes).12,29 In particular, leukotrienes are produced during allergic and inflammatory respiratory diseases by mast cells, macrophages, and neutrophils.30,31 They are potent mediators of hypersensitivity and inflammatory reactions.16 Their activities include smooth-muscle contraction, small vessel dilatation, increase in blood vessel permeability, promotion of glycoprotein secretion from epithelial glands, and increase of nasal blood flow and airway resistance.32,33,34,35,36 It has been demonstrated that leukotrienes are also produced in the conjunctiva37 and are detectable in tear fluids of patients affected by allergic conjunctivitis including VKC.38,39,40 Indeed LT concentration in tears increases in allergic subjects following allergen challenge.41,42 In addition, conjunctival administration of LTB4, as well as LTC4 and LTD4, induces vessel vasodilatation, oedema, hyperaemia, and leucocyte and eosinophilic infiltration of the conjunctiva.43,44,45 The biological activities of leukotrienes on the conjunctiva may contribute to the presence of the characteristic symptoms observed in VKC, such as mucous secretion, conjunctival hyperaemia, and chemosis.
Neural and endocrine involvement
The existence of a relationship between the central nervous system and the eye is easily established when considering common anatomical and embryogenic origins. This cross-talk is also strictly related to the immune system and is shown by nerve and mast cell interaction. Whether neurotransmitters and neurotrophins may influence conjunctival inflammation is not clear at present. Substance P, a neuropeptide with well-known activity on immune cells, has been detected in tears, and high serum levels have been found in patients with VKC.46,47
Receptors for nerve growth factor have been found in the epithelium and substantia propria of the conjunctiva, and high serum levels of nerve growth factor are detectable in the active form of the disease and are directly related to the number of mast cells in the conjunctival tissue, suggesting that neural influences may have a role in the pathogenesis of allergic diseases.48,49
A role for sex hormones has been postulated in the pathogenesis of the disease. This assumption derives from the observation of a prevalence of males vs females and a spontaneous resolution of the disease at puberty. Sex hormones may play a relevant role in the pathophysiology of allergic diseases by reciprocal interactions between the immune and the endocrine system. Oestrogens and progesterone have been shown to be active players in the ocular immune system, with an already well-established role in another immunological disease, dry eye syndrome.50 In a previous immunohistochemical study of patients with VKC, we reported that oestrogen and progesterone receptors were overexpressed on the conjunctiva by eosinophils and other inflammatory cells.51 These hormones may bind to conjunctival receptors and exert a proinflammatory effect through the recruitment of eosinophils to the conjunctival tissue.52,53
The typical, characteristic signs and symptoms of this disease render the diagnosis of VKC fairly straightforward, even for the general ophthalmologist. Atypical presentations or incomplete forms of VKC may, however, lead to an underestimation of its incidence. The identification of both the major and minor signs and symptoms of VKC allows an early and accurate diagnosis of this disease.
At present, total and specific IgE determination, as well as skin tests cannot be considered useful additional laboratory tests, because more than 50% of patients with VKC are negative.
In case of a diagnostic dilemma, a conjunctival scraping can be precious in demonstrating the presence of eosinophils infiltrating the conjunctival epithelium.
Clinical observation suggests that VKC generally subsides with the onset of puberty, but some therapeutic measures may be required beyond this age to control the course of the disease. In some cases, permanent changes to the ocular surface may occur and be accompanied by permanent visual impairment. Although vernal keratoconjunctivitis generally has a good prognosis, 52% of patients in our cohort had persistent symptoms after a mean follow-up period of approximately 5 years and 6% of patients showed a permanent reduction in visual acuity as a result of corneal damage.5
Treatment is symptomatic and topical eye drops are generally preferred as first choice. Cromolyn and the new generation of antiallergic compounds such as alomide tromethamine, nedocromil sodium, spaglumic acid, and topical antihistamines are effective in reducing signs and symptoms of the disease.54 Use of unpreserved solutions may reduce the risk of hypersensitivity to preservatives that are frequently superimposed in these patients. Nonsteroidal anti-inflammatory agents also produce a beneficial effect on the course of VKC.55 Topical steroid preparations are, naturally, the most effective therapy for moderate to severe form of VKC,5,9 however their use should be strictly limited and carefully monitored because long-term use of topical steroids is responsible for the 2% incidence of glaucoma in VKC patients.5
Therefore, this class of drugs should be used to restore corneal damage induced by epithelial toxic mediators from eosinophils and neutrophils. Once the acute phase of the disease is controlled, steroids should be discontinued and alternative topical treatment (mast cell stabilizers, antihistamine, NSAIDs) should be started.
Cyclosporine A (CsA) from 0.5 to 2% ophthalmic emulsions in olive or castor oil, used four times daily, represents a valid alternative to steroids in severe forms of VKC.
In fact, CsA is effective in controlling ocular inflammation, blocking Th2 lymphocyte proliferation, and IL-2 production. It also inhibits histamine release from mast cells and basophils and, through a reduction of IL-5 production, it may reduce the recruitment and the effects of eosinophils on the conjunctiva.56,57,58,59 Moreover, the therapeutic efficacy of CsA in VKC, a conjunctival hyperproliferative disorder, seems to be related to the drug's efficacy in reducing conjunctival fibroblast proliferation rate and IL-1β production.60
In a few patients with VKC, a systemic treatment may be required. Oral antihistamines can reduce the generalized hyper-reactivity but have little or no effect on vernal keratoconjunctivitis,61 while aspirin treatment,62,63 as well as oral administration of Montelukast (5–10 mg once/day),64 an anti-leukotriene drug usually used in mild asthma, has been demonstrated to be effective in reducing signs and symptoms of VKC.
Patients with VKC generally have spontaneous resolution of the disease after puberty without any further symptoms or visual complication. However, corneal ulcers, which are reported to develop in approximately 9.7% of patients, as well as the development of cataract or glaucoma, can produce a permanent visual impairment.65,66
As negative prognostic factor, it has been reported that the size of the giant papillae is directly related to the probability of the persistence or worsening of symptoms and that the bulbar forms of VKC have a worse long-term prognosis than the tarsal forms.5
Conjunctival fibrosis observed on the upper tarsal conjunctiva can be considered to be the natural evolution of giant papillae. It is important to note that in the few patients treated with cryogenic surgery to reduce papillary excrescencies, a marked pemphigoid-like appearance was evident all over the conjunctiva. Thus, it appears that in some VKC patients, any additional inflammation such as that induced by cryogenic therapy may result in an exaggerated tissue response.
Recently, new reports have improved the knowledge of the pathogenetic mechanisms of VKC. The typical male pattern of incidence significantly decreases with age, with disparity diminishing greatly in patients after puberty. It was shown to be a perennial and not a seasonal disease in the majority of patients, with a tendency to become chronic in long-lasting forms. VKC was shown to be not solely IgE-mediated, but its pathogenesis is multifactorial, mediated by Th2 lymphocytes, eosinophils, IgE, mast cells, and a complex network of interleukins and cell mediators. The presence of increased serum levels of cytokines, enzymes, eosinophil-derived mediators, neuropeptides, and neurotrophins also suggests that this is a systemic, and not just a local, disease.67,68,69 The long-term prognosis of the VKC patient is generally good; however approximately 6% of the patients develop a visual impairment owing to corneal damage, cataract, or glaucoma.5
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Bonini, S., Coassin, M., Aronni, S. et al. Vernal keratoconjunctivitis. Eye 18, 345–351 (2004). https://doi.org/10.1038/sj.eye.6700675
- allergic conjunctivitis
- vernal keratoconjunctivitis
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