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Volume 6 No. 3, September 2010 Review Article A Practical Approach to Management of Allergic Eye Conditions in Children Dexter Yu-Lung LEUNG Hong Kong Eye Hospital; Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong; and Hong Kong Ophthalmological Society, Hong Kong

Introduction In USA, expenditure related to ocular prescription rose from US$6 million in early 1990s to While nasal allergy all along has been important in >US$200 million in the new millennium, projecting an allergy research, ocular allergy is now increasingly annual growth of 25% per year in USA.7 recognized as a distinct symptoms-and-signs complex that imposes significant disease burden with reduction of quality of life of patients. is Classification highly prevalent in Hong Kong and has a close epidemiologic relationship with allergic rhinitis.

The emphasis of this article will also be on what a paediatrician can do prior to the point of referral: recognition of the ocular symptoms, recognition of potential sight-threatening situations, and effective initial treatment.

Disease burden

While we are still awaiting published evidence for official incidence of ocular allergy in Hong Kong, a recent survey from the Eye Institute of the University of Hong Kong, conducted during May and June 2009 on 1,000 parents with children less than 12 years old in Hong Kong, has estimated that approximately 30% SAC and PAC are more common, and while they are of children suffered from eye allergy.1 symptomatic, they are less likely to result in long term ocular complications. VKC and AKC are rarer, more The incidence of ocular allergy varies in different chronic but are potentially associated with severe geographical regions and tends to be more common blinding ocular complications. One key task the in countries with warm climates. In the US, as much patients and ophthalmologists would appreciate, as 40% of the general population suffered from allergic will be for our paediatricians colleagues to look conjunctivitis.2-4 In one study of 5000 allergic children, out for VKC and AKC and refer them to eye care. 32% had ocular symptoms as the single manifestation GPC typically occurs in contact lens wearer, and of their allergies.5 A recently published prevalence contact allergic conjunctivitis can be diagnosed on study in Japan has found that out of 1079 patients history of, for example, chemical exposures. with allergic ocular disease, the seasonal and perennial allergic conjunctivitis consist of over 90% of all cases, with a much higher mean age of over 50 Highlights in pathogenesis years old and a less severe overall clinical score than the chronic types such as vernal and atopic In all forms of allergic eye diseases, the clinical keratoconjunctivitis.6 response is mainly caused by the mast cells activation due to either an antigen − mast cells linkage or T-cell activation of mast cells. The activation of conjunctival Email: [email protected] mast cells in turn leads to the release of ,

4 Journal of Paediatric Respirology and Critical Care prostaglandins D2, leukotriene C4, tryptase, chymase, conjunctivitis related red eye. In SAC and PAC, platelet activating factor (PAF) and other itchiness is usually more prominent than grittiness and chemoattractants. This further attracts the eosinophils pain. Infective e.g. viral conjunctivitis patients usually and neutrophils.8-11 Vernal keratoconjunctivitis and atopic have more pain. Tearing is usually less profuse in SAC keratoconjucntivitis are traditionally seen as type I IgE- and PAC than in infective red eye, the later is more mediated hypersensitivity reaction. However current likely to be associated with tears and discharge. evidence shows that eosinophils and its major basic History of known atopy/allergic rhinitis, history of proteins are also important players in the chronic contacts with persons with viral conjunctivitis, swab allergic process, with its role in eliciting ocular surface from inferior conjunctival cul-de-sac for culture, and inflammation and epithelial damage.12 The chronic conjunctival impression cytology are useful adjuncts. allergic conjunctivitis has an increased concentrations of T helper-1 (Th1) and especially T helper-2 (Th2) cells, which stimulate the migration and proliferation Vernal keratoconjunctivitis of conjunctival fibroblasts as well as protecting these cells from apoptotic cell death, effects that likely Vernal keratoconjunctivitis (VKC) is a rarer disease. underlie the hyperplasia of fibroblasts, contributing It usually affects boys around age of puberty. to the formation of giant papillae. Stimulation of According to a large case series in Italy,14 the average fibroblasts in the corneal stroma with the combination age of presentation of this disease is around 11 years of a proinflammatory cytokine and either IL-4 or IL-13 old. The disease usually waxes and wanes over its results in up-regulation of the expression of the course and its severity may stabilize towards the end chemokine eotaxin and thymus- and activation- of puberty. It is a clinically more severe and chronic regulated chemokines as well as of vascular cell disease and patients will suffer from flare ups over adhesion molecule-1, which together mediate the the years of the disease. Some of these patients also infiltration and activation of eosinophils and Th2 cells.13 show a climacteric pattern, with spring and autumn Fibroblasts therefore appear to play a central role in being more common. Symptom-wise, these patients the induction and amplification of ocular allergic complain of itchiness, tearing, redness and ocular inflammation and the consequent development of discharge which are different from acute allergic giant papillae and corneal disorders in individuals with conjunctivitis in that they are more chronic. The clinical VKC. signs are helpful to distinguish VKC from SAC or PAC: include conjunctival injection, giant papillae in palpebral conjunctiva ("palpebral vernal"), Trantas' Acute allergic conjunctivitis dots ("limbal vernal") and corneal complications such as punctate epitheliopathy and shield ulcers. Giant Acute allergic conjunctivitis (AC) is the commonest papillae are one of the hallmarks of the disease. They form of allergic eye diseases. It can be divided into are papillary conjunctival mass of more than 1 mm in seasonal (SAC) and perennial (PAC), with PAC size on the tarsal conjunctiva. These are proliferation considered as a chronic variant of SAC. In most cases, of collagen underneath the conjunctival epithelium. allergens can be identified. Patients usually present Its presence signifies prolonged chronic inflammation with acute ocular symptoms such as itchiness, tearing, and conjunctival fibrosis can occur in the long term. ocular irritation and discomfort. The symptoms are The presence of giant papillae indicates poor usually short lived and are not tend to be recurrent. prognosis of the disease. Trantas' dots are round Classical signs include redness, injection, lids swelling gelatinous white elevations over superior limbal area. and chemosis. Bilateral signs and symptoms are They are made up of collections of eosinophils. common. Allergens that can initiate these symptoms Corneal complications are secondary to the include dust mites, pollens and fungi, the presence breakdown of corneal epithelium with subsequent of which suggests a seasonal variation pattern. plague formation with fibrin and mucus deposits on Patients usually have a history of atopy, asthma and the ocular surface. These will lead to delayed corneal allergic rhinitis. healing and formation of shield ulcers. Shield ulcers only occur in 3-11% of VKC patients, but it can lead One key issue is how to differentiate from to permanent visual disability in 6% of all VKC symptoms, allergic red eye from infective cases.14

5 Volume 6 No. 3, September 2010 Review Article

different sequelae of chronic allergic inflammation. They can present with severe excoriation, pigmentation and scarring of the lids. The tarsal conjunctiva will no longer show giant papillae as in vernal keratoconjunctivitis but a featureless conjunctiva with scarring formation. The eye could be itchy and red at times but patients will start to have a less severe attack than before, partly because they are getting used to the disease. However they can present with dreadful complications on cornea which include microerosions and punctate epitheliopathy, macroerosions, shield ulcers and plagues forming on the macroerosions secondary to prolonged delayed healing of the corneal epithelium and deposition of calcium on the de-epithelialized cornea. They will also suffer from complications of cataract and even glaucoma. The cataract can be anterior subcapsular or posterior subcapsular in appearance. Some of these complication may be secondary to the diseases itself but also secondary to the prolonged use of topical steroids in vernal attacks.

Atopic keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is different from VKC in which the presentation is more chronic and signs and symptoms can continue into adult life. This is even rarer in incidence and is only seen infrequently by ophthalmologists. Essentially, patients suffer from the

6 Journal of Paediatric Respirology and Critical Care

Treatment modalities the oral . They can be used on a p.r.n. basis for those patients who have occasional The treatment for allergic conjunctivitis is allergic eye symptoms and can offer great relief. multidisciplinary. Many of these patients may have Oral histamine H1-receptor antagonists such as associated atopic diseases such as asthma and rhinitis, , terfanidine and have also been which necessitates a multi-disciplinary approach shown to be effective in alleviating ocular symptoms. involving paediatricians, medical physicians, general They are excellent choices when attempting to control practitioners and clinical immunologists. multiple early-phase and some late-phase allergic symptoms in the eyes, nose and pharynx.13,15 But its Avoidance of allergens is an important starting clinical effect is offset by its longer time of action and strategy. It is advisable to ask the children not to rub accompanying systemic side effects such as sedation their eyes, since the act of rubbing will directly and dry mouth. Hence oral are not gaining degraulate mast cells on ocular surface. Measures popularity for treating allergic eye diseases.15 Recently, such as cold compression to peri-orbital areas, the newer second-generation antihistamines (, eyewashes with tear substitutes are also helpful ways , loratadine and ) are to alleviate symptoms of allergic eye diseases. It is preferred alternatives over older first-generation important to be aware that many of these patients are antihistamines with fewer sedative and anticholinergic young and may not be able to tell a full clinical history. side effects.13,15

For the ocular involvement, the mainstay of treatment Mast cells stabilizers are useful in the quiescent includes topical medications. Oral medications are phase to prevent attack. The most commonly used only indicated in very severe cases. medication is the sodium cromoglycate eye drops. The principle behind these mast cells stabilizers is that Current topical medications for allergic conjunctivitis they can prevent mast cells getting degranulated and included topical antihistamines, mast cells stabilizers, as a result the allergic and inflammatory cascade will eosinophil deactivators and lubricants (Table 1). Anti- not be initiated. Therefore it is especially useful if the inflammatory drugs such as steroid and NSAID drops patients can start the medications several days before are usually required in more severe cases. The most the expected exposure of allergens. In cases of acute common and useful medications with rapid relief of allergic attacks, its use in relieving symptoms may symptoms include antihistamines such as , be less effective.8,15 and emedastine. Through its immediate antagonism effect, these Topical vasoconstrictor agents provide rapid relief, antihistamines can reduce itchiness, redness and especially for redness; however, the relief is often swelling commonly seen in acute allergic blepharo- short-lived, and overuse of vasoconstrictors may lead conjunctivitis. The onset of action is also quicker than to rebound hyperaemia and irritation.

Table 1. List of medications used in allergic conjunctivitis Treatment modalities Potential uses Topical or oral (antazoline, levocabastine and emedastine) Symptoms relief

Topical mast cells stabilizer (sodium cromoglycate) Prevention of attack

Topical combined agents (, ) Combined effects of antihistamines, mast cells stabilizers, eosinophil deactivators. Becoming the medication of choice in chronic allergies

Topical non-steroidal anti-inflammatory drugs (NSAID) (Ketorolac) Effective in relieving symptoms, but less powerful than the combined agents

Topical steroids Useful in severe attacks

Topical cyclosporine Early evidence showed promising results, use in more severe chronic allergies

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There are new agents with the combination of Non-steroidal anti-inflammatory drugs (NSAIDs), with antihistamines, mast cells stabilizers, eosinophil its effect to inhibit prostaglandin synthesis including deactivators in one medication. Recent data prostaglandins D2 and E2, have been seen with suggested superior clinical effects. Drops such as clinical effect on patients with seasonal allergic olopatidine (trade name: patanol 0.1%), ketotifen conjunctivitis. Ketorolac (trade name: Acular 0.5%) is (trade name: zaditen 0.025%) and (trade one of the newer choice in this group that has been name: Elestat 0.05%) may be superior in clinical approved by FDA. Studies on ketorolac suggested a response than the traditional antihistamines alone and superior effect to control allergic symptoms than therefore they now become the group of choice. The bd placebo.25 A comparative study on ketorolac and dosing regimen for most of these medications is also a olopatadine by Yaylali et al group (n=40) have potential benefit for these patients compared to some revealed an equally effective profile in alleviating of the old antihistamines. Olopatidine is a selective symptoms and signs of seasonal allergic histamine H1-receptor antagonist and has mast cells conjunctivitis. However, olopatadine reduces ocular membrane stablising propterties, inhibiting the release itching significantly more than ketorolac.26 Therefore, of inflammatory lipid mediators such as leukotrienes and topical NSAIDS are generally inferior for relief of thromboxanes from polymorphonuclear leucocytes and allergic conjunctivitis when compared with olopatadine eosinophils.16,17 Ketotifen is also a similar group of and emedastine. medication which blocks histamine1 (H1) receptors, stabilizes mast cells and inhibits chemotaxis and Topical corticosteroids may be considered for more activation of eosinophils.18,19 Epinastine is another severe seasonal ocular allergy symptoms, although potent antagonist which long-term use should be avoided because of risks of showed good in vivo and in vitro evidence in ocular adverse effects, including glaucoma and antiallergic and anti-inflammatory effects in addition cataract formation. to the antihistaminergic properties.20 A randomized double-blinded control trial to look at the effect of Topical cyclosporine has gained a lot of interests in olopatadine 0.1% versus placebo has shown a recent years. Treatment benefits were seen in patients decrease in symptoms and signs score in seasonal with keratoconjunctvitis sicca (KCS) or chronic dry allergic conjunctivitis with olopatadine.21 A double- eyes (trade name: Restasis 0.05%) 27 and was masked environmental study on seasonal and successfully marketed after approval by the FDA in perennial allergic conjunctivitis patients has revealed US. Evidence are now looming that this medication that olopatidine have overall better efficacy and is also helpful in treating allergic eye diseases. Studies comfort score than ketotifen.22 However, another by Hingorani et al28 and Akpek et al29 have shown randomized double-masked study comparing ketotifen clinical improvement in both 2% and 0.05% and olopatidine showed no difference in clinical effects concentration. However various studies have revealed and improvement in inflammatory markers on conflicting results.28-32 Its effective concentration and conjunctival impression cytology.23 Another recent dosing regimen of this potential medication are yet to randomized double-blinded placebo-controlled trial be worked out. comparing the effect of topical olopatadine, ketotifen fumarate, epinastine, emedastine or fluorometholone Previous studies revealed that topical cyclosporine acetate found that all medications except could lead to a reduction of epithelial and stromal fluorometholone were equally effective in reducing Class II MHC cells, T cells and IgA and IgG plasma itchiness and redness.24 There were no clinical cells in VKC patients, highlighting an immunomodulating differences in terms of reducing tearing chemosis effect on cell-mediated and humoral immune responses. and swelling amongst the medications studied.24 The effect on mast cells and IgE mediated allergic Compared to olopatadine, some studies have responses are however not significant.32 Since VKC/ revealed that ketotifen and epinastine can have a AKC involves both IgE and non IgE mechanisms, higher degranulation inducing effects on corneal cyclosporine should have some clinical effect on VKC. epithelial cells and mast cells. Therefore it may be However, clinical effects and signs improvement need less comfortable to use than the former.17 Further to be further quantified. clinical trials are therefore necessary to look further into their side effects profiles and patient Patients with asthma and VKC could see some light tolerability. in their treatment. Montelukast, a leukotriene receptor

8 Journal of Paediatric Respirology and Critical Care antagonist has demonstrated its clinical effect in References asthma patients. Its effect in controlling other atopic symptoms were further investigated.33-35 Early study 1. Eye Institute, The University of Hong Kong, Hong Kong. Press 33 by Lambiase et al. on a group of 12 patients seemed Release dated 8 July, 2009. to show significant improvement in physician-rated 2. Singh K, Bielory L. Ocular allergy: a national epidemiologic hyperemia, secretion, and chemosis as well as study. J Allergy Clin Immunol 2007;119(1 Suppl 1):S154. patient-rated burning, tearing, photophobia, secretion 3. Singh K, Bielory L. Epidemiology of ocular allergy symptoms and redness in VKC patients. However, subsequent in United States adults (1988-1994). Ann Allergy 2007;98: double blinded randomized trial on montelukast has A22. not shown much clinical effect in ocular allergies.35 At 4. Singh K, Bielory L. Epidemiology of ocular allergy symptoms this stage, this medication does not seem to be a in regional parts of the United States in the adult population promising treatment in allergic conjunctivitis and (1988-1994). Ann Allergy 2007;98:A22. 5. Marrache F, Brunet D, Frandeboeuf J, et al. The role of ocular further studies are warranted. manifestations in childhood allergy syndromes. Rev Fr Allergol Immunol Clin 1978;18:151-5. When instilling eyedrops and ointments, it is important 6. Uchio E, Kimura R, Migita H, Kozawa M, Kadonosono K. to allow a rest of 3-5 minutes in between each Demographic aspects of allergic ocular diseases and application of different drops or ointment, in order to evaluation of new criteria for clinical assessment of ocular allow time for better drug absorption. It is usual to allergy. Graefes Arch Clin Exp Ophthalmol 2008;246(2): instill eyedrops before eye ointment, so that the ocular 291-6. surface absorption of eyedrops will not be impeded 7. Bielory L. Update on ocular allergy treatment. Expert Opin by eye ointment. In applying eyedrops to children, it Pharmacother 2002;3(5):541-53. is not necessary to struggle with them by pulling open 8. McGill JI, Holgate ST, Church MK, Anderson DF, Bacon A. both eyelids for the application, nor it is necessary to Allergic eye disease mechanisms. Br J Ophthalmol 1998;82 (10):1203-14. apply the eyedrops directly onto eyeball, which can 9. McGill J. Conjunctival cytokines in ocular allergy. Clin Exp be frightening to them. The inferior eyelid, which is Allergy 2000;30(10):1355-7. usually more lax than superior eyelid, can be gently 10. Church MK, McGIll JI. Human ocular mast cells. Curr Opin pulled down to expose the inferior conjunctival cul- Allergy Clin Immunol 2002;2(5):419-22. de-sac, and the eyedrops and ointment can be instilled 11. Proud D, Sweet J, Stein P, Settipane RA, Kagey-Sobotka A, effortlessly there even if the eyeball is completely Friedlaender MH, et al. Inflammatory mediators release on under the superior eyelid. It is also a good idea to conjunctival provocation of allergic subjects with allergen. apply the medications while the child is asleep. J Allergy Clin Immunol 1990;85(5):896-905. 12. Trocme SD, Kephart GM, Bourne WM, Buckley RJ, Gleich Pathways of communication are thought to increase GJ. Eosinophil granule major basic protein deposition in the likelihood of an inflammatory reaction at both corneal ulcers associated with vernal keratoconjunctivitis. Am J Ophthalmol 1993;115(5):640-3. sites following allergen exposure of nasal or ocular 13. Miyazaki D, Nakamura T, Komatsu N, Nawata N, Ikeda Y, tissue. Clinical trials of intranasal therapies have Inoue Y, et al. Roles of Chemokines in ocular allergy and demonstrated efficacy in allergic conjunctivitis possible therapeutic strategies. Cornea 2004;23(8 Suppl):S48- and rhinitis. Newer intranasal steroids decrease 54. ocular symptoms, potentially achieving efficacy by 14. Bonini S, Bonini S, Lambiase A, Marchi S, Pasqualetti P, suppressing the naso-ocular reflex, downregulation Zuccaro O, et al. Vernal Keratoconjunctivitis revisited- a case of inflammatory cell expression, or restoration of series of 195 patients with long term followup. Ophthalmology nasolacrimal duct patency. Proposed pathophysiologic 2000;107(6):1157-63. interactions between allergic rhinitis and ocular allergy 15. Simons FE. H1 receptor antagonists. Clinical pharmacology underscore the need for therapies with efficacy in both and therapeutics. J Allergy Clin Immunol 1989;84(6 Pt 1): symptom sets. 845-61. 16. McGill JI. A review of the use of olopatadine in allergic conjunctivitis. Int Ophthalmol 2004;25(3):171-9. 17. Rosenwasser LJ, O'Brien T, Weyne J. Mast cell stabilization Acknowledgement and anti-histamine effects of olopatadine ophthalmic solution: a review of pre-clinical and clinical research. Curr Med Res The author would like to acknowledge Dr Jeffrey Chiu Opin 2005;21(9):1377-87. Fai PONG (Hong Kong Adventist Hospital) for his 18. Schoch C. In vitro inhibition of human conjunctival mast-cell gracious input into this manuscript. degranulation by ketotifen. J Ocul Pharmacol Ther 2003;19

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(1):75-81. C, et al. Comparative study of 0.1% olopatadine hydrochloride 19. Abelson MB, Chapin MJ, Kapik BM, Shams NB. Efficacy of and 0.5% ketorolac tromethamine in the treatment of seasonal ketotifen fumarate 0.025% ophthalmic solution compared with allergic conjunctivitis. Acta Ophthalmol Scand 2003;81(4): placebo in the conjunctival allergen challenge model. Arch 378-82. Ophthalmol 2003;121(5):626-30. 27. Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III 20. Amon U, Gibbs BF, Buss G, Nitschke M. In vitro investigations safety evaluation of cyclosporine 0.1% ophthalmic emulsion with the histamine H1 receptor antagonist, epinastine (WAL administered twice daily to dry eye disease patients for up to 801 CL), on isolated human allergic effector cells. Inflamm 3 years. Ophthalmology 2005;112(10):1790-4. Res 2000;49(3):112-6. 28. Hingorani M, Moodaley L, Calder VL, Buckley RJ, Lightman S. 21. Abelson MB, Turner D. A randomized, double-blind, parallel- A randomized, placebo controlled trial of topical cyclosporine- group comparison of olopatadine 0.1% ophthalmic solution A in steroid dependent atopic keratoconjunctivitis. versus placebo for controlling the signs and symptoms of Ophthalmology 1998;105(9):1715-20. seasonal allergic conjunctivitis and rhinoconjunctivitis. Clin 29. Akpek EK, Dart JK, Watson S, Christen W, Dursun D, Yoo S, Ther 2003;25(3):931-47. et al. A randomized trial of topical cyclosporine 0.05% in topical 22. Lenoardi A, Zafirakis P. Efficacy and comfort of olopatadine steroid resistant atopic keratoconjunctivitis. Ophthalmology versus ketotifen ophthalmic solutions: a double masked, 2004;111(3):476-82. environmental study of patient preference. Curr Med Res Opin 30. Bleik JH, Tabbara KF. Topical cyclosporine in vernal 2004;20(8):1167-73. keratoconjunctivitis. Ophthalmology 1991;98(11):1679-84. 23. Avunduk AM, Tekelioglu Y, Turk A, Akyol N.Comparison of 31. Kaan G, Ozden O. Therapeutic use of topical cyclosporine. the effects of ketotifen fumarate 0.025% and olopatadine HCl Ann Ophthalmol 1993;25(5):182-6. 0.1% ophthalmic solutions in seasonal allergic conjunctivities: 32. el-Asrar AM, Tabbara KF, Geboes K, Missotten L, Desmet V. a 30-day, randomized, double-masked, artificial tear An immunohistochemical study of topical cyclosporine in vernal substitute-controlled trial. Clin Ther 2005;27(9):1392-402. keraotoconjunctivitis. Am J Ophthal 1996;121(2):156-61. 24. Borazan M, Karalezli A, Akova YA, Akman A, Kiyici H, Erbek 33. Lambiase A, Bonini S, Rasi G, Coassin M, Bruscolini A, Bonini SS. Efficacy of olopatadine HCI 0.1%, ketotifen fumarate S. Montelukast, a leukotriene receptor antagonist, in vernal 0.025%, epinastine HCI 0.05%, emedastine 0.05% and keratoconjunctivitis associated with asthma. Arch Ophthalmol. fluorometholone acetate 0.1% ophthalmic solutions for 2003;121(5):615-20. seasonal allergic conjunctivitis: a placebo-controlled 34. Riccioni G, Di Ilio C, Conti P, Theoharides TC, D'Orazio N. environmental trial. Acta Ophthalmol 2009;87(5):549-54. Advances in therapy with antileukotriene drugs. Ann Clin Lab 25. Ballas Z, Blumenthal M, Tinkelman DG, Kriz R, Rupp G. Sci 2004 Autumn;34(4):379-87. Clinical evaluation of ketorolac tromethamine 0.5% ophthalmic 35. Lehtimaki L, Petays T, Haahtela T. Montelukast is not effective solution for the treatment of seasonal allergic conjunctivits. in controlling allergic symptoms outside the airways: a Surv Ophthalmol 1993;38 Suppl:141-8. randomized double-blind placebo-controlled crossover study. 26. Yaylali V, Demirlenk I, Tatlipinar S, Ozbay D, Esme A, Yildirim Int Arch Allergy Immunol 2009;149(2):150-3.

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