Ocular allergy pathogenesis and diagnosis Luís Delgado, MD PhD departament of Immunology and Immunoallergology Unit Hospital de S. Joao. Porto (Portugal) Marzo 2006 www.alergomurcia.com Good morning, Mr. Chairmen, dear colleagues First of all let me thank for the kind invitation to participate in this symposium Late breaking news in allergy. It will be my great pleasure to review with you recent advances in the understanding of ocular allergy pathogenesis, that I think will help you to establish a correct diagnosis and treatment strategy. 1
Allergic Conjunctivitis : current nosography Ocular Allergy IgE mediated Non-IgE mediated Seasonal allergic conjunctivitis Perennial allergic conjunctivitis Vernal Keratoconjunctivitis Atopic keratoconjunctivitis Giant-papillary conjunctivitis Contact blepharoconjunctivitis Atopic Keratoconjunctivitis Vernal keratoconjunctivitis Dr Delgado Marzo 2006 www.alergomurcia.com Luís Delgado, ECS2006 As in other allergic diseases it is possible to classify Ocular Allergy in IgE mediated conditions - such as seasonal and perennial allergic conjunctivitis, and most forms of vernal and atopic keratoconjunctivitis 2
Allergic Conjunctivitis : current nosography Ocular Allergy IgE mediated Non-IgE mediated Seasonal allergic conjunctivitis Perennial allergic conjunctivitis Vernal Keratoconjunctivitis Atopic keratoconjunctivitis Giant-papillary conjunctivitis Contact blepharoconjunctivitis Vernal Keratoconjunctivitis Atopic keratoconjunctivitis Dr Delgado Marzo 2006 www.alergomurcia.com Luís Delgado, ECS2006 and non-ige mediated forms that include some cases of the last two diseases but also, giant-papillary conjunctivitis and contact blepharoconjuncitivitis. 3
Conjunctival epithelium Histamine PAF LTC4 Immediate reaction We will start to follow the pathophysiology of ocular allergy through the dynamics of IgE-mediated acute forms - IgE bound to the conjunctival mast cells triggers a rapid cellular degranulation after contact with the allergen, and a prompt release of vasoactive and proinflammatory mediators leading to conjunctival hyperaemia and oedema (chemosis) typical of acute allergic conjunctivitis (inset) 4
leading to conjunctival hperaemia and oedema (chemosis) typical of acute allergic conjunctivitis 5
Conjunctival epithelium MBP ECP MBP Histamine PAF LTC4 PAF TNF-α IL-4 IL-5 Th2 Th2 Immediate reaction Late-phase reaction Mast cells also produce and store pro-inflammatory cytokines (such as TNF-α), and «Th2» cytokines (IL-4, IL-5) which promote the development of the late allergic conjunctival reaction, with a new histamine peak in tears and the recruitment of inflammatory cells such as eosinophils and T cells.. and, clinically, a prolonged hyperaemia with vascular dilatation and oedema (inset) 6
and, clinically, a prolonged hyperaemia with vascular dilatation and oedema (inset) 7
Dendritic Cells In the eye dendritic cells are present in the limbic region of corneal epithelium and in the eyelid skin One growing area of focus in ocular allergy pathogenesis has been the possible contribution of dendritic and structural cells. Dendritic cells are present in the limbic region of corneal epithelium and in the eyelid skin 8
The number of dendritic cells increases significantly in chronic inflammation, and they are seen with macrophages in the conjunctival epithelium... The number of DCs increases significantly in chronic inflammation, and they are seen with monocytes /macrophages in the conjunctival epithelium... 9
Mφ Tho T...allowing the capture and processing of allergens, and antigen presentation to T lymphocytes....allowing the capture and processing of allergens, and antigen presentation to T lymphocytes. 10
Mφ IL-1 TNF-α Th Th2 IL-4 IL-5 IL-13 The recruitment and activation of T cells to the conjunctiva is specially relevant to persistent inflammation in the chronic forms of ocular allergy (VKC & AKC). 11
ECP Mφ IL-1 TNF-α Th Th2 IL-4 IL-5 IL-13 MBP LTC4 PAF Cytokines produced by Th2 lymphocytes IL-4, 13 and 5 will have a coordinated action in the recruitment and local activation of eosinophils, that through their toxic mediators will induce epithelial lesion, local mast cell activation and the further release of vasoactive mediators, such as leukotrienes. 12
ECP Mφ IL-1 TNF-α Th Th2 IL-4 IL-5 IL-13 MBP Histamine Triptase LTC4 TNF-α LTC4 PAF TGF-β collagen fibroblast proliferation In the chronic forms of ocular allergy (atopic and vernal keratoconjunctivitis), collagen deposition in conjunctiva, with the formation of papillae and tarsal fibrosis, are characteristic and several mediators and cytokines secreted by both mast cells and eosinophils may promote fibroblast proliferation and activation. 13
GM-CSF IL-8 ECP RANTES eotaxin MCP-1 Mφ IL-1 TNF-α Th Th2 IL-4 IL-5 IL-13 MBP Histamine Triptase LTC4 TNF-α SCF c-kit R LTC4 PAF TGF-β GM-CSF eotaxin fibroblast proliferation Moreover, a bidirectional interaction with fibroblasts and conjunctival epithelial cells may influence the local differentiation of mast cells (through SCF) and, by the production of chemokines (eotaxin, MCP-1, RANTES) and cytokines (GM-CSF, IL-8) the local recruitment, priming and activation of both conjunctival mast cells and eosinophils. 14
Dynamics of ocular allergy Acute Inflammation Dr Delgado Marzo 2006 www.alergomurcia.com Luís Delgado, ECS2006 So, in summary, we can also find some of the characteristic dynamics of the allergic inflammation at the external ocular surface: an acute and transient inflammation may be the dominant picture, usually triggered by mast cellbound IgE and airborne allergens 15
Dynamics of ocular allergy Acute Inflammation Chronic Inflammation Th Dr Delgado Marzo 2006 www.alergomurcia.com Luís Delgado, ECS2006 A late phase reaction to the allergen or a chronic inflammation, will be dominated by eosinophils and T cells 16
Dynamics of ocular allergy Acute Inflammation Chronic Inflammation Fibrosis Remodeling Th Dr Delgado Marzo 2006 www.alergomurcia.com Luís Delgado, ECS2006 On the other hand, chronic and persistent forms of ocular allergy will progress with fibrosis and tissue remodeling, with papillae formation, conjunctival scarring and blepharitis 17
Seasonal (SAC) and Perennial (PAC) allergic conjunctivitis Are the most frequent forms Bilateral itching is the first ocular symptom, with tears and some burning Conjunctival hyperaemia and chemosis, with palpebral oedema are typical In SAC the most frequent allergens are pollens; in PAC it is house dust mites. L Delgado, J Palmares 2006 We will follow now the typical clinical presentation of the different forms of ocular allergy. SAC and PAC are the most frequent, with bilateral itching, tearing, conjunctival hyperaemia and chemosis, with palpebral oedema. The most frequent allergens are pollens, in seasonal forms, and house dust mites in PAC. 18
Vernal Keratoconjunctivitis (VKC) A rare form, typically seasonal (Spring / Summer) occurs in children and young adults (>males) 75% have also asthma, allergic rhinitis, or atopic eczema. Typical symptoms are intense itching, extreme photophobia, burning and frequently, blurred vision Typical giant cobblestone-like papillae (>1mm), in the superior tarsal conjunctiva L Delgado, J Palmares 2006 VKC is a rare and also typically seasonal form, occurring in children and young adults (usually males), and most of them also have asthma, allergic rhinitis or atopic eczema. Intense itching, photophobia, burning and frequently blurred vision are seen. Typical giant cobblestone-like papillae are seen in the superior tarsal conjunctiva, that frequently associate with corneal involvement with shield ulcers, as you can see in the picture. 19
Vernal Keratoconjunctivitis (VKC) The limbal papillae with white apical gelatinous swellings are rich in eosinophils, fibroblasts and necrotized epithelium - Horner-Trantas nodules Tarsal papillae are usually predominant in IgE-mediated VKC. L Delgado, J Palmares 2006 Limbal papillae with white apical gelatinous swellings - Horner-Trantas nodules - are also typical of VKC. Tarsal papillae are usually predominant in IgE-mediated VKC. 20
Th2 lymphocytes in Ocular Allergy (VKC) * * * *p<0.01 vs conj. Calder VL et al. Clin Exp Allergy 1999, 29:1214 The analyses of T cell clones obtained from peripheral blood and conjunctival biopsies of VKC have shown a predominance of Th2 cells (with prominent IL- 13 and IL-5 production), that could also be found in the conjunctiva. Recent data, with tear fluid cytokine measurements, corroborate these findings in VKC. 21
Atopic Keratoconjunctivitis (AKC) Occurs in adults (18-50 years) with systemic manifestations of atopy and increased serum IgE. It carries the highest risk of blindness. Usually there is a family history of atopic diseases. It is a chronic conjunctivitis (may last for decades), with smaller papillae in the superior tarsus. Conjunctival scaring is frequent and the eyelids are usually inflamed and macerated, with crusts chronic blepharitis. L Delgado, J Palmares 2006 AKC is another chronic and usually severe form, typically occurring in young and middle aged males, with systemic manifestations of atopy and increased serum IgE. Among ocular allergic conditions it carries the highest risk of blindness. It is a chronic conjunctivitis, that may last for decades, with frequent conjunctival scaring, chronic blepharitis, potentially complicated with corneal ulcers, as you can see in the slide. 22
T lymphocytes in Ocular Allergy (AKC) * * *p<0.01 vs pb Calder VL et al. Clin Exp Allergy 1999, 29:1214 T cell clones obtained from peripheral blood and conjunctival biopsies of AKC have shown a predominance of Th2 cells (with prominent IL-13 and IL-5 production) in peripheral blood, but with a mixture of a Th1-cytokine pattern and IL-10 at the local level. 23
Giant Papillary conjunctivitis (GPC) It occurs due to allergy/ intolerance to contact lenses, their cleaning products or preservatives, corneal sutures or ocular prosthesis. There is a papillary reaction on the upper eyelid, with or without keratopathy. The patient complains of itching and discomfort after insertion of the contact lens. L Delgado, J Palmares 2006 GPC is considered an iatrogenic form of ocular allergy, occurring in the context of allergy/intolerance to contact lenses, their cleaning products, corneal sutures etc... Usually there is a papillary reaction on the upper eyelid, with or without keratophaty. The patient complains of itching and discomfort and this condition is usually more prevalent in atopic patients. 24
Contact Blepharoconjunctivitis (CBC) It is due to drugs (anaesthetics, atropine, antibiotics, antivirals, timolol...), preservatives (benzalkonium chloride, chlorobutanol, chlorhexidine, thimerosal...) or cosmetics. It leads to palpebral erythema and oedema, conjunctival follicles and, frequently, punctiform keratopathy L Delgado, J Palmares 2006 Contact blepharoconjunctivitis is frequently an acute form of ocular allergy, due to delayed type hypersensitivity to drugs (topical anaesthetics, antibiotics...), preservatives (benzalkonium chloride, thimerosal...) or cosmetics. The palpebral erythema and oedema dominates, with conjunctival follicles and, frequently, punctiform keratopathy. 25
Ocular Allergy Summary Immunopathology Tarsal Conjunctiva Cornea Eyelids Acute SAC/PAC CBC IgE, mast cells, Eosinophils Dendritic cells, Th1 lymphocytes + + + + - ++ VKC Th2 lymphocytes Eosinophils; IgE (tarsal VKC) ++ ++ + AKC IgE, mast cells, basophils T lymphocytes (Th2+Th1) Microbial antigens? ++ +++ ++ Dr Delgado Marzo 2006 GPC T lymphocytes (Th0?) Leukotrienes, IL-8 Mechanical inflammation? ++ www.alergomurcia.com + - L Delgado, J Palmares 2006 So, in summary, the clinical and immunopathological features of the different forms of ocular allergy are very useful for its differential diagnosis and to establish an appropriate management. With an acute presentation we usually see seasonal and perennial allergic conjunctivitis or contact blepharoconjunctivitis, with opposing involvement of IgE versus Th1-mediated hypersensitivity, and of the tarsal conjunctiva versus the eyelids. Minimal or exceptional corneal involvement is found. 26
Ocular Allergy Summary Immunopathology Tarsal Conjunctiva Cornea Eyelids Acute SAC/PAC CBC IgE, mast cells, Eosinophils Dendritic cells, Th1 lymphocytes + + + + - ++ VKC Th2 lymphocytes Eosinophils; IgE (tarsal VKC) ++ ++ + Chronic Dr Delgado Marzo 2006 AKC GPC IgE, mast cells, basophils T lymphocytes (Th2+Th1) Microbial antigens? T lymphocytes (Th0?) Leukotrienes, IL-8 Mechanical inflammation? ++ ++ www.alergomurcia.com +++ + ++ - L Delgado, J Palmares 2006 This contrasts with chronic forms of ocular allergy, that are less common, but with frequent corneal involvement (that can be sight-threatening), papillary reaction of the tarsal conjunctiva and conjunctival follicles or nodules. A Th2 and eosinophilic inflammation dominates in VKC (usually a disease of male children) and a mixed pattern, also with Th1 involvement, is found in AKC, that typically associates with atopic eczema or respiratory allergy in an adult male. Finally, GPC is the iatrogenic chronic form, with mechanical factors and local involvement of inflammatory mediators and T cells, with no particular Th1 or Th2 bias. 27
Diagnosis Red Eye (recurrent) Family Doctor & Pediatrician Signs & symptoms Recurrent, bilateral, itchy symptoms Association with other allergic disease Family history of allergy Eosinophilia, high total IgE Possible Allergic conjunctivitis or Allergic keratoconjunctivitis (pain, photophobia, eczema, giant papillae) adapted from S.Bonini 2003 I will finish my presentation with a diagnosis flow chart proposal A recurrent red eye is usually first seen by family doctors or pediatricians, that through the characteristic signs and symptoms, personal and family history of allergy, and some laboratory data can establish a presumptive diagnosis of allergic conjunctivitis or keratoconjuncitvitis 28
Specialist Diagnosis Possible allergic conjunctivitis & allergic keratoconjunctivitis Ophthalmologist History Eye examination (slit lamp) Conjunctival cytology Conjunctival provocation tests (histamine) Allergologist History Skin prick tests Immunoassays IgE & mediators Conjunctival provocation tests (allergen) Treatment strategy adapted from S.Bonini 2003 Patients with recurrent and chronic forms will benefit from an ophthalmology and allergology evaluation, with a detailed history, slit lamp examination and skin prick tests. In selected cases other techniques, such as conjunctival cytology, tear fluid analysis and conjunctival provocation may be useful for the final assessment of treatment strategies. 29