Ocular AllergySecond edition

Jorge PalmaresLuis Delgado

Ocular AllergySecond Edition

Ocular AllergySecond Edition

Jorge PalmaresOphthalmology Consultant

Cornea and Ocular Immunopathology ClinicDepartment of Ophthalmology,

Hospital de S. João, Porto, Portugal

Luís Delgado Associate Professor of Immunology Faculty of

Medicine, University of PortoDepartment of Immunology and Immunoallergology Unit

Hospital de S. João, Porto, Portugal

Acknowledgement: The Publisher thanks NOVARTIS Ophthalmics for their prompt support to the edition of this booklet.

Title:

Authorship: Publisher:

ISBN: "Depósito-legal":

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Ocular AllergySecond Edition

Jorge Palmares, Luís DelgadoMedisa, Ltd www.medisa.pt972-8105-07-X100.361/962002©Medisa and Authors

Introduction

Conjunctivitis is one of the most common ocular affections in clinical practice and when of allergic etiology presents difficulties and peculiarities both in differential diagnosis and therapeutical approaches. Clinically, its presentation can range from mild seasonal symptoms to perennial forms coursing with intense and very uncom- fortable ocular itching and tearing, or to visual loss due to corneal involvement. In the recent years, new insights into the cellular and molecular mechanisms of allergic disease have come into view, along with the development of new drugs acting in several pathways of the allergic reaction. The aim of «Ocular Allergy» is to summarize, in a monograph, the current knowledge of the immunopathology, diagnosis and therapeutical approaches of these affections. In this second edition, we tr ied to improve the iconography while maintaining the focus on clinical practice, making the reading easy and helpful to any physician involved in the follow-up of these patients – the general practitioner, the ophthal- mologist and the allergist – and also stress the need for a multidisciplinary approach to effectively control the most serious and chronic presentations.

The authors

Jorge Palmares, M.D. Luís Delgado, M.D., Ph.D.jpalmares@netcabo.pt jldelgado@mail.telepac.pt

From the Foreword of the First Edition (Portuguese Edition, 1996; Brasilian Edition,

1997; International Edition, 1997)

«This little book contains an enormous amount of information. It is designed for the practising clinician, with an interest in ocular allergy, and covers all types of allergic eye disease. Our understanding of disease mechanisms has increased enormously over the last few years and the scientific information given in this book is up-to-date and clearly explained (…). I think this book will be extremely useful to everyone interested in this field and the authors are to be com- mended on their achievement».

Professor Susan Lightman,Department of Ophthalmology - Moorfields Eye Hospital, London, UK

«This monograph on "Ocular Allergy" is filling an existing void in this field. The authors are to be congratulated for succeeding to com- pile a concise and easily readable text. The clinical picture of the vari- ous conditions are most expressive and would be of help to the prac- tising clinician».

Professor David BenEzra,Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel

«This monograph represents, in a very clear way and with an ico- nography of great quality, the mechanisms involved in ocular allergy, the clinical presentation, the diagnosis and treatment, illustrating the complexity of some of these situations. It also shows that a etiopathogenic interpretation and a correct clinical evaluation may contribute to minimize the disease morbidity».

Dr. Marianela Vaz,Director, Immunoallergology Unit, Hospital de S. João, Porto, Portugal.

«The early diagnosis and appropriate treatment for each case, although they may not cure the disease, surely will help to minimize its direct and sometimes so serious secondary effects.

(...) I believe this manual will be an excellent help to achieve these objectives».

Professor J. Castro-Correia,Professor of Ophthalmology, Faculty of Medicine, Porto, Portugal.

«The booklet "Ocular Allergy" (…) is practical and didactical, with excellent drawings regarding immunopathology and unique iconog- raphy showing typical common cases as well as rare ones. The diagnosis and treatment flowcharts, and the summary tables allow a rapid and easy answer to the most frequent questions».

Professor Rubens Belfort Jr and Dr. Denise de FreitasFederal University of São Paulo, Brasil

Contents

1. Immunopathology ................................................................... 11Glossary and abbreviations ................................................. 12Mast cells and basophils ........................................................ 15Eosinophils ................................................................................... 17Dendritic cells and monocyte/macrophages ............. 21T lymphocytes ............................................................................. 22Fibroblasts ..................................................................................... 24Cytokines .................................................................... 26

2. Clinical Features ....................................................................... 29Seasonal and perennial allergy conjunctivitis ........... 32Vernal keratoconjunctivitis .................................................. 34Atopic keratoconjunctivitis .................................................. 37Giant-papillary conjunctivitis ............................................ 40Contact ocular allergy and toxickeratoconjunctivitis ................................................................. 42

3 Diagnosis ....................................................................................... 47Clinical diagnosis ...................................................................... 49Differential diagnosis .............................................................. 52Diagnostic tests in ocular allergy ...................................... 61

4 Treatment ...................................................................................... 69Allergen avoidance ................................................................... 72Pharmacological treatment ................................................. 75• Pharmacological agonists and antagonists .............. 77• Mast cells stabilizers ............................................................. 78• Nonsteroidal anti-inflammatory drugs ...................... 79• Corticosteroids ........................................................................ 80Immunotherapy ......................................................................... 82Appendices ................................................................................... 84

References ..................................................................................... 89Index ................................................................................................. 93

Immunopathology

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1ImmunopathologyJorge palmaresLuís Delgado

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Glossary and abbreviationsbFGF basic fibroblast growth factorc-kit R stem-cell factor receptor ECP

eosinophil cationic protein EDN eosinophil derived neurotoxin EPO eosinophil peroxidaseFcRI high affinity IgE Fc receptorGM-CSF granulocyte-macrophage colony stimulating factorICAM-1 intercellular adhesion molecule 1IFN- gamma-interferonIL- ... interleukin ...LFA-1 lymphocyte function antigen 1LTC4 leukotriene C4MAC-1 cell adhesion glicoprotein - CD11b/CD18 (CR3)MadCAM-1 mucosal addressin cell adhesion molecule 1MBP major basic proteinPECAM platelet - endothelial cell adhesion moleculePDGF platelet derived growth factorPGD2 prostaglandin D2PSGL-1 P-selectin glycoprotein ligand 1SCF stem cell factorTNF- tumor necrosis factor alphaVCAM-1 vascular cell adhesion molecule 1VLA-4 very late antigen 4VLA-6 very late antigen 6

Antigen

Antigen peptide

Immunoglobulin

PMN neutrophil

B-lymphocyte

Plasma cell

Eosinophil

Mast cell

Basophil

Macrophage

Dendritic cell

Endothelial cell

T-helper lymphocyte Fibroblast

Immunopathology

Immunopathology

Allergic diseases tipically involve external body surfaces (skin and mucosa) and are the expression of a hypersensitivity reaction to common environmental antigens. The hyper- sensitivity mechanism most often identified with allergic disease will start with the production of IgE antibodies, but amplification mechanisms dependent on immuno- competent cells (T lymphocytes) and structural cells of the surrounding tissues significantly contribute to its immunopathology. Currently, more than 15% of the population suffers from allergy and some studies have shown that up to 30% of the USA population have some form of allergy. Any age group may be affected by the allergic disorders, usually in a chronic way.

IgE antibodies, binding to the tissue mast cells and circulating basophils through high affinity receptors, trigger a rapid cellular degranulation after contact with the allergen, and a prompt release of vasoactive and pro-inflammatory mediators (immediate, anaphylactic or type I hypersensi- tivity, in the Gell and Coombs classification). A late phase response, following the immediate reaction to the allergen, is now clearly established and related to the local recruitment of inflammator y cells (eosinophils, basophils and monocytes/macrophages) and immunocompetent cells (T lymphocytes) following vasodilation and the action of chemotactic mediators (e.g., chemokines). Activation of these recruited cells tr iggers the production of cytokines – molecules that modulate the biological activity of both inflammatory and structural cells, as well as lymphocytes – contributing amplification of the allergic reaction. On the other hand, eosinophils, dendritic cells and monocytes also

13

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express IgE receptors and, thus, are also able to interact with the allergen and to cooperate in its presentation to T lymphocytes. This local cellular activation results in a chronic inflammatory process and prolonged symptoms, particularly in case of continuous allergen exposure and absence of an adequate therapeutic control.

Although antibody production is dependent on antigen- stimulation of B lymphocytes (humoral immunity), IgE synthesis requires T-B lymphocyte cooperation. T-helper CD4+ lymphocytes (Th), that are required for IgE synthesis are now identified as Th2 lymphocytes, as they produce cytokines which promote the synthesis of this antibody class (IL-4 and IL-13). The other type of Th lymphocytes ( Th1 lymphocytes) produce cytokines [IL-2 and gamma-interferon (IFN-)] mainly associated with macrophage and T lymphocyte activation, e.g., in delayed hypersensitivity reactions with a chronic inflammatory response. More recently, it has been shown that mast cells, eosinophils and corneal keratinocytes also produce pro-inflammatory cytokines (IL-6, IL-8 and TNF-), «Th2» cytokines (IL-4, IL-5 and IL-13) and chemokines (eotaxin, RANTES and MCP-1), which promote the development of the late allergic conjunctival reaction.

It is now known that the immunopathogenesis of allergic disease is now known to be much more complex than the initially proposed Gell and Coombs classification and, as ocular allergy is concerned, results from several molecular and cellular interactions. While IgE antibodies and mast cells play the main role in the acute and immediate forms, T lymphocytes, eosinophils, dendritic cells and monocytes/ macrophages are probably relevant effector cells in forms with delayed symptoms and longer evolution. The knowledge of the pathophysiological role of each cell type and its mediators will help us to understand the characteristics of the different ocular allergic conditions, as well as identify the strategy for a multifactorial therapeutic approach.

Mast cells and basophils

Mast cells, which contain potent inflammator y mediators, are tissue mononuclear cells, particularly located on external body surfaces – mucosa and skin – where they perform a major role in the acute inflammatory reaction. They are characteristically involved in the acute allergic reaction, where they quickly respond to allergen contact due to the expression of a high-affinity Fc receptor for IgE (FcRI), also present in its circulating “equivalent”, the basophil.

Although identified over more than a hundred years ago, by Paul Ehrlich, who described their staining characteristics– metachromasia –, mast cells and basophils were only recently established as distinct in origin, differentiation and mediators (Table 1.1).

In contrast with most mast cells, basophils may degranulate with several IgE-independent stimuli: anaphylatoxins (C3a, C5a), bacterial peptides (f-MLP), cytokines (MCP-1) and other histamine releasing factors (HRFs). Mast cells themselves are a heterogeneous cell population, presenting different morphological, functional

Table 1.1 - Comparison of basophil and mast cell properties

Basophils Mast cells

Origin bone marrow bone marrow Local of differentiation in situ in tissues Cytokines involved IL-3, IL-5, GM-CSF SCF

Mediators:• Histamine + ++• Proteoglycans chondroitin sulphate A chondroitin sulphate E

heparin• Neutral proteases – tryptase and/or chymase

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• Major arachidonic metabolites LTC4 PGD2>>LTC4

• Cytokines IL-4 IL-4, IL-5, TNF-IL-6, IL-8, IL-13

Immediate reaction

HistaminePAF LTC-4

Vasodilation Protein exsudation Hypersecretion

Late reaction

PAF TNF- IL-4IL-5

Intense vasodilationEdema

Fig. 1.1 – Mast cell mediators involved in the immediate and late allergic conjunctival reaction.

and pharmacological characteristics in different tissues and different species. In humans, mast cell sub-populations have been defined by their neutral proteases: in lung and bowel mucosa they only contain tryptase (MCT) – mucosal mast cells – while in skin and intestinal submucosa they also contain chymase and carboxypeptidase (MCTC) - connective tissue mast cells.

In normal conjunctiva, mast cells are present in submucosa, but not in the epithelial surface, and are mostly MCTC. In seasonal or perennial allergic conjunctivitis there

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is an increase of MCT mast cells in the conjunctiva, a subtype

that, in contrast with MCTC, has a good response to cromoglycate in vitro. It has been shown that these patients respond to allergen challenge with two histamine peaks in the tears – the first at 20 minutes and the second six hours later. Tryptase is present only in the first peak, suggesting basophil participation in the conjunctival late allergic reaction. An increased number of conjunctival mast cells and their presence in the epithelium can also be observed in vernal conjunctivitis.

The role of mast cell mediators in the immediate symptoms of the conjunctival allergic reaction, such as histamine, PAF and LTC4, is well established (Fig. 1.1). It has been shown that mast cells can produce pro-inflammatory cytokines, such as IL-4, IL-5, IL-6, IL-8, IL-13 and TNF-. Recent studies in seasonal allergic conjunctivitis showed that IL-5 and IL-6 predominate in tryptase positive cells (MCT) while IL-4 and IL-13 predominate in the MCTC, being mast cells the major cellular source of IL-4. Thus, it is reasonable to postulate that these cytokines of mast cell origin are important mediators in the development of the late allergic conjunctival reaction and also play a role in eosinophil and T lymphocyte infiltration and activation typical of the more serious and chronic forms of ocular allergy.

Eosinophils

Eosinophils differentiate in the bone marrow and, after a brief passage in the blood, locate in tissues (Fig. 1.2).

One of the characteristics of allergic disease is the accumulation of a large number of activated eosinophils in the surrounding tissues. In seasonal conjunctivitis, eosinophils increase after allergen challenge or during pollen season. In chronic forms of ocular allergy with corneal involvement – vernal and atopic keratoconjunctivitis – eosinophilic infiltration is also

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characteristic but its severity relates more closely with the expression of activation markers, both in the ocular surface (IL-2R, HLA-DR) and tears (ECP).

Fig. 1.2 – Eosinophils in extravascular

location. Immunocytochemistry:

staining with a monoclonal antibody

to ECP.

Eosinophil migration into tissues involves an adhesive process and chemotaxis under the influence of local mediators. Differentiation and release of eosinophils from the bone marrow seems to depend on specific cytokines, preferentially (but not exclusively) produced by T- lymphocytes – IL-3, IL-5 and GM-CSF. However, the majority of chemotactic stimuli for eosinophils (PAF, C5a, LTB4) also stimulate and activate neutrophils and other leukocytes. Thus, the accumulation of eosinophils in tissues may depend on an increase in their survival, under the influence of locally produced cytokines (IL-5, IL-3 and GM-CSF), and/or a selective migration under influence of CC chemokines (RANTES, eotaxin...).

Eosinophil migration starts with an initial stage of vascular endothelium adhesion and another stage of interactions with the extracellular matrix and structural cells, comprising different types of receptors and ligands. There is now a large evidence that some Th2 cytokines may preferentially modulate the expression of some of these molecules in eosinophils and endothelial cells, favoring selective eosinophil migration (Fig. 1.3). Actually, the vascular expression of ICAM-1, E-selectin, and VCAM-1 is increased in allergic conjunctivitis (ICAM-1 is also increased in epithelial cells), particularly in chronic forms; ICAM-1 and E-selectin

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correlate with the number of granulocytes and lymphocytes and VCAM-1 with eosinophil infiltration.

Fig. I.3 – Role of different molecules and cytokines in eosinophil transendothelial migration.IL-1 and TNF- recruit eosinophils through the induction ofICAM-1 that binds to the leukocyte integrins LFA-1 andMAC-1, an interaction also used by neutrophils. IL-4 induces VCAM-1 in endothelia but its ligand, VLA-4, is not expressed in neutrophils; IL-4 also inhibits the activity of TNF- on neutrophil migration. IL-3 acts with IL-4 in the recruitment of non activated eosinophils, has co-stimulatory activitywith IL-1 and TNF- (e.g., E-selectin expression) and,particularly, induces the chronic expression of P-selectin in endothelia.

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Activation of eosinophils may result from the action of soluble mediators (PAF, C5a), cytokines (IL-3, IL-5 and GM- CSF), surface immunoglobulins (IgE, IgA and IgG) or from the interaction of cell surface molecules with their endothelial or extracellular matrix ligands. This activation causes the release of lipid mediators, enzymes, granule proteins and/or cytokines (Fig. 1.4). Eosinophils contain and may release several basic proteins (ECP, EDN, EPO, MBP), all of which are powerful toxins to helminths, protozoa and mammalian cells. These proteins are found within the matrix of specific granules, have two domains (one basic, the other hydrophobic) and exert a cytotoxic activity against cellular membranes, particularly the corneal epithelium.

Cytokines

• “TH2”:

• Others:

Fig. 1.4 – Eosinophil receptors and mediators that may be involved in the pathological tissue damage associated with its local recruitment and activation.

In every type of ocular allergy eosinophils are present in the conjunctiva and their mediators may be found in the conjunctival exudate and lacrimal secretions. They are found in the late stage of the ocular allergic reaction (after conjunctival challenge), with a maximal peak between 6 to24 hours, in seasonal conjunctivitis during pollen season, and in Trantas' nodules of the most serious forms of ocular allergy (see Figs. 2.9 and 2.10).

Moreover, MBP deposits found in the conjunctiva of atopic keratoconjunctivitis, vernal corneal ulcers, and the correlation of tear ECP levels with the severity of vernal keratoconjunctivitis point to a significant role of these cells in ocular allergy.

Dendritic cells and monocyte//macrophages

Dendritic cells are present in small numbers in most tissues and are characterized by an unusual membranous or spine-like morphology, a high expression of MHC class II molecules and a potent accessory function in the antigenic stimulation of T cells. They can be found in lymphoid and non lymphoid tissues as well as in peripheral blood, possibly connected by their migration pathways.

In spite of their scarcity in tissues (<1% of the total cell number), which hampers their identification, isolation and functional characterization, these cells are extremely potent in T lymphocyte stimulation, either in vivo or in vitro, and may directly activate specific CD8+ T lymphocytes (even in the absence of CD4+ lymphocytes) and take part in the induction of delayed-type hypersensitivity.

It has been shown that Langerhans cells, dermal dendritic cells and monocytes from atopic patients express the IgE high affinity receptor (FcRI), and possibly take part in the amplification of the allergic reaction. In fact, the allergen concentration in these cells, through its high affinity binding to specific IgE, results in allergen

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presentation to T- cells, leading to a late reaction and favoring chronic allergic inflammation.

In the eye, dendritic cells are present in the limbal region of corneal epithelium and in the eyelid skin, and are rare in the conjunctiva. Nevertheless, their number increases significantly in chronic inflammation, appearing together with macrophages in the conjunctival epithelium in allergic conjunctivitis or in experimental models of ocular allergy. On the other hand, in chronic forms of ocular allergy macrophages seem to be, along with the conjunctival cells, the main inflammatory cells that may express cytokines with chemotactic activity and T lymphocytes (CC chemokines).

Although the role of the dendritic cells in allergic reaction is not fully established, their location may allow the capture and processing of allergens on the ocular surface. In a process similar to epidermal Langerhans cells, ocular dendritic cells may be involved in antigen presentation to T cells and stimulation of local IgE synthesis, after migration to the thymus-dependent areas of the regional lymph nodes. This hypothesis is strengthened by the clinical and histo- pathological similarities of contact ocular allergy and atopic keratoconjunctivitis with, respectively, contact dermatitis and atopic dermatitis. In these skin disorders, a prime role is now largely established for dendritic cells in the T cell activation of delayed hypersensitivity and in the “delayed- type” amplification of the Th2 allergic reaction.

T lymphocytes

T lymphocytes play a major role in the allergen late phase reaction and in the chronic inflammation which accom- panies the most serious presentations of allergic disease, either in the skin or in the respiratory system. Recent studies also demonstrated their presence in the late ocular allergic reaction (10-12 hours after allergenic challenge) and, in conjunctival biopsies, activated CD4+ T cells are found in the most serious forms of ocular allergy

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– vernal and atopic keratoconjunctivitis.

Immune responses triggered by CD4+ T cells are partially dependent on the selection and preferential activation of

Proliferation Activation

Delayed hypersensitivity Immediate hypersensitivity

Fig. 1.5 – Polarization of the immune response in immediate or delayed hypersensitivity – it may depend on CD4+ T lymphocytes with specific profiles of cytokine production: type1 T-helper lymphocytes ( Th1), producing IL-2 and IFN-, andtype 2 (Th2), producing IL-4, IL-5, IL-10 and IL-13. IFN-, in- hibiting Th2 differentiation, and IL-10, IL-4, Th1 differentia- tion, will contribute to this polarization.

lymphocytes with a specific pattern of cytokine synthesis – the Th1 and Th2 lymphocyte subpopulations (Fig. 1.5). Thus, Th1 lymphocytes, producing IL-2, IFN- and lymphotoxin (TNF-), trigger an effector mechanism depending on T-cell

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proliferation and macrophage activation, i.e., delayed-type hypersensitivity. Th2 lymphocytes, preferentially producing IL-4 and IL-13 enhance IgE synthesis and, through IL-5, the recruitment, activation and increased survival of tissue

eosinophils, e.g., type I hypersensitivity; moreover, by producing IL-10 and IL-4, they inhibit several macrophage functions (the main inducers, via IL-12, of Th1 lymphocytes). The Th0 lymphocytes, from which these two functional subpopulations are derived, produce IL-2 together with some cytokines characteristic of both classes – IL-4 and IFN-. The characteristics of the antigen, as well as the cellular and tissue microenvironment of the antigen presentation during the secondary immune response, are determinant factors for the differentiation of Th0 lymphocyte towards Th1 or Th2 phenotype.

In humans, the presence of T cells and Th2 type cytokines has been largely recognized in tissues involved in allergic reactions, such as the skin, bronchial and nasal mucosa. More recently, the presence of Th2 type cytokines – IL-4 and IL-5 – has been described in conjunctival biopsies of vernal and atopic keratoconjunctivitis, in areas where T cells predo- minate as well as in the tears of these patients.

In atopic keratoconjunctivitis there is an increase in IL-2 and IFN- mRNA probably due to delayed-type hyper- sensitivity mechanisms, as proposed for atopic dermatitis, with which this ocular condition shares clinical and histopathological affinities.

Fibroblasts

In chronic forms of ocular allergy (atopic and vernal keratoconjunctivitis) there is collagen deposition in conjunctiva, with the formation of papillae and tarsal fibrosis. Bidirectional interactions between mast cells and fibroblasts are one of the links of a complex chain of molecular and cellular interactions which connect fibroblasts to the immune and inflammatory reaction.

Several mediators secreted by mast cells may participate in fibrosis. Tryptase, the main proteinase in mast cells, triggers fibroblast proliferation, potentiates its

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response to other growth factors and, indirectly, activates collagenases.

MBP

Conjunctival epithelium

Ag Ag Ag

EotaxinMCP-1RANTES

AgECP

GM-CSF IL-3

Ag Th

Th2 c-kit R SCF

Mø

IL-1TNF-

IL-4IL-5IL-13

HistamineTryptase

LTC4TNF-

LTC4PAF

Ag

TGF-

GM-CSF Collagen

Fibroblast proliferation

Fig. 1.6 – Cells and mediators involved in the late reaction to the allergen and in the chronic inflammation and fibrosis which occur in the more severe forms of ocular allergic disease.D endritic cells and macrophages in the conjunctival epithelium may capture allergen (e.g., via FcRI receptors) improving its presentation to T lymphocytes, favoring the development of allergic inflammation. Moreover, Th2 cytokines (IL-4, IL-5 and IL-13), GM-CSF and TGF- are also located in conjunctival mast cells and eosinophils. In these chronic forms, corneal epithelial cells express cytokines (e.g., GM-CSF and IL-3) and chemokines (eotaxin, MCP-1 and RANTES) that attract and activate cells of the late phase aller- gic reaction.

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Histamine also stimulates fibroblast growth, through H1 and H2 receptors, as well as LTC4, the main leukotriene produced by mast cells. Human mast cells produce, store and synthe- size some pro-inflammatory cytokines, such as TNF-, which is present in tears after conjunctival allergenic provocation, raising the hypothesis that this cytokine has a role in fibroblast activation and proliferation (Fig. 1.6). In vernal keratoconjunctivitis, the presence of characteristic giant papillae has been associated with the presence of growth factors to the fibroblasts both in conjunctival eosinophils and macrophages (PDGF) and mast cells (bFGF).

Moreover, it is now well established that, in humans, fibroblasts influence the tissue differentiation of mast cells from circulating hematopoietic precursors through the production of stem-cell factor (SCF). SCF is produced in two forms, soluble and membranous, by endothelial cells, fibroblasts, and by conjunctival mast cells, also favoring IgE- dependent mast cell degranulation.

Human fibroblasts, through GM-CSF production, increase eosinophil survival and, conversely, eosinophils stimulate in vitro fibroblast proliferation (Fig 1.6).

Cytokines

It has been clearly defined that, besides Th lymphocytes, corneal mast cells, eosinophils and keratinocytes also produce cytokines which play a role in the inflammatory mediation of ocular allergy. Thus, mast cells locally present in all forms of ocular allergy, frequently with signs of degranulation, synthesize and store cytokines, such as IL-4, IL-5, IL-6, IL-8, IL-13 and TNF-. These are important mediators in the development of the late conjunctival allergic reaction by their recruitment and activation effects on eosinophils, basophils and Th2 lymphocytes, as well as promoting IgE synthesis. In allergic conjunctivitis, mast cells are the main cellular origin of IL-4 (>90%), being located mainly in MCTC mast cells which, as previously described,

characterize chronic forms. Many of these cytokines are also

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located in conjunctival eosinophils (as well as GM-CSF and TGF-), mainly in forms with corneal impairment (atopic and vernal keratoconjunctivitis). In these chronic stages, it has also been shown that conjunctival epithelial cells express cytokines that activate and increase eosinophil survival (e.g., IL-3 and GM-CSF) and chemokines that attract cells of the late phase allergic reaction (eotaxin and RANTES). In addition, conjunctival mast cells synthesize SCF which may have an autocrine role over these cells, since it is one of the main regulators of its growth and maturation and potentiates the release of mediators.

Clinical Features

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2Clinical FeaturesJorge palmaresLuís Delgado

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Clinical Features

Clinical Features

Ocular allergic diseases are common in clinical practice. Awareness of its symptoms, signs and pathophysiology is cru- cial for its diagnosis and treatment.

The clinical characteristics of all types of ocular allergy are conjunctival itching, hyperemia and chemosis (edema).

Cornea

Limbus

Bulbar conjunctiva

Fig. 2.1 – Chemosis: acute conjunctival edema with gelatinous appearance.

Hyperemia is the result of vascular dilation. Edema occurs because of altered permeability of post-capillary venules and itching is due to the stimulation of the sensitive nerve terminals.

Ocular allergy is usually classified in five different clini- cal entities:

• Seasonal and perennial allergic conjunctivitis• Vernal keratoconjunctivitis• Atopic keratoconjunctivitis• Giant-papillary conjunctivitis• Contact ocular allergy

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1 - Seasonal and perennial allergic conjunctivitis

Symptoms Signs

Itching Hyperemia Tearing Chemosis Burning Palpebral edema

Papillary reaction

Seasonal allergic conjunctivitis (hay fever) is the most common form of ocular allergy (50% of cases).

Bilateral itching is the first ocular symptom, with tear- ing and burning, frequently with nasal symptoms of rhinitis (allergic rhinoconjunctivitis). Conjunctival hyperemia and chemosis, with palpebral edema (periorbital edema) are

Fig. 2.2 – Chemosis: hyperemia due to vascular dilation and conjunctival

edema.

typical, as are “allergic shiners” – periorbital darkening due to a transient increase of periorbital pigmentation resulting from the decreased venous return in the skin and subcuta- neous tissue.

Fig. 2.3 – Seasonal allergic conjunctivitis with

palpebral edema.

A B C

Fig. 2.4 – A and B - Seasonal allergic conjunctivitis: inferior conjunctival cul-de-sac with papillae (elevations of conjunc- tival tissue with a central core of blood vessels).C - Superior tarsal conjunctiva with hypertrophic papillae.

Papillae (Fig. 2.4) may be present in the inferior conjunc- tival cul-de-sac and superior tarsal conjunctiva.

The allergens most frequently involved in the seasonal spring forms are pollens, usually from grasses and weeds, while house dust mites and animal dander are present all year round and they are mainly responsible for the perennial forms.

Fig. 2.5 – Perennial allergic conjunctivitis: acute phase with intense palpebral reaction.

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2 - Vernal keratoconjunctivitis

Symptoms Signs

Severe itching Giant papillae (cobblestone) Tearing PtosisPhotofobia Hyperemia Burning

Mucous secretion Foreign body Trantas' dots sensation Punctate keratopathy

Corneal ulcer

This is a rare form, more prevalent and serious in warm and dry areas of the world (East, Mediterranean basin, Africa). It is typically seasonal (from Spring until the end of Summer) and occurs in children and adolescents (more often in males),75% of whom also have asthma, atopic eczema or allergic rhinitis. Frequently, it is not possible to define a dominant allergen, although pollen exposure may exacerbate the disease.

Fig. 2.6 – Vernal keratoconjunctivitis: typical giant papillae

(cobblestone-like paving of the upper

palpebral conjunctiva) of unequal sizes, that induce keratitis when they touch the cornea.

Fig. 2.7 – Bilateral ptosis due to chronic inflammation of the superior conjunctiva, with extreme photophobia and tearing.

The first symptom is intense itching, followed by extreme photophobia, burning, foreign body sensation and frequently blurred vision. Conjunctival hyperemia, ptosis (drooping eyelid), stringy mucous discharge and blepharospasm are also seen. The typical giant cobblestone-like papillae (>1 mm) appear in superior tarsal conjunctiva, infiltrated by fibrin and mucus (pseudomembrane).

The limbal papillae with white apical gelatinous swellings rich in eosinophils, fibroblasts and necrotized epithelium have a gelatinous appearance – Horner-Trantas' nodules (Figs. 2.9 and 2.10).

A B C

D E F

Fig. 2.8 – A - Acute phase: edema, inflammatory cells and abnormal mucous; B - Papillae stained with fluorescein. C to

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F - Chronic phase: post-treatment.

A B C

Fig. 2.9 – A and B - Trantas' dots: limbal papillae with white apical gelatinous swellings (inflammatory cells infiltrates). C - Inactive phase: post-treatment.

Fig. 2.10 – Trantas' dots: limbal aspect.

Fig. 2.11 – Ptosis and limbal gelatinous swellings.

Corneal involvement (keratopathy) results in a superfi- cial, punctiform epitheliopathy or in a round “shield ulcer”, sometimes with persistent, non healing, epithelial and stro- mal defects (vernal plaque) (Fig. 2.13). The unwarranted use of topical steroids may lead to infection

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of these lesions, producing a vascularized leucoma, symblepharon (tarsal and bulbar conjunctiva adhesion) and cataracts. The patients show an increased incidence of keratoconus (Fig. 2.19).

Fig. 2.12 – Corneal leucomas in a chronic phase (pseudo- gerontoxon).

Fig. 2.13 – Corneal ulcers ("shield ulcers"): abnormal mucus and fibrin in its base.

3 - Atopic keratoconjunctivitis

Symptoms Signs

Itching Eyelid eczema Tearing Hyperemia Photophobia Punctate keratopathy Burning Corneal ulcer

Corneal neovascularizationKeratoconusCataract

This entity has the highest risk of blindness. It occurs in

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adults (18 to 50 years) who present systemic manifestations

Fig. 2.14 – Blepharitis associated with atopic eczema.

A B

Fig. 2.15 – Blepharitis: A - Maceration and crusting of canthal angle, eyelid thickening, and distor tion of palpebral architecture with trichiasis. B - Papillary hypertrophy in the upper tarsal conjunctiva.

of atopy (hereditary predisposition for hypersensitivity to common environmental allergens), such as asthma, rhinitis, atopic dermatitis or food allergy. Usually serum IgE level is increased, and there is a family history of atopic diseases.

Vernal conjunctivitis rarely exceeds 5-10 years of evolu- tion, while atopic keratoconjunctivitis may last for decades. This is a chronic conjunctivitis, clinically similar to vernal conjunctivitis, with formation of smaller papillae in the superior tarsus. Conjunctival scarring is frequent, leading to symblepharon and distortion of palpebral architecture (ec- tropion, entropion and trichiasis). Eyelids are usually in- flamed and macerated with crusts – chronic blepharitis.

The keratopathy, with neovascularization, is very serious, reducing the probability of success of corneal

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transplants. Cataracts [anterior subcapsular (Fig. 2.19B) and posterior],

Fig. 2.16 – Palpebral edema associated with wrist eczema.

A BFig. 2.17 – Atopic keratoconjunctivitis. A - Severe form, with bilateral corneal involvement. B - Aspect of the corneal neovascularization.

Fig. 2.18 – Atopic keratoconjunctivitis: corneal neovascu-

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larization with edema, mucus and ulceration.

A B

Fig. 2.19 – A - Keratoconus. B - Anterior subcapsular cataract(biomicroscopy).

herpes simplex and keratoconus (Fig. 2.19A), retinal detachment and eczematous blepharitis are common.

4 - Giant-papillary conjunctivitis

Symptoms Signs

Tearing Hypertrophic papillaePhotophobia HyperemiaBurning Punctate keratopathy Foreign body sensation Mucous discharge Blurred vision Contact lens with

deposits

This disorder occurs due to allergy and/or intolerance to contact lenses, their cleaning products or preservatives, or eye-drop solutions. There is a papillary reaction in the su- perior eyelid (with or without keratopathy) and the patient complains of discomfort after insertion of contact lenses. This disorder may also be associated with prosthesis or corneal sutures.

Allergy to contact lens preservatives and cleaning products is less dramatic than allergy to eye-drop solutions, although a secondary response may be rapid and serious.

The adherence of environmental allergens to the contact

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lens surface, especially hydrophilic lenses, may also lead to

Fig. 2.20 – Giant-papillary conjunctivitis: papillary reaction in the upper tarsal conjunctiva.

Fig. 2.21 – Giant-papillar y conjunctivitis: papillar y hypertrophy in the upper tarsal conjunctiva.

Fig. 2.22 – "Tight" contact lens: hyperemic conjunctival reaction (ciliary injection).

contact sensitization of the tarsal conjunctiva during blinking (thousands of times a day), on the “contaminated” contact lens. Initially, the patient develops itching and intolerance to the contact lenses.

Usually, there is a papillary reaction on the upper eyelid, with or without keratopathy. Later, the clinical situation may become worse, and some blurring of vision

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48

and keratopathy may occur. Nevertheless, this is a clinically less severe form than vernal conjunctivitis.

5 - Contact ocular allergy and toxic keratoconjunctivitis

Contact blepharoconjunctivitis due to drugs (anesthe- tics, atropine, gentamicin, neomycin, tobramycin, antivirals, epinephrine, pilocarpine, timolol), to preservatives (benzal- konium chloride, chlorbutanol, chlorhexidine, EDTA, thimerosal) or cosmetics, lead to palpebral erythema and edema, conjunctival follicles and, frequently, punctiform keratopathy. In the chronic phase, occlusion of the lacrimal ducts, conjunctival scarring, corneal neovascularization and keratinization may occur.

Eyelids are particularly predisposed to contact or irritative dermatitis, including the accidental "hand - eyelid" transfer of chemical products (preser vatives, ocular cosmetics, hairdresser products, nail varnish, shampoos, sprays, dyes, nickel...).

Fig. 2.23 – Contact blepharoconjunctivitis

due to neomycin ointment.

Fig. 2.24 – Contact blepharoconjunctivitis

complicated by recurrent

staphylococcal infection.

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Fig. 2.25 – Contact blepharoconjunctivitis due to thimerosal and nickel.

Cutaneous patch testing may help in the differential di- agnosis, but experience is needed for careful interpretation of the results.

Fig. 2.26 – Adverse reaction to a topical anesthetic agent(oxybuprocain) used chronically.

Fig. 2.27 – Adverse reaction to the preservatives contained in eye drop products used chronically.

The differential diagnosis between a true allergic reac- tion and a toxic one is difficult, and some drugs may induce both types, through concentration-dependent mechanisms (Figs. 26 and 27).

Occupational conjunctivitis (ocular irritation) is caused by several irritative environmental factors (air conditioning or central heating, atmospheric pollution, chemicals, vapors and foreign bodies) that, in some cases, may induce allergic sensitization.

Fig. 2.28 – Corneal foreign body: palpebral

edema with conjunctival hyperemia.

Fig. 2.29 – Chemical conjunctivitis:

engorgement of the superficial conjunctival

blood vessels.

Clin

ical F

eatu

res

45

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Table 2.I – Summary of the immunological and clinical characteristics of allergic conjunctivitis

Immunopathology Tarsal Cornea Eyelid conjunctiva

Seasonal and perennial allergic conjunctivitis

IgE, mast cells, eosinophils + +

Vernal keratoconjunctivitis Th2 lymphocytes, eosinophils, IgE ++ ++

Atopic keratoconjunctivitis IgE, mast cells, basophils,T lymphocytes (Th2 + Th1);bacterial antigens? ++ +++ ++

Giant-papillary conjunctivitis T lymphocytes (Th0?), leukotrienes, mechanical inflammation? ++ –

Contact allergy Dendritic cells, Th1 lymphocytes +

Diagnosis

47

3DiagnosisJorge palmaresLuís Delgado

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Diagnosis

Diagnosis

1 - Clinical diagnosis

The diagnosis of ocular allergy is based on a clinical, en- vironmental and occupational history, combined with physical examination and laboratory studies. Many clinical situations, presenting as “red eye”, may mimic ocular allergy, and a careful ophthalmologic examination is crucial for the correct diagnosis.

Ophthalmologic examination includes the observation of external ocular surfaces, namely the eyelids and their mar- gins, where the eye lashes are situated and the glandular ex- cretion holes open, and the tarsal conjunctival surfaces, that may be seen by eversion of the tarsal cartilage, allowing a better visualization of the conjunctival fornices (Fig. 3.1). The bulbar conjunctiva is examined by direct observation of the eye globe; the limbus, the circumcorneal zone, is only visible to the naked eye when inflamed (Fig. 3.2). The cornea is flat and transparent and with a pen light may reveal an ulcer or a corneal opacity – leucoma.

Fig. 3.1 – Eversion of the upper eyelid.

49

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50

Fig. 3.2 – Limbus with circumcorneal

neovascularization (ciliary injection).

Fig. 3.3 – Vascularized corneal leucoma.

Tarsal conjunctiva observation may provide some clues for the differential diagnosis. Thus, the presence of follicles (lymphoid aggregates), characteristically pale and round, surrounded by blood vessels (Fig. 3.4) suggest a non-allergic disease, such as viral, chlamydial or toxic conjunctivitis. Otherwise, the papillae, pinkish and with a central vessel (Fig.3.5), are characteristic of ocular allergy when >0.3mm (macropapillae) or >1mm (giant papillae). Micropapillae (<0.3 mm of diameter) are present in 80% of the normal population.

Fig. 3.4 – Follicles in the inferior conjunctival cul-de-sac.

Fig. 3.5 – Giant papillae (cobblestone-like) of the upper tar- sal conjunctiva.

The characteristics of the conjunctival secretion, serous, watery or mucopurulent, may help the differential diagnosis of conjunctivitis.

Discharge

Serous Purulent Watery Dry eye

ALLERGY BACTERIAL VIRAL Keratoconj. sicca

Culture - smear Clinical evaluation Systemic disease

Ophthalmic evaluation

RhinitisDermatitis Giant papillae Severe photophobia Exposure to

Rhinitis/Asthma Contact lens Keratopathy irritants

SEASONAL ATOPIC GIANT - PAPILLARY

VERNAL OCCUPATIONAL

Allergy diagnosis

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Allergen avoidance and pharmacological treatment

Adapted from BenEzra et al. (1994)

2 - Differential diagnosis

There are multiple causes of “red eye” diseases. Therefore, it is important to be familiar with some entities that fre- quently mimic ocular allergy, and which require specialized care.

Chlamydial conjunctivitis has follicles, is non-pruritic and is confirmed by conjunctival cytological examination.

Bacterial and viral conjunctivitis includes signs of in- fection – adenopathies, superior respiratory symptoms, pu- rulent secretion (Figs. 3.6 and 3.7), conjunctival follicles and corneal infiltrates.

Fig. 3.6 – Bacterial conjunctivitis: purulent discharge with formation of conjunctival pseudomembranes.

Fig. 3.7 – Staphylo- coccal bacterial

blepharo- conjunctivitis.

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A B

Fig. 3.8 – Conjunctivitis by adenovirus: A - Acute follicular conjunctivitis with watery discharge and small hemorrhages.B - Punctate superficial keratitis.

C C - Corneal subepithelial infiltrates.

A B C

D

Fig. 3.9 – Herpes simplex:A - Herpetic blepharoconjunctivitis; B - Keratitis with multiple dendritic ulcers;C - Ulcers stained with fluorescein;D - Vascularized leucoma after steroid abuse.

Superior limbic keratoconjunctivitis is restricted to the superior cornea and superior bulbar conjunctiva. It shows conjunctival mucus and it is associated with thyroid disease.

Fig. 3.10 – Superior limbic keratoconjunctivitis: neovascular infiltration of the superior cornea and bulbar conjunctiva.

Phlyctenular conjunctivitis (microabscess in limbic area) is possibly due to hypersensitivity to Staphylococcus or Mycobacterium tuberculosis antigens and it is often associ- ated with chronic eczematous blepharitis, mimicking atopic eczema.

Fig. 3.11 – Phlyctenule:

nodular formation at the limbus, with

localized hyperemia.

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Staphylococcal blepharitis has a typical appearance in the palpebral margins. Other forms of blepharitis may also present some degree of conjunctival inflammation.

Fig. 3.12 – Staphylococcal blepharoconjunctivitis.

Fig. 3.13 – Stye (hordeolum): acute phase of bacterial infec- tion in the Meibomian glands.

Fig. 3.14 – Blepharoconjunctivitis: eczematous form with eye- lash loss.

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The diagnosis of rosacea-associated conjunctivitis is obvious when a 40 to 60 year-old individual presents purple- red erythema, telangiectatic vessels, papules, pustules and sebaceous gland hypertrophy in the facial skin.

Fig. 3.15 – Rosacea.

Fig. 3.16 – Rosacea. Severe blepharoconjunctivitis with leu- coma and corneal neovascularization.

Dry eye (idiopathic “sicca” keratoconjunctivitis and primary or secondary Sjögren's syndrome) causes more burning and foreign-body sensation than itching. It may be exacerbated by the use of antihistamines, sedatives and - blockers.

Fig. 3.17 – Dermatomiositis: Palpebral oedema

and dry eye (xerophthalmia).

A B

C DFig. 3.18 – Keratoconjunctivitis "sicca" (Sjögren's syndrome). A - Loss of lustre of the epithelium; B and C - Fluorescein- stained precorneal tear film; D - Rose Bengal staining.

Erythema multiform in its more serious forms – Stevens- Johnson's and Lyell's syndromes – is an acute hypersensitivity reaction to viral (herpes) or bacterial infections and/or to the use of drugs (sulphonamides), leading to severe corneal and conjunctival inflammation.

Fig. 3.19 – Erythema multiform major (Stevens-Johnson's syndrome):after the use of sulphonamides, with involvement of the

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mucosal surfaces and the eyelids.

A B

Fig. 3.20 – Toxic epidermal necrolysis (Lyell's syndrome).A - Symblepharon: fibrotic bands that pass between the palpe- bral and bulbar conjunctiva; B - Tarsal conjunctival scarring with reduced numbers of mucus-producing goblet cells.

Episcleritis / scleritis is usually more localized, painful and strongly associated with connectivitis.

Fig. 3.21 – Scleritis: engorged superficial

episcleral vessels, congestion deep in the

episcleral plexus and underlying scleral

edema.

Acute uveitis is associated with conjunctival hyperemia and a fibrinoid reaction in the anterior chamber.

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Fig. 3.22 – Acute anterior uveitis with corneal endothelial pre- cipitates - iridocyclitis (biomicroscopy).

In ocular cicatricial pemphigoid, the vascularized cor- nea and symblepharon are not associated with itching or atopy and the conjunctival biopsy is diagnostic.

Fig. 3.23 – Ocular cicatricial pemphygoid: progressive con- junctival shrinkage, vascularized cornea, entropion, sym- blepharon and reduced vision from keratinized ocular sur- face epithelium.

A very pruriginous inflammatory reaction may result from the contact of the external ocular surface with insects and parasites.

Fig. 3.24 – Insect bites (mosquito): eyelid and cutaneous edema.

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Fig. 3.25 – Phthirus pubis: eyelashes infested with the pathog- nomonic nits (egg cases), transparent and oval, inducing se- vere itching.

Fig. 3.26 – Acute conjunctivitis after contact

with ticks.

In the elderly, the ageing of the palpebral tissues can in- duce the formation of ectropion and chronic conjunctivitis.

Fig. 3.27 – Senile ectropion.

3 - Diagnostic tests in ocular allergy

Allergy diagnostic tests

In the diagnostic evaluation of a patient with ocular al- lergy, the confirmation of a suspected allergic sensitization by allergy diagnostic tests plays a fundamental role in establishing an etiology and a specific therapeutic approach, e.g., the removal of the causal agent.

Allergy diagnosis has two purposes:

1) The demonstration of IgE antibodies to environmental allergens or T cells sensitized to contact allergens.

2) To define how this relates to the triggering of symptoms.

It is based on in vivo or in vitro immunological tests, since other routine subsidiary examinations are not helpful in the diagnosis of different forms of ocular allergy.

In vivo tests

Skin prick tests for the diagnosis of immediate hyper- sensitivity are based on the introduction of a small amount of antigen into the patient’s skin where in the case of specific IgE, a wheal-and-flare reaction ensues in 15 to 20 minutes, due to the IgE sensitization of cutaneous mast cells. The test is usually performed via the epidermis by a modified puncture – «prick» – with a standard lancet, or by the intra- dermal route. The results are read after 20 minutes, and the wheal is compared with a positive and negative control (histamine and allergen extract diluent). In spite of being the most sensitive, rapid and cheapest method to confirm an allergic sensitization, it carries a small but significant risk of systemic anaphylaxis (especially the intradermal test in patients with previous history of anaphylaxis). They also require experience in the performance and interpretation of results and the use of well

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standardized extracts. Thus, its use is only warranted in specialized centres. One must take into

Table 3.1 – Suggestions for patch testing (ophthalmic prepara- tions) (Zug KA et al, 1996)

• Atropine sulfate 0.1% aq• Bacitracin 20% pet• Benzalkonium chloride 0.01% pet• Chloramphenicol 5% pet• Chlorhexidine digluconate 0.5% aq• Chlorbutanol 1% aq• Epinephrine HCl 1% aq• Gentamycin sulfate 20% pet• Homatropine 1%• Idoxuridine 1% pet• Kanamycin 10% pet• Levobunolol HCl 1% aq• Neomycin sulfate 20% pet• Paraben mix 15% pet• Phenylephrine HCl 10% aq• Phenylmercuric acetate 0.05% pet• Phenylmercuric nitrate 0.05% pet• Pilocarpine chloride 0.1% aq• Polymyxin B sulfate 20% pet• Procaine 5% aq• Quaternium 15 2% pet• Scopolamine hydrobromide 0.25% aq• Sodium cromoglycate 2% aq• Sorbic acid 5% pet• Timolol maleate 0.5% aq• Thimerosal (thiomersal, merthiolate) 0.1% pet• Tropicamide 1% aq

pet = white pretolatum; aq = aqueous

account that dermographism, extensive eczema, and use of antihistamines (some of them with a long lasting effect) prevent or invalidate its use.

Patch testing is indicated in contact conjunctivitis for the diagnosis of contact allergen. Although they are easy to per- form, their interpretation requires considerable experience. Usually, a standard battery including several

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allergens in ap- propriate concentration and the diluent is applied to the skin

on inert metal disks. The chambers are removed two days later and a first evaluation of the erythema, vesicles and in- duration is performed, and repeated 48 hours later (96 hours after application). The erythema and/or edema in the appli- cation site may result from an irritative reaction; an eczema- tous vesicular reaction is diagnostic of delayed hypersensi- tivity. The use of suspected products or their derivatives, as suggested by the clinical history, or special batteries ( Table3.1) may improve the diagnosis and decrease costs.

Challenge tests are the only way to associate the allergen to the triggering of symptoms. Nevertheless, they are reserved for situations in which a definite conclusion is not possible, due to contradictory results of other tests, or in cases of mul- tiple sensitization. Exclusion of a given allergen in the trig- gering of ocular symptoms may be required, e.g., a conjunc- tival challenge with cat allergen in a patient with a perennial conjunctivitis, multiple sensitization and a cat in the domestic environment. These tests should be performed by experienced personnel, using increasing concentrations of allergens applied at regular intervals (usually 10 minutes), scoring the resulting signs and symptoms: erythema, hyper- aemia, chemosis, tearing and itching (Abelson MB et al, 1990). As in other organs, it is possible to observe immediate and delayed (6-10 hours) reactions to the allergen.

In vitro tests

Total serum IgE measurement may support the diagno- sis of allergy, especially when higher than 200-300 kU/L. Given the low concentration of IgE in serum (about 40 mg/L in contrast to 1200 mg/L of IgG), its measurement requires very sensitive techniques, such as radioimmunoassay (RIA) or enzyme-linked immunoassay (ELISA), which may also be used for measurement in lacrimal fluid (Fig. 3.28). Neverthe- less, the wide range of serum IgE in the normal population, especially in children, limits its predictive value in clinical practice. On the other

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hand, some parasites with an extra- intestinal cycle, as Ascaris and the Toxocara canis may raise the total IgE.

Fig. 3.28 – Lacrimal IgE: lacrimal fluid sampling

for IgE measurements.

In allergic disease, the rise in serum IgE is usually related to the extension of the involved “shock” organ (skin or mu- cosa) rather than with the ocular involvement, which rarely leads to such a rise.

The measurement of specific IgE is much more useful in the setting of an etiologic diagnosis of ocular allergy. The search for allergen specific IgE, by the RAST method, is theoretically attractive: a simple blood sample replaces many skin tests, without any risks of anaphylaxis and may be performed even in the above mentioned situations that exclude the use of the skin tests.

In the Radioallergosorbent test – RAST (Fig. 3.29) – the patient's serum is incubated with a solid phase – paper disk (in the original RAST technique), cellulose polymer, polysty- rene or a magnetic sphere – to which the putative allergen has been bound. After incubation, the solid phase is washed, thus eliminating the nonspecific IgE. The solid phase is then incubated with an anti-IgE antibody labelled with an isotope (in original RAST) or an enzyme and, after another incuba-

Fig. 3.29 – RAST: the detec- tion of specific IgE binding to

an allergen-coupled paper disc uses radiolabelled anti-

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IgE antibodies.

tion, the non-bound IgE is removed by washing and the amount of bound IgE is measured. The results may be de- picted in classes, that express the absence (Class 0), or pres- ence in significant amounts of the specific IgE for the aller- gen.

In recently developed systems liquid allergens or new types of solid phases with larger antigen binding capacity have been used. In the new test systems the results are expressed in kU/L, by reference to a calibration curve with a standard sample of IgE. Usually, results higher than class 2 (>3.5 kU/L) are considered to represent significant allergic sensitization.

In spite of its good specificity, in clinical practice RAST is less sensitive and more expensive than cutaneous tests, es- pecially for the diagnosis of multiple sensitization. Its main indications are situations in which the cutaneous tests cannot be used and when there is inconsistency between these and the clinical history.

To prevent the low predictive value of total IgE, the less practical availability of skin tests and the price of perform- ing multiple determinations of specific IgE, some allergen

Table 3.2 – Some allergen combinations useful for the in vitroscreening of allergic sensitization

AlaTOP®, Phadiatop® Dermatophagoides pteronyssinus,(mixtures of 13 to 23 allergens) cat, dog and horse dander,

grass, weeds and tree pollen mixtures mould mixtures

Food mixtures Milk, egg, fish (codfish), wheat, (pediatric) peanut, soy-beanGrass pollen mixture Dactylis glomerata, Festuca eliator,

Lolium perenne, Phleum pratense, Poa pratensis

Mould mixture Aspergillus fumigatus, Cladosporium herbarum, Penicillium notatum,

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Alternaria alternata

panels for in vitro allergy screening were recently developed. The principle is the same as the RAST, using multiple aller- gens bound to the solid phase – allergen mixtures (Table 3.2). They show, by their positive or negative result, if the patient is sensitized to a given group of allergens. In practice, these tests show excellent specificity and sufficient sensitivity to be the initial method of screening when allergic sensitization is suspected (Fig. 3.30 depicts a flowchart for the use of these tests).

There is an increasing interest in the study of inflammatory markers of cells involved in the immuno- pathogenesis of ocular allergy, both in serum and, mainly, in tears. They are usually proteins from eosinophil granules – e.g., ECP and EDN –, or mast cells – e.g., histamine and tryptase –, or cytokines – TNF-, IL-4, IL-5.

HistoryPhysical examination

Suggestive ofAllergy NEGATIVE DOUBTFUL

Refer to Allergist(Skin prick tests, RAST) Atopy screening

(e.g. "Phadiatop")Atopy screening

(e.g. "Phadiatop")

POSITIVE (+) NEGATIVE

(–)POSITIVE

(+)NEGATIVE

(–)

Refer to Allergist(Skin prick tests, RAST No Atopy Refer to Allergist

(Skin prick tests, RAST) TOTAL IgE

Increased Normal

Refer to Allergist(Skin prick tests, RAST) No Atopy

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Fig.3.30 – Diagnostic approach of IgE-mediated allergy inPrimary Care.

Although some studies suggest an association of levels of lacrimal ECP and tryptase with the severity of vernal con- junctivitis and its therapeutic response, their place in clini- cal practice is limited because some of these markers are in- creased in the lacrimal fluid of bacterial conjunctivitis (e.g., ECP, EDN and sIL2R). The levels of lacrimal leucotrienes (LTB4 and LTC4) are increased in giant-papillar y conjunctivitis and vernal keratoconjunctivitis, and decrease with treatment. With regard to cytokines, increased levels of IL4 and IL5 are mainly characteristic of the chronic conjunc- tivitis with giant papillae and keratopathy – atopic and vernal keratoconjunctivitis.

After the diagnostic work-up, the clinical and patho- physiological classification of allergic conjunctivitis can be established:

Allergic conjunctivitis

IgE-mediated non IgE-mediated

Seasonal allergic conjunctivitis Perennial allergic conjunctivitis Atopic keratoconjunctivitis Vernal keratoconjunctivitis

Giant-papillary conjunctivitis Contact blepharoconjunctivitis Toxic keratoconjunctivitis Vernal keratoconjunctivitis

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4TreatmentJorge palmaresLuís Delgado

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Treatment

Treatment

The complex immunopathogenesis of allergic disease, where the immune system reacts to environmental antigens with effector mechanisms that are, in reality, physiological, raises particular therapeutical problems. The disease can rarely be controlled with a single pharmacological group, and a multidisciplinary therapeutic strategy is usually needed.

Allergen avoidance

Immuno- therapy

Pharmacological treatment

Fig. 4.1 – Therapeutical approach to allergy: its optimization depends on the interaction of different therapeutic regimes.

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1 - Allergen avoidance

When an allergen can be identified as the main trigger of the disease, the first therapeutic approach should be the adoption of practical but strict measures to avoid that aller- gen. This could be the case in perennial or seasonal allergic conjunctivitis, associated with allergy to house dust mite and grass pollens, respectively, or with contact conjunctivitis caused by drugs or chemicals.

Etiologic diagnosis is based on the clinical history, the results of skin prick or patch tests and, in allergic conjunc- tivitis, on the evaluation of the intensity of the allergen sen- sitization by the levels of specific IgE and/or challenge tests. If the patient is sensitized to house dust mites ( Table 4.1) or grass pollens (Table 4.2) avoidance measures may be really effective and account for a significant decrease of symptoms.

Table 4. 1 – Instructions to patients allergic to house dust mites.

House dust is a mixture of a large variety of allergens, with dust mites (both dead or alive) and it is the major source of its allergens. House dust mites (HDM) feed on skin scales and certain moulds, and its growth is favoured by indoor humidity. Within the house they are especially located in the bedroom, particularly in bed covers, mattresses, pillows, upholstered furniture, and carpets.

The number of indoor HDM increases in months with high humidity, in Europe generally starting in October and during the Winter.

Within the house it will be probably the bedroom the place with higher exposure to HDM.

Therefore, the major strategy to get rid of dust mites is to concentrate efforts in cleaning bedroom and, then, the rest of the house.

Removing house dust from bedroom:

• Floor – without carpeting! Prefer hardwood or lino- leum. Vacuum regularly, using a vacuum cleaner with a HEPA filter.

• Walls – smooth walls that may be cleaned easily! No wallpaper or moulds!

• Curtains – simple and washable, made with synthetic fibers.

• Furniture – prefer smooth surfaces, that are easily cleaned. Do not use the bedroom as an office room or library. Avoid many small objects, records, tapes, ste- reos, televisions on your furniture. Toys and furry toys should be placed in closed cabinets.

• Bedding – as a rule prefer synthetic fibers easily wash- able in hot water:- prefer washable synthetic pillows that should be

replaced every two to three years.- avoid furry bed covers and comforters made of

feathers, kapok and cotton, should be replaced with synthetic ones (e.g. dacron).

- wash bedding weekly in hot water since cool water does not kill dust mites.

- mattresses require vacuum cleaning twice weekly or should be placed in allergen-proof fabric casings.

In the rest of the house...

Regular house cleaning and vacuuming is essential. The furniture should be wiped and maintained as clean as possible.

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Table 4. 2 – Instructions to patients with pollen allergy

Pollens are microscopic powdery granules involved in the fertilization of flowering plants. Although there are large numbers of different plants only about 10% may induce allergies, usually trees, grasses and weeds. Plants with bright flowers or leaves rarely cause allergies.

When does the pollen season occurs in Europe?

• during Spring and Summer• starting: from February or March (some trees)• maximal peak: May to July (grasses and weeds)• end: September to October (some weeds).

How to avoid pollens?

During pollen season:

• avoid walking in green fields and do not mow lawns.• avoid walking outdoor on windy days, especially in

the early morning (5:00 to 10:00 a.m.) when pollens are usually emitted.

• avoid cycling, camping, fishing or hunting during this season.

• keep house windows closed at night and car windows closed when travelling by car.

• when staying outdoors use sunglasses (with 100% UV filtration!).

2 - Pharmacological treatment

As well as allergen avoidance, some complementary measures for the attenuation of acute symptoms may be useful, such as the use of cold patches (e.g., with normal saline) for the relief of ocular itching. The use of artificial tears (hydroxypropyl methylcellulose, polyvinyl alcohol, povidone, etc.), several times daily, ideally as unit doses (preservative free) promotes the direct removal and dilution of the allergens.

At night-time, the use of lubricating agents in the form of gel is preferable: since they are thicker, they exert a more prolonged action in ocular dryness cases.

Eyelid hygiene with patches soaked in baby shampoo may be very important in the cleaning of lipid secretions in cases of palpebral sebaceous gland dysfunction.

The control of the frequent bacterial colonization (Sta- phylococcus aureus) of the blepharitis of the atopic kerato- conjunctivitis may require the use of local and systemic antibiotics, and topical corticosteroid in some cases.

Pharmacologic agonists and antagonists

Mast cell stabilizers

Steroidal and non- steroidal anti- inflammatory

drugs

Fig. 4.2 – Strategy for the pharmacological treatment of ocu- lar allergy: the combination of different pharmacologic

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groups is usually necessary.

Table 4. 3 – Main therapeutic approaches in ocular allergy.

Allergen avoidanceCold patchesArtificial tears carbomer

carmellose dextranhydroxypropyl methylcellulose polyacrylic acidpolyvinyl alcohol povidone

Antihistamines emadastine levocabastine

Antihistamine + vasoconstrictor antazoline-naphazoline pyrilamine + phenylephrine

Mast cell stabilizers cromoglycate lodoxamide nedocromil pemirolast spaglumic acid

Mast cell stabilizers/ azelastine/antihistamine ketotifen

olopatadineNon-steroidal anti-inflammatory diclofenacdrugs flurbiprofen

ketorolacMucolytic N-acetylcysteineOral antihistamines cetirizine

desloratadine ebastine fexofenadine hydroxizine ketotifen loratadine mizolastine oxatomide

Topical corticosteroids dexamethasone fluormetholone loteprednol prednisolone rimexolone

Therapeutics in development allergen vaccines topical cyclosporin monoclonal antibodies(anti-IgE and anti-adhesion

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molecules)immunostimulating DNAsequences (ISS-ODN)

The cleaning of the conjunctival cul-de-sac and the palpebral free margins with povidone-iodine is mandatory for ocular surger y, namely cataract surger y, cor neal transplant or amnyotic membrane transplant for treating vernal corneal ulcers.

Because of the variety of mediators and cells involved in the pathophysiology of ocular allergy, the main strategy of the pharmacological therapy is to combine different thera- peutic groups, active on different mediators (Table 4.3).

A - Pharmacological agonists and antagonists

Since histamine is one of the main inflammatory me- diators in mast cells and basophils, the use of antagonists of its receptors in target organs is one of the most frequent initial therapeutic approaches.

Two kinds of antagonists of H1 receptors for histamine are available: 1) the first generation drugs, such as chlorphe- niramine and hydroxizine; they easily pass the blood-brain barrier, causing sedation; they may also have anticholinergic activity, sometimes leading to accommodation problems and increase of intraocular pressure in angle-closure glaucoma;2) second generation drugs, such as cetirizine, desloratadine and fexofenadine; they are virtually free of sedative effects and their anticholinergic action is minimal.

Some of these drugs have effects that do not depend on the H1 antagonism, such as mast cell stabilization (fexofenadine, ketotifen and loratadine), PAF antagonism (ketotifen), eosinophil migration inhibition (cetirizine, fexofenadine and desloratadine) and inhibition of the adhesion molecule expression in epithelial cells (deslora- tadine), which may be additional therapeutic advantages.

The long-lasting use of H1 antagonists, although quickly relieving allergic symptoms, is frequently accompanied by ocular, nasal and oral mucosa dryness.

Topical antihistamine use, while avoiding the sedative effects, is not free from ocular anticholinergic effects. Also,

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the available topical antihistamines have the inconvenience of associated vasoconstrictor alpha-adrenergic agonists

(antazoline-naphazoline). This association may be useful in mild cases and for a short time but when used chronically it causes rebound effects with a vasodilator response and the preservative-related toxicity is a matter of concern.

Levocabastine hydrochloride is a second generation anti- H1 available for topical use, with a rapid onset of action and good local tolerance, not affecting accommodation or raising intra-ocular pressure.

Emedastine is another recent H1 antihistamine for topi- cal use. It presents a rapid start of action and may be used in children.

The elimination half-life of cetirizine is prolonged in patients with renal impairment.

There are no data available on the safety of these agents in pregnancy. However, the use of topical or oral chlorpheni- ramine is considered safe in pregnancy.

The leukotriene receptor antagonists (montelukast, zafirlukast) constitute a new class of pharmacological agents with anti-inflammatory activity that have been shown to be effective in the treatment of asthma, allergic rhinitis and, more recently, in pilot trials in atopic dermatitis. Given the involvement of leukotrienes in the immunopathology of ocu- lar allergic disease and their lacrimal fluid increase in the more chronic forms (giant-papillary conjunctivitis, vernal and atopic keratoconjunctivitis), controlled clinical trials with these new agents are still expected.

B - Mast cells stabilizers

Sodium cromoglycate and sodium nedocromil are usually considered “anti-allergic” drugs, although they do not have antagonistic effects, because they inhibit the immediate reaction to the allergen and the chronic allergic inflam- mation. Since they are acidic drugs, which remain in the ionised form in the extracellular compar tment, their absorption from the mucosa is practically nil, which makes them very safe. As a matter of fact, topical cromoglycate is considered a safe drug for

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the treatment of allergy in pregnancy.

The mechanism by which these drugs inhibit mediator release from mast cells is not yet established, but inhibitory actions in other inflammatory cells and in neuronal reflexes may also contribute to the therapeutic effects. These phar- macologic agents act prophylactically, but the most recently developed drugs present multiple mechanisms of action, for example causing immediate relief of itching by an antihistamine effect.

Nedocromil has been shown to be in a twice daily dose as effective as four daily administrations of cromoglycate for the treatment of seasonal conjunctivitis and even more ef- fective for vernal keratoconjunctivitis, possibly because of its action on the two types of mast cells (MCT and MCTC).

Lodoxamide is also a recently developed mast cell stabi-lizer with a strong inhibitory action on histamine and leu- kotriene release and also inhibits eosinophil chemotaxis.

Spaglumic acid, as well as inhibiting LTB4 production by leukocytes, is a mast cell stabilizer and inhibits in vitro acti- vation of the complement system. It has a more rapid onset of action than cromoglycate.

Recently, three new drugs with mast cell stabilizing and H1 antihistamine actions have been introduced: ketotifen, azelastine and olopatadine. These agents may be used in a more convenient dosage regimen (twice-daily) and they are highly effective in ocular allergy.

C - Non-steroidal anti-inflammatory drugs (NSAIDs)

Topical nonsteroidal anti-inflammatory drugs have been recently developed and may be especially attractive, because of their greater safety compared with the strong anti- inflammatory steroids that have been classically associated with adverse effects, such as local infection, glaucoma and cataract formation.

Among the nonsteroidal anti-inflammatory drugs, two of them – diclofenac and ketorolac – have been especially used in ocular allergy. Ketorolac reduces local itching and local prostaglandin levels. Diclofenac has showed to be effective in the symptomatic relief of seasonal allergic con-

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junctivitis.

D - Corticosteroids

Like in other forms of allergy, topical corticosteroids are quite efficient in ocular allergy, since they suppress multiple steps of the immune and inflammatory reaction. Neverthe- less, their use must be limited for short periods, and moni- tored by ophthalmologists, because they are associated with corneal epithelium healing delay, rise in intraocular pressure (glaucoma), cataract formation and local immunosuppres- sion with consequent superinfection of the cornea and con- junctiva. They may be useful in the treatment of corneal in- volvement of vernal and atopic keratoconjunctivitis or in their most serious acute phases. The most potent corticos- teroids, such as dexamethasone and prednisolone also have a higher risk of adverse side effects than the weaker ones, such as fluormetholone, loteprednol and rimexolone. Oral corticosteroids and systemic cyclosporin A are rarely indicated in ocular allergy. However, the topical form of cyclosporin has been shown to be effective in the more severe forms of ocular allergy (atopic and vernal).

The therapeutic strategy in the different clinical forms of ocular allergy is now proposed:

Seasonal and perennial allergic conjunctivitis requires the use of cold patches and artificial tears for immediate re- lief of symptoms, associated with short-lasting therapy with topical antihistamines, with or without decongestants and mast cells stabilizers. In more prolonged forms, the use of oral antihistamines, with mast cell stabilizer effects may have some interest, especially in phases of prolonged or higher allergen exposure, as well as topical nonsteroidal anti-inflam- matory drugs.

Wind and air conditioning without filters must be avoided in vernal conjunctivitis, because of the possibility of multiple sensitization to pollens and dust allergens.

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Digital manipulation of the eyes must also be limited because it causes mechanical granule-release of mast cell mediators.

Artificial tears may be used, as well as mast cell stabiliz- ers (ketotifen, lodoxamide, nedocromil and olopatadine may be indicated in this form). In the acute phase antihistamines and/or NSAIDs must be used.

In the most severe presentations, topical corticosteroids may be used in pulses, for instance, 1% prednisolone (6 to 8 times a day, during one week, with immediate progressive tapering), under ophthalmologic control. The use of thera- peutic contact lenses must be avoided because of the risk of keeping possible allergens in the pre-corneal lacrimal film. Giant papillae may take months to disappear, but they usually do not present clinical problems.

Atopic keratoconjunctivitis is an entity with a complex approach. It requires complicated multidisciplinary treat- ment with strict environmental control and multiple drug administration: oral/topical antihistamines, mast cells sta- bilizers and, when necessary, the use of topical and/or sys- temic corticosteroids. Topical steroids may decrease kerato- conjunctivitis, but they always have long-lasting risks, thus requiring monitoring. If herpetic keratitis occurs, topical acyclovir must be used immediately.

Blepharitis must be treated by eyelash cleaning and ste- roid and antibiotic ointment. Cataract surgery in this disor- der is always difficult. The use of immunomodulators (e.g. cyclosporin) is still controversial.

Giant-papillary conjunctivitis is reversible and symp- tomatic improvement results from cleaning and avoiding contact lenses.

Contact lenses with a better tolerated material must be found. There is no universal consensus on the best therapeu- tic approach to this disease. During the acute phase, the use of mast cell stabilizers, ideally preservative-free, and topical steroids, is helpful.

In contact allergy, it is very important to avoid the aller-

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gen, if identified. Occasionally, it is necessary to modify a topi- cal prescription to a preservative-free formula or, at least, with

a different preservative. Acute phases require the use of cold patches and topical steroids (drops and ointment).

Oral corticosteroids are only used in the most serious acute situations. It must be pointed out that some preserva- tives (e.g., benzalkonium chloride) may damage the contact lens material.

3 - Immunotherapy

Allergen desensitization therapy, also named allergen vaccines, may be indicated in selected cases, as long as an IgE mediated mechanism is the main factor.

Although there are no controlled trials in situations of exclusive involvement of the ocular mucosa, its efficiency is clearly established in cases with respiratory tract involve- ment. For example, in perennial or seasonal allergic rhino- conjunctivitis, the improvement of conjunctival sensitivity to allergen has been consistently observed and correlates closely with the clinical improvement of patients. This was reported in the first scientific communication about the ef- fectiveness of immunotherapy (Noon and Cantor, 1911, The Lancet). Several reference studies have also demonstrated its efficacy in reducing ocular symptoms after provocation, namely in vaccines with pollens, mites or cat danders.

Hence, allergen vaccines may be indicated in forms of ocular allergy associated with respiratory symptoms, espe- cially if avoidance and pharmacological measures have not sufficiently controlled the symptoms. Allergen vaccination must be always administered by personnel experienced with this kind of therapy (immunoallergologists) because of the risks of anaphylaxis and other adverse reactions.

Although the effectiveness of allergen vaccines by oral route has not yet been completely established, they have proved to be effective in controlling ocular symptoms in both exper imental models and clinical trials in seasonal rhinoconjunctivitis. Due to its ease of use and lower risk of adverse reactions, this form of immunotherapy may become an interesting therapeutic approach in IgE-

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mediated ocular allergy.

In the last five years, new forms of immunotherapy, such as monoclonal antibodies – anti-IgE (omalizumab) and anti- intercelular adhesion molecules – and Th1 immunostimula- ting sequences of DNA (ISS-ODN), have demonstrated efficacy in experimental and clinical models of ocular allergy, open interesting perspectives in the application of molecular medicine to treatment of ocular allergic disease.

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Appendix 1 – Main pharmaceutical products for the management of ocular allergy

• Topical use:

Artificial tearsadsorbobase carbomer carmellose dextranhydroxypropyl methylcellulose methylcellulosepoloxamer + hydroxyethylcellulose polyacrylic acidpolyoxyl stearate 40 + polyethylene glycol polyvinyl alcoholpovidonesodium hyaluronate

MucolyticN-acetylcysteine

Antihistamines emadastine levocabastine

Antihistamine + vasoconstrictor antazoline+naphazoline pyrilamine+phenylephrine

Vasoconstrictors naphazoline oxymetazoline phenylephrine synephrine+hydrastinine tetrahydrozoline

Mast cell stabilizerslodoxamidesodium cromoglycate sodium nedocromil spaglumic acid

Mast cell stabilizer / antihistamineazelastine ketotifen olopatadine

Non-steroidal anti-inflammatory drugsdiclofenac flurbiprofen ketorolac suprofen

Corticosteroids dexamethasone fluormetholone loteprednol prednisolone rimexolone

•O ral use:

Antihistaminesazatadinebuclizine cetirizine clemastine chlorpheniramine desloratatine dimethyndene ebastine fexofenadine hydroxizine ketotifen loratadine meclizine mequitazine mizolastine oxatomide pheniramine promethazine triprolidine

Immunomodulatorcyclosporin A

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Appendix 2 – Main preservatives of ophthalmic preparations used in the treatment of ocular allergy

Benzalkonium chloride Cetrimide Chlorhexidine ChlorbutanolPolyquadThimerosalThimerosal + plasdone Thimerosal + EDTA Sorbic acidSorbic acid + EDTA

References

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ReferencesJorge palmaresLuís Delgado

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References

References

Immunopathology

• Anderson DF, Zhang S, Bradding P, McGill JI, Holgate ST, Roche WR. The relative contribution of mast cell subsets to conjunctival TH2-like cytokines. Invest Ophtalmol Vis Sci 42: (5) 995-1001, 2001.

• Bielor y L. Allergic and immunologic disorders of the eye. Pa r t I: Immunology of the eye. J Allergy Clin Immunol 106: 805-16, 2000.

• Bielory L. Allergic and immunologic disorders of the eye. Part II: Ocular allergy. J Allergy Clin Immunol 106: 1019-32, 2000.

• Bonini S, Centofanti M, Schiavone M, et al. The pattern of the ocular late phase reaction induced by allergen challenge in hay fever conjuntivitis. Ocul Immunol Inflamm 2 (4): 191-197, 1994.

• Calder VL, Jolly G, Hingorani M, Adamson P, Leonardi A, Secchi AG, Buckley RJ, Lightman S. Cytokine production and mRNA expression by conjunctival T-cell lines in chronic allergic eye disease. Clinical and Experimental Allergy29: 1214-1222, 1999.

• Fukagawa K, Saito H, Azuma N, et al. Histamine and tryptase levels in allergic conjunctivitis and vernal keratoconjunctivitis. Cornea 13 (4): 345-348, 1994.

• Hingorani M, Calder VL, Jolly G, Buckley RJ, Lightman S. Eosinophil surface antigen expression and cytokine production vary in different ocular allergic diseases. J Allergy Clin Immunol 102 (5): 821-830, 1998.

• Leonardi A, DeFranchis G, Zancanaro F, Crivellari G, De Paoli M, Plebani M, Secchi AG. Identification of local Th2 and Th0 lymphocytes in Vernal Conjunctivitis by cytokine flow cytometry. Invest Ophtalmol Vis Sci 40:3036-3040, 1999.

• Leonardi A, Brun P, Tavolato M, Abatangelo G, Plebani M, Secchi AG. Growth factors and collagen distribution in vernal keratoconjunctivitis. Invest Ophtalmol Vis Sci 41 (13): 4175-4181, 2000.

• Maggi E, Biswas P, Del Prete G, et al. Accumulation of Th-2-like helper Tcells in the conjunctiva of patients with vernal conjunctivitis. J Immunol146: 1169-1174, 1991.

• Magr ini L, Metz D, Bacon A, et al. Immunohistochemistr y and inflammation of vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci 34 (4): 857, 1993.

• McGill JI, Holgate ST, Church MK, Anderson DF, Bacon A. Allergic eye disease machanisms. Br J Ophthalmol 82: 1203-1214, 1998.

• Metz DP, Bacon AS, Holgate S, Lightman S. Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye disease. J Allergy Clin Immunol 98: 686-696, 1996.

• Romagnani S. Biology of human TH1 and TH2 cells. J Clin Immunol 15 (3):121-127, 1995.

90

• Secchi A, Leonardi A, Abelson M. The role of eosinophil cationic protein (ECP) and histamine in vernal keratoconjunctivitis. Ocul Immunol Inflamm 3 (1): 23-28, 1995.

• Stahl JL, Cook EB, Sanchez H, Luster AD, Barney NP, Graziano FM. Eotaxin is produced and released by human conjunctival epithelial cells. J Allergy Clin Immunol 99 (1-Pt2): S167, 1997.

• Trocme SD, Hallberg CK, Gill KS, Gleich GJ, Tyring SK, Brysk MM. Effects of eosinophil granule proteins on human corneal epithelial cell viability and morphology. Invest Ophtalmol Vis Sci 38 (3): 593-599, 1997.

• Uchio E, Ono SY, Ikezawa Z, Ohno S. Tears levels of interferon-, interleukin

(IL)-2, IL-4 and IL-5 in patients with vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis. Clinical and Experimental Allergy 30: 103-109, 2000.

• Vesaluoma M, Rosenberg ME, Teppo A, Gronhagen-Riska C, Haahtela T, Tervo T. Tumour necrosis factor alpha ( TNFalpha) in tears of atopic patients after conjunctival allergen challenge. Clin Exp Allergy 29(4): 537-542, 1999.

• Yoshida A, Imayama S, Sugai S, Kawano Y-I, Ishibashi T. Increased number of IgE positive Langerhans cells in the conjunctiva of patients with atopic dermatitis. Br J Ophthalmol 81: 402-406, 1997.

• Wardlaw AJ. Eosinophils. Basic Clinical Allergy. National Heart & LungInstitute, London, 1995.

• Williamson JSP, DiMarco S, Streilein JW. Immunobiology of Langerhans cells on the ocular surface. Invest Ophtalmol Vis Sci 28: 1527-1532, 1987.

Clinical Features

• Bielory L. Ocular contact dermatitis. Interest Section Symposia. AmericanAcademy of Allergy & Immunology International Conference 257-269,1995.

• Bonini S, Bonini S, Lambiase A, Marchi S, Pasqualetti P, Zuccaro O, Rama P, Magrini L, Juhas T, Bucci MG. Vernal Kerato-conjunctivitis Revisited. A case series of 195 patients with long-term followup. Ophthalmology 107:1157-1163, 2000.

• Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy50 (21 suppl): 6-9, 1995.

• Foster CS, Calonge M. Atopic keratoconjunctivitis. Ophthalmology 97: 992-1000, 1990.

• Heidemann DG. Atopic and vernal keratoconjunctivitis. Focal Points - AmAcad Ophthalmol XIX: 1, 2001.

• Raizman MB. Update on Ocular Allergy. Focal Points - Am Acad OphthalmolXII: 5, 1994

• Spraul CW, Lang GK. Allergic and atopic diseases of the lid, conjunctiva, and cornea. Curr Opin Ophthalmol 6(IV ): 21-26, 1995.

Diagnosis

• Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. Aclinical approach to studying allergic conjunctivitis. Arch Ophtalmol 108:84-88, 1990.

• BenEzra D, Bonini S, Carreras B, et al. Guidelines on the diagnosis and treatment of conjunctivitis. Ocul Immunol Inflamm 2:(suppl): 1-55,1994.

Ocular Allergy

92

• Crobach MJJS, Kaptein AA, Kramps JA, et al. The Phadiatop® test compared with RAST, with the CAP system; proposal for a third Phadiatop outcome:«inconclusive». Allergy 49 (3): 170-176, 1994.

References

• Leonardi A, Borghesan F, Faggian D, Depaoli M, Secchi A, Plebani M. Tear and serum soluble leukocyte activation markers in conjunctival allergic diseases. Am J Ophthalmol 129: 151-158, 2000.

• Palmares J, Delgado L, Campilho F, Torrinha JF, Castro-Correia J. Perfil proteico do filme lacrimal. Rev Soc Port Oftal X ( 2): 179-190, 1994.

• Palmares J, Delgado L, Oliveira JF. IgE lacrimal na rinoconjuntivite alérgica.Rev Soc Port Oftal XIII (1,2): 1-7, 1987.

• Secchi A, Leonardi A, Abelson M. The role of eosinophil cationic protein (ECP) and histamine in vernal keratoconjunctivitis. Ocul Immunol Inflamm 3 (1): 23-28, 1995.

• Tabbara K F. Tear tryptase in vernal keratoconjunctivitis. Arch Ophthalmol119:338-342, 2001.

• Venge P. Soluble markers of allergic inflammation. Allergy 49 (1): 1-8, 1994.• Wever AMJ, Weber-Hess CP, van Schayck, van Weel C. Evaluation of the

Phadiatop® test in an epidemiological study. Allergy 45 (2): 92-96, 1990.• Zug KA, Palay DA, Rock B. Dermatologic diagnosis and treatment of itchy

red eyelids. Surv Ophthalmol 40: 293-306, 1996.

Treatment

• Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Acta Ophthalmol Scand 78: 52-55, 2000.

• Akman A, Irkeç M, Orhan M, Erdener U. Effect of lodoxamide on tear leukotriene levels in giant papillary conjunctivitis associated with ocular prosthesis. Ocul Immunol Inflamm 6 (3): 179-184, 1998.

• Avunduk AM, Avunduk MC, Kapicioglu Z, Akyol N, Tavli L. Mechanisms and comparision of anti-allergic efficacy of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis. Ophthalmology2000; 107: 1333-1337.

• Azevedo M, Castel-Branco MG, Oliveira JF, Ramos E, Delgado L, Almeida J. Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy 21: 689-694, 1991.

• Berdy GJ, Spangler DL, Bensch G, Berdy SS, Brusatti RC. A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. Clin Ther 22: 826-833, 2000.

• Calonge M, Montero JA, Herreras JM, Juberias JR, Pastor JC. Efficacy of nedocromil sodium and cromolyn sodium in an experimental model of ocular allergy. Ann Allergy Asthma Immunol 77: 124-130, 1996.

• El Hennawi M. A double-blind placebo controlled group comparative study of ophthalmic sodium cromoglycate and nedocromil sodium in the treatment of vernal keratoconjunctivitis. Br J Ophthalmol 78: 365-369, 1994.

Ocular Allergy

94

• Friedlaender MH. Management of ocular allergy. Ann Allergy Asthma & Immunol 75: 212-222, 1995.

• Friedlaender MH. The current and future therapy of allergic conjunctivitis.Curr Opin Ophthalmol 9; IV:54-58, 1998.

• Friedlaender MH, Harris J, LaVallee N, Russell H, Shilstone J. Evaluation of the onset and duration of effect of azelastine eye drops (0.05%) versus placebo in patients with allergic conjunctivitis using an allergen challenge

Ocular Allergy

92

model. Ophthalmology 107:2152-2157, 2000.• Hingorani M, Moodaley L, Calder VL, Buckley RJ, Lightman S. A

randomized, placebo-controlled trial of topical Cyclosporine A in steroid- dependent Atopic Keratoconjunctivitis. Ophthalmology 105: 1715-1720,1998.

• Knight A. The role of levocabastine in the treatment of allergic rhinoconjunctivitis. Br J Clin Practice 48: 139-143, 1994.

• Koizumi T, Abe T, Sakuragi S. Suppression of experimental allergic conjunctivitis in guinea pigs by oral administration of antigen. Ocul Immunol Inflamm 3 (2): 113-119, 1995.

• Laibovitz RA, Koester J, Schaich L, Reaves TA. Safety and efficacy of diclofenac sodium 0.1% ophthalmic solution in acute seasonal allergic conjunctivitis. J Ocul Pharmacol Ther 11(3): 361-368, 1995.

• Lightman S. Therapeutic considerations: symptoms, cells and mediators.Allergy 50 (21 suppl): 10-13, 1995.

• Löfkvist T, Agrell B, Dreborg S, Svensson G. Effects of immunotherapy with a purified standardized allergen preparation of Dermatophagoides farinae in adults with perennial allergic rhinoconjunctivitis. Allergy 49: 100-107,1994.

• Melamed J, Schwartz RH, Hirsch SR, Cohen SH. Evaluation of nedocromil sodium 2% ophthalmic solution for the treatment of seasonal allergic conjunctivitis. Ann Allergy 73: 57-66, 1994

• Miyazaki D, Liu G, Clark L, Ono SJ. Pevention of acute allergic conjunctivitis and late-phase inflammation with immunostimulatory DNA sequences. Invest Ophtalmol Vis Sci 41: 3850-3855, 2000.

• Santos CI, Huang AJ, Abelson MB, Foster CS, Friedlaender M, McCulley JP. Efficacy of lodoxamine 0.1% ophthalmic solution in resolving corneal epitheliopathy associated with ve r nal keratoconjunctivitis. Am J Ophthalmol 117: 488-497, 1994.

• Shulman DG, Lothringer LL, Rubin JM, Briggs RB, Howes J, Novack GD, Hart K. A randomized double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. Ophthalmology 106: 362-369, 1999.

• Stock EL, Pendleton RB. Pharmacological treatment of ocular allergic diseases. Int Ophthalmol Clin 33: 47-58, 1993.

• Verin P, Easty DL, Secchi A, Ciprandi G, Partouche P, Nemeth-Wasmer G, Brancato R, Harrisberg CJ, Estivin-Ebrardt C, Coster DJ, Apel AJ, Coroneo MT, Knorr M, Carmichael TR, Kent-Smith BT, Abrantes P, Leonardi A, Cerqueti PM, Modorati G, Martinez M. Clinical evaluation of twice-daily emedastine 0.05% eye drops (Emadine eye drops) versus levocabastine0.05% eye drops in patients with allergic conjunctivitis. Am J Ophthalmol131: 691-698, 2001.

• Walker SM, Varney VA, Gaga M, Jacobson MR, Durham SR. Grass pollen immunotherapy: efficacy and safety during a 4-year follow-up study. Allergy50: 405-413, 1995.

References

Indexacute uveitis, 58 adenovirus, 53allergen avoidance, 71,72,76 allergen mixtures, 66 allergen vaccines, 76,82 allergic conjunctivitis,

perennial, 31, 32, 33, 33, 45, 72, 80, 83 seasonal, 17, 21, 31, 32, 33, 33, 72, 79, 80, 83

antihistamines, 76,77, 80, 84,85 artificial tears, 75,76, 80, 81, 84 atopic eczema, 38azelastine, 76,79,85 bacterial antigens, 45 basophils 13,15,26, 45 benzalkonium chloride 62, 86 blepharitis, 38, 81 blepharoconjunctivitis, 55

contact, 42, 43 staphylococcal, 52, 53, 55 herpetic, 53

C3a, 15C5a, 15,18,20CD4+ T lymphocytes, 23 cetirizine, 76,77,78 challenge tests, 63, 72 chemical conjunctivitis, 44chemokines, 13, 14,18, 22, 25,27 chemosis, 31, 32 chlorpheniramine, 77, 78, 85 clinical diagnosis, 49clinical features, 31 cold patches, 76, 80conjunctival epithelium, 22,25, 27 conjunctivitis,

contact, 62, 72 bacterial, 52by adenovirus, 53by Herpes simplex, 53 chemical, 44 chlamydial, 52giant-papillary, 31, 40, 41, 45, 67, 78, 81 occupational (ocular irritation), 44 phlyctenular, 54rosacea-associated, 56 staphyloccocal, 52 vernal, 38, 41, 67

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viral, 52

Ocular Allergy

contact allergy, 31, 42, 45, 81 contact lens, 40, 41, 81 corneal ulcers, 21, 37 corticosteroids, 80,82, 85 cromoglycate, 78,79,84 cutaneous patch testing, 43 cyclosporin, 76,80, 81, 85cytokines, 13,14,15, 17,18,19,20,22,23,24,25,26,27 delayed hypersensitivity, 14,21, 22,23dendritic cells, 14,21, 22,25, 45 dermatomiositis, 56 desloratadine, 76,77, 85 dexamethasone, 76,80,85diagnostic approach of IgE-mediated allergy, 66 diagnostic tests, 61diclofenac, 76,79,85 differential diagnosis, 52 dry eye, 56ebastine, 76,85 emadastine, 78, 84eosinophils, 14,17,18, 19, 20, 21,24,25,26,27, 45 eotaxin, 14,18,25,27E-selectin, 18, 19FcRI, 15,21, 25 fexofenadine, 76,77,85 fibroblasts, 24, 26 fluormetholone, 76,80,85 flurbiprofen 76gamma-interferon 14 giant-papillae, 51GM-CSF, 15,18,20,25,26, 27Herpes simplex, 53 house dust mite, 33, 72 hydroxizine, 76, 77,85 hypersensitivity,

delayed, 23 immediate, 23, 61

idiopathic “sicca” keratoconjunctivitis, 56IFN-, 23,24IgE, 20, 45

antibodies, 13,14, 61 measurement in lacrimal fluid, 63 receptors, 14specific measurement, 72 synthesis, 26total serum measurement, 63

interleukinsIL, 14IL-1, 19IL-2, 14,23,24IL-3, 15,18,19,20,25,27IL-4, 14,15,17,19,23,24,25,26IL-5, 14,15,17,18,20,23,24,25,26

References

96

IL-6, 14,15,17,26IL-8, 14,15,17,26IL-10, 23,24IL-12, 24IL-13, 14,15,17,23,25,26

immunopathology, 13, 45 immunotherapy, 71, 83, 84in vitro tests, 63 in vivo tests, 61inflammatory markers of cells, 66 insect bites (mosquito), 59 instructions to patients, 72,74 keratinocytes, 14,26 keratoconjunctivitis

atopic, 17,21,22,24, 27, 31,37,38, 39,45, 67, 78, 79, 80, 81 "sicca", 56toxic, 42vernal, 17,22,24, 31, 34, 35, 38, 41, 45, 67, 78, 79, 80

keratoconus, 36, 40ketorolac, 76,79,85 ketotifen, 76,77,79,81,85 lacrimal IgE, 64lacrimal leucotrienes, 67Langerhans cells, 21late phase reaction, 16, 17, 21, 22, 25, 26, 27 leucoma, 36,37,50leukotriene

LTB4, 18LTC4, 15, 17, 26receptor antagonists, 78

levocabastine, 78, 84limbic keratoconjunctivitis, 54 lodoxamide 76,79, 81,84 loratadine, 76,77,85 loteprednol, 76,80,85Lyell’s syndrome, 57, 58 lymphocytes,

B, 14infiltration and activation, 17T-helper, 14T, 13,14,18,22Th0, 24Th1, 14, 23, 24, 45Th2, 14, 23,24,26, 45

macrophages, 14, 21mast cell stabilizers, 75, 76, 78, 80, 81, 84 mast cells, 13,14,15, 17,24,26, 45 monoclonal antibodies 76,83monocytes, 14,21 nedocromil 76, 78,81,84non-steroidal anti-inflammatory drugs, 76, 75, 79, 80, 85 ocular cicatricial pemphygoid, 59olopatadine, 76,79,81,85

Ocular Allergy

omalizumab, 83ophthalmologic examination, 49 oxatomide, 76P-selectin, 19PAF, 17, 18, 20 patch testing, 62 pemirolast, 76pharmacological agonists and antagonists, 75, 77 pharmacological treatment, 71, 75phlyctenule, 54Phthirus pubis, 60 povidone-iodine, 77 prednisolone 76,80,81,85 preservatives, 42, 86 pseudo-gerontoxon, 37RANTES, 14,18,25,27RAST, 64rimexolone, 76,80,85 rosacea, 56scleritis, 58senile ectropion, 60 shield ulcers, 36, 37Sjögren’s syndrome, 56,57 skin prick tests, 61 spaglumic acid, 76,79, 84stem-cell factor (SCF), steel factor or kit ligand, 26Stevens-Johnson’s syndrome, 57Stye (hordeolum), 55 symblepharon, 36, 58 thimerosal, 42, 62, 86 ticks, 60TNF-, 14,15,17,19,26Trantas' dots, 36VCAM-1, 18, 19

98