Ocular AllergySecond edition

Jorge PalmaresLuís DelgadoJorge PalmaresLuís Delgado

Ocular AllergySecond Edition

Ocular AllergySecond Edition

Jorge PalmaresOphthalmology Consultant

Cornea and Ocular Immunopathology ClinicDepartment of Ophthalmology,

Hospital de S. João, Porto, Portugal

Luís DelgadoAssociate Professor of Immunology

Faculty of Medicine, University of PortoDepartment of Immunology and Immunoallergology Unit

Hospital de S. João, Porto, Portugal

Title:

Authorship:Publisher:

ISBN:"Depósito-legal":

Ano:Copyright:

Ocular AllergySecond Edition

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

Acknowledgement: The Publisher thanksNOVARTIS Ophthalmics fortheir prompt support to theedition of this booklet.

Introduction

Conjunctivitis is one of the most common ocularaffections in clinical practice and when of allergic etiologypresents difficulties and peculiarities both in differentialdiagnosis and therapeutical approaches. Clinically, itspresentation can range from mild seasonal symptoms toperennial forms coursing with intense and very uncom-fortable ocular itching and tearing, or to visual loss due tocorneal involvement. In the recent years, new insights intothe cellular and molecular mechanisms of allergic diseasehave come into view, along with the development of newdrugs acting in several pathways of the allergic reaction. Theaim of «Ocular Allergy» is to summarize, in a monograph, thecurrent knowledge of the immunopathology, diagnosis andtherapeutical approaches of these affections. In this secondedition, we tried to improve the iconography whilemaintaining the focus on clinical practice, making the readingeasy and helpful to any physician involved in the follow-upof these patients – the general practitioner, the ophthal-mologist and the allergist – and also stress the need for amultidisciplinary approach to effectively control the mostserious and chronic presentations.

The authors

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

«This little book contains an enormous amount of information.It is designed for the practising clinician, with an interest in ocularallergy, and covers all types of allergic eye disease. Our understandingof disease mechanisms has increased enormously over the last fewyears and the scientific information given in this book is up-to-dateand clearly explained (…). I think this book will be extremely usefulto 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 voidin 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 thecomplexity of some of these situations. It also shows that aetiopathogenic interpretation and a correct clinical evaluation maycontribute 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 minimizeits direct and sometimes so serious secondary effects.

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

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

From the Foreword of the First Edition(Portuguese Edition, 1996; Brasilian Edition, 1997;

International Edition, 1997)

«The booklet "Ocular Allergy" (…) is practical and didactical, withexcellent drawings regarding immunopathology and unique iconog-raphy showing typical common cases as well as rare ones. Thediagnosis and treatment flowcharts, and the summary tables allow arapid 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

11

Immunopathology

1ImmunopathologyJorge palmaresLuís Delgado

12

Ocular Allergy

bFGF basic fibroblast growth factorc-kit R stem-cell factor receptorECP eosinophil cationic proteinEDN eosinophil derived neurotoxinEPO eosinophil peroxidaseFcεRI high affinity IgE Fc receptorGM-CSF granulocyte-macrophage colony stimulating factorICAM-1 intercellular adhesion molecule 1IFN-γ 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-α 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

T-helper lymphocyte Fibroblast

Endothelial cell

Dendritic cell

Macrophage

Basophil

Mast cell

Eosinophil

Glossary and abbreviations

13

Immunopathology

Immunopathology

Allergic diseases tipically involve external body surfaces(skin and mucosa) and are the expression of a hypersensitivityreaction to common environmental antigens. The hyper-sensitivity mechanism most often identified with allergicdisease will start with the production of IgE antibodies, butamplification mechanisms dependent on immuno-competent cells (T lymphocytes) and structural cells of thesurrounding tissues significantly contribute to itsimmunopathology. Currently, more than 15% of thepopulation suffers from allergy and some studies have shownthat up to 30% of the USA population have some form ofallergy. Any age group may be affected by the allergicdisorders, usually in a chronic way.

IgE antibodies, binding to the tissue mast cells andcirculating basophils through high affinity receptors, triggera rapid cellular degranulation after contact with the allergen,and a prompt release of vasoactive and pro-inflammatorymediators (immediate, anaphylactic or type I hypersensi-tivity, in the Gell and Coombs classification). A late phaseresponse, following the immediate reaction to the allergen,is now clearly established and related to the local recruitmentof inflammatory cells (eosinophils, basophils andmonocytes/macrophages) and immunocompetent cells (Tlymphocytes) following vasodilation and the action ofchemotactic mediators (e.g., chemokines). Activation of theserecruited cells triggers the production of cytokines –molecules that modulate the biological activity of bothinflammatory and structural cells, as well as lymphocytes –contributing amplification of the allergic reaction. On theother hand, eosinophils, dendritic cells and monocytes also

14

Ocular Allergy

express IgE receptors and, thus, are also able to interact withthe allergen and to cooperate in its presentation to Tlymphocytes. This local cellular activation results in a chronicinflammatory process and prolonged symptoms, particularlyin case of continuous allergen exposure and absence of anadequate therapeutic control.

Although antibody production is dependent on antigen-stimulation of B lymphocytes (humoral immunity), IgEsynthesis requires T-B lymphocyte cooperation. T-helperCD4+ lymphocytes (Th), that are required for IgE synthesisare now identified as Th2 lymphocytes, as they producecytokines which promote the synthesis of this antibody class(IL-4 and IL-13). The other type of Th lymphocytes (Th1lymphocytes) produce cytokines [IL-2 and gamma-interferon(IFN-γ)] mainly associated with macrophage and Tlymphocyte activation, e.g., in delayed hypersensitivityreactions with a chronic inflammatory response. Morerecently, it has been shown that mast cells, eosinophils andcorneal keratinocytes also produce pro-inflammatorycytokines (IL-6, IL-8 and TNF-α), «Th2» cytokines (IL-4, IL-5and IL-13) and chemokines (eotaxin, RANTES and MCP-1),which promote the development of the late allergicconjunctival reaction.

It is now known that the immunopathogenesis of allergicdisease is now known to be much more complex than theinitially proposed Gell and Coombs classification and, asocular allergy is concerned, results from several molecularand cellular interactions. While IgE antibodies and mast cellsplay the main role in the acute and immediate forms, Tlymphocytes, eosinophils, dendritic cells and monocytes/macrophages are probably relevant effector cells in formswith delayed symptoms and longer evolution. The knowledgeof the pathophysiological role of each cell type and itsmediators will help us to understand the characteristics ofthe different ocular allergic conditions, as well as identify thestrategy for a multifactorial therapeutic approach.

15

Immunopathology

Mast cells and basophils

Mast cells, which contain potent inflammatorymediators, are tissue mononuclear cells, particularly locatedon external body surfaces – mucosa and skin – where theyperform a major role in the acute inflammatory reaction.They are characteristically involved in the acute allergicreaction, where they quickly respond to allergen contact dueto the expression of a high-affinity Fc receptor for IgE (FcεRI),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 onlyrecently established as distinct in origin, differentiation andmediators (Table 1.1).

In contrast with most mast cells, basophils maydegranulate 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 cellpopulation, 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

• Major arachidonic metabolites LTC4 PGD2>>LTC4

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

16

Ocular Allergy

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

and pharmacological characteristics in different tissues anddifferent species. In humans, mast cell sub-populations havebeen defined by their neutral proteases: in lung and bowelmucosa they only contain tryptase (MCT) – mucosal mastcells – while in skin and intestinal submucosa they alsocontain chymase and carboxypeptidase (MCTC) - connectivetissue mast cells.

In normal conjunctiva, mast cells are present insubmucosa, but not in the epithelial surface, and are mostlyMCTC. In seasonal or perennial allergic conjunctivitis thereis an increase of MCT mast cells in the conjunctiva, a subtype

Immediate reaction

HistaminePAFLTC-4

VasodilationProtein exsudationHypersecretion

Late reaction

PAFTNF-αIL-4IL-5

Intense vasodilationEdema

17

Immunopathology

that, in contrast with MCTC, has a good response tocromoglycate in vitro. It has been shown that these patientsrespond to allergen challenge with two histamine peaks inthe tears – the first at 20 minutes and the second six hourslater. Tryptase is present only in the first peak, suggestingbasophil participation in the conjunctival late allergicreaction. An increased number of conjunctival mast cells andtheir presence in the epithelium can also be observed invernal conjunctivitis.

The role of mast cell mediators in the immediatesymptoms of the conjunctival allergic reaction, such ashistamine, PAF and LTC4, is well established (Fig. 1.1). It hasbeen shown that mast cells can produce pro-inflammatorycytokines, such as IL-4, IL-5, IL-6, IL-8, IL-13 and TNF-α.Recent studies in seasonal allergic conjunctivitis showed thatIL-5 and IL-6 predominate in tryptase positive cells (MCT)while IL-4 and IL-13 predominate in the MCTC, being mastcells the major cellular source of IL-4. Thus, it is reasonableto postulate that these cytokines of mast cell origin areimportant mediators in the development of the late allergicconjunctival reaction and also play a role in eosinophil andT lymphocyte infiltration and activation typical of the moreserious and chronic forms of ocular allergy.

Eosinophils

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

One of the characteristics of allergic disease is theaccumulation of a large number of activated eosinophils inthe surrounding tissues. In seasonal conjunctivitis,eosinophils increase after allergen challenge or during pollenseason. In chronic forms of ocular allergy with cornealinvolvement – vernal and atopic keratoconjunctivitis –eosinophilic infiltration is also characteristic but its severityrelates more closely with the expression of activation markers,both in the ocular surface (IL-2R, HLA-DR) and tears (ECP).

18

Ocular Allergy

Eosinophil migration into tissues involves an adhesiveprocess and chemotaxis under the influence of localmediators. Differentiation and release of eosinophils fromthe 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 majorityof chemotactic stimuli for eosinophils (PAF, C5a, LTB4) alsostimulate and activate neutrophils and other leukocytes.Thus, the accumulation of eosinophils in tissues may dependon an increase in their survival, under the influence of locallyproduced cytokines (IL-5, IL-3 and GM-CSF), and/or aselective migration under influence of CC chemokines(RANTES, eotaxin...).

Eosinophil migration starts with an initial stage ofvascular endothelium adhesion and another stage ofinteractions with the extracellular matrix and structural cells,comprising different types of receptors and ligands. There isnow a large evidence that some Th2 cytokines maypreferentially modulate the expression of some of thesemolecules in eosinophils and endothelial cells, favoringselective eosinophil migration (Fig. 1.3). Actually, the vascularexpression of ICAM-1, E-selectin, and VCAM-1 is increasedin allergic conjunctivitis (ICAM-1 is also increased inepithelial cells), particularly in chronic forms; ICAM-1 andE-selectin correlate with the number of granulocytes andlymphocytes and VCAM-1 with eosinophil infiltration.

Fig. 1.2 – Eosinophilsin extravascular

location.Immunocytochemistry:

staining with amonoclonal antibody

to ECP.

19

Immunopathology

Fig. I.3 – Role of different molecules and cytokines ineosinophil transendothelial migration.IL-1 and TNF-α 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 inducesVCAM-1 in endothelia but its ligand, VLA-4, is not expressedin neutrophils; IL-4 also inhibits the activity of TNF-α onneutrophil migration. IL-3 acts with IL-4 in the recruitmentof non activated eosinophils, has co-stimulatory activitywith IL-1 and TNF-α (e.g., E-selectin expression) and,particularly, induces the chronic expression of P-selectin inendothelia.

20

Ocular Allergy

Fig. 1.4 – Eosinophil receptors and mediators that may beinvolved in the pathological tissue damage associated withits local recruitment and activation.

Activation of eosinophils may result from the action ofsoluble mediators (PAF, C5a), cytokines (IL-3, IL-5 and GM-CSF), surface immunoglobulins (IgE, IgA and IgG) or fromthe interaction of cell surface molecules with their endothelialor extracellular matrix ligands. This activation causes therelease of lipid mediators, enzymes, granule proteins and/orcytokines (Fig. 1.4). Eosinophils contain and may releaseseveral basic proteins (ECP, EDN, EPO, MBP), all of which arepowerful toxins to helminths, protozoa and mammalian cells.These proteins are found within the matrix of specificgranules, have two domains (one basic, the otherhydrophobic) and exert a cytotoxic activity against cellularmembranes, particularly the corneal epithelium.

Cat

ionic

pro

tein

s Med

iators

Cytokines

• Others:

• “TH2”:

21

Immunopathology

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

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

Dendritic cells and monocyte//macrophages

Dendritic cells are present in small numbers in mosttissues and are characterized by an unusual membranous orspine-like morphology, a high expression of MHC class IImolecules and a potent accessory function in the antigenicstimulation of T cells. They can be found in lymphoid andnon lymphoid tissues as well as in peripheral blood, possiblyconnected by their migration pathways.

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

It has been shown that Langerhans cells, dermaldendritic cells and monocytes from atopic patients expressthe IgE high affinity receptor (FcεRI), and possibly take partin the amplification of the allergic reaction. In fact, theallergen concentration in these cells, through its high affinitybinding to specific IgE, results in allergen presentation to T-cells, leading to a late reaction and favoring chronic allergicinflammation.

22

Ocular Allergy

In the eye, dendritic cells are present in the limbal regionof corneal epithelium and in the eyelid skin, and are rare inthe conjunctiva. Nevertheless, their number increasessignificantly in chronic inflammation, appearing togetherwith macrophages in the conjunctival epithelium in allergicconjunctivitis or in experimental models of ocular allergy. Onthe other hand, in chronic forms of ocular allergymacrophages seem to be, along with the conjunctival cells,the main inflammatory cells that may express cytokines withchemotactic activity and T lymphocytes (CC chemokines).

Although the role of the dendritic cells in allergic reactionis not fully established, their location may allow the captureand processing of allergens on the ocular surface. In a processsimilar to epidermal Langerhans cells, ocular dendritic cellsmay be involved in antigen presentation to T cells andstimulation of local IgE synthesis, after migration to thethymus-dependent areas of the regional lymph nodes. Thishypothesis is strengthened by the clinical and histo-pathological similarities of contact ocular allergy and atopickeratoconjunctivitis with, respectively, contact dermatitisand atopic dermatitis. In these skin disorders, a prime role isnow largely established for dendritic cells in the T cellactivation 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 phasereaction 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 studiesalso demonstrated their presence in the late ocular allergicreaction (10-12 hours after allergenic challenge) and, inconjunctival biopsies, activated CD4+ T cells are found in themost serious forms of ocular allergy – vernal and atopickeratoconjunctivitis.

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

23

Immunopathology

lymphocytes with a specific pattern of cytokine synthesis –the Th1 and Th2 lymphocyte subpopulations (Fig. 1.5). Thus,Th1 lymphocytes, producing IL-2, IFN-γ and lymphotoxin(TNF-β), trigger an effector mechanism depending on T-cellproliferation and macrophage activation, i.e., delayed-typehypersensitivity. Th2 lymphocytes, preferentially producingIL-4 and IL-13 enhance IgE synthesis and, through IL-5, therecruitment, activation and increased survival of tissue

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

ActivationProliferation

Delayed hypersensitivity Immediate hypersensitivity

24

Ocular Allergy

eosinophils, e.g., type I hypersensitivity; moreover, byproducing IL-10 and IL-4, they inhibit several macrophagefunctions (the main inducers, via IL-12, of Th1 lymphocytes).The Th0 lymphocytes, from which these two functionalsubpopulations are derived, produce IL-2 together with somecytokines characteristic of both classes – IL-4 and IFN-γ. Thecharacteristics of the antigen, as well as the cellular and tissuemicroenvironment of the antigen presentation during thesecondary immune response, are determinant factors for thedifferentiation of Th0 lymphocyte towards Th1 or Th2phenotype.

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

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

Fibroblasts

In chronic forms of ocular allergy (atopic and vernalkeratoconjunctivitis) there is collagen deposition inconjunctiva, with the formation of papillae and tarsal fibrosis.Bidirectional interactions between mast cells and fibroblastsare one of the links of a complex chain of molecular andcellular interactions which connect fibroblasts to the immuneand inflammatory reaction.

Several mediators secreted by mast cells may participatein fibrosis. Tryptase, the main proteinase in mast cells,triggers fibroblast proliferation, potentiates its response toother growth factors and, indirectly, activates collagenases.

25

Immunopathology

Fig. 1.6 – Cells and mediators involved in the late reaction tothe allergen and in the chronic inflammation and fibrosiswhich occur in the more severe forms of ocular allergicdisease.Dendritic cells and macrophages in the conjunctivalepithelium may capture allergen (e.g., via FcεRI receptors)improving its presentation to T lymphocytes, favoring thedevelopment of allergic inflammation. Moreover, Th2cytokines (IL-4, IL-5 and IL-13), GM-CSF and TGF-β, are alsolocated in conjunctival mast cells and eosinophils. In thesechronic forms, corneal epithelial cells express cytokines (e.g.,GM-CSF and IL-3) and chemokines (eotaxin, MCP-1 andRANTES) that attract and activate cells of the late phase aller-gic reaction.

Conjunctival epithelium

GM-CSF

SCF

LTC4PAF

GM-CSFIL-3ECP

Eotaxin

MCP-1

RANTES

MBP

AgAg

c-kit R

Ag

Ag

Ag Ag Ag

Histamine

Tryptase

LTC4

TNF-α

IL-4IL-5IL-13

IL-1

TNF-α

AgTh

Mø

Th2Ag

Fibroblast proliferation

Collagen

TGF-β

26

Ocular Allergy

Histamine also stimulates fibroblast growth, through H1 andH2 receptors, as well as LTC4, the main leukotriene producedby mast cells. Human mast cells produce, store and synthe-size some pro-inflammatory cytokines, such as TNF-α, whichis present in tears after conjunctival allergenic provocation,raising the hypothesis that this cytokine has a role infibroblast activation and proliferation (Fig. 1.6). In vernalkeratoconjunctivitis, the presence of characteristic giantpapillae has been associated with the presence of growthfactors to the fibroblasts both in conjunctival eosinophils andmacrophages (PDGF) and mast cells (bFGF).

Moreover, it is now well established that, in humans,fibroblasts influence the tissue differentiation of mast cellsfrom circulating hematopoietic precursors through theproduction of stem-cell factor (SCF). SCF is produced in twoforms, 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, eosinophilsstimulate in vitro fibroblast proliferation (Fig 1.6).

Cytokines

It has been clearly defined that, besides Th lymphocytes,corneal mast cells, eosinophils and keratinocytes alsoproduce cytokines which play a role in the inflammatorymediation of ocular allergy. Thus, mast cells locally presentin all forms of ocular allergy, frequently with signs ofdegranulation, synthesize and store cytokines, such as IL-4,IL-5, IL-6, IL-8, IL-13 and TNF-α . These are importantmediators in the development of the late conjunctival allergicreaction by their recruitment and activation effects oneosinophils, basophils and Th2 lymphocytes, as well aspromoting IgE synthesis. In allergic conjunctivitis, mast cellsare the main cellular origin of IL-4 (>90%), being locatedmainly in MCTC mast cells which, as previously described,characterize chronic forms. Many of these cytokines are also

27

Immunopathology

located in conjunctival eosinophils (as well as GM-CSF andTGF-β), mainly in forms with corneal impairment (atopic andvernal keratoconjunctivitis). In these chronic stages, it hasalso been shown that conjunctival epithelial cells expresscytokines that activate and increase eosinophil survival (e.g.,IL-3 and GM-CSF) and chemokines that attract cells of thelate phase allergic reaction (eotaxin and RANTES). Inaddition, conjunctival mast cells synthesize SCF which mayhave an autocrine role over these cells, since it is one of themain regulators of its growth and maturation and potentiatesthe release of mediators.

29

Clinical Features

2Clinical FeaturesJorge palmaresLuís Delgado

30

Ocular Allergy

31

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 allergyare conjunctival itching, hyperemia and chemosis (edema).

Fig. 2.1 – Chemosis:acute conjunctivaledema with gelatinousappearance.

Clinical Features

Limbus

Cornea

Bulbarconjunctiva

Hyperemia is the result of vascular dilation. Edemaoccurs because of altered permeability of post-capillaryvenules and itching is due to the stimulation of the sensitivenerve 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

32

Ocular Allergy

Fig. 2.3 – Seasonal allergicconjunctivitis with

palpebral edema.

Symptoms Signs

Itching HyperemiaTearing ChemosisBurning Palpebral edema

Papillary reaction

Seasonal allergic conjunctivitis (hay fever) is the mostcommon 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 andchemosis, with palpebral edema (periorbital edema) are

Fig. 2.2 – Chemosis:hyperemia due to vasculardilation and conjunctival

edema.

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

1 - Seasonal and perennial allergic conjunctivitis

33

Clinical Features

Fig. 2.4 – A and B - Seasonal allergic conjunctivitis: inferiorconjunctival 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 seasonalspring forms are pollens, usually from grasses and weeds,while house dust mites and animal dander are present all yearround and they are mainly responsible for the perennialforms.

A

Fig. 2.5 – Perennialallergic conjunctivitis:acute phase with intensepalpebral reaction.

CB

34

Ocular Allergy

2 - Vernal keratoconjunctivitis

This is a rare form, more prevalent and serious in warmand 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 allergicrhinitis. Frequently, it is not possible to define a dominantallergen, although pollen exposure may exacerbate thedisease.

Symptoms Signs

Severe itching Giant papillae (cobblestone)Tearing PtosisPhotofobia HyperemiaBurning Mucous secretionForeign body Trantas' dotssensation Punctate keratopathy

Corneal ulcer

Fig. 2.6 – Vernalkeratoconjunctivitis:typical giant papillae

(cobblestone-likepaving of the upper

palpebral conjunctiva)of unequal sizes, that

induce keratitis whenthey touch the cornea.

35

Clinical Features

The first symptom is intense itching, followed by extremephotophobia, burning, foreign body sensation and frequentlyblurred vision. Conjunctival hyperemia, ptosis (droopingeyelid), stringy mucous discharge and blepharospasm arealso seen. The typical giant cobblestone-like papillae (>1 mm)appear in superior tarsal conjunctiva, infiltrated by fibrin andmucus (pseudomembrane).

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

Fig. 2.8 – A - Acute phase: edema, inflammatory cells andabnormal mucous; B - Papillae stained with fluorescein. C toF - Chronic phase: post-treatment.

Fig. 2.7 – Bilateralptosis due to chronicinflammation of thesuperior conjunctiva,with extremephotophobia andtearing.

CBA

FED

36

Ocular Allergy

CA B

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

Fig. 2.10 – Trantas' dots: limbal aspect.

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 useof topical steroids may lead to infection of these lesions,producing a vascularized leucoma, symblepharon (tarsal andbulbar conjunctiva adhesion) and cataracts. The patientsshow an increased incidence of keratoconus (Fig. 2.19).

Fig. 2.11 – Ptosis and limbal gelatinous swellings.

37

Clinical Features

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

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

3 - Atopic keratoconjunctivitis

Symptoms Signs

Itching Eyelid eczemaTearing HyperemiaPhotophobia Punctate keratopathyBurning Corneal ulcer

Corneal neovascularizationKeratoconusCataract

This entity has the highest risk of blindness. It occurs inadults (18 to 50 years) who present systemic manifestations

38

Ocular Allergy

Fig. 2.15 – Blepharitis: A - Maceration and crusting of canthalangle, eyelid thickening, and distortion of palpebralarchitecture with trichiasis. B - Papillary hypertrophy in theupper tarsal conjunctiva.

Fig. 2.14 – Blepharitis associated with atopic eczema.

BA

of atopy (hereditary predisposition for hypersensitivity tocommon environmental allergens), such as asthma, rhinitis,atopic dermatitis or food allergy. Usually serum IgE level isincreased, 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 vernalconjunctivitis, with formation of smaller papillae in thesuperior tarsus. Conjunctival scarring is frequent, leading tosymblepharon 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 transplants.Cataracts [anterior subcapsular (Fig. 2.19B) and posterior],

39

Clinical Features

Fig. 2.18 – Atopic keratoconjunctivitis: corneal neovascu-larization with edema, mucus and ulceration.

Fig. 2.17 – Atopic keratoconjunctivitis. A - Severe form, withbilateral corneal involvement. B - Aspect of the cornealneovascularization.

BA

Fig. 2.16 – Palpebral edema associated with wrist eczema.

40

Ocular Allergy

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

4 - Giant-papillary conjunctivitis

BA

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

Symptoms Signs

Tearing Hypertrophic papillaePhotophobia HyperemiaBurning Punctate keratopathyForeign body sensation Mucous dischargeBlurred vision Contact lens with

deposits

This disorder occurs due to allergy and/or intoleranceto 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 patientcomplains of discomfort after insertion of contact lenses. Thisdisorder may also be associated with prosthesis or cornealsutures.

Allergy to contact lens preservatives and cleaningproducts 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 contactlens surface, especially hydrophilic lenses, may also lead to

41

Clinical Features

Fig. 2.21 – Giant-papillary conjunctivitis: papillaryhypertrophy in the upper tarsal conjunctiva.

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

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

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

Usually, there is a papillary reaction on the upper eyelid,with or without keratopathy. Later, the clinical situation maybecome worse, and some blurring of vision and keratopathymay occur. Nevertheless, this is a clinically less severe formthan vernal conjunctivitis.

42

Ocular Allergy

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 andedema, conjunctival follicles and, frequently, punctiformkeratopathy. In the chronic phase, occlusion of the lacrimalducts, conjunctival scarring, corneal neovascularization andkeratinization may occur.

Eyelids are particularly predisposed to contact orirritative dermatitis, including the accidental "hand - eyelid"transfer of chemical products (preservatives, ocularcosmetics, hairdresser products, nail varnish, shampoos,sprays, dyes, nickel...).

Fig. 2.24 – Contactblepharoconjunctivitis

complicated byrecurrent

staphylococcalinfection.

Fig. 2.23 – Contactblepharoconjunctivitis

due to neomycinointment.

43

Clinical Features

Fig. 2.25 – Contact blepharoconjunctivitis due to thimerosaland nickel.

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

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

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

44

Ocular Allergy

Fig. 2.28 – Cornealforeign body: palpebral

edema with conjunctivalhyperemia.

Fig. 2.29 – Chemicalconjunctivitis:

engorgement of thesuperficial conjunctival

blood vessels.

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

Occupational conjunctivitis (ocular irritation) is causedby several irritative environmental factors (air conditioningor central heating, atmospheric pollution, chemicals, vaporsand foreign bodies) that, in some cases, may induce allergicsensitization.

45

Clinical FeaturesTa

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47

Diagnosis

3Diagnosis

Jorge palmaresLuís Delgado

48

Ocular Allergy

49

Diagnosis

Diagnosis

1 - Clinical diagnosis

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

Ophthalmologic examination includes the observationof 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, thatmay be seen by eversion of the tarsal cartilage, allowing abetter visualization of the conjunctival fornices (Fig. 3.1). Thebulbar conjunctiva is examined by direct observation of theeye globe; the limbus, the circumcorneal zone, is only visibleto the naked eye when inflamed (Fig. 3.2). The cornea is flatand transparent and with a pen light may reveal an ulcer or acorneal opacity – leucoma.

Fig. 3.1 – Eversion of the uppereyelid.

50

Ocular Allergy

Tarsal conjunctiva observation may provide some cluesfor the differential diagnosis. Thus, the presence of follicles(lymphoid aggregates), characteristically pale and round,surrounded by blood vessels (Fig. 3.4) suggest a non-allergicdisease, 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 normalpopulation.

Fig. 3.2 – Limbus withcircumcorneal

neovascularization(ciliary injection).

Fig. 3.3 – Vascularizedcorneal leucoma.

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

51

Diagnosis

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

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

Adapted from BenEzra et al. (1994)

Systemic disease

Dry eye

ALLERGY BACTERIAL VIRAL

Clinical evaluation

RhinitisDermatitis

Rhinitis/AsthmaGiant papillaeContact lens

Severe photophobiaKeratopathy irritants

Exposure to

SEASONAL ATOPIC VERNAL OCCUPATIONALGIANT -PAPILLARY

Keratoconj.sicca

Discharge

Serous Purulent Watery

Culture - smear

Allergen avoidance andpharmacological treatment

Allergy diagnosis

Ophthalmic evaluation

52

Ocular Allergy

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 specializedcare.

Chlamydial conjunctivitis has follicles, is non-pruriticand 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 andcorneal infiltrates.

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

Fig. 3.7 – Staphylo-coccal bacterial

blepharo-conjunctivitis.

53

Diagnosis

A B C

D

Fig. 3.8 – Conjunctivitis byadenovirus: A - Acutefollicular conjunctivitiswith watery discharge andsmall hemorrhages.B - Punctate superficialkeratitis.C - Corneal subepithelialinfiltrates.

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

A B

C

54

Ocular Allergy

Superior limbic keratoconjunctivitis is restricted to thesuperior cornea and superior bulbar conjunctiva. It showsconjunctival mucus and it is associated with thyroid disease.

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

Phlyctenular conjunctivitis (microabscess in limbicarea) is possibly due to hypersensitivity to Staphylococcus orMycobacterium tuberculosis antigens and it is often associ-ated with chronic eczematous blepharitis, mimicking atopiceczema.

Staphylococcal blepharitis has a typical appearance inthe palpebral margins. Other forms of blepharitis may alsopresent some degree of conjunctival inflammation.

Fig. 3.11 –Phlyctenule:

nodular formationat the limbus, with

localized hyperemia.

55

Diagnosis

Fig. 3.12 – Staphylococcal blepharoconjunctivitis.

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

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

56

Ocular Allergy

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

Dry eye (idiopathic “sicca” keratoconjunctivitis andprimary or secondary Sjögren's syndrome) causes moreburning and foreign-body sensation than itching. It may beexacerbated by the use of antihistamines, sedatives and β-blockers.

Fig. 3.17 –Dermatomiositis:Palpebral oedema

and dry eye(xerophthalmia).

Fig. 3.15 – Rosacea.

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

57

Diagnosis

Fig. 3.19 – Erythemamultiform major(Stevens-Johnson'ssyndrome):after the use ofsulphonamides, withinvolvement of themucosal surfaces andthe eyelids.

Fig. 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.

A B

C D

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

58

Ocular Allergy

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

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 scarringwith reduced numbers of mucus-producing goblet cells.

Fig. 3.21 – Scleritis:engorged superficial

episcleral vessels,congestion deep in the

episcleral plexus andunderlying scleral

edema.

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

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

A B

59

Diagnosis

In ocular cicatricial pemphigoid, the vascularized cor-nea and symblepharon are not associated with itching oratopy 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 resultfrom the contact of the external ocular surface with insectsand parasites.

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

60

Ocular Allergy

Fig. 3.26 – Acuteconjunctivitis

after contactwith ticks.

Fig. 3.27 – Senileectropion.

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

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

61

Diagnosis

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 sensitizationby allergy diagnostic tests plays a fundamental role inestablishing 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 environmentalallergens 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, sinceother routine subsidiary examinations are not helpful in thediagnosis 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 amountof antigen into the patient’s skin where in the case of specificIgE, a wheal-and-flare reaction ensues in 15 to 20 minutes,due to the IgE sensitization of cutaneous mast cells. The testis usually performed via the epidermis by a modifiedpuncture – «prick» – with a standard lancet, or by the intra-dermal route. The results are read after 20 minutes, and thewheal is compared with a positive and negative control(histamine and allergen extract diluent). In spite of being themost sensitive, rapid and cheapest method to confirm anallergic sensitization, it carries a small but significant risk ofsystemic anaphylaxis (especially the intradermal test inpatients with previous history of anaphylaxis). They alsorequire experience in the performance and interpretation ofresults and the use of well standardized extracts. Thus, its useis only warranted in specialized centres. One must take into

62

Ocular Allergy

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

Patch testing is indicated in contact conjunctivitis for thediagnosis of contact allergen. Although they are easy to per-form, their interpretation requires considerable experience.Usually, a standard battery including several allergens in ap-propriate concentration and the diluent is applied to the skin

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

63

Diagnosis

on inert metal disks. The chambers are removed two dayslater and a first evaluation of the erythema, vesicles and in-duration is performed, and repeated 48 hours later (96 hoursafter 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, assuggested 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 allergento the triggering of symptoms. Nevertheless, they are reservedfor 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 perennialconjunctivitis, multiple sensitization and a cat in thedomestic environment. These tests should be performed byexperienced personnel, using increasing concentrations ofallergens 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 anddelayed (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/Lin contrast to 1200 mg/L of IgG), its measurement requiresvery sensitive techniques, such as radioimmunoassay (RIA)or enzyme-linked immunoassay (ELISA), which may also beused 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 clinicalpractice. On the other hand, some parasites with an extra-intestinal cycle, as Ascaris and the Toxocara canis may raisethe total IgE.

64

Ocular Allergy

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

The measurement of specific IgE is much more usefulin the setting of an etiologic diagnosis of ocular allergy. Thesearch for allergen specific IgE, by the RAST method, istheoretically attractive: a simple blood sample replaces manyskin tests, without any risks of anaphylaxis and may beperformed even in the above mentioned situations thatexclude the use of the skin tests.

In the Radioallergosorbent test – RAST (Fig. 3.29) – thepatient'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 allergenhas been bound. After incubation, the solid phase is washed,thus eliminating the nonspecific IgE. The solid phase is thenincubated 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 paperdisc uses radiolabelled anti-

IgE antibodies.

Fig. 3.28 – Lacrimal IgE:lacrimal fluid sampling

for IgE measurements.

65

Diagnosis

tion, the non-bound IgE is removed by washing and theamount 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 newtypes of solid phases with larger antigen binding capacityhave been used. In the new test systems the results areexpressed in kU/L, by reference to a calibration curve with astandard sample of IgE. Usually, results higher than class 2(>3.5 kU/L) are considered to represent significant allergicsensitization.

In spite of its good specificity, in clinical practice RAST isless sensitive and more expensive than cutaneous tests, es-pecially for the diagnosis of multiple sensitization. Its mainindications are situations in which the cutaneous tests cannotbe used and when there is inconsistency between these andthe clinical history.

To prevent the low predictive value of total IgE, the lesspractical 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 mixturesmould mixtures

Food mixtures Milk, egg, fish (codfish), wheat,(pediatric) peanut, soy-bean

Grass pollen mixture Dactylis glomerata, Festuca eliator,Lolium perenne, Phleum pratense,Poa pratensis

Mould mixture Aspergillus fumigatus,Cladosporium herbarum,Penicillium notatum,Alternaria alternata

66

Ocular Allergy

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

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 patientis sensitized to a given group of allergens. In practice, thesetests show excellent specificity and sufficient sensitivity tobe the initial method of screening when allergic sensitizationis suspected (Fig. 3.30 depicts a flowchart for the use of thesetests).

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

HistoryPhysical examination

Suggestive of Allergy NEGATIVE

Refer to Allergist(Skin prick tests, RAST)

Atopy screening(e.g. "Phadiatop")

Atopy screening(e.g. "Phadiatop")

DOUBTFUL

NEGATIVE(–)

POSITIVE(+)

NEGATIVE(–)

Refer to Allergist(Skin prick tests, RAST) TOTAL IgERefer to Allergist

(Skin prick tests, RAST No Atopy

No Atopy

Increased Normal

Refer to Allergist(Skin prick tests, RAST)

POSITIVE(+)

67

Diagnosis

Although some studies suggest an association of levelsof 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-papillaryconjunctivitis and vernal keratoconjunctivitis, and decreasewith treatment. With regard to cytokines, increased levels ofIL4 and IL5 are mainly characteristic of the chronic conjunc-tivitis with giant papillae and keratopathy – atopic and vernalkeratoconjunctivitis.

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

Allergicconjunctivitis

IgE-mediated non IgE-mediated

Seasonal allergic conjunctivitisPerennial allergic conjunctivitisAtopic keratoconjunctivitisVernal keratoconjunctivitis

Giant-papillary conjunctivitisContact blepharoconjunctivitisToxic keratoconjunctivitisVernal keratoconjunctivitis

69

Treatment

4TreatmentJorge palmaresLuís Delgado

70

Ocular Allergy

71

Treatment

Treatment

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

Allergenavoidance

Immuno-therapy

Pharmacologicaltreatment

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

72

Ocular Allergy

1 - Allergen avoidance

When an allergen can be identified as the main triggerof the disease, the first therapeutic approach should be theadoption of practical but strict measures to avoid that aller-gen. This could be the case in perennial or seasonal allergicconjunctivitis, associated with allergy to house dust mite andgrass pollens, respectively, or with contact conjunctivitiscaused by drugs or chemicals.

Etiologic diagnosis is based on the clinical history, theresults 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) orgrass pollens (Table 4.2) avoidance measures may be reallyeffective and account for a significant decrease of symptoms.

House dust is a mixture of a large variety of allergens,with dust mites (both dead or alive) and it is the majorsource of its allergens. House dust mites (HDM) feed onskin scales and certain moulds, and its growth is favouredby indoor humidity. Within the house they are especiallylocated in the bedroom, particularly in bed covers,mattresses, pillows, upholstered furniture, and carpets.

The number of indoor HDM increases in months withhigh humidity, in Europe generally starting in October andduring the Winter.

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

Table 4. 1 – Instructions to patients allergic to house dustmites.

73

Treatment

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

Removing house dust from bedroom:

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

• Walls – smooth walls that may be cleaned easily! Nowallpaper or moulds!

• Curtains – simple and washable, made with syntheticfibers.

• Furniture – prefer smooth surfaces, that are easilycleaned. Do not use the bedroom as an office room orlibrary. Avoid many small objects, records, tapes, ste-reos, televisions on your furniture. Toys and furry toysshould 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 withsynthetic ones (e.g. dacron).

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

- mattresses require vacuum cleaning twice weeklyor 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 cleanas possible.

74

Ocular Allergy

Table 4. 2 – Instructions to patients with pollen allergy

Pollens are microscopic powdery granules involved inthe fertilization of flowering plants. Although there arelarge numbers of different plants only about 10% mayinduce allergies, usually trees, grasses and weeds. Plantswith 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 pollensare usually emitted.

• avoid cycling, camping, fishing or hunting duringthis season.

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

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

75

Treatment

2 - Pharmacological treatment

As well as allergen avoidance, some complementarymeasures for the attenuation of acute symptoms may beuseful, such as the use of cold patches (e.g., with normalsaline) for the relief of ocular itching. The use of artificial tears(hydroxypropyl methylcellulose, polyvinyl alcohol, povidone,etc.), several times daily, ideally as unit doses (preservativefree) promotes the direct removal and dilution of theallergens.

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

Eyelid hygiene with patches soaked in baby shampoomay be very important in the cleaning of lipid secretions incases 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 systemicantibiotics, and topical corticosteroid in some cases.

Steroidal and non-steroidal anti-inflammatory

drugs

Mast cellstabilizers

Pharmacologicagonists andantagonists

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

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Ocular Allergy

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

Allergen avoidanceCold patchesArtificial tears carbomer

carmellosedextranhydroxypropyl methylcellulosepolyacrylic acidpolyvinyl alcoholpovidone

Antihistamines emadastinelevocabastine

Antihistamine + vasoconstrictor antazoline-naphazolinepyrilamine + phenylephrine

Mast cell stabilizers cromoglycatelodoxamidenedocromilpemirolastspaglumic acid

Mast cell stabilizers/ azelastine/antihistamine ketotifen

olopatadine

Non-steroidal anti-inflammatory diclofenacdrugs flurbiprofen

ketorolac

Mucolytic N-acetylcysteine

Oral antihistamines cetirizinedesloratadineebastinefexofenadinehydroxizineketotifenloratadinemizolastineoxatomide

Topical corticosteroids dexamethasonefluormetholoneloteprednolprednisolonerimexolone

Therapeutics in development allergen vaccinestopical cyclosporinmonoclonal antibodies(anti-IgE and anti-adhesionmolecules)immunostimulating DNAsequences (ISS-ODN)

77

Treatment

The cleaning of the conjunctival cul-de-sac and thepalpebral free margins with povidone-iodine is mandatoryfor ocular surgery, namely cataract surgery, cornealtransplant or amnyotic membrane transplant for treatingvernal corneal ulcers.

Because of the variety of mediators and cells involved inthe pathophysiology of ocular allergy, the main strategy ofthe 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 ofits receptors in target organs is one of the most frequent initialtherapeutic approaches.

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

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

The long-lasting use of H1 antagonists, although quicklyrelieving allergic symptoms, is frequently accompanied byocular, nasal and oral mucosa dryness.

Topical antihistamine use, while avoiding the sedativeeffects, is not free from ocular anticholinergic effects. Also,the available topical antihistamines have the inconvenienceof associated vasoconstrictor alpha-adrenergic agonists

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Ocular Allergy

(antazoline-naphazoline). This association may be useful inmild cases and for a short time but when used chronically itcauses rebound effects with a vasodilator response and thepreservative-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 andgood local tolerance, not affecting accommodation or raisingintra-ocular pressure.

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

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

There are no data available on the safety of these agentsin 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 agentswith anti-inflammatory activity that have been shown to beeffective in the treatment of asthma, allergic rhinitis and,more recently, in pilot trials in atopic dermatitis. Given theinvolvement of leukotrienes in the immunopathology of ocu-lar allergic disease and their lacrimal fluid increase in themore chronic forms (giant-papillary conjunctivitis, vernaland atopic keratoconjunctivitis), controlled clinical trials withthese new agents are still expected.

B - Mast cells stabilizers

Sodium cromoglycate and sodium nedocromil areusually considered “anti-allergic” drugs, although they do nothave antagonistic effects, because they inhibit the immediatereaction to the allergen and the chronic allergic inflam-mation. Since they are acidic drugs, which remain in theionised form in the extracellular compartment, theirabsorption from the mucosa is practically nil, which makesthem very safe. As a matter of fact, topical cromoglycate isconsidered a safe drug for the treatment of allergy inpregnancy.

79

Treatment

The mechanism by which these drugs inhibit mediatorrelease from mast cells is not yet established, but inhibitoryactions in other inflammatory cells and in neuronal reflexesmay also contribute to the therapeutic effects. These phar-macologic agents act prophylactically, but the most recentlydeveloped drugs present multiple mechanisms of action, forexample causing immediate relief of itching by anantihistamine effect.

Nedocromil has been shown to be in a twice daily doseas effective as four daily administrations of cromoglycate forthe treatment of seasonal conjunctivitis and even more ef-fective for vernal keratoconjunctivitis, possibly because of itsaction 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 byleukocytes, is a mast cell stabilizer and inhibits in vitro acti-vation of the complement system. It has a more rapid onsetof action than cromoglycate.

Recently, three new drugs with mast cell stabilizing andH1 antihistamine actions have been introduced: ketotifen,azelastine and olopatadine. These agents may be used in amore convenient dosage regimen (twice-daily) and they arehighly effective in ocular allergy.

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

Topical nonsteroidal anti-inflammatory drugs have beenrecently developed and may be especially attractive, becauseof their greater safety compared with the strong anti-inflammatory steroids that have been classically associatedwith adverse effects, such as local infection, glaucoma andcataract formation.

Among the nonsteroidal anti-inflammatory drugs, twoof them – diclofenac and ketorolac – have been especiallyused in ocular allergy. Ketorolac reduces local itching andlocal prostaglandin levels. Diclofenac has showed to beeffective in the symptomatic relief of seasonal allergic con-junctivitis.

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Ocular Allergy

D - Corticosteroids

Like in other forms of allergy, topical corticosteroids arequite efficient in ocular allergy, since they suppress multiplesteps 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 withcorneal 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 intheir most serious acute phases. The most potent corticos-teroids, such as dexamethasone and prednisolone also havea higher risk of adverse side effects than the weaker ones,such as fluormetholone, loteprednol and rimexolone. Oralcorticosteroids and systemic cyclosporin A are rarelyindicated in ocular allergy. However, the topical form ofcyclosporin has been shown to be effective in the more severeforms of ocular allergy (atopic and vernal).

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

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

Wind and air conditioning without filters must beavoided in vernal conjunctivitis, because of the possibilityof multiple sensitization to pollens and dust allergens. Digitalmanipulation of the eyes must also be limited because itcauses mechanical granule-release of mast cell mediators.

81

Treatment

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

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

Atopic keratoconjunctivitis is an entity with a complexapproach. It requires complicated multidisciplinary treat-ment with strict environmental control and multiple drugadministration: 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, thusrequiring monitoring. If herpetic keratitis occurs, topicalacyclovir 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 avoidingcontact lenses.

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

In contact allergy, it is very important to avoid the aller-gen, if identified. Occasionally, it is necessary to modify a topi-cal prescription to a preservative-free formula or, at least, with

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Ocular Allergy

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

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

3 - Immunotherapy

Allergen desensitization therapy, also named allergenvaccines, may be indicated in selected cases, as long as anIgE mediated mechanism is the main factor.

Although there are no controlled trials in situations ofexclusive involvement of the ocular mucosa, its efficiency isclearly established in cases with respiratory tract involve-ment. For example, in perennial or seasonal allergic rhino-conjunctivitis, the improvement of conjunctival sensitivityto allergen has been consistently observed and correlatesclosely with the clinical improvement of patients. This wasreported in the first scientific communication about the ef-fectiveness of immunotherapy (Noon and Cantor, 1911, TheLancet). Several reference studies have also demonstrated itsefficacy in reducing ocular symptoms after provocation,namely in vaccines with pollens, mites or cat danders.

Hence, allergen vaccines may be indicated in forms ofocular allergy associated with respiratory symptoms, espe-cially if avoidance and pharmacological measures have notsufficiently controlled the symptoms. Allergen vaccinationmust be always administered by personnel experienced withthis kind of therapy (immunoallergologists) because of therisks of anaphylaxis and other adverse reactions.

Although the effectiveness of allergen vaccines by oralroute has not yet been completely established, they haveproved to be effective in controlling ocular symptoms in bothexperimental models and clinical trials in seasonalrhinoconjunctivitis. Due to its ease of use and lower risk ofadverse reactions, this form of immunotherapy may becomean interesting therapeutic approach in IgE-mediated ocularallergy.

83

Treatment

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

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Ocular Allergy

Appendix 1 – Main pharmaceutical products for the managementof ocular allergy

• Topical use:

Artificial tearsadsorbobasecarbomercarmellosedextranhydroxypropyl methylcellulosemethylcellulosepoloxamer + hydroxyethylcellulosepolyacrylic acidpolyoxyl stearate 40 + polyethylene glycolpolyvinyl alcoholpovidonesodium hyaluronate

MucolyticN-acetylcysteine

Antihistaminesemadastinelevocabastine

Antihistamine + vasoconstrictorantazoline+naphazolinepyrilamine+phenylephrine

Vasoconstrictorsnaphazolineoxymetazolinephenylephrinesynephrine+hydrastininetetrahydrozoline

Mast cell stabilizerslodoxamidesodium cromoglycatesodium nedocromilspaglumic acid

85

Treatment

Mast cell stabilizer / antihistamineazelastineketotifenolopatadine

Non-steroidal anti-inflammatory drugsdiclofenacflurbiprofenketorolacsuprofen

Corticosteroidsdexamethasonefluormetholoneloteprednolprednisolonerimexolone

•O ral use:

Antihistaminesazatadinebuclizinecetirizineclemastinechlorpheniraminedesloratatinedimethyndeneebastinefexofenadinehydroxizineketotifenloratadinemeclizinemequitazinemizolastineoxatomidepheniraminepromethazinetriprolidine

Immunomodulatorcyclosporin A

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Ocular Allergy

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

Benzalkonium chlorideCetrimideChlorhexidineChlorbutanolPolyquadThimerosalThimerosal + plasdoneThimerosal + EDTASorbic acidSorbic acid + EDTA

87

References

ReferencesJorge palmaresLuís Delgado

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

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• 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

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

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

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• Verin P, Easty DL, Secchi A, Ciprandi G, Partouche P, Nemeth-Wasmer G,Brancato R, Harrisberg CJ, Estivin-Ebrardt C, Coster DJ, Apel AJ, CoroneoMT, Knorr M, Carmichael TR, Kent-Smith BT, Abrantes P, Leonardi A,Cerqueti PM, Modorati G, Martinez M. Clinical evaluation of twice-dailyemedastine 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 pollenimmunotherapy: efficacy and safety during a 4-year follow-up study. Allergy50: 405-413, 1995.

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

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

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

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

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

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

Index

94

Ocular Allergy

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

delayed, 23immediate, 23, 61

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

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

95

References

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

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

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

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

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

96

Ocular Allergy

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