STATEMENT OF THE EXPERT GROUP OF THE POLISH …

STATEMENT OF THE EXPERT GROUP OF THE POLISH ALLERGOLOGICAL

ASSOCIATION AND THE POLISH OPHTHALMOLOGICAL SOCIETY ON THE DIAGNOSIS

AND TREATMENT OF OCULAR ALLERGIC DISEASES

CONTENTS

1. Introduction. E. Bogacka ............................................................................................................... 6

2. Definitions. E. Bogacka, A.Groblewska ..............................................................................…..7

3. Classification of the ocular allergic diseases. A.Groblewska .………..........................................10

4. References......................................................................................................................................11

5. Pathophysiology of the ocular allergic diseases.

M. Jędrzejczak-Czechowicz, A. Zaleska-Żmijewska...............................................................….12

6. References …………………….…............................................................................................... 17

7. Diagnosis of the ocular allergic diseases.

A. Groblewska, E. Bogacka, M. Jędrzejczak-Czechowicz ………............................................. 22

8. Differential diagnosis. M. Misiuk-Hojło ..................................................................................... 26

9. References …………………….…............................................................................................... 28

10. Short characteristic of the ocular allergic diseases. A. Groblewska, E. Bogacka ..................... 31

11. References…............................................................................................................................... 37

12. Management of the ocular allergic diseases.

E. Bogacka, A. Groblewska, M. Jędrzejczak-Czechowicz, A. Zaleska-Żmijewska ................. 41

13. References…............................................................................................................................... 55

14. Special circumstances in the ocular allergic disease management.

E. Bogacka, A. Groblewska, A. Zaleska-Żmijewska ................................................................ 61

15. References................................................................................................................................... 68

16. Occupational ocular allergic diseases. C. Pałczyński ................................................................ 71

17. References .................................................................................................................................. 77

18. Dictionary of the medical terms and abbreviations.................................................................... 81

The group of experts:

Ewa Bogacka MD, PhD

-the coordinator of the expert group,

Department of Internal Medicine, Allergology and Geriartrics, Medical University, Wrocław

Prof. Paweł Górski MD, PhD

- supervision, leading Consultant

Department of Pneumonology and Allergy, Medical University, Łódź

Anna Groblewska MD, PhD

- Polish Mother’s Memorial Hospital - Research Institute, Department of Ophthalmology, Łódź,

Monika Jędrzejczak-Czechowicz MD, PhD

- Department of Immunology, Rheumatology and Allergy, Medical University of Łódź,

Marta Misiuk-Hojło MD, PhD

-Department of Ophtalmology, Medical University, Wrocław

Cezary Pałczynski MD, PhD

-Nofer Institute of Occupational Medicine, Łódź

Anna Zaleska-Żmijewska MD, PhD

- II Departament of Ophtalmology, Medical University, Warszawa

Acknowledgements

The authors are grateful to their Heads of Departments:

Prof. Bernard Panaszek MD, PhD

Head of the Department of Internal Medicine, Allergology and Geriatrics, Medical University,

Wrocław

Prof. Janusz Czajkowski MD, PhD

Head of the Department of Ophthalmology, Polish Mother’s Memorial Hospital - Research

Institute, Łódź

Prof. Marek L. Kowalski MD, PhD

Head of the Department of Immunology, Rheumatology and Allergy, Medical University of Łódź,

Prof. Jerzy Szaflik MD, PhD

II Departament of Ophtalmology, Medical University, Warszawa

PREFACE

It is with great pleasure I would like to recommend the Statement of the Expert Working Group of

Polish Allergological Association (PTA) and Polish Ophthalmological Society (PTO), on the

management of the ocular allergic diseases. The authors give thorough and vital opinions on the

problems observed in the diagnosis and treatment of the ocular allergic diseases. The study presents

the common statement of experts who are representatives of two medical specialties: allergology

and ophthalmology.

I hope that the statement will be helpful in a physician daily routine practice.The pathomechanisms

leading to the development of different ocular allergic diseases were described in a very concise

and clear manner, focusing on diagnostics and differential diagnosis of other disorders with similar

clinical symptoms. There are also very important chapters on the treatment and occupational ocular

allergic diseases.

I really recommend this statement.

Prof. Jerzy Szaflik, MD., PhD.

After careful reading of the Statement I would really like to recommend this document especially to

allergologists, ophthalmologists as well as all medical doctors involved in the treatment of the

allergic diseases. These disorders are observed in every second inhabitant of Poland. The ocular

allergic diseases are more and more common and usually coexist with other allergic diseases.

However, in Poland they are not always properly diagnosed. The lack of efficient ocular allergy

disease diagnosis and treatment may have important clinical implications for further patient life and

may lead to severe complications and even disability. Therefore the statement of PTA and PTO

expert group on the diagnosis and treatment of ocular allergic diseases is really important, from the

epidemiological and clinical point of view because this is a group of diseases that are still not

known very well, as well as complications which follow them.

Knowledge of allergic diseases has developed rapidly over the last 10 years. Allergology,

compared to other medical specialties, is quite new, and thanks to that very dynamic and open to

new findings and new methods of treatment. Allergology integrates knowledge from a few other

medical specialties and arises from common allergic disease mechanism which may involve

different organ diseases (eye, skin, lungs, gastrointestinal system). However, all of them have the

same cause, pathomechanism, evolution and also similar treatment. The mutual work of

allergologists and ophthalmologists made this statement, which is very wide and comprehensive

from both theoretical and clinical points of view, possible. The statement should be present in the

library of an allergologist, an ophthalmologist and a family doctor.

The origin of this statement is mainly due to Prof. Janusz Czajkowski M.D., Ph.D. who several

years ago realized the problem in many patients who were somehow outside ophthalmological

interest. Then he asked Ewa Bogacka M.D., Ph.D. to work with him. For many years Ewa Bogacka

has been devoting all her energies to integrating allergologists and ophthalmologists, has been

looking for experts and propagating knowledge of ocular allergic diseases. For a few years she has

been the head of the ophthalmological section of the Polish Allergological Association. Her efforts

resulted in the Statement of Experts and accepted by two big medical associations. The statement

contains large amount of up to date and sometimes not widely known knowledge that is not studied

at medical universities.

It may be used as a handbook to learn the presented diseases as well as a guide for updating how to

treat a patient with an ocular allergic disease. Studying new medical findings should provide

intellectual stimulation for all physicians.

Prof. Piotr Kuna MD, PhD

Head of the Polish Allergological Association

INTRODUCTION

E. Bogacka

Ocular allergic diseases affect 20-30% population in Great Britain, the USA and Japan (1-8). We

do not have epidemiological data of the ocular allergic disease prevalence in Europe, including

Poland. The ocular allergy usually affects the conjunctiva, less frequently the cornea but the

eyelids, uvea, sclera and optic nerve may also be involved (1).

The conjunctiva is the membrane lying internal part of the eyelids and external eye-ball surface. It

performs many functions like protection, co-operation in tear production, local hormone and

immunoglobulin production, active participation in the immune reactions. It is built of the

epithelium and the proper substance (1, 5).

In healthy subjects the epithelium does not contain inflammatory cells. There are mucous glands,

additional lacrimal glands, blood and lymph vessels in the proper substance of the conjunctiva.

There are produced immunoglobulins IgA and IgG and trace amounts of IgE.

In physiological conditions there are also lymphocytes CD4+ and CD8+, Langerhans cells,

mastocytes, and macrophages in the proper substance of the conjunctiva (1, 4-6).

Redness and edema are conjunctiva manifestations to irritating and inflammatory factors. There are

three types of redness: superficial, profound and mixed. The conjunctiva and lacrimal glands are

innervated by Nerve V sensory branches. The impulses received from the conjunctiva surface and

the eyelid skin lead to reverse reaction of the lacrimal glands, Meiboma glands and orbicular eye

muscles.

The tear film is produced by main lacrimal gland and additional lacrimal glands. It performs many

functions such as: moistening, protective, antibacterial, nutritious and optical. It contains

immunoglobulins, cytokines, complement, lysozyme, ceruloplasmin and small amount of

histamine. The tear film is the environment in which cytokines and regulatory proteins, produced

by lacrimal glands, ensure epithelium surface homeostasis (1, 4-6).

The cornea has protective, optical functions and participates in the immune reactions although it

does not have blood vessels. In severe ocular allergic diseases toxic proteins produced by

eosinophils destroy the corneal epithelium leading to corneal ulcers, vision disturbances and even

blindness (1, 4-6).

DEFINITIONS

E. Bogacka, A. Groblewska

Allergy is defined as a specific, unfavourable reaction of the body, depending on the secondary

immune response against a foreign antigen, usually harmless for healthy subjects.

According to current classification of allergic diseases - hypersensitivity is a wider definition. It is a

condition including both allergic and non-allergic reactions, with repetitive symptoms induced by

exposure to a specific factor, in a dose being tolerated by healthy subjects. The reaction is allergic

if there are any immune patomechanisms involved (9).

Ocular allergic diseases are divided into atopic (IgE-dependent) and non-atopic (non IgE-

dependent). There are ocular diseases with atopic background (allergic conjunctivitis) such as:

Seasonal Allergic Conjunctivitis (SAC) and Perennial Allergic Conjunctivitis (PAC). There are

diseases with mixed pathology – IgE-dependent and IgE-independent like Vernal

Keratoconjunctivitis (VKC) and Atopic Keratoconjunctivitis (AKC). Allergic contact inflammation

leads to Contact Blepharoconjunctivitis (ConBC) and in some cases to AKC. In case of large

allergen exposure together with unfavourable environmental conditions enhanced allergic

symptoms of the conjunctiva as well as the eyelids skin involvement may be observed, Acute

Allergic Conjunctivitis (AAC). Finally, the Giant Papillary Conjunctivitis (GPC) is an example of

mixed hypersensitivity mechanisms - both allergic and non-allergic (1-6).

As there are no ocular allergic disease definitions, the Expert Group propose the following

definitions:

1. Acute Allergic Conjunctivitis - AAC

It is an acute hypersensitivity reaction with the conjunctival redness and edema, severe eye

watering and itching. It may be caused by large amount of allergen getting into the conjunctival sac

or by toxic reaction to irritating substances.

2. Seasonal Allergic Conjunctivitis - SAC

It is a conjunctival allergic, IgE-dependent reaction, most commonly appears because of pollen

hypersensitivity. There are seasonal symptoms like: itching, eye watering and conjunctival redness.

Moreover, conjunctival and eyelid edema may be observed as well as small tarsal conjunctival

papillae. The disease is usually accompanied by the seasonal allergic rhinitis.

3. Perennial Allergic Conjunctivitis - PAC

It is a conjunctival allergic, IgE-dependent reaction to some allergens like: house dust mites, mould

spores, latex, animal dander. It is manifested by itching, eye watering and conjunctival redness.

Moreover, conjunctival and the eyelid edema may be observed as well as small tarsal conjunctival

papillae. The symptoms are mild, perennial, enhanced by higher or longer exposure to allergen or

non-specific irritating substances.

4. Vernal Keratoconjunctivitis - VKC

It is a chronic, severe ocular allergic disease in children and teenagers with mixed allergic

mechanism that may lead to blindness. It is characterized by the conjunctival redness and

overgrowth, persistent itching, dense discharge, eye watering, burning, blurred vision. There are

giant upper tarsal conjunctival papillae (“cobblestone” papillae), present also around the corneal

limbus, with Trantas dots. Sometimes dropping of the upper eyelid, corneal changes and

photophobia are also observed.

5. Atopic Keratoconjunctivitis - AKC

It is the most severe ocular allergic disease in patients with atopic dermatitis. It is characterized by

photophobia, eye watering, itching, conjunctival burning and watery-purulent discharge. There are

the same eyelid skin lesions as observed in the atopic dermatitis, and are usually bilateral. There are

also other symptoms like: eyelash and eyebrow growing disturbances, mixed inject, conjunctival

papillae and Trantas dots. In most cases corneal lesions, cataract and dry eye syndrome also appear.

The disease often leads to sustained injuries of the vision organ and blindness.

6. Giant Papillary Conjunctivitis - GPC

It is both allergic and non-allergic hypersensitivity ocular reaction to contact lenses, ocular

prostheses, post-operative sutures or some irregularities of the eye-ball surface. It is characterized

by white or transparent discharge observed on awaking, foreign body sensation, eye watering,

itching, burning, sometimes blurred vision.

From small to huge papillae of the upper tarsal conjunctiva, redness and bulbar conjunctival edema

are observed.

7. Contact Blepharoconjunctivitis - ConBC

The disease is a result of allergic and toxic-allergic reactions to ophthalmic drugs, detergents,

cosmetics, preservatives and latex. It is characterized by edema, eyelid skin redness and watery

discharge appearing within 24-72 hours after exposure to an allergen. Within the time of exposure

other symptoms appear such as eczema, lichenification and periorbital skin discoloration, vessel

and conjunctival papillae dilation, corneal epithelium depletion and lower eyelid eversion.

Most ocular allergic diseases coexist with dry eye syndrome. Sometimes dry eye appears as a side

effect of other ocular allergic diseases (the disturbances of the quantity and quality of the tear film).

Clinical characteristics and intensity of allergic and non-allergic reaction are modulated by the

present in the eye receptors and inflammatory cells and by environmental factors such as:

temperature, humidity, air movement, insulation and substances irritating mucous membranes and

epithelium (1, 2, 5).

CLASSIFICATION OF THE OCULAR ALLERGIC DISEASES

A. Groblewska

The classification of the ocular allergic diseases proposed by the European Academy of

Allergology and Clinical Immunology (2001) includes only allergic conjunctivitis as follow: (10)

1. IgE-dependent allergic conjunctivitis:

- seasonal: AAC and SAC,

- persistent: PAC, VKC and AKC.

2. IgE-independent allergic conjunctivitis:

- ConBC.

This classification does not include complex VKC and AKC pathophysiology. The classification

proposed by Czajkowski and Groblewska (11) seems to be closer related to the clinical

manifestation of the ocular allergic diseases as it also concerns other parts of the eye protective

mechanism and the anterior segment of the eye that may be involved in the inflammatory process:

- acute allergic conjunctivitis - AAC,

- seasonal (intermittent) allergic conjunctivitis - SAC,

- perennial (chronic) allergic conjunctivitis - PAC

- vernal keratoconjunctivitis - VKC

- atopic keratoconjunctivitis - AKC

- giant papillary conjunctivitis - GPC

- contact blepharoconjunctivitis - ConBC

REFERENCES:

1. Abelson MB. Allergic diseases of the eye. Ed. MB. Abelson, Saunders Co, Philadelphia, USA,

2001.

2. Epidemiology and Genetics in: Allergic Rhinitis and its Impact on Asthma – ARIA Workshop

Report. J Allergy Clin Immunol 2001, 108, 5 suppl. 153-161.

3. Berdy GJ., Hedquist B. Ocular allergic disorders and dry eye disease: associations, diagnostic

dilemmas and management. Acta Ophthalmol Scand 2000, 78, 32-37.

4. Bielory L. Allergic and immunologic disorders of the eye. J Allergy Clin Immunol 2000, 106, 6,

1019-1032.

5. Bonini S., Bonini St. Studies of allergic conjunctivitis. Chibret Int. J 1987, 5, 12.

6. Buckley RJ. Allergic eye disease - a clinical challenge. Clin Exp Allergy 1998, 28, suppl 6, 39-

43.

7. Nathan R., Meltzer E., Selner J., Storms W. Prevalence of allergic rhinitis in the United States. J

Allergy Immunol 1997, 99, 808- 814,

8. Uchio E. Possibility of non-steroidal treatment in allergic conjunctival diseases. Allerg Int 2004,

53, 315-319.

9. Kowalski ML. Choroby Alergiczne. In: Choroby Wewnętrzne red. A. Szczeklik, Med. Prakt,

Kraków, 2006.

10. Johansson SGO., Hourihane J., Bousquet J. et al. A revisited nomenclature for allergy. An

EAACI position statement from the EAACI nomenclature task force. Allergy 2001, 56, 813-824.

11. Czajkowski J., Groblewska A. Etiologiczny podział alergicznych chorób oczu. In: Alergiczne

choroby oczu. Czajkowski J.(red.) Górnicki Wydawnictwo Medyczne, Wrocław, 2003.

PATHOPHYSIOLOGY OF THE OCULAR ALLERGY DISEASES

M. Jędrzejczak-Czechowicz, A. Zaleska-Żmijewska

The vision organ is a convenient place for allergic reaction development because there are not

important mechanical barriers protecting from getting allergens onto the ocular surface. There are

many immunocompetitive cells within ocular tissues ready to act after the contact with allergen,

especially mast cells on the bulbar and tarsal conjunctiva. There are around 10 thousand mast cells

in 1 cu mm on the human healthy conjunctiva (1-5).

The conjunctiva has its own lymphatic tissue and the lymph flows to the submandibular and

parotid nodes. In physiological conditions there are lymphocytes CD4+, CD8+, Langerhans cells,

mastocytes, macrophages in the proper substance of the conjunctiva; immunoglobulins IgA and

IgA and IgG are also produced. The number of mastocytes increases during the allergic reaction

within the ocular tissues, IgM and the large amounts of IgE are produced, and then neutrophils and

eosinophils arrive (6, 7).

The ocular allergic diseases are a heterogenic group regarding its clinical manifestation and

pathomechanisms. The immune reaction appears when the allergen gets onto the eye-ball surface,

usually develops within the conjunctiva but the eyelids and cornea may also be involved (8). It is

very important to distinguish different ocular diseases, based on good understanding of their

pathogenesis, especially for further proper treatment - for example using antihistamine drugs or

glicocorticosteroids (8, 9).

SAC and PAC pathomechanisms

The immediate reactions observed in SAC and PAC and partially in VKC and AKC are related to

the presence of the allergen-specific IgE on the ocular mast cells surface (1). As a result of the first

contact with the allergen – IgE, specific against this allergen (s-IgE), are produced and bound to the

high affinity mast cells and basophiles receptors (FceRI). In the next contact the allergen binds to s-

IgE, which leads to mast cell degranulation and releases the allergic inflammatory mediators.

Serum IgE concentration is higher in patients with SAC and PAC comparing to healthy subjects,

and the highest IgE concentrations are observed if patients have other allergic diseases (1, 2). The

higher serum IgE level is usually accompanied by elevated s-IgE and total IgE in the tear film but

sometimes they may be below the detection level (1).

During the mast cells degranulation many substances are released like: histamine, heparin,

proteases, PGs, LTs and cytokines (9). Among mediators histamine seems to play the most

important role. It may influence blood vessels permeability, smooth muscle contractions, mucous

secretions, inflammatory cells migration and lymphocytes T function (10, 11). The concentration of

histamine in tear film of healthy subjects is around 5-15 ng/mL but in allergic conjunctivitis it

reaches up to 100 ng/mL. Histamine is released in many parts of the eye like uvea, retina, optic

nerve, and acts through its receptors.

There are many histamine receptors within the vision organ (11):

H1 – endothelium of the conjunctival vessels and many immune system cells

(lymphocytes T, macrophages, APC, eosinophils, basophiles, mastocytes),

H2 - endothelium of the conjunctival vessels and neutrophils, basophiles, monocytes, macrophages

and lymphocytes,

H3 – retina,

H4 – monocytes, lymphocytes, eosinophils.

There are also receptors for prostaglandins and estrogen within the eye tissues (12).

The H1 receptors participate in many allergic reactions within the organ of vision. The stimulation

of the H1 receptor is responsible for itching and increasing blood vessels permeability. The H2

receptor stimulation leads to vessel dilatation (10, 11).

Mast cells may be activated not only by IgE but also non-specifically by for example

anaphilatoxins (C3a and C5a) and interleukins. This is probably the way in which food, drugs or

infectious factors may lead to the development of inflammatory reactions similar to allergic ones.

Non-specific mast cells activation explains the effectiveness of the antihistamine drugs not only in

the classical IgE-dependent diseases (13).

The eosinophils are the main cells responsible for tissue damage in the allergic diseases. There is an

increased concentration of eosinophils cationic protein - ECP (being an important inflammatory

mediator) in the SAC and PAC course (14, 15).

VKC/AKC pathomechanism

The cellular immune response is usually observed in chronic allergic diseases but factors initiating

the reaction and mechanisms are not fully understood. The lymphocytes T are the main

immunocompetitive cells. In VKC lymphocytes Th2 are dominating but in AKC both Th1 and Th2

cells participate in the reaction (15, 16, 17, 18). The concentration of pro-inflammatory cytokines is

increased in chronic allergic diseases and in the GPC (19, 20, 21). There are higher serum and tear

film IgE levels in some patients with VKC, which confirms dominating IgE depending mechanism

(22, 23). There are Th2-profile cytokines and ß-chemokines detected in patients with VKC and also

with SAC (24). The eosinophils, basophiles, mast cells, plasmatic cells and lymphocytes are

infiltrating during the progression of the allergic reaction (3, 4). The fibroblasts and epithelial

conjunctival cells play an important function, actively participating in the immune response (8, 24-

31). Up to now, eosinophils were thought to be responsible for fibrosis, leading to the most severe

complications (29, 30). Most recently, the fibroblasts and mast cells are suspected to participate in

papillae formation (9, 26, 27). The corneal and conjunctival fibroblast activation (induced by Th2-

profile cytokines and histamine released from the mast cells) may lead to their proliferation and

papillae formation (32). The antihistamine drugs and mast cells stabilizers used in the ocular

allergic diseases treatment seem to prevent papillae formation - responsible for the disease severity

and its complications (9, 13, 25, 27).

The ocular lesions observed in AKC may appear together with skin lesions like eczema or atopic

dermatitis, or may develop as its severe complication (33). In most patients elevated s-IgE

concentration, against specific inhalant allergens, can be detected (34). The Staphylococcus aureus

colonization seems to influence AKC progress as in the course of atopic dermatitis (35, 36). The

mast cells, eosinophils and lymphocytes are dominating in the inflammatory cells infiltration (3, 4,

28, 32).

The role of the neurogenic factors

The neurogenic factors play an important role in the regulation of the allergic inflammation. NGF

(nerve growth factor) inhance the release of substance P and it correlates with the amount of mast

cells infiltrating bulbar and tarsal conjunctiva (30, 36). Lower amounts of muscarine M1-10 receptors

and NGF on the conjunctival epithelial cells as well as different distribution of M2, M3 and ß2-

adrenergic receptors were observed in patients with VKC (30). The agonists of ß2-adrenergic

receptor are thought to modulate the inflammatory mediators release in the conjunctiva (37).

GPC pathomechanisms

Some authors think that GPC is not an allergic disease but it is the result of mechanical irritation of

the conjunctiva caused by contact lenses or another foreign body (4). Others think that the GPC is a

contact allergy to lenses as a foreign body (38). In some patients the increased IgE levels are

observed in the tear film, but not in the serum (1). The cell infiltration assembles mostly mast cells,

basophiles, eosinophils and lymphocytes. Elevated concentrations of IL-3, IL-4, IL-5 and IgG, IgE,

IgM are also described (3, 38).

ConBC pathomechanisms

The patomechanism of the contact blepharoconjunctivitis is based on the delayed allergic reaction

(2, 4, 30). The reaction develops after the contact of an allergen with specific Th1 lymphocytes

which leads to the release of proinflammatory cytokines. The lymphocytes are sensitized after

binding the allergens to the skin proteins and presenting them by Langerhans cells to

immunocompetitive cells (2, 3, 39).

Pathomechanism of the eye-ball surface homeostasis disturbances in the course of ocular

allergic diseases.

Allergic inflammation may lead to the following secondary eye-ball surface disturbances:

1. tear film instability and dry eye syndrome,

2. conjunctival lesions in the course of VKC and AKC,

3. corneal lesions

Ad. 1. The tear film instability may be observed in each allergic conjunctivitis (41, 42). It leads to

the qualitative and quantitative composition disturbances of the tear film mucous layer.

The tear film instability can be detected with BUT test (break-up tears) while Schirmer test (watery

layer of tears film secretion) is normal. In more than 78% of patients with allergic conjunctivitis

significant thickening of the tear film fatty layer is also observed. In healthy subjects the thickness

of the outer layer of the tear film is between 40 and 100 nm when the eye is opened. During the

ocular allergic disease its thickness increases to 120-180 nm, and in some patients even up to 370

nm. (41).The most severe eye-ball surface homeostasis disturbances are observed in AKC and

VKC. It is probably the result of increased evaporation of tears from the eye-ball surface.

Ad. 2. The sustained inflammatory lesions of the corneal limbus area in the course of VKC and

AKC may lead to the gradual limbus stem cell loss - both because of its microenvironment

damages and as a result of direct toxic effect of the allergic reaction products – eosinophils and

other inflammatory cells.The diffuse spinocellular conjunctival methaplasia may influence the

result of the cytological examination confirming the limbus failure. It explains why in the ocular

allergic diseases the diagnosis is usually based on the clinical examination (43).

Ad. 3. Some severe corneal complications may appear in the course of AKC, mostly as a result of

the tear film disturbances and corneal limbus stem cell failure. The more severe corneal lesions are

observed in patients with childhood onset of the AKC. Adults with AKC present the eye-ball

surface complications more frequently than children with AKC.

A diminished corneal sensitivity, more than 4 times decrease in the number of the goblet cells and

tear secretion disturbances are observed in atopic patients (44).

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DIAGNOSTIC METHODS OF THE OCULAR ALLERGIC DISEASES

A. Groblewska, E. Bogacka, M. Jędrzejczak-Czechowicz

The ocular symptoms are observed in about 40-60% of patients with a positive medical history of

any allergic disease. It is estimated that up to 40 % of the “red eye syndrome” is caused by allergic

reaction (1, 2). The allergic conjunctivitis is found in 96% of patients with seasonal allergic

rhinoconjunctivitis (2, 3).

There are typical ocular allergic symptoms like conjunctival vessels dilatation and itching. There is

no allergy without itching. The allergological and ophthalmological parts of the medical history

are very important in a daily routine medical practice and then performing diagnostic tests

(diagnostic procedures diagram – figure 1).

Evaluation of aeroallergen skin prick tests

When assessing the skin prick test results it is necessary to remember that diagnosis based on

positive SPT results should correlate with the patient’s medical history. In SAC skin prick tests are

positive in 96% of subjects and when they are compatible with the patient’s medical history it is

sufficient to make the diagnosis (3, 4).

In PAC diagnosis by positive skin prick tests drops to 61% compared with SAC. In 30% of

patients with PAC and negative SPT results, s-IgE is found only in the tear film, but the test is not

widely available now (3, 4, 5, 6). The skin prick test accuracy in other allergy diseases decreases

and is 55% in VKC, 33% in AKC and 16% in GPC (1, 2, 7).

Serum IgE measurements

1. Nowadays the total serum IgE measurement is not a very useful diagnostic tool because normal

values do not exclude an allergic disease and on the contrary high IgE levels may be observed in

other non-allergic diseases (8). However, this measurement may be of some prognostic value in

already diagnosed AKC and VKC. The high IgE level is related to severe allergic inflammation and

corneal complications (9).

2. The measurements of serum s-IgE are indicated when skin prick tests can not be performed

(large skin lesions in atopic dermatitis) or the results are not reliable (intense dermographism) or

they are negative (some VKC, PAC, AKC cases) (3, 4, 6). The measurement of serum s-IgE may

confirm IgE-dependent allergy additionally in 10-11% patients with VKC (7).

Tear diagnosis

Apart from IgE measurements other tear studies are used only for scientific purposes. The tear film

evaluation is a separate issue used in dry eye syndrome diagnosis: the Schirmer test, BUT, LIPCOF

test, fluorescein dye, Rose Bengal and Lissamine green staining (11, 24).

IgE tear measurements (Lacrytest)

It is recommended for patients with the medical history and clinical manifestation suggesting the

ocular allergic disease but with negative skin prick test and negative serum IgE results. The

presence of IgE in the tear film confirms an allergic disease because in healthy subjects the IgE

level is not-detectable by Lacrytest (7, 8).

Patch tests

The patch tests are useful in the diagnosis of the contact allergy in AKC and ConBC (7). When

topical drugs are suspected to cause the ocular contact allergy additional patch tests with suspected

substances should be performed; usually not available in commercial kits (with the exception of

neomycin). Patch tests should be performed according to the published standards (10).

Estimation of eosinophilia and eosinophil derivative mediators

1. The measurements of serum eosinophilia are not very valuable for the diagnosis of the ocular

allergic diseases. However, the detection of even one eosinophil in the conjunctival cytological

analysis is the criterium for the ocular allergic disease. Lack of these cells does not rule out the

allergy (7, 11).

2. The ECP and EPX serum and tears levels are valuable measurements of the eosinophilic

inflammatory markers (7, 11,12).

Conjunctival Provocation Test – CPT

The conjunctival provocation test is a useful tool for the ocular allergic disease diagnosis. It is used

to confirm the allergic reaction in patients with a doubtful diagnosis, especially with negative skin

prick tests and undetectable serum sIgE levels (7, 13,14). The conjunctival provocation test is

recommended for SAC and to some extent for PAC and VKC diagnosis. The CPT result allows

recognition of the most important allergens responsible for the clinical symptoms.

Most authors did not find any correlation between CPT results and clinical symptom exacerbations

during the season (15). The conjunctival challenges are highly specific and sensitive. There are

different data in the literature regarding the correlation of CPT and SPT results. Some researchers

suggest the 100% accordance of the above methods (16), others found this correlation only in 60-

70% patients (17). The sensitivity and specificity of D.pter. allergen conjunctival provocation test

is 90% and 100%, respectively compared to 70% and 76% SPT results (19). Based on the CPT

result it is possible to exclude false positive results in patients with primary allergy diagnosis. It is

also proposed to use hyperosmolar glucose solution in CPT to exclude non-specific conjunctival

hyperreactivity in non-atopic patients (20).

CPT methodology

According to the conjunctival provocation test methodology the examination of patients with SAC

should be performed out of the pollen season. It is recommended to withdraw antihistamine drugs

before the challenge for the period of their biological activity. The patients should not wear contact

lenses on the day of provocation. The CPT is contraindicated during allergic disease exacerbation

and in patients with the history of anaphylaxis. Moreover, the conjunctival provocation test must

not be performed in patients with other diseases like severe cardiac failure, unstable coronary

disease, in pregnant women and patients treated with systemic and topical β-blockers.

The increasing doses of the allergen should be administered in 20-30 minutes intervals. There are a

few schemata how to increase the dose. The extracts of allergen used for provocation should be

standardized, liophilisated and prepared in appropriate solution concentration before the challenge.

The result of the provocation test is based on summary results of itching (according to the scale

from 1 to 4, estimated by the patients), conjunctival chemosis, edema and watering assessed by a

doctor. The symptoms appear usually within a short time (a few minutes) after reaching the

threshold dose of the allergen. Although the conjunctival provocation test is a relatively safe

procedure, some symptoms of the upper and lower respiratory systems may appear. Because of this

the CPT should be preformed by an experienced medical staff able to treat the anaphylaxis

properly. If there is a technical possibility the slit lamp examination should be performed to assess

the clinical symptoms. The patient should be monitored by a medical staff within two hours after

finishing the challenge. This 2 hour-period is not established experimentally but according to

French recommendations and seems to be the most appropriate regarding the safety of the patient

(14, 21).

The CPT is also used to evaluate the effectiveness of the topical drugs (18, 22). The use of CPT for

the diagnosis of the drug preservative hypersensitivity is being discussed (23).

Conjunctival cytodiagnostics

1. The conjunctival scrapings evaluation – the material is taken from the upper tarsal conjunctiva

and assessed under the microscope. The number of eosinophils, neutrophils, lymphocytes and

monocytes is counted (24).

2. The impressional cytology is used to assess the conjunctival epithelial cells. The special filter

paper is placed onto the upper tarsal conjunctival surface, pressed for a few seconds and then

removed away with some cells (thanks to rubbing movement). The cells are assessed later on (2).

3. The conjunctival biopsy is used in the diagnosis of the neoplastic and autoimmune ocular

diseases. It can also be useful in the assessment of the allergic cell infiltration. The material for the

histological and immunohistological examination is taken from the medial part of the upper tarsal

conjunctiva (1).

Confocal microscope examination

The confocal microscope examination enables to assess the cornea – its structure and pathological

changes. The use the confocal microscope for quantitative assessment of the conjunctiva

inflammatory changes as well as the alive epithelial cells and conjunctival vessels with functional

cytometry (observation of the cells flow in the conjunctiva vessels) is being discussed (7).

DIFFERENTIAL DIAGNOSIS

M. Misiuk-Hojło

There are some important aspects of the differential diagnosis like the general medical history of

the patient, ophthalmological and allergological medical history and clinical eye examination.

The differential diagnosis of the ocular allergic diseases includes:

1. Inflammatory processes, infections of the conjunctiva and cornea:

a) bacterial,

b) viral,

c) chlamydial,

d) fungal,

e) protozoon,

f) eyelid margin inflammation.

2. Dry eye syndrome.

3. Autoimmune diseases:

a) episclera inflammation,

b) uveitis,

c) ocular pemphigoid,

4. Glaucoma - acute angle closure

5. Others, like: foreign body of the cornea

Table 1 (according to 25-32)


+/-, burning, scratching, foreign body sensation, grittiness

Dense, mucous discharge, watering

Superficial redness, conjunctival folds parallel to the eyelid margins

failure, unstable

Epithelial lesions, filaments

bilateral

BUT, Schirmer test, LIPCOF scale, Fluorescein staining, Bengal Rose, Histamine Green



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SHORT CHARACTERISTICS OF THE OCULAR ALLERGIC DISEAS ES

A. Groblewska, E. Bogacka

1. Acute Allergic Conjunctivitis - AAC

- observed in patients of different age but most frequently in children,

- develops when large amount of allergen gets into the conjunctival sac or on the eyelid skin,

- symptoms: itching, rapidly increasing conjunctival and eyelid edema leading even to disappearing

of the palpebral aperture,

- the disease is self-limited and usually does not need pharmacological treatment (1). The cold

compresses are very helpful, washing allergen out of the conjunctival sac with the normal saline or

with artificial tear solutions. If there is no effect topical and oral antihistamine drugs are

recommended.

2. Seasonal Allergic Conjunctivitis - SAC-

-the most common ocular allergic disease(2),

- usually develops in 7-14 year old children, occasionally in infants,

-allergens: pollen – grass,weeds and trees,

- there is often correlation between the pollen season and the patient’s date of birth,

-there is coexistence with other organ allergy: in 95% seasonal allergic rhinitis; often: itching of the

bare body parts; less frequently: urticaria, bronchial asthma attacks (3),

-often non-specific general symptoms: tiredness, malaise, loss of appetite, headaches, sleep

disturbances, subfebrile body temperature,

-cross-reactivity between food of plant origin and pollen: hazel (nuts), birch (apple) and mugwort

(celeriac, tarragon),

-symptoms appear during the pollen season of a specific plant: itching and eye watering attacks,

- clinical examination: mild edema of the bulbar and tarsal conjunctiva, limpid, watery and

sometimes mucoid discharge, small papillae of the palpebral conjunctiva, in more severe cases

eyelid edema, dilatation of the conjunctival vessels, rarely episclera or ciliary vessels. The lesions

are usually bilateral without cornea involvement (3-6),

- treatment: prophylaxis, non-pharmacological management (cold compresses and artificial tear

solutions, best without any preservatives). Pharmacological treatment: topical: antihistamine drugs,

mast cell stabilizers and multidirectional antiallergic drugs, best 10-14 days before starting an

allergy season. Oral antihistamine drugs should be used for other organ symptoms of the pollinosis.

Coexistence of SAC with the seasonal allergic rhinitis is the indication of category A for the

specific immunotherapy. Decision about this treatment should be taken by an allergologist (7).

3. Perennial Allergic Conjunctivitis - PAC

-inflammation of the eye surface with symptoms similar to SAC but perennial and less intense, with

exacerbation in autumn when there is the highest allergen exposure,

- allergens: house dust mites, pet dander, fungus allergens, especially moulds,

- PAC may be part of the occupational allergy manifestation to latex or laboratory animal

epithelium (6),

- exacerbation may appear because of non-specific irritating factors,

- PAC does not influence visual processes,

- to make the diagnosis the patient’s medical history should be confirmed by skin prick test results

or specific serum IgE. If there are any problems with the diagnosis - some additional tests are

required: Lacrytest or the conjunctival provocation test (1, 5, 6, 8),

- treatment: prophylaxis (anti-mite recommendations and elimination of sensitizing animals from

the patient’s environment), non-pharmacological management (cold compresses and artificial tears,

best without any preservatives), pharmacological treatment: topical: antihistamine drugs, mast cell

stabilizers and multidirectional activity antiallergic drugs (2, 4-6, 9). If there are any other organ

symptoms of the pollinosis oral antihistamine drugs should be considered. If they are used for a

long time ophthalmological regular consultation is required as they have unfavourable influence on

the conjunctival homeostasis and may lead to the dry eye syndrome (10-12)

Immunotherapy is indicated in the allergic rhinoconjunctivitis, allergic reaction to house-dust mites

(7). Indications for immunotherapy to other allergens seem to be controversial.

4. Vernal Keratoconjunctivitis – VKC

- chronic, severe and recurrent ocular allergic disease with mixed allergic pathomechanism

connected with hormone receptor dysfunction and histamine metabolism disturbances (3, 8, 12-15),

- affects usually children and teenagers, mostly boys over 5 years old (1, 4, 12-15),

- usually disappears within 5-10 years but may also convert into AKC,

- appears in dry, warm climate (mostly Mediterranean countries),

- often coexists with other organ allergy: rhinoconjunctivitis, bronchial asthma, contact dermatitis,

atopic dermatitis, food allergy,

- symptoms are of different intensity, usually perennial, often spring and summer exacerbations

because of the non-specific irritating factors,

- symptoms: persistent itching exacerbated by wind, dust, bright light, hot weather; dense

conjunctival discharge, lacrimation, burning, eyelid edema even with palpebral aperture

disappearance. Vision disturbances, slow adaptation to daylight, photophobia and ocular pain

confirms corneal engagement and needs urgent ophthalmological treatment (5).

Ocular disturbances may be asymmetrical.

- there are three clinical manifestations: palpebral, limbal and rarely mixed,

- clinical examination: conjunctiva redness, tarsal conjunctiva papillae (“cobblestones”) and

papillae of the limbus, Trantas-Horner dots. The multiple and huge papillae may cause the upper

eyelid dropping. The papillae are seen after upper eyelid reverting, less frequently observed on the

lower eyelid. The size of the papillae is a poor prognostic factor of the disease progression. There

are different corneal lesions: punctual epitheliopathy, macroerosions, ulcers, corneal plaques,

subepithelial scars that may lead to persistent vision disturbances and the corneal curvature

changes,

- diminishing of vision acuity is observed in about 30% patients with VKC,

- the diagnosis of VKC needs both an ophthalmologist and an allergologist. Because of the fact that

SPT are positive only in some patients, early examination and assessment of ocular lesions are

important. Together with the medical history they enable to make a proper diagnosis. Detection of

a potential allergen, responsible for the IgE-dependent reaction is important only to start the

prophylaxis. The presence of more than two eosinophils in the conjunctival scrapings is

pathognomonic for VKC (1, 8),

- treatment of VKC patients should be carried out by an ophthalmologist because severe vision

disturbances are possible during the disease progression. There are some prophylaxis

recommendations: avoiding eye rubbing and exposure to dry, warm air. Cold compresses are

indicated. Pharmacological intraconjunctival treatment: mast cell stabilizers with a special

indication to lodoxamid (5, 9, 14), antihistamine drugs with multidirectional functions.

Glicocorticosteroids are necessary, sometimes also cyclosporine or mitomicine C, antimucolitic

drugs (9). Nowadays adding topical nonsteroidal anti-inflammatory drugs and oral aspirin are

recommended (15, 16). Sometimes surgical management is necessary: cryoapplication, steroid

injections, laminar keratectomy (17).Specific immunotherapy is not a standard VKC treatment,

even in patients with known IgE-dependent mechanism.

- pathological changes in the eye may be dangerous for vision processes.

5. Atopic Keratoconjunctivitis - AKC

- bilateral allergic keratoconjunctivitis in patients with the atopic dermatitis (1, 4-6, 12, 15, 18, 20),

- ocular changes appear within a few years of the atopic dermatitis progression, peak onset in 3-5

decades of life (14, 21),

- ocular symptoms are bilateral: photophobia, lacrimation, burning, mucous-purulent discharge in

the conjunctival sac and between cilia, difficult to remove. The skin around eyes and the eyelid skin

are excessively dry (1, 4) with the features of the lichenification (“senile looking eyes”), eyelid

edema, inflammation of the eyelid margins, long, silky eyelashes or loss of them, Dennie-Morgan

symptom, Hertog symptom (19, 20),

- clinical examination: dilatation of the conjunctival vessels, conjunctival papillae, Trantas dots. In

severe disease progression there are also: conjunctival scars, adhesions between tarsal and bulbar

conjunctiva within lower folds, tarsal conjunctiva keratosis (21). There are corneal lesions in about

75% patients: ulcers, scars, new vessels developing, punctual keratopathy, pseudogerontoxon,

corneal plaques (6, 14,18),

-common concomitance with cataract, keratoconus and dry eye syndrome (18-20),

- AKC is the most dangerous ocular allergic disease, often leading to blindness because of: corneal

complications, retina detachment, bacterial and viral superinfection,

-treatment: cooperation between an allergologist and an ophthalmologist is necessary. Non-

pharmacological management: eyelid skin moistening with mild emollients, artificial tears without

preservatives, strict eye hygiene (the possibility of the secondary infection, especially by

Staphylococcus aureus, which is present under the nail plate in most patients with the atopic

dermatitis) (22, 23). The eyelid rubbing and scraping is forbidden – danger of superinfection and

mechanical mastocytes degranulation, increased risk of retina detachment and cataract (24).

Avoiding the allergen, if it is known.

Persistent conjunctival treatment: multidirectional antiallergic drugs (6, 9, 15, 19, 25), mast cell

stabilizers with special indication to lodoxamid (12, 13, 25). Commonly topical glicocorticosteroids

or non-steroidal anti-inflammatory drugs, cyclosporine (topical and systemic), tacrolimus and

pimecrolimus on the eyelid skin (9, 15-16, 26-27).

There are no data on the specific immunotherapy effectiveness in AKC therapy (6).

6. Giant Papillae Conjunctivitis - GPC

It is hypersensitivity of the conjunctival epithelial cells to the long-term presence of a foreign body:

contact lenses, eye prothesis, irritating stiches (after the eye surgery) or because of the eye ball

surface irregularities (1, 28-29).

- The pathomechanism of GPC is complex, both mechanical and allergologic (1, 6, 28-29),

- symptoms may appear within months or years of contact lense wearing,

- symptoms (non-depending on the seasons): white or transparent discharge observed after waking

up, foreign body sensation, lacrimation, itching, burning and sometimes vision disturbances,

- clinical examination: from small to giant papillae of the upper tarsal conjunctiva, redness, bulbar

conjunctiva edema, sometimes corneal complications (punctual epitheliopathy, erosions),

- the disease does not influence vision processes,

- treatment: strict eye hygiene, observing time of contact lense wearing and their appropriate

maintenance, possible change of the kind of contact lenses or not using them at all. The

intraconjunctival treatment: mast cell stabilizers, multidirectional antiallergic drugs (9, 28-30).

Applying drugs directly onto the contact lens is not recommended.

7. Contact Blepharoconjunctivitis - ConBC

- it is caused by irritation (non-allergic mechanism) or allergic processes,

- allergic ConBC (33% cases) – as a result of the iatrogenic factors: ophthalmological drugs,

detergents, cosmetics, often - preservatives: benzalkonium chloride (1, 31-33),

- symptoms appear within 24 - 72 hours after exposure of the skin to the allergen. If there were

previous small traumas like: rubbing, using of occlusions, overperspiration - the allergen may get

deeper into the skin.

-symptoms: eyelid skin edema and redness, small ulcerations, lichenification of the periorbital skin

(“senile eye appearance”). In severe disease progression there are also: scars, skin

hyperpigmentation, lower eyelid ectropion,

-clinical examination: dilatation of the conjunctival vessels, conjunctiva papillae and nodules,

watery discharge, sometimes punctual corneal epithelium depletion and keratitis,

-diagnostics – proper medical history and ophthalmological examination, patch tests,

cytodiagnostics of conjunctival scrapings,

- management: eye touching and conjunctiva rubbing are forbidden. Using topical drugs should be

limited. Cold compresses with physiological saline, artificial tears without preservatives and mild

emollients on the periorbital skin are recommended (9, 12). Pharmacological treatment: oral

antihistamine drugs, often sedatives – they additionally diminish itching (9, 12, 16, 20). If the

systemic treatment is not effective topical immunosuppressive, rarely steroid, preparations are

applied onto the eyelids. (26-27, 33-34).

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Alergiczne choroby oczu. Czajkowski J. (red.) Górnicki Wyd. Med, Wrocław 2003, 81-96.

2. Co-morbidity and complications w: Allergic Rhinitis and its Impact on Asthma – ARIA

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4. McGill JI., Bacon AS., Anderson D. et al. Allergic eye disease mechanisms. Br J Ophthalmol

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5. Friedlaender MH. Conjunctivitis of allergic origin: clinical presentation and differential

diagnosis. Surv Ophthalmol 1993, 38, suppl: 105-114.

6. Bielory L. Allergic diseases of the eye. Med Clin N Am 2006, 90, 129-148.

7. WHO Position Paper: Allergen Immunotherapy. Allergy, 1998, 44, 53.

8. Leonardi A. In–vivo diagnostic measurements of ocular inflammation. Curr Op Allergy Clin

Immunol, 2005, 5, 464-472.

9.Groblewska A., Czajkowski J., Bogacka E. Farmakologiczne leczenie alergicznych chorób oczu.

In: Alergiczne choroby oczu. Czajkowski J. (red.) Górnicki Wyd. Med., Wrocław 2003, 103-126.

10. Ousler GW., Wilcox KA., Gupta G. An evaluation of the ocular drying effects of 2 systemic

antihistamines: loratadine and cetirizine hydrochloride. Ann Allergy Asthma Immunol 2004, 93, 5,

460-464.

11. Welch D., Ousler GW., Nally LA. et al. Ocular drying associated with oral antihistamines in the

normal population-an evaluation of exaggerated dose effect. Adv. Exp. Med Biol, 2002, 506, (Pt-

B), 1051-1055.

12. Bielory L. Allergic and immunologic disorders of the eye. J Allergy Clin Immunol. 2000,

106(6), 1019-1032.

13. Avunduk AM., Avunduk MC., Kapicioglu Z. et al. Mechanisms and comparison of anti-allergic

efficacy of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis.

Ophthalmology 2000, 107, 1333-1337.

14. Abelson MB., Granet D. Ocular Allergy in pediatric practice. Curr Allergy Asthma Rep. 2006,

6, 306-311.

15. Vichyanond P. Childhood Allergic Conjunctivitis and Vernal Keratoconjunctivitis. Allergy Clin

Immunol Int, 2004, 16, 4, 132-136.

16. Uchio E. Possibility of non-steroidal treatment in allergic conjunctival diseases. Allergol

Internat. 2004, 53, 315-319.

17. Czajkowski J., Groblewska A. Operacyjne leczenie alergicznych chorób oczu i ich powikłań.

In: Alergiczne choroby oczu. Czajkowski J. (red.) Górnicki Wyd. Med, Wrocław 2003,127-134.

18. Bonini S. Atopic keratoconjunctivitis. Allergy 2004, 59, 71-73.

19. Ono SJ., Abelson MB. Allergic conjunctivitis: Update on pathophysiology and prospects for

future treatment. J Allergy Clin Immunol 2005, 115, 1, 118-122.

20. Eiseman AS. The ocular manifestations of Atopic Dermatitis and Rosacea. Curr Allergy

Asthma Rep 2006, 6, 292-298.

21. Onguchi T., Dogru M., Okada N. et al. The impact of the onset time of atopic

keratoconjunctivitis on the tear function and ocular surface findings. Am J Ophthalmol 2006, 3,

569-571.

22. Nivenius E., Montan PG., Chryssanthou E. No apparent association between periocular and

ocular microcolonization and the degree of inflammation in patients with atopic

keratoconjunctivitis. Clin Exp Allergy 2004, 34(5), 725-730.

23. Shoji J., Kato H., Kitazawa M. et al. Evaluation of staphylococcal enterotoxin-speci. c IgE

antibody in tears in allergic keratoconjunctival disorders. Jpn J Ophthalmol 2003, 47, (6), 609-611.

24. Taniguchi H., Ohki O., Yokozeki H. et al. Cataract and retinal detachment in patients with

severe atopic dermatitis who were withdrawn from the use of topical corticosteroid. J Dermatol

1999, 26, 10, 658-665.

25. Leonardi A. Emerging drugs for ocular allergy. Expert Opin Emerg Drugs 2005, 10 (3), 505-

520.

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dermatitis. Cutis 2004, 73, 267-271.

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disease. Am J Ophtalmol 2003, 135 (3), 297-302.

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allergy. Ophthalmol Clin N Am 2003, 16, 463-469.

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459-463.

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blepharoconjunctivitis (abstract). J Eur Acad Dermatol Venerol 2003, 17, supp l3, 102.

MANAGEMENT OF THE OCULAR ALLERGIC DISEASES

E. Bogacka, A. Groblewska, M. Jędrzejczak-Czechowicz, A. Zaleska-Żmijewska

A. Non-pharmacological

B. Pharmacological

C. Surgical

A. NON-PHARMACOLOGICAL TREATMENT

The non-pharmacological treatment is recommended for avoiding or diminishing exposure to

allergens. Introduction of the proper prophylaxis reduces drug intake by 40 % (1).

It is advised to keep hands away from the eyes as they are the source of bacterial and viral

infections. Moreover, rubbing the eyes causes mechanical mastocyte degranulation and increases

itching. Performing the cold compresses as well as washing the conjunctival sac with artificial tears

provide relief by decreasing itching and contraction of the superficial blood vessels.

The identification and avoiding the allergen would be the best and most effective management of

allergic conjunctivitis. The prophylaxis should always be recommended in already diagnosed

allergy to pollen, house dust mites, animal dander and fungi (1-4).

The preventive recommendations in pollen allergy

1. Changing the climate-zone during the pollen season for the seaside, high mountains or the region

with different plants.

2. If it is not possible to change the climate, the influence of pollen on the patient may be decreased

by:

- limiting to minimum staying outdoor during sunny and windy weather,

- wearing glasses, especially tight fit glasses and their frequent cleaning,

- travelling by car with closed windows; it is very helpful if the car has a pollen-proof filter,

- not staying by the open windows when travelling by bus or by train,

- washing the body thoroughly, especially hair, changing clothes after coming back home, washing

eyelids and conjunctival sac with normal saline or artificial tears.

The preventive recommendations in mite allergy

For growing mites need high humidity (over 50%) and temperature over 20ºC . They die at the

temperature below 4ºC, in dry air, they do not like room airing. They feed on fungi, animal and

human exfoliated epithelium.

To diminish the amount of house dust mites the following actions should be undertaken:

- avoiding curtains, back-drops, carpets, coverings, kilims, wool and fur overlays,

- pillows should be frozen or washed frequently,

- plush toys should be periodically frozen in a deep-freeze,

- vacuum cleaner with HEPA filter should be used,

- in winter, bed mattresses should be frozen or covered with special sheets with rubber, made from

material that does not let mite excrements pass through,

- frequent room airing, especially during heating season, do not use humidifiers,

- limiting the number of pets, especially in the bedroom.

People with mite allergy should not tidy attics, dust books and paper stores, beat carpets or kilims.

The clothes that are used seasonally should be aired (coats, jackets, fur-coats, sweaters).

The preventive recommendations in mould allergy

It is important to avoid environment friendly towards fungal vegetation such as:

a) regions with high humidity:

- wet forests and brushwoods, water reservoirs, including lakes,

- seashores, valleys, ravines, especially in subtropical and tropical climate,

b) rooms with increased fungal vegetation:

- full of moulds or high humidity,

- with damp cement surfaces, with stagnant water,

- with large amount of hydrophilus plants,

- inhabited by cats and other fur-animals,

- used only seasonally for example: caravans,

- equipped with unproperly serviced air conditioning.

Some fungal spores for example Alternaria, Cladosporium float in the air in considerable amounts

in the summer time. The same recommendations are effective as in pollen allergy.

Non-specific factors irritating the conjunctiva

Not only allergens but also non-specific irritating factors reveal allergic disease symptoms. It is

very important to avoid factors such as: (5, 6)

- wood smoke (barbecue, fireplace, camp-fire),

- formaldehyde (new coverings and furniture made of plywood),

- disinfectant (swimming-pools!),

- paints and lackers,

- food preserving sulphites(released from fruit imported from far away, crisps and peanut

packages),

- tobacco smoke,

- urban smog (SO2, NO2).

Artificial tear preparations

They are used in ocular allergic disease treatment – they wash allergens away, stabilize the tear

film destroyed during allergic inflammation (1).

Nowadays artificial tears are available as:

a) drops,

b) gels,

c) drops that change into gel after applying into conjunctival sac.

The most important preparations used in ocular allergic diseases are those from groups a and c, best

without preservatives.

Ocular allergic disease immunotherapy

The specific immunotherapy (IT) is an effective tool used in allergy IgE-dependent disease

treatment. The increasing doses of allergen are applied, leading to tolerance induction and finally

disappearance of the disease symptoms. There are different schemata describing how to perform

immunotherapy. The subcutaneous immunotherapy (SIT) is used most frequently but sublinqual

(SLIT), intranasal and local intraconjunctival immunotherapy are also performed (LCIT) (7-9).

The results of many studies confirm, based on EBM conception, the clinical effectiveness of

subcutaneus (classical) immunotherapy in allergic rhinoconjunctivitis treatment and in decreasing

the risk of bronchial hypersensitivity and bronchial asthma development (7, 10-12). Using IT in

allergic conjunctivitis treatment has limited significance. However, some authors think that

immunotherapy is recommended not only for bronchial asthma, allergic rhinoconjunctivitis but also

for isolated conjunctivitis (13-14).

In most studies, the symptoms before and after immunotherapy were assessed together for the nose

and the conjunctivae. In the studies in which conjunctival symptoms were judged separately, there

was diminished conjunctival hypersensitivity in patients after IT and decrease in the need for

antihistamine drugs (Table 5).

The SAC, being a part of rhinoconjunctivitis, is a category A indication for specific

immunotherapy. There are also some trials to use IT in house dust mite PAC treatment. IT is also

used sometimes in VKC and AKC if the allergen involved in IgE-dependent reaction is known

(trees, grass pollen and mites) but the results are controversial.

Table 5

Effectiveness of the immunotherapy related to conjunctival symptoms and conjunctiva

hypersensitivity by CPT method.

Grasses, birch

Grasses

Grasses

Parietaria judaica (weed)

Poa pratensis (grass)

Grasses, cereals

Parietaria (weed)

Grasses, birch

Grasses

Grasses

Dermatophagoides pteronyssinus

Decrease in conjunctival symptoms, lower conjunctival reactivity

Decrease in nasal and conjunctival symptoms, isolated conjunctival symptoms - NS

Clinical symptoms - NS

Decrease in conjunctival hypersensitivity


Decrease in conjunctival symptoms

Decrease in conjunctival hypersensitivity; increase in IgG1 and IgG4

Lower eye drops and antihistamine drug intake, symptoms assessed together

Decrease in eye itching,

Decrease in drug intake

Decrease in conjunctival redness and watering


Dahl 2006 (16)

Lima 2002 (17)

La Rosa 1999 (18)

Roberts 2006 (19)

Klimek 2005 (20)

Ortalani 1994 (21)

Winther 2000 (22)

Pocobelli 2001 (23)

Sabbah 1995 (24)

Nunez 2000 (25)

B. PHARMACOLOGICAL TREATMENT

The following groups of drugs are used in the ocular allergic disease treatment:

- antihistamine drugs topical and systemic,

- mastocytes and eosinophils stabilizers,

- glicocorticosteroids topical and systemic,

- non-steroidal antiinflammatory drugs topical and systemic,

- immunosuppressive drugs.

Antihistamine preparations

1. Oral

Preparations of 2nd - generation:

-cetirizine dihydrochloride, loratadine and the new ones: desloratadine, fexofenadine

hydrochloride, levocetirizine dihydrochloride (1, 4, 26, 27).

The 1st -generation preparations are not recommended because they have many side effects,

including negative influence on the tear film stability (27-28). The 2nd -generation oral

antihistamine drugs are recommended in the acute ocular allergic diseases treatment (AAC,

ConBC). When 2nd - generation antihistamine drugs are used for a long time in PAC and AKC, the

side effect of dry eye syndrome may develop (29-31).

2. Topical

Preparations of 1st - generation:

- antazoline sulphate, diphenhydramine hydrochloride, pheniramine – at present each of them

together with any vasoconstrictive drug: naphazoline nitrate or tetryzoline hydrochloride – is not

recommended (according to the expert group) because of many side effects (1, 26-28),

- ketotifen fumarate.

Preparations 2nd -generation:

- azelastine hydrochloride, emedastine difumarate, epinastine hydrochloride and olopatadine

hydrochloride. The effectiveness of the topical treatment depends on how fast the drug reaches its

high concentration in the conjunctival sac and how long it stays there. It does not relate only to

antihistamine drugs (33-34). Now on the Polish market, there are some antihistamine drugs with

such properties: azelastine hydrochloride, emedastine difumarate, epinastine hydrochloride,

ketotifen fumarate and olopatadine hydrochloride. It has been shown that topical drugs are more

effective than systemic ones in the treatment of ocular allergic diseases (27, 28, 35, 36, 38).

Now olopatadine hydrochloride seems to be the most effective antihistamine drug used in relieving

the ocular allergic symptoms and in diminishing eyelid edema (28, 34-36, 39).

Mastocyte and eosinophil stabilizer

Mastocyte and other antiinflammatory cell stabilizers (1, 33):

a) nowadays lodoxamide tromethamine is the strongest mastocyte and eosinophil stabilizer

recommended in VKC and AKC treatment and GPC prophylaxis (1, 28, 40-42),

b) cromons: cromoglicate disodium - 2% solution – because of the low concentration, its

effectiveness is similar to washing the eye with normal saline (27, 28, and 34),

cromoglicate disodium - 4% solution – higher clinical effectiveness (according to some authors)

(28, 31, 32).

c) antihistamine drugs with significant clinical influence on inflammatory cells (1, 26, 31, 33, 37,

38):

- oral drugs: desloratadine, fexofenadine hydrochloride, levocetrizine dihydrochloride,

- topical preparations: azelastine hydrochloride, emedastine difumarate, epinastine hydrochloride

and olopatadine hydrochloride.

Glicocorticosteroids

They are used in the ocular allergic disease treatment both topically as drops, ointment or injections

and also systemically (26, 28). There are the following eye drop preparations available in Poland:

dexamethasone and prednisolone acetate and three drugs with the best safety profile:

fluorometholone, fluorometholone acetate and loteprednol etabonate (1, 28, 36 ).

The use of glicocorticosteroids may develop well known side effects and ophthalmological

complications: bacterial, fungal and viral infections, cataract and glaucoma. When patients are

qualified for glicocorticosteroid treatment special attention should be paid to those who are really

sensitive to side effects of these drugs (high increase in intraocular pressure after applying

glicocorticosteroid drops). Steroid preparations should be avoided in these patients and if they are

really necessary short action oral drugs should be chosen for example: prednisolone or prednisone

(26).

The decision about using steroids and supervision of such treatment should be performed only by

an ophthalmologist.

Non-steroidal antiinflammatory drugs

Topical preparations:

- diclofenac sodium – recommended in AKC, VKC and PAC treatment. It significantly diminishes

conjunctival hypersensitivity, stabilizes mast cells and lymphocytes, decreases fibroblasts and

conjunctival endothelium activity.

- acetylsalicylic acid – recommended as well as NSAiD drops in VKC treatment (1, 32, 36, 38, 44).

Both drugs may trigger bronchial asthma attack in patients with aspirin hypersensitivity.

Immunosuppressive drugs

- cyclosporine A and mitomycin C – used by ophthalmologists in treating VKC and AKC with

severe corneal disturbances (1, 32, 33, 36, 44, 45). The systemic cyclosporine is used in AKC with

diffused skin lesions (treatment should be carried out by a dermatologist or an allergologist).

- pimecrolimus and tacrolimus – replace steroid ointment in the eyelid lesions in ConBC, AKC and

atopic dermatitis (1, 26, 28, 33, 44, 47, 48).

Vasoconstrictive drugs – alpha-agonists

As they are usually OTC drugs, some preparations are not used properly which leads to drugs

abuse, conjunctiva overdrying and glaucoma exacerbations. Nowadays, they are not recommended

in the treatment of ocular allergic disease (1, 26, 44, 45, 49).

C. SURGICAL TREATMENT

Surgical treatment in the ocular allergic diseases can be divided into two main groups:

1. Treatment of ocular allergic disease complications.

1.1. Surgical treatment of the eye-ball surface disturbances.

1.2. Cataract - muddy lens removal and new artificial lens implantation into lens posterior capsule.

1.3. Retinal detachment.

2. Drugs-induced complications.

1.1. Surgical treatment of the eye-ball surface disturbances

1. Surgical removal of the overgrown huge papillae (VKC, AKC),

2. Overtarsal glicocorticosteroid injections (50, 51),

3. The amniotic membrane transplantation,

4. Closing of the lacrimal dots (transient or perennial) in severe dry eye syndromes: lacrimal dot

plugs, closing the lacrimal dots with diathermy, argon laser (coagulation) (50, 51),

5. Eyelid plastic surgery: correction of the improper eyelid margin position (entropion and

ectropion surgery); deepening of conjunctival folds (plastic surgery with simultaneous

transplantation of amniotic membrane or buccal mucosa) (50, 51),

6. Electrolysis of the improper eyelash growing,

7. Refractory surgery: therapeutic photokeratectomy (PTK),

8. Limbus cell implantation,

9. Laminar implantation,

10. Corneal penetrating implantation - in already performed corneal perforation or if there is a risk

of its developing.

Ad 1. The removal of the overgrown papillae using:

a) cryotheraphy,

b) knife cutting.

The huge papillae cryotheraphy (50)

Advantages: possibility of the intervention repetition,

Disadvantages: short-time therapeutical effect, tarsal conjunctiva scaring, risk of the corneal

disturbances, conjunctival edema after intervention.

Knife cutting – surgical removal of the overgrown papillae with intrasurgical moist application

with 0,05% mitomycin C (MMC). Surgery is indicated in the following disorders (most commonly

in AKC and VKC):

- corneal erosions or deeper declines resistant to topical conservative therapy,

- patients who cannot be treated with systemic glicocorticosteroids or cyclosporine A (or the

treatment is not effective),

- patients with severe pains and severe lacrimation, resistant to preservative treatment,

- huge papillae (“cobblestones-like”) on the upper tarsal conjunctiva with concomitant redness and

conjunctival edema - active inflammatory process.

Advantages: inhibition of conjunctival fibroblasts proliferation and new papillae growing and

increase in the corneal epithelial cell proliferation.

Disadvantages: possible treatment complications after MMC administration, conjunctival scars,

upper eyelid dropping.

Ad 2. Epitarsal glicocorticosteroid injections

Advantages: decrease in the number and size of papillae, conjunctival inflammation process and

corneal disturbances, especially those located in the limbus region.

Disadvantages: possibility of complications after strong glicocorticosteroid application, for

example: upper eyelid dropping, eyelid skin discoloration, tarsal conjunctiva ischemia, secondary

conjunctival infections, subconjunctival scars, increase in the intrabulbar pressure (50, 51).

Ad 3. Amniotic membrane graft

The amniotic membrane has the ability to diminish the tissue scars and inflammatory process, to

improve healing and increase epithelial cell proliferation (51).

The amniotic membrane is used in (52):

- trophic corneal ulcerations,

- persistent corneal epithelial cell declines,

- infectious cornea inflammations,

- corneal plaques,

- the eye-ball surface reconstructions in the conjunctival pathologies, for example - symblepharon.

The amniotic membrane is used as:

a) dressing (overlay) – used in difficult healing of the corneal epithelial cell declines or

immunogenic substantia propia infiltrations. The amnion used as the eye patch is transplanted

onto the all eye-ball surface and corneal limbus, with the epithelial layer as the upper part. It works

for about 2 weeks (until it is absorbed) as a dressing as well as a barrier for inflammatory cells and

proteinases present in the tear film. It is used in difficult healing of the corneal epithelial cell

declines, in dry eye syndrome, after mechanical or laser removal of the superficial corneal lesion.

b) therapeutic grafting (inlay) – enables reconstruction of the anatomical eye-ball surface

structures. The amniotic membrane transplantation is placed with the basement membrane as the

upper part, on which epithelium should grow. The amniotic membrane is transplanted only on the

pathologically changed corneal or conjunctival areas, with small margins around. It works for about

4-6 weeks by improving the healing processes of the corneal declines that get deeper even until

substantia propia. It also allows to rebuilt and correct the eye-ball superficial structures.

Ad 7. Refractory surgery - PTK

Therapeutic photokeratectomy with the excimer laser uses the photoablation phenomenon - the

superficial corneal layer modeling. It is used in:

- deeper corneal lesion removal, including corneal plaques, ulcers,

- microerosion removal, often covered by changed mucous and fibrin (epithelisation process is

inhibited),

- treatment of the improper epithelisation for example in recurrent erosions with basal membrane

disturbances,

- removal of the anterior corneal layer irregularities.

The PTK intervention can be supported by the amniotic membrane transplantation directly after

laser treatment which accelerates epithelisation and healing of the corneal lesions.

Advantages: local corneal condition improvement and increase in its transparency, pain decrease,

visual sharpness improvement, smaller damages of the healthy tissue comparing to those observed

after mechanical abrasion (53).

Disadvantages: risk of the decentralization of the place for photoablation, improper healing, slower

epithelisation, hypermetropia and heterometropia induction, irregular astigmatism emerging (53).

Ad 8. Limbal stem cell graft

The only effective way of stem cell failure treatment is its transplant as a bank of cells carried onto

the eye tissue (conjunctiva, cornea), the amniotic membrane or tissue adhesive glue (54). The

limbal stem cells can be taken from the opposite healthy eye of the same patient – autograft or from

a family donor, with genetic accordance regarding HLA antigens - allograft (54). Nowadays the

amniotic membrane graft together with the limbal stem cell graft is used as a standard procedure.

The amniotic membrane reproduces the natural environment for the stem cells crowling. It has

antiinflammatory and immunosuppressive functions and may also inhibit the fibrosis processes (52,

54).

In most patients the corneal graft is the first stage to allow the normal eye-ball surface reproducing.

The next stage - improving patient vision - is a lamellar or penetrating (more often in the limbus

failure) corneal graft (54).

Ad 9. Lamellar graft

The lamellar graft in indicated for treatment of the corneal diseases without pathological

endothelial lesions but requiring kerathoplasty.

Ad 10. Penetrating corneal graft

The perforation of the cornea is the most severe corneal complication which needs urgent surgical

intervention. This complication rarely appears in the perennial allergic keratoconjunctivitis but the

risk of significant corneal thinning in AKC should be taken into consideration. In urgent situations

the patient is qualified for immediate graft.

The second important qualification criterion for the penetrating corneal graft is the possibility to

improve the corneal transparency and thus the visual acuity.

1.3. The retinal detachment in the course of ocular allergic diseases

The possibility of surgical treatment based on the retina condition (51, 55):

- extrabulbar surgery interventions: epidural buckling and/or eye-ball wrapping – regarding the

amount and localization of the retinal abrasions. These interventions are 78% of all retinal

detachment surgery in AKC (56),

- vitreoretinal surgery: pars plana vitrectomy with applying perfluorocarbonate expanding gases or

the silicone oil (56),

2. Surgical treatment of the drug-induced complications (used for the ocular allergic diseases

treatment)

1. The complications after antihistamine drug use: dry eye syndrome, conjcunctival

hypersensitivity: lacrimal points plugs, salivary gland implantation into the upper eyelid (56).

2. Complications after persistent topical and systemic steroidotherapy:

steroid-induced cataract – removal of the lens with intrabulbar graft,

steroid-induced glaucoma – first of all the conservative therapy. If there is lesion progression

and/or the irregular intrabulbar pressure - laser interventions, surgical treatment for example:

trabeculectomy.

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23. Pocobelli D., Del Bono A., Venuti L. et al. Nasal immunotherapy at constant dosage: a double-

blinded, placebo-controlled study in Grass-allergic conjunctivitis. J Investig Allergol Clin Immunol

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router of immunotherapy with a standardized Grass pollen extract. Allergy 1994, 49, 309-313.

25. Nunez JA., Cuesta U. Local conjunctival immunotherapy: the effect of dermatophagoides

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allergic conjunctivitis. Allergol Immunopathol 2000 28, 301-306.

26. Bogacka E. Leczenie alergicznych chorób oczu. Alergia, Astma. Immunol 2004, 9, supl. 2, 53-

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460-464.

30. Welch D., Ousler GW., Nally LA, Abelson MB et al. Ocular drying associated with oral

antihistamines in the normal population-an evaluation of exaggerated dose effect. Adv Exp Med

Biol 2002, 506, (Pt-B), 1051-1055.

31. Ono SJ., Abelson MB. Allergic conjunctivitis: Update on pathophysiology and prospects for

future treatment. J Allergy Clin Immunol 2005, 115, 1, 118-122.

32. Bonini S. Atopic keratoconjunctivitis. Allergy 2004, 59, 71-73.

33. Bielory L. Allergic and immunologic disorders of the eye. J Allergy Clin Immunol 2000, 106,

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SPECIAL CIRCUMSTANCES IN THE OCULAR ALLERGIC DISEAS E MANAGEMENT

E. Bogacka, A. Groblewska, A. Zaleska-Żmijewska

Children

The ocular allergic diseases are frequent manifestation of allergy in children. However, there are no

epidemiological data on its world-wide morbidity, especially in children. There are epidemiological

data on the seasonal rhinoconjunctivitis in children (ISAAC-I): pollen allergy, responsible for the

seasonal rhinoconjunctivitis was found in 1,4%-39,7% of children participating in the study and

was the most frequent in the 13-14 year-old subjects (1). VKC is a typical ocular allergic disease in

children – observed mostly in boys before puberty. According to Bonini it accounts for 8% of the

ocular allergic diseases and according to Napoli – for 15,5% (2, 3). SAC, VKC and AKC handicap

to some extent the quality of life and require active treatment, while PAC is usually left out (4). In

small children the house dust mite and mould allergy is observed more frequently while in

teenagers the pollen allergy is dominating (5-7).

Proper prophylaxis is vital in the treatment of allergy in children (8). The specific immunotherapy

is effective and recommended in patients with pollen and house dust mite induced

rhinoconjunctivitis from the age of 5 years (5). Many non-pharmacological procedures also seem to

be effective (5). Children do not like intraconjunctival drugs because of burning sensation after

applying them. It may be diminished by keeping the eye drops in the fridge – cold drops are not so

painful. The eye drops with mastocyte and eosinophil stabilizers and antihistamine drugs are

recommended. The topical ocular allergic disease treatment is more effective because oral

antihistamine drugs do not diminish all ocular symptoms (6, 9). All available antihistamine drops

may be used in children but the best therapeutic index is observed for olopatadine hydrochloride,

and is also best tolerated by children (9). The systemic antihistamine drugs intake is necessary

when another organ allergy is coexisting but still additional topical treatment is most effective in

severe conjunctival symptoms (6, 9). Children are treated with the second generation oral

antihistamine drugs and these drugs should soon be launched on the market in the form of sweets

and chewing-gum. Current antihistamines available for children are shown in table 6 (according to

10).

In severe ocular allergic diseases (VKC, AKC) the long-term intraconjunctival application of

lodoxamide tromethamine, sometimes cyclosporin A or nonsteroidal antiinflammatory eye-drops or

oral acetylic acid are necessary. It is recommended to apply the emollients on the eyelid lesions to

avoid skin overdrying and if there are long-lasting eczema lesions – immuosupressive ointment

should be used: pimecrolimus or tacrolimus (2, 6, 9). Intraconjunctival corticosteroids are used only

in cases when other treatment is not effective. The decision about the intraconjunctival steroid or

cyclosporine A treatment should be taken by an ophthalmologist.

Table 6

Pregnancy and lactation

Preventive recommendations and washing the lacrimal sac with artificial tears are the optimal

procedures. Continuing the immunotherapy during pregnancy is more and more often

recommended because it effectively controls eye and nose allergy symptoms and seems to be a

diminishing risk factor of developing allergy in a newborn baby (11, 12). However, immunotherapy

should not be started in pregnancy (13).

If pharmacological treatment is needed, topical drugs are recommended: cromons as a first line

drugs and, if they are not effective, topical antihistamine drugs. If their effect is not sufficient

cetirizine dihydrochloride and loratadine may be used as relatively safe oral drugs (13). If the

rhinitis is severe and impacts conjunctivitis and worsens general condition of a pregnant woman

intranasal corticosteroids may be used. The corticosteroids both intranasal and inhaled do not have

teratogenic influence and do not increase the possibility of adrenal cortex failure in the fetus (13).

However, then the decision should be taken by an allergologist.

Coexistence of other ocular diseases

1. Topical drug-induced ocular allergic diseases

The most frequent type of the topical drug-induced ocular allergic reaction are cellular type

reactions (14, 15). The clinical symptoms are described as ConBC or only eyelid skin

inflammation.

Most topical drugs used as ointment or eye drops may develop symptoms of allergic contact

blepharoconjunctivitis. These reactions may develop because of the drug itself, its preservative

component (most frequently benzalconium chloride, tiomersal) or its base such as lanolin (16).

There are some ophthalmological drugs inducing hypersensitivity reactions, most frequently:

atropine, homatropine, aminoglycosides, antiviral drugs, sulfonamides (including carbon anhydrase

inhibitors), prostaglandin analogs (14-16).

2. Systemic drug-induced ocular allergic diseases

There are severe complications of some drug-induced syndromes that may influence the vision

organ like (14):

- Stevens-Johnson syndrome,

- Lyell syndrome.

The Stevens-Johnson syndrome is a type of erythema multiforme with mucosal membrane

involvement. In almost 90% of patients conjunctivae are also involved – there are papillary

formations. There are also local ischemic areas of the conjunctiva, blisters and subepithelial fibrosis

with the subsequent corneal opacity, conjunctival keratosis and conjunctival synechiae. There may

also be other consequences of chronic inflammatory changes and fibrosis like improper eyelid

margin position (eyelid’s tucking- entropion), with concomitant improper eyelash growing

(trichiasis) (15-16).

The Stevens-Johnson syndrome may develop as a consequence of the treatment with: sulfonamides,

antibiotics (tetracyclines, penicillins, chinolones), hydantoin, phenylbutazone, phenothiazine,

carbamazepine, barbiturates (14,17).

The Lyella syndrome known as toxic epithelial necrolisis is the most severe type of the Stevens-

Johnson disease. This syndrome was described after many drug intake like: antibiotics,

sulfonamides, barbiturates, anticonvulsive drugs, analgetics, quinine, nonsteroidal anti-

inflammatory drugs (16). The Lyell syndrome is characterized by diffuse blisters and crawling the

epithelium down the skin and mucosal membranes, including conjunctivae with concomitant

complications similar to those described in the Stevens-Johnson syndrome (16).

3. Refractive surgery in patients with the ocular allergic diseases

The contact lenses and preservative fluids intolerance are described more frequently in patients

with ocular allergic diseases. It explains why those patients are more frequently qualified for

LASIK or PRK procedures. Moreover, patients with severe ocular allergic disease with

proliferative conjunctiva and cornea lesions also need surgical treatment (18-19).

Non-treated allergic conjunctivitis is a risk factor for regression of the surgery effect and clouding

(haze) after PRK and LASIK procedures (18-21). The complications can be diminished by using

antiallergic treatment before the surgery (18-19).

4. Contact lenses in patients with allergic diseases

Some complications may be observed in allergic patients using contact lenses for a long time:

- giant papillary conjunctivitis (GPC),

- superior limbic keratoconjunctivitis (SLK),

- superficial punctate keratitis (SPK).

There are many allergic factors like some depositions on the lens surface (15-16): proteins and

products of their catabolism, pollution and preservatives present in lens care fluids (especially

deproteinization preparations). Wearing contact lenses by allergic patients should be considered

carefully because of high risk of hypersensitivity to lens care fluid components, or one day lenses

should be recommended (22).

5. Ophthalmological procedures in patients with any other organ allergy

When a patient is being prepared for the surgery the possibility of hypersensitivity to any

preparations used during the procedure should be taken into consideration, like for example iodine

(povidone), antibiotics, nonsteroidal anti-inflammatory drugs and their preservatives (15-16).

It is very important to take detailed medical history and give the patient antihistamine drugs before

and after the surgery as prophylaxis. There is a higher risk of bacterial and viral complications in

patients with AKC (23).

6. Infectious diseases of the anterior segment of the eye in patients with allergic diseases

It was described that patients with bronchial asthma, allergic rhinitis or atopic dermatitis have

binocular herpes simplex keratitis more frequently and 5 times more frequently with eyelid margin

involvement. Patients with allergy do not react well to topical antiviral treatment, they are more

predisposed to substantia propia scarring and healing of the epithelial lesions is slower (2, 24).

7. Changes in the vision organ in multiorgan allergy

Atopic dermatitis (AD)

Up to 42% patients with atopic dermatitis suffer from some vision organ disturbances, such as (4,

7, 14-15, 25):

- keratitis,

- iritis,

- cataract in 17-25% patients,

- retinal detachment in 8-15% patients (always coexisting with cataract),

- degenerative retina lesions with the presence of asymptomatic retinal breaks are observed from

25% up to 60% patients. In about 15% patients with already diagnosed retinal breaks

symptomatical retinal detachment will appear (25-27).

Atopic cataract

In patients with atopic dermatitis lens opacity is often observed as early as on the first presentation

at the ophthalmologist. Ocular lesions occur in young patients and are usually binocular.

There are four types of atopic cataract (28):

- anterior subcapsular,

- posterior subcapsular,

- cortical,

- mature (involving all lens layers).

There is no correlation between atopic cataract development and serum IgE level and positive skin

prick tests. However, the negative influence of systemic and topical corticosteroid treatment was

described (29, 30). The lens opacity in atopic dermatitis is probably due to chronic inflammatory

process in the anterior part of the vitreous body and in the ciliary body. The inflammation leads to

development of the anterior vitreoretinal traction and disturbances in the lens nutrition. The same

mechanism is suspected to play role in another frequent and dangerous ocular complication of

atopic dermatitis – retinal detachment (28, 31).

Each patient with already diagnosed atopic cataract qualified for the surgery should be examined

carefully including the peripheral retinal areas to exclude possible retinal lesions or treat them with

the laser coagulation. In 25% of patients with atopic cataract Retinal breaks before the surgical

cataract treatment were reported in 25% patients with atopic cataract (25-27).

Retinal detachment in atopic dermatitis

In most patients retinal detachments are local and flat. They are observed in about 8-15% patients.

Most detached retinas can be treated with extraorbital surgery. The prognosis is unfavourable

because new retinal breaks often develop (in 25% of the operated patients) and another surgery is

necessary (25, 28, 31, 32). It is thought that anterior vitreoretinal traction play an important role in

the pathogenesis of retinal breaks in patients with atopy and atopic cataract (31).

In patients with atopic dermatitis lesions in anterior part of the retina and ciliary body may follow

small injuries for example heavy rubbing of the eyelids and the facial skin (28, 32). This is the

reason why each patient with atopic dermatitis with the facial skin involvement should be examined

by an ophthalmologist every two months until the skin symptoms disappear (27).

Asthma, chronic rhinitis and the vision organ disturbances.

Systemic treatment of patients with asthma may affect the vision processes with possible

complications requiring surgical treatment (16, 30). The long-term antihistamine drug intake was

found to have an unfavourable influence on dry eye syndrome development or its intensification

(34, 35). Long-term treatment with systemic corticosteroids increases the risk of ocular

complications. Frequency of steroid-induced complications significantly drops after periodical use

of short acting oral glicocorticosteroids or after low doses of inhaled or intranasal

glicocorticosteroids (27, 30). The most severe steroid-induced complications are: cataract,

glaucoma, also an increased risk of the eyeball infections (15, 16, 29). Corticosteroid-induced

glaucoma is associated with the congenital predisposition to the increased intrabullbar pressure

after steroid intake. It is diagnosed by measuring the intrabulbar pressure before and two weeks

after the systemic glicocorticosteroid intake. If there is an increase in the intrabulbar pressure

further steroid treatment may lead to glaucoma (29).

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15. Sutphin JE., Chodosh J., Dana MR. et al. Choroby aparatu ochronnego oka i rogówki. Basic

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17. Costagliola C., Prute AD., Incorvaia C. et al. Ocular surface changes induced by topical

application of latanoprost and timolol: a short term study in glaucomatous patients with and without

allergic conjunctivitis. Graefes Arch Clin Exp Ophthalmol 2001, 239(11), 809-814.

18. Boorstein SM. Atopy a patient-specific risk for diffuse lamellar keratitis. Ophtalm 2003, 110, 1,

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19. Gierek-Ciaciura S. Alergie na soczewki kontaktowe i płyny pielęgnacyjne a decyzja o

laserowym zabiegu refrakcyjnym. Okulistyka 2003, supl 2, 140-144.

20. Yang HY., Fujishima H., Toda K. et al. Allergic conjunctivitis as a risk factor for regression

and haze after photorefractive keratectomy Am J Ophthalmol 1998, 125, 54-58.

21. Asano-Kato N., Toda K., Hori-Komai Y., Tsubota K. Allergic conjunctivitis as a risk factor for

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23. Eiseman AS. The ocular manifestations of Atopic Dermatitis and Rosacea. Curr Allergy

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24. Rezende R., Hammersmith K., Bisol T. et al. Comparative study of ocular Herpes Simplex

Virus in patients with and without self-reported atopy. Am J Ophthalmol 2006, 6, 1120-1125.

25. Yoneda K., Okamoto H., Wada Y. et al. Atopic retinal detachment. Report of four cases and a

review of the literature. Br J Ophthalmol 1995, 133(4), 586-591.

26. Hida T., Tano Y., Okinami S. et al. Multicenter retrospective study of retinal detachment

associated with atopic dermatitis. Jpn J Ophthalmol 2000, 44, 407-418.

27. Hayashi H., Igarashi C., Hayashi K. Frequency of ciliary body or retinal breaks and retinal

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32. Azuma N., Hida T., Katsura H. et al. Retrospective survey of surgical outcomes on

rhegmatogenous retinal detachments associated with atopic dermatitis. Arch Ophthalmol 1996,

114(3), 281-285.

OCCUPATIONAL OCULAR ALLERGIC DISEASES

C. Pałczyński

Occupational allergic eye diseases

Definition

Occupational allergic conjunctivitis – OAC is the allergic inflammatory process of the conjunctivae

against allergen specific for the work environment (occupational allergy). The definition of the

occupational factor specificity includes:

- type of the factor (it is found only in the work environment),

- the exposure level (significantly higher exposure in the work environment).

OAC may develop because of IgE-dependent and IgE-independent reactions. ConBC is the

occupational IgE-independent disease (1-8). The frequency of the OAC is unknown.

Causal factors

There are many etiological occupational factors that may cause OAC. They have also the ability to

induce occupational bronchial asthma and occupational allergic rhinitis (see table 7) (9-12).

Clinical characteristics

Clinical symptoms of OAC and occupational ConBC are the same as allergic ocular diseases

caused by other non occupational factors. The symptoms are usually bilateral. OAC is usually

perennial (clinical symptoms similar to PAC). Symptoms exacerbation is associated with exposure

time to allergen in the work environment. The result of elimination and reexposition test is often

positive, especially in case of monovalent allergy.

Diagnostics

- subjective and objective examination including precise medical history of the occupational

allergen exposure,

- clinical symptoms of OAC are not very specific (13),

- IgE-dependent allergy suspicion: s-IgE measurement, SPT.

In ocular allergic diseases, more frequently than in other allergic diseases, the specific antibodies

cannot be found using routine laboratory methods. Presence of antibodies does not confirm

undoubtedly their initial participation in the pathogenesis of the allergic disease and is only the

evidence of immune hypersensitivity without any clinical symptoms,

- ConBC suspicion: skin patch test performance,

- legal aspects: specific provocation tests with allergens suspected to be responsible for the disease

development.

The exposition tests are the most important tools in occupational allergy, performed in conditions

similar to the work environment but not the conjunctival tests. Cytodiagnostic tests of the vision

organ are recommended for the impartial confirmation of the exposition tests (14-34).

Differential diagnostics

- non-allergic reactions for example due to irritation, toxic

- allergic and other ocular diseases with non-occupational etiology.

Legal aspects

Allergic conjunctivitis may be treated as an occupational disease (clause 25/1 of the current

occupational disease list). The diagnosis of OAC can be taken during the employment period,

during the allergen exposure or after finishing the employment period but no longer than within one

year after the end of exposure.

It is assumed that allergy to widespread household or municipal allergens like house dust mites,

common ranging grasses, tree and weed pollen and also common mould, cannot be qualified as

occupational allergy. It is because these kinds of allergy are often observed in general population,

not exposed occupationally.

To assess the onset of the disease understood as characteristic symptoms and patient complaints is

very important in jurisdiction. Presence of specific antibodies detected by SPT or serum s-IgE

measurements is not sufficient in context of jurisdiction to recognize the occupational disease

(“hypersensitivity is not a disease”). If the allergic conjunctivitis against specific allergen was

observed before the employment period and now it is partially responsible for the disease it cannot

be classified as the occupational disease in the legal and medical sense.

The multifactorial hypersensitivity (simultaneous hypersensitivity to a few allergens, also non

occupational) does not exclude occupational allergy diagnosis assuming that there is a time

correlation between the occupational allergen exposition and the beginning of symptoms.

The occupational allergy diagnosis is difficult and should be performed only in institutions with the

adequate diagnostic equipment and qualified and experienced staff.

In Poland it is performed in the scientific and research institutes dealing with occupational

medicine (35-36).

1. Prophylaxis and employment qualification rules

Medical preventive management

Preliminary medical examinations of an employee are performed during the employment procedure

for the new post. Their minimum range is defined in “Methodical Guides for the Employee

Prophylactic Examinations” which is the annex to the Order of the Minister of Health and Social

Welfare from 30 May 1996. During the examination of candidates for the posts that are heavily

exposed to allergens the following points should be taken into account:

- intentional medical history concerning symptoms that may` refer to an allergic disease, including

allergic ocular disease and physical examination (subjective),

- SPT with common aeroallergens.

In atopic patients some contraindications should be considered regarding the employment on posts

that are heavily exposed to allergens. Because of the fact that atopy is very common in general

population these contraindications cannot be used arbitrary (especially if there are no clinical

symptoms). An atopic employee should be under precise medical preventive care (for example

individual calendar of periodic examinations). However, the diagnosis of the allergic disease may

be the contraindication to working on the post.

On periodic examinations intentional medical history and physical examination should be repeated.

The medical history should include a very precise description of the working place, time correlation

between the exposition and symptom appearing, the time of exposition before symptom appearing,

daily time of the exposition, use of individual protective measures. Some tests should also be

repeated periodically: SPT with occupational allergens, and in doubtful cases s-IgE serum level

should be measured. If there are detectable antibodies but without clinical symptoms, the patient

should get an individual calendar of periodic examinations or changing the post should be

considered. If there are clinical symptoms and an occupational disease may be suspected, then

diagnostics and jurisdiction procedures should be initiated.

2. Hygienic prophylaxis

The hygienic prophylaxis of the allergic occupational disease includes:

- in technological processes, replacing substances with high by low allergical potential,

- air-tight sealing and technical process automation,

- using proper ventilation and maintaining proper microclimate conditions (these conditions may

increase some substance allergenicity),

- modification of production processes or prefabricated elements leading to dimished

hypersensivity risk,

- using the individual protective measures (goggles/protective masks).

Subjects with allergic conjunctivitis and other chronic diseases of the eye protective apparatus are

contraindicated to work when exposed not only to the probably elicitating allergen but also to other

compounds with high allergic and irritating properties (35).

Occupational disease management

In Poland, there are three stages of the occupational disease management: suspicion, diagnosis and

statement of the occupational disease. The suspicion notification should be written by a physician

on a special form; the employer is also entitled to do that or the employee himself (via a physician

responsible for prophylaxis care). The occupational disease suspicion has to be reported to the

proper Health Sanitary Inspector and the Safety at Work Inspector. The patient is referred to the

first stage jurisdiction (Regional Centers of Occupational Medicine WOMP) to perform the

adequate diagnostics. If additional consultation is needed or an employee or an employer appeals

against the WOMP statement, the patient is further diagnosed in the occupational medicine

scientific institute (The Institute of Occupational Medicine).

The medical statement on the occupational etiology of the disease is sent to the proper Health

Sanitary Inspector who, based on this document and occupational exposure, gives the opinion on

the occupational disease or turns the motion down. This is the warrant opinion in getting financial

benefits (35).

Each of the European Union member states has its own individual regulations regarding the

occupational diseases. “Information notices on diagnosis of occupational diseases”, Employment

and Social Affairs DG, 1997) is the official document of the European Union concerning

occupational diseases, including occupational allergic conjunctivitis (37)

Table 7. The most important etiological factors of the occupational immediate reaction

allergy and the main exposed groups.

Factors with low molecular mass

- diisocyanides - varnishers, builders, plastic pulp workers, polyurethane product workers

- acidic anhydrides - chemical, plastic, pharmaceutical industry workers

- metal salts (e.g. platinum, nickel, chromium, cobalt) - galvanizers, welders, chemical industry

workers

- amines - chemical industry workers

- drugs (e.g. penicillins, spiramycine) - pharmaceutical industry and health care workers

- plastic compounds (e.g. acrylates) - chemical industry and plastic production workers

- dyes (e.g. henna, textile dye) - chemical industry workers, dye users (furniture industry, textile),

hairdressers,

- disinfectants (e.g. chloramine, glutaraldehyde, chlorhexidine) - chemical industry and health care

workers

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GLOSSARY

AAC - acute allergic conjunctivitis

AKC - atopic keratoconjunctivitis

Anaphylatoxins (C3a, C4a, C5a) - polypeptides (up to 10kD) produced during the complement

activation,

APC – antigen presenting cell,

as-IgE – antigen-specific immunoglobulin E,

AD – atopic dermatitis,

Fluorescein staining, Bengal Rose, Lissamine Green – used to expose corneal or conjunctival

lesions for the diagnosis of the dry eye syndrome, other infectious eye diseases and traumas,

BUT - break up time – tear film stability assessment,

tIgE – total IgE level,

Chemokines – chemotactic molecules active on different lymphocyte populations

Vitreoretinal surgery – vitreous body and conjunctiva surgery,

ConBC –-contact blepharoconjunctivitis,

CPT - conjunctival provocation test,

Cytokines – general name of molecules responsible for mutual cell cooperation,

EBM - evidence based medicine – notation used for the knowledge actually thought to be reliable

and proven based on properly performed studies,

ECP - eosinophil cationic protein with cytotoxic properties produced by eosinophils,

EDN - eosinophil derived neurotoxin,

Ectropion – eversion of the lower eyelid,

Entropion – inversion of the lower eyelid,

EPO - eosinophil peroxidase,

Epitheliopathy – epithelium pathological changes,

Emollients – skin moistening substances,

Photoablation – thin tissue layer precise cutting using the excimer laser,

Photokeratectomy – corneal lesions treatment and laser ametropia correction,

GPC – giant papillary conjunctivitis,

ICAM – intracellular adhesion molecule,

IL - interleukins – a group of naturally occurring proteins that mediate communication between

cells,

Immunoglobulins (antibodies) – molecules with properties of the specific antigen binding,

INF – interferon γ,

Keratopathy – corneal pathological changes,

Keratectomy –surgical treatment of the corneal lesions,

Cryoapplication –using low temperature therapy,

APC cells – antigen presenting cells (dendritic cells, lymphocytes B and macrophages are main cell

populations),

Immunocompetitive cells – cells (lymphocytes B and lymphocytes T) which are able to recognize

the antigens and to induce the immune reaction,

LASIK - laser keratomileusis in situ – refractory surgery with the excimer laser, in myopia and

hypermetropia correction,

Excimer laser – gas-laser emitting ultraviolet light,

LCIT - local conjunctival immunotherapy,

Lichenification – thickened and excessively wrinkled epithelium as a result of chronic atopic

dermatitis,

LT (LTB, LTC, LTD, LTE) leukotrienes,

MBP - major basic protein (produced by eosinophil),

Corneal macroerosion – huge corneal epithelium erosion,

Necrolysis – necrosis with epithelium detachment from the dermis,

NGF - nerve growth factor - cytokine,

NSAiD – non-steroidal antiinfammatory drug,

OAS - oral allergy syndrome,

Dennie-Morgan Symptom– additional lower eyelid skin fold,

Hertog Symptom – eyebrow external part dwindling,

Conjunctival papillae reaction – conjucntival epithelium overgrowing in folds and prominences

with central vessels and diffused inflammatory cell infiltration,

OAC - occupational allergic conjunctivitis,

PAC - perennial allergic conjunctivitis,

PG, PGs (PGE, PGF) – prostaglandins,

Trantas-Horner dots – degradated aggregation of eosinophils, their granulations and epithelium

cells on the top of the conjunctival papillae (in allergic inflammation),

PRK – radial photokeratectomy – refractory surgery with the excimer laser, corneal curvature

shape modeling to eliminate ametropia,

PTK – therapeutic photokeratectomy, modeling the anterior corneal surface disturbances with the

excimer laser,

Ocular pemphigoid – autoimmune ocular disease in the course of the cicatrical pemphigoid,

Pseudogerontoxon – peripheral corneal surface haziness without leaving transparent perilimbus

corneal specific for gerontoxon (arcus senilis),

rH1, rH2 – histamine receptors,

rush IT – accelerated specific immunotherapy,

SAC – seasonal allergic conjunctivitis,

SIT - specific immunotherapy,

SLIT - sublingual immunotherapy,

SLK - superior limbic keratoconjunctivitis,

SPK – superficial punctate keratitis,

SPT – skin prick test,

Substance P - neuropeptide with the immunomodulatory properties released by the sensorial

nerves endings,

Symblepharon – conjunctival-palpebral adhesions,

TARC - thymus and activation regulated chemokine - chemokine for lymphocytes Th2,

Lipcof Test - lid parallel to palpebral margins conjunctival folds – tear film disturbances assessing

parameter,

Schirmer Test – test used for assessing the watery tear film layer production,

Th – lymphocyte T helper,

Ts - lymphocyte T suppressor (inhibitory),

TNF – tumor necrosis factor,

Trichiasis – abnormal eyebrow growing, usually as a result of the chronic palpebral margin

inflammation and their deformation,

VKC - vernal keratoconjunctivitis,

Stevens-Johnson Syndrome – severe variant of multiforme erythema with the mucosa

involvement as a result of drug and some microorganism antigen hypersensitivity (viruses,

bacteria),

Lyell Syndrome - toxic epidermal necrolysis – in the course of drug hypersensitivity.

STATEMENT OF THE EXPERT GROUP OF THE POLISH …

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