Download statement of the expert group of the polish allergological association

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 IgEdependent). 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, 3943.
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 sIgE, 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, 2431). 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 Th2profile 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 ß2adrenergic 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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195 patients with long-term follow up. Ophthalmology 2000, 107(6), 1157-1163.
23. Montan PG., Scheynius A., van der Ploeg I. Similar T helper Th2-like cytokine mRNA
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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 6070% 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)
Table 2 (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
Table 3 (according to 25-32)
Table 4 (according to 25-32)
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SHORT CHARACTERISTICS OF THE OCULAR ALLERGIC DISEASES
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. Nonpharmacological 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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1.Czajkowski J., Groblewska A. Obraz i przebieg kliniczny alergicznych chorób oczu. In:
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
Workshop Report. J Allergy Clin Immunol 2001, 108, 5 suppl., 201, 2-3.
3. Bonini S. Allergic conjunctivitis: the forgotten disease. Chem Immunol Allergy 2006, 91, 10120.
4. McGill JI., Bacon AS., Anderson D. et al. Allergic eye disease mechanisms. Br J Ophthalmol
1998, 82, 1203-1214.
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, (PtB), 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), 505520.
26. Freeman AK., Serle J., VanVeldhuisen P. et al. Tacrolimus ointment in the treatment of eyelid
dermatitis. Cutis 2004, 73, 267-271.
27. Rikkes SM., Hollanoi GN., Drayton GE. et al. Topical tacrolimus treatment of atopic eyelid
disease. Am J Ophtalmol 2003, 135 (3), 297-302.
28. Katelaris CH. Giant papillary conjunctivitis – a review. Acta Ophthalmol Scand 1999, 77, 1720.
29. Lemp MA. Contact lenses and associated anterior segment disorders: dry eye, blepharitis and
allergy. Ophthalmol Clin N Am 2003, 16, 463-469.
30. Brodsky M. Allergic conjunctivitis and contact lenses - experience with olopatadine therapy.
Acta Ophthalmol Scan 2000, 78, suppl 230, 56-59.
31. Baudouin Ch. Allergic reaction to topical eyedrops. Curr Opin Allergy Clin Immunol 2005, 5,
459-463.
32. Gerkowicz M., Pożarowska D. Alergie polekowe cz. II - narząd wzroku. Okulistyka 2003, supl
2, 135-139.
33. Sutphin JE., Chodosh J., Dana MR. et al. Choroby aparatu ochronnego oka i rogówki. Wyd.
polskie pod red. J. Szaflika, Wyd Med. Urban&Partner, Wrocław 2003-2004.
34. Kyllonen H., Kari O., Reitamo S. Tacrolimus ointment in the treatment of atopic
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 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
Decrease in conjunctival hypersensitivity
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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22. Winther L., Halling HJ., Moseholm L., Mosbech H. Allergen-specific immunotherapy in birchand grass-pollen-allergic rhinitis. Efficacy estimated by a model reducing the bias of annual
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23. Pocobelli D., Del Bono A., Venuti L. et al. Nasal immunotherapy at constant dosage: a doubleblinded, placebo-controlled study in Grass-allergic conjunctivitis. J Investig Allergol Clin Immunol
2001, 11, 79-88.
24. Sabbah A., Hausson S., Le Sellin J. A double-blind, placebo-controlled trial by the sublingual
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
pteronyssinus local conjunctival immunotherapy on conjunctival provocation test in patients with
allergic conjunctivitis. Allergol Immunopathol 2000 28, 301-306.
26. Bogacka E. Leczenie alergicznych chorób oczu. Alergia, Astma. Immunol 2004, 9, supl. 2, 5357.
27. Bielory L. Allergic diseases of the eye. Med Clin N Am 2006, 90, 129-148.
28. Leonardi A. Emerging drugs for ocular allergy. Expert Opin Emerg Drugs 2005, 10, 3, 505520.
29. 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.
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
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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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34. Goś R., Hadław-Durska K., Goś A. Farmakoterapia alergicznych chorób oczu. Okulistyka
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35. Spangler DL., Abelson MB., Ober A. Randomized, double-masked comparison of olopatadine
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conjunctival allergen challenge study of scanning and imaging technology for objective
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artificial tears. Clin Ther 2003, 25, 2070-2084.
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44. Eiseman AS. The ocular manifestations of atopic dermatitis and rosacea. Curr Allergy Asthma
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SPECIAL CIRCUMSTANCES IN THE OCULAR ALLERGIC DISEASE 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 StevensJohnson disease. This syndrome was described after many drug intake like: antibiotics,
sulfonamides, barbiturates, anticonvulsive drugs, analgetics, quinine, nonsteroidal antiinflammatory 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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17. Costagliola C., Prute AD., Incorvaia C. et al. Ocular surface changes induced by topical
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19. Gierek-Ciaciura S. Alergie na soczewki kontaktowe i płyny pielęgnacyjne a decyzja o
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21. Asano-Kato N., Toda K., Hori-Komai Y., Tsubota K. Allergic conjunctivitis as a risk factor for
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24. Rezende R., Hammersmith K., Bisol T. et al. Comparative study of ocular Herpes Simplex
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25. Yoneda K., Okamoto H., Wada Y. et al. Atopic retinal detachment. Report of four cases and a
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32. Azuma N., Hida T., Katsura H. et al. Retrospective survey of surgical outcomes on
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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.