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Acta Ophthalmologica 2012, Vol.

38(1-2)
ISSN 1452-3868
Pregledni rad
UDK.617.711-002

ALLERGIC KERATOCONJUNCTIVITIS – CLINICAL,


DIAGNOSTIC AND THERAPEUTIC ENTITIES

Mirjana Janićijević-Petrović

Clinic of Ophthalmology, Clinical Centre Kragujevac,


Faculty of Medical Sciences, University of Kragujevac, Serbia

Eye allergy is a hypersensitivity reaction of the eye to specific allergens


and the atopy is determined by genetic predisposition to allergic reaction of the
eye to a number of allergens. Seasonal allergic conjunctivitis (SAC) and
perennial allergic conjunctivitis (PAC) are the most common forms of ocular
allergies (20% of the population). Vernal keratoconjunctivitis is a disease which
tends to appear in warm weather months and also in warm climates. Atopic
keratoconjunctivitis (AKC) is a bilateral chronic inflammatory disease of ocular
surface and eyelid. Contact allergy (contact dermatitis) is not an IgE mediated
allergy and can be considered in a different category than aforementioned
allergic conditions. The mainstay of management of ocular allergy involves the
use of anti-allergic therapeutic agents such as antihistamine, mast cell
stabilizers and multiple action anti-allergic agents. Acta Ophthalmologica
2012;38(1-2):36-41.

Key words: conjunctiva, inflammation, treatment

Introduction a consequent decline of the quality of life.


The endocrine, genetic, neurogenic, enviro-
Eye allergy is hypersensitivity reaction of nmental and socioeconomic risk factors
the eyes to contact with allergens and the have been identified (2). Immunological and
atopy is determined by genetic predisposition clinical profile of patients affected by VKC
to allergic reaction of the eye to a number of was defined by family medical history of
allergens. The clinical presentation of various autoimmune disorders and autoimmunity
forms of ocular allergy can be classified as: pattern (Systemic lupus erythematosus,
seasonal allergic conjunctivitis, vernal Hashimoto's thyroiditis, psoriasis, rheumatoid
keratoconjunctivitis, atopic keratocongiuntivitis arthritis, etc). Positive analyses of
and giant papillary conjunctivitis (1). Vernal antinuclear antibodies and family history of
keratoconju-nctivitis (VKC) is self limiting, autoimmune disorders of patients with those
chronic inflamma-tory disease and it mainly diseases may help clinicians to understand
affects boys aged 4 -14 years. The patients association between ocular inflammatory
present the phases characterized by disease, systemic autoimmune disorders and
exacerbation of inflammatory symptoms with atopic condition (3, 4). It represents a bilateral,

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Acta Ophthalmologica 2012, 38(1-2)

recurrent, allergic disease of conjunctiva 1.2 to 10.6 cases per 10,000 population,
characterized by limbal gelatinous hypertrophy although the prevalence of associated
and known giant conjunctiva papillae (4). corneal complications is 0.3 - 2.3 per 10,000
population. VKC has three clinical forms:
Seasonal allergic conjunctivitis palpebral, limbal and mixed (with preponde-
rance in males) (9). It is a chronic allergic
Seasonal allergic conjunctivitis (SAC) inflammation of the ocular surface mediated
and perennial allergic conjunctivitis (PAC) mainly by Th2 lymphocyte; in a complex
are the most common forms of ocular pathogenesis have a role of the over-
allergies (20% of the population). Contact expression of mast cells, eosinophils, neutro-
lenses or ocular prosthesis associated with phils, Th2 derived cytokines, chemokines,
giant papillary conjunctivitis (GPC) are adhesion molecules, growth factors, fibroblast
included in the group of ocular allergy. They and lymphocytes. IL-4 and IL-13 are
should not be considered as real allergic involved in the formation of giant papillae by
diseases, but as chronic ocular micro- inducing the production of extra-cellular
trauma related disorders, which need to be matrix and the proliferation of conjunctival
managed by ophthalmologists (5, 6). Allergic fibroblasts (9, 10). Symptoms include ocular
conjunctivitis is caused by an allergen itching, redness, swelling and discharge.
induced inflammatory response in which Itching may be quite severe, and even
allergens interact with IgE bound to incapacitating. The most characteristic sign
sensitized mast cells resulting in clinical is giant papillae on the upper tarsal
ocular allergic expression. The pathogenesis conjunctiva. These ‘‘cobblestone-like‘‘ swellings
of allergic conjunctivitis is predominantly an can measure several millimeters in diameter,
IgE mediated hypersensitivity reaction. and 10–20 of them are found on tarsal
Activation of mast cells induces enhanced conjunctiva and they can be seen easily by
tear levels of histamine, tryptase, prostagla- ‘‘flipping‘‘ the upper eyelid. The giant
ndins, leukotriens and others (early response papillae are filled with inflammatory cells,
lasts clinically 20–30 min). Mast cell edema and mucous. Neutrophils, plasma
degranulation induces activation of vascular cells, mononuclear cells and eosinophils are
endothelial cells, which in turn expresses found in abundance. Mast cells may also be
chemokines and adhesion molecules such found in the conjunctiva epithelium. The
as intercellular adhesion molecule and tears of VKC patients contain high levels of
vascular cell adhesion molecule. Secreted IgE and mast cell mediators (10). A punctate
chemokines include regulations upon activation keratitis, known as keratitis epithelialis vernalis
of normal T-cell expressed chemokines, of El Tobgy, may begin in the central
monocyte chemoattractant protein, interleukin- cornea. Vernal plaques may interfere with
8, eotaxin, macrophage inflammatory vision and lead to central scarring of the
protein-1-alpha, etc (7, 8). Signs and cornea. Plaques can be removed by
symptoms usually occur in the spring and superficial keratectomy, but they rarely resolve
summer (airborne pollens), and generally without surgical therapy. Histologically, plaques
abate during the winter months, but can are consisted of mucin and epithelial cells,
occur throughout the year with exposure to which are literally ground into the central
perennial allergens. Diagnostic features of cornea. Tranta’s dots consist of clumps of
SAC and PAC consist of itching, redness, necrotic eosinophils, neutrophils and
swelling of the conjunctiva (chemoses). epithelial cells. The dots represent almost
Conjunctival injection tends to be mild to pure collections of eosinophils. Trantas dots
moderate. Corneal involvement is very rare. tend to appear when VKC is active, and
Itching is a fairly consistent symptom of SAC disappear when symptoms abate (10). Shield
and PAC (7, 8). ulcers can occur in the superior sectors of
Vernal keratoconjunctivitis the cornea; these are noninfectious, oval-
shaped circumscribed epithelial ulcers with
Vernal keratoconjunctivitis is a disease underlying stromal opacification. Corneal
which tends to appear in warm weather epithelial punctate keratitis may evolve to
months and also in warm climates. The macroerosion, ulcers and plaques, which
prevalence of VKC in Europe ranges from are all expressions of epithelial toxicity

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Acta Ophthalmologica 2011, 37(1-2)

extricated by epitheliotoxic factors released phase, the interaction between the antigen -
by activated eosinophils (11). MHC-II complex and memory T-cells
stimulates the proliferation of T-cells. The
Atopic keratoconjunctivitis memory T-lymphocytes during proliferation
release cytokines. Th2 derived cytokine,
Atopic keratoconjunctivitis (AKC) is a such as IL-4 and IL-5, participates in the
bilateral chronic inflammatory disease of ocular activation and chemotaxis of eosinophils.
surface and eyelid. Its pathomechanism Two novel Th cell subsets, IL-17-producing
involves both a chronic degranulation of Th cells (Th17 cells) and regulatory T cells
mast cell mediated by IgE and immune (Treg cells) are also found to be contributors
mechanisms mediated by Th1 and Th2 in the pathogenesis of conjunctivitis (14).
lymphocyte derived cytokines. It is consi- Contact allergy involves the ocular surface,
dered to be the ocular counterpart of atopic eyelids and periocular skin. Examples of
dermatitis or atopic eczema, etc (12). Over allergens include poison ivy, poison oak,
time, AKC can lead to loss of vision due to neomycin, nickel, latex, atropine, etc. The
corneal complications. The classification, delay in development of the reaction is due
histology, ocular examination findings and to the slow migration of lymphocytes to the
complications of AKC are described herein, antigen depot. Contact allergic reactions are
as well as the roles and interactions of generally associated with itching. Treatment
inflammatory cells involved (13). Eczematous consists of withdrawing and avoiding contact
lesions are itchy, and scratching them with allergen. Severe reactions can be treated
makes them itchier. The eyelid skin may be with topical or systemic corticosteroids (14).
chemotic with fine sandpaper like texture. Giant papillary conjunctivitis (GPC) is an
AKC patients may develop atopic cataracts. inflammatory disease characterized by
Typically, these are anterior, shield like papillary hypertrophy of the superior tarsal
cataracts, but nuclear, cortical and posterior conjunctiva, but there is no significant
subcapsular cataracts may develop. corneal involvement. GPC is not an allergic
VKC resolves by age of 20 years, whereas disease; the incidence of systemic allergy in
AKC can persist throughout life. Many patients is similar to that of general
patients with AKC (45%) have skin test or population, and the stimuli for papillary
allergic sorbent test negative to common conjunctiva changes are inert substances
allergens (13). rather than allergens. GPC may be caused
by limbal sutures, contact lenses, ocular
Contact allergy and giant papillary prostheses, limbal dermoids, etc (14). The
conjunctivitis conjunctival tissues may contain mast cells,
basophils, or eosinophils, but not to extent of
Contact allergy (contact dermatitis) is not an allergic reaction. There is no increase of
an IgE mediated allergy and can be IgE or histaimine in the tears of patients. It
considered in a different category than the appears that protein build-up on the surface
aforementioned allergic conditions. It is a of contact lenses, and irregular edges were
type-IV delayed hypersensitivity response the main reason for close association
that occurs through interaction of antigens between contact lenses and GPC, by
with Th1 and Th2 cell subsets followed by immune or mechanical mechanisms: in
release of cytokines. It consists of two particular protein deposits on the surface of
phases: sensitization (at the first exposition contact lens could become antigenic and
to allergen, with production of memory T- stimulate the production of IgE; mechanical
lymphocytes) and elicitation of the inflammatory trauma and chronic irritation can determine
response (at the re-exposure to antigen, release of some mediators (CXCL8 and
mediated by the activation of memory TNF-α) from injured conjunctival epithelial
allergen-specific T- lymphocytes). In the cells (14).
sensitization phase, antigen presenting cells
processed antigen - MHC class II complex About diagnoses
interacts with T-lymphocytes, resulting in the
differentiation of CD4+ T-lymphocyte into The diagnosis of ocular allergy is
memory T-lymphocyte. In the elicitation primarily clinical, but there are laboratory

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Acta Ophthalmologica 2012, 38(1-2)

tests that can be useful in supporting the membrane fluidity prior to mast cell
diagnosis. Allergists can perform skin testing degranulation. Final result is a decrease in
for specific allergens by scratch tests or degranulation of mast cells, which prevents
intradermal injections of allergen. In-vitro release of histamine and other chemotactic
tests for IgE antibodies to specific allergens factors that are present in the preformed and
are widely used. Allergic tests would help in newly formed state. Mast cell stabilizers do
differentiating intrinsic and extrinsic forms not relieve existing symptoms and they can
and would, therefore be helpful in the be used on a prophylactic basis to prevent
treatments. mast cell degranulation with subsequent
In the single dose allergen provocation exposure to allergen. Mast-cell stabilizing
examination, the patients responded with a medications can also be applied topically to
typical IgE mediated allergic reaction. Signs the eye, and may be suitable for more
and symptoms from both eyes were graded severe forms of conjunctivitis. They require
at baseline and at 10 min, 8 and 48 h after a loading period during which they must be
conjunctiva provocation. Tear fluid was applied before the antigen exposure.
collected from both eyes for cytokine Therefore, poor compliance should be taken
analyses at baseline and at 8 and 48 h. A into account as a possible drawback (18). In
significant change in clinical symptoms and recent years several multimodal anti-allergic
signs (redness, chemosis) was evident 10 agents have been introduced, such as
min after provocation compared with olopatadine, ketotifen, azelastine and epina-
baseline and compared with the unprovoked stine that exert multiple pharmacological
eye in allergic patients. A significant increase effects such as histamine receptor antagonist
for IFN-γ and IL-6 and a near significant action, stabilize mast-cell degranulation and
increase for IL-10 were noticed in tear fluid suppress activation and infiltration of
of challenged eye at 48 h after provocation eosinophils (19).
vs. baseline and vs. the control eye for IFN- Non-steroidal anti-inflammatory drugs
γ, IL-6 and IL-10 in allergic patients (15,16). (NSAIDs) can be used as additive drugs, in
order to reduce the conjunctiva hyperemia
About therapy and the pruritus, related in particular to
prostaglandin D2 and prostaglandin E2 (20).
The mainstay of management of ocular Corticosteroids used in the more severe
allergy involves the use of anti-allergic variants of ocular allergy are also effective in
therapeutic agents such as antihistamine, the treatment of acute and chronic clinic
mast cell stabilizers and multiple action anti- forms. Corticosteroids possess immuno-
allergic agents. Topical antihistamines suppressive and anti-proliferative properties
competitively and reversibly block histamine since they can hinder transcription factor
receptors and relieve itching and redness that regulates the transcription of Th2-
but only for a short time. A limited duration derived cytokine genes and differentiation of
of action requires frequent dosing of up to 4 activated T-lymphocytes into Th2-lymphocytes.
times per day, and topical antihistamines But, these agents are appropriate for short
may be irritating to the eye, especially with courses (2 weeks); if needed for longer
prolonged use. Combination treatments durations, an eye examination should be
using decongestants with antihistamines carried out, including baseline assessment
have been shown to be more effective, and of cataracts and intraocular pressure
are administered to the eye as drops up to 4 measurement (21).
times daily. Decongestants act primarily as The efficacy of immunotherapy against
vasoconstrictors and are effective in reducing ocular symptoms precipitated by conjunctiva
erythema, however, adverse effects include antigen challenges was originally demonstrated
burning and stinging on instillation, mydriasis, at the beginning of the 20th century and this
and rebound hyperemia or conjunctivitis well-established method may be considered
medicamentosa with chronic use (17). for the long-term control of ocular allergy
Mast cell stabilizers have a mechanism (22). Traditionally, immunotherapy is delivered
of action that is unclear. They may increase via subcutaneous injections. Sublingual
calcium influx into the cell preventing (oral) immunotherapy (SLIT) is gaining
membrane changes and/or they may reduce momentum among allergists. SLIT requires

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Acta Ophthalmologica 2011, 37(1-2)

further evaluation for ocular allergy relief. It are needed. First-line therapy of vernal
has been shown to control ocular signs and conjunctivitis involves mast cell stabilizers
symptoms, although ocular symptoms may and, if necessary, corticosteroid eye drops.
respond less well than nasal symptoms. Treatment of non-allergic eosinophilic
Oral antihistamines are commonly used conjunctivitis involves mast cell stabilizers,
for the therapy of nasal and ocular allergy corticosteroid and cyclosporine eye drops
symptoms. Second-generation antihistamines (21). Other modes of treatment include
can, however, induce ocular drying, which acetylcysteine (mucus, plaque), surface
may impair the protective barrier provided by excimer laser - keratectomy, tarsal steroid
the ocular tear film and thus actually worsen injections (dexa, triamcinolon), cryotherapy,
allergic symptoms. Intranasal corticosteroids excision of giant papillae, amniotic
are highly effective for treating nasal membrane transplantation, etc. Treatment is
symptoms of allergic rhinitis, but there is no symptomatic and causal, with the use of
consistent evidence that they may also be artificial tears, cold compresses, dark
effective for the treatment of ocular glasses, treatment of associated blepharitis,
symptoms (22). etc (22).
Current evidence supports the use of Understanding the immune-
cyclosporin A, topically or systemically, as pathogenesis of atopic disease has already
well tolerated and effective steroid sparing influenced therapy and is essential to the
agent. development of future immune-modulating
Seasonal atopic conjunctivitis is treated treatments. The current challenge is to find
with antihistamines, cromoglycate and short more specific topical and systemic immune-
courses of corticosteroids, in severe cases modulating therapies with a better side
with subcutaneous or sublingual immunothe- effect profile. Ocular allergy represents one
rapy. Chronic conjunctivitis requires year- of the most common ocular conditions
round treatment with mast cell stabilizers, encountered in clinical work, diagnoses and
antihistamines or topical corticosteroids. For therapy, and represents the common
atopic keratoconjunctivitis corticosteroid conditions encountered by ophthalmologists,
and, if necessary, cyclosporine eye drops allergists and other causal specialists.

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ALERGIJSKI KERATOKONJUNKTIVITIS- KLINIČKI,


DIJAGNOSTIČKI I TERAPIJSKI ENTITETI

Mirjana A Janićijević-Petrović

Oftalmološka klinika KC Kragujevac


Medicinski fakultet, Univerziteta u Kragujevcu, Srbija

Alergija oka je reakcija hipersenzitiviteta na alergen i može biti


determinisana predispozicijom na alergijsku reakciju oka na mnogobrojne
antigene. U radu se govori o najčešćim alergijskim reakcijama konjunktive i
njihovim kliničkim manifestacaijama. Sezonski alegijski konjunktivitis je
najčešća forma okularne alergije. Vernalni keratokonjunktivitis je bolest koja
se najčešće javlja u toplim mesecima i toplim klimatskim uslovima. Atopijski
keratokonjunktivitis se opisuje kao hronična alergijska bolest površine oka i
kapaka, a kontaktna alergija može nastati u različitim kategorijama aregijskih
stanja oka. U terapiji ovih alergijskih stanja koriste se antialergijski terapeutski
agensi, kao što su antihistaminici, stabilizatori mastocita , kortikosteroidi i dr.
Acta Ophthalmologica 2012;38(1-2):36-41.

Key words: conjunctiva, inflammation, treatment

Kontakt: Mirjana A Janićijević-Petrović


Medicinski fakultet,
Univerziteta u Kragujevcu, Srbija

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