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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
Eye allergy is hypersensitivity reaction of
the eyes to contact with allergens and the
atopy is determined by genetic predisposition
to allergic reaction of the eye to a number of
allergens. The clinical presentation of various
forms of ocular allergy can be classified as:
seasonal allergic conjunctivitis, vernal
keratoconjunctivitis, atopic keratocongiuntivitis
and giant papillary conjunctivitis (1). Vernal
keratoconju-nctivitis (VKC) is self limiting,
chronic inflamma-tory disease and it mainly
affects boys aged 4 -14 years. The patients
present the phases characterized by
exacerbation of inflammatory symptoms with
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a consequent decline of the quality of life.
The endocrine, genetic, neurogenic, environmental and socioeconomic risk factors
have been identified (2). Immunological and
clinical profile of patients affected by VKC
was defined by family medical history of
autoimmune disorders and autoimmunity
pattern (Systemic lupus erythematosus,
Hashimoto's thyroiditis, psoriasis, rheumatoid
arthritis,
etc).
Positive
analyses
of
antinuclear antibodies and family history of
autoimmune disorders of patients with those
diseases may help clinicians to understand
association between ocular inflammatory
disease, systemic autoimmune disorders and
atopic condition (3, 4). It represents a bilateral,
Acta Ophthalmologica 2012, 38(1-2)
recurrent, allergic disease of conjunctiva
characterized by limbal gelatinous hypertrophy
and known giant conjunctiva papillae (4).
Seasonal allergic conjunctivitis
Seasonal allergic conjunctivitis (SAC)
and perennial allergic conjunctivitis (PAC)
are the most common forms of ocular
allergies (20% of the population). Contact
lenses or ocular prosthesis associated with
giant papillary conjunctivitis (GPC) are
included in the group of ocular allergy. They
should not be considered as real allergic
diseases, but as chronic ocular microtrauma related disorders, which need to be
managed by ophthalmologists (5, 6). Allergic
conjunctivitis is caused by an allergen
induced inflammatory response in which
allergens interact with IgE bound to
sensitized mast cells resulting in clinical
ocular allergic expression. The pathogenesis
of allergic conjunctivitis is predominantly an
IgE mediated hypersensitivity reaction.
Activation of mast cells induces enhanced
tear levels of histamine, tryptase, prostaglandins, leukotriens and others (early response
lasts clinically 20–30 min). Mast cell
degranulation induces activation of vascular
endothelial cells, which in turn expresses
chemokines and adhesion molecules such
as intercellular adhesion molecule and
vascular cell adhesion molecule. Secreted
chemokines include regulations upon activation
of normal T-cell expressed chemokines,
monocyte chemoattractant protein, interleukin8, eotaxin, macrophage inflammatory
protein-1-alpha, etc (7, 8). Signs and
symptoms usually occur in the spring and
summer (airborne pollens), and generally
abate during the winter months, but can
occur throughout the year with exposure to
perennial allergens. Diagnostic features of
SAC and PAC consist of itching, redness,
swelling of the conjunctiva (chemoses).
Conjunctival injection tends to be mild to
moderate. Corneal involvement is very rare.
Itching is a fairly consistent symptom of SAC
and PAC (7, 8).
Vernal keratoconjunctivitis
Vernal keratoconjunctivitis is a disease
which tends to appear in warm weather
months and also in warm climates. The
prevalence of VKC in Europe ranges from
1.2 to 10.6 cases per 10,000 population,
although the prevalence of associated
corneal complications is 0.3 - 2.3 per 10,000
population. VKC has three clinical forms:
palpebral, limbal and mixed (with preponderance in males) (9). It is a chronic allergic
inflammation of the ocular surface mediated
mainly by Th2 lymphocyte; in a complex
pathogenesis have a role of the overexpression of mast cells, eosinophils, neutrophils, Th2 derived cytokines, chemokines,
adhesion molecules, growth factors, fibroblast
and lymphocytes. IL-4 and IL-13 are
involved in the formation of giant papillae by
inducing the production of extra-cellular
matrix and the proliferation of conjunctival
fibroblasts (9, 10). Symptoms include ocular
itching, redness, swelling and discharge.
Itching may be quite severe, and even
incapacitating. The most characteristic sign
is giant papillae on the upper tarsal
conjunctiva. These ‘‘cobblestone-like‘‘ swellings
can measure several millimeters in diameter,
and 10–20 of them are found on tarsal
conjunctiva and they can be seen easily by
‘‘flipping‘‘ the upper eyelid. The giant
papillae are filled with inflammatory cells,
edema and mucous. Neutrophils, plasma
cells, mononuclear cells and eosinophils are
found in abundance. Mast cells may also be
found in the conjunctiva epithelium. The
tears of VKC patients contain high levels of
IgE and mast cell mediators (10). A punctate
keratitis, known as keratitis epithelialis vernalis
of El Tobgy, may begin in the central
cornea. Vernal plaques may interfere with
vision and lead to central scarring of the
cornea. Plaques can be removed by
superficial keratectomy, but they rarely resolve
without surgical therapy. Histologically, plaques
are consisted of mucin and epithelial cells,
which are literally ground into the central
cornea. Tranta’s dots consist of clumps of
necrotic
eosinophils, neutrophils
and
epithelial cells. The dots represent almost
pure collections of eosinophils. Trantas dots
tend to appear when VKC is active, and
disappear when symptoms abate (10). Shield
ulcers can occur in the superior sectors of
the cornea; these are noninfectious, ovalshaped circumscribed epithelial ulcers with
underlying stromal opacification. Corneal
epithelial punctate keratitis may evolve to
macroerosion, ulcers and plaques, which
are all expressions of epithelial toxicity
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Acta Ophthalmologica 2011, 37(1-2)
extricated by epitheliotoxic factors released
by activated eosinophils (11).
Atopic keratoconjunctivitis
Atopic keratoconjunctivitis (AKC) is a
bilateral chronic inflammatory disease of ocular
surface and eyelid. Its pathomechanism
involves both a chronic degranulation of
mast cell mediated by IgE and immune
mechanisms mediated by Th1 and Th2
lymphocyte derived cytokines. It is considered to be the ocular counterpart of atopic
dermatitis or atopic eczema, etc (12). Over
time, AKC can lead to loss of vision due to
corneal complications. The classification,
histology, ocular examination findings and
complications of AKC are described herein,
as well as the roles and interactions of
inflammatory cells involved (13). Eczematous
lesions are itchy, and scratching them
makes them itchier. The eyelid skin may be
chemotic with fine sandpaper like texture.
AKC patients may develop atopic cataracts.
Typically, these are anterior, shield like
cataracts, but nuclear, cortical and posterior
subcapsular cataracts may develop.
VKC resolves by age of 20 years, whereas
AKC can persist throughout life. Many
patients with AKC (45%) have skin test or
allergic sorbent test negative to common
allergens (13).
Contact allergy and giant papillary
conjunctivitis
Contact allergy (contact dermatitis) is not
an IgE mediated allergy and can be
considered in a different category than the
aforementioned allergic conditions. It is a
type-IV delayed hypersensitivity response
that occurs through interaction of antigens
with Th1 and Th2 cell subsets followed by
release of cytokines. It consists of two
phases: sensitization (at the first exposition
to allergen, with production of memory Tlymphocytes) and elicitation of the inflammatory
response (at the re-exposure to antigen,
mediated by the activation of memory
allergen-specific T- lymphocytes). In the
sensitization phase, antigen presenting cells
processed antigen - MHC class II complex
interacts with T-lymphocytes, resulting in the
differentiation of CD4+ T-lymphocyte into
memory T-lymphocyte. In the elicitation
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phase, the interaction between the antigen MHC-II complex and memory T-cells
stimulates the proliferation of T-cells. The
memory T-lymphocytes during proliferation
release cytokines. Th2 derived cytokine,
such as IL-4 and IL-5, participates in the
activation and chemotaxis of eosinophils.
Two novel Th cell subsets, IL-17-producing
Th cells (Th17 cells) and regulatory T cells
(Treg cells) are also found to be contributors
in the pathogenesis of conjunctivitis (14).
Contact allergy involves the ocular surface,
eyelids and periocular skin. Examples of
allergens include poison ivy, poison oak,
neomycin, nickel, latex, atropine, etc. The
delay in development of the reaction is due
to the slow migration of lymphocytes to the
antigen depot. Contact allergic reactions are
generally associated with itching. Treatment
consists of withdrawing and avoiding contact
with allergen. Severe reactions can be treated
with topical or systemic corticosteroids (14).
Giant papillary conjunctivitis (GPC) is an
inflammatory disease characterized by
papillary hypertrophy of the superior tarsal
conjunctiva, but there is no significant
corneal involvement. GPC is not an allergic
disease; the incidence of systemic allergy in
patients is similar to that of general
population, and the stimuli for papillary
conjunctiva changes are inert substances
rather than allergens. GPC may be caused
by limbal sutures, contact lenses, ocular
prostheses, limbal dermoids, etc (14). The
conjunctival tissues may contain mast cells,
basophils, or eosinophils, but not to extent of
an allergic reaction. There is no increase of
IgE or histaimine in the tears of patients. It
appears that protein build-up on the surface
of contact lenses, and irregular edges were
the main reason for close association
between contact lenses and GPC, by
immune or mechanical mechanisms: in
particular protein deposits on the surface of
contact lens could become antigenic and
stimulate the production of IgE; mechanical
trauma and chronic irritation can determine
release of some mediators (CXCL8 and
TNF-α) from injured conjunctival epithelial
cells (14).
About diagnoses
The diagnosis of ocular allergy is
primarily clinical, but there are laboratory
Acta Ophthalmologica 2012, 38(1-2)
tests that can be useful in supporting the
diagnosis. Allergists can perform skin testing
for specific allergens by scratch tests or
intradermal injections of allergen. In-vitro
tests for IgE antibodies to specific allergens
are widely used. Allergic tests would help in
differentiating intrinsic and extrinsic forms
and would, therefore be helpful in the
treatments.
In the single dose allergen provocation
examination, the patients responded with a
typical IgE mediated allergic reaction. Signs
and symptoms from both eyes were graded
at baseline and at 10 min, 8 and 48 h after
conjunctiva provocation. Tear fluid was
collected from both eyes for cytokine
analyses at baseline and at 8 and 48 h. A
significant change in clinical symptoms and
signs (redness, chemosis) was evident 10
min after provocation compared with
baseline and compared with the unprovoked
eye in allergic patients. A significant increase
for IFN-γ and IL-6 and a near significant
increase for IL-10 were noticed in tear fluid
of challenged eye at 48 h after provocation
vs. baseline and vs. the control eye for IFNγ, IL-6 and IL-10 in allergic patients (15,16).
About therapy
The mainstay of management of ocular
allergy involves the use of anti-allergic
therapeutic agents such as antihistamine,
mast cell stabilizers and multiple action antiallergic agents. Topical antihistamines
competitively and reversibly block histamine
receptors and relieve itching and redness
but only for a short time. A limited duration
of action requires frequent dosing of up to 4
times per day, and topical antihistamines
may be irritating to the eye, especially with
prolonged use. Combination treatments
using decongestants with antihistamines
have been shown to be more effective, and
are administered to the eye as drops up to 4
times daily. Decongestants act primarily as
vasoconstrictors and are effective in reducing
erythema, however, adverse effects include
burning and stinging on instillation, mydriasis,
and rebound hyperemia or conjunctivitis
medicamentosa with chronic use (17).
Mast cell stabilizers have a mechanism
of action that is unclear. They may increase
calcium influx into the cell preventing
membrane changes and/or they may reduce
membrane fluidity prior to mast cell
degranulation. Final result is a decrease in
degranulation of mast cells, which prevents
release of histamine and other chemotactic
factors that are present in the preformed and
newly formed state. Mast cell stabilizers do
not relieve existing symptoms and they can
be used on a prophylactic basis to prevent
mast cell degranulation with subsequent
exposure to allergen. Mast-cell stabilizing
medications can also be applied topically to
the eye, and may be suitable for more
severe forms of conjunctivitis. They require
a loading period during which they must be
applied before the antigen exposure.
Therefore, poor compliance should be taken
into account as a possible drawback (18). In
recent years several multimodal anti-allergic
agents have been introduced, such as
olopatadine, ketotifen, azelastine and epinastine that exert multiple pharmacological
effects such as histamine receptor antagonist
action, stabilize mast-cell degranulation and
suppress activation and infiltration of
eosinophils (19).
Non-steroidal anti-inflammatory drugs
(NSAIDs) can be used as additive drugs, in
order to reduce the conjunctiva hyperemia
and the pruritus, related in particular to
prostaglandin D2 and prostaglandin E2 (20).
Corticosteroids used in the more severe
variants of ocular allergy are also effective in
the treatment of acute and chronic clinic
forms. Corticosteroids possess immunosuppressive and anti-proliferative properties
since they can hinder transcription factor
that regulates the transcription of Th2derived cytokine genes and differentiation of
activated T-lymphocytes into Th2-lymphocytes.
But, these agents are appropriate for short
courses (2 weeks); if needed for longer
durations, an eye examination should be
carried out, including baseline assessment
of cataracts and intraocular pressure
measurement (21).
The efficacy of immunotherapy against
ocular symptoms precipitated by conjunctiva
antigen challenges was originally demonstrated
at the beginning of the 20th century and this
well-established method may be considered
for the long-term control of ocular allergy
(22). Traditionally, immunotherapy is delivered
via subcutaneous injections. Sublingual
(oral) immunotherapy (SLIT) is gaining
momentum among allergists. SLIT requires
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Acta Ophthalmologica 2011, 37(1-2)
further evaluation for ocular allergy relief. It
has been shown to control ocular signs and
symptoms, although ocular symptoms may
respond less well than nasal symptoms.
Oral antihistamines are commonly used
for the therapy of nasal and ocular allergy
symptoms. Second-generation antihistamines
can, however, induce ocular drying, which
may impair the protective barrier provided by
the ocular tear film and thus actually worsen
allergic symptoms. Intranasal corticosteroids
are highly effective for treating nasal
symptoms of allergic rhinitis, but there is no
consistent evidence that they may also be
effective for the treatment of ocular
symptoms (22).
Current evidence supports the use of
cyclosporin A, topically or systemically, as
well tolerated and effective steroid sparing
agent.
Seasonal atopic conjunctivitis is treated
with antihistamines, cromoglycate and short
courses of corticosteroids, in severe cases
with subcutaneous or sublingual immunotherapy. Chronic conjunctivitis requires yearround treatment with mast cell stabilizers,
antihistamines or topical corticosteroids. For
atopic keratoconjunctivitis corticosteroid
and, if necessary, cyclosporine eye drops
are needed. First-line therapy of vernal
conjunctivitis involves mast cell stabilizers
and, if necessary, corticosteroid eye drops.
Treatment of non-allergic eosinophilic
conjunctivitis involves mast cell stabilizers,
corticosteroid and cyclosporine eye drops
(21). Other modes of treatment include
acetylcysteine (mucus, plaque), surface
excimer laser - keratectomy, tarsal steroid
injections (dexa, triamcinolon), cryotherapy,
excision of giant papillae, amniotic
membrane transplantation, etc. Treatment is
symptomatic and causal, with the use of
artificial tears, cold compresses, dark
glasses, treatment of associated blepharitis,
etc (22).
Understanding
the
immunepathogenesis of atopic disease has already
influenced therapy and is essential to the
development of future immune-modulating
treatments. The current challenge is to find
more specific topical and systemic immunemodulating therapies with a better side
effect profile. Ocular allergy represents one
of the most common ocular conditions
encountered in clinical work, diagnoses and
therapy, and represents the common
conditions encountered by ophthalmologists,
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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