Mechanisms and Management of
Allergic Inflammation in the Eye
Sergio Bonini1 and Andrea Leonardi2
Department of Medicine, Second University of Naples and
Neurosciences, Eye Clinic, university of Padua. Italy
1
Department of
2
Index
1.Mechanisms of ocular allergy
2. Classification of ocular allergic diseases: SAC, PAC, AKC, VKC, GPC
3. Differential diagnosis
4. Diagnostic tools
5. How to assess cytokines and growth factors in the human eye
6. Cytokine expression and production in the animal model of ocular allergy and in
ocular allergic patients: do they match?
7. Are cytokines relevant and correlated with the clinical phases of the disease?
8. Definition of remodeling in ocular allergy
9. Metalloproteases in ocular allergy
10. Dry Eye
11. Management of ocular allergy
1. Mechanisms of ocular allergy
Three major mechanisms have been reported to be involved in causing diseases
included under the umbrella term of allergic conjunctivitis (or ocular allergy of the
external eye surface):a) the typical Type I hypersensitivity reaction, where the IgEmediated release of mast cell and basophil mediators is responsible for symptoms
(redness, chemosis, excess tearing and mucus, itching and burning), as a result of
vasodilation, exudation, stimulation of glands and nerve endings; b) eosinophilic
inflammation, both dependent and independent by a late-phase IgE mediated
reaction; c) conjunctival hyperreactivity, often related to the eosinophilic
inflammation but also possibly due to an abnormal tissue response to non-specific
stimuli (cold air, pollutants, excess lighting,etc.). These hallmarks of allergic eye
disease, although often related to each other, depend on different genetic and
environmental factors and may help to identify different phenotypes of ocular allergy
with different clinical presentation, severity and treatment.
2. Classification of ocular allergic diseases: SAC, PAC, AKC, VKC, GPC
Seasonal allergic conjunctivitis (SAC) is the most common form of allergy and is
associated with sensitization and exposure to environmental allergens, particularly
pollen. The perennial form (PAC) usually involves sensitization to mites or to
multiple antigens. Both forms are characterized by an onset in childhood or early
adulthood; patients present with ocular itching, conjunctival hyperemia, and at times
lid and conjunctival edema of varying severity, mild serous or serous-mucous
secretions, and/or slight papillary or follicular hypertrophy of the conjunctiva. This
symptomatology is chronic in PAC. The only diagnostic factor is the presence of
itching: if the patient does not complain of conjunctival or peri-ocular itching, it is
almost surely not allergic conjunctivitis.
Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease that occurs
predominately in children. VKC is characterized by intense ocular symptomatology:
itching, photophobia, foreign body sensation, conjunctival hyperemia, and mucous
secretion, typically accompanied by giant papillae on the upper tarsal conjunctiva,
or, in the limbal form, by limbal infiltrates or nodules, or both signs in the mixed
form. Corneal involvement is common, characterized by punctate keratitis or sterile
corneal ulcers, the result of epitheliotoxic proteins and enzymes released by
activated eosinophils. VKC is an IgE- and Th2-mediated disease in which only 50% of
patients present a clear allergic sensitization.
Atopic keratoconjunctivitis (AKC) is typical of adult patients, although it can be
observed in children with atopic dermatitis. In addition to the cutaneous
involvement, AKC can be associated with rhinitis, seasonal rhinoconjunctivitis and
asthma. AKC can be a very severe disease due to its prolonged chronicity and
exacerbations during the winter months. Frequently the cornea is involved as diffuse
superficial epitheliopathy and/or ulcers that result in scarring, irregular astigmatism,
or corneal pannus, all of which can compromise visual function. Giant papillary
conjunctivitis (GPC) is a non-IgE-mediated inflammation induced most frequently by
the use of contact lenses. All types of contact lenses can trigger GPC, as can the use
of ocular prostheses, the presence of corneo-conjunctival sutures or protruding
scleral buckling. The upper tarsal conjunctiva is subjected to repetitive or constant
micro-trauma generated by a conjunctival 'foreign body'; this phenomenon is then
complicated by an immune reaction against a protein or residue deposited on the
lens.
Table 1. Ocular allergic diseases
Condition
Prevalence
Severity
SAC/PAC
Most frequent
ocular allergic
disease.
10-15% of
population
Mild/
moderate
VKC
Rare
Ages 3-20
Under 14 M>F
In adults M=F
Severe
AKC
Rare
2nd to 5th
decade of life
M>F
GPC
Contact
blepharitis/
dermatitis
Causes
Sign/Symptoms
Genetic predisposition
Associated with rhinitis
Seasonal allergens (pollens,
molds, chemicals)
Perennial allergens (dust,
animal dander, foods,
chemicals
Genetic predisposition?
Associated with atopic
disorders (50%)
Th2 up-regulation
Non-specific eosinophil
activation
Itching
Redness
Tearing
Watery
discharge
Chemosis
Lid swelling
Extreme
itching
Ropy mucous
discharge
Cobblestone
papillae
Trantas’ dots
Keratitis/ulcer
Conjunctival
eosinophilia
Severe/
Sight
threatening
Genetic predisposition
Associated with atopic
dermatis
Environmental allergens:
food, dust, pollens, animal
dander, chemicals
Itching
Burning
Tearing
Photophobia
Chronic
redness
Blepharitis
Periocular
eczema
Mucous
discharge
Keratitis/ulcer
Conjunctival
and corneal
scarring
cataract
Iatrogenic
2nd to 5th
decade
Mild
Trauma induced by contact
lens edge, ocular prosthesis,
exposed sutures, aggravated
by concomitant allergy
Lens
intolerance
Blurred vision
Foreign body
sensation
Abnormal
thickening of
conjunctiva
Giant papillae
Not known
Moderate
Contact delayed type
hypersensitivity
Exogenous haptens
(cosmetics, metals,
chemicals)
Topical preparation (drugs,
preservatives)
Eyelid eczema
Eyelid itching
Conjunctival
redness
Punctate keratitis
3. Differential diagnosis
At times, pseudoallergic forms, with clinical manifestations similar to allergy but with
a non-allergic equivocal pathogenesis, are difficult to distinguish from allergic forms,
with their precisely defined pathogenic mechanisms. Several clinical forms may
mimic the clinical pictures of ocular allergy (Table2), including tear film dysfunction,
subacute and chronic infections, toxic and mechanical conjunctivitis.
Table 2. Differential diagnosis of chronic allergic disease from:
Dry Eye
Blepharitis
Uncorrected visual defects
Chlamydia
‘Medicamentosa’ (drug-induced conjunctivitis)
Viral Conjunctivitis
Contact lenses intolerance
Non-specific hypereactivity
Hyperuricemia
Toxic conjunctivitis
Mechanichal conjunctivitis
4. Diagnostic tools
If ocular allergy is suspected:
 Complete an accurate clinical history and ocular examination
 Perform skin tests
 Identify specific and total serum IgE levels
 Analyze Complete blood count (CBC, hemochrome) with the eosinophil count
 If all of these systemic tests are negative, perform local tests (cytology,
conjunctival provocation, tear IgE)
However consider that:
 Cytological tests are useful in the active phase of the disease.
 Conjunctival allergen provocation proves local hypersensitivity.
 Low tear volume limits its potential usefulness in analytical diagnosis.
 The measurement of tear specific IgE is not practical.
 The measurement of total tear IgE by paper strips is easy, but not highly
specific. (Research presently also involves a unit device to measure tear
osmolarity and possibly IgE).
5. How to assess cytokines and growth factors in the human eye
Tear samples and cytokine assessment: Tear collection is not painful or traumatic,
with only its insurmountable limitation regarding the quantity of sample obtainable.
The concentration and distribution of inflammatory mediators or inhibitors in tear
fluid have been extensively used in ocular allergy to find either a ‘disease marker’, to
better understand the immune mechanisms involved in the ocular surface
inflammation, or to identify potential targets for therapeutic interventions.
Initially, cytokines were measured in tissues and fluids individually, and thus there
was great limitation in what could be learned from one sample. Advances in
techniques have now allowed for multiple cytokine assaying. Indeed, membrane
array characterization allows for the identification of up to 80 chemokines, cytokines
and growth factors in one tear sample, and consequently, a more global picture of
immunoregulation is coming into focus.
Determination of tear mediator, cytokine, chemokine levels or expression of
adhesion molecules is not yet used for diagnosis, but only for the study of allergic
physiopathology or for the evaluation of efficacy of anti-allergic agents. Tear cytokine
analysis is currently carried out using ELISA techniques. The “multiplexed bead
based flow cytometry” allows the simultaneous measurement of various mediators in
one sample of 10-20 microliters of tear fluid. More than just the assaying of a single
cytokine, it is possible to identify relationships between cytokines or groups of
cytokines with opposing or complementary functions. A significant differences in the
-5/IL-10 between allergic and non-allergic
patients has been shown, but not in the single cytokines. In a different study, the
type Th2 cytokines, Il-4, IL-5 and IL-13, were significantly increased in all forms of
allergic disease, particularly in VKC, compared to normal tears. IFNincreased in the more severe forms of VKC and AKC. IL-8 was exceptionally high in
GPC tears. Pro-inflammatory cytokines, IL-1, ILlacrimal fluid. Among the chemokines, eotaxin was elevated in VKC and was
correlated with IL-5 and IL-4 levels.
Seasonal allergic conjunctivitis, long thought to be a self-limiting disorder resulting
only from specific mast cell activation, is now known to have a significant gamut of
Th2 cytokines involved in its insurgence: levels of IL-2, IL-4, IL-5, IL-6, IL12, IL-1 all increase in comparison with non-allergic controls. The
all-inclusive nature of these results strongly indicates that cells other than mast cells
are involved not only in VKC and AKC, but also in SAC.
Dozens of cytokines, chemokines, growth factors, angiogenic modulators, enzymes
and inhibitors can be identified in small tear samples using proteomic techniques.
Membrane assay is a relatively un-expensive technique that can be applied to tear
samples.
The conjunctival epithelium is now known to have a pivotal immunomodulatory role
in ocular allergic inflammation. Different chemokines and surface receptors are
expressed on conjunctival epithelium in acute and chronic ocular disease states.
Changes that occur in the epithelium with ocular inflammation appear to be
dependent on the chronicity of the reaction/disease state. In acute allergic disease,
the conjunctival epithelium expresses ICAM-1, involved in leukocyte adhesion and
activation, and releases IL-8, resulting in a cellular infiltrate of predominantly
neutrophils and eosinophils. In chronic allergic inflammation such as VKC and AKC,
conjunctival epithelial cells express HLA-DR, involved in T-lymphocyte activation, and
a cellular infiltrate characterized by increased numbers of activated T lymphocytes is
-inflammatory Th1
known to be a potent stimulator of surface receptor ICAM-1 and HLA-DR
on conjunctival epithelial cells.
Conjunctival fibroblasts reveal a strikingly similar cytokine and chemokine profile as
that of tears, and are known to constitutively produce IL-6, IL-8, MCP-1 and
RANTES. However, other ocular surface cells including epithelial cells, intraepithelial
lymphocytes (CD8+), dendritic cells, and resident mast cells are potential sources of
these cytokines. The demonstration of eotaxin-1 production by conjunctival
fibroblasts in response to IL-4 strongly suggests that these cells produce this
chemokine, which is then detected in tears.
6. Cytokine expression and production in the animal model of ocular allergy
and in ocular allergic patients: do they match?
In the murine model of experimental allergic conjunctivitis (EC) the activation of
mast cells by IgE alone can induce conjunctival eosinophil infiltration. However, IgEinduced mast cell activation only provokes mild conjunctival eosinophil infiltration. In
contrast, the transfer of Ag-primed T cells followed by Ag challenge in the
conjunctiva induced severe conjunctival eosinophil infiltration. Since the severity of
ocular allergy is dependent on the numbers of infiltrating eosinophils, it appears that
T cells play more important roles than IgE in the severe more chronic forms of
allergic conjunctivitis.
Although CD4+ Th2 cells clearly play an essential role in the development of EC, the
functions of CD4+ Th1 and CD8+ T cells remain controversial. CD8+ T cells may play
a significant role during the induction phase by aiding IgE production and the
generation of Th2 cytokines in the conjunctiva, thus promoting the development of
EC. During the effector phase, IFN-gamma acts to promote the severity of EC
An essential role for IL-1 receptor activation was first demonstrated using a mouse
model of allergic conjunctivitis, in which treatment with an IL-1 receptor antagonist
in allergen-challenged animals significantly reduced allergen-induced responses. It is
also well known that IL-1 can stimulate pro-inflammatory conjunctival epithelial cell
responses in vitro and that these responses are amplified when TNF is present, as
in AKC and VKC.
T reg cells play a suppressive role in the development of experimental allergic
conjunctivitis in splenocyte transfer experiments suggesting that modulation of T reg
cells may be a possible therapy for ocular allergy. However, in the EC model IL10
and TGF beta did not have immunosuppressive effects in the development of
experimentally induced allergic conjunctivitis. Rather, they augment the infiltration of
eosinophils into the conjunctiva during the effector phase of experimentally induced
allergic conjunctivitis.
7. Are cytokines relevant and correlated with the clinical phases of the
disease?
Several cytokines have been found increased in the active phase of ocular allergy. A
clinical role of TNFa have been proven since many of its biological effects can be
found in ocular allergic patients. After conjunctival mast cell degranulation TNF can
be found in tears.
IL-5, IL-6 and IL-8 are highly expressed in VKC. However none of the studied
cytokine in tears is strongly correlated with a clinical picture.
A defect in microbial defense has been implicated in the pathogenesis of atopic
dermatitis and AKC, in which colonies of s. aureus are increased. In a recent study
S aureus up-regulates TLR-2 expression and augments
responses to TLR-2 agonists in conjunctival epithelial cells in vitro. S aureus
stimulation alone up-regulates ICAM-1, HLA and CD14 expression and increases
-8 release. This infectious component to the immune offensive in AKC
might be what distinguishes it from other ocular allergic diseases, explaining why
Th1 cytokines are called up together with Th2 cytokines to combat this unique
disorder.
The role of Th17-cells is still unknown.
8. Definition of remodeling in ocular allergy
Remodeling can be considered a wound healing process gone awry, thus,
mechanisms of wound healing give insight into how remodeling and fibrosis occur as
a dysregulation of post-inflammatory healing. One of the most spectacular events in
chronic ocular allergies, VKC AKC and GPC, is the overgrowth of the conjunctival
connective tissue, with the formation of large and sessile papillae from which
overflow an abundance of collagen fibers. The term 'tissue remodeling' defines a
gamut of alterations involving structural cells and tissues such as conjunctival
thickening, subepithelial fibrosis, mucus metaplasia, neovascularization and scarring.
Many elements contribute to this dramatic response, including epithelial changes,
connective tissue deposition, edema, inflammatory cell infiltration, and glandular
hypertrophy.
Remodeling involves both production and deposition of extracellular matrix
components (EMC) as well as degradation and clearance of newly synthesized
products. Immunohistochemical studies have shown the increased deposition of
collagens in giant papillae of VKC patients, possibly as a result of increased
expression of growth factors, which may stimulate resident fibroblasts to produce
extracellular matrix proteins. The predominant collagens present in giant papillae are
types I and III. Both IL-4 and IL-13 have been reported to activate conjunctival
fibroblasts to produce collagens I and III, while INFactivity on fibroblasts.
Growth factors are known to regulate the expression of integrins, collagens and ECM
components. Expression of NGF, VEGF, TGFb, FGF, PDGF and EGF is upregulated in
the conjunctiva of VKC patients.
9. Metalloproteases in ocular allergy
MMPs are a family of zinc- and calcium-dependent enzymes involved in many
physiological and pathological processes, including tumor progression and
metastasis, inflammatory diseases, and wound healing. MMPs help support the
extravasation and infiltration of leukocytes through limited proteolysis of basement
membranes and matrix material. Their increased production and activation, or
imbalance between MMPs and their natural tissue inhibitors, TIMP, are all probably
involved in the pathogenesis of conjunctival inflammation, remodeling and corneal
changes in VKC. Inflammatory cells, particularly eosinophils, and structural cells are
the probable cellular source of these enzymes.
Both proforms and active forms of MMP-1, MMP-2 and MMP-9 are present in tear
fluids of patients with VKC, while only the inactive proforms are present in normal
non-allergic tears.
Different patterns of MMP expression seem to characterize different tissues
undergoing similar processes of chronic allergic inflammation: Compared to normal
tissues, increased immunostaining of MMP-1, MMP-3, MMP-9 and MMP-13 were found
in VKC and increased MMP-1 and MMP-9 in nasal polyps. Conversely in asthmatic
tissues, a significant increased staining of MMP-13 was observed only in the
epithelium, along with a modest increase of MMP-3 and MMP-9 in the stroma. These
finding were associated with a higher presence of inflammatory cells (EG-2+ and
CD4+ cells) in the stroma of VKC patients compared with that of nasal polyps and
asthmatic patients.
Both MMP-9 and MMP-3 are effective proteoglycanases, cleaving the core protein of
proteoglycans. The cleavage of bound latent growth factors, such as FGF or TGFfrom proteoglycan storage sites would potentially contribute to fibroblast proliferation
and the development of subepithelial fibrosis.
10. Dry Eye
Dry eye is one of the leading causes of patient visits to the eye clinic and one of the
most frequent pathological conditions in ophthalmology. The prevalence of dry eye
revolves around 14 to 33% of individuals after the 6th decade of age. The incidence
rate at which the diagnosis is made is influenced by the criteria used.
The 2007 Report of the Dry Eye Workshop (Ocul Surf 2007;5[2]:65-204) proposed
the following definition:
“Dry eye is a multifactorial disease of the tears and ocular surface that results in
symptoms of discomfort, visual disturbance, and tear film instability with potential
damage to the ocular surface. It is accompanied by increased osmolarity of the tear
film and inflammation of the ocular surface”.
Dry eye is not only associated with events occurring locally in the eye. It can be also
the reflection of a systemic disease. The composition of tear fluid may be altered and
the tear volume may or may not be reduced. A variety of causes are responsible for
the clinical features and symptoms associated with the condition of dry eye. To
reflect the above diversity, the term tear dysfunction syndrome (TDS) was proposed
for these complex conditions.
Symptoms: The symptoms can range from mild irritation to severe ocular discomfort
and pain that affects the patients’ life style. Often there may be a great discrepancy
between symptoms, which may be very severe and the clinical signs, which may be
very mild.
The reported symptoms may include part or all of the following: discomfort,
irritation, foreign-body sensation, burning, stinging, grittiness, transient visual
blurring, stickiness with stringy discharge, light sensitivity, itching, redness and
heaviness of the lids. Severe pain is not a typical feature of dry eye. Symptoms of
dry eye can be aggravated by a number of environmental factors (air conditioner, air
travel), low humidity and the blowing of hot air as from heaters or in cars or beside a
live fire. Some patients complain of “stuck lids with difficulty to get their eyes open
in the morning”.
Signs: Typical signs of dry eye include a narrow or absent tear meniscus along the
lid margin at the slit lamp, superficial fine and/or coarse punctate erosions affecting
the inferior third of the cornea and bulbar conjunctiva, filamentary keratitis, mucus
plaques and conjunctival hyperemia. Evidence of anterior or posterior blepharitis in
the form of lid margin hyperemia, pouting or clogged meibomian gland orifices,
scales, crusts, telangiectasia and madarosis of lashes may be visible. Blink
abnormalities such as infrequent blinking, incomplete blinking
and flick blinking should be looked for and detected. Other abnormalities that result
in inadequate tear distribution (conjunctival chalasis, pingeucula, neoplasia) may be
observed.
Today, more patients with dry eye condition have a history of past or recent
refractive surgery. It is expected that the number of these patients will grow steadily
in the years to come.
Treatment of dry eye: The use of tear substitutes is the first option for the
management of patients with mild TDS. The choice of tear substitute is determined
by patient tolerance, drug effect and the subjective feeling of the patient. Any
underlying ocular or systemic condition including the use of any offending systemic
medication should be investigated early. In patients with moderate symptoms
(intermediate severity) tear substitutes without preservatives are to be
recommended. When patients complain of increased intensity of symptoms on
waking, the use of gels or ointments during sleep hours may help.
In patients with severe dry eye symptoms and signs, punctal occlusion is to be
considered apart from the above measures.
In the presence of associated blepharitis, regardless of severity, treatment consists
mainly of permanent lid toilet, warm compresses and oral tetracyclines are essential
measures to be implemented along with the other modalities.
Since the pathology of dry eye/TDS is also associated with inflammatory reactions,
anti-inflammatory strategies can possibly benefit treatment outcomes. To this
purpose, cyclosporin A (CsA) (0.05%) eye drops have been found beneficial and
have been approved
for the treatment of dry eye/TDS in the USA. Topical steroids may also be used in
the presence of acute inflammatory exacerbations. Their use however, remains
controversial due to their far reaching potential for inducing secondary complications.
Table 3: Treatment principles of dry eye
1.
2.
3.
4.
5.
6.
Treatment of underlying and associated conditions when possible
Elimination or control of environmental or aggravating factors
Tear substitution
Suppression of inflammation
Decreasing tears evacuation.
Surgical intervention as applicable
11. Management of ocular allergy
The most common diseases, SAC and PAC, are classic IgE-mediated disorders, in
which the therapeutic focus is mostly confined to the suppression of mast cells, their
degranulation and the effects of histamine and other mast cell derived mediators.
Conversely, severe chronic disorders such as VKC and AKC are both IgE- and T cellmediated, leading to a chronic inflammation where eosinophil, lymphocyte and
structural cell activation characterizes the conjunctival allergic reaction. In these
cases, stabilization of mast cells and histamine or other mediator receptor
antagonists are frequently insufficient for control of conjunctival inflammation.
Currently available topical drugs for allergic conjunctivitis belong to different
pharmacological classes (Table 3): vasoconstrictors, antihistamines, mast cell
stabilizers, ‘dual-acting’ agents (with antihistaminic and mast cell stabilizing
properties), non-steroidal anti-inflammatory agents. Corticosteroids are usually not
needed in SAC and PAC, and may have potential important side effects if used for
periods longer than occasional short cycles to control severe recurrences, if any. In
SAC and PAC associated with allergic rhinitis –which represent the majority of casestopical nasal steroids (and particularly new molecules with low systemic
bioavailability, such as mometasone furoate and fluticasone furoate) have been
shown to control the nasal-ocular reflex component of eye symptoms without
increasing the risk of cataracts or of an increased ocular pressure.
Avoidance of the offending allergens, when practically feasible, should always be the
primary therapeutic measure. Non-pharmacologic treatments include tear substitutes
and lid hygiene to wash out allergens and mediators from the ocular surface
combined with cold compresses for decongestion. Olopatadine, ketotifen, epinastine
and azelastine, which have antihistamine, mast cell stabilizing and additional antiinflammatory properties (called “double or multiple action”) are presently available
and show evident benefits. Mast cell stabilizers (cromoglycate derivatives) or
antihistamines may be used in mild forms of the disease.
Decongestant/vasoconstrictors have little place in the pharmacological treatment of
SAC and PAC except for the immediate removal of injection for cosmetic reasons, but
do have an adverse effect profile locally (glaucoma) and systemically (hypertension).
Corticosteroid formulations (including the so called “soft steroids”) should be
reserved for and carefully used only in the most severe cases which are refractive to
other types of medications.
The use of non steroidal anti inflammatory drugs (NSAIDS) can be considered, in
some cases, for a short period of time, but have had limited effect on ocular pruritus.
Systemic antihistamines should be used only in patients with concomitant major
non-ocular allergic manifestations.
Treatment of VKC requires a multiple approach attitude that includes conservative
measures and the use of drugs. Patients and parents should be made aware of the
long duration of disease, the chronic evolution and its possible complications. The
potential benefits of frequent hand and face washing along with avoiding eye rubbing
have to be emphasized. Exposure to non-specific triggering factors such as sun, wind
and salt water should be avoided. The use of sunglasses, hats with visors and
swimming goggles are recommended.
The use of drugs should be well planned in patients with a history of VKC. Mast cell
stabilizers including disodium cromoglycate, nedocromil, spaglumic acid, lodoxamide
and topical antihistamines can be initially used and continued at a decreased
frequency if effective. Newer topical formulations with combined mast cell stabilizing
properties and histamine receptor antagonist, as olopatadine and ketotifen, may be
more efficient. Non-steroidal anti-inflammatory drugs such as ketorolac, diclofenac
and pranoprofen may be considered for steroid-sparing. These drugs however,
should be used for a limited period of time only. Oral aspirin at doses of 0.5-1
gram/day may be beneficial.
Moderate to severe VKC may require repeated topical steroid treatment to downregulate conjunctival inflammation. “Soft corticosteroids” such as clobetasone,
desonide, fluorometholone, loteprednol and rimexolone may be considered as first
corticosteroid preparations and used carefully. Doses are chosen based on the
inflammatory state. Instillation frequency of 4 times/day for 10-15 days is
recommended. The “harder” corticosteroids formulations of Prednisolone,
Dexamethasone or Betamethasone have to be used as a second line and as a last
resort for the management of the most severe cases.
Cyclosporine A (CsA) 1% or 2% emulsion in castor or olive oil is the first choice
for treating severe VKC and can serve as a good alternative to steroids.
Systemic treatment with oral antihistamines or anti-leukotrienes can reduce the
severity of ocular flare-up of disease manifestations in patients with additional non
ocular allergies.
Severe cases not responding to topical therapy may require treatment with systemic
corticosteroids (prednisone 1mg/kg a day) for a short period of time.
Corneal complications have to be carefully monitored and anti-inflammatory therapy
adjusted accordingly. Secondary microbial infection can be prevented by prescription
of antibiotics for a period of one week.
Surgical removal of corneal plaques is recommended to alleviate severe symptoms
and to allow for corneal re-epithelization. Giant papillae excision with or without
combined cryotherapy may be indicated in cases of mechanical pseudoptosis or the
presence of coarse giant papillae and continuous active disease.
More invasive procedures such as oral mucosal grafting should be avoided. Amniotic
membrane transplantation, on the other hand, may be considered to promote
healing. If a systemic hypersensitivity to identified allergens exists, specific
immunotherapy may be considered.
The overall management of AKC involves a multidisciplinary approach. Identification
of allergens by skin or blood testing is important for preventive measures. Cold
compresses and regular lubrication may provide symptomatic relief. Tear substitutes
help remove and reduce the effects of allergens and the release of mediators
reducing the potential for corneal involvement. Lid hygiene is essential. It prevents
infectious blepharitis, improves meibomian gland function and tear-film quality.
Prolonged use of topical anti-allergic drugs and mast cell stabilizers may be required.
Topical antihistamines may be useful for the relief of itching, redness and mucous
discharge.
Topical corticosteroids are effective, but should be used only when other topical
treatments are not providing sufficient benefits. Brief periods of intensive topical
corticosteroid therapy are often necessary to control the local inflammation in severe
cases. Topical cyclosporine may improve the signs and symptoms in steroiddependent patients, thus reducing the need for corticosteroids to control the ocular
surface inflammation.
Systemic antihistamines are often used to reduce itching and control widespread
inflammation in patients with active skin involvement. Systemic corticosteroids may
be necessary in severe cases. Systemic cyclosporine may be an alternative to
systemic corticosteroids for the relief of severe AKC.
Prevention is the most important management step in GPC. In patients with contact
lenses GPC, discontinuation of lens wear may be necessary. Restarting lens wear
with a different type or design may be tried. Mild GPC symptoms may be alleviated
by mast cell stabilizers or antihistamine agents. Tear substitutes can be used to
minimize conjunctival trauma.
Table 4. Topical Ocular Allergy Medications
Class
Vasoconstrictor/
Antihistamine
Combinations
Drug
Naphazoline/
Pheniramine
Antihistamines
Levocabastine
Emedastine
Mast cell
stabilizers
Cromolyn
Nedocromil
Lodoxamide
NAAGA
Pemirolast
Antihistamine/
mast cell
stabilizers
(dual-acting)
Azelastine
Epinastine
Ketotifen
Olopatadine
Corticosteroids
Loteprednol
Fluormetholone
Desonide
Rimexolon
Indication
- Rapid onset of action
- Rapid onset of action
- Relief of itching
- Relief of signs and
symptoms of SAC
- Relief of signs and
symptoms
- Treatment of signs and
symptoms of SAC
- Rapid onset of action
- Long duration of action
- Excellent comfort
- Treatment of allergic
inflammation
- Use in severe forms of
allergies
Comments
- Short duration of action
- Tachyphylaxis
- Mydriasis
- Ocular irritation
- Hypersensitivity
- Hypertension
- Potential for
inappropriate patient use
- Short duration of action
- Long-term usage
- Slow onset of action
- Prophylactic dosing
- Bitter taste (azelastine)
- Non reported serious
side effects
- Risk for long-term side
effects
- No mast cell
stabilization
- Potential for
inappropriate patient use
- Requires close
monitoring
References and recommended reading
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Non-infectious immune mediated conjunctivitis. Manifestations confined
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