A Scientific Review and Expert Case Debate
Release Date: May 8, 2012
Expiration Date: May 3, 2013
This educational activity is intended for allergists and ophthalmologists.
Educate physicians on the various forms of ocular allergies as well as current management options and emerging treatment.
STATEMENT OF NEED:
Allergic conjunctivitis is one of the most common conditions seen by ophthalmologists, optometrists, and allergists. During the past 40 years, both the incidence and prevalence of allergic conjunctivitis have risen exponentially, and they continue to rise. Numerous treatment strategies abound without any clear consensus from various clinical studies, creating a challenge for healthcare providers.
Current ocular allergy treatment options are effective only at mediating the symptoms, and these options have many different methods of action and modes of delivery. Allergists, ophthalmologists, and optometrists must become better versed in the classification, severity indices, and various options available for treatment of ocular allergy and they must also become cognizant of the differences between the various subtypes of dry eye disease and ocular allergy. In addition, they must be able to recognize the severity of dry eye disease and ocular allergy.
After completing this
enduring activity, participants should be better
- Differentiate between the various types of ocular allergies based on clinical presentation
- Individualize management options for ocular allergy based on disease severity, patient factors, and associated risks and benefits
- Describe the newer studies on the diagnosis and treatment of ocular allergy that are rapidly changing potential treatment algorithms
Ophthalmologists know and apply current treatment strategies through an individualized stepwise approach to optimize treatment outcomes in patients with ocular allergy.
Jointly sponsored by Dannemiller, Pennsylvania College of Optometry at Salus University, and Spire Learning.
Supported by an educational grant from Allergan, Inc.
Michael B. Raizman, MD (Chair)
Associate Professor of Ophthalmology
Tufts University School of Medicine
Jodi I. Luchs, MD, FACS
Co-Director, Department of Refractive Surgery
North Shore/Long Island Jewish Health System
Joseph P. Shovlin, OD, FAAO, DPNAP
Northeastern Eye Institute
Raoul L. Wolf, MD
Professor and Chief
Section of Allergy, Asthma and Immunology
Department of Pediatrics, University of Chicago
Physician Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Dannemiller and Spire Learning. Dannemiller is accredited by the ACCME to provide continuing medical education (CME) for physicians.
Dannemiller designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In accordance with the ACCME, Dannemiller and Spire Learning require that any person who is in a position to control the content of a CME activity must disclose all relevant financial relationships they have with a commercial interest.
Educational Planning Committee
Consultant/advisor: Allergan, Inc.; Alcon; Bausch + Lomb, Inc.
Speaker programs: Allergan, Inc., Alcon, ISTA Pharmaceuticals, Inc.
Allergan, Inc., ISTA Pharmaceuticals, Inc., Eyegate Pharmaceuticals, Inc., Optimetrics, Inc.
Investigator: Allergan, Inc., Alcon, ISTA Pharmaceuticals, Inc., Eyegate Pharmaceuticals, Inc.
Stockholder: Optimetrics, Inc.
Research funder: Bausch + Lomb, Inc.
Speaker program: Abbott Medical Optics Inc.
Consultant/advisory board: Abbott Medical Optics Inc.
Nothing to disclose with regard to commercial support
Michelle Dalton, Medical Writer
Nothing to disclose with regard to commercial support
Speaker programs: Alcon, Allergan, Inc., Abbott Medical Optics Inc.,
Bausch + Lomb, Inc., ISTA Pharmaceuticals, Inc.,
Merck & Co, Inc.
Consultant/advisory board: Alcon, Allergan, Inc., Abbott Medical Optics Inc., Bausch + Lomb, Inc., ISTA Pharmaceuticals, Inc., Merck & Co, Inc.
Activity Development and Management Team
Nothing to disclose with regard to commercial support
Pennsylvania College of Optometry at Salus University
Nothing to disclose with regard to commercial support
Stockholder (spouse): Johnson & Johnson
Employee (spouse): Novo Nordisk
Nothing to disclose with regard to commercial support
Method of Participation
To receive CME credit for participating in this educational activity, participants must:
- Review the CME information including the learning objectives
and disclosure statements;
- Study the educational content of the monograph; and
- Complete the evaluation and posttest with a score of 70% or higher.
Participants may retake the posttest if needed. Certificates will be sent to participants via e-mail.
For questions regarding the content of this activity, contact Dannemiller, accredited provider for this CME activity, at firstname.lastname@example.org.
REQUIRED COMPUTER HARDWARE/SOFTWARE:
Please ensure the computer you plan to use meets the following requirements:
- Operating System: Windows or Macintosh
- Media Viewing Requirements: Flash Player or Adobe Reader
- Supported Browsers: Microsoft Internet Explorer, Firefox, Google Chrome, Safari and Opera
- Most importantly an internet connection
The content and views presented in this enduring activity are those of the faculty authors and do not necessarily reflect those of Dannemiller, Pennsylvania College of Optometry at Salus University, Review of Ophthalmology, Allergan, Inc., or any manufacturers of products mentioned herein. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.
Off-Label/Investigational Use Disclosure
This enduring activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the enduring activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program.
The educational content of this activity has been peer reviewed and validated to ensure that it is a fair and balanced representation of the topic, based on the best available evidence.
Allergies are said to affect up to 50 million Americans, and
up to 40% of the global population has signs of
allergies.1-3 Ocular allergies involve the conjunctiva and
often coexist with allergic rhinitis, atopic dermatitis, and/
or allergic asthma.4 In the pediatric population, one study
found that 32% of children with allergies had ocular
symptoms as their sole manifestation.5 About 15% of the
worldwide population is affected by ocular allergies, with
increasing numbers in industrialized nations.5-7 In addition,
the economic impact of allergies is significant—about
$5.9 billion is spent yearly on ocular allergy treatments.8
Most allergies treated by eye care specialists involve
seasonal allergic conjunctivitis (SAC) and perennial
allergic conjunctivitis (PAC), with chronic vernal
keratoconjunctivitis (VKC), atopic keratoconjunctivitis
(AKC), and giant papillary conjunctivitis (GPC)
comprising a much smaller percentage.9 The chronic
forms may involve the lid, conjunctiva, and cornea and
may necessitate comanagement with eye care specialists,
allergists, dermatologists, and pediatricians. Chronic cases
may also induce ocular surface tissue remodeling; safe,
long-term treatment regimens for severe cases
SAC and PAC are localized type 1 hypersensitivity
reactions with fewer eosinophils than the more chronic
forms. Typical presentation includes hyperemia, chemosis,
watery discharge, tearing, and itching (the hallmark
symptom). Patients with SAC will often have few, if any,
findings upon ophthalmic examination, and thus the
patient's history leads to the diagnosis. Papillae—a
somewhat common finding in the more-severe forms
of ocular allergy—are also commonly found in children
and teenagers and are not considered a hallmark for the
diagnosis of SAC or PAC.
Left untreated, ocular allergies can have a negative impact
on a patient's quality of life and ability to work; chronic
forms can lead to ocular surface damage. Although
treatment of ocular allergies can improve functionality and
patient health, a consensus on treatment strategies
remains elusive.10 Current treatment options can be
effective at addressing the symptoms of ocular allergy, at
limiting inflammation, and at preventing damage to the
ocular surface.11, 12
Pathophysiology of ocular allergy
At the most simplistic level, an ocular allergic reaction follows
the same pathophysiologic pathway as an allergic
reaction in any other location: a type 1 hypersensitivity
reaction is mediated by highly directed subsets of
immunological mechanisms that predominantly involve
mast cells and immunoglobulin E (IgE). When patients
are exposed to an antigen, the antigen binds to the IgE
molecules, crosslinking the molecules on the mast cell
surface. Mast cells respond by releasing a large number
of mediators of the allergic response that are preformed
or synthesized de novo.
Histamine and eosinophil chemotactic factor are the
predominant preformed mediators stored in mast cell
granules. Prostaglandins and leukotrienes are synthesized
from arachidonic acid by the action of cyclooxygenase
and lipoxygenase, respectively. The net effect of the
release of these mediators is to cause vasodilation and
fluid transudation, resulting in swelling and pruritus. The
acute response is often augmented by a delayed response
that occurs several hours later. Although it is still
regulated and initiated by IgE, the delayed response
depends on upregulation of adhesion molecules and
increased production of mast cells, neutrophils,
eosinophils, macrophages, and basophils.13-17
From a clinical perspective, swelling and itch are the
hallmark signs of an allergic response, and within the
spectrum of ocular allergy, itching remains the
pathognomonic symptom. This mast cell-driven
inflammation caused by exposure to an ocular allergen
results in transient itching, tearing, and conjunctival
edema.18 Clinical examination may confirm vasodilation
and reveal that chemosis is present.
|Ocular Allergy Diagnosis
|Seasonal allergic conjunctivitis
||Aeroallergens: Spring: trees, pollen
Summer: grass/weeds, some trees
Fall: weeds, some trees
|Perennial allergic conjunctivitis
||Animal dander, dust mites, feathers
||Multifactorial (IgE and Th2 [T helper 2]
nonspecific triggers such as
sun, dust, and wind); genetic
||Multifactorial with stimulants such as stress,
aeroallergens, and food allergies
|Giant papillary conjunctivitis*
||Trauma from sutures, glue, scleral buckles,
devices, and contact lenses (CLs)
|Associated with CL use;
|*Not generally considered a true allergic response
Source: Luchs, Raizman, Shovlin, Wolf
As in other allergic responses, in SAC and PAC an IgE-mediated mast cell response leads to the production of
histamine, leukotrienes, and prostaglandins. This initial
response is rapid, generally within 30 minutes of the initial
allergen exposure. During the subsequent several hours,
upregulation of adhesion molecules occurs, with increased
infiltration of mast cells, neutrophils, eosinophils,
macrophages, and basophils into the conjunctival
epithelium.13-17 The delayed phase results in additional
mast cell activation within the conjunctiva, increasing the
severity of the reaction.19
No one single gene has been identified as the genetic
basis for allergies. Rather, the inheritance pattern of
allergies implies a polygenic mode. Interleukins (ILs),
especially IL-5, IL-4, IL-10, and IL-13, are the most
prominent of the genes associated with allergy. IL-10 has
been identified as the switch cytokine, regulating which
immunoglobulin B cells will alter one isotype to another
(IgM to IgG, for example). Other cytokines that can have a
similar function include IL-2, tumor necrosis factor (TNF),
In all forms of allergic conjunctivitis, an outpouring of
cytokines from conjunctival T cells can cause tearing. These T-helper cells (both Th1 and Th2) are more
prominent in AKC and VKC than in SAC or PAC. There is
also some evidence of mixed helper T-cell populations in
each disease type.20, 21 As is found in the pathogenesis of
most allergic disorders, the development of ocular
allergy is the result of an imbalance between Th1 and
Th2 cells and their respective cytokines.11 IL-4-producing
T cells are the key to a switch to IgE production and
also have been identified as a key component in allergic
Eosinophils enter the conjunctiva hours after exposure to
an allergen as part of the delayed phase response and
amplify the reaction by attracting lymphocytes to the site
between 24 and 72 hours postexposure. These
lymphocytes play a crucial role in chronic atopic disease
and may initiate the formation of scar tissue. They also
have been found to be more prolific in the conjunctiva of
patients with more chronic disorders.
Allergy immunology models
There is a large body of literature that explores the
problem of why there is a switch to production of IgE
instead of IgG in patients who express allergies, including ocular allergies. (See Suggested Reading -- Immunology). It seems clear
that some patients have a genetic predisposition toward
developing an IgE response, and these patients develop
allergies. What is not clear is what acts on the
predisposing genes to initiate a class switch to IgE and an
allergic response. The most prominent among the
paradigms is the "hygiene hypothesis."
Normal Immune Response
Raoul Wolf, M.D.
The end result of the normal immune response is the production of IgG, IgM, and IgA, which are responsible for the
removal of all types of foreign antigens. IgE synthesis results from the same pathway, but unlike the other immune
globulins, its only known normal function is to aid in the destruction of nematodes and other large parasites. In the
absence of parasites, the usual result of IgE production is an allergic reaction.
Immune responses are initiated by a single antigen. Since the strongest immune responses depend on the three-
dimensional structure of the antigen, proteins—and especially enzymes—are the most common. Epitopes, the
smallest unit that can function as an antigen, are processed by an antigen-presenting cell. The main antigen-presenting cells are macrophages, but others include dendritic cells (e.g., Langerhans cells in the skin), Kupfer cells,
endothelial cells, and even cerebral glial cells.
The antigen is presented to T-cell lymphocytes in the major histocompatibility complex (MHC; the identifying
complex of "self") of the macrophage. Several ILs and cytokines, especially IL-1, also communicate with T cells.
In response to this stimulus, the T cells revert to blast cells and undergo rapid cell division. During this process,
many more mediators and modulators are released that guide the response. At this stage, the B cell lymphocytes
are triggered, and they also undergo blast cell transformation and cell division. The B cells divide into plasma cells
and memory B cells. Plasma cells are antibody "factories," producing an antibody that precisely fits the antigen.
Antibodies are produced in the sequence of IgM, IgG, and finally IgA.
The immunoglobulins consist of two portions: the Fab (fragment antigen binding) end, which binds to the antigen,
and the Fc portion, which binds to cells. The antibody binds to antigen in a ratio of 3:2, forming an insoluble
complex and activating the complement pathway. An initial response to a novel antigen takes 10-14 days.
Athanassakis I, Vassiliadis S. T-regulatory cells: are we re-discovering T suppressors? Immunol Lett 2002 Dec;84(3):179-183.
Cooper MD. Exploring lymphocyte differentiation pathways. Immunol Rev 2002 Jul;185:175-185.
Flint PW, Haughey BH. Immunology of the upper airway and pathophysiology and treatment of allergic rhinitis. In: Baroody FM, Naclario
RM, eds. Cummings Otolaryngology: Head and Neck Surgery. 5th ed. St. Louis, MO: Mosby; 2010; 597-623.
Koop E, Koop N. Anatomy and immunology of the ocular surface. Chem Immunol Allergy 2007;92:36-39.
Wolf RL. Function and development of the immune system in humans. In: Wolf RL, ed. Essential Pediatric Allergy, Asthma, and
Immunology. New York, NY: McGraw-Hill:2004: 1-20.
Studies from Southern Germany and Sweden have shown
that children who grow up working on animal farms and
are exposed to animals and higher levels of endotoxin
have a lower incidence of allergies and asthma than
control children who grow up in the city. The
interpretation of these data has led to the hypothesis
surrounding development of the immune system
postnatally. According to this "hygiene hypothesis" theory,
the infant is born with T cells set at 0, termed Th0. Under
the influence of genetics and environmental exposure,
these cells become either Th1 or Th2 cells. Th2 cells are
distinguished by IL-4, IL-5, and IL-13 that drive the B cells
toward making IgE. It is not clear what antigens would
drive Th0 cells to develop into Th2 cells, but viruses,
allergens (cockroaches, dust mites, and animal dander),
and reduced exposure to endotoxin have been postulated.
There are concerns about the "hygiene hypothesis"
because studies supporting it do not account for the
complexity of immune maturation, and this maturation
probably depends on multiple factors that have yet to be
delineated. In addition, most of these studies have been
done in homogeneous populations and may not be
applicable to the general population. Clinically, the "hygiene hypothesis" theorizes that both atopy and
asthma are Th2 driven and that the imbalance between
Th1 and Th2 immunity is the primary causative
factor. Atopic people have increased IL-4, IL-5, IL-13, and
IgE antibody responses; increased immediate skin test
reactivity; and decreased interferon-gamma (Custovic A,
von Mutius E. The Hygiene Hypothesis Revisited: Pros and
Cons. Presented at the 60th Anniversary Meeting of the
American Academy of Allergy, Asthma, and
Immunology; March 7-12, 2003; Denver, CO). What role, if
any, the "hygiene hypothesis" plays in ocular allergies has
not been addressed.
Histamine, a common mediator released during mast cell
degranulation along with eotaxin, is stored preformed in
mast cell granules. Histamine is one of the most important
of the mediators and is predominant in SAC.23 In the pure
IgE-mediated mast cell response associated with SAC,
histamine is the definitive cause of most of the
typical signs and symptoms of ocular allergy, and,
therefore, antihistamine therapy remains a prime
When histamine is released into the conjunctiva, clinical
responses include itching, vasodilation, and swelling. The
conjunctiva hosts numerous histamine receptors; H1, H2,
and H3/H4 are thought to have a role in ocular allergies.
Therapeutically, H1 receptors are more predominant in
the eye; H2 is generally associated with vasodilation and
nasal symptoms, although it has also been demonstrated
in the blood vessels of the conjunctiva. The accumulation
of fluid in the perivascular area stimulates nerve endings
and causes the common "itchy" complaint. There is some
evidence of H4 receptors in the conjunctiva.24
The release of histamine is a controlled process. A
pinocytic vacuole forms on the outside of the mast cell,
attaches to the granuole, and then partially dissolves and
releases a small amount of histamine. Uncontrolled or
massive release of histamine causes anaphylaxis and
shock and can be fatal.
Leukotrienes and prostaglandins are synthesized for
each reaction by the mast cell, and thus antihistamines,
leukotriene antagonists, cyclooxygenase inhibitors, and
mast cell stabilizers are useful treatment modalities. The
severity of ocular allergy disease correlates with the
concentration of mast cells in the eye. In the late phase,
the disease is mediated by eosinophils. Corticosteroids
are reserved for late-phase, eosinophil-mediated
conditions. Histaminases and arylsulfatase break down
histamine. They are released predominantly by
eosinophils and may be useful in modulating
Role of IgE
During SAC and PAC the localized reaction begins with
specific IgE bound to mast cells; few eosinophils or
eosinophil mediators are generally present. The IgE-mediated response depends on the immunoglobulin
being produced and being bound to mast cells before a
clinical reaction can occur. It is thus a two-stage process: 1) exposure to the antigen causes the production of IgE
specifically directed against the antigen. The specific
antibody then binds to mast cells in several sites,
including the conjunctiva. No reaction takes place in this
phase. 2) on reexposure, the antigen binds to IgE on mast
cells, causing them to disintegrate and release histamine.
An allergic reaction occurs. Because of this mechanism,
monoclonal anti-IgE directed against the IgE receptor is
used in asthma treatment to displace IgE off the mast
cells, preventing them from disintegrating and essentially
rendering IgE harmless.
Both prostaglandins and leukotrienes are newly formed
mediators. Leukotrienes are considered more potent than
histamine. LTD4 (leukotriene D4), a prominent leukotriene
by-product, is considered potent at vasodilation and fluid
transudation,25 whereas histamine has a small effect.
Prostaglandins, however, are known to induce
vasodilation and are responsible for the clinical findings of
redness. Both prostaglandins and leukotrienes overlap in
this manner, and most targeted therapeutics are directed
specifically at these mediators. Both prostaglandins and
leukotrienes can be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2
inhibitors, and/or leukotriene modifiers. In rat conjunctiva,
direct application of leukotriene B4 increased the number
of eosinophils and neutrophils.26
SAC is the most common form of ocular allergy,
affecting about 90% those afflicted with allergic
conjunctivitis. Bilateral presentation is common,
although severity may differ slightly between the eyes.
Although SAC can include photophobia and blurred vision
on rare occasions, it is generally not a cause of
permanent visual impairment.5 PAC is more likely to be
associated with perennial rhinitis than SAC, but otherwise
the demographics of patients who have PAC versus SAC
is similar. In PAC, seasonal "spikes" have been noted in
up to 80% of those afflicted.5
Patients with PAC and SAC have elevated IgE levels in
both tears and serum as well as aeroallergen sensitivity.
About one-quarter of those with SAC have eosinophil
infiltration in the conjunctiva but almost 80% have
elevated IgE levels. Tear-fluid IgE has been reported in
96% of samples from patients with SAC.5 Clinically,
about twice as many patients with PAC than with SAC
have specific serum IgE for house dust, and the
percentage of patients with SAC who test positive for
IgE in tear serum is negligible. Neutrophils, basophils,
and eosinophils have been found in late-phase
Although patients with VKC or AKC should be closely
monitored because of potential vision loss, VKC and AKC
affect only a small number of patients (estimated at
about 2% of those with ocular allergies). VKC has a
higher prevalence in males than females; occurs more
often in those who live in warmer, arid climates; and has
usually run its course by early adulthood. However, in a
study of 509 patients with VKC, the incidence of VKC
was higher in females than males over the age of 16.11 A histaminase deficiency has been reported in patients
with VKC,27 and intense itching, tearing, and severe
photophobia are characteristic of this inflammation.
Local lymphocyte phenotypes are found in patients with
VKC.28 During the active phase of VKC, the sheer
number of cytokines (rather than the quality) will
differentiate it from SAC or PAC.
AKC also occurs more frequently in men (usually
between the ages of 30 and 50 years) and is associated
with atopic dermatitis or atopic eczema. Typically,
patients with AKC have a family history of systemic
diseases (such as eczema), allergies, asthma, urticaria,
or hay fever (or some combination). Atopic blepharitis,
meibomian gland dysfunction, and associated dry eye
symptoms commonly coexist, and the conjunctiva may
be hyperemic and edematous. The periocular skin
involvement can be debilitating to some patients.
Eosinophils are characteristic of both VKC and AKC. After
the initial release of mast cell mediators, other cells are
recruited (specifically eosinophils), which are present
within hours of exposure to an allergen. Lymphocytes are subsequently recruited and are believed to play a
crucial role in the more-chronic disease states.
Pathologic examination of the conjunctiva in these
conditions will show an escalation of eosinophils being
recruited. AKC patients may develop keratinized or
cicatrized ocular surface similar to a pemphigoid
presentation. Systemically, the true atopic individual will
have extreme itch and eczematoid changes on the skin,
may have developed hyperkeratosis, and is likely
introducing allergens into the eye from the additional
rubbing. The patient may also develop lid skin changes
from using tissues to wipe the eyes for excessive
tearing. The lid margin is more involved in AKC than in
the other forms of allergic conjunctivitis.
GPC is caused by repeated mechanical irritation (such
as occurs with contact lens [CL] use, limbal sutures,
glue, scleral buckles, and prosthetic devices). It is not
considered a true allergic reaction but can be
aggravated substantially by allergens.
AKC and VKC can produce sight-threatening
complications. The most characteristic sign of patients
with tarsal VKC is giant cobblestone papillae, which are
filled with eosinophils. These papillae can easily be
seen by flipping the eyelids of these patients. Shield
ulcers—an immunologic response to the eosinophils—
can form on the conjunctiva in direct apposition to the
cobblestone papillae and are generally difficult to treat,
have difficulty healing, and often heal with corneal
scarring and irregularities of corneal shape. In the worst
cases, these ulcers can produce permanent visual loss.
Limbal VKC differs not only in geographic location but
in the gelatinous infiltrates that mark the limbus.
People with darker pigmentation are more likely to
have limbal VKC.
Patients with AKC not only have immediate allergy
considerations but also have needs that should be
considered when planning for future ophthalmic
surgery. The chronicity of AKC can have significant
implications for the health of the ocular surface, and
therapy with corticosteroids increases the risk for
glaucoma and cataracts. The CLEK (Collaborative
Longitudinal Evaluation of Keratoconus) study did not
find a strong association between keratoconus and
AKC, but the increased eye rubbing has been
suggested as a driving force for the progression of
IgE levels alone may not be sufficient to determine the
presence of allergy. Skin testing is more useful for
demonstrating a particular sensitivity to a specific IgE.
A downside to using skin tests is that they assume the
mast cells on the skin are identical to those in the nose
or eye, which may not be accurate. A general correlation
between the environmental allergens and response is
usually more accurate. Direct conjunctival sac and
nasal challenges are not clinically practical but do
show much higher specificity and sensitivity.
Current and future treatment modalities
When both allergic rhinitis and allergic conjunctivitis are
present, comanagement with allergists, pediatricians, and
eye care professionals is usually recommended.
Dermatologists may also be helpful in comanaging AKC.
A stepwise approach is common when treating patients
with SAC and PAC. Educating patients about the
environmental allergen irritants that can be easily avoided
(ie, allergens, cigarette smoke, pets) or modified (ie, keeping windows closed, cleaning ducts, replacing
pillows frequently, installing hardwood floors, washing hair
and pulling it back [pollen collector], and avoiding peak
outdoor times when pollen counts are high) should be the
first step. Although rubbing the eye may exacerbate the
symptoms and perpetuate the condition, this does not
have to be discussed in the first few patient visits. Cold
compresses can be helpful if patients are unable to avoid
the airborne allergens but do not exhibit more moderate
Adding over-the counter (OTC) artificial tears (ATs) helps
alleviate the itch and may also help wash away the
antigen. Many SAC and PAC patients also have dry eye,
and preservative-free ATs are safe to use in patients who
wear CLs. ATs can provide symptomatic relief but will not
address the underlying allergic response.
Antihistamines (emedastine 0.05%, levocabastine 0.05%)
can provide rapid relief of ocular symptoms when applied
topically. Benefits include excellent antihistamine activity
plus the ability to stabilize the mast cells. Most
antihistamines also inhibit eosinophil activation and
migration. However, most have a limited duration of action
and require up to four daily doses. CL wearers may need
to discontinue use during more-severe outbreak periods.
Oral antihistamines are effective in controlling some
symptoms of allergic conjunctivitis but may contribute to
drying of the ocular surface. Some patients benefit from
the addition of topical antihistamines while they are using
Decongestants (oxymetazoline, tetrahydrozoline, and
naphazonline) in combination with antihistamines act
as vasoconstrictors but are known to sting or burn on
instillation. Other adverse events include mydriasis and
rebound hyperemia, rendering these pharmaceuticals
more suitable for short-term relief. In addition, these drugs
are not recommended for use in patients with narrow-angle glaucoma.30 In general, vasoconstrictors should not
be used to treat patients with ocular allergy because the
newer antihistamines are more effective and safer.
Mast cell stabilizers (cromoglycate 2% or 4%, lodoxamide 0.1%, nedocromil 2%) can be used for long-term therapy
but require a front-loading period before they can be
effective. Nedocromil was more effective than cromolyn
for treating VKC.30
SAC and PAC are "ideally" treated with a combined
antihistamine/mast cell stabilizer. Advantages of these
therapeutic molecules are the rapidity of symptomatic
relief coupled with the disease-modifying benefits of mast cell stabilization. Some combination agents attack both H1
and H2. Using combination therapy allows for once-daily
dosing, which increases patient compliance.
Olopatadine 0.1% was the first combined antihistamine/
mast cell stabilizer to be approved in the U.S., but others
include bepotastine 1.5%, epinastine 0.05%,
azelastine 0.05%, pemirolast 0.1%, and ketotifen. To date,
head-to-head clinical studies comparing these
combination antihistamine/mast stabilizers have been
conducted. Olopatadine 0.2% is approved for once-daily administration.
Alcaftadine, "a potent histamine H1, H2, and H4 receptor
antagonist that has also demonstrated anti-inflammatory
properties,"31 is the newest antihistamine/mast cell
stabilizer approved in the U.S. for allergic conjunctivitis.
Alcaftadine 0.25% has a rapid onset of action and long-
term duration of action.32 Alcaftadine has demonstrated
an ability to inhibit eosinophil chemotaxis and activation.33 Olopatadine 0.2% and alcaftadine 0.25% are the longest-acting antihistamine/mast cell stabilizers, allowing
NSAIDs help reduce itching in patients with allergic
conjunctivitis, but to date only one (ketorolac 0.5%) has
been approved for the treatment of SAC. The NSAID works
on the arachidonic cascade, but the specific mode of
action is unknown. Lower doses of ketorolac are currently
being marketed for postoperative pain after cataract
surgery but are not approved for treatment of ocular
allergy. In general, nonsteroidal medications are no
longer used for treating ocular allergy.
Topical steroids can be useful for VKC and AKC, but
long-term use may be associated with serious adverse
events, including cataract formation, glaucoma, and
potentiation of herpes simplex infections. (The following
statement refers to off-label or investigational use.) Off-label use of steroids via upper tarsal conjunctival
injections has anecdotally shown promising results in
severe VKC. Low-dose topical steroids (fluorometholone
or loteprednol) are mostly recommended for patients
presenting with highly inflamed eyes but should not be
considered a primary long-term therapy. Systemic steroids
(prednisone) can be helpful in severe cases with
debilitating itching. Steroid creams have shown some
benefit for patients with eyelid eczema. (The following
statements refer to off-label or investigational use.)
Topical pimecrolimus or tacrolimus may be used off-label
on the eyelid skin. Topical cyclosporine 0.05% drops
applied to the conjunctiva off-label can also provide relief
as a steroid-sparing agent for patients with AKC or VKC.
Matrix metalloproteinase 9 (MMP-9) activity is elevated in
patients with allergic conjunctivitis and dry eye;34-36 developing therapies that specifically target MMP-9 may
Allergy immunotherapy is useful in reducing the response
to allergens, but its role in allergic conjunctivitis has not
been proven. The therapy is administered
subcutaneously in progressively increasing doses to remain below the threshold of a clinical reaction.
Immunotherapy works best in situations with severe
symptoms, poor control with conventional
pharmacotherapy, and good correlation of symptoms with
a few specific antigens.
Sublingual immunotherapy (SLIT) is considered an
alternative to subcutaneous allergy immunotherapy and
is administered orally under the tongue, but long-term
results with SLIT are not yet available. Most of the trials
with this form of therapy have been for allergic rhinitis.
Clinical challenges in ocular allergies:
On the following pages, you will find several case studies
examining specific diagnostic and treatment challenges of
allergic conjunctivitis. These case studies have been
designed to address challenging issues that often
confound allergists and eye care professionals.
Case study 1: A 30-year-old man presents during spring
tree pollen season with itching and irritation of the eyes.
These symptoms occur every year, but they are especially
bad this year. After taking oral antihistamines, his nasal
itching and rhinorrhea have decreased, but his eyes are
still bothering him. He cannot play golf or mow his lawn,
and he has trouble reading and using the computer at
work. He tried over-the-counter antihistamine/
vasoconstrictor eyedrops, but these did not provide much
relief and his eyes are now redder. An eye examination
reveals mild conjunctival hyperemia, trace papillae,
decreased tear volume, rapid tear breakup time, and
DR. SHOVLIN: The antihistamine is probably a culprit
because it reduces tear volume by 30%-40%. Before he cuts
his grass, I'd advise the ad hoc usage of an
antihistamine/mast cell stabilizer. I'd stop the oral
antihistamine, take a closer look at the tear film, and see
if we need to stabilize that in one form or another. If he's a
big golfer, wrap-around glasses or sunglasses may give him
DR. LUCHS: I would approach it a little differently. This
is a great case history that illustrates the real functional
impact of ocular allergies on someone's daily life. If he
happened to be a CL wearer, the significance of all of
these factors may be elevated. The OTC antihistamine
vasoconstrictor drops are not providing relief. He clearly
has some signs of dry eye based on the decreased tear
volume and the tear breakup time, although there is no
staining. I'd keep him on the oral antihistamine because
clearly he's getting some relief from his nasal symptoms
and we don't want to necessarily withdraw that benefit
from the patient. We need to add ATs and to treat his
ocular surface. Punctal plugs won't work just yet
because they could make his allergies worse by allowing
us to retain antigen on the ocular surface, so we want
to initiate treatment of both his allergies and dry eye
before we place plugs. This is somebody that you will
need to manage with preservative-free artificial tears and
maybe some ointment at night; you should advise lifestyle
changes and use topical antihistamines.
DR. RAIZMAN: All oral antihistamines can dry the eyes,
even the so-called nonsedating oral antihistamines.
DR. WOLF: There's no reason not to stop his oral
antihistamines. I would switch him to a topical nasal
DR. RAIZMAN: We have three different approaches here.
The first is to just stop the oral antihistamines. The
second is to continue the oral antihistamines but add
topical ocular therapy and lubrication. The third is to stop
oral antihistamines and use a nasal spray and a topical.
DR. SHOVLIN: The naso-ocular lavage can help with the
parasympathetic influence as a "noise cancelling" effect
with allergic rhinitis. I believe just using the topical
antihistamine/mast cell stabilizer would help his nasal
itching as well.
DR. RAIZMAN: Some patients will describe rhinorrhea, but
he also has nasal itching, which is a bit different. Pure
ocular allergies do not involve nasal itch.
DR. SHOVLIN: I bet you would find therapeutically that he
would do almost as well just using the topical
antihistamine/mast cell stabilizer.
DR. WOLF: What tends to get lost with the nonsedating
oral antihistamines is the anticholinergic effect. It
depends how much the anticholinergic properties are
playing a part in drying the eye as to whether these
sedating antihistamines will also work. That might be
Case study 2: A 13-year-old boy with no known allergies,
no rhinitis/asthma/eczema, and negative skin and RAST
test results has severe ocular itching in the spring with lid
swelling, red eyes, and uncontrollable rubbing. The boy
has not been able to go to school for the past few days.
Findings of an eye examination include lid edema and
giant papillae in both eyes. The right cornea shows heavy
punctate staining with fluorescein but no defect.
DR. RAIZMAN: This is a classic presentation of VKC. What
are the special issues with a child with allergy as opposed
to an adult in terms of drug administration, compliance,
and issues with the parents?
DR. WOLF: Clinically, there are not many differences.
Children need help administering the eyedrops, so parents
need to take greater responsibility. It's likely this patient
wouldn't initially present to an allergist. I'd recommend
topical antihistamines in the eye, possibly topical therapy
in addition to treating any concomitant skin involvement in
blepharitis. I usually tell parents to put the drops into the
inner angle of a closed eye and let the child blink to get
the drop into the eye. That's usually easier. I'd refer this
child, but first I'd try topical therapy, more topical
antihistamines, and combination drugs. If necessary, I'd
use a systemic steroid antihistamine and see him in
DR. RAIZMAN: These kids who come in the spring need a
high-dose topical steroid. I wouldn't wait 2 weeks before
bringing him back. In these presentations, an immediate
referral is appropriate.
DR. LUCHS: You need steroids on board right away
because of the ominous corneal finding. The confluent
staining of the cornea suggests that we have an area of
the cornea that's ripe to become a shield ulcer. I would
start the steroid right away, and I'd immediately add a
topical antihistamine/mast cell stabilizer and a
DR. SHOVLIN: Unfortunately, I hate to add additional
drops, but I probably would cover him at least initially
prophylactically if we're using other medications.
DR. RAIZMAN: I think that complicates things. Once the
epithelial defect is there, you should absolutely use an
antibiotic. Maybe an ointment would be helpful.
DR. LUCHS: Maybe even a steroid ointment at night.
DR. WOLF: From an allergist's point of view, we don't have
the eye findings at that point because this child is
presenting with a red eye and itching that is fairly severe.
In this case, we've had a full eye exam already, which is
not going to happen in an allergist's office.
|Stepwise Treatment Strategies for Allergic Conjunctivitis
||Avoidance, cold compresses, tears, over-the-counter medications
| Topical antihistamines/mast cell stabilizers
| Oral antiallergics (allergists may already have patients on orals;
may exacerbate the ocular
condition while improving the nasal condition)
||+ Mast cell stabilizers (treats allergy before mediator is released)
| + Combination antihistamine/mast cell stabilizers
| + Topical corticosteroids (most beneficial for severe outbreaks)
||Topical corticosteroids (short course; fluorometholone/dexamethasone/loteprednol/prednisolone)
|Topical immunomodulating agents (tacrolimus, cyclosporine)
| Oral steroids
|+ = all the above, plus additional therapy as mentioned
The eye rarely stands alone—comorbidities include rhinitis, rhinosinusitis, and asthma
DR. RAIZMAN: Let's say this is a child coming for the first
time in the spring with swollen eyes and allergy. It would
be absolutely appropriate to do what you said initially:
Treat for a week or two. But if a child with known VKC
who has been fine for a year comes into your office in the
spring, he or she should get an immediate referral and
DR. WOLF: By that point, the child is already seeing an eye
care specialist. If I'm trying to control their asthma with
a lot of steroids, I want someone to look in their eyes for
DR. SHOVLIN: If they're on oral steroids, then the
pediatrician or allergist needs to be involved. You have
to find that balance. In states where optometrists can't
prescribe oral steroids, they should be referred to an
Case study 3: A 44-year-old woman with known allergy
to cat dander, dust, and mold presents in January with
itching of both eyes and inability to tolerate her CLs. She
cannot wear makeup because her eyes are tearing and
she has to rub them. Her eyelashes have crust, mostly
in the morning. An eye examination reveals debris on
the lashes, obstructed meibomian glands, conjunctival
hyperemia with minimal papillae, decreased tear volume,
and punctate staining of the inferior cornea.
DR. SHOVLIN: She needs a hiatus from CL wear. She has
at least a secondary dry eye (maybe from CLs or aqueous
deficiency or obstructed meibomian glands), so you need
to address the ocular surface as well. Before we can even
think about returning her to CL wear, we have to address
the lid disease and the secondary dry eye as well as the
allergy. I'd start with an antihistamine/mast cell stabilizer,
maybe concomitant use of ester-based steroids. This is a
great patient (eventually) for daily disposable CLs.
DR. WOLF: There may be an extra wrinkle—she might
have contact dermatitis that is aggravating her condition
(in addition to her eye makeup).
DR. RAIZMAN: How do you decide if patients have
sensitivity to their makeup?
When to refer?
Refer patient to an eye care specialist if:
- Changes in vision
- Persistent ocular complaints
- Ocular steroid use for more than 2 weeks
- Potential uveitis diagnosis
- Complaints of ocular pain
Refer patient to an allergist if:
- Systemic evaluation is warranted
- Immunotherapy is being considered
- Severe persistent allergic complaints
- Predominance of nonocular allergic complaints
Refer patient to a dermatologist if:
- Severe atopic keratoconjunctivitis and
persistent contact dermatitis
DR. WOLF: Pattern, first of all. If there are local reactions,
particularly reactions that are more on the epithelium, and
if there is the initial itchiness. These are not IgE-mediated reactions, so you could do patch testing or components.
Nail polish is a common reactor that causes ocular
reactions and local reactions because of touching.
DR. RAIZMAN: Why doesn't skin around the fingernail react
but the eyelids do? I always presumed it's because the skin
is so thin on the eye.
DR. WOLF: Probably the touching. Eyelids are much more
sensitive. You also probably have a higher
concentration of mast cells than you do around the
fingernails. As makeup ages, it decays and breaks down,
and the components tend to be more allergenic. I don't
have a hard and steadfast rule, but using makeup that's
several years old is not a good idea. I would also
emphasize the removable antigens. It's highly likely she's
allergic to the cat. Cat dander is very insidious, and even in
homes that don't have cats there is still fine,
measurable cat dander because it's brought in by visitors.
DR. RAIZMAN: The flare-up occurs in January, so this may
point to cat dander or mold.
DR. LUCHS: The exam findings are consistent with
blepharitis. She has lid debris, she has obstructed
meibomian glands, and she has dry eye (whether it is
evaporated tear loss or decreased secretion). Treat the
blepharitis with warm compresses +/- lid scrubs,
assuming there's no contact dermatitis; treat the
meibomian gland disease with either topical azithromycin
or oral doxycycline; get those functioning. And she needs
to stop wearing her CLs. If allergy is a component, add a
combination agent, maybe topical cyclosporine. This is a
common presentation in my practice, where the primary
complaint is CL intolerance. It's up to us to determine why.
Is there a CL problem? Fitting issue? Hygiene issue? None
of these issues would give rise to blepharitis, but they
would cause her red, irritated eyes. Just because she has
allergy, it doesn't necessarily mean that allergy is causing a
problem, although it certainly raises it to the top of the list
to something that we want to treat. I would approach this
in a stepwise fashion: ask the patient to stop wearing CLs,
treat the blepharitis, and support the ocular surface with
artificial tears. Then see what needs to be added.
DR. SHOVLIN: This is the perfect example of where more
than one issue keeps her from wearing CLs.
DR. WOLF: She probably went to her allergist when she
was having these problems. From what we know from the
ophthalmologic exam, she's now being seen again by her
allergist. The allergist is likely to make an assumption that
she's reacting to her eye makeup and not think about the
CL causal factor. What I'm taking from this is that I need to
begin thinking that something in the eye may be the
primary cause of this patient's condition and that
everything else is just aggravated by the lens wear. CL use
has become as common as slipping on a pair of glasses.
Allergists tend not to think about the fact you have a
foreign body sitting in your eye.
DR. LUCHS: CLs can exacerbate ocular surface disease,
and, conversely, ocular surface diseases can worsen CL
tolerance. Dry eyes can make allergy worse. Allergy
can make dry eyes worse. There's a very big interaction
between all of these ocular surface diseases.
- Austin JB, Kaur B, Anderson HR, et al. Hay fever, eczema, and wheeze: a nationwide UK study (ISAAC, international study of asthma and allergies in childhood). Arch Dis Child 1999 Sept;81(3):225-230.
- Nathan RA, Meltzer EO, Seiner JC, Storms W. Prevalence of allergic rhinitis in the United States.
J Allergy Clin Immunol 1997 June;99:S808-S814.
- Singh K, Bielory L. Epidemiology of ocular allergy symptoms in United States adults (1988-1994). American College of Allergy, Asthma & Immunology Annual Meeting; Nov 9-15, 2006; Philadelphia, PA. Abstract 34.
- Groneberg DA, Bielory L, Fischer A, Bonini S, Wahn U. Animal models of allergic and inflammatory conjunctivitis. Allergy 2003 Nov;58(11):1101-1113.
- Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin Immunol 2000 Dec;106(6):1019-1032.
- Mishra GP, Tamboli V, Jwala J, Mitra AK. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011 Jan;5(1):26-36.
- Alexander M, Berger W, Buchholz P, et al. The reliability, validity, and preliminary responsiveness of the Eye Allergy Patient Impact Questionnaire (EAPIQ). Health Qual Life Outcomes 2005 Oct 31;3:67.
- Bielory L. Update on ocular allergy treatment. Expert Opin Pharmacother 2002 May;3(5):541-553.
- du Toit G. Clinical allergy images--allergic conjunctivitis. Curr Opin Allergy Clin Immunol 2005;18(3):148-50.
- Mantelli F, Lambiase A, Bonini S, Bonini S. Clinical trials in allergic conjunctivits: a systematic review. Allergy 2011Jul;66(7):919-924.
- Leonardi A, Motterle L, Bortolotti M. Allergy and the eye. Clin Exp Immunol 2008 Sept;153 (Suppl 1):17-21.
- Offiah I, Calder VL. Immune mechanisms in allergic eye diseases: what is new? Curr Opin Allergy Clin Immunol 2009 Oct;9(5):477-81.
- McGill JI, Holgate S, Church M, Anderson D, Bacon A. Allergic eye disease mechanisms. Br J Ophthalmol 1998 Oct;82(10):1203-1214.
- Bacon AS, McGill JI, Anderson DF, Baddeley S, Lightman SL, Holgate ST. Adhesion molecules and relationship to leukocyte levels in allergic eye disease. Invest Ophthalmol Vis Sci 1998 Feb;39(2):322-330.
- Bacon AS, Ahluwalia P, Irani AM, et al. Tear and conjunctival changes during the allergen- induced early- and late-phase responses. J Allergy Clin Immunol 2000 Nov;106(5):948-954.
- Anderson DF, MacLeod JD, Baddeley SM, et al. Seasonal allergic conjunctivitis is accompanied by increased mast cell numbers in the absence of leucocyte infiltration. Clin Exp Allergy 1997 Sept;27(9):1060-1066.
- Leonardi A, Curnow SJ, Zhan H, Calder VL. Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast cultures. Clin Exp Allergy 2006 June;36(6):777-784.
- Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J Allergy Clin Immunol 2005 Jan;115(1):118-122.
- Robles-Contreras A, Santacruz C, Ayala J, et al. Allergic conjunctivitis: an immunological point of view. In: Pelikan Z, ed. Conjunctivitis: A Complex and Multifaceted Disorder: Rijeka, Croatia:InTech, 2011.
- Fujishima H, Saito I, Takeuchi T, Shinozaki N, Tsubota K. Measurement of interleukin-4 and histamine in superficial cells of conjunctiva in patients with allergic conjunctivitis. Curr Eye Res 1996 Feb;15(2):209-213.
- Fujishima H, Takeuchi T, Shinozaki N, Saito I, Tsubota K. Measurement of IL-4 in tears of patients with seasonal allergic conjunctivitis and vernal keratoconjunctivitis. Clin Exp Immunol 1995 Nov;102(2):395-398.
- Matsuura N, Uchio E, Nakazawa M, et al. Predominance of infiltrating IL-4-producing T cells in conjunctiva of patients with allergic conjunctival disease. Curr Eye Res Oct-Nov 2004;29(4-5):235-243.
- Abelson MB, Allansmith MR. Histamine and the eye. In: Silverstein A, O'Connor G, eds. Immunology and Immunopathology of the Eye. New York: Masson Publishing, 1979.
- Leonardi A, Di Stefano A, Vicari C, Motterle L, Brun P. Histamine H4 receptors in normal conjunctiva and in vernal keratoconjunctivitis. Allergy 2011 Oct;66(10):1360-1366.
- Numata T, Konno A, Yamakoshi T, Hanazawa T, Terada N, Nagata H. Comparative role of peptide leukotrienes and histamine in the development of nasal mucosal swelling in nasal allergy. Ann Otol Rhinol Laryngol 1999 May;108(5):467-473.
- Ciprandi G, Buscaglia S, Pesce GP, Bagnasco M, Canonica GW. Ocular challenge and hyperresponsiveness to histamine in patients with allergic conjunctivitis. J Allergy Clin Immunol 1993 Jun;91(6):1227-1230.
- Abelson MB, Leonardi AA, Smith LM, Fregona IA, George MA, Secchi AG. Histaminase activity in patients with vernal keratoconjunctivitis. Ophthalmology 1995 Dec;102(12):1958-1963.
- Leonardi A, DeFranchis G, Zancanaro F, et al. Identification of local Th2 and Th0 lymphocytes in vernal conjunctivitis by cytokine flow cytometry. Invest Ophthalmol Vis Sci 1999 Nov;40(12):3036-3040.
- Barr JT, Zadnik K, Wilson BS, et al. Factors associated with corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. Cornea 2000 Jul;19(4):501-507.
- Bielory L, Katelaris CH, Lightman S, Naclerio RM. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. MedGenMed 2007 Aug 15;9(3):35.
- Greiner JV, Edwards-Swanson K, Ingerman A. Evaluation of alcaftadine 0.25% ophthalmic solution in acute allergic conjunctivitis at 15 minutes and 16 hours after instillation versus placebo and olopatadine 0.1%. Clin Ophthalmol 2011 Jan 13;5:87-93.
- Torkildsen G, Shedden A. The safety and efficacy of alcaftadine 0.25% ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. Curr Med Res Opin 2011 Mar;27(3):623-631.
- Butrus S, Portela R. Ocular allergy: diagnosis and treatment. Ophthalmol Clin North Am 2005 Dec;18(4):485-492.
- Acera A, Rocha G, Vecino E, Lema I, Durán JA. Inflammatory markers in the tears of patients with ocular surface disease. Ophthalmic Res 2008 Oct;40(6):315-321.
- Leonardi A, Sathe S, Bortolotti M, Beaton A, Sack R. Cytokines, matrix metalloproteases, angiogenic and growth factors in tears of normal subjects and vernal keratoconjunctivitis patients. Allergy 2009 May;64(5):710-717.
- Gürdal C, Genç I, Saraç O, Gönöl I, Takmaz T, Can I. Topical cyclosporine in thyroid orbitopathy-related dry eye: clinical findings, conjunctival epithelial apoptosis, and MMP-9 expression. Curr Eye Res 2010 Sep;35(9):771-777.