life

Review
Allergic Conjunctivitis: Review of Current Types, Treatments,
and Trends
Fiza Tariq

Pennsylvania College of Optometry, Salus University, Elkins Park, PA 19027, USA; [email protected];
Tel.: +1-215-421-2508

Abstract: Allergic conjunctivitis is an allergen-induced immune response secondary to the binding

of immunoglobulin-E (IgE) to sensitized mast cells. Approximately 40% of North Americans and
20% of the world’s population are impacted by some form of allergy and it continues to increase
in prevalence, especially among children. Specified IgE antibodies can be found in almost all cases
of exposure to seasonal or perennial allergens. Activation and degranulation of mast cells lead to
increased tear levels of histamine, tryptase, leukotrienes, cytokines, and prostaglandins. The release of
these factors initiates the recruitment of inflammatory cells in the conjunctival mucosa, which causes
the late-phase reaction. Signs and symptoms of ocular allergies include itching, tearing, chemosis,
and hyperemia, which can lead to decreased productivity and poor quality of life. Many treatment
options are available to improve symptoms, including, mast cell stabilizers, antihistamines, dual-
acting agents, steroids, nonsteroidal anti-inflammatory drugs (NSAIDS), and other off-label treatment
modalities. This review article provides an overview of different types of allergic conjunctivitis, its
pathology and immunology, and recommended methods of treatment.

Keywords: allergic conjunctivitis; ocular allergy; IgE antibodies; Th2 lymphocytes; antihistamines;
mast cell stabilizers

1. Introduction
Allergic eye disease is an ocular manifestation of the body’s immune response to other
Citation: Tariq, F. Allergic
normally harmless substances known as allergens. Approximately 40% of North Americans
Conjunctivitis: Review of Current
and 20% of the world’s population are impacted by some form of allergy, making it one of
Types, Treatments, and Trends. Life
the most commonly encountered clinical conditions [1–3]. Allergic conjunctivitis can result
2024, 14, 650. https://doi.org/
from various impacting factors including genetics, air pollution, atopy, pollen exposure,
10.3390/life14060650
inflammation, and pet hair [3]. Examples of common allergens to the conjunctival surface
Academic Editors: Alba Martín-Gil include tree/grass pollen, house dust mites, animal/pest dander, and mold spores [3,4].
and Laura De Diego-García The classification of allergic conjunctivitis was revised a few years ago by the European
Received: 27 March 2024
Academy of Allergy and Clinical Immunology (EAACI), which details two types of ocular
Revised: 14 May 2024
surface hypersensitivity disorders: ocular allergy and ocular non-allergic hypersensitiv-
Accepted: 17 May 2024 ity [2].
Published: 21 May 2024 Ocular allergy can be caused by IgE or non-IgE-mediated mechanisms. The first two
most common and milder types of IgE-mediated ocular allergy include seasonal allergic
conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC). The two more severe and
chronic forms of IgE-mediated mechanisms include vernal keratoconjunctivitis (VKC)
Copyright: © 2024 by the author. and atopic keratoconjunctivitis (AKC). Non-IgE-mediated forms of ocular allergy are less
Licensee MDPI, Basel, Switzerland. common and include contact blepharoconjunctivitis (CBC), VKC, and AKC. The second
This article is an open access article type, ocular non-allergic hypersensitivity, includes giant papillary conjunctivitis (GPC),
distributed under the terms and irritative conjunctivitis, irritative blepharitis, and other mixed forms [2].
conditions of the Creative Commons
SAC is the most common form of ocular allergy and accounts for approximately
Attribution (CC BY) license (https://
90% of all cases, with PAC as the second most common [1,2]. In addition to being the
creativecommons.org/licenses/by/
most common, they are also the milder forms of ocular allergies behind VKC and AKC.
4.0/).

Life 2024, 14, 650. https://doi.org/10.3390/life14060650 https://www.mdpi.com/journal/life

Life 2024, 14, 650 2 of 14

Despite its high prevalence and common presentation, allergic eye disease is often an
underdiagnosed and undertreated health problem. The presenting symptoms of itching,
redness, and swelling may seem mild but can significantly impact a person’s daily quality of
life [2,3]. About 10% of patients with ocular allergy symptoms usually tend to self-medicate
and/or fail to seek medical attention. The predominance of self-management increases
the risk of suboptimal treatment, leading to recurring symptoms and worsening chronic
exacerbations that can impact the cornea and vision [5]. Multiple overlapping conditions,
such as infectious diseases and dry eye syndromes, make it challenging to arrive at the
correct diagnosis/diagnoses [2,5]. Therefore, successful management includes thorough
patient history and appropriate ophthalmological techniques for diagnosing and providing
accurate treatment options [1,2,5].
In this comprehensive review paper, I thoroughly assess the peer-reviewed literature
on the latest trends, current types, and treatments available for allergic conjunctivitis. The
databases and libraries used for the article search include PubMed, Science Direct Journals,
and OVID Journals. The search criteria date ranges were restricted to 2004–2024 to ensure
that the most recent data were accessed. The keywords in the search included ocular allergy,
allergic conjunctivitis, IgE antibodies, Th2 lymphocytes, antihistamines, and mast cell
stabilizers. My inclusion criteria included well-written original yet comprehensive articles,
including clinical research, book chapters, and reviews emphasizing the immunological
basis of ocular allergy. My exclusion criteria included studies lacking a pathological,
physiological, or immunological understanding/basis, studies missing methodological
rigor, studies not written in English, and poor organization. This thorough methodological
process ensured a scientifically sound synthesis of our present-day understanding of allergic
conjunctivitis. This article highlights the current trends, types, and treatments of allergic
conjunctivitis from a pathophysiology and immunological perspective.

2. Etiology
Most cases of allergic conjunctivitis occur simply due to exposure to allergens on
the ocular surface. Specifically, SAC, also known as hay fever conjunctivitis, is an acute
disease that tends to worsen during the spring and summer seasons, and the most common
allergens responsible are tree and grass pollen. On the other hand, PAC is chronic with
remission and exacerbation periods and is present throughout the year [2,3]. The difference
between the two is rooted in the allergen types: SAC occurs typically due to outdoor
airborne allergens that are worse in the spring, and PAC occurs due to indoor airborne
allergens throughout the year [2,3]. The exact cause of VKC is unknown but it is correlated
with certain climate and environmental exposures. VKC can be classified into three different
forms based on its clinical presentation: palpebral, limbal, and mixed [2,6]:
a. Palpebral VKC largely affects the upper tarsal conjunctiva and significantly involves
the cornea and its damage from the overlying inflamed conjunctiva.
b. Limbal VKC predominately affects individuals of Black and Asian descent and
primarily manifests in temperate climates.
c. Mixed VKC exhibits a combination of features seen in both palpebral and limbal
disease, including involving the upper tarsal conjunctiva and the limbal area.
The exact etiology of AKC remains unclear but it has been connected to various factors,
including genetic predisposition and atopic dermatitis (present in more than 90% of cases).
GPC can be correlated to ocular foreign bodies that can either carry allergens or cause
damage to the ocular surface, leading to easier allergen infiltration [3]. This condition can
be associated with various ocular foreign bodies such as contact lenses, ocular prostheses,
exposed scleral buckles, glaucoma filtering blebs, and sutures, amongst others [7].
Life 2024, 14, 650 3 of 14

3. Pathophysiology
The ocular surface consists of the cornea and the conjunctival mucosal barrier, which
protects the eye from foreign invasion and is a common site of allergic inflammation due to
its easy access to airborne allergens [8]. The ocular surface is blanketed by the tear film,
which consists of a lipid, aqueous, and mucin layer formed by the meibomian glands,
lacrimal glands, and goblet cells, respectively [9,10]. The tear film plays a vital role in
visual acuity. It lubricates and protects the epithelium of the ocular surface [11]. The ocular
surface is an “immune-privileged” site as it maintains corneal transparency and integrity
by suppressing unnecessary inflammatory responses while maintaining the capability to
mount an effective immune response against pathogens [8,12,13]. The cornea is avascular
and has no lymphatic drainage; thus, no active blood-circulating leukocytes can enter or
collect in the corneal tissue [12,14]. The healthy cornea also does not have any mature
leukocytes, which decreases its ability to produce pro-inflammatory cytokines and are
limited in their ability to produce lymphoid cells [15,16]. The cornea is kept clear by
producing anti-inflammatory cells such as regulatory T cells, IgA-producing plasma cells,
and immunosuppressive cytokines [17–19].
Unlike the cornea, the conjunctiva harbors a diverse group of immune cells (primarily
T cells) during its steady state. The conjunctival epithelial consists of goblet cells, CD8+ T
cells, and Langerhans cells, and the subepithelial layer of the conjunctiva consists of blood
vessels, lymphatics, macrophages, dendritic cells, fibroblasts, and mast cells [17–19]. This
distribution of immune cells in the conjunctival mucosa is known as the conjunctival-
associated lymphoid tissue (CALT) [18,20]. The CALT consists of conjunctival lymphoid
follicles (CLFs) and diffuse lymphoid effector tissue. CLFs consist of B cells and T cells,
whereas diffuse lymphoid effector tissue consists of mast cells, macrophages, IgA-secreting
plasma cells, and effector T cells [20–23].
The major effector cell responsible for the majority of allergic inflammation responses
is the mast cell [11,17]. In the acute phase, the cross-linking of IgE on the surface of
mast cells releases preformed mediators of histamine, tryptases and leukotrienes, which
play a major role in the clinical symptoms associated with allergy [24]. The late phase is
characterized by the release of various chemokines and inflammatory proteins and the
infiltration of eosinophils, basophils, T cells, neutrophils, and macrophages that lead to
further conjunctival inflammation [11,25].
The conjunctival epithelial has tight junctions that prevent allergens from gaining
access to the subepithelial layer [26,27]. In allergic conjunctivitis, this barrier function is
compromised due to the activation of the protease-activating receptor [26,28]. This leads
to the release of cytokines, chemokines, and adhesion molecules as part of the allergen-
included immune response [22]. These mediators are released by the conjunctival epithelial
cells and encourage the influx of more immune cells to the site of inflammation [26,28].
The immunopathogenic mechanisms of SAC and PAC are usually type-1 hypersensi-
tivity, IgE-mediated responses involving mast cells, whereas, in chronic allergic disorders
like VKC or AKC, the mechanisms are complex, including both IgE- and T-cell-mediated
responses. The immunological response to ocular allergy can be broken down into three
phases: sensitization, the early/acute phase, and the late/chronic phase.
Life 2024, 14, 650 4 of 14

3.1. Sensitization
The first phase of the IgE-mediated immune response is sensitization [29]. This phase
defines the initial exposure of the allergen to the conjunctival mucosa. Once an allergen
is deposited on the conjunctiva, it is processed and cleaved into peptide fragments by the
Langerhans cells, dendritic cells, and other antigen-presenting cells (APCs) on the mucosal
epithelium [29,30]. These peptide fragments are displayed on the surface of the APCs
by major histocompatibility complex (MHC) class II molecules [30]. The peptide/MHC
II complex interacts with the T-cell receptor (TCR) on naïve CD4+ T-lymphocytes. In
conjunction with other co-stimulatory molecules, the MCH-TCR interaction activates the
CD4+ T-lymphocytes into T Helper type 2 (Th2) lymphocytes [29,30]. The Th2 lymphocytes
then interact with B-lymphocytes, which trigger the release of Th2-lymphocyte-mediated
cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13) [30]. The release of IL-4 and other accessory
molecules leads to the conversion of B-lymphocytes into antibody-producing plasma cells.
These plasma cells undergo immunoglobulin class switching, which leads to the production
of antigen-specific IgE. These IgE antibodies are now specific to the initial allergen and
prime mast cells and basophils by binding to their surface receptors. These cells are now
ready for subsequent exposure to allergens and mark the completion of the process of
sensitization [29,30].

3.2. Early Phase

Once an allergen is re-presented to sensitized mast cells, an allergic reaction is initiated.
The natural environmental allergen binds to the IgE molecules on the mast cell receptors,
leading to the cross-linking of molecules and subsequently signaling the degranulation
of mast cells [29–31]. The activation and degranulation of mast cells lead to a cascade of
events, including the activation of the arachnoid acid pathway, the release of chemokines
(such as eotaxin), and the release of preformed mediators such as histamine and tryptase.
This marks the initiation of the early phase of allergic conjunctivitis. The increased levels of
histamine cause the dilation of blood vessels, the stimulation of nerve endings, and the acti-
vation of mucous-producing cells, leading to the clinical manifestations of an ocular allergic
reaction [30,31]. The presenting signs and symptoms include itching (a hallmark sign of ocu-
lar allergy), hyperemia, chemosis, tearing, mucus discharge, and eyelid swelling [2,3,29–31].
The mast cell degranulation also leads to the activation of vascular endothelial cells and
the release of adhesion molecules, chemokines, and cytokines [29–31]. This also leads to
the biosynthesis of lipid mediators such as prostaglandins and leukotrienes, resulting in
the recruitment of inflammatory cells into the conjunctival mucosa and initiating the late
phase of the allergic reaction [30].

3.3. Late Phase

The late phase of the allergic response typically occurs about 6–12 h after the initial
exposure. The release of chemokine factors from the early phase is responsible for the
recruitment and infiltration of eosinophils, basophils, neutrophils, Th2 lymphocytes, and
monocytes into the conjunctiva [29,30]. This phase also includes the maturation of Th2
lymphocytes and the production and release of Th2-mediated cytokines such as IL-4, IL-5,
and IL-13. IL-4 and IL-13 play an active role in the formation of giant papillae by stimulating
conjunctival fibroblasts and overexpressing IgE [29,30,32,33]. IL-5 recruits and activates
eosinophils which leads to continued inflammation, persistent symptoms, and an increased
likelihood of long-term tissue damage, as seen in VKC [30,32] (Figure 1).
Life 2024, 14,
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Step 2. Early Phase

Step 3. Late Phase
- Allergen re-exposure
Step 1. Sensitization - Chemokines recruit Th2-
- IgE on sensitized mast cells
1. Allergen Exposure lymphocytes, basophils,
leads to degranulation which
neutrophils, manocytes, and
2. Process allergen and display initiates the following:
eosinophils to site of
the produced antigen by 1. The arachnoid acid pathway inflammation
dendritic cells (antigen- (cyclooxygenase and
presenting cells) - Activation of endothelial cells
lipooxygenase)
and fibroblasts
3. MHC on DC and TCR interact 2. The release of chemokines
- Persistent release of
4. CD4+T cells turn into Th2 and chemotactic factors (which
inflammatory mediators and
lymphocytes recruit inflammatory cells)
damage of recruited cells causes
5. B cells turn into plasma cells 3. Release of histamine long-term symptamology and
and produce IgE - Leads to clinical signs and ocular surface damage
6. IgE sensitizes mast cells symptoms of allergic
conjunctivitis

Figure 1. Summary of the sensitization and early and late phases of ocular allergy [7–9].
Figure 1. Summary of the sensitization and early and late phases of ocular allergy [7–9].

4. Seasonal/Perennial Allergic Conjunctivitis (SAC/PAC)

most prevalent
The most prevalentform
formof ofallergic
allergicconjunctivitis
conjunctivitisisisattributed
attributedtotoseasonal
seasonal and
and per-
peren-
ennial
nial conjunctivitis.The
conjunctivitis. Thedifference
differenceisismostly
mostlybased
basedononthe
theperiodicity
periodicity and
and chronicity
chronicity ofof
the symptoms and the the type
type ofof allergens.
allergens.SACSACsymptoms
symptomsare arefrequently
frequentlycaused
causedbyby transi-
tran-
sient allergenssuch
ent allergens suchasas tree
tree andand grass
grass pollen
pollen andand usually
usually occur
occur in the
in the spring
spring andand sum-
summer
mer seasons
seasons [2,32,34].
[2,32,34]. SACSAC is frequently
is frequently associated
associated with
with allergicrhinitis
allergic rhinitis(hay
(hay fever)
fever) and
and
asthma [32,35]. On the other hand, perennialperennial allergic
allergic conjunctivitis
conjunctivitis (PAC) symptoms
symptoms are
typically caused by indoor allergens such as house mites, dust, pet dander, and and mold
mold
spores
spores and
andcause
causesymptoms
symptomspersistently
persistently throughout
throughoutthethe
year with
year periods
with of remission
periods and
of remission
exacerbation [2,32,34]. Many patients can also be polysensitized in that they
and exacerbation [2,32,34]. Many patients can also be polysensitized in that they experi- experience
ence perennial allergic symptoms with seasonal exacerbations [2]. Clinical presenting
Life 2024, 14, 650 6 of 14

perennial allergic symptoms with seasonal exacerbations [2]. Clinical presenting signs and
symptoms are usually bilateral and include itching (main symptom), hyperemia, tearing,
conjunctival papillae, and chemosis [2,32,34]. Conjunctival hyperemia is usually mild to
moderate in presentation, whereas conjunctival chemosis is moderate to severe and corneal
involvement is rarely present. In severe cases, symptoms of blurred vision and photophobia
can also be present [34]. Patients can also present without any symptoms at the visit; thus,
it is important to obtain a thorough history including symptoms around different times of
the year, systemic conditions, and current medications.

5. Vernal Keratoconjunctivitis (VKC)

VKC is a rare, bilateral, chronic, and severe form of allergic eye disease that can
permanently cause vision loss if left untreated [34]. It is more commonly present in young,
prepubescent males with a high incidence between 11 and 13 years of age [35,36]. The word
vernal means “spring”, as VKC typically presents with exacerbated symptoms during hot
spring–summer seasons [36,37]. The condition is more prevalent in the continents of Asia,
Africa, and South America where warm, dry, and windy climates are common [38]. Studies
indicate that nearly 50% of patients with VKC have atopic sensitization and a correlation
with atopic-associated conditions such as asthma, rhinitis, and eczema [29,30,37,39].
VKC is recognized due to its chronic allergic inflammation secondary to the activation
of Th2 lymphocytes and mediated cytokines [37,38]. The activated Th2 lymphocytes initiate
a cascade of cellular mechanisms that are responsible for the overexpression of IgE and
the recruitment and activation of eosinophils and mast cells through pro-inflammatory
cytokines (IL-4, IL-5, IL-13) [29,30]. Pathological examination of the tears of VKC patients
indicates increased levels of tumor necrosis factor (TNF-alpha), histamine, tryptase, and
IgG and IgE [30,38,39]. Th2 lymphocytes, mast cells, eosinophils, and their correlated
mediators play a key role in the ocular manifestation of VKC [30,38].
VKC typically presents with intense ocular symptoms including itching, tearing,
hyperemia, mucous/serous discharge, blurry vision, and photophobia associated with
corneal involvement [37,38]. The defining presenting signs of VKC are giant conjunctival
papillae of the upper tarsus and superior limbal region [37,39]. Another classic sign is
transient limbal deposits full of eosinophils and epithelium debris, better known as Horner–
Trantas Dots [38,39]. Repetitive, chronic eyelid–corneal interaction and cell-mediated
inflammation can lead to corneal complications such as punctate epithelial erosions (PEEs),
neovascularization, infectious keratitis, and corneal scarring [39]. Chronic and untreated
superficial keratopathies can extend deeper into Bowman’s layer and cause shield ulcers,
usually in the central or superior parts of the cornea [38,39]. Shield ulcers are a sight-
threatening condition found in 3–20% of VKC patients and can lead to permanent vision
loss [37,39]. Other complications correlated with severe VKC include dry eye disease,
keratoconus, and limbal stem cell deficiency [38,39].

6. Atopic Keratoconjunctivitis (AKC)

AKC is a bilateral, chronic, inflammatory condition of the ocular surface [32,40]. Most
patients present with accompanying systemic conditions such as atopic dermatitis and
eczema [40,41]. Signs of blepharitis and scurf are also commonly found on the lashes
with severe corneal findings such as neovascularization, scarring, and thinning [41]. It
frequently presents in late adolescence with peak presentation between the ages of 30 and
50 [40,41]. The immunopathology of AKC is like other allergic conjunctivitis types as it is
an IgE-mediated innate and Th2-lymphocyte-mediated inflammation of the eyelids and
ocular surface. Pathological findings indicate an increase in IgE, TNF-alpha, eosinophils,
mast cells, basophils, B cells, and T cells in the tears and conjunctiva [29].
Common presenting symptoms of AKC include typical pruritis, hyperemia, ropy
mucoid discharge, burning, and tearing. However, its distinguishing feature is thickened,
exudative, and eczematous eyelid lesions [39,41]. The eyelids also have a rough, sand-
like appearance, and scratching makes them itchier [39]. Many AKC patients also have
Life 2024, 14, 650 7 of 14

associated meibomian gland dysfunction and chronic blepharitis [39,40]. Other corneal
complications include pannus, neovascularization, punctate erosions, and ulcerations,
which can lead to corneal scarring and eventually permanent visual impairment [41]. If left
untreated or overtreated with steroids, these patients can develop keratoconus, glaucoma,
anterior and posterior subcapsular cataracts, and herpetic ocular disease [40,41].

7. Giant Papillary Conjunctivitis (GPC)

GPC is an inflammatory, non-infectious disease characterized by papillary hypertrophy
of the superior tarsal conjunctiva [7,42]. Even though there is papillary involvement, GPC is
not truly categorized as an allergic disease but rather presents when the superior palpebral
conjunctiva becomes in chronic contact with a foreign body [7,29]. Even though it mostly
occurs in conjunction with contact lens usage, it can occur because of an ocular prosthesis,
exposed suture, glaucoma filtering blebs, exposed scleral buckles, and many others [7,32,34].
Patients typically present with symptoms like an allergic etiology presentation including
mucous discharge, tearing, itching, and blurry vision. A key distinguishing factor, though,
is complaints of diminished contact lens tolerance and increased lens awareness. It is also
commonly termed contact lens papillary conjunctivitis with papillae more than 1mm in
size [7].
The pathophysiology of GPC is multifactorial and is likely initiated with mechanical
damage to the palpebral conjunctiva, leading to innate and adaptive immunity responses.
It is hypothesized that the proteinaceous debris on the anterior surface of the contact lens
acts as a presenting antigen to an IgE-bound mast cell on the conjunctival epithelium.
Pathological testing indicates that these patients have high amounts of IgE and Ig-G and in-
creased amounts of IL-3 and IL-4. Involved cell mediators include mast cells, basophils, Th2
lymphocytes, and the Th2-derived cytokines that perpetuate the inflammation process [7].

8. Contact Dermatoconjunctivitis (CDC)

CDC is a type IV delayed hypersensitivity reaction that impacts the eyelids and con-
junctiva [34]. Presenting symptoms typically include pruritis, hyperemia, papillary/follicular
reaction of the inferior palpebral conjunctiva, punctate keratitis, and dermatitis of the
surrounding periocular skin [30,34]. The reaction is a Th1-lymphocyte-mediated reac-
tion in which Langerhans cells process and present environmental allergens to T helper
cells in the regional lymph nodes [34]. The Th1-lymphocytes, in turn, release cytokines
and chemokines, activating and immigrating more inflammatory cells in the affected re-
gion [30,34]. Common allergens include mydriatic drugs, antibiotics, antiviral agents,
glaucoma drops, anesthetics, preservatives, and cosmetics. In sensitized individuals, the
immune response can take up to 48–72 h to develop, in contrast to toxic or irritant allergens
that can induce an innate immune response within 2–3 h [34].

9. Treatment
The management of allergic conjunctivitis includes preventative measures as well
as non-pharmacological and pharmacological treatment. The most effective treatment
option for complete prevention of symptoms is avoiding the allergen to prevent triggering
the initial cascade response [43–45]. However, complete avoidance is not always pos-
sible and requires identifying the offending agent. Recommendations can be provided
to create an environment where allergen exposure is reduced. During the symptomatic
period, preventative measures against airborne allergens include keeping windows closed,
using screen filters, avoiding eye rubbing, wearing sunglasses, washing hands after be-
ing outdoors, and increasing patient awareness of monitoring seasonal pollen counts to
avoid contact [1,43,44,46]. Allergens such as dust mites can be reduced by regularly wash-
ing/replacing bed covers, vacuuming the entire house at least weekly, decreasing humidity,
and removing/regularly cleaning any areas that particularly gather dust (carpets, curtains
etc.). Animal dander can be reduced by keeping animals outside, avoiding touching them
or rubbing one’s eyes after exposure, and washing hands/clothes after coming in con-
Life 2024, 14, 650 8 of 14

tact [43,44]. Other non-pharmacological interventions include using cool compresses to

decrease edema and hyperemia in irritated eyes. Artificial tears can also be recommended
to dilute and flush out allergens from the tear film and treat if they have any co-morbid
disease [46,47].
Despite many options available for avoidance or non-pharmacological intervention,
symptoms can persist, and the use of anti-allergy medication is needed to alleviate symp-
toms. With increased knowledge of the mechanism of action of ocular allergy, there has been
an increase in the number of available anti-allergic medications that target the tissues and
cells involved in an immunological response. A combination of topical and oral treatment
options may be utilized to address first-line treatment options for allergies. Anti-allergic
medications include topical vasoconstrictors, mast cell stabilizers, antihistamines, and
dual-action agents combining mast cell stabilizing with antihistamine properties (Table 1).

Table 1. Summary of topical treatment of allergic conjunctivitis [31,48].

Drug Class Mechanism of Action Common Examples Ocular Side Effects

Phenylephrine, Brimonidine,
Vasoconstrictors a-adrenergic agonists (mainly Rebound redness,
Ephedrine, Naphazoline,
(Decongestants) stimulation of a-1 receptors) conjunctivitis medicamentosa
Tetrahydrozoline
Competitive blockage of histamine
Levocabastine,
Antihistamines receptors (all block H1 with some Dryness, irritation
Emedastine
blocking H2, H3 and/or H4)
Sodium cromoglycate,
Inhibit degranulation of mast cell Nedocromil sodium,
Mast Cell Stabilizers Stinging, Burning
and consequent histamine release Pemirolast,
Lodoxamide
Inverse agonists of histamine Olopatadine, Ketotifen,
Dual-Acting Agents receptors and prevent mast cell Azelastine Burning, headache, dry eye
degranulation Epinastine, Alcaftadine
Inhibits cyclooxygenase enzymes
Ketorolac, Diclofenac Stinging, burning,
NSAIDS (COX-1 and COX-2) resulting in
Flurbiprofen corneal melt
inhibition of prostaglandins
Inhibits phospholipase A resulting Dexamethasone, Prednisolone, Increased intraocular pressure,
Corticosteroids in the inhibition of prostaglandins Loteprednol, cataract formation, delayed
and leukotriene synthesis Fluorometholone, Rimexalone wound healing
Inhibiting production of IL-2
Immunomodulators Cyclosporin A, Tacrolimus resulting in inhibition of T-cell Burning, irritation
activation

9.1. Topical Vasoconstrictors (Decongestants)

Topical vasoconstrictors (decongestants) were the first ocular medication approved for
the treatment of allergic conjunctivitis. Over-the-counter (OTC) topical vasoconstrictors are
effective at temporarily decreasing conjunctival hyperemia by stimulating alpha-adrenergic
receptors [48]. Alpha-adrenergic agonists cause vasoconstriction of conjunctival blood
vessels, resulting in decongestion and whitening of the eye [34,48]. However, the use of
these agonists can lead to side effects such as rebound hyperemia and tachyphylaxis and,
chronically, can lead to conjunctivitis medicamentosa [32,48]. Commonly used topical
vasoconstrictors are oxymetazoline, naphazoline, tetrahydrozoline, and phenylephrine.
These are best utilized as short-term solutions and should be avoided in narrow-angle
glaucoma and cardiovascular issues [34,48]. These should not be recommended as a
standalone treatment and used in combination with antihistamines for the treatment of
allergic conjunctivitis [1,34].
Life 2024, 14, 650 9 of 14

9.2. Mast Cell Stabilizers

Mast cell stabilizers work by preventing the degranulation of sensitized mast cells,
thus stopping the release of histamine and other inflammatory mediators [43,49]. Since
mast cell stabilizers act before the mast cell is degranulated, they rarely have an impact on
the inflammatory mediators once they are already released [48,49]. In other words, mast
cell stabilizers are not effective once the patient is symptomatic, and clinical trials have
had a difficult time showing their efficacy [48]. Since there are other quicker and more
effective treatment agents available on the market, mast cell stabilizers are rarely used as
monotherapy. The most common mast cell stabilizers used for allergic conjunctivitis are
sodium lodoxamide 0.1% (Alomide), cromoglycate 2%, and nedocromil 2% [43,45]. Mast
cell stabilizers can be utilized as a prophylactic measure to prevent mast cell degranulation
for repeated exposures to the allergen [32,48].

9.3. Antihistamines
Antihistamines are competitive antagonists of histamine receptors that are present
in the conjunctiva and eyelids. Once stimulated, these receptors lead to capillary dilation
and increased vascular permeability, which leads to common allergic symptoms of itching
and edema. Thus, antihistamines work by preventing the binding of histamine to H1
receptors and preventing the cascade of inflammatory events. Ocularly, only H1 receptors
are available [50].
Oral antihistamines are easily accessible and a great add-on therapy in addition to
topical allergy medications. First-generation antihistamines such as Diphenhydramine
(Benadryl) are avoided due to their ability to cross the blood–brain barrier and produce
unwanted side effects such as sleepiness, confusion, urinary retention, and worsening
dryness [50,51]. On the other hand, second-generation antihistamines are much more
desirable as they do not cross the blood–brain barrier and produce fewer anticholinergic
effects [51]. Examples of second-generation oral antihistamines include fexofenadine
(Allegra), loratadine (Claritin), and cetirizine (Zyrtec), all of which are readily available
OTC. Oral antihistamines can be utilized as an adjunct therapy, especially when non-ocular
allergy symptoms such as rhinitis are present [48].
First-generation topical antihistamines, antazoline and pheniramine, are available
OTC; however, they are poorly tolerated and have a limited potency and short duration
of effects [51,52]. These are often combined with the vasoconstrictors naphazoline and
tetrahydrozoline, more commonly known as Visine or Clear Eyes. Second-generation
topical antihistamines, levocabastine and emedastine, have a longer duration of action
(4 to 6 h) and, thus, comparatively decreased dosing compared to first-generation an-
tihistamines [50,51]. These were the first antihistamines to impact both the early and
later responses of the immune system. Even though the newer-generation antihistamines
showed improvements, they were discontinued in the United States [48].

9.4. Dual-Acting Agents (Mast Cell Stabilizers/Antihistamines)

Dual-acting agents combine the properties of mast cell stabilizers and H1 receptor
antagonists (antihistamines) to demonstrate great efficacy and safety when compared to
placebo [52]. Examples of dual-acting agents include azelastine, epinastine, alcaftadine,
bepotastine, ketotifen, and olopatadine [48,51]. Some dual-acting agents, such as epinas-
tine, act on both H1 receptors and H2 receptors by reducing pruritis and vasodilation,
respectively, while others, such as azelastine, also inhibit platelet-activating factor (PAF)
activity and reduce the expression of interleukin adhesion molecule 1 (ICAM-1) [48,50].
These agents have been demonstrated to act quickly to reduce symptoms with a lasting
effect because of their ability to inhibit the release of mediators and stop the recruitment of
inflammatory cells [48,49].
Olopatadine 0.1% (Pataday Twice Daily Relief) was the first topical anti-allergy medi-
cation that was approved for twice-daily usage [43]. These agents are all preserved with a
surfactant called benzalkonium chloride that may cause ocular surface toxicity [52]. These
Life 2024, 14, 650 10 of 14

are now considered the first line of treatment for allergic eye disease and are the most
common ophthalmic agents recommended by eye care practitioners and allergists [43].
Thus, these agents can be used prophylactically to prevent mast cell degranulation and
acutely following the onset of symptoms [53].
Compared to placebo, olopatadine has been found to improve symptoms of eyelid
edema, hyperemia, chemosis, pruritis, and overall quality of life. Multiple randomized
control trials have compared ketotifen and olopatadine. One meta-analysis found improve-
ment in symptoms of itching after 14 days in favor of olopatadine 0.1% when compared to
ketotifen 0.025% [54]. Before 2020, olopatadine was only available as a prescription medica-
tion, and ketotifen, in the form of Zaditor or Alaway, was clinically commonly prescribed
as the first line of relief as an OTC medication. Within the last 4 years, olopatadine became
available OTC and has gained popularity to become clinically superior to ketotifen in terms
of efficacy.

9.5. Topical NSAIDs

Topical nonsteroidal anti-inflammatory drugs (NSAIDS) act by blocking the cyclooxy-
genase enzymes (COX-1 and COX-2) within the cyclooxygenase pathway, resulting in
the inhibition of inflammatory mediators such as prostaglandins and leukotrienes [48,49].
These drugs have proven efficacy against conjunctival hyperemia, pruritus, pain, and
irritation [48]. Topical NSAID agents commonly associated with the relief of ocular allergy
symptoms include ketorolac, diclofenac, indomethacin, and flurbiprofen [48,49]. Although
ketorolac has been approved for treating allergic conjunctivitis, studies have indicated that
it is less effective compared to topical antihistamine agents [48,49,55]. Moreover, these
agents can cause burning and stinging sensations upon instillation, so long-term compli-
ance is an issue. Thus, NSAIDs may be used for temporary relief of itching and hyperemia
compared to no treatment; however, they do not aid with symptoms of mucous discharge,
chemosis, and corneal damage, so alternative methods should be considered [48,49,55,56].

9.6. Corticosteroids
Glucocorticoids can be an effective form of treatment against more severe and chronic
forms of allergic conjunctivitis as they are well-known to be fast and effective anti-inflammatory
agents [49,51,57]. This efficacy is the result of a variety of effects on the allergy cascade,
including delaying/inhibiting the release of inflammatory mediators to suppress the late-
phase immunological response [49,57]. Specifically, this class of medications interferes with
protein synthesis and stops phospholipase A2, the enzyme responsible for arachnoid acid,
and inhibits the production of leukotrienes and prostaglandins [48,49,58]. Steroids also
impact other aspects of the immunological response including inhibiting the proliferation
of mast cells, decreasing the production of eosinophils, and reducing the availability of
histamine [59,60]. With these tremendous anti-inflammatory effects comes the cost of
ocular adverse effects. Corticosteroid side effects include delayed wound healing, cataract
formation, elevated intraocular pressure, and superinfections, indicating the need for close
monitoring [34,49,58–60]. Ketone-based medications such as prednisolone and dexametha-
sone are highly potent with a high efficacy; however, they are also accompanied by a large
likelihood of steroid-induced ocular complications [31,48,59]. On the other hand, ester-
based or “soft” steroids are preferred for the treatment of moderate inflammation in allergic
conjunctivitis, as they are more easily metabolized and carry fewer side effects [31,60,61].
Loteprednol etabonate 0.2% (which is approved for SAC) or fluorometholone (FML) 0.1%
may be used on a short-term basis and in adjunct with mast cell stabilizers to combat signs
of acute inflammation due to allergies [61,62]. Even with the milder form, close monitoring
and caution should be exercised with any steroids to avoid long-term side effects [62].

9.7. Immunomodulators/Immunotherapy
Immunomodulatory agents are a nonsteroidal alternative to the therapeutic manage-
ment of allergic conjunctivitis. They inhibit T-lymphocyte activation and proliferation,
Life 2024, 14, 650 11 of 14

which prevents histamine release from mast cells and basophils, preventing chronic inflam-
matory damage to the ocular surface [29,31]. Both cyclosporin A and tacrolimus have been
evaluated for safety and efficacy in more severe forms of allergic conjunctivitis including
VKC and AKC and have been effective in reducing ocular signs and symptoms [63–65].
These drugs are calcineurin inhibitors, which allows them to be safe for long-term topical
use without lasting side effects [29,31]. Allergen-specific immunotherapy is another highly
effective treatment against severe allergic conjunctivitis/rhinoconjunctivitis and is recom-
mended by the World Health Organization as an essential component of allergy manage-
ment [49,52]. Both sublingual immunotherapy (SLIT) and subcutaneous immunotherapy
(SCIT) seem to be effective routes of administration for treating nasal and ocular symptoms
of severe allergy symptoms [48,52]. This mode of therapy works by introducing increasing
doses of the allergen to a sensitized individual which would lead to desensitization and
reduced allergic symptomology even after treatment cessation [51,52].

9.8. Contact Lenses

Typically, the treatment of allergic conjunctivitis includes temporary or permanent
cessation of contact lens use [66]. However, patients may not be happy with the need to wear
spectacles, and different contact lens types may be used to suppress/combat symptoms.
When fitting a patient with a diagnosed ocular allergy, it is important to consider a daily
disposable lens and avoid extended wear [67]. Moreover, the regular replacement of contact
lenses and good contact lens hygiene is recommended to stop allergic exacerbations. Recent
studies have also explored contact lenses as a therapeutic vehicle to release pharmaceuticals
in a controlled dose, such as an antihistamine [68–70]. This could potentially increase
patient compliance with topical treatments and allow controlled release throughout the day
without needing to remember frequent dosing [71]. Another option is rigid gas-permeable
scleral contact lenses that can shield the eye from mechanical trauma of the lids (especially
in cases of GPC), prevent tear film evaporation, and provide a lubricated chamber for
corneal protection and healing [72,73].

10. Conclusions
Allergic conjunctivitis is a highly prevalent ocular disease that continues to be un-
derdiagnosed and undertreated. Its signs and symptoms can cause everyday discomfort
and can significantly impair quality of life. Allergic conjunctivitis is largely a type-1 IgE-
mediated hypersensitivity reaction where eosinophils, mast cells, and Th2 lymphocytes
play a pivotal role in the sensitization and early and late phases of the immunological
response. A thorough history and slit-lamp examination are key to correctly identify
allergic eye disease and rule out any other underlying pathology. A wide range of non-
pharmacological and pharmacological treatments are available that can be tailored to the
needs of each patient. Eyecare specialists, primary care providers, and allergists each play
an important role in patient education and management. This review article highlights the
most up-to-date information regarding diagnosis, pathogenesis, and therapeutic options
for various forms of allergic conjunctivitis.

Funding: This research received no external funding.

Conflicts of Interest: The author declares no conflicts of interest.

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