Ocular allergy

Ocular allergy
Pornsiri Sae-lim , MD
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

Outline
• Anatomy and Immunology of the Eye
• Allergic Diseases of the Eye
• Allergic Conjunctivitis (Seasonal/ Perennial)
• Atopic Keratoconjunctivitis
• Vernal Keratoconjunctivitis
• Giant Papillary Conjunctivitis
• Management
• Conjunctival Provocation Test

Anatomy
Neil P. Barney, et al. Middleton’s Allergy. 9th Ed.;2020

Immunology of the Eye
• Tear Film
• Eye surface has tear volume 2.6 - 7.4 mcL
• Normal turnover rate for tears = 12 - 16% per minute
• Aqueous portion: electrolytes, carbohydrates, urea, amino acids, lipids,
enzymes, tear-specific prealbumin, IgA, IgG, IgM, IgE, tryptase, histamine,
lysozyme, lactoferrin, plasmin, and ceruloplasmin
• Mucin and lipid components
• Inflammatory conditions may alter the volume or composition
Bielory L. J Allergy Clin Immunol. 2000;106:805-16

• Lymphocytes
• Intraepithelial lymphocytes - predominantly CD8+
• Substantia propria - equally distributed CD4+ and CD8+
populations Cellular Adhesion Molecules
• Ocular epithelium
• expression of intercellular adhesion molecule-1 (ICAM1,CD54)
Bielory L. J Allergy Clin Immunol. 2000;106:805-16

Mast Cells
• Normally, mast cells found in choroid, ciliary body, iris, and optic
nerve
• Rarely present in conjunctiva , NOT found in cornea and retina
• Conjunctival epithelial cells and mast cells - source of chemokines
(macrophage inflammatory protein 1, RANTES, eotaxin, IL-8) involved
in allergic inflammation
• MCT (tryptase) and MCTC (tryptase/chymase) phenotypes
• Conjunctival epithelium: MCT phenotype
• Substantia propria: 95% MCTC Bielory L. J Allergy Clin Immunol. 2000;106:805-16

Mast cells mediator
Histamine
• Vascular permeability, smooth muscle contraction, mucus secretion,
inflammatory cell migration, cellular activation, and modulation of T
cell function
Arachidonic acid metabolites and tryptase
• Specifically involved in regulation many same processes

Classification of ocular hypersensitivity disorder
Diagnosing and managing allergic conjunctivitis in childhood: the allergist’s perspective.Pediatric Allergy and Immunology 2019

Pathogenesis
• TH2-Mediated Responses
• Alternative T-Helper Cell Pathways
• Ocular Surface Barrier Dysfunction
• Tissue Remodeling in Severe Disease
The spectrum of allergic ocular diseases-2020." Annals of Allergy, Asthma & Immunology 2020

TH2-Mediated Responses
• MCs are critical in ocular allergy
• SAC and PAC result from classic type I hypersensitivity, whereby
• Allergen-complexed IgE binds the high-affinity Fc-epsilon
receptor I on MCs with consequent mediator release
• The largest contributors to disease severity are allergen load on
the ocular surface and local IgE production and tear IgE levels

TH2-Mediated Responses
Late-phase reaction prominent in chronic ocular allergy, especially VKC and AKC
• he TH2 cytokines : (IL)-4, IL-5, and IL-13
• Induce B-cell activation and IgE production
• eosinophilic infiltration, and mucus production
• CD11b dendritic cells play a key role in TH2-driven ocular allergy
• MC mediators also contribute to late-phase inflammation with up-regulation of
adhesion molecules
• mediate conjunctival accumulation of eosinophils, neutrophils, basophils, and Tcells
• The degree of cellular infiltration correlates with disease severity

Alternative T-Helper Cell Pathways
• The principal TH1 cytokine, interferon gamma, is elevated in tear
cytokine profiles during the delayed phase at 24 to 48 hours after
allergen exposure
• Interferon gamma has been linked with chronic and severe forms of AC
• The role of TH17 cells is poorly defined

Ocular Surface Barrier Dysfunction
• Chronic ocular allergy is associated with barrier dysfunction and tear
film instability, which may result in corneal damage
• Histamine and TH2 cytokines, particularly IL-13, directly activate
conjunctival goblet cells and drive mucin secretion
• Downregulation of the major protective ocular mucin MUC5AC is
found in severe cases
• Increase in other goblet cell mucins that may contribute to
symptoms

Tissue Remodeling in Severe Disease
• The formation of giant papillae , activated fibroblasts, and an
inflammatory cell infiltrate
• Mechanism of formation is unclear
• IL-13 stimulates periostin production from tissue fibroblasts
and activates epithelial cells and fibroblasts.
• Copious amounts of periostin have been found in tears from
patients with ocular allergy, particularly AKC, and strongly
correlated with tear IL-13

IgE‐mediated allergy and ocular allergy symptoms
Diagnosing and managing allergic conjunctivitis in childhood: the allergist’s perspective.Pediatric Allergy and Immunology 2019

Bielory, Leonard, et al. "ICON: diagnosis and management of allergic conjunctivitis." Annals of Allergy, Asthma & Immunology 124.2 (2020)

Allergic conjunctivitis
• Bilateral, self-limiting conjunctival inflammatory
process
• Sensitized individuals, no gender difference
• Two forms
• Seasonal “hay fever conjunctivitis” (spring, fall) - related to
pollens (e.g., grass, trees, ragweed)
• Perennial - related to animal dander, dust mites, etc

AC - Epidemiology
• in general tend to be considerably underreported
• Most reports agree that allergic conjunctivitis affects up to 20% of the
population
• Prevalence
• In a survey conducted by the American College of Allergy, Asthma, and
Immunology (ACAAI) - 35% of people responding in family interviews
reported having allergies
• 60% of all allergic rhinitis sufferers have associated allergic conjunctivitis

AC - Pathogenesis and Etiology
• Antigen cross-linking of immunoglobulin E (IgE) antibody bound to
the high-affinity IgE receptor (FcεRI) on mast cells
• Release of both preformed (granule associated, e.g., histamine and
tryptase) and newly synthesized mediators (e.g., arachidonic acid
metabolites)

AC – Histopathologic & laboratory
manifestation
• Increased mast cells (MCT phenotype) and eosinophils in the
conjunctival epithelium of individuals with SAC and PAC
• 95% of mast cells in substantia propria are MCTC;
• total number of mast cells increased in allergic conjunctivitis
• Cytokines released by mast cells contribute signals initiating
infiltration of inflammatory white blood cells, such as eosinophils

AC : Clinical Manifestation
• Itching can range from mild to severe.
• Other symptoms
• Tearing (watery discharge), redness, swelling, burning, a sensation of fullness
in the eyes or eyelids, an urge to rub the eyes, sensitivity to light, and
occasionally blurred vision
• Conjunctival hyperemia and chemosis with palpebral edema
• Hyperemia is the result of vascular dilatation
• Chemosis is secondary to altered permeability of postcapillary venules
• Allergic shiner : decreased venous return in the skin and subcutaneous tissue

AC : treatment
• Best treatment = Avoidance of specific allergen
• Avoidance of scratching or rubbing
• Application of cool compresses
• Use of artificial tears
• Refrigeration of topical ocular medications are practical measures to
alleviate discomfort
• Oral antihistamines may help to relieve eye itch, first-generation
drugs also may decrease tear production

AC : treatment
• Dual-acting topical ocular medication
• Treatment of choice for mild to moderate allergic conjunctivitis
• Benefits most if started before height of symptom severity
• Rapid onset of relief because high histamine H1 receptor affinity
• In severe disease - combination therapy ; topical medications
(antihistamines, mast cell stabilizers, nonsteroidal antiinflammatory
drugs [NSAIDs], or combinations), AND oral antihistamines
• Nonsteroidal drugs inhibit cyclooxygenase -> decreased
formation of prostaglandins and thromboxanes, but not
leukotrienes

AC : treatment
• Topical steroids
• In extreme cases - topical steroid four times a day
• intraocular pressure measured every 3 months and evaluated for
cataract annually
• Immunotherapy - may be beneficial in decreasing the severity of
future ocular allergy symptoms
• Sublingual immunotherapy specifically for PAC has been
demonstrated to be effective in relieving symptoms

Efficacy of the SQ HDM SLIT-tablet on House Dust Mite Induced Allergic Conjunctivitis. Journal of Allergy and Clinical Immunology 141.2 (2018)

Atopic Keratoconjunctivitis (AKC)

Atopic Keratoconjunctivitis (AKC)
• bilateral, chronic inflammation of the conjunctiva and lids
associated with atopic dermatitis
• Reported prevalence of atopic dermatitis in the general population
ranges from 3% to 17%.

AKC : Epidemiology
• The onset of disease usually is in the 2-5 decades of life
• Majority of patients with atopic dermatitis are diagnosed by the age
of 5 years.
• Series report the onset of symptoms between the ages of 7 and 76
• Male-to-female ratio is 2.4 : 1
• No racial or geographic predilection is reported

AKC : Pathogenesis and Etiology
• Type I and type IV hypersensitivity mechanisms
• Increase mast cells, eosinophils and CD4+ are found in the
conjunctival epithelium
• The substantia propria
• Increased number of mast cells
• Increased CD4/CD8 ratios, B cells, HLA-DR staining, and Langerhans
cells

AKC: Tear Analysis
• Increased levels of IgE as well as numerous other mediators of allergic
inflammation:
• Eosinophil cationic protein (reduced after papilla resection),
• Activated B cells, eotaxin, eosinophil-derived neurotoxin, soluble IL-2
receptor, IL-4, IL-5, IL-6
• HDM specific secretory immunoglobulin A (sIgA)
• Osteopontin

AKC : Clinical Manifestation
• Itching is the major symptom of AKC
• Watering, mucous discharge, redness, blurring of vision,
photophobia, and pain
• Exacerbation of symptoms most frequently occurs in the
presence of fur-bearing animals and pets

AKC: Diagnosis ( History )
• Severe, persistent, periocular itching associated with dermatitis
• Family history atopic diseases
• Comorbid: asthma (65%) or allergic rhinitis (65%)
• The serum level of IgE often is elevated
• Giemsa staining tarsal conjunctiva : eosinophil
• Ddx
• The lack of contact lens wear aids in differentiating AKC from GPC
• AKC usually are older and exhibit major lid skin involvement compared with
patients with VKC

• The periocular skin often shows a scaling, flaking dermatitis with a
reddened base and lagophthalmos
• Lateral canthal ulceration and cracking as well as lash loss (madarosis)
• The lid margins: meibomitis, keratinization, and punctal ectropion.
• The conjunctiva of the tarsal surfaces : papillary reaction and possibly
pale white edema
• Horner-Trantas dots
AKC: Diagnosis ( Physical examination )

• Significant vision loss :
• Pathologic conditions of the cornea.
• Punctate epithelial keratopathy is the most common corneal finding.
• Persistent epithelial defects, scarring, microbial ulceration, and
neovascularization are the main corneal causes for decreased vision
• Herpetic keratitis : 14% to 17.8%
• Keratoconus : 6.7% to 16.2%
• Cataract : steroids are frequently used in the treatment of the disease
AKC: Diagnosis ( Physical examination )

AKC: Treatment
• The topical application of a vasoconstrictor-antihistamine
combination may bring transient relief of symptoms
• The topical administration of steroids : prednisolone acetate
• 4 times per day for 7 to 10 days is clearly beneficial in controlling symptoms
and signs
• Overuse : causing cataract and glaucoma

• Topical mast cell stabilizers 1-4 times daily are recommended
yearround in patients with perennial symptoms
• Cyclosporine and tacrolimus are effective for treating AKC as well as
reducing the amount of topical steroid use
• Exacerbation occurs
• 1-4 times daily concurrent with a short burst of topical steroids (for 7 to 10
days)
AKC: Treatment

Vernal Keratoconjunctivitis
• Chronic, bilateral, inflammatory condition most commonly involving the upper
tarsal conjunctiva.
• Onset before age of 10 years with resolution usually occur during late puberty
• Males predominate in younger ages
• Male-to-female ratio nearly equal in older patients
• Young males in dry, hot climates
• Atopic history such as eczema or asthma present in 40 - 75% of patients
• Family history of atopy found 40 - 60%
• The incidence of VKC varies depending on geographic region
• Limbal VKC : central and southern African countries
• Palpebral VKC : Europe and the Americas

VKC : Pathogenesis
• Epithelium contains large numbers of mast cells (predominantly MCTC)
and eosinophils
• Eosinophil major basic protein deposited diffusely throughout the
conjunctiva
• Basophils, neutrophils, and mononuclear cells in hyperplastic
epithelium
• Some neurotransmitters and receptors: integrins, growth factors, Toll-
like receptor 2 (TLR2), and the inflammation-modulating peptide
thymosin-β4 are found greater amounts in VKC epithelium

VKC : Pathogenesis
• Substantia propria - increased mast cells (predominant again MCTC)
with fibroblast growth factor (b-FGF)
• Increased collagen and fibroblasts
• Corneal epithelium express ICAM-1
• Tear analysis: allergen-specific IgE and IgG, elevated histamine,
tryptase, and soluble IL-6 receptor (sIL-6R)
• VKC reported occur in patients with hyper-IgE syndrome

VKC : Clinical Features
• Severe itching and photophobia - main symptoms
• Foreign body sensation, ptosis, thick mucous discharge, and
blepharospasm
• Uninvolved skin and lid margin compared with AKC
• Conjunctiva - papillary response, principally in limbus or upper tarsus,
greater than 1 mm in diameter and flattened tops
• “Cobblestone” papillae
• Thick, ropy mucus

VKC : Clinical Features
Long Term Sequalae
• Corneal changes : punctate epithelial keratitis
• Subepithelial ringlike scar
• Pseudogerontoxon :
• waxing and waning superficial stromal, gray-white
deposition
• Iritis

VKC : treatment
• Allergen avoidance
• Cold Compress
• Allergen immunotherapy in VKC has limitations
• Significant seasonal exacerbation: short-term, high-dose pulse
regimen of topical steroids - Dexamethasone 0.1% or Prednisolone
phosphate 1% 8 times daily for 1 week and tapered rapidly
• Cromolyn sodium, mast cell stabilizer - effective
• Exacerbation: steroid pulse dose and begin using a mast cell–
stabilizing drug topically or dual-acting drug

VKC : treatment
• Oral medications: steroids, antihistamines, and nonsteroidal
antiinflammatory agents
• Severe bilateral vision-threatening disease - oral steroids
• Topical calcineurin inhibitors of cyclosporine and tacrolimus –
effective
• Corneal shield ulcer - antibiotic-steroid ointment and occlusive
therapy -> superficial keratectomy promote epithelial healing

Giant Papillary Conjunctivitis

Giant Papillary Conjunctivitis
• Chronic inflammatory process leads to the production of
giant papillae on the tarsal conjunctiva lining the upper
eyelids
• Risk factors
• Most often associated with soft contact lens wear
• Ocular suture

GPS: Epidemiology
• GPC may affect as many as 20% of soft contact lens wearers
• Disposable contact lenses during sleep increase risks 3 times
more likely to have GPC symptoms
• Risk factors
• Patients with asthma, SAR
• No gender or race predilection has been reported

GPS: Pathogenesis and Etiology
• Mechanical trauma secondary to poor contact lens fit or
chronic irritation of the upper eyelid
• Cytologic scrapings from the conjunctiva of patients with
GPC exhibit an infiltrate containing lymphocytes, plasma
cells, mast cells, eosinophils, and basophils

GPS: Tear Analysis
• No significant increase in mast cells in the substantia propria is seen
• Number of mast cells present in the conjunctival tissue is not
increased overall
• Increased histamine is measured in tears
• Mast cell degranulation is less (30%) than that observed in patients
with VKC (80%)
• Tryptase also has been found
• Eotaxin is not found

GPS: Clinical Features
• Ocular itching after lens removal, redness, burning, increased mucus
discharge in the morning, photophobia, and decreased contact lens
tolerance.
• Blurred vision can result from deposits on the contact lens, or from
displacement of the contact lens secondary to the superior eyelid
papillary hypertrophy .
• The initial clinical presentation may be months or even years after the
patient has begun wearing contact lenses.

GPS: Diagnosis
• Mild cases - small papillae, absence of visible papillae
• Chronic GPC - tear deficiency may be contributing factor
• Redness of the upper eyelid - earliest signs of GPC
• Abnormal thickening of conjunctiva may progress to opacification as
inflammatory cells enter the tissue
• Recurrent irritation -> formation of enlarged papillae, increased
mucus, inflammatory mediators, and decrease in wear time

GPS: Treatment
• Reducing symptoms
• Reduction to abstinence in wearing contact lens
• Once-a-day use contact lenses may be a consideration for persistent
cases of GPC
• Topical mast cell stabilizers
• Dual-action drugs - relieve the itch and decrease the inflammation
• Topical steroid Loteprednol etabonate, 0.5% used 4 times daily for 4
weeks, reduced signs of GPC

Current Knowledge in Allergic Conjunctivitis, Turkish Journal of Ophthalmology 51.1 (2021)

• Retrospective medical records review
• Children with a history of allergic conjunctivitis, aged 4-18 years,
• Pediatric allergy clinic of Siriraj Hospital between Jan 2014 and Feb 2015 were
performed
Asian Pacific journal of allergy and immunology (2020)

• PAC was the most common type (61.6%), followed by SAC (21.3%), VKC (12.2%), and AKC (4.9%)
• Male preponderance was found in all groups.
• Mean age of onset was 6.8 ± 2.8 years
• VKC have earlier onset (5.8 ± 2.4 years) than the other
• Allergic rhinitis was the most common co-morbidity (97.6%)

• Common sensitized allergen is
house-dust mites (86.1%)
• Distribution types of aeroallergen
sensitization were not different
between each type of ocular allergy
• No correlation between number of
allergen sensitizations and mean
wheal diameters of specific allergen
with the severity of disease

Among 20 patients with VKC
• 8 of them have palpebral typed (90%) & only 2 patients have limbal typed (10%)
• Most common signs of VKC were giant papillary, and Trantas dot
• Corneal ulcer (25%) were found only in VKC patients
• 1 patient in VKC group had unilateral ptosis, but it was reversible during 1 year of
treatment
Blepharitis might be a specific sign of AKC, found only in AKC patients (100%; p < 0.001) Asian Pacific journal of allergy and immunology (2020)
• M/C presentation : eye itching, shiner,
hyperemia
• Severe form (VKC, AKC) usually present
with eye itching, hyperemia, and
photophobia
• Photophobia is found only in severe
form (VKC, AKC)

Figure . Prognosis of patients with severe conjunctivitis. (A) Vernal keratoconjunctivitis (VKC) (B) Atopic keratoconjunctivitis (AKC)
Complete remission : discontinue topical tacrolimus eye ointment more than 1 year without any symptoms
Partial remission : relapsing condition during cessation period of topical tacrolimus eye ointment
• Overall remission was found 35% in VKC group , 63% in AKC group
• Median duration of treatment was 20.5 months in VKC group , 11 months in AKC group

1. Topical antihistamines, mast cell stabilizers
and dual-acting agents
• All topical drugs are effective in reducing signs and symptoms
• Topical antihistamines and dual‐acting drugs may have lead to a quicker onset
symptom relief when compared to mast cell stabilizers
• Dual‐acting agents with combined mast cell stabilizer and antihistaminic function
provide better symptom control
• Mast cell stabilizers such as chromones require multiple daily doses and have a
delayed onset of action, hence are less preferable
• SAC and PAC can be managed using the same drugs
• Topical antihistamines and mast cell stabilizers can be used in VKC and AKC
• All these drugs can be used in combination
A. Leonardi, et al. Allergy. 2019;1-20

2. Topical alpha-adrenergic agonists
(vasoconstrictors)
• Vasoconstrictors alleviate only hyperemia
• They should be used with caution and for a short period of 5‐7 days
because of side effects and tachyphylaxis

3. Topical prostaglandin and oral leukotriene
inhibitors
• NSAIDs are effective for their short‐term use but do not target
specific inflammatory mechanisms
• In adult SAC patients, leukotriene inhibitors are less efficacious than
oral antihistamines

4. Systemic antihistamines
• Systemic antihistamines should be used in case of comorbidities that
require it use
• Some systemic antihistamines may induce drying effects, particularly
relevant at the ocular surface barrier

5. Corticosteroids
• Topical corticosteroids eye drops
• should be used with caution under ophthalmologist's monitoring and preferably
for shorter duration due to the high risk of local and potential blinding side effects
• For the treatment of SAC and PAC, topical corticosteroids are rarely needed
• Corticosteroid eye drops can be used preferably as short, pulsed therapy in
acute exacerbations of OA, especially in VKC and AKC or when the cornea is
involved under ophthalmologist supervision
• INCs are effective and well tolerated in the treatment of ocular symptoms
associated with ARC
• INCs should not be used if only ocular signs and symptoms are present
• Topical skin corticosteroid applications should be used in the acute phase of
eyelid eczema, with a preference for low potency corticosteroids

6. Calcineurin Inhibitors
• CsA eye drops are not recommended for SAC and PAC
• CsA eye drops may be used as a steroid‐sparing agent in steroid-
dependent cases of VKC or AKC
• Tacrolimus off‐label eye drops/ointment should be reserved for use in
severe VKC and AKC cases refractory to CsA

7. Allergen-specific immunotherapy
• AIT may be considered in cases of failure of first‐line treatments or to
modify the natural course of ocular allergic disease
• AIT can only be considered only when IgE‐mediated hypersensitivity is
evidenced
• Before AIT is recommended, control of symptoms of allergic
conjunctivitis and other systemic symptoms to assess suitability
should be taken into account
• AIT is effective for the treatment of allergic conjunctivitis due to
grass pollen and house dust mite

8. Biologics
• Omalizumab
Used in refractory VKC and AKC and reported in a few case
reports/series
Control of the disease was partial or complete in most patients, but
poor response was noted in some with very severe presentation
• Dupilumab
Dupilumab‐associated ocular inflammation leading to cicatricial
ectropion has been reported
suggesting that this drug may not be ideal for the treatment of AKC
with eyelid eczema

9. Nonpharmacological
• First line of management is identification of offending allergens and
avoidance measures
• During exacerbations in VKC, to minimize the exposure to nonspecific
triggering factors, such as sun, wind, and salty water, patients should use
measures such as sunglasses, hats with visors, and swimming goggles.
Frequent hand, face, lid hygiene, and eye washing should also be suggested
• Cold compresses may provide decongestant effect
• Tear substitutes aid in stabilization of the tear film providing a better
mucosal barrier against allergens, acting as an eyewash and diluting the
concentration of mediators in the tear film
• Psychological support

Conjunctival Provocation Test
• Developed by Abelson and co-workers
• The CPT protocol: double-blind, randomized design - application of test
drug to one eye and of placebo to the other
• Before a CPT, skin-testing is required to determine allergen
• 2 baseline visits (7 days apart) are required to establish threshold dose of
allergen
• At 1st baseline visit, increasing doses of allergen extract are applied bilaterally into
the conjunctival sac of the eye at 10-minute intervals, followed by observation for
hyperemia, itching, chemosis, and lid swelling quantified according to well-
established scales
• Threshold of reactivity of 2+ is considered to reflect the severity of allergic
conjunctivitis in season.

• 2nd baseline (7 days later) visit - establish reproducibility of ocular
allergic reaction to threshold dose
• After 10 minutes, challenged with previously determined threshold dose of
allergen.
• Symptom evaluation (approximately 20 minutes for immediate and up to 6
hours for late reactions)

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