Allergic and Immunologic Eye Disease

Key Points

  • The hallmark of allergic conjunctivitis is itching. Bacterial and viral conjunctivitis do not commonly present with pruritus.

  • Bacterial and viral conjunctivitis generally have a self-limited course ranging from 5 to 14 days. Signs and symptoms of acute allergic conjunctivitis wax and wane of over longer periods of time coinciding with the circulating allergen (e.g. seasonal pollens).

  • Chronic conjunctival vascular injection, ‘red or pink eye’, may occur in children with dry eye disease related to intense viewing of cell phones and other electronic devices.

  • Disorders of the tear film as in meibomian gland disease (MGD) can result in chronic blepharoconjunctivitis.

  • Topical steroids should be used with caution in treating conjunctivitis in children because they may raise the intraocular pressure (glaucoma) or exacerbate a herpes simplex virus (HSV) keratoconjunctivitis.

  • Some systemic antihistamines may produce dry eye symptoms that confound the diagnosis of allergic conjunctivitis.

Allergic disease affects as many as 25% of the pediatric population. The direct costs of upper airway allergies are approximately $5.9 billion, with children < 12 years accounting for 38% ($2.3 billion) of the total. In a study of 5,000 allergic children, ocular allergy was reported in 32% as the single manifestation of their allergies. In the USA ocular allergy symptoms have doubled over the past 25 years with up to 40% of the population reporting ocular symptoms in the NHANES study, coinciding with the international market growth in the treatment of anterior ocular inflammatory disorders with anti-allergics occupying 25% of the market. This chapter provides an overview of pediatric ‘red eye’ eye disease and a focus on the approach to proper diagnosis and management of allergic disorders.

Eye Anatomy, Histology and Immune Function

The eye is a common target of local and systemic inflammatory disorders that impact on the patient’s quality of life, due to its considerable vascularization and vessel sensitivity, and the potential for visual loss. Anterior ocular inflammatory disorder can pose a formidable diagnostic challenge to clinicians, and thus a solid understanding of the eye’s anatomy, histology and immune function is essential.

The eye is essentially constructed of two immunologically active portions ( Figure 54-1 ):

  • 1.

    Anteriorly the eyelids, conjunctiva (palpebral and bulbar) and tear fluid layer provide the primary barrier against environmental aeroallergens, chemicals and infectious agents and are contiguous with the collagenous sclera, involved in autoimmune disorders.

  • 2.

    Internally the highly vascular uvea is involved in immune complexes and cell-mediated systemic inflammatory disorders and is contiguous with the retina, which is an extension of the central nervous system.

Figure 54-1

Sagittal cross-sectional view of the human eye revealing the parts commonly involved in immunologic reactions: eyelids (blepharitis and dermatitis); conjunctiva (conjunctivitis); cornea (keratitis); sclera (episcleritis and scleritis); optic nerve (neuritis); iris (iritis); vitreous (vitreitis); choroid (choroiditis); and retina (retinitis). The last four parts constitute the inner portion of the eye (the uveal tract) and are classified as forms of uveitis.

Immunologic hypersensitivity reactions involving the eye incorporate the spectrum of the classic Gell and Coombs classification ( Table 54-1 ).

TABLE 54-1

Categories of Pediatric Ocular Inflammation

Category Recognition Component Soluble Mediators Time Course Cellular Response Clinical Example
IgE/mast cell IgE Leukotrienes
Allergic conjunctivitis
Vernal keratoconjunctivitis
Cytotoxic antibody IgG
Complement Hours
Mooren’s ulcer
Immune complex IgG
Complement Hours
Serum sickness uveitis
Corneal immune rings
Lens-induced uveitis
Behçet’s syndrome
Kawasaki’s disease
Delayed hypersensitivity Lymphocytes
Corneal allograft rejection
Sympathetic ophthalmia
Sarcoid-induced uveitis


The eyelids are the first line of defense for the eye as they provide a mechanical barrier that maintains moisture and cleanses the anterior ocular surface. However, the palpebral skin is extremely thin compared to the dermis elsewhere (0.55 mm thick compared to the 2 mm integument of the face), and is also commonly involved in fluid retention, such as in periorbital edema and anasarca.


The conjunctiva is an active immunologic tissue as it consists of a thin mucous membrane that extends from the eyelid margin to the limbus of the eye. It is divided into: (1) the palpebral conjunctiva lining the inner surface of the eyelids; (2) the bulbar conjunctiva covering the sclera; and (3) the fornix or conjunctival sac at the junction between the bulbar and palpebral conjunctiva. The conjunctiva consists of two distinct histologic layers: the epithelium composed of two to five layers of stratified columnar cells, with interspspersed mucin producing goblet cells and the substantia propria composed of connective tissue.

Inflammatory cells such as mast cells, eosinophils and basophils normally do not reside in the ocular epithelium. In the substantia propria, mast cells (~6,000/mm 3 ) are present, predominantly (> 95%) of connective tissue type (MC TC ). However, in the more chronic forms of allergic conjunctivitis, an increase in mucosal type mast cells (MC T ) can be found in the epithelial layer. Epithelial cells have also been found to have an extensive proinflammatory capability in the production of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-10 as well as various adhesion mol­ecules, such as intracellular adhesion molecules (ICAM-1).

Various mononuclear cells, including Langerhans cells, CD3 + lymphocytes and CD4 + /CD8 + lymphocytes, are also an active component of the anterior surface immune response and are primarily found in the epithelial layer. Langerhans cells, which serve as antigen-presenting cells in the skin, have a similar role in the eye. The primary lymphoid organ for intraocular reactions is the spleen. Although lymphatics do drain from the lateral conjunctiva to the preauricular nodes (e.g. parotid node) just anterior to the tragus of the ear, the nasal conjunctival lymphatics drain to the submandibular nodes. It is generally believed that activated conjunctival lymphocytes travel first to these regional lymph nodes, then to the spleen, and ultimately back to the conjunctiva.

Tear Film

The conjunctival surface is bathed in a thin layer of tear film that appears approximately 2 to 4 weeks after birth. A recent model of tear film structure describes an aqueous layer with a gradient of mucin that decreases from the ocular surface to the overlying lipid layer. Goblet cells distributed along the conjunctival surface produce this mucin, which decreases the surface tension of the tear film, thus maintaining a moist hydrophobic corneal surface. The outermost lipid component of the tear film decreases the evaporation rate of the aqueous tears. The aqueous portion of the tear film contains a variety of solutes, including electrolytes, carbohydrates, ureas, amino acids, lipids, enzymes and tear-specific prealbumin, and immunologically active proteins, including immunoglobulin A (IgA), IgG, IgM, IgE, tryptase, histamine, lysozyme, lactoferrin, ceruloplasmin, vitronectin and cytokines.

Uveal Tract

The uveal tract comprises the iris, ciliary body and choroid, each of which possesses a rich vascular architecture and pigment. The pigment acts as a filtering system. The ciliary body is involved in the production of aqueous humor and is a common site for the deposition of immune complexes. In addition, disturbances in the production or outflow of aqueous humor may lead to increased intraocular pressure (IOP; i.e. glaucoma). There are congenital forms of glaucoma that are not specifically associated with immunologic disorders but must be considered in the differential diagnosis of pediatric conjunctivitis (‘pink eye’ or ‘red eye’).

Differential Diagnosis

The differential diagnosis of the pediatric red eye can be broadly divided into four categories: allergic, infectious, immunologic and nonspecific ( Figure 54-2 ). Each category possesses distinct signs and symptoms. These indicators are summarized in Table 54-2 and can be used as a guide to delineate pediatric red eye.

Figure 54-2

The differential diagnosis of pediatric ‘red eye’ includes infectious agents (e.g. chlamydial disease, adenovirus), allergic conditions (e.g. SAC, PAC, GPC, VKC), immunologic disorders (e.g. Kawasaki’s disease, uveitis, ataxia-telangiectasia) and nonspecific causes (e.g. foreign body, chemical irritation, nasolacrimal obstruction).

TABLE 54-2

Differential Diagnosis of Pediatric Conjunctivitis

Predominant Cell Type Chemosis Lymph Node Cobblestoning Discharge Lid Involvement Pruritus Gritty Sensation Pain Seasonal Variation
AC Mast cell
+ Clear mucoid + +/− +
VKC Lymph
+/− ++ Stringy mucoid + ++ +/− +/− if cornea is involved +
GPC Lymph
+/− ++ Clear white ++ + +/−
Bacterial: Strep., Staph., Haemophilus PMN +/− + ++
+ +/− +/−
Viral PMN
+/− ++ +/− Clear mucoid + +/− +/−
Chlamydial Monolymph +/− +/− + ++
+ +/− +/−
Kawasaki’s disease PMN, lymph +/− ++ Serous mucoid +/− +/−
Uveitis Lymph ++
Sarcoidosis Lymph Grey flat papules +/−
JIA Lymph +/−
Episcleritis Lymph ++
Contact dermatoconjunctivitis Lymph +/− ++ + +/− if cornea is involved
Angioedema Mast cell ++ +++ +/−
Staphylococcal blepharitis Monolymph +/− ++ mucopurulent ++ + ++ +/− if cornea is involved
Congenital entropion epiblepharon Serous watery ++ + +++
Congenital glaucoma Serous +/− +/− +++
Corneal abrasion Serous watery + +/− +++
Chemical Serous mucoid ++ +/− +++
Nasolacrimal obstruction PMN if secondary infection Mucopurulent + +/− +/−

AC – Allergic conjunctivitis, EOS – eosinophils, VKC – vernal keratoconjunctivitis, GPC – giant papillary conjunctivitis, PMN – polymorphonuclear leukocytes, JIA – juvenile idiopathic arthritis.


A detailed and accurate history is the most important element in distinguishing allergic from nonallergic causes of pediatric conjunctivitis. When evaluating a newborn, a full prenatal history, including developmental delays and maternal infections (e.g. HSV, Chlamydia or human immunodeficiency virus [HIV]), needs to be obtained. Ocular trauma from forceps or vacuum delivery has been known to occur. In addition, ocular medications such as silver nitrate and erythromycin given at childbirth may cause chemical irritation. In the older child, recent exposure to individuals with conjunctivitis or upper respiratory tract infection, either within the family or at school, may suggest exposure to adenovirus infection in an endemic area. The conjunctivitis-otitis media syndrome, occurring frequently in preschool children, is usually caused by nontypable Haemophilus influenzae or Streptococcus pneumoniae . Family history is particularly important when inherited disorders are suspected. Accidental trauma resulting in corneal abrasions or ocular foreign bodies may also occur, especially in the curious and mobile toddler. Yet, while accidents occur frequently, child abuse must also be considered; in these circumstances a thorough social history is merited. In teenagers, a sexual history may suggest a chlamydial or neisserial infection. Patient use and abuse of over-the-counter topical medications (e.g. vasoconstrictors, artificial tears, cosmetics or contact lens wear) has the potential to produce inflammation (conjunctivitis medicamentosa or toxic keratopathy). As with all allergies, environmental factors and time of onset must be addressed, including seasonal variation and exposure to tobacco smoke, cleaning supplies, pets, air-conditioning, carpets and other sources of irritants.

Many of the signs and symptoms of allergic conjunctivitis are nonspecific as they involve the four classical signs of inflammation (calor, dolor, rubor and tumor), originally recorded by the Roman encyclopedist Celsus in the 1st century AD, and include heat, pain, redness, swelling, tearing, irritation, stinging, burning and photophobia. The hallmark of allergic conjunctivitis is itching. Pruritus can be mild or prominent and may last from hours to days. A stringy or ropy discharge is also characteristic of a persistent ocular allergy, and may range from serous to purulent. While a purulent discharge may be present, morning crusting and difficulty opening the lids are more characteristic of bacterial causes, especially Gram-negative organisms (e.g. Neisseria and Haemophilus ). Environmental allergens affect both eyes at once, although a unilateral reaction may result if one eye is inoculated with animal hair or dander. Ocular pain is not typically associated with allergic conjunctivitis and suggests an extraocular process such as a corneal abrasion, scleritis or foreign body, or an intraocular process such as uveitis.

Eye Examination

The eye should be carefully examined for evidence of eyelid involvement such as blepharitis, dermatitis, swelling, discoloration, ptosis or blepharospasm ( Table 54-3 ). Conjunctival involvement may present with chemosis, hyperemia, cicatrization or formation of papillae on the palpebral and bulbar membranes. The presence of increased or abnormal secretions should also be noted. A fundoscopic examination should be performed to detect such conditions as uveitis (often associated with autoimmune disorders) and cataracts (associated with atopic disorders and chronic steroid use).

TABLE 54-3

Ocular Clinical Signs

Disorder Description
Blepharitis Inflammation of the eyelids; sometimes associated with the loss of eyelashes (madarosis)
Chalazion A chronic, granulomatous inflammation of the meibomian gland
Chemosis Edema of the conjunctiva due to transudate leaking through fenestrated conjunctival capillaries
Epiphora Excessive tearing; may be due to increased tear production or more commonly congenital obstruction of the nasolacrimal drainage system. This may occur in as many as 20% of infants, but resolves spontaneously in most cases before 1 year of age. Children with chronic sinusitis and/or rhinitis may have intermittent nasolacrimal duct obstruction since the distal nasolacrimal duct drains below the inferior meatus. Congenital glaucoma may also present with epiphora but has other characteristic findings (e.g. corneal enlargement, photophobia and eventually corneal edema presenting as a corneal haze) usually within the first year of life *
Hordeolum Synonymous with a stye
Keratitis Inflammation and infection of the corneal surface, stroma and endothelium, with numerous causes
Leukocoria A white pupil; seen in patients with Chédiak-Higashi syndrome (a neutrophil defect), retinoblastoma, cataracts and retrolental fibroplasia
Papillae Large, hard, polygonal, flat-topped excrescences of the conjunctiva seen in many inflammatory and allergic ocular conditions
Phlyctenule The formation of a small, gray, circumscribed lesion at the corneal limbus that has been associated with staphylococcal sensitivity, tuberculosis and malnutrition
Proptosis Forward protrusion of the eye or eyes
Ptosis Drooping of the eyelid, which may have neurogenic, muscular or congenital causes. Conditions specific to the eyelid that may cause a ptotic lid include chalazia, tumors and preseptal cellulitis
Scleritis Inflammation of the tunic that surrounds the ocular globe. Episcleritis presents as a red, somewhat painful eye in which the inflammatory reaction is located below the conjunctiva and only over the globe of the eye. The presence of scleritis should prompt a search for other systemic immune-mediated disorders
Trichiasis In-turned eyelashes; usually results from the softening of the tarsal plate within the eyelid
Trantas’ dots Pale, grayish-red, uneven nodules made up of eosinophils with a gelatinous composition seen at the limbal conjunctiva in vernal conjunctivitis

* Data from Seidman DJ, Nelson LB, Calhoun JH, et al. Pediatrics 1986;77:399–404.

The examination starts with an inspection of the face and area surrounding the eye. A horizontal skin crease on the nose (nasal salute) suggests a history of allergic rhinitis. Allergic shiners are ecchymotic-looking areas beneath the eyes thought to result from impaired venous return from the subcutaneous tissues ( Figure 54-3 ). Angioedema commonly involves the conjunctiva, but it more commonly affects the periorbital space and is more prominent around the lower lids secondary to gravity. Eyelid or nasal vesicular eruptions are often seen in ophthalmic zoster, but can also reflect recurrent bacterial infection-associated staphylococcal blepharoconjunctivitis due to constant rubbing of the eyelids. Scratches and scars on the face or eyelid suggest ocular injury. In addition, palpation of the sinuses and the preauricular and cervical chain lymph nodes is of diagnostic importance.

Figure 54-3

Patient with periorbital swelling.

Next, the conjunctiva should be thoroughly inspected. The bulbar conjunctiva examination is performed by looking directly at the eye and asking the patient to look up and then down, while gently retracting the opposite lid. Examine the palpebral (tarsal) conjunctiva by grasping the upper lid at its base with a cotton swab on the superior portion of the lid while gently pulling the lid out and up as the patient looks down. To return the lid to its normal position, have the patient look up. The lower tarsal conjunctiva is examined by placing a finger near the lid margins, everting the lower eyelid and drawing downward. A ‘milky’ appearance of the conjunctiva is characteristic of allergy and is the result of the obscuring of blood vessels by conjunctival edema ( Figure 54-4 ). In contrast, a velvety, beefy-red conjunctiva with purulent discharge suggests a viral or bacterial etiology, while follicular or papillary hyperplasia of the conjunctival surface reflects a more persistent or chronic inflammatory condition. Follicles appear as grayish, clear or yellow bumps varying in diameter from a pinpoint to 2 mm, with conjunctival vessels on their surface, while papillae contain a centrally located tuft of vessels. Although a fine papillary reaction is nonspecific, giant papillae (greater than 1 mm) on the upper tarsal conjunctiva indicate an allergic source. Papillae are generally not seen in active viral or bacterial conjunctivitis. The presence of follicles, a lymphocytic response in the conjunctiva, is a specific finding that occurs primarily in viral and chlamydial infections, but is also seen in chronic and persistent forms of ocular allergy.

Figure 54-4

Conjunctival edema or chemosis with milky appearance obscuring conjunctival vessels in an acute allergic reaction.

The cornea is best examined with a slit lamp biomicroscope, although many important clinical features can be seen with the naked eye or with the use of an ophthalmoscope. The cornea should be perfectly smooth and transparent. Dusting of the cornea may indicate punctate epithelial keratitis. A localized corneal defect may suggest erosion or a larger ulcer that could be related to major basic protein deposition. Surface lesions can best be demonstrated by applying fluorescein dye to the eye, preferably following the instillation of a topical anesthetic drop ( Figure 54-5 ). The end of the fluorescein strip is touched to the marginal tear meniscus. When the patient blinks, the dye is dispersed throughout the ocular surface and stains wherever an epithelial defect exists, as in a corneal or conjunctival abrasion. A light utilizing a cobalt filter, found on most modern ophthalmoscopes, will best demonstrate abnormal accumulations of the dye. Mucus adhering to the corneal or conjunctival surfaces is considered pathologic.

Figure 54-5

Triangular corneal abrasion highlighted with fluorescein dye.

The limbus is the zone immediately surrounding the cornea that becomes intensely inflamed with a deep pink coloration in cases of anterior uveitis or iritis, the so-called ‘ciliary flush’. Discrete swellings with small white dots are indicative of degenerating cellular debris, which is commonly seen in vernal conjunctivitis ( Figure 54-6 ). The anterior chamber is examined for clearness or cloudiness of the aqueous humor and for the presence of blood, either diffuse or settled out (i.e. hyphema) or the settling out of pus (i.e. hypopyon). A shallow anterior chamber suggests narrow-angle glaucoma and is a contraindication for the use of mydriatic agents. An estimation of the anterior chamber depth can be made by illuminating it from the side with a pen light; if the iris creates a shadow on the far side from the light, then there is a high index of suspicion for increased IOP (i.e. glaucoma).

Figure 54-6

Limbal conjunctivitis (a form of vernal conjunctivitis).

Allergic Disorders

Conjunctivitis caused by IgE-mast cell-mediated reactions is the most common hypersensitivity response of the eye. Direct exposure of the ocular mucosal surface to the environment stimulates these mast cells, clinically producing the acute- and late-phase signs and symptoms of allergic conjunctivitis. In addition, the conjunctiva is infiltrated with inflammatory cells such as neutrophils, eosinophils, lymphocytes and macrophages. Interestingly, acute forms of allergic conjunctivitis lack an eosinophilic predominance, as seen in asthma. However, eosinophils and other immunologically active cells are prevalent in the more chronic forms.

Seasonal Allergic Conjunctivitis

Seasonal allergic conjunctivitis (SAC) is the most common allergic conjunctivitis, representing over half of all cases. As its name implies, SAC is characterized by symptoms that are seasonal and related to specific aeroallergens. Symptoms predominate in the spring and in some areas during the fall (Indian summer). Grass pollen is thought to produce the most ocular symptoms. Patients report itchy eyes and/or a burning sensation with watery discharge, commonly associated with nasal or pharyngeal symptoms. A white exudate may be present that turns stringy in the chronic form of the condition. The conjunctiva appears milky or pale pink and is accompanied by vascular congestion that may progress to conjunctival swelling (chemosis). Symptoms are usually bilateral but not always symmetric in degree of involvement. SAC rarely results in permanent visual impairment but can interfere greatly with daily activities.

Perennial Allergic Conjunctivitis

Perennial allergic conjunctivitis (PAC) is considered a variant of SAC that persists throughout the year. Dust mites, animal dander and feathers are the most common allergens. Symptoms are analogous to those of SAC, and 79% of PAC patients have seasonal exacerbations. In addition, both PAC and SAC are similar in distribution of age, sex and associated symptoms of asthma or eczema. The prevalence of PAC has been reported to be lower than that of SAC (3.5 : 10,000) although it is subjectively more severe, but with the increasing prevalence of allergies as reported in the International Study of Asthma and Allergies in Childhood this may be underrepresented; in fact, perennial forms of ocular allergy may be more common than pure seasonal forms.

Vernal Keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a severe, bilateral, recurrent, chronic inflammatory process of the upper tarsal conjunctival surface. It has a marked seasonal incidence, and its frequent onset in the spring has led to use of the term ‘vernal catarrh’ . It occurs most frequently in children and young adults who have a history of seasonal allergy, asthma and eczema. The age of onset for VKC is usually before puberty, with boys being affected twice as often as girls. After puberty it becomes equally distributed between the sexes and ‘burns out’ by the third decade of life (about 4 to 10 years after onset). VKC may threaten sight if the cornea is involved and is more common in persons of Asian or African origin.

Symptoms of VKC include intense pruritus exacerbated by time and exposure to wind, dust, bright light, hot weather or physical exertion associated with sweating. Associated symptoms involving the cornea include photophobia, foreign body sensation and lacrimation. Signs include: conjunctival hyperemia with papillary hypertrophy (‘cobblestoning’) reaching 7 to 8 mm in diameter in the upper tarsal plate; a thin, copious milk-white fibrinous secretion composed of eosinophils, epithelial cells and Charcot-Leyden granules; limbal or conjunctival ‘yellowish-white points’ (Horner’s points and Trantas’ dots) lasting 2 to 7 days; an extra lower eyelid crease (Dennie’s line); corneal ulcers infiltrated with Charcot-Leyden crystals; or pseudomembrane formation of the upper lid when everted and exposed to heat (Maxwell-Lyon’s sign; Figure 54-7 ). Although VKC is a bilateral disease, it may affect one eye more than the other.

Figure 54-7

Conjunctival hyperemia with papillary hypertrophy (cobblestoning) on the everted palpebral conjunctiva of the upper eyelid in a patient with vernal conjunctivitis.

VKC is characterized by conjunctival infiltration by eosinophils, degranulated mast cells, basophils, plasma cells, lymphocytes and macrophages. Degranulated eosinophils and their toxic enzymes (e.g. major basic proteins) have been found in the conjunctiva and in the periphery of corneal ulcers, a fact that may suggest their etiopathogenic role in many of the problems associated with VKC. MC T cells are increased in the conjunctiva of these patients. Tears from VKC patients have been found to contain higher levels of leukotrienes and histamine (16 ng/mL) when compared to controls (5 ng/mL). Tears from VKC patients also contain major basic protein, Charcot-Leyden crystals, basophils, IgE and IgG specific for aeroallergens (e.g. ragweed pollen) and eosinophils (in 90% of cases). The tear-specific IgE does not correlate with the positive immediate skin tests that VKC patients may have, thus it represents more than a chronic allergic response as reflected in a study that suggested that exposure to house dust mite allergen aggravates VKC symptoms.

Giant Papillary Conjunctivitis

Giant papillary conjunctivitis (GPC) is associated with the infiltration of basophils, eosinophils, plasma cells and lymphocytes. GPC has been directly linked to the continued use of contact lenses with a seasonal increase of symptoms during the spring pollen season, including itching. Signs include a white or clear exudate upon awakening that chronically becomes thick and stringy. Patients may develop Trantas’ dots, limbal infiltration and bulbar conjunctival hyperemia and edema. Upper tarsal papillary hypertrophy (‘cobblestoning’) has been described in 5% to 10% of soft and 3% to 4% of hard contact lens wearers. The contact lens polymer, the preservative (thimerosal) and proteinaceous deposits on the surface of the lens have been implicated in GPC, but this remains controversial. Analysis of the glycoprotein deposits on disposable soft contact lenses has revealed that the higher the water content, the higher the protein integration (lysozyme, tear-specific prealbumin and the heavy chain components of IgG) into the lens.

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Apr 15, 2019 | Posted by in PEDIATRICS | Comments Off on Allergic and Immunologic Eye Disease
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