Pediatric Ocular Allergic and Immunologic Disorders

Introduction

Acute conjunctivitis caused by IgE-mast cell-mediated reactions is the most common hypersensitivity response of a child's eye.¹ An estimated 50 million mast cells reside at the interface of the conjunctiva.² Direct exposure of the ocular mucosal surface to environmental allergens stimulates these mast cells, producing allergic conjunctivitis. Additionally, the conjunctiva is infiltrated with inflammatory cells including neutrophils, eosinophils, lymphocytes, and macrophages. Acute forms of allergic conjunctivitis lack an eosinophilic predominance as seen in asthma. However, eosinophils and other immunologic active cells are prevalent in chronic forms. The signs and symptoms of ocular allergy are well known to ophthalmologists. This tutorial describes specific allergic and immunologic disorders that are present in children.

Seasonal Allergic Conjunctivitis

Seasonal allergic conjunctivitis (SAC) represents more than half of all cases of common allergic conjunctivitis. As its name implies, its symptoms are seasonal and related to specific aeroallergens. Symptoms predominate in the spring and, in some areas, during the fall. Grass pollen is thought to be the leading cause of these ocular symptoms. Commonly associated with nasal or pharyngeal symptoms, patients report itchy eyes and/or a burning sensation with watery discharge. A white exudate that turns stringy in the chronic form of the condition may also be present. The conjunctiva will appear milky or pale pink and is accompanied by vascular congestion. This congestion 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 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 common allergens. Symptoms are analogous to SAC and 79% of patients with PAC will have seasonal exacerbations. Additionally, both PAC and SAC are similar in distribution of age, gender, 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 subjectively more severe,³ but with the increasing prevalence of the allergies as reported in the International Survey for Asthma and Allergic Conditions study, this may be clearly underrepresented. Children with chronic sinusitis and allergic conjunctivitis may have "allergic shiners," or darkening of the skin of the lower eyelids secondary to repeated episodes of eyelid edema (Slide 1).

Slide 1. Child with bilateral "allergic shiners" of lower eyelids secondary to chronic allergic sinusitis.

Vernal Keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a severe bilateral, recurrent, chronic ocular inflammatory process of the upper tarsal conjunctival surface. VKC may also occur in a limbal variety, which occurs with circumferential perilimbal white-to-yellow infiltrates. VKC has a marked seasonal incidence, and because its onset frequency occurs in the spring, VKC is referred to as vernal catarrh. This disorder 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 among the genders and becomes asymptomatic before age 30 (about 4 to 10 years after onset). VKC may threaten sight if the cornea is involved and is common in patients of Asian or African origin.⁴

Symptoms of VKC include 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 mm to 8 mm in diameter in the upper tarsal plate (Slide 2); 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). Although VKC is a bilateral disease, it may affect one eye more than the other.

Slide 2. Giant papules of upper palpebral conjunctiva as occurs in vernal and giant papillary conjunctivitis.

VKC is characterized by conjunctival infiltration with eosinophils, degranulated mast cells, basophils, plasma cells, lymphocytes, and macrophages. Degranulated eosinophils and their toxic enzymes (eg, 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 vernal conjunctivitis.^5,6 MC_T cells are increased in the conjunctiva of these patients.⁷ Tears from patients with VKC have been found to contain higher levels of leukotrienes and histamine (16 ng/mL) when compared to controls (5 ng/mL).⁸ Tears from patients with VKC also contain major basic protein, Charcot-Leyden crystals, basophils, IgE and IgG specific for aeroallergens (eg, ragweed pollen), and eosinophils (in 90% of patients).⁹ The tear-specific IgE does not correlate with the positive immediate skin tests a patient with VKC may have, thus reflecting that it represents more than a chronic allergic response.

Giant Papillary Conjunctivitis

Giant papillary conjunctivitis (GPC) is associated with the infiltrations of basophils, eosinophils, plasma cells, and lymphocytes and is suggestive of a process mediated by mixed mast cells and lymphocytes. GPC has been directly linked to the continued use of contact lenses. Symptoms, including itching and a white or clear exudate upon awakening that chronically becomes thick and stringy, increase during spring pollen season. 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 contact lens wearers and 3% to 4% of hard contact lens wearers (Slide 2). The contact lens polymer, preservative (thimerosal), and proteinaceous deposits on the surface of the lens have been implicated as causing GPC, but the implication 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 into the lens. The deposits have been analyzed and contain lysozyme, tear-specific prealbumin, and the heavy chain components of IgG.¹⁰

Immunologic Disorders Of The Eye

Kawasaki's Disease

Kawasaki's disease, also known as mucocutaneous lymph node syndrome, is an acute exanthematous illness that almost exclusively affects children. Fifty percent of cases occur in boys younger than 2 years old, with an increased prevalence in individuals of Japanese ancestry. Five of the following six criteria must be present for diagnosis: fever, bilateral conjunctival injection, changes in upper respiratory tract mucous membrane, changes in skin and nails, maculopapular cutaneous eruptions, and cervical lymphadenopathy. The cutaneous eruption characteristically involves the extremities and desquamates in the later stages. The disease may occur in cyclic epidemics, and the current theory is that an infectious agent (a Rickettsia-like organism has been demonstrated by electron microscopy) causes a hypersensitivity response. In most patients, Kawasaki's disease is benign and self-limited. However, 2% of Japanese patients with Kawasaki's disease (mostly male patients) experience sudden cardiac death,¹¹ which is caused by acute thrombosis of aneurysmally dilated coronary arteries secondary to direct vasculitic involvement.

The most typical ocular finding is bilateral nonexudative conjunctival vasodilatation, typically involving the bulbar conjunctiva. Anterior uveitis is seen in 66% of patients, and is usually mild, bilateral, and symmetric¹²; superficial punctate keratitis is seen in 12% of patients. Vitreous opacifications and papilledema have been reported. Choroiditis has been reported and pathologically demonstrated in a case of infantile periarteritis nodosa, which may be indistinguishable from Kawasaki's disease. On magnetic resonance imaging of the brain, deep white matter lesions, typically of the vasculopathic lesions of systemic vasculitis as opposed to the periventricular lesions more characteristic of multiple sclerosis, have been seen.

Uveitis

Uveitis may be anatomically classified as anterior, intermediate, posterior, and diffuse. Patients typically complain of diminished or hazy vision accompanied by black floating spots. Severe pain, photophobia, and blurred vision occur in patients with acute iritis or iridocyclitis. The major signs in anterior uveitis are pupillary miosis and ciliary/perilimbal flush, which is a peculiar injection seen adjacent to the limbus that can be easily confused with conjunctivitis. Vitreal cells and cellular aggregates are characteristic of intermediate uveitis and can be seen with the direct ophthalmoscope. Cells, flare, keratic precipitates on the corneal endothelium, and exudates with membranes covering the ciliary body can be visualized with the slit lamp and indirect ophthalmoscopy.

Anterior uveitis may be confused with conjunctivitis because its primary manifestations include red eye and tearing. However, ocular pain and photophobia are also present. Anterior uveitis may be an isolated phenomenon, as seen by an ophthalmologist, or is associated with a systemic autoimmune disorder, which would be noticed by a general practitioner. It is found in approximately 50% of the patients in human leukocyte group A (HLA) spondyloarthropathy (eg, ankylosing spondylitis, Reiter's syndrome), as well as in inflammatory bowel disease (eg, Crohn's disease). Anterior uveitis is linked to the HLAB27 genotype and systemic immunologic disorders, such as ankylosing spondylitis (sacroileitis) and Reiter's syndrome; infections, such as Klebsiella bowel infections (resulting from molecular mimicry), brucellosis, syphilis, and tuberculosis; and HLA-B5, -Bw22, -A29, and -D5 genotypes. The inflammatory response in the anterior chamber of the eye results in an increased concentration of proteins (flare [ie, Tyndall effect]), a constricted pupil (miosis) with an afferent pupillary defect (poor response to illumination), or cells in the aqueous humor. White blood cells can form a hypopyon or stick to the endothelial surface of the cornea, forming keratic precipitates. The sequelae of anterior uveitis may be acute, which may result in synechia (adhesions of the posterior iris to the anterior capsule of the lens), angle-closure glaucoma (blockage of the drainage of the aqueous humor), and cataract formation.⁴

Posterior uveitis commonly presents with inflammatory cells in the vitreous, retinal vasculitis, and macular edema, which threatens vision. Posterior uveitis caused by toxoplasmosis occurs as the result of congenital transmission. Serologic assays for toxoplasmosis (enzyme-linked immunosorbent assay or immunofluorescent antibody) assist in the diagnosis.¹³

Panuveitis is involvement of all three portions of the uveal track, including the anterior, intermediate, and posterior sections. In Israel, panuveitis was linked (more than 95% of cases) to a systemic autoimmune disorder, such as Behcet's disease.¹⁴

Sarcoidosis

Rarely, sarcoidosis occurs in children, and 50% to 80% of patients will have eye involvement. Sarcoidosis is associated with anterior, intermediate, posterior, or diffuse nongranulomatous uveitis. Classically, noncaseating granulomas appear as mutton fat precipitates, obstructive glaucoma, Koeppe nodules at the pupillary margin, or sheathing of vessels (candle wax drippings). The ocular inflammatory response may occur independently of any evidence of systemic involvement. Diagnostic tests for sarcoidosis include biopsy of the conjunctival or lacrimal granulomas, serum angiotensin-converting enzyme and lysozyme, chest radiograph for hilar adenopathy, and gallium scan. Biopsy of the lacrimal gland, the conjunctiva, or the periocular skin is useful only when direct visualization reveals a nodule. Other granulomatous processes involving the eye include toxocariasis, tuberculosis, and histoplasmosis, which may occur months to years after the primary infection.⁴

Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis (JRA) accounts for 70% of chronic arthritis in children. Three subtypes of JRA exist: systemic JRA, which occurs in 10% to 20% of affected children and is usually characterized by a febrile onset, lymphadenopathy, and evanescent rash; polyarticular JRA, which occurs in 30% to 40% of affected children and is characterized by involvement of multiple (>4) joints with few systemic manifestations; and pauciarticular JRA, which occurs in 40% to 50% of affected children and is characterized by no more than four joints involved, usually larger joints and a positive antinuclear antibody in 75% of children. Anterior uveitis can develop in all types, although it is seen most often in pauciarticular JRA where it is found in about 25% of cases. JRA is associated with chronic bilateral iridocyclitis and Russell bodies (large crystalline deposits of immunoglobulin in the iris). The exact mechanism of ocular destruction is thought to be autoimmune based, although the specificity is much debated. S-antigen, histone 3, and type II collagen have all been proposed targets of humoral autoimmunity. Ocular manifestations do not parallel the patient's arthritis; instead, onset generally occurs within 7 years after joint inflammation, so frequent screening and early detection are crucial to decrease vision loss. The onset of ocular inflammation is insidious and asymptomatic in many children. The American Academy of Pediatrics recommends that high-risk patients with positive antinuclear antibody (ANA) titres be seen every 3 to 4 months by an ophthalmologist for a slit lamp examination.¹⁵

Blepharitis

Blepharitis is an inflammation of the eyelids, sometimes associated with the loss of eyelashes (madarosis). It is one of the most common causes of pediatric red eye and is often misdiagnosed as an ocular allergy. In children, staphylococcal blepharitis and meibomian gland obstruction are the most common forms of blepharitis.

As its name implies, staphylococcal blepharitis is characterized by colonization of the lid margin with Staphylococcus aureus. Antigenic products, such as staphylococcal superantigens, and not the colonization itself, are being discussed as having a primary role in the induction of chronic eyelid eczema. Supporting the role of a noninfectious etiology are the relatively normal tear concentrations of antiinfection proteins (lysozyme and lactoferrin), including IgA and IgG antibodies.¹⁶ Patients typically complain of persistent burning, itching, tearing, and a feeling of dryness. These symptoms tend to be more severe in the morning and an exudative crust may be present, which causes a child's eye to shut. The signs of staphylococcal blepharitis include dilated blood vessels, erythema, scales, collarettes of exudative material around the eyelash bases, and foamy exudates in the tear film. Conjunctival injection and a form of chronic papillary conjunctivitis may occur. Additionally, corneal immune deposits may cause severe photophobia. Treatment of staphylococcal blepharitis is directed toward eyelid hygiene with detergents (baby shampoo) and steroid ointments applied to the lid margin. Within several weeks to months, patients usually improve and become asymptomatic.

Meibomian gland obstruction may result in an acute infection (internal hordeolum or stye) but, more commonly, it produces a chalazion, which is a localized granulomatous inflammation caused by an accumulation of lipids and waxes within the meibomian gland. Clinically, a chalazion results in edema, erythema, and burning of the eyelid, which, over time, may evolve into a firm, painless nodule. Bilateral eye involvement and conjunctivitis may also be present, which further contribute to a chalazion's allergic mimicry; once again, eyelid hygiene is the mainstay of therapy.

Phthirus pubis, the pubic or crab louse, has a predilection for eyelash infestation¹⁷ and may also cause blepharitis. Often, the lice may be visualized with direct inspection. Involvement of the eyelashes in prepubertal children should raise the suspicion of sexual abuse.

Episcleritis

Inflammation of the scleral surface is termed episcleritis. It occurs mainly in adolescents and young adults, presenting as a localized injection of the conjunctiva around the lateral rectus muscle insertion (Slide 3). Typically, the inflammation is bilateral and accompanied by ocular pain. The presence of pain and absence of pruritus distinguishes episcleritis from allergic conjunctivitis. Episcleritis is self-limited and usually not associated with systemic disease.

Slide 3. Episcleritis with focal conjunctival and episcleral vascular engorgement.

Contact Dermatoconjunctivitis

Contact dermatitis involving the eyelids frequently causes a patient to seek medical attention for a cutaneous reaction that elsewhere on the skin would be of less concern. The eyelid skin, being soft, pliable, and thin, increases the eyelid susceptibility to contact dermatitis. The eyelid skin is capable of developing significant swelling and redness with minor degrees of inflammation; cosmetics are a major offender. Interestingly, contact dermatitis of the lids and periorbital area more often is caused by cosmetics applied to the hair, face, or fingernails than by cosmetics applied to the eye area. Additionally, preservatives such as thimerosal, which are found in contact lens cleaning solutions, have been shown by patch tests to be among the culprits. Because of the high incidence of irritant false-positive reactions, patch testing is used as a confirmatory tool, not as the first line of investigation. Currently, no diagnostic test exists for irritant contact dermatitis.

Angioedema

Angioedema is the swelling of the dermis of which the conjunctiva is one of the most commonly involved sites in a variety of systemic hypersensitivity reactions. A documented local IgE-mast cell sensitization has been reported to papain enzyme in contact lens cleaning solution in which serum specific IgE to papain and chymopapain were detected.¹⁸ The anatomy of the eyelid consists of loose epidermal tissue that provides an extensive reservoir for edema to minor allergic reactions, but should also include the differential diagnosis of periorbital cellulitis, which may be life threatening.

Ataxia-Telangiectasia-Louis-Bar Syndrome

Patients with ataxia-telangiectasia present with large tortuous vessels on the bulbar conjunctiva, most prominently in the exposed canthal regions.¹⁹ Typically, symptoms become evident between 1 and 6 years of age and may become more prominent with time. There are no other signs or symptoms of conjunctivitis. Children with ataxia-telangiectasia eventually develop ataxia and some recurrent sinopulmonary infection. Hypogammaglobulinemia and absent or deficient 19A have been reported in this condition.²⁰

Acquired Immunodeficiency Syndrome

Children with acquired immunodeficiency syndrome (AIDS) rarely have eye involvement. Cytomegalovirus retinitis is the most frequently encountered disorder, affecting approximately 7% of children with AIDS, and can lead to permanent vision loss if untreated. Cytomegalovirus retinitis is characterized by regions of intraretinal hemorrhage and white areas of edematous retina. HIV cotton-wool spot retinitis, herpes zoster retinitis, and toxoplasmosis retinitis have also been documented in children with AIDS.⁴

Conclusion

Many causes of ocular allergy exist in children. Most are easily diagnosed as a result of the well-recognized symptom of itchy eyes. Ophthalmologists must be familiar with the more unusual conditions, which are more severe allergic disorders or diseases that mimic the findings of typical ocular allergy.

Slides

Slide 1. Child with bilateral "allergic shiners" of lower eyelids secondary to chronic allergic sinusitis.

Slide 2. Giant papules of upper palpebral conjunctiva as occurs in vernal and giant papillary conjunctivitis.

Slide 3. Episcleritis with focal conjunctival and episcleral vascular engorgement.

References

1. Friedlaender MH. Current concepts in ocular allergy. Ann Allergy. 1991; 67:5-13.
2. Allansmith MR. Immunology of the external ocular tissues. J Am Optom Assoc. 1990; 61:16-22.
3. Dart JK, Buckley RJ, Monnickendan M, Prasad J. Perennial allergic conjunctivitis: Definition, clinical characteristics and prevalence: A comparison with seasonal allergic conjunctivitis. Trans Ophthalmol Soc UK. 1986; 105:513-520.
4. Bielory L, Wilson TM, Wagner RS. Allergic and immunologic eye disease. In: Lueng DYM, Sampson HA, Geha R, Szefler S, eds. Pediatric Allergy: Principles and Practice. St. Louis, Mo: Mosby; 2003:595-611.
5. Trocme SD, Gleich GJ, Zeiske JD. Eosinophil granule major basic protein inhibits corneal epithelial wound healing in vitro (abstract). Invest Ophthalmol Vis Sci. 1991; 32:1161.
6. Trocme SD, Kephart GM, Allansmith MR, Bourne WM, Gleich GJ. Conjunctival deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis and contact lens associated giant papillary conjunctivitis. Am J Ophthalmol. 1989; 108:57-63.
7. Irani AM, Butrus SI, Tabbara KF, Schwarts LB. Human conjunctival mast cells: Distribution of MCT and MCTC in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clin Immunol. 1990; 86:34-40.
8. Abelson MB, Baird RS, Allansmith MR. Tear histamine levels in vernal conjunctivitis and other ocular inflammations. Ophthalmology. 1980; 87:812-814.
9. Udell II, Gleich GJ, Allansmith MR, Abelson MB. Eosinophil major basic protein and Charcot-Leyden crystal protein in human tears. Am J Ophthalmol. 1981; 92:824-828.
10. Tripathi PC, Tripathi RC. Analysis of glycoprotein deposits on disposable contact lenses. Invest Ophthalmol Vis Sci. 1992; 33:121-125.
11. Dreborg S, Agrell B, Foucard T, et al. A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. I. Clinical results. Allergy. 1986; 41:131-140.
12. Bligard CA. Kawasaki disease and its diagnosis. Pediatr Dermatol. 1987; 4:75-84.
13. Rosenbaum JT. An algorithm for the systemic evaluation of patients with uveitis: Guidelines for the consultant. Semin Arthritis Rheum. 1990; 19:248-257.
14. Weiner A, BenEzra D. Clinical patterns and associated conditions in chronic uveitis. Am J Ophthalmol. 1991; 112:151-158.
15. American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology: Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 1993; 92:295-296.
16. Dougherty JM, McCulley JP. Tear measurements in chronic blepharitis. Ann Ophthalmol. 1985; 17:53-57.
17. Hogan DJ, Schachner L, Tanglertsampan C. Diagnosis and treatment of childhood scabies and pediculosis. Pediatr Clin North Am. 1991; 36:941-957.
18. Berstein DR, Gallagher JS, Grad M, et al. Local ocular anaphylaxis to papain enzyme contained in a contact lens cleaning solution. J Allergy Clin Immunol. 1984; 74:258-260.
19. Boder E, Sedgwick R. Ataxia-telangiectasia: A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics. 1958; 21:526-554.
20. Harley RD, Baird HW, Craven EM. Ataxia-telangiectasia: Report of seven cases. Arch Ophthalmol. 1967; 77:582-592.