setting.

Carmichael A. Cytomegalovirus and the eye. Eye (Lond). 2012;26(2):237–240.

Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Corneal endotheliitis associated with evidence of cytomegalovirus infection. Ophthalmology. 2007;114(4):798–803.

Koizumi N, Suzuki T, Uno T, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115(2):292–297.

DNA Viruses: Adenoviruses

The Adenoviridae are double-stranded DNA viruses associated with significant human disease and morbidity. Forty-nine serotypes subdivide into 6 distinct subgroups (A–F) on the basis of genetic sequencing. Adenovirus subgroups associate broadly with specific clinical syndromes. For instance, subgroup D adenoviruses are strongly associated with epidemic keratoconjunctivitis. The nonenveloped protein capsid of the adenovirus forms a regular icosahedron. For most adenoviral subgroups, a projecting capsid protein serves as the ligand for the cellular adenovirus receptor, and the interaction of an adjacent capsid protein with cell surface integrins mediates internalization of the virus.

Knipe DM, Howley PM, eds. Fields’ Virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.

PATHOGENESIS Originally isolated in 1953 from surgically removed human adenoids, adenoviruses cause a broad spectrum of diseases, including infections of the upper respiratory tract and ocular surface, meningoencephalitis, acute hemorrhagic cystitis of young boys, diarrhea of children, acute respiratory disease of children and military recruits, and respiratory and hepatic failure in an immunocompromised host. Adenoviruses are transmitted by close contact with ocular or respiratory secretions, fomites, or contaminated swimming pools. Transmission occurs more readily in populations living in close quarters, such as schools, nursing homes, military housing, and summer camps. Transmission of adenoviruses by contaminated instruments or eyedrops in physicians’ offices may occur. For this reason, IOP measurements should be taken with an instrument with a disposable cover.

CLINICAL PRESENTATION Each subgroup (A–F) of adenoviruses and, to a lesser degree, each serotype possesses unique tissue tropisms that reveal the association of specific adenoviruses with distinct clinical syndromes. Most adenoviral eye disease presents clinically as 1 of 3 classic syndromes:

simple follicular conjunctivitis (multiple serotypes) pharyngoconjunctival fever (most commonly serotype 3 or 7)

epidemic keratoconjunctivitis (EKC; usually serotype 8, 19, or 37, subgroup D)

Different adenoviral syndromes are indistinguishable early in infection and may be unilateral or bilateral.

Adenoviral follicular conjunctivitis is self-limited, not associated with systemic disease, and often so transient that patients do not seek care. Epithelial keratitis, if present, is mild and fleeting. Pharyngoconjunctival fever is characterized by fever, headache, pharyngitis, follicular conjunctivitis, and preauricular adenopathy. The systemic signs and symptoms may mimic influenza. Any associated epithelial keratitis is mild.

Epidemic keratoconjunctivitis is the only adenoviral syndrome with significant corneal involvement. The infection is bilateral in most patients and may be preceded by an upper respiratory

tract infection. One week to 10 days after inoculation, severe follicular conjunctivitis develops, associated with a punctate epithelial keratitis. The conjunctival morphology is follicular but may be obscured by chemosis. Petechial hemorrhages and, occasionally, larger subconjunctival hemorrhages can occur. Preauricular adenopathy is prominent. Pseudomembranes or true membranes (Fig 4-17) occur predominantly on the tarsal conjunctiva and may be missed on cursory examination. Patients report tearing, light sensitivity, and foreign-body sensation. Large central geographic corneal erosions can develop and may persist for several days despite patching and lubrication. Within 7–14 days after onset of eye symptoms, multifocal subepithelial (stromal) corneal infiltrates become apparent on slit-lamp examination (Fig 4-18). Photophobia and reduced vision from adenoviral subepithelial infiltrates may persist for months to years.

Figure 4-17 Conjunctival membranes in a patient with epidemic keratoconjunctivitis (EKC). (Courtesy of James Chodosh, MD.)

Figure 4-18 Subepithelial corneal infiltrates in a patient with EKC. (Courtesy of Vincent P. deLuise, MD.)

Epithelial keratitis occurs because of adenovirus replication within the corneal epithelium. Subepithelial infiltrates are likely caused by an immunopathologic response to viral infection of keratocytes in the superficial corneal stroma. The evolution of keratitis in EKC is summarized in Figure 4-19. Chronic complications of conjunctival membranes include subepithelial conjunctival scarring, symblepharon formation, and dry eye due to alterations within the lacrimal glands or lacrimal ducts.

Figure 4-19 Schematic drawing illustrating the natural progression of specific corneal epithelial and stromal pathology in EKC. Stage 0, Poorly staining, minute punctate opacities within the corneal epithelium. Stage I, Fine punctate epithelial keratitis (PEK). Stage II, Fine and coarse PEK. Stains brightly with rose bengal. Stage III, Coarse granular infiltrates within deep epithelium, early subepithelial infiltrates, diminished PEK. Stage IV, Classic subepithelial infiltrates without PEK. Stage V, Punctate epithelial granularity adjacent to and distinct from the subepithelial infiltrates. (Adapted from Jones DB, Matoba AY, Wilhelmus

KR. Problem solving in corneal and external diseases. Course 626, presented at the American Academy of Ophthalmology. Atlanta, GA; 1995.)

LABORATORY EVALUATION Diagnosis of EKC is suggested in the setting of bilateral follicular conjunctivitis associated with petechial conjunctival hemorrhages, conjunctival pseudomembrane or frank membrane formation, or, later in the clinical course, the presence of bilateral subepithelial infiltrates. Other adenoviral ocular syndromes have less specific signs, but laboratory diagnosis is only rarely indicated. Although viral cultures readily differentiate adenovirus from HSV infection, the clinical disease typically subsides or resolves before results become available. A rapid immunodetection assay to detect adenovirus antigens in the conjunctiva is available. Paired serologic titers 2–3 weeks apart allow confirmation of acute adenovirus infection, but this test is rarely performed.

MANAGEMENT Therapy for adenoviral ocular infection is primarily supportive. Cool compresses and artificial tears may provide symptomatic relief. Topical antibiotics may be indicated only when the clinical signs, such as mucopurulent discharge, suggest an associated bacterial infection or when a viral cause is less certain.

For patients with conjunctival membranes due to EKC, manual removal by the physician with forceps or a cotton swab every 2–3 days, combined with judicious use of topical corticosteroids, may speed resolution and prevent scarring. Topical corticosteroids also reduce photophobia and improve vision impaired by adenoviral subepithelial infiltrates. Because corticosteroids may prolong viral shedding from adenovirus-infected patients and can lead to worsening of HSV infections, their use should be reserved for patients with clinical signs of adenovirus infection who present with specific indications for treatment, including conjunctival membranes and reduced vision due to bilateral