Viral Conjunctivitis

Etiology

The conjunctiva is a thin semitransparent membrane that covers the white part of the eye called the sclera. The conjunctiva starts at the limbus of the cornea and covers both the sclera and posterior surface of the eyelids. The portion covering the scleral is referred to as the bulbar conjunctiva, and the portion on the posterior surface of the lids is the palpebral conjunctiva.

The most common cause of viral conjunctivitis is adenoviruses. The adenovirus is part of the Adenoviridae family that consists of a nonenveloped, double-stranded DNA virus. Frequently associated infections caused by the adenovirus include upper respiratory tract infections, eye infections, and diarrhea in children. Children are most susceptible to viral infections, and adults tend to get more bacterial infections. Viral conjunctivitis can be obtained by direct contact with the virus, airborne transmission, and reservoir such as swimming pools. [5][6]

Most cases of viral conjunctivitis are highly contagious for 10-14 days. Washing hands and avoidance of eye contact are key to preventing transmission to others.

Adenoviral Conjunctivitis

Up to 90% of viral conjunctivitis cases are caused by adenoviruses.[7] In children pharyngoconjunctival fever (PCF) due to HAdV types 3, 4, and 7 results in acute follicular conjunctivitis with fever, pharyngitis, periauricular lymphadenopathy. Epidemic keratoconjunctivitis (EKC) is the most severe ocular infection caused by adenovirus and is classically associated with serotypes 8, 19, and 37. The cornea can be affected by the viral replication in the epithelium and anterior stroma leading to superficial punctate keratopathy and subepithelial infiltrates.[8] Monotherapy with povidone-iodine 2% have demonstrated the resolution of symptoms.[9] Further combinations of povidone-iodine with corticosteroids are undergoing phase 3 randomized controlled studies. Visual symptoms caused by subepithelial infiltrates can be debilitating and the use of tacrolimus, 1% and 2% cyclosporine A eye drops have been shown to effective.[10][11][12]

Herpetic Conjunctivitis

Herpes conjunctivitis is common in adults and children and associated with follicular conjunctivitis. Herpes simplex virus (HSV) is estimated to be responsible for 1.3 - 4.8% of acute conjunctivitis cases.[13] Treatment with topical antiviral agents is aimed at reducing virus shedding and the development of keratitis. Varicella-zoster can cause conjunctivitis either by direct contact of the eye or skin lesions or inhalation of infected aerosolized particles, especially with the involvement of the first and second branches of the trigeminal nerve.

Acute Hemorrhagic Conjunctivitis (AHC)

This is a very contagious form of viral conjunctivitis and symptoms include foreign body sensation, epiphora, eyelid edema, conjunctival chemosis, and subconjunctival hemorrhage. A small proportion of patients experience systemic symptoms of fever, fatigue, limb pain. Transmission is primarily via hand to eye contact and fomites.[14] Picornaviruses EV70 and coxsackievirus A24 variant (CA24v) are thought to be the responsible pathogens.[15]

COVID-19 Conjunctivitis

The most recent isolated strain of coronavirus, COVID-19 has been reported to cause conjunctivitis along with fever, cough, respiratory distress, and death.[16] Retrospective and prospective studies show that 1% to 6% of patients display COVID-19 related conjunctivitis, with conjunctival swabs being positive in 2.5% of cases.[17] Transmission through ocular tissues is incompletely understood. Ophthalmologists are at higher risk for COVID-19 infection due to the close proximity to patients, equipment intense clinics, direct contact with patients' conjunctival mucosal surfaces, and high-volume clinics. Systemic COVID-19 is contracted through direct or airborne inhalation of respiratory droplets. Additional protective measures such as social distancing, wearing masks, reduced clinic volumes, and sterilization of surfaces should be practiced to reduce transmission risk.  

Epidemiology

Conjunctivitis, whether bacterial or viral, is a common problem that affects millions of Americans each year. In the United States, it is estimated that 1% of visits of a primary care physicians are related to conjunctivitis. While viral conjunctivitis is the most common cause, bacterial conjunctivitis is the second most common cause and distinguishing the two can be a challenge for primary care physicians. Frequently antibiotics are prescribed without good indication which could present an unnecessary financial burden on the patient and increase drug-resistant bacteria. Employers and schools typically require those with conjunctivitis to remain out of their locations until the infection clears, potentially adding to the economic burden placed on those infected.[18]

Pathophysiology

Regardless of the etiology, most cases of conjunctivitis can be categorized as either papillary or follicular. Neither classification is pathognomonic for a particular disease entity. Papillary conjunctivitis produces a cobblestone arrangement of flattened nodules with central vascular cores. It is most commonly associated with an allergic immune response or is a response to a foreign body. Independent of the etiology, the histologic appearance of papillary conjunctivitis is the same: closely packed, flat-topped projections, with numerous eosinophils, lymphocytes, plasma cells, and mast cells in the stroma surrounding a central vascular channel.

Follicular conjunctivitis is seen in a variety of conditions, including inflammation caused by pathogens such as viruses, bacteria, toxins, and topical medications. In contrast to papillae, follicles are small, dome-shaped nodules without a prominent central vessel. Histologically, a lymphoid follicle is situated in the subepithelial region and consists of a germinal center with immature, proliferating lymphocytes surrounded by a ring of mature lymphocytes and plasma cells. The follicles in follicular conjunctivitis are typically most prominent in the inferior palpebral and forniceal conjunctiva.[19]

History and Physical

The diagnosis of viral conjunctivitis is based on clinical and laboratory signs. Correct and early identification of etiology allows appropriate treatment and the avoidance of longer-term complications.

Patients with viral conjunctivitis present with sudden onset foreign body sensation, red eyes, itching, light sensitivity, burning, and watery discharge. Whereas with bacterial conjunctivitis, patients present with all the above symptoms, but with mucopurulent discharge and mattering of the eyelids upon waking. Those presenting with viral conjunctivitis usually have a recent history of upper respiratory tract infection or recent contact with a sick individual. Visual acuity is usually at or near their baseline vision. The cornea can have subepithelial infiltrates that can decrease the vision and cause light sensitivity. The conjunctiva is injected (red) and can also be edematous. In some cases, a membrane or pseudomembrane can be appreciated in the tarsal conjunctiva. These are sheets of fibrin-rich exudates that are devoid of blood or lymphatic vessels. True membranes can lead to the development of subepithelial fibrosis and symblepharon, and also bleed heavily on removal.[20] Follicles, small, dome-shaped nodules without a prominent central vessel, can be seen on the palpebral conjunctiva. The majority of viral conjunctivitis patients will have follicles present, but the presence of papillae does not rule out a viral etiology.[21] Palpation of the preauricular lymph nodes may reveal a reactive lymph node that is tender to the touch and will help differentiate viral conjunctivitis versus bacterial. With HSV, vesicles may appear on the face or eyelids and vision may be affected. Corneal involvement may occur. With herpes zoster, there is a linear dermatomal pattern of vesicles. The conjunctiva is often red with a mucopurulent discharge.

Fever, malaise, fatigue, presence of enlarged lymph nodes, and other constitutional signs help to differentiate viral conjunctivitis from other causes. Anisocoria and photophobia are associated with serious eye conditions including anterior uveitis, keratitis, and scleritis.[22] Systemic diseases associated with conjunctivitis include skin and mucous membrane diseases (acne rosacea, ichthyosis, xeroderma pigmentosum), collagen vascular diseases (systemic lupus erythematosus,  rheumatoid arthritis, Sjogren's disease, granulomatosis with polyangiitis), and autoimmunity (graft versus host disease, Steven-Johnson syndrome, and ocular cicatricial pemphigoid). 

Evaluation

Laboratory testing is typically not indicated unless the symptoms are not resolving and infection last longer than 4 weeks. Laboratory testing can be indicated in certain situations such as a suspected chlamydial infection in a newborn, an immune-compromised patient, excessive amounts of discharge, or suspected gonorrhea co-infection. In the office, physicians can run tests to positively identify adenovirus with a specificity and sensitivity of 89% and 94%, respectively. However, ophthalmologists usually can make the diagnosis clinically with confirmational additional testing.[23] 

Regarding adenovirus testing, the gold standard has traditionally been cell culture because once the virus is isolated, the diagnosis is definitive and the characterization of the virus can be undertaken.[24] Disadvantages include cost and increased time associated with cell culture-based testing. The mainstay of viral conjunctivitis testing in the developed world is the detection of viral DNA by polymerase chain reaction (PCR). PCR for adenovirus has been shown to be 93% sensitive and 97.3% specific from conjunctival swabs, with similar values, found for HSV diagnosis.[24] A recent development has been the creation of a rapid detection testing platform for adenovirus, the AdenoPlus assay (Rapid Pathogen Screening Inc., Sarasota, Florida, USA). This is a swift office-based test designed to detect 53 serotypes of adenovirus and provide a result within 10 minutes.[25] Studies have demonstrated high specificity values of 92% to 98% in detecting adenoviral conjunctivitis. [26][27][28] However, the test has lower sensitivity reported compared with PCR analysis.[26][27][28] Rapid detection testing can be more useful in the future once viral conjunctivitis treatments reach the clinical setting.[29]

Treatment / Management

Treatment for viral conjunctivitis is aimed at symptomatic relief and not to eradicate the self-limiting viral infection. The resolution of conjunctivitis can take up to 3 weeks. Treatment includes using artificial tears for lubrication four times a day or up to ten times a day with preservative-free tears. Cool compresses with a wet washcloth to the periocular area may provide symptomatic relief. Preventing the spread of infection to the other eye or other people requires the patient to practice good hand hygiene with frequent washing, avoidance of sharing towels or linens, and avoiding touching their eyes. A person is thought to shed the virus while their eyes are red and tearing.

If a membrane or pseudomembrane is present, it can be peeled at the slit lamp to improve patient comfort and prevent any scar formation from occurring. These membranes can either be peeled with a jeweler forceps or a cotton swab soaked with topical anesthetic. Topical steroids can help with the resolution of symptoms. However, they can also cause the shedding of the virus to last longer. Patients should be informed that they are highly contagious and should refrain from work or school until their symptoms resolve. While using steroids, they may still shed the virus without the visual symptoms that would indicate that they have an infection. Steroids should be reserved for patients with decreased vision due to their subepithelial infiltrates or severe conjunctival injection causing more the expected discomfort.[30][31](B3)

The use of povidone-iodine, a non-specific disinfectant, is a promising new treatment for adenoviral conjunctivitis.[25] This is an inexpensive and widely available antiseptic solution which is used as part of the aseptic preparation for ocular surgery. It is able to kill extracellular organisms but has no effect intracellularly. It does not induce drug resistance because its mechanism of action is not immunologically dependent. A single dose of 2.5% povidone-iodine in infants with adenoviral conjunctivitis resulted in a reduction in symptom severity and reduced recovery time without significant side effects.[32](B3)

Topical corticosteroids alone are contraindicated in epithelial herpes simplex keratitis and are associated with prolonged viral shedding and infection.[29] When used in combination with an anti-infective, corticosteroids have demonstrated good tolerability and efficacy in treating the inflammatory and infectious components of conjunctivitis.[33][34] (A1)

Differential Diagnosis

While the most common causes of conjunctivitis are viral or bacterial and due to allergic reactions, there are other causes of conjunctivitis that should be considered when treatment does not improve symptoms. Uveitis is a local autoimmune reaction that causes the eye to become inflamed and is commonly mistaken for conjunctivitis. Uveitis can be a local reaction that is idiopathic or a manifestation of a systemic autoimmune disease such as rheumatoid arthritis, lupus, or ankylosis spondylitis. Systemic autoimmune disease such Sjogren syndrome or Stevens-Johnson syndrome can also mimic conjunctivitis by presenting with conjunctival erythema and discharge. 

A systemic workup should be initiated if any of these diseases are suspected. The most life or sight-threatening masqueraders of conjunctivitis include cavernous carotid fistula, orbital cellulitis, and orbital hemorrhage. In cavernous carotid fistulas, an abnormal communication between the arterial and venous circulation form causing vasodilation of the venous system. Subsequently, the fistula can cause rupture and hemorrhage, leading to irreversible damage to the eye and/or death. Due to venostasis, the ophthalmic vein dilates and causes congestion of the episcleral vessels mimicking conjunctivitis. Proptosis and a pulsatile globe can help differentiate between a fistula and conjunctivitis. Orbital cellulitis is an infection posterior to the septum and involves the orbital contents. Patients present with similar symptoms of conjunctivitis, but will also have pain with eye movements or even restricted eye movements. Lastly, an orbital hemorrhage is an ophthalmic emergency. The cause is mostly traumatic, but it is possible to have a spontaneous hemorrhage, especially in patients on anticoagulants, that present with proptosis, tight eyelids, and erythema of the conjunctiva.

Prognosis

The majority of cases of virus conjunctivitis resolve on their own. In rare cases, chronic infection may occur. Most cases resolve within 14-30 days. In some patients, photophobia, diminished vision and glare may be a problem.

Complications

• Punctate keratitis
• Bacterial superinfection
• Conjunctival scarring
• Corneal ulceration
• Chronic infection