1. Overview
Human adenoviruses can infect humans in at least 47 of the approximately 100 serotypes of adenoviruses. They can be classified into 6 classes based on DNA homogeneity and hemagglutination reactions, A-F. Adenoviruses have no envelope and are triangular icosahedral viruses (70-90 nm in diameter ) with linear double-stranded DNA at their central site. the capsid is composed of 240 capsid particles, including six neighboring bodies and 12 five neighboring bodies.
Adenovirus is highly epitheliophilic and has a small host range. They can cause respiratory and intestinal infections, hepatitis, cystitis and keratoconjunctivitis. These viruses are endemic, with epidemic episodes occurring year after year. Ocular disease is transmitted mainly by direct contact with the source of infection (e.g. saliva, contaminated towels) or by swimming in a contaminated swimming pool. Lifetime immunity, but specific to adenovirus type.
At least 19 serotypes have been reported as pathogens of epidemic or sporadic conjunctivitis or keratoconjunctivitis. The serotypes associated with epidemic keratoconjunctivitis (EKC) are usually Ad8,19,37, with pharyngeal conjunctival fever (PCF) Ad3 ,7, and with nonspecific follicular conjunctivitis (NFC) Ad1,2,4,5 and 6. Ocular lesions are usually most severe in patients with Ad8 adenovirus infection. PCF and NFC are usually associated with respiratory and gastrointestinal disease, especially in children .
EKC usually occurs in adults aged 20-40 years and is equally likely in men and women. PCF, on the other hand, is usually seen in children, with approximately 10% of all children under 5 years of age seropositive. ad1,2,3,5,6 is mostly considered the main cause of regional childhood respiratory infections.
Since there are no known animal carriers of this virus, humans are the only hosts. Serologic studies have shown that the general population in the United States and Europe has low natural immunity against EKC infection. This lack of immune protection allows ocular adenovirus infections to manifest in epidemic form (less than 10% immunity to Ad8 ). In Asia and Africa adenovirus disease is endemic. Between 25-85% of the general population is serologically positive for Ad8.
The incidence of acute cases in the general population is very low (0.03%-1.10%). However, infection rates are higher in institutions in close contact, such as tents, homes and prisons (10-32% ). The main mode of transmission is direct contact with contaminated secretions, such as towels, sheets, clothing, soap, swimming pools, and intimate contact, and possibly airborne transmission through saliva and nasal secretions. The chromosomes of adenovirus can continuously mutate, but usually within subclinical levels. Occasionally, chromosomal variation increases pathogenicity, leading to dissemination or epidemics of the disease.
An ophthalmologist’s office or hospital can also be a source of epidemics, such as when an IOP measurement is performed on an adenovirus-infected patient without adequate sterilization, followed by a series of IOP measurements. Another major mode of transmission is through contact with the contaminated hands of a physician or caregiver. Simply shaking the hand of an infected person once can transmit the pathogen.
Additional risk exists in the waiting room, where potent viruses can survive for hours in a dry, viable form on equipment and magazines shared by patients. Physicians and those working with medical staff should wash their hands frequently and adequately and clean ocular equipment, especially ophthalmometers (alcohol swab or Dakin solution scrub followed by adequate rinsing). This is especially important when examining patients with red eye or during an adenovirus epidemic.
Patients should be advised to avoid close contact with people, whether at home or at work, for at least 2 weeks, to use their own bath and washcloths, and to avoid sharing such items with uninfected people. Studies on the disinfection of soft and hard contact lenses have found that Ad8 survives in hydrogen peroxide and heat disinfection systems. Therefore, it is strongly recommended that contact lens wearers with acute adenovirus infection should discard the original contact lens after recovery and purchase a new one.
2.Clinical syndrome
A. Epidemic keratoconjunctivitis (EKC)
The more serious adenovirus eye infection is EKC, which is usually associated with Ad8 and 19. However, a variety of serotypes including Ad2-4,7-11,14,16,29 have also been reported. With the exception of 8 and 19, other serotypes produce similar clinical features but generally do not cause an epidemic of disease.
The systemic manifestations of EKC are uncommon, occasionally resembling a flu-like illness with fever, upper respiratory symptoms, myalgia, diarrhea, nausea and vomiting, and differ from PCF in that the latter is usually accompanied by systemic symptoms, often involving both eyes. The incubation period after exposure is about 8 days. This is followed by acute tearing, foreign body sensation, photophobia, followed by eyelid and conjunctival edema, congestion, follicular and papillary conjunctival reactions, with or without hemorrhage or membrane formation, and preauricular lymph node tenderness.
Eyelid edema is severe and even similar to cellulitis. In some patients, plasmacytic or hemorrhagic exudate forms true (bleeding when peeled) or pseudomembranous tissue on the conjunctiva, which may rub against the corneal epithelium and form ulcers. Its main cellular component is neutrophils. Prolonged conjunctival destruction can result in the formation of dry eyes or lid adhesions. Conversely, tear dots form scarring, leading to chronic tearing. The duration of disease in the posteriorly involved eye is 4-5 days in those with bilateral involvement, which is much milder than in the first involved eye and is partly related to the host’s immune protective response.
Patients experience moderate discomfort during conjunctivitis and severe pain with the onset of keratitis. Corneal epithelial infection begins about 8 days after acute onset in approximately 80% of patients, leading to keratitis. This adenoviral keratitis presents with significant discomfort or pain, photophobia, tearing, and eyelid spasm. These symptoms persist until the acute epithelial lesions subside, which usually takes 1-2 weeks, at which point the conjunctivitis has begun to improve.
There are 4 stages of keratitis development, with stage 1 presenting as a diffuse, subtle, superficial epithelial punctate keratitis, caused by a live viral infection. Approximately 1 week later progresses to stage 2, where these lesions fuse into focal, punctate, mildly elevated white epithelial lesions with positive fluorescent staining. This lesion persists for about 10 days, and electron microscopic examination reveals the acute epithelial lesion stage as viral replication within the epithelium. The punctate damage consisted of piles of, swollen, infected epithelial cells.
These cells fuse to form syncytia and lose their cellular contents, resulting in the formation of folds on the surface of many cells. As the cells rupture, these viruses reach outside the cells and spread freely to other locations.
The presence of the eyelid membrane can mechanically lead to map-like ulcers, similar to HSK. viral replication to form antigens leads to delayed hypersensitivity reactions, subepithelial infiltration, and development of a chronic course. By 2 weeks, the host immune response terminates all viral replication, and within a few days, epithelial damage develops into epithelial and subepithelial lesions as stage 3, which evolve into stage 4 over the next few days, characterized by subepithelial white macular lesions or nebulous clouding with negative fluorescent staining.
Typical keratitis presents as clusters or rows of yellow-white spots in the central corneal region, but can reach the periphery and be most dense by week 3 or 4. Posteriorly involved eyes usually have less infiltration, presumably due to milder corneal infection and less antigen deposition. Occasionally, lesions fuse to form scalloped, money string shaped cloudy opacities. These thin subepithelial corneal opacities can persist for months, causing glare and vision loss, and may eventually resorb gradually.
B. Pharyngeal conjunctival fever (PCF)
The ocular lesions of PCF are similar to those of EKC, but the keratitis is milder and usually bilateral, and the subepithelial infiltrates occur less frequently and are more transparent.PCF is usually caused by Ad3,4,7 but is associated with Ad1,5,6 and 14.PCF is an acute, highly contagious disease characterized by fever, pharyngitis, acute follicular conjunctivitis (which can be hemorrhagic) and localized lymph-like hyperplasia with painful, enlarged of preauricular adenopathy. It is predominantly seen in young people and people in specialized institutions, and is prevalent in families, schools and military organizations.
EKC is transmitted through contact with infected upper respiratory tract or secretions in swimming pools. The transmission rate is 100% within the first few days of the onset of the disease, dropping to 0 by 10-15 days after the onset of the disease. the incubation period after exposure of contacts to the virus is 5-12 days (most commonly 8 days), with a sudden or progressive fever of approximately 37.7°C-40°C that can last up to 10 days. other systemic symptoms associated with fever are myalgia, malaise and common gastrointestinal distress. Pharyngitis can be mild or very painful. Typically, there is posterior pole oropharyngeal erythema covered by clear follicles and painless cervical lymphadenopathy.
Ocular lesions may begin with mild itching and burning sensations and progress to marked irritation, tearing, and photophobia. The eyelids swell within 48 hours. Conjunctivitis initially presents as diffuse congestion, most severe in the lower curvilinear bullae, which gradually extends to the lid conjunctiva and bulbar conjunctiva. Conjunctival edema presents as a mild gelatinous appearance with follicular formation, mostly in the lower lid more than the upper lid.
The secretions are plagioid and may form a small amount of scab on the eyelid. If there is no pseudomembrane, there is rarely a mucopurulent discharge. Exudate of mononuclear cells is seen on scraping examination and is nonspecific. If membranes are present, the predominant inflammatory cell type is neutrophilic. There is some degree of lower lid tenderness, occasional bruising, and an appearance resembling recent orbital trauma.PCF develops in one or both eyes, with the later-onset eye starting 1-3 days after the first-onset eye. In this case, the later eye is less severe than the first eye and recovers more quickly.
Punctate keratitis may appear a few days to 1 week after the onset of symptoms, starting as small epithelial punctate lesions that stain positive for fluorescence, progressing to epithelial and subepithelial, focal white lesions that stain positive or negative for fluorescence, and eventually becoming a non-staining subepithelial infiltrate. Similar to EKC, but milder and shorter in duration. In the acute epithelial lesion phase, the virus can be cultured. However, stromal infiltrates are usually considered to be immune complexes bound to residual viral antigens. These infiltrates are mainly distributed in the central cornea. The entire course of the lesion is acute and brief, with resorption within days to 3 weeks. Subepithelial infiltrates are usually milder, but take several months to resolve. Its histopathologic features and immunologic origin are similar to those of EKC. If the lesion occurs on the visual axis, vision is affected.
C. Nonspecific follicular conjunctivitis (NFC)
Any of the ocular adenoviruses can cause NFC, but it is usually mild and is rarely detected at the time of medical consultation.NFC can occur in children or adults and can be caused by either of the serotypes that cause EKC or PCF. Because it does not progress to keratitis and the conjunctivitis is mild, these patients are usually seen by a pediatrician or family physician for treatment. The clinical signs disappear after about 7 to 10 days, and it is important because it is a source of infection for adenovirus serotypes that may eventually cause a serious, widely spread epidemic in the population.
3. Treatment
Research on the specific treatment of ocular adenovirus infections is still in the developmental stage. Although the virus is sensitive to trifluorothymidine nucleoside in vitro, antibiotics and commercially available antivirals are ineffective against it. FDA-approved antimetabolites for the treatment of cytomegalovirus (CMV) infection are likewise considered promising first-line agents for the treatment of ocular adenoviral disease. In an adenoviral rabbit model, topical 0.5% cidofovir twice daily for 7 days had significant anti-adenoviral Ad1,5,6 effects.
The application of 0.5% and 1% cidofovir twice daily in the prophylactic study of antiviral Ad5 had a prophylactic effect on antiviral infection; while a 1% concentration cleared all viral replication. Although the results of the clinical studies are not yet available, cidofovir is expected to be used non-approved due to FDA approval issues for the treatment of CMV retinitis. If the clinical results are positive, the drug could be used as an FDA-approved topical anti-adenoviral agent. Because subepithelial corneal opacification following acute lesions is immune and conjunctival lesions are self-limiting, cidofovir is not effective for adenoviral ocular sequelae but can be used for chronic adenoviral conjunctivitis.
In patients with severe conjunctival reactions such as marked inflammation, edema, pseudomembranes, or early lid bulb adhesions, steroids may relieve symptoms and inflammation. Steroids are not advocated during the acute infection phase because in a study of two rabbit infection models of Ad5, the treatment group with 1% prednisolone, 4 times daily, significantly increased viral replication in the treated eye compared to the control group, despite only 3 days of dosing, and even the use of potency-limiting steroids such as 0.12% prednisolone, 0.1% flutriafolone, or 1% limetholone 4 times daily for 3 for 3 days, also significantly improved Ad5 replication.
Although steroids provide symptomatic relief, they delay viral clearance and promote viral transmission. Topical steroids can be used for subepithelial infiltrates 10-14 days after onset and can reduce discomfort, photophobia, glare, and vision loss due to infiltration in many patients. Steroid treatment of thin subepithelial opacities can usually be slowly tapered over several weeks after improvement without difficulty. However, for some patients, steroids do not cause the subepithelial infiltrates to disappear.
The treatment of adenoviral keratoconjunctivitis is summarized below and can be used as a general palliative treatment:
(1) Antiviral is ineffective, with the possible exception of cidofovir.
(2) Topical NSAIDs (ketorolac and diclofenac) 4 times daily and oral NSAIDs (ibuprofen 400 mg orally 2-3 times daily) may be considered to reduce ocular inflammation. Not effective for viral replication or corneal infiltration.
(3) Iriditis (rarely) should be treated with a ciliary muscle paralyzing agent.
(4) If membranes are present, apply topical antibiotic ointment to lubricate and protect the cornea.
(5) Use ice, antipyretics and sunglasses if necessary
(6) Prevent the spread of disease by careful hand washing, especially disinfecting medical instruments used by the affected eye.
(7) Infected medical personnel should immediately stop working for 2 weeks until the disease has passed its transmission period.
(8) Infected patients should avoid eating or close contact with family members or colleagues, stop working or going to school for 2 weeks, use personal towels, and wash their hands frequently with antiseptic soap.
(9) For patients with severe inflammation or vision loss, topical steroids may be used to temporarily reduce symptoms and infiltration. However, patients need to be informed of slow dose reduction and possible recurrence of symptoms. For patients with intractable chronic prolonged and recurrent disease, topical cyclosporine A. has the effect of reducing corneal infiltration and avoiding the side effects of steroids.