Accepted Manuscript Adenoviral Keratoconjunctivitis Vishal Jhanji, MD, FRCOphth, Tommy C.Y. Chan, FRCSEd, Emmy Y.M. Li, FRCSEd, Kanika Agarwal, BA, Rasik B. Vajpayee, MS, FRCSEd, FRANZCO PII:

S0039-6257(15)00068-5

DOI:

10.1016/j.survophthal.2015.04.001

Reference:

SOP 6565

To appear in:

Survey of Ophthalmology

Received Date: 4 November 2014 Revised Date:

8 April 2015

Accepted Date: 13 April 2015

Please cite this article as: Jhanji V, Chan TCY, Li EYM, Agarwal K, Vajpayee RB, Adenoviral Keratoconjunctivitis, Survey of Ophthalmology (2015), doi: 10.1016/j.survophthal.2015.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Adenoviral Keratoconjunctivitis 1,2,3

Vishal Jhanji, MD, FRCOphth

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Tommy C. Y. Chan, FRCSEd

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Emmy Y. M. Li, FRCSEd

Kanika Agarwal, BA

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Rasik B. Vajpayee, MS, FRCSEd, FRANZCO

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Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong Hong Kong Eye Hospital, Kowloon, Hong Kong 3 Centre for Eye Research Australia, University of Melbourne, Australia 4 The Commonwealth Medical College, 525 Pine St Scranton, PA 18509 5 Vision Eye Institute, Royal Victorian Eye and Ear Hospital, North West Academic Centre University of Melbourne, Australia

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Conflict of Interest: None

Corresponding Author:

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Rasik B Vajpayee, MS, FRCS (Edin), FRANZCO Vision Eye Institute, Royal Victorian Eye and Ear Hospital, North West Academic Centre University of Melbourne, Australia Tel: 61 3 9929 8368, Fax: 61 3 9662 3959 Email: [email protected]

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Key words: Adenoviral conjunctivitis; conjunctivitis; complications; diagnosis; treatment; prevention

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Abstract

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Viral conjunctivitis caused by adenovirus is the most common infectious conjunctivitis. Adenoviruses are highly contagious pathogens. The modes of transmission are mainly through hand to eye contact, ocular secretions, respiratory droplets, and contact with ophthalmic care providers and their medical instruments. The most frequent manifestation of ocular adenoviral infection is epidemic keratoconjunctivitis, followed by

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pharyngoconjunctival fever. Epidemic keratoconjunctivitis is also the most severe form and presents with watery discharge, hyperemia, chemosis, and ipsilateral lymphadenopathy. Pharyngoconjunctival fever is characterized by abrupt onset of high fever, pharyngitis, bilateral conjunctivitis, and periauricular lymph

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node enlargement. Isolated follicular conjunctivitis without corneal or systemic involvement also occurs. The rate of clinical accuracy in diagnosing viral conjunctivitis is less than 50%. Rapid diagnostic tests now

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being used decrease unnecessary antibiotic use in. Treatment for viral conjunctivitis is mostly supportive.

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The majority of cases are self-limited, and no treatment is necessary in uncomplicated cases.

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Introduction

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Adenoviruses are icosahedral, non-enveloped, double-stranded DNA viruses that can cause an array of diseases including conjunctivitis, gastroenteritis, hepatitis, myocarditis and pneumonia.97 Adenovirus is a highly contagious pathogen with over 50 known serotypes with unique antigenic determinants. A. The most frequent manifestation of ocular adenoviral infection is epidemic keratoconjunctivitis (EKC), followed by

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pharyngoconjunctival fever (PCF). The distinguishing feature of presentation of EKC is the involvement of the entire ocular surface, including both the conjunctival and corneal epithelia. In severe cases, there may be formation of pseudomembranes and symblephara as well as multifocal subepithelial infiltrates that can

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reduce vision for years.9, 12, 18 PCF is characterized by fever, pharyngitis, acute follicular conjunctivitis, and preauricular adenopathy. Isolated adenoviral conjunctivitis without corneal or systemic involvement also

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occurs. The modes of transmission are mainly through hand to eye contact, ocular secretions, respiratory droplets, and contact with ophthalmic care providers and their medical instruments.8 Adenoviral conjunctivitis a biphasic disease that begins with an infective phase that is then followed by an inflammatory phase, which tends to begin 7–10 days after the initial infection as the virus continues to shed.

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The patient remains infectious for up to 2–3 weeks.49

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Epidemiology

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Adenoviruses are the most common cause of acute viral infection of the conjunctiva, accounting for up to 75% of case of conjunctivitis.120 In Japan adenoviral conjunctivitis affects approximately 1 million individuals each year, and epidemics are monitored by the National Surveillance Center.48 Precise statistical data on the actual prevalence and incidence at the international level, however, is not available as cases may

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go undetected because patients do not seek medical care. According to data from Germany, the infection is more common in adults, though all age groups may be affected. There is no gender predilection.2 In general,

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EKC typically occurs in the 20-40 year age group, whereas PCF typically occurs in children.28, 29

Adenoviruses are classified into 7 species (A to G) and different serotypes according to their

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immunochemical properties, nucleic acid similarities, hexon and fiber protein length, biological properties, and phylogenetic analysis.4, 100, A Adenoviral conjunctivitis may occur epidemically or sporadically throughout the year. The spectrum and severity of disease varies based on the serological subtypes. Serotypes 8, 19, and 37 (species D) are associated with EKC; serotypes 3, 5, 7 and 11 (species B and C)

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cause PCF; serotypes 1–11 (species B to E) frequently cause isolated follicular conjunctivitis characterized by conjunctivitis without the sore throat or preauricular lymph node enlargement .2, 6, 25, 95, 112 In an epidemiological study in Japan, adenoviral conjunctivitis related to serotype 3, 4 and 37 increased in

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summer with temperature rises.5 Data from Germany also suggests that adenoviral conjunctivitis is more frequent during warmer months.28 EKC outbreaks can occur in the general population, in hospital

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environments (especially the ophthalmological units),17, 36, 94 in neonatal intensive care units,10, 26 and in nursing homes.20, 27 PCF outbreaks, on the other hand, are more common in schools, kindergartens, and summer camps.29

Both EKC and PCF tend to occur in closed institutions. Direct contact with ocular secretions is the most common mode of transmission. The infection may be also spread through contact with eye care providers and instruments like tonometers, lid specula, and slit lamps. In one study 46% of infected persons had positive hand swab cultures.8 The risk of infection from domestic contact is approximately 10%, increasing 4

in cases with prolonged infection.35 Nosocomial EKC infections are common, and outbreaks in

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ophthalmology units may impose restrictions on clinical practices, including delay of eye surgery, early release of inpatients from hospital, and closure of ophthalmology wards.48 In the United States, a nosocomial outbreak involving 41 individuals cost a hospital $29,527 ($1085 for medical costs, $8210 for investigative costs, $3048 for preventive measures, and $17,184 for lost productivity), indicating a

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substantial expenditure that could have been prevented by proper infection control measures.74

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Clinical symptoms and disease spectrum

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Epidemic keratoconjunctivitis

Of the 60 or so serotypes of adenovirus that have been isolated, at least 19 can cause EKC. The most frequently associated serotypes are adenovirus 8, 19, and 37; less common serotypes include 2-5, 7, 9, 10,

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11, 14, 16, 21, and 29.B The incubation period varies between 4 to 24 days, and the symptoms tend to last for 7-21 days. The patient may remain infectious for 10-14 days . The virus is not usually detectable by PCR of ocular secretions prior to the onset of symptoms.51 EKC is predominantly a unilateral condition in its

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initial phase, but can become bilateral in up to 70% of cases.29 The most common symptoms are “pink eye” or “red eye”, excessive tearing, foreign body sensation, and photophobia. In more severe cases, patients can

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present with ocular or periorbital pain and decreased visual acuity. There is usually a recent history of an eye examination, an affected family member, or an occupational exposure. The infection may occasionally be preceded by flu-like symptoms such as fever, malaise, myalgia, respiratory symptoms, nausea and vomiting, and diarrhea. The ocular signs are predominantly bulbar conjunctival redness, chemosis, tarsal follicular

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reaction, petechiae, or even subconjunctival hemorrhage (Figure 1).

Pharyngoconjunctival fever

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PCF is most frequently caused by adenovirus serotypes 3, and less commonly by serotypes 2, 4, 7 and 14.

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Sporadic outbreaks occur in association with serotypes 1, 5, 6, 8, 11, and 19.7, 62 PCF is an acute and highly contagious disease characterized by fever, pharyngitis, rhinitis, follicular conjunctivitis, and regional lymphoid hyperplasia with tender preauricular adenopathy. The ocular inflammation starts unilaterally and progresses to bilateral involvement over 1-3 days. The common ocular signs are crusting and swelling of the eyelids, epiphora, conjunctival injection, conjunctival chemosis, follicular or papillary reaction and subconjunctival haemorrhage. Transmission can occur through contact with ocular secretions or respiratory droplets. The incubation period ranges from 5 to 12 days, and the symptoms typically last for 3-5 days. Most cases are self-limited and mild. Long-term complications are rare.C

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Complications

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The formation of pseudomembranes, sheets of fibrin-rich exudate lacking blood or lymphatic vessels adhered to the upper and lower tarsal conjunctiva, is a frequent complication in EKC, especially in infection associated with serotypes 8, 19 and 37.101 . Pseudomembranes are distinguished from true membranes in they can be removed from the conjunctiva without damaging the underlying epithelium, thus causing minor

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bleeding, if any. Though it was conventionally taught that EKC is associated with pseudomembranes rather than true membranes, a recent study on the membrane structure demonstrated that, apart from a

conglomerate of leukocytes (including neutrophils, macrophages, T cells, and activated dendritic cells)

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enmeshed in an eosinophilic extracellular matrix, there was formation of coagulum beneath the epithelium, early angiogenesis with the expression of angiogenic factors like Vascular Endothelial Growth Factor and

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Transforming Growth Factor-β and presence of degenerative conjunctival epithelium. The latter suggests that true conjunctival membranes can and do form in EKC, depending on the degree and intensity of inflammation. Such true membranes, when removed, induce bleeding and their persistence can lead to

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subepithelial fibrosis and symblepharon formation.11

Another common complication from EKC is multifocal subepithelial infiltrates considered pathognomic of adenoviral infection (Figure 2). They are observed in up to 50% of cases and more frequently in the serotype

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8 infection subtype.29, 101 These focal lesions may represent a cellular immune reaction against viral antigens

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deposited in the corneal stroma under the Bowman membrane.45 In an in vivo confocal microscopy study evaluating the clinical course of EKC, the diffuse epithelial keratitis at week 1 was correlated with subepithelial accumulations of dendritic cells located at the level of the Bowman layer, and the focal epithelia keratitis at week 2 was correlated with clusters of hyperreflective basal epithelial cells intermingled with leukocytes above an intricate network of dendritic cells., There was a hyperreflective cellular plaque in the anterior stroma at the area of subepithelial infiltrate .21 There might be a transient decrease in corneal sensitivity in the early stage that normalizes in an average of 8.5 days.72 The subepithelial infiltrates can persist for weeks to years. They may cause visual impairment if the infiltrates involve the visual axis. Most of these infiltrates tend to resolve spontaneously without scarring. The use of topical corticosteroids may 7

hasten recovery, but does not affect the long-term outcome.57 For cases with persistent corneal opacities

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induced by EKC, phototherapeutic keratectomy with low-dose mitomycin C may lead to improvements in photophobia, visual acuity, and contrast sensitivity.122

Bacterial superinfection in adenoviral conjunctivitis is rare, yet it can be severe in pediatric patients and lead

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to amblyopia and strabismus.34, 56 The more commonly reported pathogens include gram-positive cocci, especially Streptococcus pyogenes.28 Although uncommon, Gram-negative rods have been identified in

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adenoviral conjunctivitis-related superinfections. 117

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Microbiological characteristics

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Adenovirus was first isolated by Rowe et al in 1953 and was first described to cause EKC by Jawetz et al in 1955.43, 90 Human adenoviruses belong to the genus Mastadenovirus of the family of Adenoviridae and are classified into species A to G. They are non-enveloped double-stranded DNA viruses that can cause infection in a variety of human tissues, causing conjunctivitis, gastroenteritis, hepatitis, myocarditis, and

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pneumonia. Human adenoviruses range from 65 to 80 nm in diameter. The virion is composed of an icosahedral-shaped protein capsid made up of 252 capsomeres, a nucleoprotein core that contains the DNA

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viral genome and internal proteins.

Adenoviruses are able to affect human cells in 2 ways. In a lytic infection involving epithelial cells, the virus

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completes its replication cycle within the cell, inducing cellular death and releasing between 104 to 106 new viruses, of which up to 5% are infectious. (In a latent infection involving lymphoid cells,, only a small amount of virus is released, and the cellular death rate is offset by normal multiplication. Immune responses to adenoviral infection depend on a number of factors such as the inoculation site, the serotype, and the

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immune status of the host. There are several mechanisms for the adenovirus to antagonize the host immune response, including the inhibition of intrinsic cellular apoptosis in infected cells, the inhibition of responses to interferon and tumor necrosis factor, and the prevention of major histocompatibility complex class I

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adenovirus in humans.

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expression on cell surfaces.29 There is no definite evidence supporting oncogenic transformation of

Adenoviral conjunctivitis is mostly caused by serotypes 3, 4, 8, 19 and 37, although association with numerous serotypes has been reported, as described above. Recently, there have been EKC outbreaks from new genome types or nucleotide polymorphisms.6, 46 New human adenovirus types develop from genomic variations, substitutions and recombination between different types of existing human adenoviruses.4, 113 Given the advances in DNA sequencing, phylogenetic analysis provides an effective and reliable method of classifying adenovirus and monitoring molecular evolution. In Japan, two new human adenovirus types that cause EKC, named Human adenovirus-53 and Human adenovirus-54, were identified using phylogeny9

based classification and have replaced Human adenovirus-8 as the predominant serotype responsible for

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epidemics in this country.

4, 42, 46, 113

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Diagnosis

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The diagnosis of adenoviral conjunctivitis is usually made on the basis of symptoms and clinical findings. Laboratory testing is typically not necessary, but can be helpful in confirming the diagnosis and reducing health care costs.109 Testing includes cell culture, PCR, direct immunofluorescence, and rapid antigen detection immunoassays. Viral cell cultures of the conjunctival specimen allow confirmation of the

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adenovirus with immunofluorescence, but are less commonly performed because of the necessity for elaborate equipment, trained laboratory personnel, and the significant delay in obtaining results.16, 23, 54, 60, 110 Detection of adenoviral DNA in conjunctival specimen by PCR is more commonly used, but is a complex

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process that also requires expensive equipment and technical expertise.14, 15, 24, 52 Furthermore, both methods require proper specimen transport.119 Previously, the most rapid diagnosis was made by direct detection of

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adenoviral antigen in conjunctival cells by immunofluorescence assay, but this depends heavily on experience and is not as sensitive.22, 96, 111 Recently, rapid detection testing kits became available for diagnosis of adenoviral infection at the point of care. The rapid antigen detection immunoassay is an FDAapproved office-test that uses a small test strip touched to various regions along the palpebral conjunctiva.

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Once the sterile sample collector is assembled to the test cassette body, the test is activated with a buffer solution. Based on the principles of lateral flow immunochromatography which detects the hexon protein of adenovirus that has conserved antigenic determinants among all serotypes,92, 98, 106 it is capable of detecting

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53 adenoviral serotypes and provides results within 10 minutes.49 Systematic use of this test could reduce costs derived from the empirical use antibiotics in patients with EKC. Early implementation of infection

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control measures would also help limit the spread of infection.109 The test provides results in only 10 minutes and is highly sensitive and specific compared to viral culture and PCR,92 with a sensitivity of 88% and specificity of 91% compared with cell culture confirmed with immunofluorescence. It is also simple and inexpensive, as no special equipment or specially trained personnel is necessary. A second generation of rapid antigen detection immunoassay recently developed with enhanced specimen collection and modifications to the test strip.has a high sensitivity and specificity.93

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Differential diagnosis

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Differential diagnoses of adenoviral conjunctivitis include viral conjunctivitis from non-adenoviral species, allergic conjunctivitis and clamydia inclusion conjunctivitis.28, 29, D Although follicular conjunctivitis is mostly caused by adenoviruses, herpetic viruses, picornavirus and poxvirus are less common causes. Rarely, Epstein-Barr virus, influenza virus, paramyxovirus, and human immunodeficiency virus cause

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conjunctivitis during systemic infection.

Herpes simplex virus and varicella/zoster virus are also common causes of conjunctivitis. Patients with

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herpetic conjunctivitis usually exhibit unilateral symptoms and complain more frequently about pain. Dendritic keratitis and vesicles in the skin of eyelids are signs of herpetic conjunctivitis. Herpetic

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conjunctivitis has a self-limited course of about 1 week. Injudicious use of topical corticosteroids in acute conjunctivitis can exacerbate herpetic disease and increase the risk of bacterial infection. Fever and constitutional symptoms are more commonly associated with varicella/zoster virus infection. Picornavirus, particularly enterovirus 70 and coxsackievirus A24, may produce acute hemorrhagic conjunctivitis in

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children and young adults. Molluscum contagiosum, a poxvirus, can produce a chronic follicular conjunctivitis with typical umbilicated nodules near the lid margin.

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Allergic conjunctivitis with symptoms and signs similar to adenoviral conjunctiviti. usually presents bilaterally and symmetrically with itch as the most common symptom, whereas foreign body sensation is

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more common with adenoviral conjunctivitis. Papillary conjunctival reaction is more intense in the upper tarsal conjunctiva in disease of allergic origin, whereas follicular tarsal conjunctival reaction is characteristic of adenoviral conjunctivitis.

Chlamydia inclusion conjunctivitis that usually exhibits larger follicles predominantly over the conjunctiva in the inferior fornises has a subacute to chronic course and is resistant to the usual topical treatments. Moreover, these patients may have a history of genito-urinary infection.

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Treatment

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Adenovirial conjunctivitis is a self-limited disease that usually exhibits complete resolution within 3 weeks. Conservative treatments, including artificial lubricants and cool packs, can provide efficient symptomatic relief without any adverse effects. Topical antibiotics are used to treat or prevent bacterial superinfection.40 Topical antihistamine and vasoconstrictors also reduce discomfort and disease duration in spite of the risk of

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local toxicity.61 The use of topical steroids is controversial. Topical steroids are frequently given in the acute phase; however, this only has a transient alleviating effect . The disease and infection durations could be prolonged because of increased adenovirus replication rate and extended viral shedding as demonstrated

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in animal models.84, 86, 87 Steroid treatment should be restricted to complicated cases with pseudomembranes or subepithelial infiltrates where visual acuity is significantly impaired.58, 84 Topical non-steroidal anti-

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inflammatory agents are also ineffective in controlling adenovirus replication in animal models.81 Although non-steroidal anti-inflammatory agents have no significant effect on the subepithelial infiltrates, they may be a safer alternative to topical steroids for symptomatic relief.30

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Virustatic agents such as trifluridine, vidarabine and ganciclovir are only mildly effective against adenovirus, and current data in regards to their efficacy in treatment adenoviral conjunctivitis are still controversial.105, 114, 115 Topical ganciclovir decreases adenovirus load experimentally;39, 105 however, it lacks

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efficacy in the treatment of conjunctivitis in clinical trials.121 Topical cidofovir has significant antiviral activity against adenovirus in vitro and in animal models.19, 32, 47, 80, 82 Topical administration of cidofovir

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significantly reduced adenovirus viral titers and shortened the duration of shedding and also provides prophylaxis against adenovirus exposure.85 In a clinical study, topical cidofovir, used alone or in combination with topical cyclosporine, did not accelerate improvement of clinical symptoms of acute adenoviral keratoconjunctivitis compared with the natural course of disease.37, 38 Despite a lack of an overall benefit on the course of the illness, cidofovir can lower the frequency of severe corneal opacities. Antiviral agent 2’3’-dideoxycytidine has a potent anti-adenoviral effect and is more efficacious than cidofovir treatment in animal models.88

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Interferons are natural proteins produced by cells in response to viral infection that control viral spread.

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Topical interferon β reduces the length of disease and prevents corneal complications in some studies .78, 79, 118

Interferon γ also has an inhibitory effect on adenovirus and is a potential treatment of adenoviral

conjunctivitis; .64, 65, 107 however, no therapeutic effects were observed in studies using interferon α.1, 76, 99 Topical immunoglobulin demonstrates anti-adenoviral properties in animal model, but human studies are

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lacking.68 Povidone-iodine is a broad-spectrum antiseptic agent highly effective against free adenovirus, but less effective against intracellular adenoviral particles in infected cells in vitro.50, 66 Combination of topical

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povidone-iodine and dexamethasone decrease the secretion of virus and reduce disease progression.13 Topical steroids relieve symptoms, and povidone iodine kills the virus in tears, thus reducing the risk of

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disease spread. A recent study showed that conjunctival irrigation with 2.5% povidone iodine is effective in the treatment of adenoviral conjunctivitis in infants.71 Another antimicrobial agent that appears to be effective, N-chlorotaurine, exerts a significant inhibitory effect on adenovirus108 and shortens the duration

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of illness and improve disease symptoms,102 but less effective than cidofovir in animal studies.89 Apart from the management of acute disease, topical steroids are used to decrease the subepithelial infiltrates associated with adenoviral conjunctivitis,57, 89, 104 but these often recur once it is stopped. This

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leads not only to dependence, but also results in steroid-induced complications, such as cataract and ocular hypertension. Cyclosporine eye drops can be used as a steroid-sparing agent for the treatment of

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subepithelial infiltrates after adenoviral conjunctivitis, but does not alleviate the acute disease symptoms nor affect the natural course of the disease.37, 38Topical 0.05%-2% cyclosporine, however, reduces the formation of subepithelial infiltrates and their symptoms such as foreign body sensation and visual impairment.44, 59, 70, 77

The use of topical cyclosporine is relatively safe despite the risk of local epidemic by increasing the

amount of viral shedding as seen in an animal study.83 Excimer laser phototherapeutic keratectomy,reserved for chronic subepithelial infiltrates that cause significant visual disturbances, results in improvement of photophobia, visual acuity, and contrast sensitivity when combined with low-dose mitomycin C.3, 75

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Prevention

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Since there is no effective treatment for adenoviral conjunctivitis and its complications, good hygiene practices, such as rigorous disinfection of hands and instruments, are essential for prevention of spread of the infection.28, 29, 63 The type of disinfectant used is also of paramount importance because adenoviruses are relatively resistant to many commonly used disinfectants.91 Human adenoviruses are resistant to desiccation

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and can survive for a significant time outside the body. They can be recovered at an infectious concentration even after 28 days on a metal or plastic surface.31 Simply wiping the surface with common disinfectants, such as isopropyl alcohol or hydrogen peroxide may not be sufficient.91, 103 Patients with suspected infection

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should be isolated in a special ‘contagion room’ in the clinic, and all instruments and surfaces should be disinfected thoroughly with 70% ethyl alcohol or 1:10 diluted bleach solution69, 91 Prior cleaning of organic

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matter is important before application of disinfectants.91 The use of gloves, disposable tonometer heads and single-patient eye drop dispensers may reduce transmission.8, 63 Moreover, patients in the acute phase of illness should be informed about the natural course of the disease so that they will be less likely to return for follow-up when they are still contagious. Indeed, a proper infection control program can greatly reduce

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nosocomial adenoviral infection or outbreaks.17, 33, 55, 116

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Conclusion

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Adenoviral conjunctivitis is a self-limited disease that tends to resolve spontaneously within 1-3 weeks in most cases. Since there is no known efficient antiviral treatment against human adenoviruses , management is focused on symptomatic relief with cold compresses, lubrication, and topical non-steroidal antiinflammatory agents. Topical corticosteroids may be indicated if vision-threatening complications arise.29

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Late scarring may be treated by phototherapeutic keratectomy.122 Prevention is important to control the propagation of the infection. Implementation of systematic hospital infection control protocol against adenoviral infection is required in addition to general measures like hand washing and disinfection of

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instruments.33 Advancement in early pathogen detection, strict adherence to hygienic measures and establishment of an adenoviral infection control program can greatly reduce the incidence of community

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outbreaks.

Acknowledgments/ funding: Vishal Jhanji is supported by Direct Grant (No. 2041710) for Research for this work

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Method of Literature Search

PubMed and MEDLINE were queried with combinations not limited to the following search terms: Adenoviral conjunctivitis; conjunctivitis; complications; diagnosis; treatment; prevention and epidemiology.

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A review of the search results was performed and relevant articles were included. Case reports without

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additional value over another report of the same condition were not included. Disclosure: None Figure legends

Figure 1: Slit lamp photography showing a case of epidemic keratoconjunctivitis. Prominent follicular reaction was demonstrated on the inferior palpebral conjunctiva. Figure 2: Slit lamp photograph showing multiple, subepithelial corneal infiltrates associated with adenoviral conjunctivitis.

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Other cited materials

A. Human Adenovirus Working Group. Human Adenovirus Genotype Classification http://hadvwg.gmu.edu/ [assessed on June 1, 2014]. B. Bawazeer A, Hodge WG. Epidemic keratoconjunctivitis http://emedicine.medscape.com/article/1192751-overview - aw2aab6b2b3aa [assessed on June 28, 2014]. C. Scott IU. Pharyngoconjunctival fever http://emedicine.medscape.com/article/1192323-overview - a0104 [assessed on June 28, 2014]. 27

D. Scott IU. Viral conjunctivitis http://emedicine.medscape.com/article/1191370-

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overview#aw2aab6b2b2 [assessed on January 1, 2015]

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Outline

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1. Introduction 2. Epidemiology 3. Clinical symptoms and disease spectrum

b. Pharyngoconjunctival fever 4. Microbiological characteristics

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5. Diagnosis (including Rapid Diagnostic devices) 6. Differential diagnosis

c. Chlamydia conjunctivitis 7. Treatment

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a. Ocular lubricants

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a. Allergic conjunctivitis b. Herpetic conjunctivitis

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a. Epidemic keratoconjunctivitis

b. Topical corticosteroids c. Topical cyclosporine

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d. Topical NSAIDs e. Topical antivirals

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f. Excimer laser surgery 8. Complications

9. Prevention of infection 10. Conclusions

11. Method of literature search 12. Disclosure 13. Figure caption 14. References 29

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