a r c h s o c e s p o f t a l m o l . 2 0 1 3;8 8(3):108–115

ARCHIVOS DE LA SOCIEDADESPAÑOLA DE OFTALMOLOGÍA

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Review

Adenoviral keratoconjunctivitis: An update�

J.J. González-Lópeza,b,∗, R. Morcillo-Laiza, F.J. Munoz-Negretea,b

a Servicio de Oftalmología, Hospital Universitario Ramón y Cajal, Madrid, Spainb Departamento de Cirugía, Facultad de Medicina, Universidad de Alcalá, Madrid, Spain

a r t i c l e i n f o

Article history:

Received 29 December 2011

Accepted 6 July 2012

Available online 14 May 2013

Keywords:

Adenovirus

Conjunctivitis

Viral conjunctivitis

Keratitis nummularis

Keratoconjunctivitis

a b s t r a c t

The objective of this review is to describe the clinical and epidemiological characteristics of

adenoviral conjunctivitis, as well as to present a practical update on its diagnosis, treatment

and prophylaxis.

There are two well-defined adenoviral keratoconjunctivitis clinical syndromes: epidemic

keratoconjunctivitis and pharyngoconjunctival fever, which are caused by different ade-

novirus serotypes. The exact incidence of adenoviral conjunctivitis is unknown. However,

cases are more frequent during warmer months. Contagion is possible through direct con-

tact or fomites and the virus is extremely resistant to different physical and chemical agents.

The symptomatology of conjunctival infection is similar to any other conjunctivitis, with a

higher incidence of pseudomembranes. In the cornea, adenoviral infection may lead to ker-

atitis nummularis. Diagnosis is mainly clinical, but its etiology can be confirmed using cell

cultures, polymerase chain reaction or immunochromatography. Multiple treatments have

been tried for this disease, but none of them seems to be completely effective. Prevention

is the most reliable way to control this contagious infection.

© 2011 Sociedad Española de Oftalmología. Published by Elsevier España, S.L. All rights

reserved.

Queratoconjuntivitis adenovíricas: actualización

Palabras clave:

Adenovirus

Conjuntivitis

Conjuntivitis vírica

Queratitis nummularis

Queratoconjuntivitis

r e s u m e n

El objetivo de esta revisión es resumir las características clínicas y epidemiológicas de

las queratoconjuntivitis adenovíricas (QCA), así como presentar una actualización práctica

sobre el diagnóstico, tratamiento y prevención de estas infecciones oculares.

Dentro de las QCA, existen dos síndromes clínicos claramente diferenciados, la quera-

toconjuntivitis epidémica y la fiebre faringoconjuntival, que están causados por diferentes

serotipos de adenovirus. Su incidencia exacta es desconocida, y los casos son más frecuentes

durante los meses cálidos. El contagio se produce mediante contacto directo y por fómites,

y los virus son extremadamente resistentes a diferentes agentes físicos y químicos. La

sintomatología conjuntival es semejante a la de otras conjuntivitis, con una mayor predilec-

ción por la formación de seudomembranas. En la córnea, la infección adenovírica puede

producir infiltrados subepiteliales. El diagnóstico es fundamentalmente clínico, aunque el

� Please cite this article as: González-López JJ, et al. Queratoconjuntivitis adenovíricas: actualización. Arch Soc Esp Oftalmol.2013;88:108–15.

∗ Corresponding author.E-mail address: juliojose.gonzalez@live.com (J.J. González-López).

2173-5794/$ – see front matter © 2011 Sociedad Española de Oftalmología. Published by Elsevier España, S.L. All rights reserved.

a r c h s o c e s p o f t a l m o l . 2 0 1 3;8 8(3):108–115 109

diagnóstico etiológico puede confirmarse mediante cultivos celulares, reacción en cadena

de la polimerasa o inmunocromatografía. Se han probado múltiples tratamientos para

esta enfermedad, aunque ninguno parece ser completamente eficaz. El método más eficaz

para controlar esta infección es la prevención del contagio.

© 2011 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L. Todos los

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ntroduction

nfectious keratoconjunctivitis due to adenovirus is anxtremely frequent ophthalmological disease produced byarious serological subtypes of human adenovirus (HAV)hich can present with various symptoms and signs. As

here is no exact correlation between the HAV serotypesnd the clinical expressions they produce, adenoviral ker-toconjunctivitis (AKC) is the term used to define ocularurface infections produced by any of the known HAVerotypes.

AKC comprises 2 clearly differentiated clinical syndromes,.e., epidemic keratoconjunctivitis (EKC) and pharyngocon-unctival fever (PCF).

The objective of this review is to summarize the clinicalnd epidemiological characteristics of AKC and to present aractical update on the diagnosis, treatment and preventionf said ocular infections.

icrobiology

denovirus were first described in 1953 by Rowe et al.1

ho observed that the human lymphoid tissue suffered aharacteristic spontaneous degeneration when maintainedn culture several weeks after surgical extraction. In 1955,awetz et al.2 were the first to attribute the etiology ofKC to the infection of ocular surface tissue caused byAV.

Since their discovery, 51 different types of adenovirus haveeen described.3 Among them, 7 have high affinity with theonjunctival epithelium and can produce AKC (serotypes 3,4

,5 7, 8,2,6 11, 19,6 377,8).Adenovirus are virus with double-stranded DNA having

0–100 nm diameter, without cover and with icosahedral cap-id having 20 sides and 12 vertices, made up of 252 subunitsalled capsomeres. DNA has a molecular weight of 23 × 106 Da,nd represents 10–15% of the virus mass.9

HAV are able to interact with human cells in 3 ways:

Lytic infection, involving epithelial cells. The virus completesits multiplication cycle, producing cellular death and releas-ing between 104 and 106 new viruses, of which between 1%and 5% are infectious.

Latent infection, involving lymphoid cells such as those inwhich the virus was first isolated.1 Only small amounts ofvirus are released and the cellular death rate is offset by

normal multiplication.

Oncogenic transformation. The viral DNA is included in thecellular genetic material and replicates inside it withoutproducing a new infectious virus.

derechos reservados.

HAV are very stable against chemical and physical agents aswell as in adverse pH conditions. This allows them to survivefor long periods of time outside the body and water. Studieshave demonstrated that they are able to remain feasible main-taining infectious concentrations even after 28 days on a metalor plastic surface.10,11

Epidemiology

AKC is one of the most frequent ocular diseases, exhibitingubiquitous distribution. Due to its high frequency and thatmany of the cases do not obtain medical help it is impossibleto develop precise statistics about its incidence. In addition,there are no reliable data about the social and health costscaused by this disease.

HAV can give rise to epidemic outbreaks both in the gen-eral population and in hospital environments. In fact, AKC isthe most frequent hospital ophthalmological disease.7,12 Theincidence of AKC, particularly the one related to serotypes 3,4 and 37, increases in summer when temperature rises.13 EKCoutbreaks have been mainly associated to serotypes 8, 19 and37, while PCF cases have been related more with serotypes 3,7 and 11.14

The most frequent transmission of HAV is direct from per-son to person through the respiratory or fecal-oral pathways,although transmission can also occur through fomites. Thevirus can be easily isolated from ocular secretions of patientsfor at least 9 days since the onset of symptoms.15 In the oph-thalmology practice there is a risk of transmission throughcontact tonometry, use of eyedrops and through the hands ofhealth professionals.7,10,16 In the general population the riskof contagion from the patients to domestic contacts is ofapproximately 10%, with the risk increasing in cases of pro-longed disease.6

Clinical syndromes

HAV infections can produce 2 different clinical syndromeswith ocular involvement: EKC and PCF.

Epidemic keratoconjunctivitis

EKC is a form of conjunctivitis that produces epidemic out-breaks in hospitals,7 swimming pools,4,5 barracks, schools andother communities. The incubation period varies between 4and 24 days and, even though it is likely that the disease

17

is no longer contagious during this period, Kimura et al.did not find virus through the polymerase chain reaction(PCR) in conjunctival exudates obtained previously at theonset of symptoms. EKC is a slow onset and predominantly

110 a r c h s o c e s p o f t a l m o l . 2 0 1 3;8 8(3):108–115

Fig. 1 – Bulbar conjunctival hyperemia (A) andfollicle-petechial reaction in the upper (B) and lower (C)bulbar conjunctiva in a patient with epidemickeratoconjunctivitis.

Fig. 2 – Pseudomembranes in superior tharsal conjunctivain patients with epidemic keratoconjunctivitis.

ularly severe in children and could go as far as causingamblyopia.20

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unilateral condition, although it can become bilateral in up to70% of cases.14 The most frequent symptoms are tearing, for-eign body feeling and photophobia. The most frequent signsare predominantly bulbar conjunctival reddening (Fig. 1A) andin tharsal conjunctivitis the appearance of follicular reaction(more importantly in inferior tharsal conjunctivitis, Fig. 1Band C), conjunctival chemosis, petechiae and even full sub-conjunctival hemorrhages. The duration of the inflammationvaries between 1 and 4 weeks.

The appearance of pseudomembranes (Fig. 2) is a frequentcomplication in patients with EKC, above all if the infectionis caused by serotypes 8, 19 and 37.8,14 Pseudomembranes

are clots of exudates firmly adhered to the upper and lowertharsal conjunctivae. It is possible to separate them from the

Photography courtesy of Dr. Mateos Sánchez.

underlying conjunctiva without damaging the epithelium bymeans of peeling, producing minor bleeding, if any.

The appearance of subepithelial infiltrates (Fig. 3) isan additional frequent EKC complication which can beobserved in up to 50% of cases. Said infiltrates a particu-larly frequent in serotype 8 infections.8 In addition, they areconsidered to be pathognomic of adenoviral infection andgenerally appear when the conjunctivitis begins to resolve.It is believed that these infiltrates are due to a cellularimmune response against HAV antigens which remainedtrapped in the corneal stroma under Bowman’s membrane.18

If the infiltrates involve the visual axis, photophobia andvisual acuity loss can occur and, if untreated, they resolvewithin a period that can vary between weeks and months.Even though said infiltrates are sensitive to the use oftopical corticosteroids, the improvement seems to be tem-porary and does not affect the long-term length of theprocess.19

Bacterian overinfection is not frequent but it could occur.The most frequently involved passive genes are gram-positivecocci such as Streptococcus pyogenes. Overinfection is partic-

Fig. 3 – Subepithelial infiltrates which appeared 2 weeksafter the resolution of epidemic keratoconjunctivitis.

o l . 2 0 1 3;8 8(3):108–115 111

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Table 1 – Symptoms scale of the International OcularInflammation Society.

Foreign bodyfeeling

From 0 (without symptoms) to 10 (unbearable)

Photophobia From 0 (without photophobia) to 10 (cannot openeyes)

Tearing From 0 (without tearing) to 10 (abundantand continuous)

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a r c h s o c e s p o f t a l m

haryngoconjunctival fever

CF is a well-described syndrome attributed to HAV sub-ender B, particularly serotype 321 which causes smallutbreaks, mainly among children. Outbreaks are frequent inchools, kindergartens and summer camps.

PCF courses with an acute onset comprising fever, pharyn-itis, rinitis, cervical adenopathies and bulbar and palpebralonjunctivitis with slight-moderate follicular reaction. Theuration of the condition is of 3–5 days. Ocular inflamma-ion also begins in one eye and generally becomes bilateral inhe course of the disease. Bacterian overinfection and ocularomplications are much less frequent than in EKC.

The main sources of infection associated to PCF areontaminated waters of swimming pools and water reser-oirs.21

iagnostic

he diagnosis of these diseases is made usually on the basisf anamnesis and on the patient clinical findings. Differ-ntial diagnosis should include the following pathologicalrocesses:

Allergic conjunctivitis. Symptoms are generally similar in theearly stages. However, allergic conjunctivitis is more fre-quently bilateral and symmetrical in addition to subacuteor chronic course. These patients generally exhibit papillaryconjunctival reactions which is more intense in the uppertharsal conjunctiva. Itching is the most characteristic symp-toms of allergic conjunctivitis,22 whereas the foreign bodyfeeling would indicate adenoviral origin.

Herpetic conjunctivitis. These patients exhibit typically uni-lateral symptoms and complain more frequently aboutpain. Occasionally, the characteristic blisters can be seenin the conjunctiva and mainly in the skin of the eyelids.Herpetic conjunctivitis could include bacterian overinfec-tion with greater frequency than adenoviral conjunctivi-tis. Herpetic conjunctivitis has a self-limited course of8–9 days.14

Chlamydia inclusion conjunctivitis. This disease exhibits largerfollicle sizes, mainly in the inferior sac fundus. In addition,these patients may refer Chlamydia genital-urinary infec-tion history in themselves or their sexual partners.

A severity evaluation could be necessary to perform clinicaltudies or essays. The heterogeneous nature of the evalua-ion of conjunctivitis severity is a significant problem whenomparing studies on this disease or preparing meta-analysis.or this reason, it is proposed that future studies apply theymptoms and signs scales proposed by the International Ocularnflammation Society (Tables 1 and 2).23

Even though the diagnosis of AKC continues to be mainlylinical, tests are available in the market to confirm the ade-oviral etiology of conjunctivitis. RPS (rapid pathogen screening)

deno Detector is approved by the FDA for use in ophthalmologyractices.24 This test is based on the principles of lateral flow

mmunochromatography which detects a region of the virushich is very well preserved among the various serotypes25

Itching From 0 (without itching) to 10 (permanentand unbearable)

and provides results in only 10 min. In addition it has demon-strated a sensitivity of 88% and a specificity of 91% vis-à-visadenovirus cell cultures as well as a sensitivity of 89% andspecificity of 94% vis-à-vis PCR.26 Its use has been recom-mended in primary health care so that a positive result couldjustify conservative management of conjunctivitis by primaryhealth care physicians.26 Udeh et al. found that the systematicuse of this test could reduce costs derived from the inadequateuse of antibiotics in patients with EKC in 71.30 US dollars perpatient.27

For epidemiological studies, the tests considered as goldstandard continued to be cell cultures and PCR. HAV cell cul-tures, traditionally considered as gold standard for diagnosis,are laborious and take 3 weeks to produce results. In addi-tion, culture results may vary depending on how the sampleand the seeding are performed as well as on the identifica-tion of the cytopathic effects by technicians.28 For this reason,the use of HAV cell cultures is being substituted by newPCR techniques which are able to amplify small amounts of aviral DNA with great sensitivity and without losing specificity,to the extent that nowadays said techniques are considered tobe the new gold standard.26 PCR-RFLP (restriction fragment lengthpolymorphism) detects HAV serotypes in 24–48 h, and RT PCR(real time PCR) provides information about the rate of virus pro-liferation and the number of copies present at a given point intime.14

Treatment

To this date there is no specific drug against HAV replication.There is a search for molecules active against HAV replicationwithout adverse effects.29 Some candidates that have exhib-ited benefits in these areas are zalcitabine,30 sanilbudine,29

cidofovir,31 interferon beta,29,32,33 antiosteopontine peptide29

and N-chlorotaurine,34 although randomized clinical trialsmust be carried out to confirm the efficacy and safety of thesemolecules in the treatment of AKC.

AKC is a self-limited disease that exhibits complete res-olution within 3 weeks in most cases. At this time, AKCtreatment is focused on managing patient symptoms andavoiding the appearance of complications while the patientimmune system resolves the infection. To this end, the fol-lowing treatments are available.

Conservative measures

Even though there are no trials confirming the usefulnessof these measures, the use of cold packs and artificial tears

112 a r c h s o c e s p o f t a l m o l . 2 0 1 3;8 8(3):108–115

Table 2 – Signs scale of the International OcularInflammation Society.

Conjunctival hyperemia (bulbar/palpebral)0: none1: slight vascular congestion2: moderate vascular congestion3: intense vascular congestion

Conjunctival edema0: without edema1: slight (edema in one segment of the bulbar conjunctiva)2: moderate (uniform and diffuse edema throughout the bulbar

conjunctiva)3: severe (conjunctival chemosis with profusion of conjunctiva

outside of the palpebral slit)

Palpebral edema0: without edema1: slight (discrete swelling of the upper or lower eyelid without

changes in the palpebral slit)2: moderate (upper and/or lower eyelid swelling with

diminished palpebral slit)3: severe (swelling of both eyes it’s that causes partial or total

closure of the palpebral slit)

Secretion0: no secretion1: slight (discrete sticky secretion limited to sac fundus, only

visible with slit lamp)2: moderate (secretion visible without slit lamp)3: severe (abundant secretion which can produce adherence

of both eyelids)

Palpebral conjunctiva0: smooth and uniform appearance1: slight (localized formation of papillas or follicles under 1 mm

diameter, without fluorescein staining at the peak)2: moderate (diffuse formation of papillas or follicles under

1 mm diameter, with or without fluorescein staining at thepeak)

3: severe (abundant papilla or follicles over 1 mm diameter,with or without fluorescein staining at the peak)

Type of staining (rose Bengala or lissamine green)0: none1: micro- or macro-dots2: filliform3: patch shapes

Extension of staining (rose Bengal or lissamine green)0: none1:under 25% of conjunctival surface2: between 25% and 50% of conjunctival surface3: over 50% of conjunctival surface

Depth of erosion/ulceration0: none1: superficial epithelium2: deep epithelium3: tenon and/or sclera

Characteristics of membranes and pseudomembranes0: none1: present in one sac fundus2: present in both sac fundus3: present beyond the sac fundus

Extension of membranes and pseudomembranes1: under 25% of conjunctival surface2: between 25% and 50% of conjunctival surface3: over 50% of conjunctival surface

– Table 2 (Continued)

Secondary corneal involvement0: none1: under 25% of corneal surface

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2: between 25% and 50% of corneal surface3: over 50% of corneal surface

could provide efficient symptom relief with hardly any risk ofadverse effects.

Topical corticosteroids

Rabbit studies have demonstrated that the use of topi-cal corticosteroids could increase the replication rate ofadenovirus in the conjunctiva and extend the duration ofinfection.35–37 On the other hand, the use of topical corticos-teroids could worsen conjunctivitis if its etiology is herpetic38

and could increase the risk of bacterian overinfection.39

Accordingly, the use of topical corticosteroids should berestricted.

In accordance with the above, the use of topical corti-costeroids should be restricted to complicated cases withpseudomembranes or subepithelial infiltrates35,40 where itappears to be efficient. In what concerns infiltrates, the use ofcorticosteroids seems to significantly diminish its incidenceduring treatment although infiltrates can reappear whentreatment is discontinued. However, the reestablishment oftopical corticoid therapy is useful to achieve the eliminationof infiltrates. Taking into account the adverse effects of top-ical corticoid therapy, treatment of subepithelial infiltratesshould be reserved for cases where visual acuity is signifi-cantly impaired.

Topical nonsteroid anti-inflammatories

Rabbit studies have demonstrated that the use of topicalketorolac or diclofenac does not increase adenovirus replica-tion in the conjunctiva or extend the infection duration andtherefore could be a safe alternative for treating the symptomsof these patients.41

Topical antihistaminic and vasoconstrictors

A randomized clinical trial carried out in Pakistan42 reportedthe usefulness of associating topical antihistaminics such asnafiracine with topical vasoconstrictors such as feniracine toshorten EKC duration and improve symptoms in a statisticallysignificant manner. However, due to the risk of local toxicityand hypersensitivity, the use thereof should not be consideredsafe in the presence of severe itching because the risks couldoffset said benefits.

Topical cyclosporine A

Rabbit studies have demonstrated that the use of 0.5% top-ical cyclosporine A in artificial tears and 2% in corn oil

reduces the incidence of post adenoviral subepithelial infil-trates, extending at the same time the duration of theinfection.43 A retrospective nonrandomized study in humans

a r c h s o c e s p o f t a l m o l . 2

Table 3 – Measures for preventing the contagionof adenoviral keratoconjunctivitis.

Measures for infected health professionalsOff duty for 2 weeks

Quarantine measuresIdentification of suspects patients when entering hospitalIndependent waiting room for suspect patientsIndependent consulting room for suspect patientsMinimize patient stay at the hospital

Measures for evaluating patientsWash hands with water and soap or antiseptic solution beforeand after seeing each patientClean surfaces and slit lamp with 70% isopropyl alcohol beforeand after seeing each patientUse single-dose eyedropsAvoid the use of contact tonometers or diagnostic andtherapeutic contact lenses in suspect patientsUse disposable tonometry cones or cleaned with sterile waterand 70% isopropyl alcohol during 5–10 minSterilize diagnostic and therapeutic contact lenses with

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hydrogen peroxide plasma devices or clean with sterile waterand bleach or 10% hydrogen peroxide during 10 min

emonstrated that the use of topical cyclosporine A doesot increase the visual acuity in a statistically significantanner in patients with subepithelial infiltrates, although

t did improve objective signs.44 A randomized clinical trialn humans demonstrated that the use of cyclosporine A inombination with cidofovir did not significantly diminish thencidence of subepithelial infiltrates in comparison with cido-ovir on its own.31

Considering the above results, topical cyclosporine Ahould be used only in patients with subepithelial infiltrateshat produce significant visual acuity loss and do not respondo topical corticoid therapy.

ovidone-iodine

ovidone-iodine is a broad spectrum antiseptic. A phase 2 clin-cal trial with 6 patients found that the use of 0.4% topicalovidone iodine in combination with 0.1% topical dexametha-one eradicated the secretion of virus in 5 patients on the fifthay of follow-up.45 However, a clinical trial carried out in chil-ren did not find differences in the rate of healing betweenhose treated with 1.25% povidone iodine or with antibiotic.46

ew randomized clinical trials are necessary to determine thectual efficacy and safety of povidone iodine treatments inatients with AKC.

opical antibiotic therapy

he use of topical antibiotics to prevent bacterian overinfec-ion should be reserved for high risk patients such as children.

xcimer laser

recent series of cases has reported the usefulness of Excimer

aser phototherapeutic keratectomy to improve best correctedisual acuity in patients with persistent subepithelial infil-rates secondary to AKC.47

0 1 3;8 8(3):108–115 113

Prophylaxis

As there is no efficient antiviral treatment against HAV, pro-phylaxis is essential to control the infections caused by thispathogen. Washing of hands and disinfection of instrumentsdo not appear to be sufficient to control the propagation ofAKC outbreaks.7,11,48 A prospective study demonstrated thatthe application of a hospital infection control protocol againstadenovirus can diminish the incidence of epidemic outbreaksand isolated adenoviral conjunctivitis cases through a four-year period.49 Recently, Dart et al.12 demonstrated again thatthe application of an AKC identification and control protocoldiminishes the incidence of hospital contagion.

The measures that have demonstrated to diminish the inci-dence of AKC contagion12,49 are summarized in Table 3.

Conclusions

AKC is an ocular surface infection produced by multiple HAVserotypes, a DNA virus without envelope highly resistant tophysical and chemical agents that is contaged through directcontact or fomites. The most frequent clinical syndromesare EKC and PCF. EKC gives rise to severe ocular surfaceinflammation which can be complicated with the formation ofpseudomembranes or subepithelial infiltrates caused by cel-lular immune reaction against virus antigen remains trappedbelow Bowman’s membrane. The diagnosis is mainly clinicalthough the etiology can be confirmed by tests such as RPSAdeno Detector, cell culture or PCR. There is no efficient antivi-ral drug against HAV. Therefore, symptomatic treatment isrecommended with conservative measures and topical nons-teroid anti-inflammatory drugs. If complications arise the useof topical corticoid therapy could be indicated. Prevention iscrucial to control the propagation of this infection.

Conflict of interest

No conflict of interest has been declared by the authors.

e f e r e n c e s

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