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REVIEW

CURRENT
OPINION Adenoviral keratitis: a review of the epidemiology,
pathophysiology, clinical features, diagnosis,
and management
Amro A. Omari and Shahzad I. Mian

Introduction
Adenoviral keratitis is a common and bothersome ocular infection that produces a lot of burden on
healthcare systems and patients. The goal of this article is to provide a review of the topic, with an
emphasis on current attempts at advancing strategies in diagnosis and management.
Patients/materials and methods
Sixty-eight articles and one textbook published on adenoviral keratitis were reviewed. The findings on the
epidemiology, pathophysiology, clinical features, diagnosis, and management were summarized. Any
contradicting opinions for which the literature was unclear were either omitted or recorded as lacking
strong evidence.

Results and conclusions

Although significant effort has been made to develop new methods for diagnosis and management,
adenoviral keratitis is predominantly diagnosed clinically with prevention being the mainstay of
management. The use of newer DNA analysis techniques and topical anti-inflammatory agents for treatment
of corneal infiltrates show promising results, but a better understanding of the pathogenesis and clinical
features can lead to more targeted methods of diagnosis and therapy.

Keywords
adenoviral keratitis, adenovirus, corneal infiltrates, diagnosis, management

INTRODUCTION are cost-effective. This study will review current

Adenovirus is highly contagious and is the most
common cause of infectious conjunctivitis world-
wide [1]. Adenoviral keratitis is painful, can com-
promise vision, and develop following an episode of
conjunctivitis. It typically presents in the setting of
acute viral follicular conjunctivitis, epidemic kera-
toconjunctivitis (EKC), pharyngoconjunctival fever
(PCF), and chronic/relapsing adenoviral conjunciti-
vitis [2]. The lost productivity and discomfort from
this burdensome disease costs healthcare systems
and patients millions of dollars each year.
The mainstay of management has been to pro-
mote good hygiene to prevent the spread of infec-
tion, and symptomatic measures like artificial tears
and cold compresses to reduce discomfort. However,
with the advent of newer and cheaper gene-
sequencing techniques, topical antivirals, and topi-
cal anti-inflammatory agents, there are more diag-
nostic and therapeutic options available for
clinicians. The question is whether they make a
difference in clinical outcomes and whether they
knowledge about adenoviral keratitis, with an
emphasis on the efficacy of these newer strategies
in diagnosis and management.
METHODS
We reviewed the literature for recent articles and/or
textbooks that describe either study data or expert
opinion on adenoviral keratitis, with an emphasis
on newer strategies in diagnosis and management.
Inclusion criteria for articles and textbooks were
that they had to have a version in English, there
was a full version of the article online, and that they
were peer-reviewed. Articles were excluded if they
Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye
Center, University of Michigan, Ann Arbor, Michigan, USA
Correspondence to Shahzad I. Mian, Kellogg Eye Center, 1000 Wall
Street, Ann Arbor, MI 48105, USA. E-mail: smian@med.umich.edu
Curr Opin Ophthalmol 2018, 29:000–000
DOI:10.1097/ICU.0000000000000485

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Corneal and external disorders
KEY POINTS
 Adenoviral keratitis is common, can compromise vision,
and costs healthcare systems millions of dollars
each year.
 The diagnosis is mainly clinical, but automated
techniques such as rapid immunodetection assays and
PCR look promising.
 Most cases are managed with symptomatic measures
and the prevention of spread, but topical combinations
of anti-inflammatory/virucidal agents such as povidone-
iodine with steroids show encouraging results.
 A better understanding of the molecular mechanisms
behind ocular adenoviral infections can help us
develop improved and/or alternative management
options.
had faulty methods or did not generate clear con-
clusions. We gathered information from 68 articles,
1 textbook, and expert opinion (S.M.). We searched
for common themes across the literature and have
summarized them in the results section. If there
were contradicting opinions in the literature, then
we either did not include them in our summary or
denoted the evidence as controversial.
RESULTS
Epidemiology
Adenoviruses are the most common cause of infec-
tious conjunctivitis worldwide [3]. Millions of peo-
ple are infected with viral conjunctivitis each year
[4], with a substantial percentage having corneal
involvement as well. The most commonly affected
age group with EKC is adults between 20 and 40, and
with PCF, is children [3]. There is no sex predilection
for either [5].
Infections tend to occur in places where patients
have close contact, such as hospitals (especially
ophthalmic units), schools, nursing homes, and
work places. The infections that spread through
ophthalmic units are the most bothersome, as they
lead to delays in surgery, later discharge of inpa-
tients, and potential closures of the units [4]. In the
United States, a nosocomial outbreak of EKC involv-
ing 41 individuals can cost a hospital $29 527 ($1085
for medical costs, $8210 for investigative costs,
$3048 for preventive measures, and $17 184 for lost
productivity) according to Piednoir et al. [6]. These
studies clearly indicate that adenoviral keratocon-
junctivitis is a burdensome disease that can be alle-
viated by improvements in management and
prevention. Furthermore, millions of dollars are
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wasted each year by administering antibiotics or
anti-herpetic agents that have no therapeutic bene-
fit [7]. Therefore, more advanced techniques in
diagnosis may prove to be beneficial.
Pathophysiology
Adenoviruses are icosahedral, nonenveloped, dou-
ble-stranded DNA viruses which are classified into
seven species [3]. Adenovirus 8, 19, and 37 are most
commonly implicated in EKC [8,9]. Adenovirus type
3 is most commonly implicated in PCF. Acute fol-
licular conjunctivitis is presumed to occur due to
infection by a range of serological variants [2].
Transmission of ocular adenoviral infections is pri-
marily through respiratory droplets or contact with
ocular secretions. Common occurrences in ophthal-
mic units are through the tonometer and finger-to-
eye transmission by healthcare workers [8]. Interest-
ingly, one study demonstrated the presence of sero-
type 19 in the genitourinary tracts of males and
females when peak levels of 19 were also found in
ocular secretions of patients with active EKC [10].
Thus, sexual transmission may be associated with
adenoviral EKC spread [8].
Once the virus is inoculated onto the conjunc-
tival epithelial surface, it replicates inside the epi-
thelial cells. It may spread into the corneal
epithelium and underlying stroma, such as com-
monly found with the most severe form known as
EKC. It may also spread to the other eye when
patients rub their eyes due to the discomfort. Ade-
novirus triggers an innate immune response
through effector cells such as neutrophils, macro-
phages/monocytes, and natural killer cells that
either destroy the infected corneal cells or produce
inflammatory cytokines that both damage the
infected cells and recruit more inflammatory cells
[11]. Adenoviral infection also produces damage to
the corneal epithelium/stroma through a delayed
adaptive response primarily mediated by Th1 helper
cells. Th1 cells activate macrophage-mediated
phagocytosis via the release of IFN-gamma [11]. This
may explain why approaches targeting use of immu-
nomodulators may play a role in treatment.
Clinical features
Patients typically complain of unilateral redness,
watering, irritation, and photophobia (Fig. 1). The
severity of the symptoms depends on the extent of
corneal involvement. The contralateral eye may or
may not be involved 1–2 days later [2], but is typi-
cally less severely affected than the eye the infection
started in [2]. As the name suggests, in acute follicu-
lar conjunctivitis, patients tend to exhibit a strong
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FIGURE 1. Acute viral conjunctivitis associated with severe unilateral conjunctival injection that may also be accompanied by
pain, tearing, and photophobia. This typically precedes the development of corneal infiltrates.
follicular reaction in the palpebral conjunctiva, but
may or may not have other symptoms than those
listed above for general adenoviral keratitis. In EKC,
patients experience similar symptoms, but the pho-
tophobia is usually stronger and they experience a
foreign body sensation due to a much more severe
corneal involvement with keratitis occurring 80% of
the time [2]. A case reported by Lee et al. [12]
illustrated three full layer corneal epithelial detach-
ments during an outbreak of EKC, suggesting that
this disease can have very severe corneal pathology.
In PCF, the photophobia tends to be less severe, as
keratitis only occurs 30% of the time [2]. Sore throat
and a low-grade fever are common in PCF, and
patients tend to have eyelid edema and conjuncti-
vitis that may be hemorrhagic [8]. In chronic ade-
noviral keratitis, patients may complain of
decreased vision, halo, glare, and photophobia from
the recurrent corneal damage [13].
The keratitis typically starts with epithelial
microcysts. Note that these are nonstaining and
diffuse, and are typically accompanied by preauric-
ular lymphadenopathy that may or may not be
painful on palpation. However, these may progress
to focal punctate epithelial keratopathy that stains
with either fluorescein or rose Bengal [14]. In more
severe cases, subepithelial/anterior stromal infil-
trates (Fig. 2) and gray epithelial infiltrates develop
after a span of around 2–3 weeks [8]. It is believed
that the early diffuse opacities are a result of viral
replication, whereas the later subepithelial opacities
develop due to the inflammatory response to the
virus [8]. Occasionally, small pseudodendritic epi-
thelial formations occur that can blur the differen-
tial diagnosis with herpetic keratitis. The chronic
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Adenoviral keratitis: a review Omari and Mian
keratoconjunctivitis may also lead to symblepharon
or pseudomembrane formation. The corneal opaci-
ties may become visually symptomatic, particularly
if they are in the visual axis. Patients may have a
reduction in visual acuity [8] and have irregular
distortions of the corneal surface, leading to astig-
matism and higher refractive errors [13]. Effective
prevention and management can reduce the down-
stream effects on the cornea.
Diagnosis
One method for definitively diagnosing adenoviral
keratitis is by culturing conjunctival swabs of
infected patients. This technique is both sensitive
and specific. The specificity approaches nearly 100%
when done by an experienced examiner [2]. How-
ever, there are some challenges with this technique.
It is expensive, requires a specific transport medium,
and can take weeks before a positive result emerges,
by which time the corneal infiltrates may have
resolved. Also, conjunctival cultures are negative
in PCF after 14 days even though fecal spread occurs
for 30 days and is thought to be responsible for
epidemics in swimming pools [8]. Cultures still
appear to be a useful method as a gold standard
in research studies when comparing the efficacy to
newer diagnostic modalities.
Rapid detection immunoassays appear to be a
promising alternative. This technique is sensitive
(around 88%) and specific (91%) [3]. It is also very
inexpensive, easy to use, and can detect 53 adeno-
virus serotypes within 10 min [3]. The speed with
which results are obtained can lead to quicker
enforcement of hygiene and preventive measures,
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Corneal and external disorders
FIGURE 2. Anterior stromal subepithelial corneal infiltrates accompanied by epithelial edema and conjunctival injection.
which is especially useful in hospital units. Some of
the drawbacks are that it depends on the quality of
the sample and the expertise of the observer [15].
More studies are needed to determine the cost effi-
ciency of this technique.
With the exponential growth in ability to
sequence genomes and at cheaper costs, nucleic acid
amplification techniques like PCR are promising
[16]. Multiple studies have found that PCR is highly
sensitive for detecting adenovirus, even more than
direct immunofluorescence [15,17–19]. However,
this technique takes longer and requires dedicated
facilities [15]. As sequencing techniques continue to
improve, these boundaries may be overcome.
Serology is another method through which an
adenoviral infection can be detected. A positive
result is obtained by detecting adenovirus-IgM or
increasing IgG [2]. This technique has limited use for
detecting adenoviral conjunctivitis, and even less so
for adenoviral keratitis. The antibodies in the serum
may have already returned to normal by the time
the keratitis develops. Furthermore, this technique
is not specific, as patients may have rising antibodies
for a number of different clinical presentations. It is
also slightly more invasive, as it requires a blood
draw to obtain the serum levels of the antibodies.
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If the diagnosis is truly uncertain, and a concern
for herpetic keratitis is present, a giemsa stain of a
conjunctival specimen can be obtained [20]. In the
case of adenoviral infection, the specimen will show
predominantly mononuclear cells [2] as compared
to multinucleate giant cells (also known as Tzanck
cells) in herpetic keratitis. This technique is costly
and takes much longer than the other techniques.
Therefore, it is only reserved for cases when the
clinical picture is similar to a herpetic infection.
MANAGEMENT
Hygiene and prevention of transmission
Patients are counseled on measures that minimize
contact with respiratory or ocular secretions of
infected individuals. These include, but are not
limited to, judicious washing of hands, avoidance
of eye rubbing, and avoidance of sharing towels.
These measures help to prevent the hand to ocular
spread of the infection. If patients are healthcare
workers, they are also advised to stay away from
work [21]. As discussed above, there has been an
association between genital colonization and ocular
adenoviral infections. It is unclear whether there is
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causation, but future studies that explore preven-
tion based on genital transmission may be explored.
One of the most common places where the virus
can spread is in ophthalmic practices, including in a
hospital setting. The most common item implicated
in the spread of the infection is the tonometer [21].
Contact lenses can also serve as a nidus for infection.
Adenovirus can persist on contact lenses when
chemical and hydrogen peroxide disinfectants are
used [22]. Therefore, the literature is pretty clear on
the notion that disposable ocular equipment should
be used in these patients. This includes tonometer
heads, eye-drop dispensers, and contact lenses
[21,23]. Patients admitted to the hospital with
EKC and those seen in clinics should be treated
separately and discharged as soon as possible [21].
Adenovirus is particularly resistant to disinfection,
so only virucidal agents such as povidone-iodine
and sodium hypocholorite should be used [21].
Ophthalmic care providers should wear gloves
and disinfect their hands, the equipment, and sur-
faces after they have seen the patient [21]. Patients
are advised to only follow-up if absolutely necessary
after the acute phase [21]. A study by Omar Akhtar
et al. [24] compared 70% isopropyl alcohol swabs,
peroxide, and disposable tonomoter tips in the pre-
vention of nosocomial EKC. They concluded that all
three are potential methods of disinfection. How-
ever, they found that the cost of peroxide bleach or
disposable tonometer tips were significantly higher
than using 70% ispropyl alcohol swabs. They went
as far to conclude that the comparative costs of
using disposable tonometer tips were unacceptably
high [24].
Symptomatic measures
Symptomatic measures to reduce the discomfort
produced by the corneal and conjunctival inflam-
mation can also help patients. Either warm or cold
compresses can be used, as long as they are not
shared with other individuals. Artificial tears can
also help lubricate the corneal epithelium and pro-
tect it from breakdown. This can be particularly
useful in patients with other comorbid corneal
pathology like dry eye. Ideally, artificial tears with-
out preservatives should be used.
Anti-inflammatory agents
The role of topical steroids in adenoviral keratitis is
controversial. It may lead to symptomatic relief, but
may subsequently cause a rebound increase in
the corneal infiltrates and the amount of time for
which the patient is contagious [3,21,25]. This is
shown by both in-vivo and in-vitro studies [23].
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Adenoviral keratitis: a review Omari and Mian
Furthermore, steroids have both ocular and systemic
complications. Ocular complications include ele-
vated intraocular pressure and cataract formation
with long-term use, and there may be significant
adverse effects with system corticosteroid use.
Patients on topical steroids should be followed up
more closely to ensure that steroid induced glau-
coma does not develop. Currently, topical steroids
may be beneficial for patients with decreased vision
and severe photophobia associated with adenoviral
keratitis, and oral steroids may be added if there is
concomitant severe conjunctival pseudomembrane
formation or anterior uveitis [21].
There have been some promising attempts at
combining topical povidone-iodine with topical
steroids [26–28]. In a clinical trial by Kovalyuk
et al. [26], a combination of topical povidone-iodine
and dexamethasone lead to a significant reduction
in corneal infiltrates and superficial punctate kera-
titis as compared to the groups that received topical
steroids or artificial tears alone. There was also
reduction in the redness, discharge, and pseudo-
membranes that patients experienced [26]. It is
believed that topical steroids ameliorate the symp-
toms, whereas povidone-iodine acts as an antiseptic
to kill the extracellular adenoviral particles [3]. This
approach may be better suited for tackling both the
spread of adenovirus and the associated inflamma-
tory adverse events.
Cyclopsorine is a calcinuerin inhibitor that is
widely used for immunosuppression after organ-
donor transplants. It inhibits T-cell activation and
the production of inflammatory cytokines [29].
There have been good results with topical 0.03–
1% cyclosporine for persistent subepithelial infil-
trates resistant to topical steroids [30–32]. It is also
much safer than topical steroids, with fewer side
effects. One study by Asena et al. [33] conducted a
retrospective review of clinical outcomes of patients
with acute adenoviral keratitis treated with topical
cyclosporine, topical steroids, or artificial tears
alone. They found that patients with topical cyclo-
sporine or topical steroids had a shorter duration
and less severe disease than those with artificial tears
at 21 days follow-up. They concluded that topical
cyclosporine might reduce the incidence of corneal
subepithelial infiltrates with a better side effect pro-
file. The full effects of topical cyclosporine in ade-
noviral keratitis need further exploration.
The use of topical or oral NSAIDs is controversial in
a wide variety of corneal diseases. In the case of ade-
noviral keratitis, NSAIDs have no effect on corneal
infiltrates [3,21]. They may be used for pain relief,
but should be used with caution due to the toxic effects
of administration on the ocular surface. Furthermore,
the chronic use of oral NSAIDs in the face of persistent
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Corneal and external disorders
corneal infiltrates has unwanted gastrointestinal and
nephrotoxic side effects. Topical or oral NSAIDs are not
necessary in the management of adenoviral keratitis.
Antivirals
Ganciclovir is a nucleoside analog of guanine [34]
that is used for a wide variety of herpetic diseases.
Topical ganciclovir may mildly help reduce viral
loads in vitro [35–37]. However, it has not been
proven to be efficacious against keratitis or conjunc-
tivitis in animal models or controlled clinical trials
[34]. Other virustatic agents like trifluridine and
vidarabine have either been completely ineffective
or mildly effective at best in treating ocular adeno-
viral diseases [3,21]. This has been true for in-vitro,
in-vivo models, and clinical trials [38,39]. There
appears to be no role in the immediate future for
these virustatic agents.
Cidofovir is a nucleotide analog of cytidine that
inhibits adenoviral DNA polymerase directly
[40,41]. It has potent antiviral activity in vitro and
in animal models [34,42–48]. The efficacy is
believed to be due to rapid corneal penetration
and a prolonged intracellular half-life [40]. The drug
was successful in preclinical studies [42–44,48] and
phase 1 and 2 clinical trials [35,49]. This led to a
large randomized clinical trial for ocular adenoviral
infections. The results initially were promising,
showing significant reduction in the number of
subepithelial infiltrates [34]. However, the use of
topical cidofovir for over 1 week was associated with
rare cases of lacrimal canalicular obstruction [34].
Furthermore, there were concerns about resistance
to the drug based on findings in animal models
[41,45]. Clinical concerns about a narrow efficacy/
toxicity ratio and marketing considerations led
pharmaceutical companies to abandon cidofovir
development in the United States [34]. Out of all
of the topical anitivirals, cidofovir has the most
promise with current ongoing clinical trials in
Europe to establish efficacy [31,32]. However, the
literature cites a need for an antiviral that has more
potency and less toxicity than cidofovir [49].
Ribavirin is a compound that inhibits inosine
monophosphate dehydrogenase [50], and is useful
for treating life-threatening systemic adenoviral
infections [34]. Ribavirin has limited activity against
adenovirus in vitro [23]. Many studies have reported
a failure of clearing adenovirus with ribavirin ther-
apy [51–54]. Another problem is that it lacked effi-
cacy against serotypes 8, 19, and 37 in vitro
[23,34,41,55]. This is a major problem for the treat-
ment of adenoviral keratitis, as serotypes 8, 19, and
37 commonly cause keratitis. Therefore, it is
unlikely that topical ribavirin will have any role
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in adenoviral keratitis therapy, or any ocular adeno-
viral infections altogether.
A new drug under consideration is topical 2, 3-
dideoxycytidine (ddC) [49]. This drug, just like cido-
fovir, is a nucleoside analog of cytosine that inhibits
adenoviral replication [49]. Several studies have
shown both in-vitro and in-vivo activity of ddC
against ocular adenovirus [56–59]. In a study by
Romanowski et al. [49], ddC was shown to have
potent antiadenoviral activity in vitro and in rabbit
models. It was even more potent than cidofovir [49].
This could be a promising new drug, but more
preclinical and clinical trials are needed before con-
clusions can be made.
IMMUNOMODULATORS
Interferons are inflammatory proteins produced by
a variety of cells. They serve important functions in
viral infections, including the regulation of viral
spread and enhancing the antiviral responses. Topi-
cal IFNb prevented the formation of corneal infil-
trates in some studies [60–63]. IFNg may have some
use in conjunctivitis [64–66], but there is no appar-
ent use in keratitis. IFNa has no apparent therapeu-
tic effects [63,67,68]. No interferons were found
to be effective in randomized clinical trials
[21,38,62,67]. They may have some use for prophy-
laxis of corneal infiltrates in susceptible individuals
[21,69], but this requires further study.
Surgery
Phototherapeutic keratectomy (PTK) with mitomycin
C is the main surgical option for adenoviral keratitis.
This treatment is particularly good for persistent cor-
neal opacities complicated by late fibrosis. PTK is good
for reducing the number of corneal opacities, and
leads to an improvement in visual acuity and overall
vision [70]. Otherwise, surgery is mostly reserved for
severe conjunctival pathology, such as a persistent
membranes or symblepharon formation.
DISCUSSION
There are a lot of ongoing attempts to improve the
diagnosis and management of adenoviral keratitis.
In the vast majority of cases, the diagnosis is clinical.
At present, it is only recommended that investiga-
tions be pursued if the diagnosis is in doubt or there
is a failure of resolution of the corneal infiltrates [2].
However, with the advent of new techniques to
confirm the diagnosis, the question is whether they
are effective enough to change management, as the
keratitis is often self-limited and passes within a
couple of weeks. Definitive diagnosis can help
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enforce stricter hygiene and other preventive mea-
sures, can save patients and the healthcare system
money wasted on antibiotics, and can be useful from
an epidemiologic perspective [15]. It is therefore
important to develop rapid and cost-effective meth-
ods in diagnosis.
At present, the mainstay of treatment is hygiene
and prevention of transmission, but there have been
some exciting options available to clinicians. Topi-
cal cyclosporine may be a good steroid-sparing alter-
native for persistent subepithelial infiltrates. The use
of topical virucidal agents like povidone-iodine may
be useful adjuncts to anti-inflammatory agents, so
that they can reduce the corneal infiltrates without
prolonging the duration of disease. Most of the
antivirals do not look like they will change manage-
ment in the immediate future, but topical cidofovir
and ddC show promise. Advancements in the
molecular mechanisms of adenoviral infection are
needed to increase the efficacy of antiadenoviral and
anti-inflammatory medications.
Overall, it may be difficult to evaluate diag-
nostic and therapeutic interventions for adenovi-
ral keratitis due to a multitude of factors. First,
adenoviral keratitis is acute and self-limited.
Therefore, it is hard to prove efficacy of the treat-
ments when the infection resolves quickly and any
delay in diagnosis further confounds the results.
Studies looking at prophylactic interventions to
prevent infiltrates may find enrollment difficult as
well, as many of the milder viral illnesses preced-
ing keratitis might not be referred to an ophthal-
mologist [34]. Furthermore, adenoviral keratitis
may mimic other viral or nonviral causes of kera-
titis, which can further confound the results on
the efficacy of treatments. Future diagnostic stud-
ies and clinical trials of therapeutic interventions
must address these considerations before they can
be fairly evaluated.
CONCLUSION
There are some promising new attempts in the
diagnosis and management of adenoviral ocular
infections. A better understanding of the molecular
mechanisms by which adenovirus colonizes the
ocular surface and causes inflammation may lead
to more targeted methods of diagnosis and manage-
ment in the future.
Acknowledgements
None.
Financial support and sponsorship
None.
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Adenoviral keratitis: a review Omari and Mian
Conflicts of interest
There are no conflicts of interest.
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