Acta Ophthalmologica 2017

Treatment of adenoviral keratoconjunctivitis with a

combination of povidone-iodine 1.0% and
dexamethasone 0.1% drops: a clinical prospective
controlled randomized study
Natalya Kovalyuk,1 Igor Kaiserman,1,2 Michael Mimouni,3 Ornit Cohen,1 Shmuel Levartovsky,1,2
Hilda Sherbany4 and Michal Mandelboim4,5
1
Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel
2
Department of health science, Ben Gurion University, Be’er Sheva, Israel
3
Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel
4
Central Virology Laboratory, Ministry of Health, Chaim Sheba Medical Center, Ramat-Gan, Israel
5
Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel-Aviv University,
Tel-Aviv, Israel

ABSTRACT. Introduction
Purpose: To determine the efficacy of combination povidone-iodine (PVP-I)
1.0% eyedrops and dexamethasone 0.1% eyedrops in the treatment of Conjunctivitis is one of the most
adenoviral keratoconjunctivitis. common conditions treated by oph-
Materials and methods: In a prospective, randomized, controlled, double- thalmic practitioners. Epidemic out-
break of conjunctivitis often appears
blinded clinical trial patients with recent adenoviral keratoconjunctivitis
at different locations around the world.
(diagnosed clinically and confirmed by PCR), we randomly divided into three
Adenoviruses are considered as the
treatment groups: study group – received PVP-I 1.0% and dexamethasone most frequent cause of conjunctivitis
0.1%, control 1 group – received dexamethasone 0.1% and control 2 group – and keratoconjunctivitis. Indeed, stud-
received lubricating eyedrops (hypromellose 0.3%). The treatment was ies have demonstrated that adenovirus
administered four times a day in each group. All patients were examined represents 20–75% of all causes of
and filled a questionnaire before treatment and on the 3rd, 5th and 7th days of infectious keratoconjunctivitis world-
treatment. wide (Gigliotti et al. 1981; Ishii et al.
Results: We included in the study 78 eyes (26 in each group). Adenovirus type 8 1987; Woodland et al. 1992; Torres
was the most common pathogen (83% of cases). The fastest improvement in Rojas et al. 1998).
patients red eyes, discharge, superficial punctate keratitis and pseudomembranes Over 50 human adenoviruses sero-
was observed in the study group (p < 0.001). Those patients reached a near types have been identified and they are
complete recovery in 5–7 days, which was also confirmed by reduction in subdivided into seven species (A–G)
Adenovirus titres by PCR. The slowest improvement was in the control 2 group. (Russell 2009). Correlations exist
Subepithelial infiltrates (SEI) were observed in 44% of the control 1 group, 20% between the adenovirus species, their
tissue tropism and their clinical prop-
of the control 2 group and in 0% of the study group. The rate of reduction in
erties. Epidemic keratoconjunctivitis
Adenovirus titres was the slowest in the control 1 group.
(EKC) is usually caused by serotypes
Conclusion: The combination of PVP-I 1.0% and dexamethasone 0.1% four 8, 37, 64 (Dawson et al. 1972; Hyde &
times a day can reduce symptoms and expedite recovery in epidemic keratocon- Berger 1988; Colon 1991) and can
junctivitis patients. cause significant complications such as
SEI. Those are difficult to treat, may
Key words: adenoviral keratoconjunctivitis – conjunctivitis – dexamethasone – povidone-iodine persist for up to 2 years (Colon 1991)
and can result in corneal scarring
Acta Ophthalmol. resulting in permanent visual loss
ª 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd (Dawson et al. 1972). Epidemic kera-
toconjunctivitis may be further
doi: 10.1111/aos.13416
complicated by lacrimal drainage

1
Acta Ophthalmologica 2017
abnormalities (Hyde & Berger 1988),
dry eye and symblepharon formation
(Hammer et al. 1990).
The reservoir for infection is humans
and the infection is transmitted through
direct contact with eye secretions of an
infected person or indirectly via contact
with contaminated surfaces, instru-
ments or solutions including eyedrops
and applanation tonometry and con-
taminated swimming pools (Viney et al.
2008; Artieda et al. 2009). The incuba-
tion period is between 4 and 17 days
(Viney et al. 2008). Actively infected
people readily transmit adenoviruses
and the shedding period may persist
for 10–14 days after onset of clinical
symptoms (Viney et al. 2008).
Despite highly infectious community
epidemics, which causes significant
patient discomfort and, sometimes,
permanent visual compromise and per-
sisting symptoms, there is no specific
antiviral therapy approved by the Food
and Drug Administration. As a result,
there is presently no approved drug
that shortens the course of the infec-
tion, improves the distressful clinical
symptoms, avoids the development of
corneal opacities and stops viral repli-
cation.
The supportive therapy such as cool
compresses, artificial tears or topical
corticosteroids in severe cases is cur-
rently widely accepted (Jhanji et al.
2015). The search for effective anti-
adenoviral treatments has been ongoing
for many years in both animal models
and human trials. Currently, there are
several promising anti-adenoviral can-
didates in clinical trials and preclinical
studies (Hillenkamp et al. 2002; Epstein
et al. 2006; Romanowski et al. 2006;
Nwanegbo et al. 2007; Romanowski &
Gordon 2008) including a pilot study of
using combination of povidone-iodine
(PVP-I) 0.4%/dexamethasone 0.1%
ophthalmic suspension treatment of
adenoviral keratoconjunctivitis (Pel-
letier et al. 2009).
Povidone-iodine has been recog-
nized as a valuable and available
antiseptic, which kills bacteria, certain
viruses, fungi, protozoa and yeast and
that is widely used in disinfection,
general surgery and ophthalmology.
Previous studies have demonstrated
efficacy in endophthalmitis prophylaxis
before (Apt et al. 1989) and after
(Isenberg et al. 1997) ocular surgery,
for treatment of active infections
including viral keratoconjunctivitis
2
(Hale 1969; Schuhman & Vidic
1985; Isenberg et al. 2002). Topical
dexamethasone, an anti-inflammatory
medication, also proved as an effective,
well-tolerated ophthalmic medication
acting alone (Bielory et al. 2010) or in
combination with other agents (Noti-
vol et al. 2004). This potential of PVP-I
prompted the authors to perform
this prospective controlled comparative
study.
Materials and Methods
Design
A prospective, randomized, controlled
and double-blinded clinical study.
Primary outcome
The rate of improvement in symptoms
and signs of adenoviral keratoconjunc-
tivitis in treatment groups.
Study medication
Determining optimal concentration of
Polyvinyl Pyrrolidone and Iodine (PVP-I)
To determine the minimal concentra-
tion of PVP-I that is still effective
against adenovirus, we investigated
in vitro antiviral activity of diluted (with
sterile sodium chloride 0.9%) PVP-I at
different concentrations (0.5–4%) on
adenoviral-infected (serotype 8) human
kidney cells. Human kidney cells were
chosen as a model because these cells
are highly permissive to adenovirus
infection (Jogler et al. 2006). Crystal
violet-based assays were used to evalu-
ate cell death. We found that 0.5%
PVP-I did not prevent viral infection of
the kidney cells (around 85% of the
cells died), while treatment with 1.0%
PVP-I resulted in significant elevation
of cells viability (around 45% of the
cells remained alive). Povidone-iodine
(PVP-I) 2–4% had no additional
advantage. Indeed, others have shown
that these lower concentrations of PVP-
I (≤1%) are sufficient for efficacy
against adenovirus (Monnerat et al.
2006; Clement et al. 2011; Wada et al.
2016). The cellular toxicity of the same
concentrations of PVP-I on non-
infected cells was evaluated. We found
that PVP-I at concentrations higher
than 1% was toxic to the cells.
Thus, the PVP-I 1.0% was chosen as
both effective for inactivation of aden-
ovirus and suitable for topical
administration. It was prepared by
diluting PVP-I 10% under sterile con-
ditions to become 1.0% solution with
pH around 6, closer to the physiolog-
ical pH of tears, and was packaged in
5-ml eyedrop containers.
Detecting adenovirus
Adenovirus keratoconjunctivitis was
diagnosed by a typical clinical presen-
tation (Jhanji et al. 2015). In addition,
conjunctival swabs were taken from
each patient for PCR detection of
adenovirus. The tear samples were
obtained from the inferior palpebral
fornix using a sterile Virocult swab for
an analysis of viral titre by real-time
PCR. The various serotypes of aden-
oviruses were detected by sequencing
(Blyn et al. 2008).
Extraction and real-time transcription-
PCR (RT-PCR) assay
Viral genomic DNA was extrac ted from
the patient samples using NucliSENS
easyMAG (BioMerieux, Lyon, France).
For detection of the adenovirus, real-time
transcription-PCR (RT-PCR) was per-
formed, as previously described (Schuh-
man & Vidic 1985; Heim et al. 2003)
using TaqMan Chemistry on the ABI
7500 instrument with generic primers
hex1 deg and hex2 deg. DNA was
sequenced using ABI Prism 3100 Avant
genetic analyser (Applied Biosystems,
California, USA) according to the
method described by D.D. Erdman
(Schuhman & Vidic 1985).
Patients
Patients aged 18 or older with clinical
suspicion of acute adenoviral kerato-
conjunctivitis and those with disease
duration of up to 3 days were included.
Exclusion criteria were as follows: pre-
vious treatment, allergy to iodine or
steroid, known steroid-induced glau-
coma, history of herpes simplex kerati-
tis, pregnancy. In addition, patients in
which adenovirus was not identified by
PCR were excluded (although treat-
ment was not delayed while waiting for
results).
Patients were randomly divided into
three groups:
(1) The study group: PVP-I 1.0%
eyedrops and dexamethasone 0.1%
eyedrops four times a day to the
involved eye.
 Acta Ophthalmologica 2017

(2) Control group 1: Dexametha- Examination on each visit included type I error of 0.05 and a type II error of
sone 0.1% eyedrops four times a day Snellen visual acuity (VA), evaluation 0.1, we will need a sample size of 25 eyes.
to involved eye. of conjunctival injection, discharge,
(3) Control group 2: Artificial tears presence of superficial punctate keratitis
(hypromellose 0.3%) four times a day (SPK), pseudomembranes on tarsal
Results
to the involved eye. conjunctiva and corneal SEI. Those During the study, 74 participants were
signs were graded on a 4-point (0–3) enrolled. In five patients, adenovirus
For ethical purposes, the institu-
clinical scale to evaluate the severity of was not detected via PCR (study
tional review board limited the use of
the disease. The clinical score is similar group, n = 1; control group 1, n = 2;
PVP-I 1% to be used in this trial only
to the score used by Hillenkamp et al. control group 2, n = 2), and therefore,
when combined with additional treat-
(2002) in their clinical evaluation of the they were excluded. In addition, one
ment. Therefore, there was no arm of
effects of cidofovir and cyclosporin as a patient from the study group was lost
PVP-I 1% eyedrops alone.
topical treatment of acute adenoviral to follow-up and was excluded. There-
The randomization was done by
keratoconjunctivitis. fore, a total of 78 eyes of 68 patients
preparing a list of randomly assigned
were included in the statistical analysis.
group numbers for each consecutive
Confirming compliance The disease occurred unilaterally in 58
patient number. Patients were assigned
To confirm and assure compliance with of the participants (85%) and bilater-
to their group in the order of their
medication, patients were asked to sign ally in 10 of the participants (15%).
inclusion in the study. Each treatment
a follow-up form each time they This included 35 right eyes (44%) and
group received one bottle and the
instilled their medications and state 43 left eyes (56%), (p = 0.18). Each of
labels were removed from the treat-
the exact time. the three groups included 26 eyes
ment bottles, and the patients were
at baseline examination. There was
not told which treatment arm they
no statistically significant difference
were assigned to. No attempt was Statistical analysis
between the 3 groups in their baseline
made to conceal the dark colour of
Quantitative variables were analysed characteristics (age and gender, see
the PVP-I 1.0% eyedrops or to manip-
based on measures of central tendency Table 1). From each control group,
ulate the colours of the treatment of
and distribution (mean, median, mode, 25 patients (96%) completed the 7-days
the other treatment arms. However,
standard deviation, etc.), while qualita- follow-up, while 17 patients (65%)
patients were instructed to not instil
tive variables were analysed based on the from the study group completed the
the drops 2 hs prior to follow-up
absolute and relative frequencies of 7-days follow-up. The two control
examination as, from our experience,
occurrence. In both cases, 95% confi- group patients (4%) and nine study
this is the time required for the
dence intervals were used. Baseline group patients (35%) did not attend
colouring effect of the ocular surface
demographics in study and control their last examination due to ‘recovery’
to pass. In cases of bilateral disease,
groups were compared using one-way following their day 5 visit, as described
both eyes were allocated to the same
analysis of variance (ANOVA) for contin- by the patients on the telephone (we
treatment group.
uous and nominal variables and the chi- verified that they were all free of any
The study was approved and con-
square test for categorical variables. symptoms on day 7 by conducting our
ducted in accordance with the Decla-
Changes from baseline in the quality standard questionnaire).
ration of Helsinki (trial registration
ordinal variables (clinical parameters)
number: 1700). The patients were pro-
were evaluated by nonparametric
vided with an informed explanation Symptoms (questionnaire)
repeated measures (Friedman’s test).
and signed a written informed consent.
SPSS software version 21 (IBM corpora- A comparison of the symptoms
All the patients were examined at the
tion, Armonk, NY, USA) was used reported by the patients at each visit
day of presentation before treatment
throughout. was performed between the three
(baseline examination) and on the
groups. The change in symptoms com-
third, fifth and seventh days of treat-
Power calculation pared with baseline was calculated and
ment or until the recovery was com-
As the incidence of signs and symptoms expressed as a percentage.
plete (but at least three examinations)
in acutely ill adenovirus keratoconjunc-
by a blinded examiner. The further
tivitis patients is high (around 70–80%), Itching and foreign body sensation
management of the patient after the
we calculated that to detect a 30% Figures 1 and 2 show a comparison of
seventh day was at the discretion of the
decrease in signs and symptoms with itching and foreign body perception
examining physician and was not
included in the statistical evaluation.
Table 1. Baseline characteristics.
On each visit, all patients filled a
symptoms questionnaire. The patients Serotype (%)
were asked about five symptoms: eye Female
itching, foreign body sensation, tearing, N Age (years) (%) 8 3 5 4
redness in the eye and eyelid swelling
Study group 21 40.61  18.25 43 76 14 10 0
using a 4-point (0 – none, 1 – mild, 2 –
Control 1 group 24 49.58  22.13 54 100 0 0 0
moderate, 3 – severe) scale. Tear spec- Control 2 group 23 48.82  22.89 35 74 9 0 17
imens were collected for analysis of the
viral titre by real-time PCR. No significant differences between baseline demographics in all three treatment arms (p > 0.05).

3
Acta Ophthalmologica 2017
Fig. 1. Median itching grading.
Fig. 2. Median foreign body sensation grading.
Fig. 3. Median tearing grading.
respectively. Briefly, the study group
demonstrated a similar and superior
reduction in terms of both parameters
(p < 0.001) with a gradual reduction
from a median of 2.0 at baseline to 0.0
by day 5, while control group 1 had a
reduction from 2.0 at baseline to 1.0 on
day 7 and control group 2 did not
demonstrate any reduction.
Tearing
Figure 3 shows a comparison of tearing
perception. The study group
4
demonstrated a superior reduction in
terms of tearing (p < 0.001) with a
gradual reduction from a median of
3.0 at baseline to 0.0 by day 7, while
control group 1 had a reduction from
3.0 at baseline to 2.0 on day 3 and
thereafter experienced no further reduc-
tion and control group 2 experienced a
slight reduction from 3.0 to 2.0 by day 7.
Redness
The study group demonstrated a supe-
rior reduction in terms of redness
(p < 0.001) with a gradual reduction
from a median of 3.0 at baseline to 0.0 by
day 7. Control group 1 had a reduction
from 3.0 at baseline to 1.0 on day 7, and
control group 2 experienced a slight
reduction from 3.0 to 2.0 by day 7.
Eyelid swelling
The study group demonstrated a supe-
rior reduction in terms of eyelid reduc-
tion (p < 0.001) with a gradual
reduction from a median of 2.0 at
baseline to 0.0 by day 7. Control group
1 had a reduction from 2.0 at baseline
to 1.0 on day 5, and control group 2
experienced a slight reduction from 2.0
to 1.5 by day 7.
Clinical score
Each of the five clinical signs were
scored on all visits and compared
between all three groups. The change
in clinical signs compared with baseline
was expressed as a percentage.
Conjunctival injection
Figure 4 compares conjunctival injec-
tion over time between the three groups.
The study group demonstrated a supe-
rior reduction in terms of conjunctival
injection (p < 0.001) with a gradual
reduction from a median of 2.0 at base-
line to 0.0 by day 7, while control group 1
had a reduction from 2.0 at baseline to
1.0 on day 7 and control group 2 did not
demonstrate any reduction.
Conjunctival discharge
The study group demonstrated a supe-
rior reduction in terms of conjunctival
discharge (p < 0.001) with a gradual
reduction from a median of 2.0 at
baseline to 0.0 by day 5, while control
group 1 had a reduction from 1.5 at
baseline to 1.0 on day 3 and thereafter
remained steady and control group 2
did not demonstrate any reduction.
Superficial punctate keratitis (SPKs)
Figure 5 compares SPKs over time
between the three groups. The study
group demonstrated less SPKs through-
out the study period (p < 0.001). No rise
in SPKs was seen in the study group
while a median of 1.0 was identified in
both control groups on days 5 and 7.
Pseudomembranes on tarsal conjunctiva
The study group demonstrated less
pseudomembranes throughout the
study period (p < 0.001). No rise in

Fig. 4. Median conjunctival injection grading.
Fig. 5. Median severity of superficial punctate keratitis.
pseudomembranes was seen in the study
group while a median of 1.0 was iden-
tified in control group 1 and a median of
2.0 in control group 2 by day 7.
Corneal subepithelial infiltrates (SEI)
No SEI were found among patients
from the study group during the 7 days
of follow-up.
Subepithelial infiltrates (SEI) were
observed in patients from the two
control groups. In control group 1 on
the fifth day, a few SEI (<10) appeared
in 1 patient (4%) and many SEI (>10)
were also seen in another patient (4%).
In control group 2, a few SEI appeared
in four patients (16%). On the seventh
day, a few SEI appeared in 40% (10 of
25 patients) of control group 1 and
12% (three of 25) of control group 2.
Many SEI were found in 4% (1 of 25)
and 8% (2 of 25), respectively. The
main appearance of SEI was 44% (11/
25) in control group 1 and 20% (5/25)
in control group 2.
PCR
Figure 6 demonstrates the adenoviral
titre in tears on each follow-up visit.
The study group showed the most
rapid decrease in viral titres. On the
third day, the mean titre was reduced
by 56%. On the fifth day, by 92% and
on the seventh day it was almost
eradicated. In control group 1, viral
titres decreased on the third day by
21%, at the fifth day by 38% and at the
seventh day by 65%. In control group
2, there were reductions in viral titres
on the third day by 26%, on fifth day
by 46%, and on seventh day the viral
titre was decreased by 77%.
Discussion
Despite the fact that many people are
suffering from adenoviral keratocon-
junctivitis every year, there is no effec-
tive antiviral drug at the present time
that can reduce patient morbidity.
In previous studies, the efficacy of
PVI 0.4% and dexamethasone 0.1% in
the treatment of adenoviral keratocon-
junctivitis was reported. In a pilot
human study by Pelletier et al. (2009),
clinical resolution and reduction of
viral titre were observed within 5 days
of treatment. A controlled in vivo
Acta Ophthalmologica 2017
study, in a NZW rabbit model by
Clement et al. (2011) comparing PVI
0.4%/dexamethasone 0.1% with 0.5%
cidofovir, tobramycin/dexamethasone
and a balanced salt solution for treat-
ment of adenoviral keratoconjunctivi-
tis, demonstrated the superiority of
PVI 0.4%/dexamethasone 0.1% in
minimizing clinical symptoms and
reducing virus titres . In a pilot uncon-
trolled study by Trinavarat & Atcha-
neeyasakul (2012), the efficacy of PVI
0.2% in the treatment of EKC was
investigated. The recovery rate within a
week of treatment was 77%.
We report a prospective, random-
ized controlled study in which we
investigated the efficacy of the combi-
nation PVP-I 1.0% with dexametha-
sone 0.1% (study group) and compared
it with dexamethasone 0.1% only (con-
trol group 1) and artificial tears only
(control group 2).
Our results indicate a much faster
improvement of patients’ symptoms in
the study group and a faster improve-
ment of all clinical signs in this group
compared with the two control groups.
In most patients of the study group, the
recovery was almost complete by the
fifth day of treatment with 34% of eyes
(nine of 26) ending their follow-up at
this day due to their complete recovery.
These data correlate with a rapid
reduction in the viral titre that was
almost eradicated (92% reduction) on
the fifth day of treatment in the study
group.
Control group 1 improved more
slowly than the study group, but much
faster than control group 2. The excep-
tion was the presence of corneal SEI
that were found among patients from
both control groups starting on the
fifth day of observation. By the seventh
day, SEI appearance was much more
prevalent in control group 1 [44% of
eyes (11 of 25)] in contrast to 20% of
eyes (five of 25) from control group 2.
No SEI were seen among the study
group patients during the whole study
period.
Our results suggest that PVI is
capable of inhibiting the replication of
adenovirus, while dexamethasone 0.1%
alone, especially when prescribed early
on, may exacerbate the replication of
adenovirus and the inhibition of
immune response, as reported by
Romanowski et al. (2006). This would
explain the considerably high rates of
SEI in the dexamethasone 0.1% alone
5
Acta Ophthalmologica 2017
Fig. 6. Viral titres (PCR) presented in mean and standard error.
group. Furthermore, we speculate that
PVI eradicates the virus in its extracel-
lular phase at a more rapid rate,
reducing the viral load below a thresh-
old which would lead to SEI and that if
given alone (without dexamethasone
0.1%) could possibly lead to similar
results. Despite the better clinical and
subjective patient comfort response in
control group 1 compared with control
group 2, the viral titres (PCR)
decreased faster in patients in control
group 2. This finding reinforces the
idea that corticosteroids alone may
prolong the duration of viral shedding,
while improving patient’s subjective
feeling.
Epithelial keratitis (SPK) occurs due
to adenovirus replication within the
corneal epithelium. In the present
study, we found a rise in epithelial
keratitis in the dexamethasone and
artificial tears group by the 7th day of
treatment. It can be assumed that in the
study group PVI counteracted the
effect of dexamethasone on SEI. Thus,
by combining PVI and dexamethasone,
we achieve the combination of the
antiviral effect of PVI and the anti-
inflammatory effect of dexamethasone.
An in vitro study that investigated
PVI for treatment of adenoviral kera-
toconjunctivitis 34 reported that diluted
PVI at concentration of 0.8% com-
pletely extinguishes infectivity of free
adenovirus after an exposure of 10 min
and is less effective against intracellular
adenovirus. This fact tends to suggest
that the earlier the PVI treatment
starts, the more likely it is that the
virus can be eradicated.
The serotype 8 was identified in most
eyes (83%) in our study. It is known
that adenovirus type 8 is responsible
for EKC, in its most frequent and
6
aggressive form (Nicholson 1993; Aoki
& Tagawa 2002).
The present study also contains lim-
itations. Although this study was dou-
ble-blinded, concealing the dark brown
colour of the PVP-I drops proved to be
difficult and therefore not performed.
In addition, this study was limited to
patients with a disease duration of up
to 3 days, as opposed to the inclusion
of patients with a disease duration of
up to 2 weeks used in a recent ran-
domized placebo-controlled trial of
topical steroids in presumed kerato-
conjunctivitis (Adleberg & Wittwer
1995). Thus, its conclusions may not
be applied to treatment initiated later
than 3 days in the course of the disease.
Although desirable, an arm of PVP-I
alone was not ethically authorized, we
can only speculate that such a treat-
ment would have been as efficient as its
combination with dexamethasone 1%
meriting further research in this regard.
A potential limitation of this study is
that some serotypes may have more
aggressive disease course than others
and as such the difference in distribu-
tion of serotypes between treatment
arms might have influenced the results
of this study. Last, this study’s follow-
up was limited to 7 days of treatment
and therefore further studies should
plan longer follow-up times to monitor
the longer-term effects of this treatment
specifically in terms of prevention of
formation of SEI.
In conclusion, our results indicate
that the combination of PVI 1.0%/
dexamethasone 0.1% is effective in
treating adenoviral keratoconjunctivi-
tis. This combination improved the
patient’s ailment and clinical signs to
almost complete recovery in 5–7 days,
which correlated with the eradication
of the virus by PCR. Further studies
are needed to test the long term safety
of this treatment.
References
Adleberg JM & Wittwer C (1995): Use of the
polymerase chain reaction in the diagnosis
of ocular disease. Curr Opin Ophthalmol 6:
80–85.
Aoki K & Tagawa Y (2002): A twenty-one
year surveillance of adenoviral conjunctivitis
in Sapporo, Japan. Int Ophthalmol Clin 42:
49–54.
Apt L, Isenberg SJ, Yoshimori R & Spierer A
(1989): Outpatient topical use of povidone-
iodine in preparing the eye for surgery.
Ophthalmology 96: 289–292.
Artieda J, Pineiro L, Gonzalez M, Munoz M,
Basterrechea M, Iturzaeta A & Cilla G
(2009): A swimming pool-related outbreak
of pharyngoconjunctival fever in children
due to adenovirus type 4, Gipuzkoa, Spain,
2008. Euro Surveill 14: 8.
Bielory BP, Perez VL & Bielory L (2010):
Treatment of seasonal allergic conjunctivi-
tis with ophthalmic corticosteroids: in
search of the perfect ocular corticosteroids
in the treatment of allergic conjunctivitis.
Curr Opin Allergy Clin Immunol 10: 469–
477.
Blyn LB, Hall TA, Libby B et al. (2008):
Rapid detection and molecular serotyping of
adenovirus by use of PCR followed by
electrospray ionization mass spectrometry.
J Clin Microbiol 46: 644–651.
Clement C, Capriotti JA, Kumar M et al.
(2011): Clinical and antiviral efficacy of an
ophthalmic formulation of dexamethasone
povidone-iodine in a rabbit model of aden-
oviral keratoconjunctivitis. Invest Ophthal-
mol Vis Sci 52: 339–344.
Colon LE (1991): Keratoconjunctivitis due to
adenovirus type 8: report on a large out-
break. Ann Ophthalmol 23: 63–65.
Dawson CR, Hanna L & Togni B (1972):
Adenovirus type 8 infections in the United
States. IV. Observations on the pathogenesis
of lesions in severe eye disease. Arch Oph-
thalmol 87: 258–268.
Epstein SP, Pashinsky YY, Gershon D, Wini-
cov I, Srivilasa C, Kristic KJ & Asbell PA
(2006): Efficacy of topical cobalt chelate
CTC-96 against adenovirus in a cell culture
model and against adenovirus keratocon-
junctivitis in a rabbit model. BMC Ophthal-
mol 6: 22.
Gigliotti F, Williams WT, Hayden FG et al.
(1981): Etiology of acute conjunctivitis in
children. J Pediatr 98: 531–536.
Hale LM (1969): The treatment of corneal
ulcer with povidone-iodine (Betadine). N C
Med J 30: 54–56.
Hammer LH, Perry HD, Donnenfeld ED &
Rahn EK (1990): Symblepharon formation
in epidemic keratoconjunctivitis. Cornea 9:
338–340.

Heim A, Ebnet C, Harste G & Pring-Aker-
blom P (2003): Rapid and quantitative
detection of human adenovirus DNA by
real-time PCR. J Med Virol 70: 228–239.
Hillenkamp J, Reinhard T, Ross RS et al.
(2002): The effects of cidofovir 1% with and
without cyclosporin a 1% as a topical
treatment of acute adenoviral keratocon-
junctivitis: a controlled clinical pilot study.
Ophthalmology 109: 845–850.
Hyde KJ & Berger ST (1988): Epidemic
keratoconjunctivitis and lacrimal excretory
system obstruction. Ophthalmology 95:
1447–1449.
Isenberg SJ, Apt L, Yoshimori R, Pham C &
Lam NK (1997): Efficacy of topical povi-
done-iodine during the first week after
ophthalmic surgery. Am J Ophthalmol 124:
31–35.
Isenberg SJ, Apt L, Valenton M, Del Signore
M, Cubillan L, Labrador MA, Chan P &
Berman NG (2002): A controlled trial of
povidone-iodine to treat infectious conjunc-
tivitis in children. Am J Ophthalmol 134:
681–688.
Ishii K, Nakazono N, Fujinaga K et al. (1987):
Comparative studies on aetiology and epi-
demiology of viral conjunctivitis in three
countries of East Asia–Japan, Taiwan and
South Korea. Int J Epidemiol 16: 98–103.
Jhanji V, Chan TC, Li EY, Agarwal K &
Vajpayee RB (2015): Adenoviral keratocon-
junctivitis. Surv Ophthalmol 60: 435–443.
Jogler C, Hoffmann D, Theegarten D, Grun-
wald T, Uberla K & Wildner O (2006):
Replication properties of human adenovirus
in vivo and in cultures of primary cells from
different animal species. J Virol 80: 3549–
3558.
Monnerat N, Bossart W & Thiel MA (2006):
[Povidone-iodine for treatment of
adenoviral conjunctivitis: an in vitro study].
Klin Monatsbl Augenheilkd 223: 349–352.
Nicholson F (1993): Introduction to aden-
oviruses: an overview of morphology, clas-
sification and epidemiology. Eye 7(Pt 3
Suppl): 1–4.
Notivol R, Amin D, Whitling A, Wells D,
Kennedy M & Cockrum PC (2004): Pro-
phylactic effectiveness of tobramycin-dexa-
methasone eye drops compared with
tobramycin/vehicle eye drops in controlling
post-surgical inflammation in cataract
patients: prospective, randomised, double-
masked, two-arm, parallel-group, placebo-
controlled, multicentre study. Clin Drug
Invest 24: 523–533.
Nwanegbo EC, Romanowski EG, Gordon YJ
& Gambotto A (2007): Efficacy of topical
immunoglobulins against experimental ade-
noviral ocular infection. Invest Ophthalmol
Vis Sci 48: 4171–4176.
Pelletier JS, Stewart K, Trattler W, Ritterband
DC, Braverman S, Samson CM, Liang B &
Capriotti JA (2009): A combination povidone-
iodine 0.4%/dexamethasone 0.1% oph-
thalmic suspension in the treatment of aden-
oviral conjunctivitis. Adv Ther 26: 776–783.
Romanowski EG & Gordon YJ (2008):
Update on antiviral treatment of adenoviral
ocular infections. Am J Ophthalmol 146:
635–637.
Romanowski EG, Yates KA, Teuchner B,
Nagl M, Irschick EU & Gordon YJ (2006):
N-chlorotaurine is an effective antiviral
agent against adenovirus in vitro and in the
Ad5/NZW rabbit ocular model. Invest Oph-
thalmol Vis Sci 47: 2021–2026.
Russell WC (2009): Adenoviruses: update on
structure and function. J Gen Virol 90: 1–20.
Schuhman G & Vidic B (1985): Clinical
experience with povidone-iodine eye drops
Acta Ophthalmologica 2017
in patients with conjunctivitis and kerato-
conjunctivitis. J Hosp Infect 6(Suppl A):
173–175.
Torres Rojas G, Goyenechea A, Savon C,
Valdes O & Oropesa I (1998): [The incidence
of adenoviruses in viral conjunctivitis]. Rev
Cubana Med Trop 50: 182–185.
Trinavarat A & Atchaneeyasakul LO (2012):
Treatment of epidemic keratoconjunctivitis
with 2% povidone-iodine: a pilot study. J
Ocul Pharmacol Ther 28: 53–58.
Viney KA, Kehoe PJ, Doyle B et al. (2008):
An outbreak of epidemic keratoconjunctivi-
tis in a regional ophthalmology clinic in New
South Wales. Epidemiol Infect 136: 1197–
1206.
Wada H, Nojima Y, Ogawa S et al. (2016):
Relationship between Virucidal Efficacy and
Free Iodine Concentration of Povidone-
Iodine in Buffer Solution. Biocontrol Sci
21: 21–27.
Woodland RM, Darougar S, Thaker U, Cor-
nell L, Siddique M, Wania J & Shah M
(1992): Causes of conjunctivitis and kerato-
conjunctivitis in Karachi, Pakistan. Trans R
Soc Trop Med Hyg 86: 317–320.
Received on August 22nd, 2016.
Accepted on January 13th, 2017.
Correspondence:
Natalya Kovalyuk, MD
Department of Ophthalmology
Barzilai Medical Center
Histadrut st. 2, Ashkelon
Israel
Tel: +972-525865527
Fax: +972-86745922
Email: natalya.k7@gmail.com