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Open Access Full Text Article Original Research

Clinical and virological analysis of epidemic

keratoconjunctivitis caused by adenovirus type 54
in a regional ophthalmic clinic in Kyushu, Japan
This article was published in the following Dove Press journal:
Clinical Ophthalmology

Takashi Uemura 1 Background: Human adenovirus type 54 (HAdV-54) is a novel type of adenovirus that belongs
Hironori Migita 2 to species D and has thus far been detected only in Japan in patients with epidemic kerato-
Tomohiro Ueno 1 conjunctivitis (EKC). There was a large nationwide outbreak of HAdV-54 EKC from 2015 to
Tomoko Tsukahara- 2016 in Japan. The clinical characteristics of an outbreak of HAdV-54 conjunctivitis treated in
Kawamura 1,3 a regional ophthalmic clinic in Fukuoka, Japan, in 2016 were analyzed.
Patients and methods: A consecutive series of 55 cases diagnosed clinically as EKC confirmed
Yusuke Saeki 1
by HAdV-54 detection from conjunctival scrapings by polymerase chain reaction (PCR) method
Tsuguto Fujimoto 3
between 17 June 2016 and 29 August 2016 were enrolled. Viral DNA copies were counted by real-
Eiichi Uchio 1
time PCR method. The clinical findings were recorded at the first visit to the clinic and evaluated.
1
Department of Ophthalmology, Results: In the analysis of the relationship between mean clinical score groups and several
Fukuoka University School of
Medicine, Fukuoka, Japan; 2Migita Eye factors, such as days after onset, sex, HAdV DNA number on a logarithmic scale, and age, most
Clinic, Chikushino, Japan; 3Infectious factors did not show a significant difference in clinical score between groups. However, mean
Disease Surveillance Center, National clinical score of cases aged 23 years was significantly higher than that of cases aged 23 years
Institute of Infectious Diseases,
Tokyo, Japan (P0.01). The correlation coefficient between DNA copies on a logarithmic scale and clinical
score was 0.280, and a significant correlation was observed (P0.05). Multiple subepithelial
corneal infiltrates (MSI) were observed in 24 out of 31 cases (77%).
Conclusion: These results suggested that the clinical features in the early phase of HAdV-54
keratoconjunctivitis were milder but the rate of MSI observed in the late phase was higher
than those in previous epidemics of several HAdV types. The significant difference in clinical
severity between age groups might be a virological characteristic of HAdV-54.
Keywords: adenovirus, epidemic keratoconjunctivitis, type 54, multiple subepithelial infiltrates

Introduction
Epidemic keratoconjunctivitis (EKC) is an acute viral disease of the eye which is
caused by several adenovirus types, such as type 8, 37, and 64.1 Outbreaks caused by
several adenovirus types have been reported in various eye-care institutions in several
countries.2–6 Human adenovirus type 54 (HAdV-54) is a novel type of adenovirus7 that
belongs to species D which causes EKC.8–10 Until recently, it had been detected only
in Japan, but it was reported to have been detected in Greece lately.7 HAdV-54 was
Correspondence: Eiichi Uchio identified as a HAdV-8 variant strain before 2008, because antibodies to HAdV-54
Department of Ophthalmology, showed cross-reactivity with those to HAdV-8 in a neutralization test.8,10 Virological
Fukuoka University School of Medicine,
7-45-1 Nanakuma, Jonan-ku, aspects of HAdV-54 have been reported in the above studies using phylogenetic
Fukuoka 814-0180, Japan analysis; however, in contrast, the clinical features of acute conjunctivitis due to
Tel +81 92 801 1011
Fax +81 92 865 4445
HAdV-54 have been reported in a recent study by Akiyoshi et al.11 They reported an
Email euchio@fukuoka-u.ac.jp outbreak of EKC in a nursery school and stated that the clinical presentation in the

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early stage of HAdV-54 infection resembled that of acute Clinical observation and grading
allergic conjunctivitis and then subsequently described the Ocular findings of slit lamp examination were recorded on
typical features of severe EKC including severe corneal the patients’ first visit. Two objective ocular clinical find-
opacity especially in adult cases treated with corticosteroid ings of corneal and conjunctival lesions were graded on a
eye drops.11 However, the study population of this study in 4-point scale (0= none, 1= mild, 2= moderate, 3= severe;
which HAdV-54 was detected by polymerase chain reac- left and right eye separately in each case). Corneal findings
tion (PCR) method was 10 and information from clinical were graded as follows: mild = superficial punctate keratitis
analysis was limited. There was a large nationwide outbreak (SPK), moderate = corneal erosion, and severe = corneal
of HAdV-54 EKC from 2015 to 2016 in Japan.12 However, ulcer. Conjunctival lesions were graded according to the
there has been no study on the genomic evolution among criteria reported by Aoki et al14 with modification as fol-
HAdV-54 from recent strains which might be the reason for lows: mild = inflammation confined to the lower palpebral
the increasing epidemics of EKC caused by HAdV-54. In this conjunctiva, moderate = inflammation extending to the
report, we analyzed the clinical characteristics of an outbreak upper palpebral conjunctiva but not affecting the fornix,
of HAdV-54 conjunctivitis treated in a regional ophthalmic and severe = inflammation of the fornix of the upper
clinic in Fukuoka, Japan in 2016. palpebral conjunctiva and/or pseudomembrane formation.
Preauricular lymphadenopathy was graded as 0 (absent) or
Patients and methods 1 (present) on each side. These three scores were summed
Study populations and used as the clinical score of the eye. In bilateral cases,
In June 2016, a private ophthalmology clinic in Chikushino, the score of the more severe eye, mostly the firstly infected
Fukuoka, Japan encountered an epidemic of EKC which was eye, was used as the clinical score of the case. Multiple sub-
prolonged for 3 months. The clinic was one of the ophthalmol- epithelial corneal infiltrates (MSI) were recorded during
ogy practices in the region and served a population of about the follow-up period. Therefore, if the patient did not
20,000 people. Chikushino is located in the suburban area attend after the acute phase, MSI could not be observed in
of Fukuoka, which has a population of 1,550,000 people that case.
and is the largest city in southwestern Japan. This was
a consecutive case series study of 55 cases (23 men and Virological analysis
32 women) who attended Migita Eye Clinic between 17 June Conjunctival scrapings of the affected eyes were tested by
2016 and 29 August 2016 and were diagnosed clinically as an immunochromatography test (Quick Nave Adeno; Denka
having EKC according to the typical clinical findings, such Seiken Co. Ltd., Tokyo, Japan) at the patients’ first visit.
as acute unilateral or bilateral viral conjunctivitis (with Regardless of the result of immunochromatography test, the
characteristic clinical features, such as sudden onset of remaining conjunctival swab samples were frozen and stored
acute follicular conjunctivitis with watery discharge, hype- at -30°C until they were used for quantitative PCR amplifi-
remia and chemosis, and preauricular lymphadenopathy). cation. Sequencing and phylogenetic analysis to detect the
The diagnosis was confirmed by HAdV-54 detection from presence of HAdV and typing were carried out on all stored
conjunctival scrapings by the method reported previously samples on December 2016 as follows. DNA was extracted
using PCR as described later.13 To prevent nosocomial out- from these specimens using a QIA amp® DNA mini kit
patient infection, frequent hand washing by physicians and (Qiagen NV, Venlo, the Netherlands), and the copy number
disinfection of clinical apparatus was performed, and all cases was measured with real-time PCR based on the primers and
were advised of standard precautions to avoid intrafamilial conditions in a previous report.15 Forward and reverse primers
infection. Immunochromatography test for HAdV was also were GACATGACTTTCGAGGTCGATCCCATGGA and
carried out in all cases. Exclusion criteria included a history CCGGCTGAGAAGGGTGTGCGCAGGTA, respectively.15
of seasonal allergic conjunctivitis, contact lens use, a history Forty cycles of PCR were performed, and each cycle con-
of herpetic eye disease, and a history of ocular surgery. sisted of the following incubations: 95°C for 10 seconds and
Cases that showed a negative result of PCR for HAdV or a 56°C for 30 seconds. Sequencing for typing was carried out
positive result of PCR for other types than HAdV-54 were according to a previous report.13 Primers were DGF (for-
also excluded. Written informed consent for the use of the ward); AGACATGACHTTYGAGGTGGAYCC and DGR
clinical samples was obtained from all patients included in (reverse); CGCAGGTASACBGYYTCRA, and a probe
this study. This study was approved by the Ethics Review targeted for species D HAdV was 98D; TCAGAGTGCAC
Committee of Fukuoka University (16-2-15). CAGCCGCACC.13 Fifty cycles of PCR were performed,

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Dovepress Clinical analysis of HAdV-54 keratoconjunctivitis

and each cycle consisted of the following incubations: Table 2 Relationship between clinical score and patient groups
95°C for 5 seconds and 60°C for 30 seconds. The sequences Classification Clinical score Statistical
were analyzed using a sequencer (Gene Codes Corpora- (number of cases) (mean ± SD) significance

tion, Ann Arbor, MI, USA) and BioEdit Version 7.2.1 (Ibis Days after onset
2 (42) 2.52±0.59 NS
Therapeutics, Carlsbad, CA, USA). Phylogenetic analyses
3 (13) 2.38±0.49
were performed and trees were generated using MEGA5 Sex
(CEMI, Tempe, AZ, USA). Men (23) 2.61±2.41 NS
Women (32) 28.9±0.61
HAdV DNA number on logarithmic scale
Statistical analysis 8.6 (29) 2.41±0.56 NS
SPSS 19.0 software was used for data analysis (IBM, 8.6 (26) 2.58±0.57
Armonk, NY, USA). Since it has not been established Age (years)
whether the clinical score of viral conjunctivitis shows a 23 (32) 2.69±0.53 P0.01
23 (23) 2.22±0.51
normal distribution, non-parametric analysis was conducted
Abbreviations: HAdV, human adenovirus; NS, not significant.
in this study. Mann–Whitney U test was used to identify dif-
ferences in mean values among patient groups. Spearman’s
rank correlation test was used to establish the significance of The correlation between DNA copies on a logarithmic
correlation between paired groups. A value of P0.05 was scale and day of sample collection after the onset was
accepted as statistically significant. analyzed; the correlation coefficient was -0.237, but no
significant correlation was observed (Figure 1). In contrast,
Results the correlation coefficient between DNA copies on a loga-
Demographic profiles of the cases in this study are shown rithmic scale and clinical score was 0.280, and a significant
in Table 1. Mean age was 21.7 years because a consider- correlation was observed (P0.05; Figure 2).
able proportion of cases (32 cases; 58.2%) were children The clinical severity of conjunctivitis was mild in 3.6%,
(below 16 years of age). Most cases attended Migita eye moderate in 94.6%, and severe in 1.8%. All cases showed
clinic within 3 days after the onset; however, six cases (11%) moderate grade conjunctivitis (Figure 3) except for three
attended 4 days after the onset. cases. No case exhibited a conjunctival pseudomembrane.
Mean clinical score of cases who attended the clinic Preauricular lymphadenopathy was observed in 27 cases
within 2 days after the onset did not show a significant (49%). In contrast, corneal involvement was found in only
difference from those who attended 3 days after the onset. one case as SPK (1.8%), and corneal erosion or ulcer was not
No significant difference in mean clinical score was observed observed. Bilateral involvement was present in 14.5% (eight
between men and women. When the patients were divided cases). MSI were observed in 24 out of 31 cases (77%) that
into two groups according to the results of real-time PCR were followed up several times after the acute phase because
of HAdV DNA number on a logarithmic scale, there was of the need for extended topical treatment. Serious systemic
no significant difference in mean clinical score between
the 8.6 group and 8.6 group (Table 2). However, the 
'1$FRSLHVRIDGHQRYLUXV

mean clinical score of cases aged 23 years (2.69±0.53)


was significantly higher than that of cases aged 23 years
(2.22±0.51; P0.01; Table 2). 
LQORJ


Table 1 Demographic features of cases of epidemic kerato­
conjunctivitis due to adenovirus type 54 
Range
Sex 
Men 23 (42%)
Women 32 (58%) 
       
Age (mean ± SD) 21.7±22.7 0–68 'D\VDIWHURQVHW
Day of first visit after onset (mean ± SD) 1.69±1.52 0–6
Figure 1 Correlation between AdV DNA copies on logarithmic scale and day of
No. of HAdV copies (log copies/mL; mean ± SEM) 8.50±0.93 5.0–10.1
sample collection after onset. Correlation coefficient was -0.237, but this correlation
Abbreviations: HAdV, human adenovirus; SD, standard deviation; SEM, standard was not significant. DNA copies of adenovirus in log are represented in Y-axis.
error of the mean. Abbreviation: AdV, adenovirus.

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513
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Uemura et al Dovepress

'1$FRSLHVRIDGHQRYLUXVLQORJ  in nursery school children and their parents. A similarity of

these studies is that both epidemics were prolonged for over
 3 months in the summer season.
There have been several studies reporting the clinical

characteristics of adenoviral keratoconjunctivitis as shown in
 Table 3. Tullo and Higgins reported higher incidences of con-
junctival pseudomembrane (37%) and corneal involvement
 including dendritic keratitis (68%) in an outbreak caused by
HAdV-10 and -19.16 The HAdV-19 strain that causes acute

follicular conjunctivitis is currently named HAdV-64.17 The
 rate of keratitis was reported to be 9.1%, 27%, 61%, and 70%
     
with HAdV-3, -4, -8, and -19, respectively.18 The incidence of
&OLQLFDOVFRUH
preauricular lymphadenopathy ranged from 20% to 64%, and
Figure 2 Correlation between AdV DNA copies on logarithmic scale and clinical the highest rate was observed in HAdV-19-induced keratitis.18
score. Correlation coefficient was 0.280 and a significant correlation was observed
(P0.05). DNA copies of adenovirus in log are represented in Y-axis. Darougar et al also reported the clinical characteristics of
Abbreviation: AdV, adenovirus.
adenoviral keratoconjunctivitis in eight types from 98 con-
secutive patients.19 Both SPK and MSI were observed in 95%
complicating infection such as pneumonia or hemorrhagic
of HAdV-8 EKC cases, and a conjunctival pseudomembrane
cystitis was not observed among the study population.
was found in 38%.19 In contrast, the rate of pseudomembrane
in species B types (HAdV-3 and -7) was lower (0%–17%),
Discussion and the rates of SPK and MSI were also lower (56%–83%
The complete genomic sequence of HAdV-54 (Kobe-H strain)
and 17%–25%, respectively) compared with HAdV-8.19
was deposited in GenBank (accession no AB333801) as the
Aoki et al recently reported that they observed preauricular
prototype strain.8 As mentioned earlier, HAdV-54 has caused
lymphadenopathy and MSI in 23.5% and 43% of 68 cases,
epidemics continuously only in Japan in the past decade.11
respectively, in adenoviral keratoconjunctivitis due to several
However, there have been few studies describing its clinical
types.14 Huang et al reported a recent outbreak of EKC caused
features. It has been reported that a high incidence of MSI
by HAdV-56, which belongs to species D, in two factories
(53%) was observed in an epidemic of EKC due to HAdV-54
in China in which acute conjunctivitis was observed in
occurring in a nursery school in Kobe City, Japan in 2008.11
91% of the cases; however, corneal complications were not
However, the detailed features of the clinical findings of
mentioned.20
EKC due to HAdV-54 have not been previously reported.
Regarding the clinical severity of conjunctivitis, most
There was a difference in the study population between the
cases (94.6%) were moderate grade in our study. The reason
present study and that of Akiyoshi et al.11 We reported a
for this high uniformity of clinical severity was presumed
regional community-scale epidemic in a broad age group;
to be due to the short-length single epidemic in this study.
in contrast, Akiyoshi et al reported a nosocomial infection
Compared with past reports of conjunctival findings, the over-
all severity of conjunctivitis in which 96% of cases showed
moderate conjunctivitis was milder than that reported by Aoki
et al who stated that more than 40% of cases with HAdV-8
or HAdV-19 showed severe conjunctivitis.18 Although the
recent study reported by Aoki et al16 included several types,
the major proportion of cases was induced by species D
(87%) HAdV and HAdV-54 comprised 19%, and the distribu-
tion of severity of conjunctivitis was similar to our results.
Regarding conjunctival pseudomembrane, the reported inci-
dence ranged from 37% to 38% in the studies by Tullo and
Higgins (HAdV-10 and -19)16 and Darougar et al (HAdV-8).19
Figure 3 Conjunctival finding of case of AdV type 54. Moderate follicular conjun­
ctivitis with eye discharge of a 32-year-old man is shown.
In contrast, no case showed pseudomembrane in our study.
Abbreviation: AdV, adenovirus. Combining these results, HAdV-54-induced conjunctivitis

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Dovepress Clinical analysis of HAdV-54 keratoconjunctivitis

Table 3 Reports of clinical characteristics of adenoviral keratoconjunctivitis in past studies and present study
Clinical findings Incidence (%) Study Adenovirus
species and type
Conjunctival 37 Tullo and Higgins16 D10 and D19*
pseudomembrane 17 Darougar et al19 B7
38 D8
0 Uemura (present study) D54
Keratitis 68 Tullo and Higgins16 D10 and D19*
56 Aoki et al18 B3
9.1 E4
27 D8
61 D19*
70 Darougar et al19 B3
75 E4
100 C5
83 B7
95 D8
100 B11
50 D15 and D15/29
1.8 Uemura (present study) D54
Preauricular 37 Tullo and Higgins16 D10 and D19*
lymphadenopathy 20 Aoki et al18 B3
34 E4
44 D8
64 D19*
24 Aoki et al14 B3, E4, D19a#,
D53 and D54
49 Uemura (present study) D54
Multiple subepithelial 58 Tullo and Higgins16 D10 and D19*
corneal infiltrates 25 Darougar et al19 B3
25 E4
100 C5
17 B7
95 D8
53 Akiyoshi et al11 D54
43 Aoki et al14 B3, E4, D19a#,
D53 and D54
77 Uemura (present study) D54
Notes: HAdV-19 (D19)* has been renamed as HAdV-64 (D64). This is almost identical to HAdV-D19a#, which is a genotype of HAdV-19 causing keratoconjunctivitis.

seems clinically milder than that with other HAdV species D, was 77% in our study, which was the highest among previous
such as HAdV-8 or HAdV-64. A similar tendency was also studies,11,14,16,19 except for 95% reported by Darougar et al in
noted in the severity of corneal involvement in the acute cases with HAdV-8.19 This incidence was higher than that
phase. Keratitis was observed in 1.8% of cases in our study, in the epidemic of HAdV-54 (53%).11 The reason for this
whereas the incidence of keratitis ranged from 9.1% to 95% discrepancy in the incidence of MSI in the same HAdV-54
in previous studies of adenoviral keratoconjunctivitis.16,18,19 conjunctivitis is unclear, but it might have resulted from the
This low rate was similar to that in species B adenoviral difference in age distribution, with more adult cases included
conjunctivitis, 0%–17% for HAdV-3 and -7, respectively, in our study than in that of Akiyoshi et al.11 However, there
reported by Darougar et al.19 Compared with the past inci- remains a possibility that considerable viral evolution might
dence of preauricular lymphadenopathy ranging from 20% have occurred in the interval between the epidemics, in 2008
to 64%,14,16,18 the rate in our study in HAdV-54 cases (49%) and 2016. Thus, complete genomic sequence evaluation of
was the highest among HAdV types except for HAdV-19 these HAdV-54 samples will be necessary for further analysis.
(64%),18 indicating that different clinical characteristics were The pathogenesis of MSI in adenoviral keratoconjunctivitis
observed in our study for conjunctival or corneal involvement has not been clarified; however, it has been regarded as an
and preauricular lymphadenopathy. The incidence of MSI immune reaction because of the effectiveness of topical

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515
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Uemura et al Dovepress

corticosteroid treatment.21 These high rates of preauricular copy number group obtained by quantitative PCR method
lymphadenopathy and MSI suggest that the immunological (Table 1). However, we found a significant correlation
reaction occurring in the course of HAdV-54 keratoconjunc- between DNA copies on a logarithmic scale and clinical score
tivitis is relatively more active compared with other HAdV (Figure 2). These results seem contradictory. Although non-
types, even though its clinical features on ocular surface are parametric analysis was used in this study, the ordinal scale
milder in the early phase. characteristic of the clinical score might affect the results of
We analyzed the relationship between mean clinical score comparisons between groups. There are several additional
and several factors, such as days after onset, sex, HAdV DNA possible explanations for this discrepancy. Neutralizing
number on a logarithmic scale, and age in this study. No factor antibody, that acts to suppress viral proliferation during the
showed a significant difference in clinical score between the clinical course, is reported to rise around 10 days after the
two groups except for patients’ age. It is interesting that the onset in human adenoviral conjunctivitis.26 However, it is
younger group had a significantly more severe score than also reported that a rise in antibody titer is observed in 75%
the older group; however, this aspect of analysis in adenovi- of patients with adenoviral keratoconjnctivitis,26 meaning
ral conjunctivitis has not been reported in past publications. that some patients are non-responders to neutralizing anti-
Considering the high uniformity of clinical grading of con- body. Combined with this information, the inhibitory effect
junctival lesions in this study, the significant difference might of neutralizing antibody is very complicated and variable
have derived from high clinical scores of corneal findings or in adenoviral conjunctivitis. Another aspect is that the
preauricular lymphadenopathy. The reason for the result is host immune status affected clinical findings regardless of
unclear; however, there are several possible explanations for adenovirus DNA copies. This was presumed from the atypi-
the age-related characteristic of adenoviral keratoconjunctivi- cal clinical appearance in specific immunological situations
tis, especially that due to HAdV-54. A recent study revealed such as immunocompromised cases.27 The wide range of date
age-related changes in conjunctival structure,22 leading to the of sample collection for real time PCR method might also
hypothesis that an immature conjunctival structure might have affected our results. Further study will be needed for
have resulted in more severe conjunctival or corneal lesions more detailed evaluation of the relation between the number
in the younger group, especially in the pediatric population, of viral DNA copies and the clinical severity of adenoviral
in our study. However, this could not explain the specific keratoconjunctivitis, using a more quantitative method. Since
pathological mechanism in HAdV-54 keratoconjunctivitis. specific anti-adenoviral agents have not been introduced
In juvenile cases, more primary infection is seen than in locally or systemically at present, it can be considered that
adult cases, leading to the hypothesis that clinically severe the adenovirus DNA copies in our study were not affected
cases are more often observed in this age group. This could by therapeutic measures.
be supported by the fact that many nosocomial infections We found several important findings from a regional epi-
of adenoviral keratoconjunctivitis have been reported in demic of HAdV-54 keratoconjunctivitis. The clinical features
pediatric wards including neonatal intensive care units23–25 in the early phase of keratoconjunctivitis were milder but the
and nursery schools.11 However, it is important that all age rate of MSI observed in the late phase was higher than those
groups were enrolled in this study in a regional epidemic of in previous epidemics of several HAdV types including a
HAdV-54 keratoconjunctivitis; therefore, a clinical difference recent study of HAdV-54 keratoconjunctivitis in Japan.11
between age groups was able to be revealed with less bias in Clinical severity was significantly higher in the young age
this study. Regarding the age distribution of the epidemic, group than in the older age group; however, no significant
there have been a few studies reporting the mean age of difference was observed between the higher viral DNA copies
cases on a regional clinic basis. Comparing the mean age of group and lower group. For more detailed analysis to clarify
21.7 years in this study, Huang et al reported a median age the reason for these observations, genome-level sequential
of 24 years20 and Darougar et al reported that the majority of analysis will be needed.
patients were aged between 20 and 39 years, but half of the
patients with HAdV-7 were aged 20 years.19 These showed Acknowledgments
a similar tendency to the age distribution in our study. This work was supported by a Grant-in-Aid for Encour-
Another important finding of the present study is that there agement of Scientists (15K10911) from the Ministry of
was no significant difference in clinical severity between the Education, Science, Sports, and Culture of Japan. We thank
higher virus DNA copy number group and lower virus DNA Dr W Gray for editing this manuscript.

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Dovepress Clinical analysis of HAdV-54 keratoconjunctivitis

Disclosure 14. Aoki K, Kaneko H, Kitaichi N, Ohguchi T, Tagawa Y, Ohno S. Clinical

features of adenoviral conjunctivitis at the early stage of infection. Jpn J
The authors report no conflicts of interest in this work. Ophthalmol. 2011;55(1):11–15.
15. Watanabe M, Kohdera U, Kino M, et al. Detection of adenovirus DNA
in clinical samples by SYBR Green real-time polymerase chain reaction
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