IASR

ISSN 0915-5813

Vol. 42 No. 4 (No. 494) April 2021
Infectious Agents Surveillance Reporthttps://www.niid.go.jp/niid/en/iasr-e.html

Adenovirus hepatitis .................................................................................. 70
Changes in the notification criteria for adenovirus-associatedepidemic keratoconjunctivitis................................................................. 71
Adenovirus detection in pharyngoconjunctival fever surveillancein Osaka Prefecture, 2016-2020 ............................................................. 72
Analysis of annual changes in the number of epidemic keratoconjunctivitis
and pharyngoconjunctival fever cases using the National Databaseof Health Insurance Claims and Specific Health Checkups of Japan ... 73
Adenovirus-associated infectious gastroenteritis..................................... 75
A case of urethritis caused by adenovirus B7d known to be associatedwith potentially fatal severe respiratory infections .............................. 76
Detection of novel recombinant strains of human adenoviruses types
89 and 5 in Aichi Prefecture ................................................................... 78

National Institute of Infectious Diseases andTuberculosis and Infectious Diseases
Control Division,
Ministry of Health, Labour and Welfare

Domestic spread of SARS-CoV-2 R.1 lineage that contains E484K
mutation in the SARS-CoV-2 spike protein (as at February 2, 2021),
Japan ........................................................................................................ 79
Case report of a rabies patient with disease onset in Japan, 2020 ........ 81
Having a known source of infection and subsequent transmission
among COVID-19 cases (reported from February 17 to May 31,2020): investigation and discussion........................................................ 82
SARS-CoV-2 viral isolation from COVID-19 cases in Toyama Prefecturereport from the Toyama Prefectural Public Health Institute .............. 84
Information on HIV/AIDS cases under the Infectious Diseases
Control Law (the National AIDS Surveillance Committee,March 16, 2021) ....................................................................................... 86<THE TOPIC OF THIS MONTH>
Adenovirus infections, 2008 to 2020, Japan
Table 1. Adenovirus species and key associated diseases, by typeSpecies
A
B
C
D
E
F
G

Key associated diseases
Infectious gastroenteritis
ARI, PCF, EKC, HC
ARI, PCF
EKC, urethritis
ARI, EKC, PCF
Infectious gastroenteritis
Infectious gastroenteritis

Major adenovirus types
12, 313, 7, 11, 34, 35
1, 2, 5, 6
8, 64（19a）*, 37, 53, 54, 56, 85440, 4152

ARI：acute respiratory infection, PCF：pharyngoconjunctival fever,
EKC：epidemic keratoconjunctivitis, HC：hemorrhagic cystitis

Minor adenovirus types
61
14, 16, 55, 66, 68, 7957
81
*19a reclassified as 64

No. of reported cases/
sentinel site

1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0

No. of reported cases/
sentinel site

Figure 1. Weekly number of reported cases per sentinel, week 14, 1999 to week 53, 2020, Japan

2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.20.0Pharyngoconjunctival fever (PCF): pediatric sentinel sites

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Year

Epidemic keratoconjunctivitis (EKC): ophthalmology sentinel sites

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Year

(National Epidemiological Surveillance of Infectious Diseases: as at January 22, 2021)

Human mastadenoviruses (Ad), which belong to the genus Mastadenovirus in the family Adenoviridae, are non-enveloped doublestranded DNA viruses that are relatively physicochemically stable. Ads are currently grouped into seven species from A to G and over
80 types have been described (as an example, type 3 is denoted as Ad3). Ads have been reported as serotypes up to Ad51, but thoseclassified after Ad52 have been reported as genotypes based on whole genome sequencing.
Ad infection is associated with respiratory diseases, such as ARI (acute respiratory infections), ocular diseases, such as EKC(epidemic keratoconjunctivitis), and gastrointestinal diseases such as infectious gastroenteritis. Ads are also associated with urologicaldiseases, such as hemorrhagic cystitis and urethritis, along with hepatitis (Table 1 and Table 2 in p.69 and see p.70 of this issue). The
epidemic trajectory and inflammatory response vary depending on the Ad species (Nakamura et al.: JMV2018).
Ad infections are monitored under the National Epidemiological Surveillance of Infectious Diseases (NESID) system, specifically
via sentinel surveillance for pharyngoconjunctival fever (PCF) and infectious gastroenteritis at approximately 3,000 pediatric sentinelsites nationwide and for EKC at approximately 700 ophthalmology sentinel sites nationwide (for notification criteria, see https://www.
mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-16.html, https://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-0530.html). The notification criteria for EKC were revised in April 2020 and the pathogenic virus was defined as Ad, with more detailed
aspects included in the definition (see p.71 of this issue). Laboratory-based surveillance is also being performed (see p.72 of this issue).
Reported cases of PCF and EKC: Since reporting of PCF cases at pediatric sentinel sites began in 1987, the largest numberof PCF cases was reported in 2006 (Fig. 1, top). Although a summer peak in notifications has been consistently observed, an additional
peak in winter has also been observed since 2003 (https://www.niid.go.jp/niid/en/10/2096-weeklygraph/1645-02pcf.html, https://nesid4g.mhlw.go.jp/Byogentai/Pdf/data27e.pdf). In 2020, during the coronavirus disease 2019 (COVID-19) epidemic, summer andwinter peaks were also observed, although they were low (Fig. 1, top). Among PCF patients, children one year of age are reported inlarge numbers (Fig. 2 in p.68, top).

1′（ 67′）（Continued on page 68′）

IASR Vol. 42 No. 4（Apr. 2021） 2′（ 68′）
（THE TOPIC OF THIS MONTH-Continued）
In contrast, EKC patients monitored at ophthalmology
sentinel sites have been reported most frequently during
Pharyngoconjunctival fever (PCF): pediatric sentinel sites
May-August. Since 2015, however, notifications increased
2018 (n=73,959)
through autumn (Fig. 1 in p.67, bottom and https://www.
2019 (n=75,449)
niid.go.jp/niid/ja/10/2096-weeklygraph/1656-15ekc.html).
2020 (n=35,125)
EKC patients are children, mainly among those aged 0-4years, and adults across a wide age range, mainly in their
30s (Fig. 2, bottom).
According to an analysis using data from the National
Database of Health Insurance Claims and Specific Health012
345678910-14 15-1920Age group (years)
Checkups of Japan, the number of PCF and EKC patients
Epidemic keratoconjunctivitis (EKC): ophthalmology sentinel sites
in Japan during 2012-2016 was approximately 100,000
7,000
2018 (n=30,631)
6,000
and 500,000-750,000 per year, respectively (see p.73 of this2019 (n=23,077)
5,000issue).
4,0002020 (n=9,081)
3,000
Isolation/detection of Ad: From 2008 to 2020,
2,000
1,000
prefectural and municipal public health institutes (PHIs)
00-4
5-9
10-14
15-19
20-29
30-39
40-49
50-59
60-69
70reported 20,499 cases of the isolation/detection of Ad (TableAge group (years)
2 in p.69), with Ad2 being the most frequent (26%), followed(National Epidemiological Surveillance of Infectious Diseases: as at January 22, 2021)
by Ad3 (19%) and Ad1 (14%).
Figure 3. Adenovirus types detected from epidemic keratoconjunctivitis cases,
The number of Ad isolation/detection reports from2008-2020, JapanPCF patients was 3,597, with Ad3, Ad2, Ad1, Ad4, and0％
102030
4050
60
7080
90
100
No. of cases Ad5 being frequent (Table 2 in p.69).
Year
2008
（n=158）From EKC patients, a total of 2,244 cases of Ad
2009（n=90）
isolation/detection were reported; species D Ads, including
2010（n=159）Ad54, Ad37, Ad8, Ad53, and Ad64 (19a), were frequently
2011（n=157）
reported (Table 2 in p.69). Ad85 found in Japan is also2012
（n=142）2013（n=138）the cause of EKC (Kaneko: JJID2020). In addition, Ad3
2014（n=208）of species B and Ad4 of species E were reported from EKC
2015（n=244）
patients (Fig. 3 and Table 2). In 2020, the notification2016（n=250）criteria for EKC in NESID were revised, and EKC was2017（n=247）
defined as being caused by species D Ads.
2018
（n=249）2019（n=175）In other countries, Ad8 is the major pathogen of2020（n=27）
EKC, but in Japan, the frequency of Ad8 detection has
Ad37Ad3Ad54Ad56Ad4Ad8Ad53Ad64(19a)Ad others
decreased, whereas that of Ad54 detection has increased(Infectious Agents Surveillance System: as at January 22, 2021)
in recent years (Table 2 in p.69).
The number of Ad reports from patients with infectious
gastroenteritis was 3,751 and the main pathogen was species F (Ad40 or 41) (Table 2 in p.69). There were also 143 detections of Ad31
belonging to species A (see p.75 of this issue).
Ad7 belonging to species B is known to cause severe pneumonia. During 1995-1998, when Ad7 was circulating at a high level,
863 cases of Ad7 detection were reported (https://www.niid.go.jp/niid/images/iasr/table/virus/adv91-00.pdf) and several fatal cases of
Ad7 infection were also reported (IASR 17: 99-100, 1996 & 18: 79-80, 1997). During 2008-2020, 46 cases of Ad7 detection were reported(Table 2 in p.69); continued careful monitoring of Ad7 is warranted (see p.76 of this issue).
Laboratory diagnostic methods: Although the lateral flow test to detect Ad antigen (IC-kit) cannot discriminate Ad types, ithas the advantage of providing rapid results in the clinical setting. In Japan, approximately 2,700,000 kits are utilized annually, andwith improvements, the sensitivity has been increasing.
Currently, typing has shifted from serotyping to genotyping. For routine laboratory testing at PHIs, partial sequencing of thepenton base, hexon, and fiber regions is carried out (Laboratory manual for the diagnosis of PCF and EKC, ed. 3, https://www.niid.
go.jp/niid/images/lab-manual/adeno_v3.pdf). As adenoviruses frequently undergo recombination among different types within aspecies, sequencing of multiple regions is necessary (see p.78 of this issue).
Therapy and prevention: Currently, there are no specific antiviral agents available in Japan that can be used to treat Ad
infection. It is important to strengthen activities, such as the development of therapeutics against Ad infection, because it can be fatal
in immunosuppressed patients after organ transplantation (see p.70 of this issue).
As Ad is transmitted via contact or droplets, hand hygiene is important for infection prevention. However, standard alcohol-based
disinfectants are ineffective and utilization of an effective disinfectant is important (see p.75 of this issue). In particular, as the eyedischarge and tears of infected patients contain large amounts of Ad, it is important in ophthalmology to detect infected patients early
and reduce further transmission through patient interviews and diagnostic kits in accordance with the guidelines for ophthalmologists(https://www.nichigan.or.jp/member/journal/guideline/detail.html?ItemId=283&dispmid=909). For children, hygiene management
should be implemented following the School Health and Safety Act and the Infection Control Guidelines in Nurseries (http://www.
mhlw.go.jp/stf/seisakunitsuite/bunya/0000123472.html) to target the source of infection, route of transmission, and susceptibility (thethree major factors for the establishment of infection).
Although Ad is often regarded as a mild pediatric infectious disease, it can cause a wide range of diseases depending on thespecies and type. Furthermore, as it can be severe, infection control is important.
22,00020,00018,00016,00014,00012,00010,000
8,000
6,000
4,000
2,000
0No. of reported cases

No. of reported casesFigure 2. Age distribution of reported cases, 2018-2020, JapanThe statistics in this report are based on 1) the data concerning patients and laboratory findings obtained by the National Epidemiological
Surveillance of Infectious Diseases undertaken in compliance with the Act on the Prevention of Infectious Diseases and Medical Care for Patientswith Infectious Diseases, and 2) other data covering various aspects of infectious diseases. The prefectural and municipal health centers andpublic health institutes (PHIs), the Department of Environmental Health and Food Safety, the Ministry of Health, Labour and Welfare, andquarantine stations, have provided the above data.

Infectious Disease Surveillance Center, National Institute of Infectious Diseases
Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, JAPAN Tel (+81-3)5285-1111

341
18
81
24
9
1
14-345
16
117
20
2
6
2
2
18
1
22
130
25
8
128
20
15
17
102
1,726

379
31
123
34
2
4
4
4
2
20
19141
42
9
91
20
33
1
130
1,850

367
85
93
34
4
1
3
25
1
14
1
20
120
25
1
9
103
12
2
2
128
1,717

322
101
105
24
92
511
1
44
91
60
8
104
172
257
1,763

397
101
90
60
14
4
141616674
34
515
33
6
254
1,811

238
154
107
32
1
172
12
291270
34
3
14
32
190
1,637

131
102
129
43
2
15
3126
1
1890
64
10
15
51
157
1,609

474
13103
32
32
2
5
1120
1
115
2
64
46
11
7
35
178
1,688

306

2

139

35

2

7-

6-

-

1

1-

27-

--

102-

59

86

-

4-

-

-

-

286

1,762

154

5

93

29

2

13-

3-

-

2-

-

10-

-

-

49-

45

58-

-

-

-

-

-

226

1,281

431

23

146

33

26

6-

17-

1-

5-

10-

1-

55-

39

50--4---259

1,713CB

ECCB

DDB

A

DDDBADBB

DFFF

DDDDDAd 2Ad 3Ad 4Ad 5Ad 6Ad 7Ad 8Ad 9Ad 11

Ad 12Ad 13

Ad 15Ad 19

Ad 21

Ad 31

Ad 33

Ad 34

Ad 35

Ad 37

Ad 40

Ad 41

Ad 40/41†

Ad 46

Ad 53

Ad 54

Ad 56

Ad 64 (19a)Ad NTTotal

NT: Not typed
PCF: pharyngoconjunctival fever, EKC: epidemic keratoconjunctivitis, LRI: lower respiratory infection, URI: upper respiratory infection†Ad 40/41 is considered directly from feces by ELISA kit in which Ad 40 and 41 can not be distinguished from each other.

Ad others

405

495

505

462

387

399

447

511

385

471

387

412

1,552

107

2

7

32

54

21

1

24

136

-

35--

240

235

256

205

213

237

252

240

260

228

205

195

2019

2018

2017

2016

2015

2014

2013

2012

2011

2010

2009

2008

Year

CSpecies

Ad 1Adenovirus

Table 2. Number of adenovirus isolation/detection, by year and clinical diagnosis, 2008-2020, Japan

390

20-

2

4

4

10-

3

17-

5-

-

-

4-

1-

-

-

2-

-

-

6

37

1

55

145

74

2020

3,597

139

3

3

4

36

1

-

-

4-

8-

--

--2---

4-

2

747

193

218

1,468

988

470

PCF

3,751

504

1-

33--

534

966

1

1---

143-

--

-

3-

-

1

2

59

200

31

202

746

351

2,244

236

22

48

194

461

90

2-

-

-

392

1

12-

-

42

2

1-

11

3

117

62

5

143

437

16

10

EKC

1,385

258

11-

6-

-

2

7-

-

--

-

3-

-

1-

-

1-

-

5

45

117

20180

458

280

LRI

Major clinical diagnosis
Infectious
gastroenteritis

4,151

343

-

-

1

1---

2-

3---

3-----1-

1980

396116868

1,525802

URI（Infectious Agents Surveillance System: as at January 22, 2021）

20,499

2,294

30

59

256

539

982551

1,076

2462

4

22219

351

3

1354

3

127

46

406

1,363

652

3,940

5,411

2,840

Total

IASR Vol. 42 No. 4（Apr. 2021） 3′（ 69′）

（THE TOPIC OF THIS MONTH-Continued）