IASR

ISSN 0915-5813

Vol. 41 No. 12 (No. 490) December 2020
Infectious Agents Surveillance Reporthttps://www.niid.go.jp/niid/en/iasr-e.html

Recent topics regarding exanthema subitum.......................................... 213
Virological testing methods for exanthema subitum.............................. 214
Detection of HHV-6, 7 in rash diseases (2017-2019, Tokyo, Japan)...... 215
Vaccine development for HHV-6B............................................................ 216

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

HHV-6 and drug-induced hypersensitivity syndrome............................ 218
Human genome integration of HHV-6: ciHHV-6.................................... 220
COVID-19 findings from active epidemiological investigation,
Japan (Second report) (as at 5 October 2020, provisional).................. 221<THE TOPIC OF THIS MONTH>
Exanthema subitum 2000-2020

1,200,000

No. of cases＊＊

1,150,000

Population of 0-year-olds＊＊＊

1,100,000
1,050,000
1,000,000
950,000
900,000
850,000

Population of 0-year-olds

130,000
120,000
110,000
100,000
90,00080,00070,00060,00050,00040,00030,00020,00010,0000800,000

20002001200
2200
3200
4200
5200
6200
7200
8200
9201
0201
1201
2201
3201
4201
5201
6201
7201
8201
9202
0

No. of cases

Figure 1. Yearly number of reported exanthema subitum cases, week 1 of 2000 to week 40of 2020,＊ JapanYear＊ as at week 40 of 2020＊＊ National Epidemiological Surveillance of Infectious Diseases/Pediatric Sentinel Sites: as at 7 October 2020＊＊＊ Vital Statistics of Japan

Exanthema subitum (ES) is a febrile exanthematous disease in infancy with a generally good prognosis, characterized by a feverthat lasts about three days and exanthema with fever reduction. In the acute phase, loose stool/diarrhea, bulging anterior fontanel,eyelid edema, and occipital lymphadenopathy are observed. Mottled exanthema on both sides of the uvula, so-called Nagayama’s
spots, may appear in the early phase of the disease.
The cause of ES had long been unknown, but in 1988, it was reported for the first time that ES was caused by infection withhuman herpesvirus 6 (HHV-6). Later, in 1994, human herpesvirus 7 (HHV-7) was also reported to cause ES. ES is designated as acategory 5 notifiable disease according to the Infectious Diseases Control Law, and the number of case-patients, by age group, isreported weekly from approximately 3,000 pediatric sentinel sites (Notification criteria: https://www.mhlw.go.jp/bunya/kenkou/
kekkaku-kansenshou11/01-05-22.html) via the National Epidemiological Surveillance of Infectious Diseases (NESID) system. The
epidemiologic situation of ES was summarized based on the information from pediatric sentinel sites. This is the first time ES has
been included in the Infectious Agents Surveillance Report (IASR).
Epidemiological characteristics of ES in Japan: With the decrease in the population of 0-year-olds, the number of ES cases
reported has been decreasing annually (Fig. 1). In 2000, 126,785 cases were reported from pediatric sentinel sites, but the number
decreased to 64,519 (provisional data) in 2019. Furthermore, changes were observed in the age distribution, and the percentage ofchildren under 1 year of age decreased over the years, from 77.1% in 2000 to 31.3% in 2020 (Fig. 2).
Although there is no apparent trend in the number of ES reports, it is slightly higher in summer than in winter (https://www.niid.
go.jp/niid/ja/10/2096-weeklygraph/1651-08subit.html). Since ES is reported based on characteristic clinical symptoms, the causative
pathogen is not investigated in many cases. It is possible that the increase in the number of patients in the summer is due to cases ofES-like febrile exanthematous symptoms caused by viruses other than HHV-6 or HHV-7, such as enterovirus infection. ES is regarded
as an indicator that pediatric sentinel site reporting is operating in a stable manner because yearly fluctuations in the number ofnotifications is small. With the coronavirus disease 2019 (COVID-19) epidemic in 2020, reports of other infectious diseases frompediatric sentinel sites decreased, but reports of ES remained constant (https://www.niid.go.jp/niid/images/idsc/idwr/IDWR2020/idwr2020-44.pdf), suggesting that the accuracy of the pediatric sentinel infectious disease surveillance system was maintained at acertain level.
HHV-6 and HHV-7: HHV-6 has conventionally been classified into two variants, HHV-6A and HHV-6B, but at the 2012
International Committee on Taxonomy of Viruses, they were reclassified as different species. HHV-6A, HHV-6B, and HHV-7 were allclassified into the Bethaherpesvirus subfamily in the Herpesviridae family; once any of these viruses infect a human, they establish
latency in the infected for a lifetime. The age of children infected with HHV-6B is generally lower than that of children infected withHHV-7. If an infant has two episodes of ES, the second ES is often caused by HHV-7. While HHV-6B and HHV-7 have been reported
as the cause of ES, the association between HHV-6A and ES remains unclear (see p.214 of this issue). HHV-6B and HHV-7 arethought to be transmitted mainly through saliva. HHV-6B infects T cells through the binding of a membrane protein called glycoprotein
H (gH)/gL/gQ1/gQ2 complex expressed on the surface of virions to CD134 (OX40) expressed on the surface of activated T cells (see1′（211′）（Continued on page 212′）

IASR Vol. 41 No. 12（Dec. 2020） 2′（212′）（THE TOPIC OF THIS MONTH-Continued）
Figure 2. Age distribution of reported exanthema subitum cases, week 1 of 2000 to week 40of 2020,＊ Japan
Year0％

1020

30

40

50

60

70

80

90

100

Cases

126,785
125,228
116,663
116,755
113,305
106,421103,393
103,770
103,305
94,71390,284
93,922
92,22789,47687,992
84,95776,27073,303
71,17764,51949,500

2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
0-5 M＊＊6-11 M＊as at week 40 of 2020

2Y1Y＊＊M refers to months and Y refers to years

Porsontinel

42.57
41.48
38.43
38.39
37.5334.72
34.30
34.45
34.24
31.34
29.82
29.98
29.34
28.48
27.99
27.00
24.17
23.22
22.57
20.44
15.71

3Y 4Y ≥6Y5Y(National Epidemiological Surveillance of Infectious Diseases/Pediatric Sentinel Sites: as at 7 October 2020)

Table. Pathogens detected by specimen type in exanthema subitum cases, 2000-2020
Pathogen detections

No. ofdetections （％）

853
Human herpes virus 6 (HHV 6)
122Human herpes virus 7 (HHV 7)
92
Rhinovirus
48
Cytomegalovirus (CMV)38
Enterovirus - not typed33
Adenovirus 233
Coxsackievirus A929Adenovirus - not typed
21
Respiratory syncytial virus (RSV)19
Epstein-Barr virus (EBV)19
Coxsackievirus A6
18
Echovirus 916
Echovirus 18
1,599
Total

53.3
7.6
5.8
3.0
2.4
2.1
2.1
1.8
1.3
1.2
1.2
1.1
1.0
−

Specimen type＊respiratory
specimens＊＊

735
108
89
47
38
29
33
26
21
17
17
16
16
1,192

blood

97
140
1000
101
100115

cerebrospinal
fluid

17
000000000000
17

otherMedianAge（Y）

22
2
500
6
120122043

1111111.51111111Pathogens with fewer than 15 detections and negative results are not listed.

＊ A case may have had the same pathogen detected from more than one specimen type＊＊ sputum/tracheal aspirate or throat swab
(Infectious Agents Surveillance System: as at 24 September 2020)

p.216 of this issue). HHV-6A or HHV-6B is integrated into the genome in some humans (chromosomally integrated HHV-6; ciHHV-6),
which can be dominantly inherited from parent to offspring (see p.220 of this issue). A disease associated with HHV-6B other than ES
is drug-induced hypersensitivity syndrome (DIHS), one of the severe drug eruptions with multiple organ dysfunction. With DIHS,HHV-6B may be reactivated 2-3 weeks after the disease onset (see p.218 of this issue). In addition, among patients who haveundergone hematopoietic stem cell transplantation, it has been reported that HHV-6B that had remained in latent form may bereactivated, leading to encephalitis (see p.213 of this issue).
Laboratory test for ES: ES generally has a good prognosis, and HHV-6B and HHV-7 viral gene amplification tests and serology
tests for these viruses are not covered by the national health insurance system. Once infected with HHV-6B or HHV-7, the viruses arecontinuously excreted in the saliva; thus, the presence of viral genes in saliva or pharyngeal swab specimens cannot be used for thediagnosis of ES. Virological diagnosis of ES caused by HHV-6B or HHV-7 requires confirmation of virus isolation from peripheral
blood mononuclear cells, detection of viral genes in plasma/serum free of cellular components, or a significant increase in the antibody
titers against HHV-6B or HHV-7 between paired sera collected in the acute and convalescent phases.
Virological tests are performed at some public health institutes (PHIs) for patients who are clinically suspected of having ES (seep.215 of this issue). Based on reports from the PHIs to the Infectious Agents Surveillance System, the pathogens detected in patientsclinically diagnosed as ES, along with the specimen type, are presented (Table). HHV-6 was the most frequently detected pathogen,followed by HHV-7. In addition, pathogens, such as enterovirus, that cause so-called viral exanthem have also been detected. Thisindicates that some patients diagnosed with ES include ES-like patients caused by pathogens other than HHV-6B or HHV-7.
Future perspectives: ES is often accompanied by febrile seizures, and in rare cases, has been reported to be associated withencephalitis/encephalopathy, thrombocytopenic purpura, and fulminant hepatitis. It is necessary to clarify the epidemiologicalcharacteristics of ES patients in Japan, and thereafter, to consider the testing system for HHV-6B and HHV-7 and the need for future
vaccine development, along with the approach to implementing vaccination.
The 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