Research Study

Population-based surveillance of Verocytotoxin-producing Escherichia coli in Japan,
1999-2004
Mio Sakuma MD1, 2, Mitsuyoshi Urashima MD, PhD, MPH1, 2, 3, Nobuhiko Okabe MD,
PhD2, 3
1. Division of Clinical Research & Development
2. Department of Pediatrics
The Jikei University School of Medicine, Tokyo, Japan
3. Infectious Disease Surveillance Center,
National Institute of Infectious Diseases, Tokyo, Japan

Address Correspondence:
Mitsuyoshi Urashima MD, PhD, MPH
Division of Clinical Research & Development,
The Jikei University School of Medicine,
3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, JAPAN
Phone: + 81-3-3433-1111 ext. 2405
Fax: +81-3-5400-1250
e-mail: urashima@jikei.ac.jp1Abstract

The nationwide surveillance system of the National Institute of Infectious Diseases wasreengineered to strengthen the ability to determine the number of laboratory-confirmed
verocytotoxin-producing Escherichia coli (VTEC) cases across the nation as of April
1999. Nationwide, 19,304 cases of laboratory-confirmed VTEC were reported between
April 1999 and October 2004. The annual incidence was 2.74 per 100,000 populations.
After adjusting for climate factors, VTEC incidence rates were significantly higher in
prefectures with a 1) higher percentage of elderly people; 2) higher population density;3) higher number of people in a household; and 4) higher number of beef cattle per
population. In conclusion, by conducting nationwide surveillance in Japan, the highannual incidence of VTEC was implied to be associated with climate, socioeconomic,
and population factors. However, these associations were based upon an ecologicalstudy and further longitudinal study is obligatory to address these complicatedassociations as future directions.

2Introduction

Since the early 1980s, it has been known that Verocytotoxin-producing
Escherichia coli (E. coli) (VTEC) induces hemorrhagic enterocolitis in humans and isassociated with a wide range of clinical illnesses, including non-bloody diarrhea,
hemorrhagic colitis, hemolytic uremic syndrome, and death (1). Verocytotoxin isconsidered to trigger serious condition in patients infected with the pathogenic E. coli(1). E. coli O157 and other serotype of pathogenic E. coli were found regularly in thefeces of healthy cattle (2), and are considered to transmit to humans throughcontaminated food (3), water (4), and direct contact with infected people (5) or animals(6). Thus, VTEC infections are prevalent among countries that raise cattle, including
Japan (7), the United States (8), Canada (9), England (10), Scotland (11), Argentina (12),Australia (13), and New Zealand (14).
Triggered by two major outbreaks of VTEC in Japan (4, 15), the nationwide
surveillance system of the National Institute of Infectious Diseases was reengineered in
April 1999 to better ascertain the state of laboratory-confirmed VTEC cases across thenation by enacting the new Infectious Disease Prevention Law. This system enabled us
to conduct a population-based surveillance study of the incidence of VTEC. In thisecological study, we used this nationwide surveillance data to explore factors that affectthe incidence of VTEC.

Methods

VTEC Surveillance Data
Data on cases of VTEC in humans reported in Japan from April 1999 to
October 2004 (287 weeks) were retrieved from the Infectious Agents Surveillance
Report published by the National Institute of Infectious Diseases in Japan.
When the clinician suspects hemorrhagic enterocolitis due to pathogenic E. coli
for the patients judging from clinical symptoms such as hemorrhagic colitis, the stool
samples or rectal swabs obtained from these patients are sent to laboratories at thehospital, private bio-companies for clinical diagnosis, national institutions in each3

prefecture or the National Institute of Infectious Diseases. To keep sensitivity andspecificity in detecting VTEC high quality, the protocol and trained skills in theselaboratories are under the guidance of National Institute of Infectious Diseases. At theselaboratories, the specimens are cultured on specific media such as CHROMagar O157
(CHROMagar, Paris, France) or cefixime-tellurite sorbitol MacConkey (CT-SMAC)
agar (Oxoid, Unipath Ltd., Hampshire, UK) (16, 17) and specific antibodies against
each serotype of E. coli are employed (16). If the existence of pathogenic E. coli is
confirmed, the ability for production of Verocytotoxin was next investigated fromisolates by using the method of reversed passive latex agglutination (VTEC-RPLA)
and/or of a multiplex PCR assay (16, 18, 19).
If the production of Verocytotoxin was confirmed by laboratory bases, the casewas considered as a symptomatic VTEC. Depending on the doctor’s discretion, people
around the case may be further examined for VTEC. When the doctor diagnosed VTEC
infection either symptomatic or asymptomatic, he or she is on duty to report this eventto the local health center immediately and deal with the cases to prevent further spreadof the disease, which is according to new Infectious Disease Prevention Law. Then, thenumber of cases with VTEC in Japan are counted and totaled for each prefecture on a
weekly basis.

Climate variables
We obtained weekly summarized data for a variety of climate parameters from
Meteorological Agencies in the capitals of the 47 prefectures. These parameters
included average air temperature of the day (ºC: mean=16.1, range: -7.5 to 31.2),
relative humidity (%: mean=68.8, range: 34.6 to 93.3), sea level atmospheric pressure(hPa: mean=1014.1, range: 995.1 to 1028.6), vapor pressure (hPa: mean=14.4, range:
2.2 to 32.6), wind speed (m/s: mean=2.9, range: 0.9 to 10.3), cloud cover (mean=6.9,
range: 0 to 10), number of sunny days (days mean=6, range: 1 to 7), and amount ofprecipitation (mm: mean=31.7, range: 0 to 704.5). We used data on climatic conditions
from the 2-week period prior to when each case of VTEC was reported to approximate
the incubation period between infection and reporting a diagnosis of VTEC.

Socioeconomic data4

We retrieved annual social and economical data in a total of 47 prefectures inJapan (20), including the following information: population density; percentage ofchildren (aged 15 and younger); percentage of elderly (aged 65 and older); the average
number of people in the household; the number of livestock (beef cattle plus dairy cows,
pork, and chickens) per population in the prefecture; and the average income.

Statistical analyses
In each prefecture, variables associated with the incidence of VTEC per
100,000 populations during a week were analyzed with multiple linear regression
models using climate and socioeconomic variables. All statistical analyses were
performed using STATA 8.0 software (STATA Corporation, College Station, TX).

Results

Incidence of VTEC
Nationwide, 19,304 cases of VTEC were reported between April 1999 andOctober 2004. The annual incidence was 2.74 per 100,000 populations. The highest
number that occurred in a prefecture was 63 VTEC cases/1,000,000 populations duringa week in a single prefecture. More than 16 VTEC cases were observed in 10% of a
total of 13,489 weeks (287 weeks times 47 prefectures). On the other hand, no cases
were reported in 57.6% of the 13,489 weeks. Age distribution of patients with VTEC
was shown (Fig. 1). The number of VTEC cases was the highest in age group less than 5
years old. In the older age groups, less number of cases was reported. Totally 65
outbreaks defined as more than 11 laboratory-confirmed VTEC cases in a certain timeframe and local area were reported during the study period as shown in Table. 1. The
biggest outbreak occurred at September 2003 in Kanagawa prefecture: 252 symptomatic
VTEC/197 asymptomatic VTEC. The next was at March 2001 in Chiba prefecture: 195
symptomatic VTEC/62 asymptomatic VTEC.

Ecological studies of VTEC incidence
Data showed an annual oscillation of VTEC cases during the study period (Fig.
2). The temporal distribution of VTEC cases showed a marked seasonal oscillation5

pattern with peaks centered in July and August. The average air temperature of a week(≧25℃) during the summer season was overlaid in the graph. In 2003, we experienced
a cool summer, during which the number of cases of VTEC was noted to be lower thanin other years. The annual incidence showed no clear tendency to increase or decreaseduring the study period.
Geographic distribution of VTEC cases/100,000 population per year in 47
prefectures is shown in Fig. 3. A relatively higher incidence of VTEC was clustered insome western sections of several Japanese prefectures, including Saga, Nagasaki,
Fukuoka, Miyazaki, Tottori, Shimane, Okayama, Shiga, Fukui, Ishikawa, and Kanazawa,and some northeastern sections of two Japanese prefectures, including Iwate and Akita.
The four prefectures with the highest annual incidences were located in rural areas:
Saga (9.2/100,000), Ishikawa (7.9/100,000), Akita (5.8/100,000), and Iwate(5.8/100,000), whereas the prefectures with the lowest incidences were near urban
areas: Yamanashi (1.3/100,000), Ibaraki (1.1/100,000), Niigata (0.9/100,000), andShizuoka (1.4/100,000).

Variables associated VTEC
Three of the eight climate variables—average air temperature of the day (t =6.03), wind speed (t = 7.16), and the number of sunny days (t = 4.01)—weresignificantly associated (P < 0.001) with of the incidence of VTEC cases/100,000
population per week per prefecture under multiple linear regression analysis (Table 2).
By adjusting for these 8 climate variables as well as calendar months,
associations of 7 socioeconomic variables with VTEC incidence/100,000 population per
week per prefecture were analyzed with multiple regression analysis (Table 3). The
strongest risk factor for VTEC occurrence in the model was a higher percentage ofelderly people in the prefecture (t = 20.77; P < 0.001). Although the presence ofchildren in the prefecture was a risk factor, the association was weak (t = 2.35; P =0.019). Higher population density (t = 8.81; P < 0.001) and the average number ofpeople in a household of the prefecture (t = 5.98; P < 0.001) were positively associatedwith VTEC incidence. On the other hand, average income in the prefecture showed anegative association with VTEC incidence (t = –10.37; P < 0.001). The number of beef6

cattle per population in the prefecture was positively associated with VTEC incidence (t= 2.35; P = 0.019); in contrast, the number of chickens per population was negatively
associated with VTEC incidence (t = –3.41; P = 0.001).
The expected number of VTEC cases based on this multiple regression model
was compared with the observed number of cases (Fig. 4). Due to strong collinearlywith beef cattle, the variable of pork was not used in this modeling. The correlation was
0.56; 32% of the variability could be explained by these socioeconomic and climate
factors.

Discussion
Based on national surveillance data in Japan, the annual incidence oflaboratory-confirmed VTEC was calculated as 2.74/100,000 population. In England andWales, population-based surveillance studies for VTEC showed an annual incidence of
1.28-2.10/100,000 population during the 4-year period from 1995 to 1999 (21, 22).
Similarly, the number of cases in other countries was as follows: Spain (0.01/100,000);
Italy (0.02/100,000); Netherlands (0.06/100,000); Finland (0.1/100,000); Denmark(0.12/100,000);Austria(0.14/100,000);

Germany(0.4/100,000);

Belgium(0.52/100,000); Sweden (1.36/100,000) (23). In the United States, 3,674 cases werereported annually to the surveillance system (24). Thus, compared with surveillancedata in other developed countries, the incidence in Japan seems to be relatively high.
However, we can not compare the annual incidence among countries exactly, since thesurveillance system is different in each country. Moreover, we compared surveillancedata in different geographic regions of Japan by assuming 1) people seek care with thesame frequency in all regions when they are ill 2) doctors request stool specimens withthe same frequency in all regions 3) laboratories test for VTEC and report VTEC withsame frequency in all regions. Thus, some degree of observation bias may exist evenunder control of the law, which is a limitation of this study. In addition, number of cases
is including not only symptomatic VTEC but also asymptomatic VTEC, which may also
raise the incidence of VTEC in Japanese surveillance system.
The seasonal oscillation pattern of VTEC, that is, high in summer and low in
winter, was similar to other ecological studies (25, 26). Considering that shedding fromanimals is also seasonal (27) and that food-borne disease tends to be prevalent in the7summer (28), climatic factors play an important part in determining the incidence of
VTEC. Some of climate variables were associated with the occurrence of VTEC, which
is not beyond the hypothesis yet and need to prove by further investigation.
Beef cattle and dairy cows, but not chicken, per population in the prefecture
was positively associated with incidence of VTEC. In Japan, the prevalence of VTEC
isolated from fecal samples was 5% to 10% (29), as high as the United States andSweden, and higher than Poland and other countries (30). Shedding of VTEC from
infected cattle persists for <1 week to 10 weeks (31), and VTEC strains can betransferred with considerable frequency over global distances (32). Moreover, thecorrelation between variables of the agricultural structure and human VTEC incidence
has been shown to be high based on geographical information (26). Our results appear
to be consistent with these previous studies.
Although this is an ecological study, there was a relationship between
population factors and VTEC incidence. It was demonstrated that higher population
density and more than the average number of people per household in the prefecture
were positively associated with the incidence of VTEC. Population density and thenumber of people per household may enhance the chance of contact between sensitive
person-to-person spreading of VTEC with or without symptoms. This assumption is notinconsistent with classical mathematical models of population dynamics for infectious
diseases transmitted by pathway of person-to-person (33).
In conclusion, by conducting nationwide surveillance in Japan, we showed ahigh annual incidence of VTEC 2.74/100,000 population that was associated withclimate, socioeconomic, and population factors. However, these associations were based
upon an ecological study and further longitudinal study is obligatory to address thesecomplicated associations as future directions.

8

Acknowledgment:
The authors are grateful to the Chairman and Professor, Yoshikatsu Eto, MD,
Department of Pediatrics, The Jikei University School of Medicine, for critical readingof the manuscript.

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13

Table 1. Outbreaks*1 of infection with Verocytotoxin-producing Escherichia coli (VTEC) in Japan, 1999-2004.
The number
No.

Year.
Month

Prefecture

Setting

Serotype

VT type*2ofpatientswithsymptoms

The number The
ofpositive ofcases

subjects

1

1999.7

Hokkaido

Nursery

O26 : HNT

VT 2

NR*3

64

NR

2

1999.7

NaganoHome

O157 : H7

VT 1&2

NR

21

NR

3

1999.8

Hyogo

Nursery

O157 : H7

VT 2

NR

12

NR

4

1999.9Osaka

Nursery

O26 : H11

VT 1

NR

11

NR

5

1999.9Chiba

Nursery

O26 : H11

VT 1

NR

13

NR

6

1999.10

NagasakiNursery

O26 : H11

VT 1

NR

17

NR

7

1999.11

FukuokaNursery

O111 : H-

VT 1

NR

16

NR

8

2000.5

ToyamaHospital

O157 : H7

VT 1&2

NR

15

743

9

2000.6

Kanagawa

O157 : H7

VT 2

56

87

842

10

2000.6

Ishikawa

Nursery

O26 : H11

VT 1

1

16

180

11

2000.6

Osaka

Nursery

O26 : H11

VT 1

2

20

211

Health facilities forthe agednumber
test

14

12

2000.8

ToyamaNursery

O111 : H-

VT 1

2

14

240

13

2000.8

Osaka

Camp

O157 : H7

VT 2

2

11

59

14

2000.8

ShimaneUnknown

O26 : H-

VT 1

7

11

NR

15

2000.9FukuokaNursery

O26 : H11

VT 1

8

33

251

16

2000.10

Chiba

Event place

O157 : H7

VT 2

41

58

1304

17

2000.11

Shizuoka

Unknown

O26 : H11

VT 1

2

19

355

18

2001.2

Kyoto

Nursery

O26 : HNT

VT 1

5

17

256

19

2001.3

Chiba

Home

O157 : H7

VT 1&2

195

257

NR

20

2001.4

Osaka

Nursery

O157 : H7

VT 1&2

13

27

236

21

2001.5

Ishikawa

Dormitory

O157 : H7

VT 2

18

15

261

22

2001.6

ShimaneHome

O26 : H11

VT 1

1

11

125

23

2001.7

Osaka

Nursery

O26 : H11

VT 1

17

30

231

24

2001.7

Ehime

Hospital

O157 : HNT VT 1&2

6

26

1382

25

2001.7

Fukushima

Unknown

O157 : H7

VT 2

4

15

92

26

2001.7

Nara

Nursery

O157 : H7

VT 1&2

21

21

244

15

27

2001.8

ShimaneNursery

O26 : H-

VT 1

6

28

206

28

2001.8Akita

Nursing Home

O157 : H7

VT 1&2

5

16

220

29

2001.8Saga

Nursery

O26 : HNT

VT 1

3

33

142

30

2001.8

FukuokaNursery

O26 : H11

VT 1

NR

44

830

31

2001.8NaganoRestaurant

O157 : H7

VT 1&2

29

22

525

32

2001.8

SaitamaNursing Home

O157 : H7

VT 1&2

26

67

260

33

2002.4

Saga

Nursery

O121 : H19

VT 2

16

23

163

34

2002.4

Ishikawa

Kindergarten

O157 : H7

VT 2

5

12

303

35

2002.4

Hyogo

Restaurant

O157 : H7

VT 1&2

30

52

NR

36

2002.6

Saga

NurseryO111: H-

VT 1

10

47

519

37

2002.6

FukuokaNursery

O157 : H-

VT 2

74

112

542

38

2002.7

Iwate

Elementary school

O111: H-

VT 1

4

15

331

39

2002.7

Hokkaido

Nursery

O26 : 11

VT 1

21

54

429

40

2002.7

NaganoElementary school

O26 : H11

VT 1

45

55

11889

41

2002.7

Miyagi

Nursery

O26 : H11

VT 1

12

21

167

16

42

2002.7Iwate

432002.8

Tochigi

44

2002.8Hyogo

45

2002.8Osaka

46

2002.947

O26 : HNT

VT 1

NR

23

NR

O157 : H7

VT 1&2

123

111

1521

O157 : H7

VT 1&2

NR

13

274

Nursery

O26 : HUT

VT 1

13

23

153

Ishikawa

Nursery

O157 : H7

VT 1&2

18

36

607

2003.5

Gifu

Dormitory

O157 : H7

VT 2

6

15

1247

48

2003.5

Gifu

Nursery

O157 : H-

VT 1&2

11

43

300

49

2003.7

Fukui/Kyoto

Restaurant

O157 : H7

VT 1&2

8

11

NR

50

2003.7

Hyogo

Nursery

O26 : H11

VT 1

18

16

>195

51

2003.8

FukuokaHome

O157 : H7

VT 1&2

11

16

NR

52

2003.8Nursery

O26 : H11

VT 1

18

29

238

53

2003.9Chiba

Nursery

O103 : H2

VT 1

13

13

119

54

2003.9Kanagawa

Kindergarten

O26 : H11

VT 1

252

449

6037

55

2003.11

Kyoto

Nursery

O157 : H7

VT 1&2

37

60

396

Ishikawa

University
Health facilities forthe aged
Health facilities forthe aged17

56

2003.12

FukuokaHigh school

O157 : H7

VT 1&2

16

61

967

57

2004.5

Ehime

Kindergarten

O26 : H11

VT 1

NR

38

460

58

2004.6

Chiba

Elementary School

O121 : H19

VT 1

63

17

121

O157 : H7

VT 1&2

0

2

121

59

2004.6

Hyogo

Nursery

O26 : H11

VT 1

2

11

>149

60

2004.7

Miyagi

Nursery

O26 : H11

VT 1

NR

12

119

61

2004.7

Ishikawa

High school

O111 : H-

VT 1&2

110

103

715

62

2004.7

Miyagi

Nursery

O26 : H11

VT 1

9

23

188

63

2004.8Kanagawa

Nursery

O157 : H7

VT 2

2

17

276

64

2004.8Ehime

Nursery

O26 : H11

VT 1

NR

15

416

65

2004.8Mie

Nursery

O157 : H7

VT 2

18

23

278

*1: outbreaks defined as more than 11 laboratory-confirmed VTEC cases in a certain time frame and local area
*2: VT type was detected by using VTEC –RPLA or PCR methods.
*3: NR: Not recorded18

Table2.

Climatevariables

associated

with

the

number

of

cases

of

Verocytotoxin-producing Escherichia coli (VTEC)*1 under multiple linear regression*2
Climate variable*3t

P value

Average air temperature of the day (ºC)

6.03

< 0.001

Relative humidity (%)

1.64

NS

Wind speed (m/s)

7.16< 0.001

Sea level atmospheric pressure (hPa)

–0.89

NS

Vapor pressure (hPa)

–1.23

NS

Cloud cover

–1.70

NS

Number of sunny days

4.01

< 0.001

Amount of precipitation (mm)

1.18

NS

*1: 5,768 of 13,489 weeks (287 weeks times 47 prefectures) or 42.8% of the weeks
were included in the analysis as no cases of EHEC were reported during 7,721 weeks(57.6%)*2: R2 = 0.12
*3: Data for the 2-week period prior to the week EHEC was reported was used toapproximate the period between infection and diagnosis.

19

Table 3. Socioeconomic variables associated with the number of cases of
Verocytotoxin-producing Escherichia coli (VTEC)*1 under multiple linear regression*2
Socioeconomic variable*3t

P value

Average number of people in a household*5

5.98< 0.001

Population density

8.81< 0.001

Percentage of children (15 years and younger)

2.35

0.019

Percentage of old (65 years and younger)

20.77< 0.001

Average income-10.37< 0.001

Beef cattle / population*6

2.35

0.019

Chicken / population

-3.41

0.001

*4

*1: 5,768 of 13,489 weeks (287 weeks times 47 prefectures) or 42.8% of the weeks
were included in the analysis as no cases of EHEC were reported during 7,721 weeks(57.6%)*2: R2 = 0.32: Calculated based on the multiple linear regression model using the sevenvariables listed above plus eight climate variables and calendar months.
*3: Annual data in each prefecture were used.
*4: Correlation between average income and population density, average number ofpeople in a household, and percentage of elderly was 0.9, –0.4, and –0.6, respectively.
*5: Correlation between average number of people in a household and population
density was –0.4.
*6: Beef cattle / population had a strong correlation with pork / population.

20

Figure legends
Figure 1. The age distribution of the VTEC cases.

Figure 2. The annual oscillation of Verocytotoxin-producing Escherichia coli (VTEC)
cases during the study period. In addition to the VTEC cases, the average airtemperature of a week (>=25℃) during the summer season was overlaid in the graph.

Figure 3. Geographic distribution of the average number of VTEC cases per 100,000
per year in each 47 prefectures during 1999-2004.

Figure 4. The association between observed number of VTEC cases (Y axis) and
expected number of VTEC cases (X axis) computed by a multiple linear regression
model using 8 climate variables as well as calendar months and 7 socioeconomic
variables21

Number of cases

5000

4000

3000

2000

1000

0
−

−

−

−

−

−

Age groups

−

−

−

−

−

−

−

−

−

9 14 19 24 29 34 39 44 49 54 59 64 69 74 79 84 89

−

−
4

−

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
−

0

400
350
300
250

30
29

200
28
150

27

100

26

50

25

0
’99
’00
’01
’02
’03
’04
JUL. JAN. JUL. JAN. JUL. JAN. JUL. JAN. JUL. JAN. JUL.

Average Temperature 2 weeks before

Epidemic Curve (EHEC number per week)4500.00 /100,000 < <1.98 /100,000
1.98 /100,000 < <2.93 /100,000
2.93 /100,000 < < 3.91 /100,000
3.91/100,000 <