1480 • CID 2009:49 (15 November) • Gould et al

MAJOR ARTICLE

Hemolytic Uremic Syndrome and Death

in Persons with Escherichia coli O157:H7 Infection,

Foodborne Diseases Active Surveillance Network

Sites, 2000–2006

L. Hannah Gould,1,a Linda Demma,1 Timothy F. Jones,3 Sharon Hurd,4 Duc J. Vugia,5 Kirk Smith,6

Beletshachew Shiferaw,7 Suzanne Segler,2 Amanda Palmer,8 Shelley Zansky,9 Patricia M. Griffin1,

and the Emerging Infections Program FoodNet Working Group

1

Enteric Diseases Epidemiology Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control

and Prevention, and 2

Georgia Emerging Infections Program, Atlanta, Georgia; 3Tennessee Department of Health, Nashville; 4Connecticut Emerging

Infections Program, New Haven; 5

California Department of Public Health, Richmond; 6Minnesota Department of Health, St. Paul; 7Oregon

Department of Human Services, Portland; 8Maryland Department of Health and Mental Hygiene, Baltimore; and 9New York State Department

of Health, Albany

Background. Hemolytic uremic syndrome (HUS) is a life-threatening illness usually caused by infection with

Shiga toxin–producing Escherichia coli O157 (STEC O157). We evaluated the age-specific rate of HUS and death

among persons with STEC O157 infection and the risk factors associated with developing HUS.

Methods. STEC O157 infections and HUS cases were reported from 8 sites participating in the Foodborne

Diseases Active Surveillance Network during 2000–2006. For each case of STEC O157 infection and HUS, demographic and clinical outcomes were reported. The proportion of STEC O157 infections resulting in HUS was

determined.

Results. A total of 3464 STEC O157 infections were ascertained; 218 persons (6.3%) developed HUS. The

highest proportion of HUS cases (15.3%) occurred among children aged !5 years. Death occurred in 0.6% of all

patients with STEC O157 infection and in 4.6% of those with HUS. With or without HUS, persons aged 60

years had the highest rate of death due to STEC O157 infection. Twelve (3.1%) of 390 persons aged 60 years

died, including 5 (33.3%) of 15 persons with HUS and 7 (1.9%) of 375 without. Among children aged !5 years,

death occurred in 4 (3.0%) of those with HUS and 2 (0.3%) of those without.

Conclusions. Young children and females had an increased risk of HUS after STEC O157 infection. With or

without HUS, elderly persons had the highest proportion of deaths associated with STEC O157 infection. These

data support recommendations for aggressive supportive care of young children and the elderly early during illness

due to STEC O157.

Shiga toxin–producing Escherichia coli O157 (STEC

O157) infection is the leading cause of hemolytic uremic syndrome (HUS) in the United States. HUS is a

life-threatening illness characterized by hemolytic aneReceived 20 February 2009; accepted 26 June 2009; electronically published

14 October 2009. a Present affiliation: Malaria Branch, National Center for Zoonotic, Vector-Borne,

and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Reprints or correspondence: Dr L. Hannah Gould, Enteric Diseases Epidemiology

Branch, 1600 Clifton Rd NE, MS F-22, Atlanta GA, 30333 (lgould@cdc.gov).

Clinical Infectious Diseases 2009; 49:1480–5

This article is in the public domain, and no copyright is claimed.

1058-4838/2009/4910-0003

DOI: 10.1086/644621

mia, thrombocytopenia, and renal insufficiency, and

it is the most common cause of acute renal failure

among children in the United States [1]. Except for

supportive care and dialysis, no specific treatment exists

for STEC O157 infection and HUS.

Several studies have explored risk factors for developing HUS among persons with STEC O157 infection.

Most studies [2–4], but not all [5], have shown young

children (age, !5 years) to be at the highest risk of

developing HUS, although these studies have largely

focused on the development of HUS in children, and

few analyses have included adults. To our knowledge,

the mortality rate for STEC O157 infection and for
E. coli O157 infection and HUS • CID 2009:49 (15 November) • 1481

STEC O157–associated HUS has not been reported by age

group. Population-based studies that include adults are needed.

The Foodborne Diseases Active Surveillance Network (FoodNet) is a collaborative project among the Centers for Disease

Control and Prevention, participating state health departments,

the US Department of Agriculture, and the US Food and Drug

Administration, with a catchment area in 2006 of ∼45 million

persons. We reviewed active, population-based surveillance for

STEC O157 infection and active, provider-based surveillance for

HUS to determine the proportion of persons with STEC O157

infection who developed HUS, to explore demographic risk factors for development of HUS, and to assess mortality rates by

age.

METHODS

Surveillance. During the period 2000–2006, FoodNet conducted active laboratory-based surveillance for STEC O157 infections in Connecticut, Georgia, Maryland, Minnesota, Oregon, and Tennessee, and selected counties in California and

New York. FoodNet personnel routinely contacted all clinical

laboratories (1500) serving the FoodNet sites to ascertain all

cases of STEC O157 infection among residents. A report form

that collected information on demographic characteristics (eg,

age or gender) and clinical outcomes (eg, hospitalization or

death 7 days after specimen collection) was completed for

each infection.

HUS is a reportable condition in all FoodNet sites; cases

involving pediatric patients (age, !18 years) and adults are

routinely ascertained through passive surveillance. To enhance

case finding, FoodNet also conducted active, provider-based

surveillance for clinically diagnosed postdiarrheal pediatric

HUS cases. FoodNet personnel routinely contacted all pediatric

nephrologists practicing in the FoodNet sites at least monthly

to ascertain cases. In California, Georgia, Minnesota, and New

York, infection control practitioners were also routinely contacted to report pediatric and adult cases. To confirm complete

case ascertainment, hospital discharge data from 2000–2006

were reviewed to ascertain cases using International Classification of Diseases, Ninth Revision, codes 283.11 (hemolytic uremic syndrome); 584.X, 283.X, and 287.X (acute renal failure,

acquired hemolytic anemia, and purpura/other hemorrhagic

conditions); 446.6 (thrombotic thrombocytopenic purpura);

008.X (diarrhea caused by E. coli); and 009.X (infectious colitis

enteritis and gastroenteritis or diarrhea of presumed infectious

origin). All possible HUS cases were validated by medical record

review. A case report form was completed for each case by

contacting the patient’s physician and by medical record review.

For cases identified by hospital discharge data review, this form

might have been completed several years after a patient’s illness.

A report form that collected information on demographic characteristics (eg, age or gender) and clinical outcomes (eg, hospitalization or death at time of hospital discharge) was completed for each case.

Case definitions. A case of STEC O157 infection was defined as the isolation from a stool specimen of a resident of a

FoodNet site of E. coli O157 which had the H7 antigen, produced Shiga toxin, or had a gene that codes for Shiga toxin

production.

Persons with physician-diagnosed postdiarrheal HUS or

thrombotic thrombocytopenic purpura were considered to be

confirmed cases if they met the following criteria: diarrhea with

onset in the 21 days before the diagnosis of HUS or thrombotic

thrombocytopenic purpura; anemia [6]; platelet count,

!150,000 platelets/mm3; acute renal impairment (serum creatinine level of 1.0 mg/dL in patients aged !13 years or creatinine level of 1.5 mg/dL in patients aged 13 years), and

microangiopathic changes consistent with hemolysis on peripheral blood smear (eg, schistocytes, burr, or helmet cells)

[7]. Persons were considered to be probable cases if they met

all of the above criteria except that microangiopathic changes

were not documented. Both confirmed and probable cases were

included in the analysis. Only cases of HUS in persons who

met the case definition for STEC O157 infection were included

in this analysis.

Analysis. Data from FoodNet surveillance for STEC O157

were linked to data from the HUS surveillance system to determine the proportion of patients with STEC O157 infection

who developed HUS. Cases were analyzed for proportion and

incidence by age group, FoodNet site, HUS status, and for

proportions hospitalized and died. Age group categories (!5,

5–9, 10–17, 18–59, and 60 years) were created to examine

the risk of HUS and death in young children, older children,

adults, and elderly persons. The Wilcoxon Rank-sum test was

used to assess the differences in age and length of hospital stay

between STEC O157–infected patients with and without HUS.

Differences in categorical variables were examined using the

Fisher exact test or the x2 test. A stepwise logistic regression

model was used to examine factors associated with HUS. Factors significant at the .10 level, including state, age (!5 vs 5

years), and sex, were entered into the model. Variables remained

in the model if the P value from its residual x2 test was !.05.

The 2-sided P value was reported. A separate model was also

used to assess factors associated with HUS in adults (age, 18

years). All statistical analyses were performed with SAS software, version 9.1 (SAS Institute).

RESULTS

Cases of STEC O157 infection. During 2000–2006, a total of

3464 culture-confirmed cases of STEC O157 infection were

ascertained. Of those, 1854 (54%) were in females. The median
1482 • CID 2009:49 (15 November) • Gould et al

Table 1. Incidence of Culture-Confirmed Shiga Toxin–Producing Escherichia coli O157 (STEC O157) Infection and Hemolytic Uremic

Syndrome (HUS), by Age Group and Foodborne Diseases Active Surveillance Network Site, 2000–2006

Site

Incidence, no. of cases per 100,000 persons, by age

!5 years 5–9 years 10–17 years 18–59 years 60 years All sites

STEC O157

(n p 851)

HUS

(n p 135)

STEC O157

(n p 519)

HUS

(n p 43)

STEC O157

(n p 563)

HUS

(n p 23)

STEC O157

(n p 1128)

HUS

(n p 13)

STEC O157

(n p 396)

HUS

(n p 15)

STEC O157

(n p 3464)

HUS

(n p 229)

California 5.42 0.83 4.02 0.22 1.88 0.00 0.36 0.00 0.72 0.03 1.12 0.07

Connecticut 3.73 1.00 3.38 0.25 2.86 0.07 0.57 0.01 1.13 0.07 1.31 0.10

Georgia 1.42 0.26 0.91 0.09 0.58 0.03 0.24 0.00 0.15 0.01 0.40 0.03

Maryland 1.85 0.35 1.30 0.13 0.70 0.00 0.29 0.00 0.22 0.04 0.50 0.04

Minnesota 11.12 1.36 6.40 0.46 4.10 0.14 1.85 0.02 2.39 0.09 3.13 0.17

New York 5.08 0.65 3.17 0.20 2.49 0.18 1.12 0.01 0.99 0.00 1.60 0.08

Oregon 11.53 1.45 5.82 0.43 3.42 0.11 1.45 0.02 1.85 0.00 2.66 0.14

Tennessee 4.40 0.88 2.01 0.28 1.09 0.03 0.48 0.00 0.71 0.06 0.95 0.09

Average 5.57 0.85 3.38 0.26 2.14 0.07 0.80 0.01 1.02 0.04 1.46 0.09

age of patients was 15 years: 25% were aged !5 years, 15%

were aged 5–9 years, 16% were aged 10–17 years, 32% were

aged 18–59 years, and 11% were aged 60 years. The average

incidence was 1.5 cases per 100,000 persons, but the incidence

of STEC O157 infection varied by site and age group (Table

1). In every site, the highest incidence was among children aged

!5 years, with a mean incidence in this group of 5.6 cases per

100,000 persons, ranging from 1.4 cases per 100,000 persons

in Georgia to 11.5 cases per 100,000 persons in Oregon. Among

children aged !5 years, the incidence was highest among children aged 1 year (6.9 cases per 100,000 persons) and lowest

among children aged !1 year (1.8 cases per 100,000 persons).

Of the 3464 persons with STEC O57 infection, 1449 (42%)

were hospitalized (36% of those aged !5 years, 38% of those

aged 5–9 years, 38% of those aged 10–17 years, 42% of those

aged 18–59 years, and 66% of those aged 60 years). Persons

aged !18 years were the least likely to be hospitalized (P p

.004) while persons aged 60 years old were most likely to be

hospitalized ( ). P ! .001

STEC O157 infections that resulted in HUS. Of the 3464

STEC O157 cases ascertained, 218 (6.3%) had HUS, including

159 confirmed and 59 probable cases. Persons with confirmed

or probable HUS were similar with respect to sex (61.0% and

67.8% female, respectively; ) and age (median 3 and 4 P p .36

years, respectively; ). In most sites, P p .61 !30% of cases were

classified as probable, with the exception of Minnesota and

Tennessee where 39.0% and 51.7%, respectively, were classified

as probable. Of the 217 HUS cases with information on mode

of ascertainment, 194 (89.4%) cases were ascertained through

active surveillance, 11 (5.1%) were ascertained through hospital

discharge data review only, and 12 (5.5%) were ascertained

through another means; confirmed and probable cases did not

differ with regards to mode of ascertainment. Confirmed and

probable cases were grouped for further analyses.

The proportion of patients with STEC O157 infection and

HUS varied by site, from 4.9% in New York to 9.4% in Tennessee. By age group, the percentage was 15.3% among patients

aged !5 years, 7.9% among those aged 5–9 years, 3.4% among

those aged 10–17 years, 1.2% among those aged 18–59 years,

and 3.8% among those aged 60 years (Figure 1). The incidence of HUS was 0.28 cases per 100,000 persons aged !18

years and 0.85 cases per 100,000 children aged !5 years. Among

children !5 years old, the incidence of HUS was highest in

children aged 1 year (1.24 cases per 100,000 children) and

lowest in children !1 year old (0.09 cases per 100,000 children).

The median age of patients who developed HUS was 4 years

(range, !1 to 87 years), compared with 16 years for those who

did not (range, !1 to 93 years; (Table 2). All patients P ! .001

with HUS were hospitalized, compared with 38% of patients

without HUS. The median length of hospitalization was 10

days (range, 1–85 days) for persons with HUS. Compared with

persons who did not develop HUS, those with HUS were younger, more likely to be female, more likely to be hospitalized,

had a longer length of hospital stay, and were more likely to

die (Table 2).

In multivariate analysis, age !5 years and female sex were

associated with an increased risk of HUS (odds ratio [OR],

5.37 [95% confidence interval {CI}, 4.04–7.14] and 1.70 [95%

CI, 1.27–2.27], respectively). State was also significant (P !

.01) and was treated as a confounder. When the multivariate

analysis was restricted to adults (age, 18 years), both age 60

years and female sex were associated with an increased risk of

HUS (OR, 3.18 [95% CI, 1.50–6.77] and 5.26 [95% CI, 1.58–

17.53], respectively).

An additional 157 HUS cases without culture confirmation

of STEC O157 infection were reported; three persons (1.9%)

died. Of these 157 cases, culture for STEC O157 was performed

for 135 (86%), but STEC O157 was not isolated. Serologic

testing was performed for 63 cases (40.1%); antibodies to STEC

O157 were identified in 23 (14.6%). Non-O157 STEC was isolated from 9 patients, and other pathogens were isolated from

8 patients. These patients without culture confirmation of STEC

O157 infection were less likely than those with culture confirmation to be female (53% vs 63%). The median age was 4
E. coli O157 infection and HUS • CID 2009:49 (15 November) • 1483

Figure 1. Proportion of patients with Shiga toxin–producing Escherichia coli O157 (STEC O157) infection with hemolytic uremic syndrome (HUS), by

age group, Foodborne Diseases Active Surveillance Network, 2000–2006.

years in both groups; all of the persons with HUS and without

culture confirmation of STEC O157 infection were children

aged !18 years.

STEC O157 infections that resulted in death. The outcome

was known for all persons with HUS and for 3103 (96%) of

the 3246 persons without HUS. The 137 persons with an unknown outcome did not differ demographically from the rest

of the patients. Twenty-one persons (0.6%) died (Table 3),

including 11 (0.4%) of the 3098 persons who did not have

HUS and 10 (4.6%) of the 218 persons with HUS. Deaths

among persons with HUS occurred a median of 11 days after

diarrhea began (range, 8–89 days); information on time to

death was not available for persons without HUS.

Of the persons without HUS, mortality was highest among

persons aged 60 years (1.9%). Among persons with HUS, the

proportion of persons aged 60 years who died (33.3%) was

11-fold higher than the proportion of children aged !5 years

who died (3.0%). More than one-half of STEC O157–infected

persons aged 60 years who died did not have HUS. The

proportion of persons aged 60 years who died increased with

age: 3 (1.6%) of 193 persons aged 60–69 years old died, 4 (3.4%)

of 118 persons aged 70–79 years died, and 5 (6.3%) of 79

persons aged 80 years died. Among children aged !5 years

with HUS, girls were more likely than boys to die (4.0% vs

1.9%), but this difference was not statistically significant. All

of the deaths among persons aged 60 years involved women:

5 (38.5%) of 13 women aged 60 years with HUS died, compared with none of 2 men aged 60 years with HUS.

DISCUSSION

In this population-based study of STEC O157 infection, we

found that young children and females had the highest risk of

HUS following STEC O157 infection. Elderly persons had the

highest rate of death associated with STEC O157 infection, with

or without HUS. These data support recommendations for

aggressive supportive care of young children and elderly persons

early during illness due to STEC O157.

To our knowledge, this is the first population-based study

of demographic risk factors associated with developing HUS

following STEC O157 infection conducted in the United States.

The strengths of this study are that it included patients with

both sporadic and outbreak-associated STEC O157 infections

and that both children and adults were included. Because

FoodNet provides a geographically diverse, active surveillance

network for both culture-confirmed STEC O157 infections and

clinically diagnosed HUS, this study provided an analysis of

demographic risk factors for HUS that exceeds the scope of

previous studies, most of which included only small sample

sizes, were conducted during outbreaks, or focused on children.

Children aged !5 years had the highest rates of HUS following STEC O157 infection, confirming findings of smaller

studies, most of which involved only children [2–4, 8–10]. This

study also found a statistically significant association between

female sex and the risk of developing HUS after STEC O157

infection. Although many studies have found no such association [4, 5, 10], we are aware of 3 other analyses in which

female patients were more likely than male patients to develop

HUS [8, 11, 12], although this was not confirmed by an extension of one of them [2]. Another study found that girls were

more likely than boys to develop hemolytic anemia [13].

The high risk of death among elderly individuals is consistent

with findings from previous studies [14, 15], but this is (to our

knowledge) the first study to compare the magnitude of this

risk across age groups. Persons aged 60 years were more likely

to be hospitalized than were those in any other age group, and

the proportion of persons aged 60 years with HUS who died
1484 • CID 2009:49 (15 November) • Gould et al

Table 2. Comparison of Patients with Shiga Toxin–Producing Escherichia coli O157 Infection With

and Without Hemolytic Uremic Syndrome (HUS)

Characteristic

Persons

with HUS

Persons

without HUS Pa

Age, median years (range) 4 (!1 to 87) 16 (!1 to 93) !.001

Age, !5 years 130/218 (59) 721/3239 (22) !.001

Female sex 137/218 (63) 1717/3240 (53) .002

Hospitalization 218/218 (100) 1238/3246 (38) !.001

Duration of hospitalization, median days (range) 10 (1–85) 3 (1–55) !.001

Death 10/218 (5) 11/3109 (0.4) !.001

NOTE. Data are no. of patients with characteristic/no. with data available (%), unless otherwise indicated.

a The Wilcoxon rank-sum test was used to test for differences in median age and duration of hospitalization between

persons with HUS and those without; the x2 test was used for the remaining variables.

Table 3. Characteristics of Persons with Shiga Toxin–Producing

Escherichia coli O157 Infection Who Died, by Age and Hemolytic

Uremic Syndrome (HUS) Status

Age group

No. of deaths/no. of persons (%)

Persons

with HUS

Persons

without HUS All

!5 years 4/130 (3.0) 2/678 (0.3) 6/808 (0.7)

5–9 years 1/41 (2.4) 0/450 (0.0) 1/491 (0.2)

10–17 years 0/19 (0.0) 1/525 (0.2) 1/544 (0.2)

18–59 years 0/13 (0.0) 1/1075 (0.1) 1/1088 (0.1)

160 years 5/15 (33.3) 7/375 (1.9) 12/390 (3.1)

Alla 10/218 (4.6) 11/3103 (0.4) 21/3321 (0.6)

a Information on age was not available for 6 persons without HUS.

was 10-fold higher than for all other age groups, providing

quantitative data on the excess risk of death in the elderly

population. More than one-half of deaths among persons aged

60 years were in those without HUS, underscoring the severity

of STEC O157 infection in this age group. Early hospitalization

and aggressive supportive care of elderly persons with this infection are essential.

Our finding that the incidence of STEC O157 infection differed by state has been noted before [16, 17]. The incidence

of HUS cases also varied by state; overall, the states with the

highest incidence of STEC O157 infection were those with the

highest incidence of HUS, and vice versa. In addition to differences in surveillance and case ascertainment methods among

FoodNet sites, STEC O157 infection appears to be more common in northern than southern US states [16]. Variations in

laboratory testing may also contribute to geographic differences, and many cases of STEC O157 infection may not be

detected. Cases of STEC O157 infection may be missed because

persons did not seek care, because they did not submit a stool

specimen, or because the clinical laboratory did not test the

stool specimen for STEC O157. In 2000, only 57% of clinical

laboratories in FoodNet sites routinely tested all stool specimens

for STEC O157, and the proportion varied by site [18]. It has

been estimated that 150% of the interstate variability in STEC

O157 incidence in the FoodNet sites can be accounted for by

differences in physician practices and laboratory culturing

practices [17].

Our finding that the rate of hospitalization increased with

age—in particular, that children aged !5 years were hospitalized

the least frequently—could be because milder cases were disproportionately ascertained in younger age groups. This could

occur if physicians are more likely to order STEC O157 tests

for children or if laboratories only routinely test for STEC O157

in children, resulting in a bias towards pediatric cases of STEC

O157 infection.

Variations in diagnosis of STEC O157 infections also result

in many cases of diarrhea-associated HUS being ascertained

without documentation of whether STEC O157 was responsible. Although most cases of diarrhea-associated HUS are due

to STEC O157 infection, typically only approximately twothirds are confirmed by culture [7]. Overall, ascertainment of

HUS cases is very good, because such patients are usually hospitalized; however, by the time a patient develops HUS, STEC

O157 organisms may no longer be shed in the stool, contributing to an underestimation of the number of STEC O157–

associated HUS cases. Serologic tests can help establish an etiology of STEC in persons with HUS [19]. Our finding of an

additional 157 cases of HUS without culture confirmation of

STEC O157, including 23 persons with serologic evidence of

STEC O157 infection, supports this finding. Because this analysis included only cases with culture confirmation of STEC

infection, we may have underestimated the proportion of persons with STEC O157 infection who developed HUS. In addition, 48 cases of STEC infection in persons with physiciandiagnosed postdiarrheal HUS did not meet our case definition

for definite or probable HUS, in some cases because of missing

information; some of these persons probably truly had HUS

(eg, 23 underwent dialysis).

We were unable to directly evaluate some putative predictors
E. coli O157 infection and HUS • CID 2009:49 (15 November) • 1485

of HUS, including antibiotic use, elevated leukocyte count, and

Shiga toxin profiles [20], because the surveillance system does

not collect these data. In addition, we could not review death

certificates to directly attribute the causes of each death. Deaths

that occurred outside the follow-up period would not have

been reported. Because the surveillance population included

only 15% of the US population in selected states, cases captured

by this system may not be representative of all cases of STEC

O157 infection or HUS in the United States [21]. Lastly, because

active surveillance was conducted only for pediatric cases, the

HUS surveillance system may have been more likely to detect

cases of HUS in children than adults.

More information is needed for physicians to better predict

the risk of HUS and death among persons with STEC O157

infection, especially among persons at the extremes of age. These

data from FoodNet surveillance provide important evidence that

early and aggressive supportive care is needed to prevent HUS

and death in young children and elderly persons with STEC O157

infection. Health care providers should have a low threshold for

aggressive oversight of patients in these high-risk groups. To

diagnose STEC infection, all stool specimens submitted for diagnosis of acute community-acquired diarrhea (Salmonella, Shigella, and Campylobacter species) should be cultured for O157

STEC on selective and differential agar and assayed for non–

O157 STEC with tests that detects the Shiga toxins. Clinical

laboratories should promptly report positive findings for STEC

to the physician and to public health authorities [22].

Acknowledgments

We thank Olga Henao, Liane Ong, Elaine Scallan, and Frederick Angulo

for helpful comments on the manuscript. We thank Xin Tong and Alison

Drake for analytical support. We also thank the Emerging Infections Program surveillance officers and the participating local and state health departments and laboratories. None of these individuals received compensation for this study.

Financial support. The Centers for Disease Control and Prevention,

the United States Department of Agriculture, and the United States Food

and Drug Administration. The findings and conclusions in this report are

those of the authors and do not necessarily represent those of the funding

agencies.

Potential conflicts of interest. All authors: no conflicts.

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