THE WALKERTON HEALTH STUDY 

2002-2008 

Final Report 

Submitted to the 

Ontario Ministry of Health 

and Long-Term Care 

Prepared by 

William F. Clark MD1, Jennifer J. Macnab PhD2, Jessica M. 

Sontrop PhD2

 on behalf of the WEL Investigators of the 

Walkerton Health Study

1. Division of Nephrology, Department of Medicine, University of Western 

Ontario, London, Ontario, Canada. 

2. Department of Epidemiology & Biostatistics, University of Western Ontario, 

London, Ontario, Canada. 

 
 ii

The Walkerton E. Coli Long-term (WEL) Investigators of 

the Walkerton Health Study 

Dr. W. Clark 

 Dr. A. Garg 

 Dr. J. Howard 

 Dr. D. Matsell 

 Dr. L. Moist 

 Dr. M. Salvadori 

 Dr. R. Suri 

In collaboration with: Research Consultants: 

Dr. S. Collins Dr. J. Garland 

 Dr. J. Marshall Dr. J. Macnab 

 Dr. J. Mahon 

Research Assistants: Dr. J. Parr 

 Salina Chen Dr. J. Pope 

 Gina Garofeanu Dr. J. Ray 

 Dr. Patricia Rosas-Arellano Dr. J. Sontrop 

 Marroon Thabane 

Clinic Coordinator: Staff of Walkerton Health Study: 

 Arlene Richards Sheryl Campbell 

 Lisa Findlay 

Administration: Kathleen Keeshan 

 Shawn Leinweber-Miller Peter Richards 
 iii

© The Walkerton Health Study, London Health Sciences Centre, 2008 

Suggested Citation: The Walkerton Health Study 2002-2008 Final Report 

London, Ontario. 

Authors: William F. Clark, Jennifer J. Macnab, Jessica M. Sontrop, on behalf of the WEL 

Investigators of the Walkerton Health Study 

All rights reserved. No part of this document may be reproduced without permission 

from the authors. 

Produced for: The Ontario Ministry of Health and Long-Term Care 

This report is available from: http://www.lhrionhealth.ca/feature/Walkerton.pdf
 iv

TABLE OF CONTENTS 

LIST OF FIGURES........................................................................................................................ VII

EXECUTIVE SUMMARY ..................................................................................................1

BACKGROUND............................................................................................................................................. 1

METHODS ................................................................................................................................................... 1

RESULTS ..................................................................................................................................................... 1

Sample Description................................................................................................................................ 1

Self-Reported Health Outcomes............................................................................................................. 2

Impact Of Surveillance On Blood Pressure Control In The Walkerton Health Study ........................... 2

Clinical Care ......................................................................................................................................... 2

LONG-TERM HEALTH SEQUELAE FOLLOWING EXPOSURE TO WATER CONTAMINATED WITH E. COLI

O157:H7 AND CAMPYLOBACTER................................................................................................................ 3

DISSEMINATION OF RESULTS ...................................................................................................................... 5

BACKGROUND:...............................................................................................................6

OPERATIONS ..................................................................................................................6

WALKERTON SCREENING CLINIC................................................................................................................ 6

OPERATIONS AND RESEARCH COMMITTEE ................................................................................................. 7

METHODS ........................................................................................................................7

STUDY DESIGN AND COHORT DEFINITION .................................................................................................. 7

DATA COLLECTION..................................................................................................................................... 7

WEB-BASED DATA CAPTURE AND PATIENT MANAGEMENT SYSTEM ......................................................... 9

RESULTS ....................................................................................................................................................... 9

SAMPLE DESCRIPTION ................................................................................................................................ 9

SELF REPORTED HEALTH OUTCOMES ....................................................................................................... 13

IMPACT OF SURVEILLANCE ON BLOOD PRESSURE CONTROL IN THE WHS ............................................... 17

FLUID INTAKE AND WATER CONSUMPTION .............................................................................................. 18

CLINICAL CARE ............................................................................................................19

KIDNEY DISEASE - ADULT ........................................................................................................................ 20

KIDNEY DISEASE - PAEDIATRIC ................................................................................................................ 20

GASTROINTESTINAL DISEASE ................................................................................................................... 21

DIABETES.................................................................................................................................................. 21

RHEUMATOLOGY ...................................................................................................................................... 21

COUNSELING............................................................................................................................................. 21

INVESTIGATION OF HIGH VOLUME PROTEINURIA ..................................................................................... 22

RESEARCH INITIATIVES FROM THE WALKERTON HEALTH STUDY .....................22

THE RISK OF LONG-TERM RENAL DISEASE AFTER DIARRHEA-ASSOCIATED HAEMOLYTIC UREMIC 

SYNDROME ............................................................................................................................................... 22

Long-Term Renal Prognosis Of Diarrhea-Associated Haemolytic Uremic Syndrome: A Systematic 

Review, Meta-Analysis, And Meta-Regression .................................................................................... 22

An Outbreak Of Diarrhea-Associated Childhood Haemolytic Uremic Syndrome: The Walkerton 

Epidemic. ............................................................................................................................................. 23

Renal Sequelae After Childhood Escherichia Coli O157 Haemolytic Uremic Syndrome ................... 24

Future Research Projects Related To Long-Term Renal Disease After Diarrhea-Associated 

Haemolytic Uremic Syndrome............................................................................................................. 26

THE RISK OF LONG-TERM RENAL DISEASE AFTER ACUTE GASTROENTERITIS ......................................... 26
 v

Risk Of Hypertension And Reduced Kidney Function After Acute Gastroenteritis From BacteriaContaminated Drinking Water............................................................................................................. 26

Renal Sequelae After Childhood Escherichia Coli O157 Gastroenteritis ........................................... 28

Future Research Projects On The Risk Of Long-Term Renal Disease After Acute Gastroenteritis .... 29

THE RISK OF DIABETES MELLITUS AFTER EXPOSURE TO E. COLI O157:H7 .............................................. 30

Diabetes During Diarrhea-Associated Haemolytic Uremic Syndrome: A Systematic Review And 

Meta-Analysis ...................................................................................................................................... 30

The Risk Of Diabetes Mellitus After Exposure To E. coli O157:H7.................................................... 30

THE EFFECTS OF WATER CONTAMINATION ON PREGNANCY .................................................................... 32

The Risk Of Pregnancy-Related Hypertension After Exposure To Contaminated Water .................... 32

THE RISK OF REACTIVE ARTHRITIS AFTER ACUTE GASTROENTERITIS...................................................... 33

Campylobacter Reactive Arthritis: A Systematic Review .................................................................... 33

Risk Of Arthritis After Acute Bacterial Gastroenteritis ....................................................................... 34

PATHOPHYSIOLOGY AND CLINICAL EXPRESSION OF POST-INFECTIOUS IRRITABLE BOWEL SYNDROME... 35

Epidemiology Of Post-Infectious Irritable Bowel Syndrome............................................................... 35

Intestinal Permeability In Irritable Bowel Syndrome .......................................................................... 37

Genetic Risk Factors For Post-Infectious IBS In The Walkerton Outbreak Of Waterborne 

Gastroenteritis ..................................................................................................................................... 38

Future Research Projects Related To Irritable Bowel Syndrome (IBS) And Inflammatory Bowel 

Disease (IBD) ...................................................................................................................................... 38

CHARACTERIZATION OF A NOVEL FINDING OF HIGH VOLUME PROTEINURIA AFTER THE WALKERTON E.

COLI O157:H7 MUNICIPAL WATER CONTAMINATION ................................................................................ 39

Causes Of Reversible Nephrogenic Diabetes Insipidus: A Systematic Review.................................... 39

Excessive Fluid Intake As A Novel Cause Of Proteinuria ................................................................... 40

Future Research Related to High Volume Proteinuria........................................................................ 41

THROMBOTIC THROMBOCYTOPENIC PURPURA/ HAEMOLYTIC UREMIC SYNDROME (TTP/HUS): DEFINITION 

AND PROGNOSIS........................................................................................................................................ 43

TTP/HUS And Prognosis: The Syndrome And The Disease................................................................ 43

Treating TTP/HUS With Plasma Exchange: A Single Centre’s 25-Year Experience.......................... 43

MEASUREMENT AND METHODOLOGICAL CHALLENGES IN OBSERVATIONAL RESEARCH ......................... 44

Representativeness And Selection Bias................................................................................................ 44

Recall Bias And The Accuracy Of Self-Report Data............................................................................ 45

Screening And Validation Of Laboratory Data ................................................................................... 47

Measurement, Validation, And Interpretation Of Blood Pressure Data.............................................. 47

The Walkerton Health Study................................................................................................................ 49

TTP/HUS: Observational Studies Generate Hypotheses That Lead To Randomized Controlled Trials

............................................................................................................................................................. 49

Future Research Projects Related To Measurement And Methodological Challenges In Observational 

Research .............................................................................................................................................. 50

POPULATION HEALTH ............................................................................................................................... 50

Elevated Blood Pressure In Relation To Overweight And Obesity Among Children In A Rural 

Canadian Community .......................................................................................................................... 50

Factors that Led to the Walkerton Tragedy......................................................................................... 51

Environmental Prevention Of Human Disease From Verocytotoxin-Producing Escherichia Coli..... 52

Local Water Diversely Known: Walkerton, Ontario 2000 And After .................................................. 53

Future Research Projects Related To Population Health.................................................................... 53

SUMMARY OF RESEARCH ACCOMPLISHMENTS.....................................................53

DISSEMINATION OF RESULTS....................................................................................57

DISCUSSION AND COMMENTARY..............................................................................58

APPENDIX I: DISSEMINATION OF RESULTS AND EFFORTS TO ENCOURAGING 

RETENTION AND RECRUITMENT IN THE WHS .........................................................60

EFFORTS TO ENCOURAGE RECRUITMENT AND RETENTION....................................................................... 60
 vi

NEWSPAPER ARTICLES CONTAINING LAY-DESCRIPTIONS OF WHS RESEARCH FOCI AND MEDICAL 

CONDITIONS RELATED TO THE WALKERTON WATER CONTAMINATION OUTBREAK ................................ 66

APPENDIX II HUS/TTP UPDATE 2008 SYMPOSIUM..................................................76
 vii

LIST OF FIGURES 

Figure 1. Age and sex standardized rates of long-term health sequelae following 

exposure to water contaminated with E. coli O157:H7 and Campylobacter. ............4

Figure 2. Rate of microalbuminuria among childhood survivors of haemolytic uremic 

syndrome (HUS). ......................................................................................................4

Figure 3. Study design and data collection in the Walkerton Health Study.......................8

Figure 4. Study flow chart. ..............................................................................................10

Figure 5. Total number of follow-up assessments. .........................................................11

Figure 6. Years followed from study entry to study exit. .................................................11

Figure 7. Age distribution of study participants relative to the age distribution of the town 

of Walkerton and Brockton Township......................................................................12

Figure 8. Age distribution of WHS participants at time of outbreak: Males versus 

Females. .................................................................................................................12

Figure 9. Self-reported illness at the time of the outbreak in May 2000..........................13

Figure 10. Self-reported health status at last assessment..............................................14

Figure 11. Health compared to last year at last assessment. .........................................15

Figure 12. Self-reported health outcomes.......................................................................16

Figure 13. Prevalence and control of hypertension among WHS participants (Adults, 

18+).........................................................................................................................17

Figure 14. Rate of hypertension control among hypertensive participants. ....................18

Figure 15. Participant beliefs about water consumption and bottled water.....................19

Figure 16. Specialty Visits, 2002 - 2008..........................................................................20

Figure 17. Rate of microalbuminuria among childhood survivors of haemolytic uremic 

syndrome (HUS). ....................................................................................................26

Figure 18. Age and sex-standardized rates of newly diagnosed hypertension 3.7 years 

after an outbreak of acute gastroenteritis from bacteria contaminated drinking water 

(n=1958)..................................................................................................................28

Figure 19. Mean arterial pressure during pregnancy 5 years after an outbreak of acute 

gastroenteritis from bacteria-contaminated drinking water (n=135). .......................33

Figure 20. Age and sex-standardized rates of newly diagnosed arthritis 4.5 years after 

an outbreak of gastroenteritis from bacteria-contaminated drinking water (n=2299).

................................................................................................................................35

Figure 21. Rate of newly diagnosed Rome I Irritable Bowel Syndrome (IBS) 2-3 years 

after acute gastroenteritis from exposure to contaminated drinking water (n=2069).

................................................................................................................................36

Figure 22. Correlation between 24-hr urine volume (L) and 24-hr urine protein (g)........42

Figure 23. Adjusted odds for pre-hypertension and hypertension from overweight and 

obesity in pediatric participants of the Walkerton Health Study (adjusted for family 

history of hypertension and kidney disease) (n=675)..............................................51
 1

EXECUTIVE SUMMARY 

BACKGROUND

In May of 2000 many of the current WEL (Walkerton E. coli Long-Term) Investigators 

were busy treating children and adults severely ill as a result of the contamination of the 

municipal water supply of a small Ontario rural community called Walkerton. The 

explosive onset and magnitude of involvement (almost 50% of the community) focused 

acute medical care predominantly on severely afflicted children and adults. Previous 

biological and observational studies had suggested that survivors of E. coli O157:H7and 

campylobacter gastroenteritis may have poor long term health outcomes, regardless of 

whether they initially experienced overt severe clinical symptoms culminating in 

haemolytic uremic syndrome (HUS). This concern about a significant unrecognized longterm burden of illness secondary to the bacterial water contamination stimulated a small 

group of physicians (original WEL Investigators) to develop a simple screening program 

to identify silent complications of the water contamination. They then arranged a meeting 

with Walkerton area physicians. The meeting escalated from an informal exchange of 

screening advice to a formal presentation, attended by more than 120 municipal leaders, 

concerned citizens, physicians and allied health workers. The WEL Investigators were 

strongly encouraged by these representatives to go back to the drafting boards for a new 

proposal with a more complete long-term screening program, embracing direct health 

care interventions and epidemiologic research. The advice led to a formal submission to 

the Ontario Ministry of Health requesting support for a seven-year prospective 

longitudinal study to characterize and manage the long-term medical complications from 

the water contamination in Walkerton Ontario in May 2000. The Ministry of Health and 

Long-Term Care, after reviewing a detailed proposal, agreed to fund what is now the 

Walkerton Health Study. The proposal incorporated a union of clinical practice and 

research to: 

a) characterize the long-term burden of illness attributable to the water 

contamination by a serial, active screening process, 

b) to co-ordinate health services by identification and referral of individuals at risk 

for complications for more complete investigation and treatment in order to 

reduce and prevent long term medical complications. 

METHODS

The study was a retrospective population-based cohort study with prospective follow-up. 

Beginning in 2002 we invited all residents of Walkerton and the surrounding areas, 

regardless of whether or not they drank the water, to participate in the long term followup by attending an annual clinic. The screening clinic operated from March to August of 

every year. Off-site clinics were offered at the Nursing Home, Retirement Home and 

local high schools. Specialty clinics operated from May to August of every year, allowing 

participants immediate access to care provided by nephrologists, paediatricians, 

gastroenterologists, endocrinologists, and rheumatologists. 

RESULTS

Sample Description

Between March 2002 and August 2008 4,561 residents of Walkerton and the 

surrounding area participated in the study. The age and sex distribution of the 
 2

participants was characteristic of the population of Walkerton at the time of the outbreak. 

Most participants (70%) were from the immediate Walkerton area defined by the postal 

code of N0G 2V0. Although the majority (98%) reported drinking Walkerton tap water at 

the time of the outbreak, only 65% experienced any illness as a result. The symptoms 

ranged from mild stomach upset (5%) to more severe gastroenteritis with bloody 

diarrhea. Participants attended an average of 5 follow-up assessments with an average 

of 6 years between their first and last assessment. 

Self-Reported Health Outcomes

Beginning in 2004, participants were asked to rate their overall health status in general 

and compared to the previous year. Of 3,763 participants who had an opportunity to 

respond to this question, 85% reported being in good to excellent health at their last 

assessment and 83% reported their health being stable or better than last year. Chronic 

gastrointestinal complaints were common, with 28% of participants complaining of 

regular problems with abdominal pain or discomfort, constipation, or diarrhea on average 

4 or more days a month at their last assessment. The percent of participants with 

gastrointestinal complaints decreased from 47% in the first year of screening to 27% in 

year 7. In response to concerns about irritable bowel syndrome, a booklet, authored by 

Dr. John Howard, was distributed to over 1,200 participants, and was made available in 

doctors’ offices and the public library. In addition, over 1,000 participants, as well as 

their family members, were invited to attend group information sessions designed to help 

individuals cope with the symptoms of irritable bowel syndrome. These sessions were 

also advertised locally and open to the public free of charge. Those with more serious 

complaints were seen individually by a gastroenterologist. The incidence of other selfreported health outcomes was within expected limits. The association of acute 

gastroenteritis with subsequent hypertension, diabetes, and/or arthritis was examined in 

more detail as part of specific research protocols. 

Impact Of Surveillance On Blood Pressure Control In The Walkerton Health Study

A trend towards improved detection and treatment of hypertension was observed over 

the course of the WHS. In the first year of screening, the proportion of hypertensive 

participants with controlled blood pressure was only 9%. After four years of screening, 

the control rate stabilized to approximately 50%. The prevalence of hypertension among 

all adult participants increased from 27% in 2002 to 42% in 2008, largely the result of 

surveillance. During this time, the proportion of participants who achieved successful 

control of their blood pressure increased from 3% to 22%. 

Clinical Care

At the completion of the study in August, 2008, 3,219 referrals had been made for 2,244 

participants to specialist assessment or follow-up laboratory investigation. Over the 

course of the study, 1190 referrals were made for possible kidney disease (based on 

elevated blood pressure, serum creatinine or proteinuria) among 464 adult patients; 437 

were seen by a nephrologist at least once. Of 252 children identified with possible 

kidney disease, 97% were seen by a nephrologist or are awaiting an appointment. 

Gastroenterologist consults were offered to 538 participants, and 523 were seen in 

clinic. Dysglycemia was identified in 783 participants and 610 agreed to further testing. 

Specialty clinics were established to provide follow-up and counseling to newly identified 

diabetics. Participants referred for possible reactive arthritis were invited to an 

assessment by a rheumatologist. 
 3

LONG-TERM HEALTH SEQUELAE FOLLOWING EXPOSURE TO WATER CONTAMINATED 

WITH E. COLI O157:H7 AND CAMPYLOBACTER

Research suggests that survivors of severe E. coli O157:H7 infection and 

Campylobacter gastroenteritis have poorer long-term health regardless of whether they 

initially experienced overt Haemolytic uremic syndrome. The WHS provided a unique 

and rare opportunity to characterize new and existing epidemiological associations 

between acute gastroenteritis and chronic diseases. 

Diseases studied included renal disease (hypertension, albuminuria, and glomerular 

filtration rate), diabetes, irritable bowel syndrome (IBS), and reactive arthritis. Long-term 

renal sequelae were evaluated separately for children and adults. 

A summary of the long-term health sequelae among adults is presented in Figure 1. 

Within 2 years of the outbreak, a more than three-fold increase in the risk of developing 

IBS was observed among Walkerton residents who experienced bacterial gastroenteritis 

during the outbreak. Within 4 years of the outbreak, a 33% increase in the risk of 

developing hypertension and a 38% increase in the risk of developing reactive arthritis 

was seen among those with symptoms of severe gastroenteritis as compared to those 

who were not ill at the time of the outbreak. A similar graded association was seen for 

reduced kidney function. No associations were observed between gastroenteritis and the 

subsequent risk of albuminuria or dysglycemia (diabetes mellitus, impaired glucose 

tolerance or impaired fasting glucose). Among women who became pregnant after the 

outbreak, higher mean arterial pressure and pregnancy-related hypertension were 

observed among women who reported symptoms of gastroenteritis compared to those 

who were asymptomatic; however, the observed differences were not statistically 

significant, possibly due to the small sample size. 

No renal sequelae were observed among children within 4 years of experiencing 

gastroenteritis without Haemolytic uremic syndrome (HUS) during the outbreak. Despite 

the absence of evidence of renal damage in this group of children, most progressive 

renal disease involves a protracted time course; therefore a longer follow-up of this is 

planned to clarify the risk of nephropathy after childhood E. coli O157 bacterial 

gastroenteritis. 

Childhood survivors of HUS were more likely to show microalbuminuria (Figure 2) and 

lower glomerular filtration rate (GFR) than healthy controls; however, the prognosis of 

these cases was better than reported in previous research. None of the HUS survivors 

in the WHS cohort had overt proteinuria or GFR less than 80 ml/min, and their blood 

pressure was no higher than expected for community norms. 
 4

Figure 1. Age and sex standardized rates of long-term health sequelae following 

exposure to water contaminated with E. coli O157:H7 and Campylobacter. 

11 12 11

16

18

22

17

23

10

28

36

27

32

36

0

5

10

15

20

25

30

35

40

None Moderate Severe

Gastroenteritis Exposure Gradient

Percent with condition

Dysglycemia

Arthritis

PRH*

IBS**

Hypertension

*Pregnancy-related hypertension. **Irritable bowel syndrome. 

 

Figure 2. Rate of microalbuminuria among childhood survivors of haemolytic uremic 

syndrome (HUS). 

5%

32%

3%

20%

0%

5%

10%

15%

20%

25%

30%

35%

Percent with 

microalbuminuria

3-yrs 5-yrs

Time since the outbreak

Healthy controls

HUS survivors
 5

DISSEMINATION OF RESULTS

An important goal of the Walkerton Health Study was to disseminate research findings to 

a wide audience that included both the Walkerton community and the research 

community. Dissemination of results to the Walkerton community was primarily 

accomplished through newspaper articles and Town Hall meetings, which were held 

annually in Walkerton. During Town Hall meetings, WEL investigators presented results 

from the previous year, highlighted any new initiatives for the upcoming year and 

answered questions from the public. Participants also received an annual summary 

report, and highlights of the previous year’s findings were reported in the Walkerton 

Herald Times. 

Dissemination of results to the research community occurred primarily through 

publications in peer reviewed scientific journals and presentations at conferences. In 

addition, highlights from the study were shared with the medical community at a special 

symposium in 2008 that focused on thrombotic thrombocytopenic purpura / haemolytic 

uremic syndrome (HUS/TTP). The purpose of the HUS/TTP symposium was to present 

findings on the long-term outcomes following exposure to E. coli O157:H7. A half-day 

session was reserved for the presentation of results from the Walkerton Health Study. 
 6

BACKGROUND: 

The most serious case of water contamination in recent Canadian history occurred in 

May of 2000, when the municipal water of Walkerton, Ontario was contaminated with E. 

coli O157:H7, campylobacter species and salmonella. Heavy rainfall contributed to the 

transport of livestock fecal contaminants from a nearby farm into a shallow municipal 

well. Inadequate chlorination resulted in the bacterial contamination of the Walkerton 

drinking water system and the inevitable exposure of thousands of individuals from 

Walkerton and the surrounding areas by means of primary or secondary contact. The 

result was an estimated excess of 2,300 cases of gastrointestinal illness, more than 750 

emergency room visits, 65 hospital admissions, 27 recognized cases of haemolytic 

uremic syndrome (HUS), and seven deaths. During the catastrophe, initial medical care 

focused on the acute management of infected individuals. Due to the intense load on 

the health care system, children were encouraged to seek medical care; whereas, adults 

were not. However, previous biological and observational studies suggest that survivors 

of campylobacter gastroenteritis and severe E. coli O157:H7 infection may have poorer 

long-term heath, regardless of whether they initially experienced overt haemolytic uremic 

syndrome. The Walkerton Health Study (WHS) was funded by the Ontario Ministry of 

Health and Long-Term Care to direct attention towards the potential, significant, 

unrecognized, long term burden of illness from complications caused by the initial 

infection. The screening program was established not only to monitor asymptomatic, 

silent disease, but also to provide access to care for patients who were symptomatic and 

had complications related to E. coli O157:H7 or campylobacter species or a combination 

of both. In this way the WHS incorporated an effective union of clinical practice and 

research to meet both the needs of the community and provide a unique opportunity to 

characterize the association between acute bacterial gastroenteritis and chronic 

diseases, including arthritis, hypertension, renal disease, diabetes, post-infectious 

irritable bowel syndrome, and inflammatory bowel disease. 

OPERATIONS 

The Walkerton Health Study was a collaborative effort of an experienced team of 

researchers and clinicians who were involved in the initial response and care of the 

community at the time of the outbreak in 2000. The WEL Investigators, consisting of Dr. 

W. Clark, Dr. A, Garg, Dr. Howard, Dr. Matsell, Dr. L. Moist, Dr. M. Salvadori and Dr. R. 

Suri in collaboration with Dr. S. Collins and Dr. J. Marshall brought with them expertise in 

Nephrology, Paediatrics, and Gastroenterology. Additional expertise was provided by 

research consultants in Nephrology (Dr. J. Garland), Epidemiology (Dr. J. Macnab & Dr. 

J. Sontrop), Endocrinology (Dr. J. Mahon), Geography (Dr. Joy Parr), Rheumatology (Dr. 

J. Pope), and Neurology, (Dr. J. Ray). Support staff over the years included Project 

Administrators (Ms. Ruby Gordon, Ms. Jennifer Dunn & currently, Ms. Shawn 

Leinweber-Miller), a Systematic Review Analyst (Dr. P. Rosas-Arellano), and research 

assistants (Ms. Marroon Thabane, Dr. Gina Garofeanu and Ms. Salina Chen). 

WALKERTON SCREENING CLINIC

The Walkerton Health Study Clinic was located in the South Bruce Grey Health Centre in 

Walkerton, Ontario and was managed by an on site Nurse Coordinator (Mrs. Arlene 

Richards). The clinic employed additional Clinical Care Assistants (most recently - Mrs. 

Lisa Finlay and Mr. Peter Richards) and clerical personnel (most recently - Mrs. Sheryl 

Campbell and Mrs. Kathleen Keeshan). The Nurse Coordinator and Clinical Care 

Assistants performed height, weight and blood pressure measurements as well as 
 7

conducting an annual health interview. Clerical personnel were involved in appointment 

scheduling, patient follow-up, data entry, and quality control procedures. Specialty 

clinics, staffed by a nephrologist, paediatrician, gastroenterologist, endocrinologist, 

rheumatologist, and/or neurologist were operated every summer from May to August for 

patients in need of further assessment or care. 

OPERATIONS AND RESEARCH COMMITTEE

The Operations Committee and the Research Committees chaired by Dr. W.F. Clark 

served to oversee the conduct of all aspects of the study. The operations committee met 

monthly and was open to WEL investigators, clinic staff, and representatives from the 

Ministry of Health. The research committee provided a forum to guide the development 

of a number of relevant and collaborative research foci, in the context of the Walkerton 

E. coli outbreak, yet distinct from the clinical responsibilities of the group. Evidence for all 

research was supported by preliminary reviews, conducted by our systematic review 

analyst, Dr. P. Rosas-Arellano and more latterly by Ms. Salina Chen and Dr. Jessica 

Sontrop. 

METHODS 

STUDY DESIGN AND COHORT DEFINITION

The Walkerton Health Study was a retrospective population-based cohort study with 

prospective follow-up. Beginning in 2002 we invited all residents of Walkerton and the 

surrounding areas, regardless of whether or not they drank the water, to participate in 

the long-term follow-up by attending an annual clinic. The majority of participants joined 

the study in 2002; however, new participants were allowed to enter the study each year 

to ensure that no one missed the opportunity for screening and/or clinical care. On an 

annual basis, an extensive advertising campaign was mounted in the local newspapers, 

radio, and Cable TV. Posters were displayed in hospitals, physician offices, pharmacies, 

the library and other strategic locations around town additionally flyers were inserted into 

all of the town’s post office boxes. Interviews were conducted with both the local and 

national media. Yearly, we presented the findings to the people of Walkerton at a Town 

Hall meeting and a summary letter was sent to each participant. In addition, in 2003, a 

telephone campaign was conducted to encourage participation among residents of the 

NOG 2V0 postal code by contacting 1,147 non-participating households. The screening 

clinic operated from March to August of every year and provided evening and Saturday 

appointments in addition to regular workday hours. Off-site clinics were offered at the 

Nursing Home, Retirement Home and local high schools. The reception staff personally 

contacted all participating households, so that direct contact could be made to book 

appointments. Reminder calls were made the day before all clinics and no-shows were 

diligently followed-up. Individuals who moved away from the area were able to complete 

the screening survey by telephone and have their laboratory testing and other 

measurements completed through their family physician. The WHS enrolled participants 

from as far away as Newfoundland, Manitoba, Saskatchewan, North West Territories 

and the United States. A modest honourarium was offered to all participants who 

attended the screening clinic to offset their costs for lost time. 

DATA COLLECTION

To assist in the identification of pre-existing disease and to collect evidence of level of 

exposure, consent was obtained from 98% of participants for an audit of laboratory data 
 8

and medical charts. Participant information was linked to information collected at the 

time of the outbreak by means of name, date of birth, telephone and/or address. 

Participant information was linked to laboratory data collected through the Triple G 

system servicing the Walkerton area from 1990-2002 by means of the hospital 

identification number. 

All data was collected using computer assisted personal interviews (CAPI). Upon entry 

to the study all participants completed a series of baseline questions that documented 

their demographic information, exposure and illness at the time of the outbreak, previous 

medical history, family history, and risk factors. In subsequent years participants were 

asked to report on their general overall health, gastrointestinal complaints, and any 

health conditions diagnosed by a health professional; including diabetes, hypertension, 

cardiovascular disease, inflammatory bowel disease, cancer, arthritis, and gallstones. 

The development of questions on the health survey was guided by the US Third National 

Health and Nutrition Survey and Statistics Canada’s National Population Health Survey. 

All participants were requested to complete a random urinalysis, serum creatinine, 

random glucose, and 24 hour urine collection upon entry to the study. A serum 

creatinine and random urinalysis was ordered annually. Additional testing varied by 

study year, so as not to place too high a burden upon the participants, and included 

fasting serum glucose, oral glucose tolerance testing (when indicated), and repeat 24 

hour urine collection. In the final year a more definitive test of renal function, Cystatin C, 

was added to the laboratory protocol. This measure will be used to obtain a more 

accurate assessment of the estimated glomerular filtration rate (GFR). 

Figure 3. Study design and data collection in the Walkerton Health Study 

Laboratory Audit

(1990 – 2000)

Outbreak Case Listing File and 

cross sectional survey 

(2000)

Stool Culture Audit 

(2000)

Medical Chart Audit

Previous history 

Exposure

Consent 

(2002-2007)

Baseline Questionnaire

Previous Health 

Family History 

Risk Factors 

Exposure

Screening Survey

General Health 

Diabetes 

Hypertension 

Cardiovascular 

Gastrointestinal 

Cancer 

Arthritis 

Gallstones

Physical Exam

Height, Weight 

Blood Pressure X 3

Laboratory Protocol

Random Urinalysis 

Serum Creatinine 

(Fasting Glucose) 

(Oral Glucose Tolerance) 

(24 Hr Urine) 

(Cystatin C)

Baseline Labs:

Random Urinalysis 

Random Glucose 

Serum Creatinine 

24 Hr Urine for protein

Study Entry

Data Collection 
 9

WEB-BASED DATA CAPTURE AND PATIENT MANAGEMENT SYSTEM

PrivIT Healthcare, previously know as Medix Technologies, supported the development 

and ongoing maintenance of our web-based data capture and electronic medical record 

system. The production database was housed on a server located in the Walkerton 

Hospital. Only clinic staff had access to this server. An export server, test server and 

backup server were housed in a secure data centre located in the Stiller Centre, at the 

University of Western Ontario (UWO) Research Park. Working closely with the 

Privacy/Ethics Review Boards recommendations, PrivIT Healthcare supports scientists 

and researchers to store, manage and preserve their data to ensure their enhancement 

and their continuing long-term use. Password protection and data encryption are used to 

ensure the privacy of the electronic patient medical record. In 2003 an interface with the 

Triple G laboratory system was developed to batch import lab results directly from Triple 

G into our database. In 2007, a new real-time interface with the CERNER system at the 

South Bruce Grey Health Centre was implemented to allow for the direct transfer of 

laboratory data. Laboratory data collected outside of the CERNER system were entered 

by hand into the database by means of the manual laboratory data interface. The 

system included automated queries that facilitated clinic operations by automatic 

monitoring of clinical care pathways. Medical records were electronically tracked and 

clinic staff was alerted of any missing laboratory or form data. Data validation 

procedures, implemented at the time of data entry, minimized the time required for data 

cleaning prior to analysis and ensured the highest standards of quality for clinic 

operations. The system facilitated research operations by allowing for the easy 

generation of flat tables appropriate for data analysis. Personal identifiers are removed 

prior to exporting data for analytical purposes. At the completion of the study we will be 

able to generate an electronic Health Report that will be shared with both the 

participants and the community physicians. By March 2009, all hard copies of clinical 

records will have been scanned and stored as electronic documents; paper records will 

be destroyed. The web site will be disassembled with all data stored in electronic 

annonymized flat tables. For patients who have consented to long-term data linkage, 

numeric identifiers will be stored in a separate linkage file. All data will be stored on a 

secure server at the Lawson Health Research Institute. All data will be destroyed after 

the period of consent has expired. 

RESULTS 

SAMPLE DESCRIPTION

At the conclusion of the study in August 2008, 4,561 participants had registered in the 

Walkerton Health Study. Figure 4 shows study accrual over the past seven years. 

Annual attendance figures ranged from a high of 3,959 in year 1 to a low of 2,432 in year 

6. New participants were welcome to enter the study every year; 602 new participants 

joined the study after the first year. Each year, about 7% of participants were either lost 

to follow-up, died, or withdrew from the study. In total, 21% withdrew before completing 

the year 7 survey, 23% were lost to follow up, and 3% died. On average, participants 

attended 70% of all follow-up assessments. 
 10

Figure 4. Study flow chart. 

REGISTER SCREEN TERMINATE

2002 3959 3959

519

98 Lost to follow up 

388 Withdrawn 

33 Deaths 

2003 356 3373

2004 181 3462

STUDY YEAR

2005 23 3161 331

139 Loss to follow up 

163 Withdrawn 

29 Deaths 

2006 18 2739 360

154 Lost to follow up 

187 Withdrawn 

19 Deaths 

REGISTER SCREEN TERMINATE

2002 3959 3959

2003 356 3373

2004 182 3462

STUDY YEAR

2005 22 3161

2006 18 2739

2007 13 2432 349

259 Lost to follow up 

70 Withdrawn 

20 Deaths 

277

66 Lost to follow up 

192 Withdrawn 

19 Deaths 

2008 11 2453 274

232 Lost to follow up 

32 Withdrawn 

10 Deaths 
 11

Figure 5 and Figure 6 summarize the number of follow-up visits (out of a maximum of 7) 

and the number of years of follow-up between the first and last assessment, 

respectively. Overall, 1,568 participants completed all 7 follow-up assessments, 612 

attended 6 assessments, 524 attended 5 follow-up assessments, 406 participants 

attended 4 assessments, 404 attended 3 assessments, 428 attended 2 assessments 

and 619 attended only 1 assessment. The years of follow-up between the first and last 

assessment ranged from 1 to 7 years with a median of 6 years of follow up. 

Figure 5. Total number of follow-up assessments. 

Figure 6. Years followed from study entry to study exit. 

Figure 7 shows the sample age distribution relative to the age distribution from 

population estimates for the town of Walkerton and Brockton Township from the 1996 

and 2001 census. Participation varied with age and sex; with lower participation rates in 

the 20-24 and over 75 age categories, and with females being more likely to participate 

than males (Figure 8). Overall, the study age and sex distribution is representative of the 

population of Walkerton at the time of the outbreak. 

2091

435

419

352

345

299

620

7

6

5

4

3

2

1

Years followed

Number of participants followed

1513

634

523

426

410

433

622

7

6

5

4

3

2

1

Assessments
 12

Figure 7. Age distribution of study participants relative to the age distribution of the town 

of Walkerton and Brockton Township. 

0

5

10

15

20

25

30

0-4 5-14 15-19 20-24 25-44 45-54 55-64 65-74 75-84 85+

Age Group

Percentage

Walkerton (1996)

Brockton (2001)

Walkerton (2001)

WHS (2001)

Population estimates taken from the 1996 and 2001 Canadian Census. Statistics 

Canada Catalogue nos.:92-352-XIE &92-377-XIE.

Figure 8. Age distribution of WHS participants at time of outbreak: Males versus 

Females. 

30 20 10 0 10 20 30

0-4

5-14

15-19

20-24

25-44

25-54

55-64

65-74

75-84

85+

PERCENTAGE

MALE FEMALE
 13

Most (70%) participants were from the immediate Walkerton area, as defined by the 

postal code of N0G 2V0. Although the majority (98%) of participants reported drinking 

Walkerton tap water at the time of the outbreak, only 65% experienced any illness as a 

result. The symptoms ranged from mild stomach upset (5%) to more severe 

gastroenteritis with bloody diarrhea (see Figure 9). 

Figure 9. Self-reported illness at the time of the outbreak in May 2000. 

NOT ILL

35%

BLOODY DIARRHEA

17%

D+ GASTROENTERITIS

43%

MILD ILLNESS

5%

SELF REPORTED HEALTH OUTCOMES 

Beginning in 2004, participants were asked to rate their overall health status in general 

and compared to the previous year. Of the 3,763 participants who responded to this 

question, 85.3% reported being in good to excellent health at their last assessment and 

82.5% reported their health being stable or better than last year (Figure 10and Figure 

11). Among the 552 participants who reported their health as fair to poor, 44% reported 

that their health had remained stable or improved compared to last year; whereas, 57% 

reported that their health had continued to decline. Chronic gastrointestinal complaints 

continue to be a concern with 28% of participants complaining of regular problems with 

abdominal pain or discomfort, constipation, or diarrhea on average 4 or more days a 

month at their last assessment. This concern is slowly improving resulting in a decline in 

complaints from 47% in the first year of screening to 27% in year 7. In response to the 

on-going concerns about irritable bowel syndrome, a booklet, authored by Dr. John 

Howard especially for the citizens of Walkerton was distributed to over 1,200 
 14

participants, as well as being made available in doctors’ offices and the public library. 

Every year group information sessions were held to help individuals better cope with the 

symptoms of irritable bowel syndrome. Over 1,000 participants, as well as their family 

members, were invited to attend. In addition, the sessions were advertised locally and 

open to the public free of charge. Individuals with more serious complaints were seen 

one on one by a gastroenterologist. 

The incidence of self-reported diagnoses is presented in Figure 12. Yearly incidence is 

presented after the outbreak. Although self-reported data cannot be considered 

definitive, it does provide us with a quick snapshot of the health profile of the community. 

The incidence of most health outcomes is well within expected limits. Hypertension, 

diabetes, and arthritis may be slightly higher than expected and as such were 

investigated as part of specific research protocols. 

Figure 10. Self-reported health status at last assessment 

0

5

10

15

20

25

30

35

40

Percent

Excellent Very good Good Fair Poor
 15

Figure 11. Health compared to last year at last assessment. 

0

10

20

30

40

50

60

70

Much better now

than 1 yr ago

Somewhat better

now than 1 yr

agao

About the same Somewhat worse

than 1 yr ago

Much worse than

1 yr ago
Figure 12. Self-reported health outcomes. 

05

101520253035

Percent

Hypertension Diabetes Cancer Arthritis Heart Attack Stroke 

after April 2007May 2006-April 2007May 2005-April 2006May 2004-April 2005May 2003-April 2004May 2002-April 2003May 2000-April 2002before outbreak (May 200
17

IMPACT OF SURVEILLANCE ON BLOOD PRESSURE CONTROL IN THE WHS 

Hypertension is the most common treatable risk factor for cardiovascular disease. 

Treating hypertension results in a substantial decrease in cardiovascular morbidity and 

mortality. Although treating and controlling hypertension is relatively straightforward and 

achievable, the silent nature of the condition means that many escape detection in the 

absence of active surveillance or regular medical check-ups. This may be particularly 

true in rural communities if access to health care professionals is limited. Unlike most 

medical conditions, community surveillance has been the most common approach to 

increase awareness, treatment and control of high blood pressure. 

While treatment for hypertension has improved dramatically since the 1960’s, the 

majority of hypertension cases live with undetected or poorly controlled hypertension. 

The prevalence of hypertension in Canada is estimated to be between 21%-34%. 

A trend towards improved detection and treatment of hypertension was observed over 

the course of the WHS. The prevalence of hypertension among adult participants 

increased from 27% in 2002 to 42% in 2008, largely the result of improved identification 

of previously unidentified hypertension by means of serial surveillance (Figure 13). 

During this time, the proportion of participants who achieved successful control of their 

blood pressure to normotensive levels increased from 3% to 22%. In contrast, the 

proportion with uncontrolled hypertension decreased from 25% to 20%. 

Figure 13. Prevalence and control of hypertension among WHS participants (Adults, 

18+). 

0

5

10

15

20

25

30

35

40

45

Percent

2002 2003 2004 2005 2006 2007 2008

Controlled

Uncontrolled

Among participants with hypertension, the proportion receiving treatment increased 

substantially, from 18% in 2002 to 77% in 2008. In the first year of screening, the 

proportion of hypertensive participants with controlled blood pressure was only 9% 

(Figure 14). After four years of screening, the control rate stabilized to approximately 

50%. Following the opposite trend, the rate of uncontrolled hypertension among 

hypertensive participants decreased from 91% in 2002 to 48% in 2008. These results 
18

demonstrate a clear benefit of community-screening programs on awareness, treatment 

and control of hypertension. 

Figure 14. Rate of hypertension control among hypertensive participants. 

0

10

20

30

40

50

60

70

80

90

100

2002 2003 2004 2005 2006 2007 2008

Percent

Uncontrolled

Controlled

FLUID INTAKE AND WATER CONSUMPTION

Five years after the outbreak, participants were asked about their beliefs and behaviours 

with respect to water consumption. The majority of WHS participants indicated they 

consumed an average of 5-8 glasses of fluid per day (61%); however 23% reported 

drinking 9-12 glasses/day and 6% reported drinking more than 12 glasses per day, 

despite being aware of the recommended daily intake of 6-8 glasses per day. Nearly all 

(99%) participants believed that water was a key ingredient in a healthy diet and 

believed that most people did not drink enough water. Eighty percent (80%) of 

participants indicated they made a ‘conscious effort to drink water every day’ and 30% 

believed that ‘you cannot drink too much water’. Additional beliefs about water 

consumption and bottled water are summarized in Figure 15. 
19

Figure 15. Participant beliefs about water consumption and bottled water. 

0 10 20 30 40 50 60 70 80 90

Make a concious effort

to drink water everyday

Believe drinking water

helps with weight loss

Prefer bottled water to

tap water

Take bottled water when

going out 

Believe bottled water is

healthier than tap water

Percent

CLINICAL CARE 

At the completion of the study in August 2008, 2,244 of the participants had been offered 

multiple referrals to specialty clinics or follow-up laboratory investigation. The number of 

referrals per patient ranged from 1 to 11. A total of 1,947 specialty assessments were 

completed over the seven years as well as 801 special investigations for oral glucose 

tolerance and high volume proteinuria. A summary of the specialty visits and special 

investigations is presented in Figure 16. 
20

Figure 16. Specialty Visits, 2002 - 2008. 

REFERRALS

3219 referred (2748 seen)

Nephrology

1200

High Volume 

Proteinuria

110

Child Consult

485

Adult Consult

715

430

seen 52 

declined

89

seen 61 declined

17

declined

OGTT

918

712

seen 199declined

Rheumatology

284

217

seen 25declined

Gastroenterology

591

562

seen 4UAC

7

UAC

UAC=Unable to contact

60

declined

7

UAC

4

UAC

3

UAC

32

declined

Endocrinology

116

84

seen

654

seen

Specialty Clinics

Special Investigations

KIDNEY DISEASE - ADULT

Participants who were 18 years of age or older and were identified, based on either 

physical exam or laboratory results, as having proteinuria, elevated serum creatinine, or 

elevated blood pressure were offered a referral to an adult nephrologist. Over the course 

of the study, 464 participants were offered anywhere from 1 to 6 assessments with an 

adult nephrologist. A total of 654 consults were completed for 437 patients. The majority 

of these patients (71%) required only 1 assessment; however, 126 were seen up to 6 

times in repeated assessments. 

KIDNEY DISEASE - PAEDIATRIC

There were 252 children who were identified by an internal algorithm, which screened for 

elevated blood pressure, abnormal kidney function, or a past history of developing 

haemolytic uremic syndrome during the contaminated water outbreak. All children were 

offered appointments with a paediatric nephrologist. A total of 430 consults were 

completed for 243 children; 7 families declined the appointments or were unavailable. 

Most children (68%) were seen at least once and children who had experienced HUS at 

the time of the outbreak were offered appointments annually. 
21

GASTROINTESTINAL DISEASE 

 In addition to yearly information sessions on irritable bowel syndrome, specialty clinics 

were offered in gastroenterology for patients with more serious gastrointestinal 

complaints. Five hundred and thirty-eight (538) patients were offered one or 2 individual 

consults with a gastroenterologist. A total of 562 consults were completed for 523 

patients. 

DIABETES 

Beginning in the second year of the study, patients with HUS at the time of the outbreak 

and all participants over the age of 10 years who were not aware of being previously 

diagnosed with diabetes were asked to withhold from eating or drinking for 12 hours 

prior to their appointment. At that time a fasting serum glucose test was performed. 

Seven hundred and eighty-three (783) patients identified as dysglycemic based on 

fasting glucose levels between 5.3 and 6.9, potentially indicative of the presence of 

diabetes, were recalled for glucose tolerance testing and 610 completed the test. All 

newly identified diabetics were referred back to the care of their family doctor and the 

family doctor was provided with a copy of current practice guidelines for the 

management of diabetes. Repeat oral glucose tolerance testing was offered to 135 

patients and 102 completed the test. Specialty clinics were set up to provide follow-up 

and counseling to any patient identified as being diabetic on the basis of their oral 

glucose tolerance testing. One hundred and nine patients (109) identified by the 

screening procedures were offered one or more follow-up consults with an 

endocrinologist. Seventy-eight (78) patients attended, with 6 returning for a repeat 

consult. Testing identified 45 new diabetics in that they have no previous history of 

diabetes based on either self-report or an audit of medical and laboratory records. Fiftyone (51) participants were flagged as being in the “pre-diabetic” range and were 

monitored closely in subsequent years. 

RHEUMATOLOGY

In the first year of the study, 125 participants who indicated they had red, hot, swollen 

joint(s) were assessed by a rheumatologist. The vast majority of patients had either 

osteoarthritis or lower back syndromes and a minority was diagnosed with inflammatory 

arthritis. Those with reactive arthritis were treated and followed-up as deemed 

necessary by the rheumatologist. In subsequent years a more sensitive series of 

screening questions were added to the health survey. Patients were invited to be seen if 

they screened positive on the inflammatory arthritis questions. One hundred and fiftynine (159) participants with possible inflammatory arthritis were seen by Dr. Pope in 

consultation, 59 declined the appointment. All participants were given advice on what to 

do with their mechanical or musculoskeletal complaints. 

COUNSELING

In the first year of the study, there were 231 self-referrals for stress related to the water 

contamination of May 2000. Of these, 160 when re-contacted were not interested in 

attending counseling sessions. The most common diagnosis was anxiety or depression. 

Of those, the majority have improved or their symptoms are unchanged and only in one 

situation have symptoms noted to worsen. 
22

INVESTIGATION OF HIGH VOLUME PROTEINURIA

In Year 1 and Year 2 of the study, 108 subjects were noted to have high urine volumes 

ranging from 3 to more than 9 L/day with a mean of 3.7 L/day; and elevated urine protein 

in excess of 0.2 g/day with a mean of 0.4 g/day. They presented within the normal range 

for 24-hour urine creatinine, had a normal albumin:creatinine ratio, and had no history of 

diabetes. This unusual picture of polyuria and proteinuria was originally thought to be 

suggestive of possible nephrogenic diabetes insipidus brought on by tubular damage in 

the kidneys. Therefore, in 2004, all 108 were invited to participate in a more detailed 

investigation. Seventy-one (71) consented and after being requested to limit their water 

intake to less than 2 L/day for 1 week. Forty-three (43) had normal urine osmolality after 

eight hours requested water deprivation (450-1069mOsm/kg) and 28 had abnormal urine 

osmolality (59-450mOsm/kg). Patients with abnormal urine osmolality results were 

booked for a special clinic for an observed 8-hour water deprivation test. All of the 22 

patients who attended were able to concentrate within 8 hours. Repeat 24 hr urine 

specimens were ordered for 87 suspect HVP subjects in years 2005-7. Our investigation 

suggests that this unusual case group is not directly related to the water contamination, 

but is spilling protein into their urine due to hyper-filtration brought on by excessive fluid 

intake. We suspect this problem is not unique to Walkerton and may have import for 

future cases of accelerated loss of kidney function. 

RESEARCH INITIATIVES FROM THE WALKERTON HEALTH 

STUDY 

The initial focus of the Walkerton Health Study (WHS) was on the acute management of 

infected persons; however, the follow-up of long-term health outcomes is of equal 

importance. Research suggests that survivors of severe E. coli O157:H7 infection and 

campylobacter gastroenteritis have poorer long-term health regardless of whether they 

initially experienced overt haemolytic uremic syndrome. The WHS provides a unique 

and rare opportunity to characterize new and existing epidemiological associations 

between acute gastroenteritis and chronic diseases. In the context of the Walkerton E. 

coli outbreak, and distinct from the clinical responsibilities of the group, a number of 

relevant and collaborative research foci have developed. Summaries of these research 

projects are presented below. 

THE RISK OF LONG-TERM RENAL DISEASE AFTER DIARRHEA-ASSOCIATED 

HAEMOLYTIC UREMIC SYNDROME

Long-Term Renal Prognosis Of Diarrhea-Associated Haemolytic Uremic 

Syndrome: A Systematic Review, Meta-Analysis, And Meta-Regression

Background and Objectives: The long-term renal prognosis of patients with diarrheaassociated haemolytic uremic syndrome (HUS) remains controversial. The purpose of 

this study was to quantify the long-term renal prognosis of patients with diarrheaassociated HUS and to identify reasons for different estimates provided in the literature. 

Methods: Data Sources: We searched MEDLINE and Experta Medica (EMBASE) 

bibliographic databases and conference proceedings, and we contacted experts until 

February 2003. We also searched the Institute for Scientific Information index and 
23

reference lists of all studies that fulfilled our eligibility criteria. The search strategy 

included the terms haemolytic-uremic syndrome, purpura, thrombotic thrombocytopenic, 

Escherichia coli O157, longitudinal studies, kidney diseases, hypertension, and 

proteinuria. Study Selection: Any study that followed up 10 or more patients with 

primary diarrhea-associated HUS for at least 1 year for renal sequelae. Data 

Abstraction: Two authors independently abstracted data on study and patient 

characteristics, renal measures, outcomes, and prognostic features. Disagreements 

were resolved by a third author or by consensus. 

Results of Data Synthesis: Forty-nine studies of 3,476 patients with a mean follow-up 

of 4.4 years (range, 1-22 years at last follow-up) from 18 countries, 1950 to 2001, were 

summarized. At the time of recruitment, patients were aged 1 month to 18 years. In the 

different studies, death or permanent end-stage renal disease (ESRD) ranged from 0% 

to 30%, with a pooled incidence of 12% (95% confidence interval [CI]: 10% - 15%). A 

glomerular filtration rate lower than 80 mL/min per 1.73 m2

, hypertension, or proteinuria 

was extremely variable and ranged from 0% to 64%, with a pooled incidence of 25% 

(95% CI: 20% - 30%). A higher severity of acute illness was strongly associated with 

worse long-term prognosis. Studies with a higher proportion of patients with central 

nervous system symptoms (coma, seizures, or stroke) had a higher proportion of 

patients who died or developed permanent ESRD at follow-up (explaining 44% of the 

between-study variability, p = 0.01). Studies with a greater proportion of patients lost to 

follow-up also described a worse prognosis (p = 0.001) because these patients were 

typically healthier than those followed up. One or more years after diarrhea-associated 

HUS, patients with a predicted creatinine clearance higher than 80 mL/min per 1.73 m2

, 

no overt proteinuria, and no hypertension appeared to have an excellent prognosis. 

Conclusions: Death or ESRD occurs in about 12% of patients with diarrhea-associated 

HUS, and 25% of survivors demonstrate long-term renal sequelae. Patients lost to 

follow-up contribute to worse estimates in some studies. The severity of acute illness, 

particularly central nervous system symptoms and the need for initial dialysis, is strongly 

associated with a worse long-term prognosis. 

Reference: 

Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori 

M, Haynes RB, Clark WF. Long-term renal prognosis of diarrhea-associated haemolytic 

uremic syndrome: a systematic review, meta-analysis, and meta-regression. Journal of 

the American Medical Association. 2003; 290:1360-1370. 

An Outbreak Of Diarrhea-Associated Childhood Haemolytic Uremic Syndrome: 

The Walkerton Epidemic.

Background and Objectives: In Canada, the majority of cases of childhood haemolytic 

uremic syndrome (HUS) are associated with a diarrheal illness (D+) due to verotoxinproducing E. coli (VTEC). While the ingestion of undercooked beef is an important 

cause, we report on the largest outbreak of E. coli illness due to a contaminated 

municipal water supply. We describe the clinical features and short-term outcomes of 22 

children who simultaneously developed D+HUS. 

Methods: During the outbreak children who presented to their family doctor's office, or 

to the local emergency room, with diarrhea had stool samples screened for bacterial 
24

pathogens including E. coli O157:H7. In addition a complete blood count, urea, 

creatinine, electrolyte panel, and urinalysis were performed. Children with haemolytic 

uremic syndrome (HUS) were identified by the development of anemia with microscopic 

evidence of hemolysis on blood smear, thrombocytopenia with a platelet count ≤150 x 

109

/L, and by evidence of kidney injury with a rise in serum creatinine, and/or by the 

development of hematuria or proteinuria. Urine albumin to creatinine ratios were 

calculated on a random urine specimen. 

Results: A total of 24 children (<16 yr) with HUS were identified, and were treated at 

three medical sites. We report on 22 of the 24 children. The mean age at presentation 

was 4.8 ± 3.3 years. However, thirteen patients (56%) were less than 4 years, 7 (31%) 

between 4-8 years and 2 (9%) older than 10 years of age. 

Eight of the 22 children admitted with HUS required dialysis. All had significantly higher 

serum urea and creatinine levels at admission than those who did not require dialysis. 

The mean length of time on dialysis was 11.4 ± 5.7 days with a range of 2 to 19 days. 

During hospitalization 11 children required packed red blood cell transfusions (PRBC), 

while 7 children required platelet transfusions. Children requiring dialysis were more 

likely to receive a platelet transfusion than children who did not require dialysis (p<0.05). 

One child died shortly after admission to hospital. All surviving children recovered renal 

function and were discharged from hospital off dialysis. 

Patients evaluated at one-year follow up had hemoglobin, white cell and platelet counts 

within normal ranges. The mean GFR (± SD) for all patients was 98.4 ± 11.6 ml/min/1.73 

m2

, 99.8 ± 13.9 for patients who required dialysis, 97.6 ± 10.8 for patients who did not 

require dialysis. 

Interpretation and Discussion: Of 564 children with diarrheal illness among a total of 

1,440 residents of Walkerton who were younger than 19 years old, only 24 children, or 

approximately 4%, went on to develop the complete picture of HUS. This estimate of 4% 

is lower than previous published estimates from retrospective data. At one year follow 

up, there were no overt clinical signs of altered kidney function in any of the children; 

however, 2 had mildly decreased GFRs and 6 had proteinuria. 

Conclusion: Only a small proportion of children who were exposed to E. coli O157:H7 

contaminated water went on to develop clinically apparent disease. It is unclear whether 

the one year renal outcomes reflect irreversible and progressive kidney injury; however, 

the prospective evaluation of this cohort of children who developed HUS will enable 

more accurate estimates of the likelihood of long-term renal consequences resulting 

from E. coli O157:H7 exposure and the development of HUS. 

Reference: 

Matsell D, White CT. An outbreak of diarrhea-associated haemolytic uremic syndrome: 

The Walkerton epidemic. Summary in Kidney International. 2009 (in press). 

 

Renal Sequelae After Childhood Escherichia Coli O157 Haemolytic Uremic 

Syndrome

Background and Objectives: Nearly all childhood cases of haemolytic uremic 

syndrome (HUS) are caused by Shiga toxin-producing Escherichia coli O157:H7 and this 
25

syndrome is an important cause of renal failure worldwide. The long-term prognosis of 

patients with HUS is controversial. In some studies, minimal sequelae are observed, 

whereas others describe survivors with hypertension, proteinuria, or decreased 

glomerular filtration rate (GFR); in some studies, large proportions of children showed 

such sequelae. To our knowledge, no previous study has used an asymptomatic 

healthy control group to quantify the incremental risk of renal sequelae in those who 

recover from HUS. 

Knowledge of the long-term renal prognosis of patients with diarrhea-associated 

haemolytic uremic syndrome is important for patient counseling and follow-up. The 

purpose of this study was to compare the risk of renal sequelae at 3 and 5 years 

following the initial infection between pediatric survivors of HUS and healthy controls in 

the Walkerton cohort. In addition, trends in these sequelae were examined over time. 

Methods: Paediatric survivors of HUS were compared to children who were healthy at 

the time of the outbreak. Outcomes included proteinuria, blood pressure, glomerular 

filtration rate, and biochemical measures. 

Results (three years after the outbreak): Compared to healthy controls, children who 

recovered from HUS demonstrated more microalbuminuria [32% vs. 5% (Figure 17); 

relative risk 4.8 (95% CI: 1.1 - 22.0)], a nonsignificant trend toward lower GFR (124 vs. 

134 mL/min per 1.73 m2

), and no difference in blood pressure. 

Results (five years after the outbreak): Compared to healthy controls, children who 

recovered from HUS demonstrated more microalbuminuria (3% versus 20% (Figure 17); 

relative risk, 6.0; 95% CI: 1.1 - 32.8). There were no differences between groups in 

blood pressure or GFR (estimated with serum creatinine). GFR estimated by cystatin C 

level was lower in HUS survivors compared with controls (100 versus 110 mL/min/1.73 

m2

; p = 0.02), but no child had a GFR less than 80 mL/min/1.73 m2. Other results, 

including fasting glucose, albumin, and C-reactive protein levels, did not differ between 

groups. 

Interpretation and Discussion: Although HUS survivors were more likely to show 

microalbuminuria and lower GFR than healthy controls, the prognosis of these cases 

was better than reported in other studies. None of the HUS survivors in the WHS cohort 

had overt proteinuria or GFR less than 80 mL/min, and their blood pressure was no 

higher than expected for community norms. 

Although these 5-year results are encouraging, the clinical relevance and prognostic 

importance of microalbuminuria and small GFR decreases are uncertain and require 

further consideration and follow-up. 

Conclusion: No major long-term renal sequelae were observed in child HUS survivors 

in the WHS cohort. The prognosis of these children was better than in other literature 

reports. Ongoing follow-up will clarify the clinical relevance of microalbuminuria and mild 

decreases in GFR 5 years after HUS recovery. 
26

Figure 17. Rate of microalbuminuria among childhood survivors of haemolytic uremic 

syndrome (HUS). 

5%

32%

3%

20%

0%

5%

10%

15%

20%

25%

30%

35%

Percent with 

microalbuminuria

3-yrs 5-yrs

Time since the outbreak

Healthy controls

HUS survivors

References: 

Garg AX, Clark WF, Salvadori M, Macnab J, Suri RS, Haynes RB, Matsell D. 

Microalbuminuria three years after recovery from Escherichia coli O157 haemolytic 

uremic syndrome due to municipal water contamination. Kidney International. 2005; 

67:1476-82. 

Garg AX, Salvadori M, Okell JM, Thiessen-Philbrook HR, Suri RS, Filler G, Moist L, 

Matsell D, Clark WF. Albuminuria and estimated GFR 5 years after Escherichia coli 

O157 haemolytic uremic syndrome: an update. American Journal of Kidney Diseases. 

2008; 51:435-44. 

Future Research Projects Related To Long-Term Renal Disease After DiarrheaAssociated Haemolytic Uremic Syndrome

Paediatric haemolytic uremic syndrome secondary to Walkerton water contamination: A 

case series report. Investigators: Salvadori M, Matsell D, Sontrop JM, Garg AX, Clark 

WF. 

A 10-year follow-up of haemolytic uremic syndrome: Post Walkerton tragedy. 

Investigators: Garg AX, Salvadori M, Suri RS, Moist LM, Clark WF. 

THE RISK OF LONG-TERM RENAL DISEASE AFTER ACUTE GASTROENTERITIS 

Risk Of Hypertension And Reduced Kidney Function After Acute Gastroenteritis 

From Bacteria-Contaminated Drinking Water

Background and Objectives: Escherichia coli O157:H7 and Campylobacter jejuni 

infections may have long-term consequences beyond the period of acute illness. 
27

Receptors for the E. coli O157:H7 Shiga toxin, are found in the kidney, and exposure to 

this pathogen may result in substantial loss of nephrons and subsequent hyperfiltration, 

which can lead to long-term systemic hypertension and reduced kidney function. 

The aim of this prospective cohort study of the Walkerton population was to quantify the 

long-term risk of developing significant renal disease (hypertension, proteinuria, or a 

decrease in glomerular filtration rate) after exposure to contaminated water. This project 

was funded by a grant from the Kidney Foundation for $100,000 for the period of 2002 to 

2004. 

Methods: A total of 1,958 adults with no known history of hypertension or kidney 

disease before the outbreak participated in this long-term follow-up study. Of the 

participants, 675 had been asymptomatic during the outbreak, 909 had had moderate 

symptoms of acute self-limited gastroenteritis, and 374 had had severe symptoms that 

necessitated medical attention. The outcomes of interest were a diagnosis of 

hypertension or the presence of reduced kidney function and albuminuria during the 

follow-up period. 

Results: After a mean follow-up of 3.7 years after the outbreak, hypertension was 

diagnosed in 492 for an age- and sex-standardized rate of 31.1%. Hypertension was 

detected in 27.0% of participants who had been asymptomatic during the outbreak and 

in 32.3% and 35.9% of those who had had moderate and severe symptoms of acute 

gastroenteritis respectively (trend p = 0.009) (Figure 18). Compared with the 

asymptomatic participants, those with moderate and severe symptoms of gastroenteritis 

had an adjusted relative risk of hypertension of 1.15 (95% CI: 0.97 - 1.35) and 1.28 (CI: 

1.04 -1.56) respectively. A similar graded association was seen for reduced kidney 

function, defined as the presence of an estimated glomerular filtration rate below 60 

mL/min per 1.73 m2

 (trend p = 0.03). No association was observed between 

gastroenteritis and the subsequent risk of albuminuria. 

Interpretation and Discussion: Within 4 years of the outbreak, a 33% relative increase 

and a 9% absolute increase in newly diagnosed hypertension was observed among 

WHS participants who experienced severe gastroenteritis during the outbreak. 

Increased rates of hypertension were accompanied by evidence of reduced kidney 

function. The findings from this study are in line with other reports in which long-term 

renal sequelae were observed among individuals after recovery from haemolytic uremic 

syndrome, the most toxic form of acute E. coli O157:H7 infection. In this study, it is 

hypothesized that the long-term renal complications after E. coli gastroenteritis may be 

the result of subclinical or unrecognized haemolytic uremic syndrome. 

Conclusion: Acute bacterial gastroenteritis necessitating medical attention was 

associated with an increased risk of hypertension and reduced kidney function within 4 

years of infection. This study’s findings suggest that transient bacterial contamination 

has implications well beyond the period of acute self-limited illness. 
28

Figure 18. Age and sex-standardized rates of newly diagnosed hypertension 3.7 years 

after an outbreak of acute gastroenteritis from bacteria contaminated drinking water 

(n=1958). 

27

32.3

35.9

0

5

10

15

20

25

30

35

40

Percent with Hypertension

None Moderate Severe

Symptoms of Gastroenteritis

Reference: 

Garg AX, Moist L, Matsell D, Thiessen-Philbrook HR, Haynes RB, Suri RS, Salvadori M, 

Ray J, Clark WF. Risk of hypertension and reduced kidney function after acute 

gastroenteritis from bacteria-contaminated drinking water. Canadian Medical Association 

Journal. 2005; 173:261-68. 

Renal Sequelae After Childhood Escherichia Coli O157 Gastroenteritis

Background and Objectives: A quarter of children who survive diarrhea-associated 

haemolytic uremic syndrome develop long-term renal sequelae; however, the prognosis 

of acute, self-limited Escherichia coli O157:H7 gastroenteritis has not been previously 

studied. The purpose of this study was to examine whether the risk of long-term renal 

sequelae was increased in children four years after the Walkerton contaminated water 

outbreak. 

Methods: High blood pressure was defined as systolic or diastolic pressure >95th 

percentile expected for age, sex, and height. Reduced kidney function was assessed 

using measures of estimated glomerular filtration rate, random urine albumin to 

creatinine ratios, and microalbuminuria. 

Results: Of the 951 participants, 313 were asymptomatic during the outbreak, 305 had 

moderate symptoms of acute gastroenteritis, and 333 had severe symptoms that 

necessitated medical attention. An additional 23 children who developed haemolytic 

uremic syndrome during the outbreak were excluded from this analysis. There were no 
29

differences in mean systolic blood pressure between those who had no, moderate, or 

severe symptoms of acute gastroenteritis during the outbreak (109, 110, and 107 mm 

Hg). Similarly, there were no group differences in diastolic blood pressure, estimated 

glomerular filtration rate, or random urine albumin to creatinine ratio (p ranged from 0.14 

to 0.52), or in the adjusted relative risk of high blood pressure, a glomerular filtration rate 

<80 ml/min per 1.73 m2

, or microalbuminuria (p ranged from 0.23 to 0.89). 

Interpretation and Discussion: Children who presented for medical attention for 

gastroenteritis during the Walkerton E. coli O157:H7 outbreak, had no evidence of renal 

sequelae 4 years later. 

Given that the control group in this study may have ingested contaminated municipal 

water during the outbreak, it is theoretically possible that asymptomatic E. coli O157:H7 

exposure resulted in silent renal disease. While this could account for the absence of 

differences in renal sequelae between asymptomatic and symtpomatic children, it is 

unlikely given that the renal parameters measured in the asymptomatic children were 

similar or lower than those of healthy children based on population reference standards. 

Despite the absence of evidence of renal damage in this group of children, most 

progressive renal disease involves a protracted time course, and a longer follow-up of 

this cohort would help to clarify the risk of nephropathy after childhood E. coli O157 

bacterial gastroenteritis. 

Conclusion: An absence of renal sequelae were observed among children who 

experienced gastroenteritis during the Walkerton E. coli O157:H7 outbreak 4 years 

previously. With no existing data to support screening after self-limited E. coli O157:H7 

gastroenteritis, we recommend that only those children who develop recognized features 

of haemolytic uremic syndrome be followed for long-term renal health. 

Reference: 

Garg AX, Clark WF, Salvadori M, Thiessen-Philbrook HR, Matsell D. Absence of renal 

sequelae after childhood Escherichia coli O157:H7 gastroenteritis. Kidney International.

2006; 70:807-12. 

Future Research Projects On The Risk Of Long-Term Renal Disease After Acute 

Gastroenteritis

Long-term outcomes from the Walkerton water contamination outbreak: Risk of 

hypertension and reduced kidney function. Investigators: Clark WF, Macnab JJ, Moist, 

Salvadori M, Sontrop JM, Suri RS, Garg AX. 

Risk of cardiovascular disease after acute gastroenteritis from bacteria-contaminated 

drinking water. Investigators: Garg AX, Moist L, Clark WF. 

Effect of acute gastroenteritis on renal function among individuals with pre-existing renal 

impairment. Investigators: Sontrop JM, Garg AX, Macnab JJ, Moist L, Salvadori M, Suri 

RS, Clark WF. 
30

THE RISK OF DIABETES MELLITUS AFTER EXPOSURE TO E. COLI O157:H7

Diabetes During Diarrhea-Associated Haemolytic Uremic Syndrome: A Systematic 

Review And Meta-Analysis

Background and Objectives: To quantify the incidence of diabetes during the acute 

phase of diarrhea-associated haemolytic uremic syndrome (D + HUS) and to identify 

features associated with its development. 

Methods: A systematic review and meta-analysis of articles assessing diabetes during 

D + HUS was conducted. Relevant citations were identified from Medline, Embase, and 

Institute for Scientific Information Citation Index databases. Bibliographies of relevant 

articles were hand searched. All articles were independently reviewed for inclusion and 

data abstraction by two authors. 

Results: Twenty-one studies from six countries were included. Only 2 studies reported a 

standard definition of diabetes; 14 defined diabetes as hyperglycemia requiring insulin. 

The incidence of diabetes during the acute phase of D + HUS could be quantified in a 

subset of 1,139 children from 13 studies (1966-1998, age 0.2-16 years) and ranged from 

0 to 15%, with a pooled incidence of 3.2% (95% CI: 1.3 - 5.1, random-effects model, 

significant heterogeneity among studies, p = 0.007). Children who developed diabetes 

were more likely to have severe disease (e.g., presence of coma or seizures, need for 

dialysis) and had higher mortality than those without diabetes. Twenty-three percent of 

those who developed diabetes acutely died, and 38% of survivors required long-term 

insulin (median follow-up 12 months). Recurrence of diabetes was possible up to 60 

months after initial recovery. 

Conclusions: Children with D + HUS should be observed for diabetes during their acute 

illness. Consideration should be given to long-term screening of D + HUS survivors for 

diabetes. 

Reference: 

Suri RS, Clark WF, Barrowman N, Mahon JL, Thiessen-Philbrook HR, Rosas-Arellano 

MP, Zarnke K, Garland JS, Garg AX. Diabetes during diarrhea-associated haemolytic 

uremic syndrome: a systematic review and meta-analysis. Diabetes Care. 2005; 

28:2556-62. 

The Risk Of Diabetes Mellitus After Exposure To E. coli O157:H7

Background and Objectives: Diarrhea-associated HUS may be complicated by acute 

insulin deficiency. At least 1/3 of survivors may be left with permanent diabetes mellitus 

(DM), with relapse possible several years after initial resolution. While HUS is the most 

severe form of infection with E. coli O157:H7, most diseases operate through a gradient 

of symptoms and sequelae. Groups of people with E. coli O157:H7 gastroenteritis likely 

include persons with sub-clinical or undetected HUS who may sustain incomplete islet 

cell injury during the acute infection. Loss of beta cell mass in these individuals could 

limit rises in insulin production in response to any future potential reductions in insulin 

sensitivity, putting them at increased risk of developing overt type 2 diabetes and 

glucose intolerance. 
31

To test this hypothesis, we prospectively followed 3,259 individuals aged 7 and older, 

without previous evidence of diabetes, who ingested contaminated water in May 2000. 

We sought to determine if, compared to asymptomatic individuals, persons with 

symptomatic gastroenteritis during the outbreak had an increased long-term risk of 

developing dysglycemia, defined as the composite of DM, impaired glucose tolerance, or 

impaired fasting glucose. This project was funded by a grant from the Canadian 

Diabetes Association for $65,000 for the period of 2003 to 2005. 

Methods: Year 1 to Year 3 participants, who were aged 7 and older on April 15th, 2000, 

had no history of chronic diarrhea, irritable bowel syndrome, inflammatory bowel 

disease, celiac disease or dysglycemia before April 15th, 2000, had no confirmed HUS 

at the time of outbreak, were included in this study. In 2002, all participants without 

known DM underwent a random plasma glucose test. In 2003 and 2005, all participants 

were asked to complete an 8-hour fasting plasma glucose, excluding those with known 

diabetes, those who were pregnant, and those less than age 10. Eligible participants 

who had fasting plasma glucose of 5.3 to 6.9 mmol/L without previous evidence of DM 

were asked to undergo an oral glucose tolerance test. In 2005 the lower threshold limit 

was increased to 5.5 mmol/L due to budgetary and logistical constraints. Participants 

were classified based on their symptoms during the outbreak into 1 of 3 groups: 

1) asymptomatic; 2) possible gastroenteritis; and 3) confirmed gastroenteritis. 

Results: Three thousand two hundred and fifty nine (3,259) eligible participants were 

included in the dysglycemia study. One thousand one hundred and thirty nine (1,139) 

had no symptoms at the time of outbreak, 1,492 had possible gastroenteritis and 628 

had confirmed gastroenteritis. 

There were no observed differences in the age- and sex-standardized rates of newly 

diagnosed dysglycemia between groups. There were no differences between groups in 

the age- and sex-standardized rates of DM, IFG, or IGT. There was no difference in the 

age- and sex-adjusted mean fasting glucose between groups. 

Conclusion: There is no evidence that individuals infected with E. coli O157:H7 who 

develop symptomatic gastroenteritis without HUS are at increased long-term risk of 

abnormal glucose homeostasis. However, individuals presenting with diarrheaassociated HUS should have aggressive surveillance and treatment of hyperglycemia, 

and consideration should be given to long-term screening of survivors for DM with oral 

glucose tolerance tests. 

References: 

Suri RS, Mahon JL, Clark WF, and Garg AX. Long-term risk of dysglycemia after E. coli

O157:H7 gastroenteritis: The Walkerton Health Study. Canadian Society of Nephrology 

40th Annual Meeting. May 28- June 1, 2008. 

Suri RS, Mahon JL, Clark WF, Moist LM, Salvadori M, Garg AX. Relationship between 

E. coli O157:H7 and Diabetes Mellitus. Summary in Kidney International. 2009 (in 

press). 
32

THE EFFECTS OF WATER CONTAMINATION ON PREGNANCY 

The Risk Of Pregnancy-Related Hypertension After Exposure To Contaminated 

Water

Background and Objectives: Exposure to E. coli O157:H7 may result in sub-clinical 

kidney injury manifesting as hypertension during pregnancy. Hypertensive disorders 

during pregnancy complicate between 6% and 22% of pregnancies and are associated 

with 15% of maternal deaths. 

This study of WHS participants was designed to evaluate the risk of pregnancy-related 

hypertension (PRH) among previously healthy females who conceived within five years 

of the outbreak. The incidence of PRH, chronic and gestational hypertension was 

compared between those who reported moderate to severe symptoms of gastroenteritis 

at the time of the outbreak to those who were asymptomatic. Differences in mean 

arterial pressure (MAP) were also evaluated. 

Funding for this initiative was received from the Lawson Health Research Institute, 

London, Ontario.

 

Methods: Ontario Ministry of Health Antenatal forms were used to determine outcomes 

and risk factors. PRH was defined as any systolic or diastolic blood pressure (BP) >140 

mmHg and >90 mmHg, respectively. Chronic and gestational hypertension were 

defined, respectively, as elevated BP observed prior to or >20 weeks gestation. Risk of 

PRH was evaluated using a modified Poisson regression model that controlled for 

known risk factors. 

Results: A total of 2,553 women participated in the WHS between 2002-6, and 148 were 

pregnant between Jan 2001 and May 2006. After exclusions for miscarriage/abortion, 

pre-existing medical conditions, and incomplete data, 135 pregnancies were included, of 

which 48 (36%) were asymptomatic and 87 (64%) were symptomatic at the time of the 

outbreak. PRH was detected in 20.7% pregnancies, of which 6.7% were chronic 

hypertension and 14.1% gestational hypertension. Although non-significant, a consistent 

trend toward higher rates of PRH and mean arterial pressure, particularly prior to 20 

weeks gestation, was observed among women who reported symptomatic 

gastroenteritis compared to asymptomatic women (Figure 19). 

Interpretation and Discussion: In this study, higher MAP, PRH, chronic and 

gestational hypertension were observed among women who reported symptoms of 

gastroenteritis compared to those who were asymptomatic; however, no differences 

were statistically significant, possibly due to small sample size. Given the small number 

of pregnancies in the WHS cohort, several more years of data collection would be 

necessary to ensure a sufficiently large sample; however, any conclusions reached from 

such an analysis would be limited by the longer time span between exposure and 

outcome. 
33

Figure 19. Mean arterial pressure during pregnancy 5 years after an outbreak of acute 

gastroenteritis from bacteria-contaminated drinking water (n=135). 

70

75

80

85

90

1-10 11-15 16-19 20-25 26-30 31-35 36-40

Gestational Age (weeks)

Mean Arterial Pressure mm Hg (95%CI)

Symptomatic

Asymptomatic

Conclusions: This study’s findings suggest that any effect of acute gastroenteritis on 

blood pressure occurs prior to or early in pregnancy (<20 weeks gestation). Blood 

pressure should be monitored closely in pregnant women after exposure to 

contaminated water. 

Reference: 

Moist L, Sontrop JM, Garg A, Suri R, Salvadori M, Gratton R, Clark WF, Macnab JJ. 

Risk of pregnancy-related hypertension within five years of exposure to bacteriacontaminated drinking water. Summary in Kidney International. 2009 (in press).

THE RISK OF REACTIVE ARTHRITIS AFTER ACUTE GASTROENTERITIS

Campylobacter Reactive Arthritis: A Systematic Review

Background and Objectives: To review the literature on the epidemiology of 

Campylobacter-associated reactive arthritis (ReA). 

Methods: A Medline (PubMed) search identified studies from 1966 to 2006 that 

investigated the epidemiology of Campylobacter-associated ReA. Search terms 

included: "reactive arthritis," "spondyloarthropathy," "Reiter's syndrome," 

"gastroenteritis," "diarrhea," "epidemiology," "incidence," "prevalence," and 

"Campylobacter." 
34

Results: The literature available to date suggests that the incidence of Campylobacter 

ReA may occur in 1 to 5% of those infected. The annual incidence of ReA after 

Campylobacter or Shigella may be 4.3 and 1.3, respectively, per 100,000. The duration 

of acute ReA varies considerably among reports, and the incidence and impact of 

chronic ReA from Campylobacter infection is virtually unknown. 

Conclusions: Campylobacter-associated ReA incidence and prevalence varies widely 

among reviews due to case ascertainment differences, exposure differences, lack of 

diagnostic criteria for ReA, and perhaps genetics and ages of exposed individuals. At the 

population level it may not be associated with HLA-B27, and inflammatory back 

involvement is uncommon. Follow-up for long-term sequelae is largely unknown. Five 

percent of Campylobacter ReA may be chronic or relapsing (with respect to 

musculoskeletal symptoms). 

Reference: 

Pope JE, Krizova A, Garg AX, Thiessen-Philbrook H, Ouimet JM. Campylobacter 

reactive arthritis: A systematic review. Seminars in Arthritis and Rheumatism. 2007; 

37:48-55. 

Risk Of Arthritis After Acute Bacterial Gastroenteritis

Background and Objectives: Reactive arthritis (ReA) is a known consequence of 

bacterial gastroenteritis. Previous research indicates that self-limiting ReA may develop 

within 4 weeks of an enteric infection (including Campylobacter, Salmonella, Shigella, 

and to a lesser extent Escherichia coli O157:H7). The prevalence of acute ReA 

following Campylobacter infection is estimated to be 7%; symptoms of chronic ReA may 

develop in 6% of cases following E. coli infection. 

The purpose of this study was to evaluate the association between acute gastroenteritis 

and self-reported chronic arthritis within 4 years of the outbreak. 

Methods: Participants with no known history of arthritis before the outbreak participated 

in a long-term follow-up study. Of the 2,299 participants, 788 were asymptomatic during 

the outbreak, 1,034 had moderate symptoms of acute gastroenteritis and 477 had 

severe symptoms that necessitated medical attention. The outcomes of interest were 

new arthritis by self-report and a new prescription of medication for arthritis during the 

follow-up period. 

Results: After a mean follow-up of 4.5 yrs after the outbreak, arthritis was diagnosed in 

454 participants for an age- and sex- standardized rate of 17.9% within 4.5 years of the 

outbreak. Arthritis was reported in 15.7% of those with no diarrhea, 17.6% in those with 

moderate symptoms of gastroenteritis and 21.6% in those with severe symptoms ( trend 

p = 0.009) (Figure 20). Compared with the asymptomatic participants, those with 

moderate and severe symptoms of gastroenteritis had an adjusted relative risk of 

arthritis of 1.19 (95% CI: 0.99 - 1.43] and 1.33 (95% CI: 1.07 - 1.66), respectively. No 

association was observed between gastroenteritis and the subsequent risk of 

prescription medication for arthritis (p = 0.49). 
35

Figure 20. Age and sex-standardized rates of newly diagnosed arthritis 4.5 years after 

an outbreak of gastroenteritis from bacteria-contaminated drinking water (n=2299). 

15.7

17.6

21.6

0

5

10

15

20

25

None Moderate Severe

Symptoms of gastroenteritis

Percent

Interpretation and Discussion: This study’s findings support the hypothesis that either 

acute or chronic arthritic symptoms occurred in study participants who were exposed to 

Campylobacter or E. coli during the contaminated water outbreak. This is the largest 

study to date to suggest a ‘dose-response’ of diarrhea severity and report of subsequent 

arthritis. 

Previous reports indicate a higher frequency of ReA following Campylobacter than E. 

coli infection; however, this study was unable to differentiate the rate of arthritis by 

infection type due to the small number of specimens collected during the outbreak. 

Many patients with diarrhea (especially dysentery) could have had contraindications to 

non-steroidal anti-inflammatory drug prescriptions, which may explain the lack of 

association with prescription arthritis medications. 

Conclusion: Acute bacterial gastroenteritis necessitating medical attention was 

associated with a higher risk of arthritic symptoms, but not arthritic medications, up to 4 

yrs following the outbreak. The nature and chronicity of these arthritic symptoms 

requires further study. 

Reference: 

Garg AX, Pope JE, Thiessen-Philbrook H, Clark WF, Ouimet J. Arthritis risk after acute 

bacterial gastroenteritis. Rheumatology (Oxford). 2008; 47:200-204. 

PATHOPHYSIOLOGY AND CLINICAL EXPRESSION OF POST-INFECTIOUS IRRITABLE 

BOWEL SYNDROME. 

Epidemiology Of Post-Infectious Irritable Bowel Syndrome

Background and Objectives: Post-infectious irritable bowel syndrome (PI-IBS) is a 

common clinical phenomenon. Between 5% and 30% of patients who suffer an acute 
36

episode of infectious gastroenteritis develop chronic gastrointestinal symptoms despite 

clearance of the inciting pathogen. Previous studies of the epidemiology of PI-IBS have 

assessed relatively small study cohorts with limited ability to statistically discern which 

risk factors affect the outcome. Few studies have assessed the long-term natural history 

of PI-IBS. To better define the incidence and epidemiology of PI-IBS, chronic 

gastrointestinal symptoms of WHS participants with no known prior diagnosis of IBS or 

inflammatory bowel disease (IBD) were examined. 

Methods: The WHS cohort was divided into controls without gastroenteritis, subjects 

with clinically suspected gastroenteritis, and subjects with only self-reported 

gastroenteritis that could not be substantiated by another source. IBS was defined 

according to Rome I criteria using a modified Bowel Disease Questionnaire. The 

incidence and epidemiology of PI-IBS was characterized. Risk factors were assessed 

using multiple logistic regression. 

Results: Of 2,069 eligible study participants, 488 (23.6%) met Rome I criteria for IBS at 

their first WHS visit in 2002 or 2003. The incidence of IBS was 10.1% among subjects 

with no gastroenteritis, 27.5% among those with self-reported gastroenteritis, and 36.2% 

among those with clinically suspected gastroenteritis (Figure 21). Independent risk 

factors for PI-IBS included younger age, female sex, bloody stools, abdominal cramps, 

weight loss, and prolonged diarrhea. PI-IBS was more likely than sporadic IBS to show 

diarrhea-predominant features. 

Figure 21. Rate of newly diagnosed Rome I Irritable Bowel Syndrome (IBS) 2-3 years 

after acute gastroenteritis from exposure to contaminated drinking water (n=2,069). 

10.1

27.5

36.2

0

5

10

15

20

25

30

35

40

None Self-report Clinically suspected

Percent with Rome I IBS

Interpretation and Discussion: Within an interval of 2 years, a more than three-fold 

increase in the risk of developing IBS was observed among Walkerton residents who 

experienced bacterial gastroenteritis during the outbreak. 

The prevalence of IBS in WHS participants with clinically suspected gastroenteritis is 

among the highest ever reported. This study has a number of methodologic advantages 

over previous reports, namely its access to a large, well-defined, at-risk cohort with a 

simultaneous and well-characterized acute enteric illness. 
37

Conclusions: PI-IBS was more common among residents exposed to gastroenteritis 

than among those who remained well during the outbreak. Increased severity of the 

acute illness, female gender and younger age were independent predictors of IBS. The 

results of this study confirm a strong and significant relationship between acute enteric 

infection and subsequent IBS symptoms. 

Reference: 

Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM. Incidence and 

epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial 

dysentery. Gastroenterology. 2006; 131:445-50. 

Marshall JK. Post-infectious irritable bowel syndrome following water contamination. 

Summary in Kidney International. 2009 (in press).

Intestinal Permeability In Irritable Bowel Syndrome

Background and Objectives: Current scientific thinking suggests that post-infectious 

irritable bowel syndrome (PI-IBS) is the clinical expression of altered gut neuromuscular 

function due to persistent low-grade inflammation. Altered intestinal permeability can 

contribute to this inflammation by exposing the intestinal wall to luminal antigen. 

Increased intestinal permeability may also be a precursor to Crohn’s disease. The aim of 

this project was to learn about the pathophysiology underlying symptoms of PI-IBS. 

Specifically, this study’s purpose was to evaluate the association between intestinal 

permeability and IBS symptoms 2 years after the outbreak. 

Methods: Consecutive WHS participants with Rome I IBS and controls without IBS 

attending a community clinic were enrolled in this study. Participants were invited to 

undergo measurement of intestinal permeability from fractional excretion of mannitol and 

lactulose after oral ingestion. Intestinal permeability was measured as the ratio of 

fractional urinary excretions of lactulose and mannitol, and compared among cases vs. 

controls. Predictors of abnormal intestinal permeability were assessed. 

Results: A total of 218 subjects (132 IBS cases and 86 non-IBS controls) completed the 

study protocol. About 27 (12%) had been diagnosed with IBS before the outbreak and 

115 (53%) were ill during the outbreak. Lactulose-mannitol ratios were increased among 

cases vs. controls and cases were more likely to have a ratio >0.020. Among cases, 

those with increased intestinal permeability were more likely to report increased stool 

frequency. Both IBS symptoms and male gender, but not diarrhoeal illness during the 

outbreak, were significant predictors of abnormal permeability. 

Conclusions: IBS symptoms are associated with a subtle increase in intestinal 

permeability irrespective of prior gastroenteritis. This may improve understanding of the 

etiology of both sporadic and post-infectious irritable bowel syndrome. 

Reference: 

Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM. Intestinal 

permeability in patients with irritable bowel syndrome after a waterborne outbreak of 

acute gastroenteritis in Walkerton, Ontario. Alimentary Pharmacology and Therapeutics. 

2004; 20:1317-22. 
38

Genetic Risk Factors For Post-Infectious IBS In The Walkerton Outbreak Of 

Waterborne Gastroenteritis

Background and Objectives: The purpose of this study was to confirm and/or identify 

new post-infectious irritable bowel syndrome (PI-IBS) susceptibility genes. We selected 

a list of 78 variants as candidates to be screened on the Walkerton population cohort 

(Marshall JK, et al. Gastroenterology 2006; 131: 445-50), a well-characterized 

longitudinal study. These candidates can be classified in 4 categories: 1) reported IBS 

genes (including serotoninergic pathway genes); 2) genes involved in intestinal epithelial 

barrier; 3) reported auto-immunity risk variants (including cytokines); 4) inflammatory 

bowel disease (IBD) genes. 

Methods: Variants were genotyped using the Sequenom hME or Taqman assays. 

Analysis compared subjects who experienced GE but did not develop PI-IBS (889 

controls) to those who experienced GE and reported PI-IBS 2-3 years after the outbreak 

(228 cases). Individuals included in the analysis were over 16 years old, had no prior 

history of IBS or IBD, were not newly diagnosed with IBD, had over 90% genotyping 

success rate, and had less than 5% Mendelian inconsistencies. Among the 1,098 

successfully genotyped cases and controls, 739 (140 cases, 599 controls) do not have 

known relationship with any other individual. The remaining 359 samples (80 cases, 279 

controls) belong to 120 families. Analysis was performed using a quasi-likelihood 

association test for cases and controls that accounts for known relatedness within the 

sample. The test is expressed as a chi-square statistic with 1df. After excluding variants 

with low success rate (<95%) or deviating from Hardy-Weinberg equilibrium (p<0.01), we 

analyzed 73 variants with a minor allele frequency >1%. 

Results: Four candidates showed significant association with PI-IBS. Two are located in 

Toll-like receptor 9: the coding SNP rs352139 (P545P) (p = 0.0135) and the promoter 

SNP rs5743836 (-T1237C) (p = 0.0324). These 2 SNPs are in low linkage disequilibrium 

with each other (r2<0.14). The third is rs16260 (p = 0.0352), a promoter SNP (-C160A) 

of E-cadherin, and the fourth is rs1800795 (p = 0.0489), a promoter SNP (-G174C) of IL6. After correction for multiple comparisons, none of these associations remained 

significant. 

 

Conclusion: This study offered a unique opportunity to evaluate new susceptibility 

genes in PI-IBS. Further population studies will be needed to confirm and validate these 

potential candidate gene variants. 

Reference: 

Villani A, Lemire M, Thabane M, Geneau G, Belisle A, Fortin G, Franchimont D, and 

Marshall J. Genetic risk factors for post-infectious IBS in the E. coli O157:H7 outbreak in 

Walkerton (Canada) in 2000. Gastroenterology. 2008; 134(4) Suppl. 1, A-122 – abstract. 

Future Research Projects Related To Irritable Bowel Syndrome (IBS) And 

Inflammatory Bowel Disease (IBD)

A mechanism-based candidate gene association study of IBS. Investigators: Yuri A, 

Saito-Loftus, Larson JL, Atkinson EJ, Villan A, Lemire M, Thabane M, Collins M, 

Franchimont D, Marshall JK. 
39

Intestinal microbiota in residents of Walkerton, Ontario. Investigators: Bercik, Denou, 

Verdu, Marshall and Collins. 

Prevalence and incidence of IBD after an exposure to gastroenteritis in Walkerton 

Ontario. Investigators: Marshall JK, Thabane M, Clark WF, Garg AX, Salvadori M, 

Collins SM. 

Association between Diabetes Mellitus and IBD/IBS. Investigators: Marshall JK, 

Thabane M, Clark WF, Garg AX, Salvadori M, Suri R. 

Exposure to intestinal infection in childhood/adolescence may result in development of 

IBS later in life. Investigators: Thabane M, Marshall JK, Simunovic M, Danesh NA. 

Development and validation of a risk score for post-infectious IBS. Investigators: 

Thabane M, Marshall JK, Simunovic M, Danesh NA. 

Renal tubular proteinuria is increased in patients with post-infectious IBS. Investigators: 

Thabane M, Marshall JK, Simunovic M, Danesh NA. 

Familial aggregation in post-infectious IBS. Investigators: Thabane M, Marshall JK, 

Simunovic M, Danesh NA. 

CHARACTERIZATION OF A NOVEL FINDING OF HIGH VOLUME PROTEINURIA AFTER THE 

WALKERTON E. COLI O157:H7 MUNICIPAL WATER CONTAMINATION 

Causes Of Reversible Nephrogenic Diabetes Insipidus: A Systematic Review

Background and Objectives: In nephrogenic diabetes insipidus (NDI), the kidney is 

unable to produce concentrated urine because of the insensitivity of the distal nephron to 

antidiuretic hormone (arginine vasopressin). In settings in which fluid intake cannot be 

maintained, this may result in severe dehydration and electrolyte imbalances. The risk 

for conversion of reversible to irreversible NDI seems to be a potential complication. This 

review summarizes the reversible causes of acquired NDI to facilitate earlier recognition 

and more effective treatment by clinicians. 

Methods: Two reviewers independently searched MEDLINE, Experta Medica 

(EMBASE), and ISI bibliographic databases. Human studies that described NDI caused 

by drugs, substances, or metabolic disturbances were included. To evaluate the causal 

role of the risk factor, data were abstracted according to Koch's postulates. 

Results: One hundred fifty-five studies published between 1957 and March 2004 

described 30 risk factors. Of 155 studies, 58 studies provided a "definite" diagnosis of 

NDI; 83 studies, a "probable" diagnosis; and 14 studies, a "possible" diagnosis. Nine 

factors were considered "definite" causes of NDI; 15 factors, "probable" causes; and 6 

factors, "possible" causes. The most reported risk factors were lithium (84 studies), 

antibiotics (16 studies), antifungals (11 studies), antineoplastic agents (9 studies), 

antivirals (8 studies), and metabolic disturbances (8 studies). Duration of NDI reversal, 

as well as conversion to irreversible symptoms, seemed to depend on the duration of 

exposure. 
40

Conclusion: Most risk factors for reversible NDI were medications, and their 

identification and removal resulted in resolution of the condition. Long-term treatment 

with lithium appeared to result in irreversible NDI. 

Reference: 

Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, Clark WF. Causes of 

reversible nephrogenic diabetes insipidus: a systematic review. American Journal of 

Kidney Diseases. 2005; 45:626-37.

 

Excessive Fluid Intake As A Novel Cause Of Proteinuria 

Background and Objectives: Proteinuria has been identified as a strong independent 

risk factor for the development and progression of renal disease. As part of routine 

screening in the WHS, urine protein levels in 24-hour collections of urine were measured 

in all adults who attended the annual follow-up clinic. We identified 100 adults who had 

proteinuria and polyuria (urine volume >3 L/24-hr), but no medical history or medication 

use to explain their condition. 

In an attempt to discern the cause of the unexplained proteinuria and polyuria we 

conducted a series of studies to determine whether this observation was related to 1) 

urine osmolality 2) to examine the effect of fluid intake restriction on polyuria and 

proteinuria 3) to evaluate the effect of fluid intake on polyuria and proteinuria in healthy 

university students (non-WHS participants), and 4) to evaluate whether polyuria was 

independently associated with proteinuria in the entire WHS sample and to compare the 

magnitude of this association to other known risk factors. 

Methods: In the initial study, which assessed objectives 1 and 2, participants underwent 

a confirmatory 24-hr urine collection followed by a urine osmolality measurement after 

overnight water deprivation. Participants were then asked to voluntarily reduce their 

total daily fluid intake to fewer than 8 large glasses (<2L/day) for one week, on the last 

day of which a third 24-hr urine sample was collected and tested for protein. 

To address the third objective, 3 consecutive 24-hr urine samples were collected from 6 

healthy university students and tested for protein (γ-globulin and albumin). Samples 1 

and 3 were collected during usual fluid intake and the second during fluid loading. 

Results: Fifty-six of the 100 WHS participants completed both initial and confirmatory 

urine concentration tests, which showed their urine osmolality could reach normal levels 

(meaning that diabetes insipidus was unlikely). Urine volume decreased from 3.7 L/24-

hr at baseline to 1.8L/24-hr after fluid intake restriction. The amount of protein excreted 

decreased from 0.41 g/24-hr at baseline to 0.16 g/24-hr after fluid intake restriction. 

In the study of university students, both proteins (γ-globulin and albumin) increased 

significantly following fluid loading and returned to baseline on day 3. 

In the analysis of all WHS participants from year 1 and year 2, significant correlations 

were observed between 24-hr urine volume and 24-hr urine protein (Figure 22). In 

multivariable analysis, polyuria had the strongest association with proteinuria (adjusted 
41

RR=5.4; 95% CI: 4.8 - 6.1), followed by age >30 years, glomerular filtration rate 

<60ml/min, smoking, diabetes and female sex. 

Interpretation and Discussion: In a small group of healthy WHS participants with 

polyuria and proteinuria, proteinuria was reduced following voluntary restriction of fluid 

intake. Similar results were observed in a study of university students, which 

demonstrated an increase in urine protein following increased fluid intake. Protein levels 

returned to baseline after normal fluid intake resumed. These results suggest that the 

increase in urinary protein excretion in healthy subjects is induced solely through acute 

fluid loading. 

In analysis of the entire WHS cohort, polyuria was the strongest predictor of proteinuria. 

These results are relevant in assisting practitioners to interpret 24-hr urine tests for 

protein. These tests are commonly performed, and often lead to treatment decisions. 

Physicians should be aware that the strongest factor associated with proteinuria on a 24-

hr urine in the general population is not in fact comorbid disease, but polyuria. 

The long-term renal consequences of chronic exposure to mild proteinuria in polyuric 

individuals are unknown. Further research is needed to provide insight into the question 

of whether the proteinuria caused by polyuria is harmful to kidney function. Such a 

finding would have important public health implications given the silent nature of kidney 

disease and the widespread, but unsubstantiated belief that drinking eight glasses of 

water per day is healthy 

Conclusions: Further research is required to characterize the nature of the relationship 

between polyuria, proteinuria and kidney function. In the final year of the WHS, tests 

were conducted to assess the type of protein associated with polyuria and to determine 

whether polyuria is associated with a decline in kidney function. An analysis of the WHS 

data from year 1 to 7 will be designed to evaluate the long-term effects of polyuria on 

proteinuria and kidney function. 

References: 

Clark WF, Kortas C, Suri RS, Moist LM, Salvadori M, Weir MA, Garg AX. Excessive fluid 

intake as a novel cause of proteinuria. Canadian Medical Association Journal. 2008; 

178:173-75. 

Sontrop JM, Suri RS, Sultan NM, Macnab JJ, Moist L, and Clark WF. Polyuria is a major 

risk factor for proteinuria in the general population. 2008. London, Ontario May 28-June 

1, The 40th Annual Meeting of the Canadian Society of Nephrology. 

Weir MA, Sontrop JM, and Clark WF. Fluid loading causes an increase in urinary protein 

excretion. 2008. London, Ontario May 28-June 1, The 40th Annual Meeting of the 

Canadian Society of Nephrology. 

Future Research Related to High Volume Proteinuria

The Long-term effect of polydipsia induced polyuria and proteinuria on kidney function. 

Investigators: Clark WF, Sontrop JM, Macnab JJ, Moist L, Salvadori M, Suri RS, Garg 

AX. 
Figure 22. Correlation between 24-hr urine volume (L) and 24-hr urine protein (g). 

0.00.51.01.52.02.53.03.5

0.0 1.0 2.0 3.0 4.0 5.0 6.0

24-hr Urine volume (L)

24-hr Urine Protein (g)

0.00.20.40.60.81.01.21.41.61.8

0.0 1.0 2.0 3.0 4.0 5.0 

24-hr Urine Volume (L)

24-hr Urine Protein (g)

Entire sample (n=2191; rhosp = 0.70; p<0.001). Sub-sample: Excludes participants with hy

eGFR<60 mL/min, and kidney disease (n=p<0.001. 

Urine volume >3L 

Urine volume >3L 

Protein >0.5g Protein >0.2g 
43

THROMBOTIC THROMBOCYTOPENIC PURPURA/ HAEMOLYTIC UREMIC SYNDROME 

(TTP/HUS): DEFINITION AND PROGNOSIS

TTP/HUS And Prognosis: The Syndrome And The Disease

Background and Objectives: Patients presenting with the syndrome of microangiopathic 

hemolysis and thrombocytopenia, without shiga-toxin associated colitis, have thrombotic 

thrombocytopenic purpura/ haemolytic uremic syndrome (TTP/HUS). 

This paper will review recent developments in understanding prognosis from both a 

syndrome-level perspective and also a mechanism-specific perspective, and will use the 

term TTP/HUS to refer to the syndrome of microangiopathic haemolytic anemia and 

thrombocytopenia without a clinically identified cause. 

Vulnerability to Bias: Prognosis for TTP/HUS is vulnerable to bias, including selection bias 

arising from inclusion of patients with secondary causes. Restricting analysis to patients with 

severe ADAMTS-13 deficiency does not remove this bias, as several investigators report 

severe ADAMTS-13 deficiency in secondary cases. Controlling for secondary causes 

remains important for prognostication even when restricting analysis to specific 

mechanisms. 

A second form of bias relates to differences in the time at which mortality is measured. 

Prospective data demonstrate 4% mortality after the first cycle of plasma exchange but 22% 

mortality at 6 months. This difference illustrates the frequency of late deaths and the 

importance of clearly defining the time at which mortality is measured, which may vary from 

study to study. 

Heterogeneous mechanisms: Preliminary assessment of prognosis by mechanism suggests 

that mortality varies by pathogenic mechanism. Among familial or recurrent cases, 

complement factor H mutation portends a worse outcome, while factor I mutation and 

membrane co-factor protein mutation, and cases not yet characterized, carry a relatively 

benign prognosis. Acquired severe ADAMTS-13 deficiency portends a similar prognosis as 

acquired idiopathic TTP/HUS without severe deficiency, demonstrating a mortality of 

approximately 20%. 

Relapsed Cases: Emerging evidence illustrates the importance of first distinguishing 

idiopathic from relapsed idiopathic and secondary causes, given that prognosis varies 

appreciably between these groups. Specifically, the high survival rate of relapsed patients 

may represent evidence for the importance of early treatment initiation. 

Reference: 

Forzley BR, Clark WF. TTP/HUS and Prognosis: The syndrome and the disease (in 

progress). 

Treating TTP/HUS With Plasma Exchange: A Single Centre’s 25-Year Experience 

Background and Objectives: Thrombotic thrombocytopenic purpura/Haemolytic uremic 

syndrome (TTP/HUS) is a relatively uncommon disorder characterized by unexplained 

haemolytic anaemia and thrombocytopenia. Both disorders are examples of thrombotic 
44

microangiopathies, but in the past have been differentiated on clinical grounds with HUS 

classically affecting the kidney and TTP affecting the brain, kidney and other organs. 

Although outcomes have improved with plasma exchange, modern treatment remains suboptimal with mortality rates of 16-29% in published randomized clinical trials. 

Study objectives were to describe the clinical features, treatment regime and 6-month allcause mortality rate of TTP/HUS patients at the London Health Sciences Centre (LHSC), 

Canada. 

Methods: Data for this retrospective cohort study was obtained from inpatient and 

outpatient records for all patients referred for plasma exchange therapy at LHSC in Canada 

between 1981 and 2006. 

Results: Patients (n=110) were categorized as: idiopathic primary (38%) or relapsed (16%), 

and secondary responsive (30%) or non-responsive (16%). Mortality data were available for 

all but three patients. The all-cause 6-month mortality rate was 19% overall and was 12% 

and 26% among idiopathic and secondary TTP/HUS patients, respectively. Zero mortality 

events occurred among the 17 idiopathic patients who relapsed. Relapsed patients had the 

least severe presenting characteristics, the fastest response time, and severity of clinical 

features decreased between the first and final presentation. 

Conclusion: These findings suggest an excellent outcome for relapsed TTP/HUS patients. 

Patient education, surveillance, and aggressive plasma exchange therapy are hypothesized 

to improve the likelihood of survival: these hypotheses should be tested in a randomized 

controlled trial. 

Reference: 

Forzley BR, Sontrop JM, Macnab JJ, Clark WF. Treating TTP/HUS with plasma exchange: A 

single centre 25-year experience. British Journal of Hematology. 2008; 143:100-6. 

MEASUREMENT AND METHODOLOGICAL CHALLENGES IN OBSERVATIONAL RESEARCH 

The aim of this research program was to evaluate some of the methodological issues 

particular to the WHS and to provide further insight into methodological challenges 

encountered in observational research in general. 

Representativeness And Selection Bias

Background and Objectives: Differences between participants and non-participants is a 

potential source of bias in observational studies such as the WHS. Non-participation may 

results from denial, selective migration or differences in health seeking behaviours. If 

participants differ from non-participants in ways that are related to acute illness and longterm health outcome, then the measure of association may be distorted and the validity of 

the study results threatened. The purpose of this study was to evaluate the 

representativeness of the WHS sample and to discern whether the association between 

symptomatic gastroenteritis and health outcomes differed between early participants and 

those who agreed to participate after more intense recruiting efforts. 
45

Methods: Using multiple data sources, including the 1996 and 2001 Canadian Census, and 

records from the Regional Health Unit, hospital and Walkerton Health Study, we determined 

both sample representativeness and the anticipated effects of intensifying study participant 

recruitment. Selection bias was assessed by examining for differences between initial and 

late participants, and their subsequent risk of having hypertension, proteinuria and reduced 

renal clearance. 

Results: Of the 4,315 participants, 2,756 were permanent residents of Walkerton, 

representing 55% of the town's total population. The sample was demographically similar to 

the population of interest, although statistically women were more likely to participate than 

men (55% of sample were women compared to 52% of population, p<0.01), and the 

proportion of both young and very elderly adults was smaller than expected (13% of sample 

were > 65 years of age compared to 18% of population, p<0.01). Comparing the initial 3,959 

participants to the 356 persons additionally recruited with substantial effort, the latter were 

more likely to be free of symptoms during the outbreak (21% vs. 7%, p<0.001), but were 

otherwise similar in terms of age, sex, the use of medical care resources and underlying 

health state predating the outbreak. The risk of long-term hypertension or renal sequelae did 

not significantly differ between initial and late study recruits. 

Discussion and Interpretation: WHS participants appear to be representative of the 

population of interest. While those recruited through additional efforts were less likely to 

have been acutely ill during the outbreak, they were otherwise comparable to those 

recruited soon after the outbreak. 

Conclusion: Participants of the WHS represent the population of interest, and comprise 

those who were acutely ill during the infected water outbreak. The available study sample 

should provide reasonably unbiased estimates of the associated risk between acute 

bacterial gastroenteritis and long-term health sequelae. 

Reference: 

Garg AX, Macnab JJ, Clark W, Ray JG, Marshall JK, Suri RS, Devereaux PJ, Haynes B. 

Long-term health sequelae following E. coli and campylobacter contamination of municipal 

water. Population sampling and assessing non-participation biases. Canadian Journal of 

Public Health. 2005; 96:125-30. 

 

Recall Bias And The Accuracy Of Self-Report Data

Background and Objectives: The validity of the association between acute infection and 

long-term health sequelae is dependent on the accuracy of exposure definition. Although 

positive stool cultures for known enteric pathogens would provide the best confirmation of 

acute enteric illness in an individual, the submission of stool samples during the outbreak 

was discouraged, in part because the local health services were overwhelmed and the 

outbreak source and causative organisms were already identified. 

The accuracy of self-reported data with respect to severity of gastroenteritis symptoms was 

a major concern in the WHS and was further limited by the prospect of financial 

compensation from the government and the time lag of 2 years between the outbreak and 

study inception. 

Biased recall was empirically demonstrated in 405 participants who were questioned about 

acute symptoms by public health officials just after the outbreak and again by WHS 
46

personnel 2 years after the outbreak: 27% recalled acute symptoms that they denied just 

after the outbreak. 

The overall effect of biased recall on study outcomes is uncertain. Misclassification of truly 

asymptomatic individuals as ill could attenuate or nullify any apparent relationships between 

acute gastrointestinal illness and chronic health outcomes. Alternatively, if individuals with 

long-term health problems exaggerated their recall of initial symptoms, any association 

between exposure and outcome would be artificially amplified. 

The purpose of this study was to characterize and validate a gradient of acute 

gastroenteritis using prior health records to confirm recalled gastrointestinal symptoms at the 

time of the outbreak. 

Methods: Participant survey responses were corroborated with health records at the time of 

the outbreak. Of the 4,135 participants, 1,388 were asymptomatic during the outbreak, 

1,752 had symptoms of acute self-limited gastroenteritis that could neither be confirmed nor 

refuted by prior health records, and 995 had symptoms that necessitated medical attention 

(and thus were confirmed by prior health records). 

To test the reliability of the exposure gradient, the relationship between each grade and five 

health outcomes were assessed, four of these represented plausible sequelae of acute 

gastroenteritis and the fifth represented a distracter, tinnitus, where an association was not 

expected. 

Results: Compared to those with unconfirmed gastroenteritis, participants with confirmed 

gastroenteritis were more likely to describe fever, bloody diarrhea, and prolonged diarrhea 

(all p<0.03). The gradient also correlated with long-term plausible outcomes, including 

chronic gastrointestinal symptoms, chronic symptoms of arthritis or depression, and the 

avoidance of municipal water ingestion after the outbreak (p for trend consistently < 0.03). 

Conversely, for the outcome of chronic tinnitus, an association was neither expected nor 

observed (trend p = 0.26). 

Interpretation and Discussion: The exposure gradient related to the severity of acute 

symptoms experienced during the outbreak. In addition, there was a clear dose-response 

relationship between the exposure gradient and five plausible health sequelae. Conversely, 

as expected, no association was observed for the distracting outcome, tinnitus. 

Although the exposure gradient would be strengthened by the addition of a referent group 

who did not drink the bacterial contaminated water, an insufficient number enrolled in the 

study (<1%). 

Conclusion: We were able to successfully characterize a gradient that can be used in 

future analyses assessing the risk of long-term health sequelae from the outbreak. 

Reference: 

Garg AX, Marshall J, Salvadori M, Thiessen-Philbrook HR, Macnab J, Suri RS, Haynes RB, 

Pope J, Clark W. A gradient of acute gastroenteritis was characterized, to assess risk of 

long-term health sequelae after drinking bacterial-contaminated water. Journal of Clinical 

Epidemiology. 2006; 59:421-28. 
47

Screening And Validation Of Laboratory Data

Background and Objectives: The Kidney Disease Outcomes Quality Initiative has 

recommended the use of GFR estimating equations to detect silent chronic kidney disease 

(CKD) in the community. The benefit of general reporting of CKD must be balanced with the 

harm of mislabeling people who do not have CKD. 

The purpose of this study was to compare the popular Cockcroft-Gault (CG) and 

Modification of Diet in Renal Disease (MDRD) GFR estimating equations to the recently 

devised Rule equation in the Walkerton cohort, which represents a representative 

community-based sample. 

Methods: The study sample (n=2,166) was divided into 2 sub-samples: those with (n=385) 

and without (n=1781) previous renal impairment. 

Results: The prevalence of CKD was CG > MDRD >> Rule estimates. The magnitude of 

difference in prevalence of CKD as detected by the MDRD and CG versus the Rule equation

increases markedly when the subsamples with (30.8 and 29.7 versus 17.5%) and without 

(12 and 11.3 versus 3.0%) previous kidney impairment are compared. General demographic 

and potential or known risk factors were used in a logistic regression model to assess the 

association with CKD. The MDRD estimates note female gender (odds ratio 2.19; 95% CI: 

1.63 - 2.95) and both MDRD and the Rule equations identify hypertension and diabetes as 

significant CKD risk factors. All estimating equations identify age to be associated with CKD. 

The annualized serial decline in GFR was CG > MDRD > Rule estimates. Only the Rule 

GFR estimates detected a greater decline in renal impaired versus unimpaired populations. 

Interpretation and Discussion: This study provides a direct comparison of the prevalence 

of CKD as detected by three different GFR estimating equations in a community-based 

sample. Adoption of the Rule equation to fulfill guidelines issued by the Kidney Disease 

Outcomes Quality Initiative is less likely to identify a large number of a community 

population as having CKD. Use of this GFR estimating equation dramatically reduces the 

number in the Walkerton cohort who are labeled with a diagnosis of CKD and the potential 

emotional, financial, and interventional burden that accompanies that diagnosis. 

Conclusion: The calibrated Rule equation seems to perform better than CG and MDRD 

(CKD 3 versus 11.3 to 12%) but lacks validation against gold standards for communitybased screening. 

Reference: 

Clark WF, Macnab JJ, Chen SJ, Suri R, Moist L, Garg AX. Evaluation of GFR estimating 

equations in the general community: implications for screening. Clinical Journal of the 

American Society of Nephrology. 2006; 1:787-95. 

Measurement, Validation, And Interpretation Of Blood Pressure Data

Background and Objectives: The accurate measurement of blood pressure (BP) in 

epidemiological studies requires standardized conditions, valid instruments, multiple 

measurement and accurate data capture. There are many published guidelines and 

recommendations for standardized conditions for BP measurement and guidelines for 
48

interpretation; however, there is less information on established methods for ensuring data 

quality at the time of data capture. 

When three BP assessments from the same visit are available, it has been recommended to 

drop the first measure to reduce systematic error introduced by initial anxiety. However, this 

assumes that all three measures were obtained using the same device. Because the 

observed BP can also vary with the type of instrument used averaging values obtained 

using different techniques may not result in an increase in reliability. 

This study evaluated whether 1) upper and lower warning limits defined by the 2nd and 98th

percentile of the sample distribution were adequate for flagging potential data entry errors 

across age and sex, 2) whether knowledge of the within subject variability could be used to 

flag potential data entry errors, and 3) whether reliability increases with the number of BP 

measurements in the presence of different measurement methods. 

Methods: As part of the annual health survey, 3 BP measurements were obtained within a 

30 minute period using both an automated oscillometric device and a standard mercury 

sphygmomanometer. Data was entered into a web-distributed data capture system. 

Information collected from the first 4,000 participants was used to refine the range and limit 

checks performed at the time of data entry. 

The 98th percentile of the distribution of within subject variability was used to define a 

warning limit based on excessive within subject variability. This range was then graphically 

compared to the reference ranges for systolic and diastolic pressure. 

The intraclass correlation coefficient was used to estimate the reliability of different 

combinations of BP measurements. Reliability estimates and 95% confidence intervals were 

calculated for mean pressure estimated by: all 3 measures, dropping the first measure, and 

2 dinamap assessments and compared to the highest reliability of any single assessment. 

Results: Simple upper and lower warning limits applied across age and sex were not 

adequate for flagging potential data entry errors. Age and sex-specific reference ranges 

should be used to minimize data entry error. Within-subject variability of >20 mmHg 

(systolic) and >13 mmHg (diastolic) can be used to flag potential data entry errors. 

The first systolic BP was higher than subsequent measurements. Systolic BP was higher 

when measured with the Dinamap 1846sx. Diastolic BP was higher when measured using a 

standard mercury sphygmomanometer. 

Conclusions: To minimize data entry error, age and sex specific reference ranges should 

be used rather than simple upper and lower warning limits. Repeated pressure 

measurements are more reliable than any single measure. When different measurement 

devices are used, the increase in within subject variability leads to a decrease in overall 

reliability. 

Reference: 

Macnab, J. J. and Clark, W. F. Improving the quality of blood pressure data through the use 

of age and sex specific reference ranges and repeated measurements. Proceedings of 

Canadian Cardiovascular Congress: Canadian Hypertension Society. 2004. Calgary, 

Alberta. 
49

The Walkerton Health Study

This article was written by the clinical coordinator of the WHS, Arlene Richards, and 

describes the challenges, infrastructure support, staffing, and recruitment and retention 

efforts required to screen over 4,000 people in a yearly clinic visit. Also described are the 

clinical and laboratory algorithms used to identify participants requiring specialist 

assessment. The article discusses the design of the computer-based survey, advanced 

data entry and display control, and explains why these are essential to ensure accurate data 

entry. 

Reference: 

Richards A. The Walkerton Health Study. Canadian Nurse. 2005; 101:16-21. 

TTP/HUS: Observational Studies Generate Hypotheses That Lead To Randomized 

Controlled Trials

Thrombocytopenic purpura/ haemolytic uremic syndrome (TTP/HUS) is a disease syndrome 

whose history exemplifies how small observational studies can generate hypotheses that 

lead to randomized control trials (RCTs). Moschowitz’s original case report coupled with the 

case findings of Bukowski and Byrne led to an RCT and the Canadian Apheresis Group, 

which together proved that plasma exchange was superior to plasma infusion for the 

treatment of adults with TTP/HUS. In this study we present a single case report of 

continuous plasma exchange coupled with the observations about the pathogenic role of 

von Willebrand multimer protease. 

In 1992 we saw a 72-year old patient with the diagnosis of TTP, who presented with a rapid 

progression to coma, a platelet count of less than 15,000, hemoglobin less than 71 and an 

LDH of greater than 3687, with a serum creatinine of 704 and oligoanuria. The patient had a 

low grade fever and received an initial plasma exchange with deepening in his coma and no 

response either in clinical or laboratory picture to the exchange. The patients low prognostic 

score coupled with his initial lack of response to his initial plasma exchange prompted us to 

embark on a 48-hour, 69 Litre plasma exchange with 179 units of cryosupernatant plasma 

and 14 units of fresh frozen plasma (2 units every 4 hours). Within 24 hours the patient 

awoke from his deep coma and was lucid. He had one further plasma exchange prior to his 

successful discharge from hospital, and he has remained in lasting remission from his TTP. 

In 2008, we retrospectively reviewed our single centre experience with 128 cases of 

TTP/HUS and noted 12% mortality among idiopathic cases and zero mortality events among 

15 patients with relapsing TTP. No association was observed between number of risk 

factors and mortality among patients in this study; however, sicker patients received 

significantly greater volumes of plasma exchange. 

Based on results from our single case report and retrospective review, we hypothesize that 

improved outcomes in TTP/HUS may be possible through urgent initiation of therapy after 

diagnosis and more aggressive use of plasma exchange. We propose to test these 

hypotheses in a multi-centre randomized controlled trial that compares large volume high 

frequency plasma exchange with conventional plasma exchange, and also compares a 

patient education intervention and follow-up strategy to conventional follow-up management. 
50

Reference: 

Clark WF, Forzley BR, Sontrop JM, Kadri A, Moist L, Suri R, Salvadori M, Garg AX. 

TTP/HUS: Observational Studies Generate Hypotheses that Lead to Randomized 

Controlled Trials. Summary in Kidney International. 2009 (in press). 

Future Research Projects Related To Measurement And Methodological Challenges In 

Observational Research

Selective attrition and the effects of loss to follow-up on potential cause-effect relationships 

in the Walkerton Health Study. Investigators: Macnab JJ, Sontrop JM, Moist L, Clark WF. 

Sources of within-subject variability in serial blood pressure measurement. Investigators: 

Sontrop JM, Moist L, Clark WF, Macnab JJ. 

POPULATION HEALTH

Elevated Blood Pressure In Relation To Overweight And Obesity Among Children In A 

Rural Canadian Community

Background and Objectives: Childhood overweight and obesity may result in premature 

onset of cardiovascular risk factors such as hypertension. Rural populations in North 

America may be at increased risk for overweight. We evaluated if overweight and obesity 

were associated with pre-hypertension and hypertension in a well-characterized population 

of children in rural Canada. 

Methods: The study population for this cross-sectional study was comprised of children (4-

17 years) who were participants of the Walkerton Health Study (Canada) in 2004. Prehypertension and hypertension were defined based on percentiles from the average of three 

blood pressure measures taken on a single occasion. Percentiles for body mass index and 

blood pressure were calculated using the 2000 Centers for Disease Control and Prevention 

growth charts. Multinomial logistic regression was used to evaluate the odds for prehypertension and hypertension from overweight and obesity. 

Results: Of 675 children (98.7% white), 122 (18.1%) were overweight and 77 (11.4%) were 

obese. Prehypertension and hypertension were detected in 51 (7.6%) and 50 (7.4%), 

respectively. After adjustment for family history of hypertension and kidney disease, obesity 

was associated with both prehypertension and hypertension. Overweight was associated 

with hypertension but not prehypertension (Figure 23). These associations were observed 

across the genders and children aged <13 and >13 years, except that overweight was not 

associated with hypertension among girls. 

Conclusion: In this population of children living in a rural community in Canada, overweight 

and obesity were strongly associated with elevated blood pressure. Whether blood 

pressure normalizes with improvements in diet, physical activity, and environment is an area 

for further study. 
51

Reference: 

Salvadori M, Sontrop JM, Garg AX, Truong J, Suri R, Mahmud F, Macnab J, Clark WF. 

Elevated blood pressure in relation to overweight and obesity among children in a rural 

Canadian community. Pediatrics. 2008; 122 (4) (in press). 

Figure 23. Adjusted odds for pre-hypertension and hypertension from overweight and 

obesity in pediatric participants of the Walkerton Health Study (adjusted for family history of 

hypertension and kidney disease) (n=675). Reprinted with permission from the Journal 

Pediatrics. 

0.1 0.2 0.5 1 2 5 10

Odds of Pre-hypertensionb

Odds of Hypertensionc

Overweightd

Obesee

Overweightd

Obesee

1.6 [0.8, 3.5]

4.5 [2.2, 9.2]

3.7 [1.8, 7.6]

7.0 [3.3, 14.9]

Adjusted ORa

[95% CI]

aReference category: Normal BMI: >5th to <85th percentile expected for age, sex. bAverage SBP 

or DBP levels >90th to <95th percentile expected for age, sex, and height or average blood 

pressure levels >120/80 mm Hg among adolescents. cAverage SBP or DBP levels >95th percentile 

expected for age, sex, and height, or previous medical diagnosis or use of hypertensive 

medications. dBMI >85th to <95th percentile expected for age, sex. eBMI >95th percentile 

expected for age, sex.

Factors that Led to the Walkerton Tragedy 

In May 2000 bacterial contamination of municipal water in Walkerton, Ontario resulted in the 

worst public health disaster involving municipal water in Canadian history. At least 7 people 

died and 2300 became ill. This paper reviews factors that led to the Walkerton tragedy as 

described by the public inquiry led by Judge Dennis O’Connor, which examined the events 

and delineated the causes of the outbreak including: physical causes, the role of the Public 

Utilities operators, the Public Utilities Commissioners, the Ministry of the Environment (MOE) 

and the provincial government. 

Improper practices and systemic fraudulence by the public utility operators, the recent 

privatization of municipal water testing, the absence of criteria governing quality of testing 
52

and lack of provisions made for notification of results to multiple authorities all contributed to 

the crisis. The MOE noted significant concerns two years prior to the outbreak, however no 

changes resulted because voluntary guidelines as opposed to legally binding regulations 

governed water safety. The inquiry concluded that budgetary restrictions introduced by the 

provincial government four years prior to the outbreak were enacted with no assessment of 

risk to human health. The ministers and the cabinet had received warnings about serious 

risks. Budgetary cuts destroyed the checks and balances that were necessary to ensure 

municipal water safety. 

Reference: 

Salvadori M, Sontrop JM, Garg AX, Moist LM, Suri R, Clark WF. Factors that led to the 

Walkerton tragedy. Summary in Kidney International. 2009 (in press). 

Environmental Prevention Of Human Disease From Verocytotoxin-Producing 

Escherichia Coli

Verocytotoxin-producing Escherichia coli (VTEC) haemolytic uraemic syndrome (HUS) is an 

important cause of mortality and renal failure worldwide. For those patients who need 

medical attention, no treatment aside from supportive care has proven effective for this 

disease. This has prompted a broader look at environmental prevention, with a particular 

emphasis on the transmission of bacteria from animal carriers to human beings. This paper 

reviews animal- and meat-handling strategies to reduce the burden of VTEC human 

disease.

Cattle are the main livestock reservoir for VTEC, particularly E. coli O157:H7. Its prevalence 

in the faeces of North American cattle ranges from 10 to 28%, with a recent study finding 

96% of feedlots and 52% of pens having at least one positive faecal sample. Other farm 

animals and pets also shed VTEC. Efforts to reduce the survival and transmission of VTEC 

have focused on farm management and disinfectant practices, and strategies to increase 

animal resistance to infection, such as the use of antibiotics, vaccines and probiotics. 

Trucks that transport animals between farms and processing plants can serve as a source of 

infection for cattle and processing plants. Universal contamination of truck sidewalls and 

floors with generic E. coli has been reported. Cleaning trucks with heat and sodium 

hypochlorite drastically reduces coliform numbers transported by poultry, and is most 

effective when it is performed after each load. When transport trucks do remain 

contaminated, it is often because procedures were not followed. 

In Canada and the United States, mandatory performance standards for meat processing 

plants implemented through Hazard Analysis Critical Control Point (HACCP) systems. 

Since the mandatory implementation of HACCP in the United States, the incidence of E. coli 

O157 has decreased by >40%. 

In the kitchen, special care is needed to avoid transmission of bacteria from meat to other 

foods being prepared. Organisms persist on kitchen surfaces if there is inadequate 

cleaning. Proper hand washing remains essential. The United States Food and Drug 

Administration recommends cooking ground beef to an internal temperature of 71◦C (160◦F). 
53

Reference: 

Khanna R, Waechter L, Sargeant J, Clark WF, Garg AX. Environmental prevention of 

human disease from verocytotoxin-producing Escherichia coli. Nephrology Dialysis 

Transplantation. 2008; 23:1819-22. 

Local Water Diversely Known: Walkerton, Ontario 2000 And After

This study is a historian’s analytical account of the water contamination outbreak in 

Walkerton, Ontario, in 2000-2002. The local priorities defining good water were considered. 

These vernacular understandings emphasized taste, softness, and thrift in municipal water, 

and they highly valued local sovereignty in matters of water quality, and solidarity as a 

quality of local citizenship. By using contemporaneous evidence from media reports and the 

judicial enquiry into the incident; the author traced how the qualities of good water were 

redefined, and with them community standards of safety, expertise, and risk. The emphasis 

on community consent to vernacular water monitoring practices and the implications of this 

shared responsibility differ from the journalistic and judicial accounts which emphasize 

individual culpability. 

Reference: 

Parr J. Local water diversely known: Walkerton, Ontario 2000 and after. Environment and 

Planning D: Society and Space. 23(2): 251-271. 2005. 

Future Research Projects Related To Population Health

The Walkerton longitudinal study on the effects of aging on renal function. Investigators: 

Clark WF, Garg AX, Macnab JJ, Moist L, Salvadori M, Sontrop JM, Suri RS. 

Impact of surveillance on blood pressure control in the Walkerton Health Study. 

Investigators: Moist L, Sontrop JM, Macnab JJ, Clark WF. 

Longitudinal study of body mass index and hypertension in children in a rural community. 

Investigators: Salvadori M, Sontrop JM, Macnab JJ, Suri R, Clark WF. 

Community perception of the Walkerton Health Study. Investigators: Parr J. 

SUMMARY OF RESEARCH ACCOMPLISHMENTS 

Published 

Manuscripts 

1. A gradient of acute gastroenteritis to assess risk of long-term 

health sequelae after drinking bacteria contaminated water. Garg AX, 

Marshall J, Salvadori M, Thiessen-Philbrook H, Macnab J, Suri R, Haynes 

B, Pope J, Clark WF. J Clin Epidemiol. 2006; 59(4):421-8. 

2. Incidence and epidemiology of Irritable Bowel Syndrome after a 

large waterborne outbreak of bacterial dysentery. Marshall JK, 

Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM for the WEL 

Investigators. Gastroenterology. 2006; 131(2):445-50. 

3. Absence of renal sequelae after childhood Escherichia coli 

O157:H7 gastroenteritis. Garg AX, Clark WF, Salvadori M, Thiessen-
54

Philbrook HR, Matsell D. Kidney Int. 2006; 70(4):807-12. 

4. Evaluation of GFR estimating equations in the general community: 

implications for screening. Clark WF, Macnab JJ, Chen S, Suri R, Moist 

L, Garg AX. Clin J Am Soc Nephrol. 2006; 1:787-795. 

5. Risk of hypertension and reduced kidney function after acute 

gastroenteritis from bacteria-contaminated drinking water. Garg AX, 

Moist L, Matsell D, Thiessen-Philbrook HR, Haynes RB, Suri RS, Salvadori 

M, Ray J, Clark WF. Can Med Assoc J. 2005; 173(3):261-8. 

6. Diabetes during diarrhea-associated haemolytic uremic syndrome: 

a systematic review and meta-analysis. Suri RS, Clark WF, Barrowman 

N, Mahon JL, Thiessen-Philbrook HR, Rosas-Arellano MP, Zarnke K, 

Garland JS, Garg AX. Diabetes Care. 2005; 28(10):2556-62. 

7. Causes of reversible nephrogenic diabetes insipidus: a systematic 

review. Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, 

Clark WF. Am J Kidney Dis. 2005; 45(4):626-37. 

8. Long-term health sequelae following municipal water contaminated 

with Escherichia coli O157 and Campylobacter species: Population 

sampling and assessing non-participation biases. Garg AX, Macnab 

JJ, Clark WF, Ray JG, Marshall JK, Suri RS, Devereaux PJ, Haynes RB. 

Can J Public Health. 2005; 96(2):125-30. 

9. Microalbuminuria three years after recovery from E. coli O157 

haemolytic uremic syndrome due to municipal water contamination.

Garg AX, Clark WF, Salvadori M, Macnab JJ, Suri RS, Haynes RB, Matsell 

D. Kidney Int. 2005; 67(4):1476-82. 

10. The long-term renal prognosis of diarrhea associated haemolytic 

uremic syndrome: a systematic review, meta-analysis and metaregression. Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, 

Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF. JAMA. 2003; 

290(10):1360-70. 

11. Intestinal permeability in patients with irritable bowel syndrome 

after a waterborne outbreak of acute gastroenteritis in Walkerton, 

Ontario. Marshall JK, Thabane M, Garg AX, Meddings J, Clark WF, Collins 

SM. Ailment Pharmacol Ther. 2004; 20:1317-22.

12. Genetic risk factors for post-infectious IBS in the E. coli O157:H7 

outbreak in Walkerton (Canada) in 2000. Villani A, Lemire M, Thabane 

M, Geneau G, Belisle A, Fortin G, Franchimont D, and Marshall JK.

Gastroenterology. 2008; 134(4), Suppl. 1, pp A-122.

13. The Walkerton Health Study. Richards A. Can Nurse. 2005; 101(5):16-

21. 

14. Local water diversely known: Walkerton Ontario, 2000 and after. 

Parr J. Environment and Planning D: Society and Space. 2005; 23:251-71.

15. Campylobacter reactive arthritis: a systematic review. Pope JE, 

Krizova A, Garg AX, Thiessen-Philbrook H, Ouimet JM. Semin Arthritis 

Rheum. 2007; 37:48-55.

16. Arthritis risk after acute bacterial gastroenteritis. Garg AX, Pope JE, 

Thiessen-Philbrook H, Clark WF, Ouimet J. Rheumatology (Oxford). 2008; 

47:200-204.

17. Albuminuria and estimated GFR 5 years after Escherichia coli 

O157:H7 haemolytic uremic syndrome. Garg AX, Salvadori M, Okell J, 

Thiessen-Philbrook H, Suri RS, Filler G, Moist L, Matsell D, Clark WF. Am J 

Kidney Dis. 2008; 51:435-44.
55

18. Excessive fluid intake as a novel cause of proteinuria. Clark WF, 

Kortas C, Suri RS, Moist LM, Salvadori M, Weir MA, Garg AX. CMAJ. 

2008; 178:173-75.

19. Environmental prevention of human disease from verocytotoxinproducing Escherichia coli. Khanna R, Waechter L, Sargeant J, Clark 

WF, Garg AX. Nephrol Dial Transplant. 2008; 23:1819-22.

20. Treating TTP/HUS with plasma exchange: A single centre 25-year 

experience. Forzley B, Sontrop JM, Macnab J, Clark WF. British Journal of 

Hematology. 2008; 143:100-6.

21. Pediatric hypertension in relation to obesity in a rural Canadian 

Community. Salvadori M, Sontrop JM, Garg AX, Truong J, Suri RS, 

Mahmud F, Macnab JJ, Clark WF. Pediatrics Electronic Pages. 2008; 122 

(4) (in press).

22. Factors that led to the Walkerton tragedy. Salvadori M, Sontrop JM, 

Garg AX, Moist LM, Suri R, Clark WF. Summary in Kidney Int. 2009 (in 

press).

23. TTP/HUS: Observational studies generate hypotheses that lead to 

randomized controlled trials. Clark WF, Forzley BR, Sontrop JM, Kadri A, 

Moist L, Suri R, Salvadori M, Garg AX. Summary in Kidney Int. 2009 (in 

press).

24. Relationship between E. coli O157:H7 and Diabetes Mellitus. Suri 

RS, Mahon JL, Clark WF, Moist LM, Salvadori M, Garg AX. Summary in 

Kidney Int. 2009 (in press).

25. Post-infectious irritable bowel syndrome following water 

contamination. Marshall JK. Summary in Kidney Int. 2009 (in press).

26. An outbreak of diarrhea-associated haemolytic uremic syndrome: 

The Walkerton epidemic. Matsell D, White, CT. Summary in Kidney Int. 

2009 (in press).

Manuscripts for 

Imminent 

Submission 

1. Long-term risk of dysglycemia after E. coli O157:H7 gastroenteritis: 

The Walkerton Health Study. Suri RS, Mahon JL, Clark WF, Garg AX. 

2. Risk of pregnancy-related hypertension within five years of 

exposure to bacteria-contaminated drinking water. Moist L, Sontrop 

JM, Garg A, Suri R, Salvadori M, Gratton R, Clark WF, Macnab JJ. 

3. TTP/HUS and prognosis: The syndrome and the disease. Forzley B, 

Clark WF. 

4. Polyuria is associated with mild proteinuria in the general 

population. Sontrop JM, Suri R, Sultan N, Macnab J, Moist L, Clark WF. 

5. Fluid loading causes an increase in urinary protein excretion. Weir 

MA, Sontrop JM, Kortas CM, Clark WF. 

Presentations 1. Department of Epidemiology and Biostatistics, The University of 

Western Ontario. Methodology Seminar Series: The Walkerton Health 

Study: The Role of the Epidemiologist. April 23, 2003. Macnab JJ. 

2. American Society of Nephrology Annual Meeting 2004. 

Association of Common Measures of Kidney Function; Year 1 and 2 

of the Walkerton Screening Clinic. Clark WF.

3. Department of Epidemiology and Biostatistics, The University of 

Western Ontario. Methodology Seminar Series: The Walkerton Health 

Study: Methodological Challenges and Research Opportunities. January 

13, 2004. Macnab JJ.

4. Proceedings of Canadian Cardiovascular Congress: Canadian 

Hypertension Society 2004. Poster presentation: Improving the 
56

Quality of Blood Pressure Data through the Use of Age and Sex 

Specific Reference Ranges and Repeated Measurements. Macnab JJ 

and Clark WF. 

5. American Gastrointestinal Association 2005. Oral presentation: 

Post-infectious Irritable Bowel Syndrome after the Walkerton 

Outbreak of Waterborne Gastroenteritis. Marshall JK.

6. School of Rehabilitation Science Graduate Seminar Series: The 

Walkerton Health Study. May 26, 2005. Macnab JJ. 

7. Faculty of Epidemiology, McGill University, The Walkerton Health 

Study. Clark WF. 

8. American Society of Nephrology 38th Annual Meeting: Screening 

Healthy Populations for Chronic Kidney Disease: A Tale of Three 

Estimating Equations. Clark WF et al.

9. Canadian Society of Nephrology Annual Meeting 2006. Oral 

presentation: Chronic High Fluid Intake may be Injurious to Your 

Kidneys. Clark WF et al.

10. Canadian Society of Nephrology Annual Meeting 2006. Poster 

presentation – Absence of Renal Sequelae after Childhood E. coli

O157:H7 Gastroenteritis. Garg AX et al.

11. Canadian Society of Nephrology Annual Meeting, 2006 Poster 

presentation: K\DOQI and Prevalence of Chronic Kidney Disease in a 

Community. Clark WF et al.

12. American Gastrointestinal Association 2006. Oral Presentation: 

Prognosis in Post-Infectious Irritable Bowel Syndrome: A Four Year 

Follow Up After Walkerton Waterborne Outbreak of GastroenteritisMarshall JK et al. Abstract in Gastroenterology 2006; 130 (4, Suppl 2): A52, Abstract 344. 

13. American Gastrointestinal Association 2007. Oral presentation: 

Prognosis in Post-Infectious Irritable Bowel Syndrome: A Six Year 

Follow Up After Walkerton Waterborne Outbreak of Gastroenteritis. 

Marshall JK et al. Abstract appears Gastroenterology 2007; 132 (4, Suppl 

2): A-384, Abstract 

14. American Society of Nephrology Annual Meeting 2007. Poster 

presentation: Absence of Major Renal Sequelae 5 Years after E. coli

O157 Haemolytic Uremic Syndrome. Garg AX et al.

15. American Society for Apheresis 2008. Poster presentation: 

Treating TTP/HUS with Plasma Exchange: A Single Centre 25-year 

Experience. Forzley BF et al.

16. The 40th Annual Meeting of the Canadian Society of Nephrology, 

2008. Poster presentation: Polyuria is a major risk factor for 

proteinuria in the general population. Sontrop JM et al.

17. The 40th Annual Meeting of the Canadian Society of Nephrology, 

2008. Poster presentation: Fluid Loading Causes an Increase in 

Urinary Protein Excretion. Weir MA, Sontrop JM, Clark WF. 

18. The 40th Annual Meeting of the Canadian Society of Nephrology, 

2008. Poster presentation: Albuminuria and Estimated GFR 5 years 

After E. coli O157:H7 Haemolytic Uremic Syndrome: An Update. Garg 

AX et al.

19. Canadian Society of Nephrology 40th Annual Meeting. May 28- 

June 1, 2008. Long-Term Risk of Dysglycemia after E. coli O157:H7 

Gastroenteritis: The Walkerton Health Study. Suri RS et al.
57

External Grants 

- Funded 

1. Kidney Foundation Grant ($100,000) 2002 – 2004 

2. Canadian Diabetes Association Grant ($65,000) 2003 – 2005 

3. High Volume Proteinuria, DAF ($15,000) 

4. Crohn’s and Colitis Foundation of Canada ($360,000) 2005-2008 

5. Hypertension during Pregnancy after exposure to water contaminated 

with E. coli O157:H7 and Campylobacter, LHRI ($13,000) 

6. Long-term Risk of Chronic Arthritis after Campylobacter Infection: The 

Walkerton Health Study, Canadian Institute of Health Research ($98,201) 

DISSEMINATION OF RESULTS 

An important goal of the Walkerton Health Study was to disseminate research findings to a 

wide audience that included both the Walkerton community and the research community. 

Dissemination of results to the Walkerton community was primarily accomplished through 

newspaper articles and Town Hall meetings, which were held annually in Walkerton. During 

Town Hall meetings, WEL investigators presented results from the previous year, 

highlighted any new initiatives for the upcoming year and answered questions from the 

public. 

Participants received an annual summary report, and highlights of the previous year’s 

findings were reported in the Walkerton Herald Times in January and/or February of each 

year (see examples in Appendix I). These articles also contained information on 

participation, recruitment, and upcoming specialty clinics. Finally, a monthly series of 

articles written by WEL investigators appeared in the Walkerton Herald Times providing a 

lay-description of hypertension, diabetes, dyspepsia, arthritis, irritable bowel syndrome, E. 

coli O157 and Campylobacter (see Appendix I). 

Dissemination of results to the research community occurred primarily through publications 

in peer reviewed scientific journals and presentations at conferences. Presentations were 

also made to both faculty and students at both the University of Western Ontario and McGill 

University. In addition, highlights from the study were shared with the medical community at 

a special symposium that focused on thrombotic thrombocytopenic purpura / haemolytic 

uremic syndrome (TTP/HUS). This symposium took place in London, Ontario (June 1-2, 

2008) and was planned to coincide with the Canadian Society of Nephrology 40th Annual 

Meeting (London, Ontario, May 28 to June 1, 2008). 

The purpose of the HUS/TTP symposium was to present findings on the long-term 

outcomes following exposure to E. coli O157:H7. A half-day session was reserved for the 

presentation of results from the Walkerton Health Study. Additional topics included 1) the 

presentation of recent scientific advances about thrombotic microangiopathies to improve 

therapeutic and diagnostic strategies, 2) a comparison of current models of care in the 

treatment of HUS/TTP, and 3) a discussion of some of the basic controversies surrounding 

treatment of HUS/TTP. Symposium presenters included WEL investigators as well as 

researchers from Health Canada, University of Oklahoma Health Science Center, 

Washington University School of Medicine, and the Canadian Apheresis Group. The 

symposium was attended by 120 people from Canada and the United Sates and included 

physicians, nurses and academics. Summaries of the presentations will be published in the 

journal Kidney International. The symposium agenda is provided in Appendix II. 
58

DISCUSSION AND COMMENTARY 

The most serious case of water contamination in recent Canadian history occurred in May of 

2000, when the municipal water of Walkerton, Ontario, was contaminated with E. coli

O157:H7, campylobacter species and salmonella resulting in 2,300 cases of gastrointestinal 

illness, more than 750 emergency room visits, 65 hospital admissions, 27 recognized cases 

of haemolytic uremic syndrome (HUS) and seven deaths. The Walkerton Health Study 

(WHS) was funded by the Ontario Ministry of Health and Long-Term Care to meet both the 

needs of the community and provide a unique opportunity to characterize the association 

between acute bacterial gastroenteritis and chronic diseases, including arthritis, 

hypertension, renal disease, diabetes, post-infectious irritable bowel syndrome, and 

inflammatory bowel disease. Over seven years, more than 4500 citizens of Walkerton and 

surrounding area have voluntarily participated in the health study. In the clinical realm, a 

wide range of undetected health problems were identified. The major concerns identified in 

the initial screening related to complications that primarily addressed four (4) major clinical 

groupings: 

1) hypertension and kidney disease 

2) irritable bowel syndrome 

3) diabetes mellitus 

4) acute reactive arthritis. 

Among participants with hypertension, the number that received treatment increased 

substantially from 18% in 2002 to 70% by 2008, with over a 50% decline in uncontrolled 

hypertension from the inception of the study to its last clinic in 2008. The screening process 

identified 459 adults with potential renal disease and 436 were seen at least once by a 

nephrologist in Walkerton. Although the majority required only one assessment for specific 

diagnostic advice and treatment, 126 were reassessed up to 6 times for specific further 

treatment and advice. In terms of children with kidney disease, 245 of the 250 identified 

were seen by a paediatric nephrologist and the minority that had renal disease at the time of 

this assessment or those who had experienced HUS at the time of the outbreak were 

provided with annual follow-up appointments and specific treatment where necessary. Over 

811 patients were identified by our screening questionnaire and invited to attend yearly 

information sessions on the Irritable Bowel Syndrome. The Walkerton Health Study clinic 

was responsible for creation and distribution of 1200 copies of a booklet outlining treatment 

strategies for Irritable Bowel Syndrome and 555 participants received an individual 

consultation with a gastroenterologist for specific diagnosis, treatment and advice. 

Concerns about the increased incidence of Diabetes Mellitus noted in a systematic medical 

literature review of haemolytic uremic syndrome, the most severe complication of the water 

contamination led to a widespread screening program and identified over 783 patients who 

had dysglycemia and almost 619 agreed to glucose tolerance testing, which resulted in the 

identification of 45 new diabetics requiring follow-up and treatment with 51 being in the prediabetic range and asked to visit their family physician for annual monitoring. In the area of 

acute reactive arthritis, over 260 participants were identified after screening and were 

assessed by a rheumatologist and provided with specific advice on what to do with their 

mechanical or musculoskeletal complaints. As in most generalized screening programs, the 

majority of clinical assessments and interventions by specialists who came to the Walkerton 

area community were thought to be unrelated to the water contamination but could be 

considered non-specific detection benefits of a screening study. In the last year of the study 

over 88% of the participants reported their health as being good to excellent. 
59

Research from the Walkerton Health Study has spanned a number of clinical problems, but 

among the most salient findings was the 30% increased risk of hypertension and renal 

impairment observed in those who experienced the gastroenteritis thought due to E. coli 

O157:H7. This is important not only for the citizens of Walkerton but also for the long-term 

follow-up of individuals who experience gastroenteritis secondary to E. coli O157:H7 every 

year in Canada. The very low incidence of long-term complications among children who 

suffered haemolytic uremic syndrome is also an important new finding that suggests that the 

prognosis in water borne E. coli O157:H7 cases of haemolytic uremic syndrome may be 

milder, but requires even longer term observation in a minority that have early signs of 

progressive impairment. The negative findings of an association of incident cases of 

Diabetes Mellitus secondary to gastroenteritis is important since this alleviates concerns 

raised by several studies that noted an increased incidence of Diabetes Mellitus in those 

with the most severe form of illness related to E. coli O157:H7 that resulted in haemolytic 

uremic syndrome. The finding that Irritable Bowel Syndrome is associated with increased 

permeability has major import in terms of the pathogenesis of the Irritable Bowel Syndrome 

and also its potential association with Inflammatory Bowel Disease has opened up a new 

area of research investigation. 

The WEL Investigators and the Investigators of the Irritable Bowel Syndrome Group have 

been highly productive with 24 current peer reviewed publications, 6 in press and 10 

undergoing preparation following the final compilation of the 7-year longitudinal results. 

Although the Walkerton Health Study appears to have had a productive clinical and 

research output not all participants have had resolution of their health related problems. The 

study has benefited from the dedicated efforts of the screening team in Walkerton as well as 

a diverse group of clinical and research investigators from the University of Western Ontario, 

London Health Sciences Centre and McMaster University. Major recognition for the success 

of this seven year longitudinal study must be directed to the participants. These members of 

the Walkerton community and surrounding area have freely given of themselves to 

participate over an extended period of time in an intrusive and invasive clinical and 

experimental study, following a tragic set of circumstances. The annual town hall meetings 

and daily interactions in the clinic provided the opportunity for community input that shaped 

the focus of the annual screening study. It has been a privilege to participate with these 

individuals, whose efforts will result in improved clinical outcomes and significant new 

research findings that will benefit not only their community but many others. 
60

APPENDIX I: DISSEMINATION OF RESULTS AND EFFORTS TO 

ENCOURAGING RETENTION AND RECRUITMENT IN THE WHS 

An important goal of the Walkerton Health Study was to disseminate research findings to a 

wide audience that included the Walkerton community as well as the research community. 

Dissemination of results to the Walkerton community was primarily accomplished through 

newspaper articles and Town Hall meetings, which were held annually in Walkerton. During 

Town Hall meetings, WEL investigators presented results from the previous year, 

highlighted any new initiatives for the upcoming year and answered questions from the 

public. 

Participants also received an annual summary report, and highlights of the previous year’s 

findings were reported in the Walkerton Herald Times in January and/or February of each 

year. Two examples of articles highlighting study results from the previous year are 

provided below. 

EFFORTS TO ENCOURAGE RECRUITMENT AND RETENTION

Recruitment and retention were essential for the success of the WHS. Before the screening 

clinic opened each year, an extensive advertising campaign was mounted in the local 

newspapers, radio, and Cable TV. Posters were displayed in hospitals, physician offices, 

pharmacies, the library and other strategic locations around town and flyers were inserted 

into all of the town’s post office boxes. Every opportunity was taken for interviews with the 

local and national media. 

An example of a flyer used to advertise the WHS is provided below. This is followed by an 

example of a newspaper advertisement highlighting the study and participation 

opportunities. 
61

Results of Year 1 Walkerton Health Study (2002)

In 2002, the first year of the Walkerton Health Study, 4,420 people registered and 3,959 

completed the screening. Listed below are graphs indicating 

• the prevalence of illness and diarrhea among the participants and 

• the number of participants referred for further investigations. 

Exposure Diarrhea 

did not drink water 1.74%

drank water - well

32.28%

drank water - mild illness 5.15%

drank water - mild diarrhea

10.71%

drank water - severe diarrhea

32.26%

drank water - bloody diarrhea

17.86%
62

Referral Clinical Care Pathways 

*Neph Nephrology or Kidney 

*Neuro Neurology 

*GI Gastrointestinal 

*Rheum Rheumatology 

*Counsel Counseling 

Walkerton and 

surrounding area 

Registered Year 1 

4420 

Participated Year 1 

3959

*Neph

300 

*Neuro 

98 

*GI 

402 

*Rheum 

109 

Adult 

197 

Child 

103 

Clinical Algorithms 

1140

213 

121 

21 428 130 46

*Counsel 

231 
63

Results of Year 2 Walkerton Health Study (2003) 

In year 2, an additional 356 people joined the study for a total of 3,373 who completed the 

screening. Almost 80% of the participants from the Walkerton area returned for the year 2 

screening while some deferred their scheduled reassessment until the following year. 

Based on the 2001 Census, approximately 57% of the residents of Walkerton have 

participated in the Walkerton Health Study. 

Exposure History: 

Ninety-eight percent of the participants reported drinking the water and 66% reported being 

ill at the time of the outbreak. The most common complaint was diarrhea, followed by 

cramps. Compared to year 2 participants, participants entering the study in year 1 were 

only slightly more likely to have been sick at the time of the outbreak. As well, they were 

significantly more likely to have experienced bloody diarrhea, cramps and/or fever. They 

were also significantly more likely to have visited a doctor or hospital for blood or stool 

testing. Overall 28% of participants made a phone call to a doctor while only 19% visited a 

hospital or Emergency Department. 

Previous Health Conditions: 

Approximately 16% of the participants had previously been diagnosed with hypertension 

(High Blood Pressure) and approximately 10% with affective disorder, such as stress and 

anxiety disorder. Other conditions and diseases previously diagnosed were kidney disease, 

diabetes, heart attack, stroke, irritable bowel syndrome, Crohn’s disease, ulcerative colitis, 

gallstones, and bloody diarrhea. 

Diabetes Study: 

In year 2, the Walkerton Health Study concentrated on identifying the long-term risk of 

Diabetes Mellitus after exposure to E. coli. All participants over the age of 10, who did not 

have a diagnosis of diabetes, were asked to withhold eating and drinking for 8 hours prior to 

their appointment. A fasting blood sugar was performed. Eight new cases of diabetes were 

identified. In addition, 283 participants were identified as requiring more in depth testing 

(Oral Glucose Tolerance Testing). Because of this intensive testing, a further 10 people 

(6%) were identified as having sugar diabetes bringing the total number of diabetics to 18. 

Another group of 25 (15%) were identified as having borderline sugar levels and have been 

provided with lifestyle modification recommendations. All newly identified diabetics have 

been referred back to the care of their family physicians. 

Gastrointestinal Health Problems: 

In addition to offering specialty consultations, participants were offered Educational Group 

Sessions with a Gastroenterologist. As well, an information booklet on Irritable Bowel 

Syndrome was specifically developed by Dr. Howard for the people of Walkerton and area. 

Approximately 550 participants with on-going bowel complaints received the booklet. In 

addition, the booklets were distributed to the local family physician’s offices and to the local 

library. 171 participants were identified as requiring a Gastrointestinal consultation and 95 

an Educational Group Session. 

Nephrology (Kidney): 141 adults and 82 children were identified as requiring follow-up with 

a kidney specialist. 
64
65

Example of a Newspaper Article to Encourage Participation/Retention

The Walkerton Health Study (WHS) Year 4 screening clinic opened on March 14th, 2005 and will 

remain open till July 22nd, 2005. The screening clinic hours are from 7:30 AM to 3:30 PM with limited 

evening and weekend appointments. 

Goals: The Year 4 goals remain very similar to those of previous years: 

• To treat people with illness related to the water contamination in May 2000 

• To identify the silent and long-term complications 

• To refer those identified for more complete investigation and treatment 

• To reduce and prevent long-term complications 

The Screening Clinic: The appointment includes weight, height, blood pressure measurements and 

a short interview followed by laboratory testing. The main focus this year is on sugar diabetes. 

Therefore, we are asking all non-diabetics, over the age of 10 years, and non-pregnant women to 

provide a blood sample after an eight hour fast. 

Pregnancy after the Water Contamination: The people of Walkerton have expressed concerns 

about the impact contaminated water could have on future pregnancies. This year the WHS will 

retrospectively investigate whether women who drank contaminated water have an increase risk of 

developing hypertension (high blood pressure). We will find these answers by comparing the 

outcomes of women who had severe diarrhea at the time of the outbreak to women who were well. 

Also, we will compare Walkerton women with women from rural, Southwestern Ontario. We 

encourage all women who became pregnant after May of 2000 to attend the screening clinic so 

that we can answer these questions. 

What is Happening Now 

• Booking Year 4 screening appointments 

• Booking educational group sessions on irritable bowel syndrome with a Gastroenterologist 

• Booking Adult Nephrology consults 

What is Happening Next 

• Performing a more sensitive diabetic test on those whose tests indicate they may be prediabetic 

• Paediatric Nephrology consults 

• Nephrology follow-up consults with all HUS children 

• Newly diagnosed sugar diabetes consults 

• Town Hall Meeting with the WEL Investigators in November, 2005 to report Year 4 findings 

Why Screening is Important 

• Early detection of sugar diabetes 

• Early detection of kidney disease and subsequent treatment and prevention of progression 

• Intervention for gastrointestinal illness related to the water contamination 

• Monitoring for high blood pressure 

• Monitoring for many other illnesses like heart disease, stroke, arthritis, inflammatory bowel 

disease, etc 

Please consider this your personal invitation to stay involved with 

the Walkerton Health Study. Book your appointment today 

by calling (519) 881-1476.
66

NEWSPAPER ARTICLES CONTAINING LAY-DESCRIPTIONS OF WHS RESEARCH FOCI AND 

MEDICAL CONDITIONS RELATED TO THE WALKERTON WATER CONTAMINATION OUTBREAK

A series of articles were written by WEL investigators appeared regularly in the Walkerton 

Herald Times. The purpose of these articles was to provide a lay-description of WHS 

research foci and medical conditions related to the outbreak including hypertension, 

diabetes, dyspepsia, arthritis, irritable bowel syndrome. 

Diabetes and the Walkerton Water Contamination of May 2000.

By Dr. William F. Clark, MD, FRCPC, WEL Investigator

What does sugar diabetes (diabetes mellitus) have to do with the water contamination of 

2000 in Walkerton? This is a question that Dr. Rita Suri and the WEL Investigators of the 

Walkerton Health Study, through the participation of Walkerton and area citizens, have 

attempted to answer. 

E. coli O157:H7, a contaminant in the municipal water in the Spring of 2000, is known to 

cause Hemolytic Uremic Syndrome (HUS) in less than 2–7 % of those who develop acute 

gastroenteritis. Kidney involvement is a major feature of HUS. Small blood vessels in the 

kidney are occluded (blocked) by blood clots resulting in scarring and loss of function. In a 

minority of people, isolated case reports have also shown that the blood vessels supplying 

the Islets of Langerhans in the pancreas are occluded by blood clots resulting in loss of 

function. The Islets of Langerhans supply insulin and the loss of function can cause diabetes 

mellitus. Dr. Suri and the WEL Investigators carried out a systematic review of the medical 

literature to determine the incidence of diabetes mellitus following HUS. This review, which 

was published in Diabetes Care in 2005, revealed a major increase in the incidence of 

diabetes mellitus in children who had suffered from severe HUS. 

Dr. Suri and the WEL Investigators wished to determine if all individuals, not just the small 

number with HUS who suffered severe gastroenteritis, were at an increased risk of 

developing diabetes mellitus. This concern resulted in two years of studies looking at the 

glucose metabolism of participants in the Walkerton Health Study. These investigations 

resulted in the diagnosis of many silent (undiagnosed, pre-existing) cases of diabetes 

mellitus and others in the pre-diabetic stage. Since 2002, the Walkerton Health Study has 

identified 71 new diabetics and 144 in the pre-diabetic stage. The advantage of diagnosing 

silent diabetes and those in the pre-diabetic stage is that it gives individuals the opportunity 

to make significant lifestyle changes, which will benefit them and prevent or reduce future 

complications. As well, there is encouraging news. It appears that, at this time (preliminary 

results), there may not be an increase in diabetes mellitus in the general population of 

Walkerton who suffered severe gastroenteritis at the time of the water contamination in May 

2000. Dr. Suri, on behalf of the WEL Investigators, thanks all who participated in this study, 

the first of its kind in the world. 
67

Dyspepsia

By Dr. Alex Ford MBChB, MD.,MRCP in association with 

Dr. J.K. Marshall MD, MSc, FRCPC, WEL Investigator 

What is Dyspepsia? 

Dyspepsia is a term that doctors use to describe a variety of symptoms that are thought to 

come from the esophagus (stomach tube), stomach and duodenum (upper, small bowel). 

Symptoms can include heartburn, acid reflux and pain in the upper part of the abdomen. 

These symptoms are very common in the general population, with almost half of people 

experiencing them at one time or another. Some sufferers will make an appointment to see 

their family physician as a result of symptoms, and may be sent for tests to find a cause. 

Testing and Diagnoses 

The most common test ordered is an endoscopy, a telescopic camera examination that 

allows the doctor to look inside the esophagus, stomach and duodenum. This may help 

diagnose certain conditions such as gastro-esophageal reflux disease (where acid refluxes 

out of the stomach and damages the lower end of the esophagus by causing inflammation), 

peptic ulcer disease (stomach or duodenal ulcers), or more seriously, but very rarely, a 

cancer of either the stomach or esophagus. Usually, the endoscopic examination offers no 

obvious explanation for the symptoms of dyspepsia. In this situation, the patient is said to 

suffer from a condition called “functional dyspepsia”. Their physician may offer medication 

to relieve their symptoms. 

An endoscopic procedure also allows the doctor to take samples of the lining of the stomach 

(these are called biopsies) to look for infection in the stomach caused by a bacterium called 

Helicobacter pylori (H. pylori). H. pylori can cause peptic (stomach) ulcer disease, stomach 

cancer, and also functional dyspepsia. If a person is found to have H. pylori infection, it is 

usually treated with a week-long course of antibiotics. The purpose of the treatment is to 

improve dyspepsia symptoms and to prevent ulcers or stomach cancer from developing in 

the future. 

Investigation 

Over the past few years, researchers have been working to find the cause of functional 

dyspepsia. Some doctors have proposed that, just like in irritable bowel syndrome, an acute 

infection of the gut (such as infectious gastroenteritis) can provoke functional dyspepsia due 

to chronic inflammation of the stomach and duodenum post infection. There have been 

several studies published that have reported on this phenomenon, but most of these studies 

are very small, and they have only reported this possible association up to one year after the 

infection. 

It is now eight years since the water was contaminated in Walkerton. This year, as well as 

the usual information collected at the screening clinic, we ask all participants, over the age 

of eighteen, about dyspepsia symptoms, by means of a very short questionnaire. The intent 

is to see if we can show an association between previous infectious gastroenteritis and 

dyspepsia. This will allow us to determine whether dyspepsia symptoms are more common 

in those who had acute gastroenteritis in 2000. We look forward to sharing these results of 

this latest Walkerton Health Study investigation with you at the Town Hall Meeting on 

Thursday, October 16th at the Victoria Jubilee Hall. 
68

Healthy Blood Pressure and Kidneys 

By Dr. Amit Garg MD, FRCPC, PhD, WEL investigator 

What Is Blood Pressure? 

Blood is carried from the heart to all parts of your body in vessels called arteries. Blood 

pressure is the force of the blood pushing against the walls of the arteries. Each time the 

heart beats (about 60–70 times a minute at rest), it pumps out blood into the arteries. Your 

blood pressure is at its highest when the heart beats, pumping the blood. This is called 

systolic (sis-TOL-ik) pressure. When the heart is at rest, between beats, your blood 

pressure falls. This is the diastolic (di-a-STOL-ik) pressure. 

Blood pressure is always given as two numbers, the systolic and diastolic pressures. 

Usually, they are written one above or before the other, such as 120/80 mmHg (measured in 

millimeters of mercury, a unit for measuring pressure). When the two measurements are 

written down, the systolic pressure is the first or top number, and the diastolic pressure is 

the second or bottom number (for example, 120/80). If your blood pressure is 120/80, you 

say that it is "120 over 80.” 

Blood pressure changes during the day. It is lowest as you sleep and rises when you get 

up. It also can rise when you are excited, nervous, or active. A blood pressure of 140/90 

mmHg or higher, when present over multiple readings, is considered high blood pressure. 

Both numbers are important. If one or both numbers are usually high, you have high blood 

pressure. If people live into their seventh, eighth, or ninth decades, most will develop high 

blood pressure. 

 

Why Blood Pressure Is Important

When high blood pressure is not found and treated, it can cause arteries throughout the 

body to "harden" faster, especially those in the heart, brain and kidneys. This can cause a 

heart attack, stroke or kidney failure. 

Blood Pressure in Walkerton after the 2000 Water Contamination 

We have noticed that adults, who became ill during the Walkerton outbreak, have been 

more likely than others to develop high blood pressure four years after the outbreak. There 

may be a few reasons for this. Escherichia coli O157:H7 infections can affect the kidneys 

that regulate blood pressure in the body. Also, the outbreak may be an ongoing source of 

stress for some people, which can sometimes raise a person’s blood pressure. 

Treatment for High Blood Pressure 

The good news is that many people can prevent or control high blood pressure by changing 

to healthier habits. This includes following a balanced diet, loosing excess weight, being 

physically active, quitting smoking, and limiting alcohol intake. Sometimes, blood pressure 

stays too high even when a person makes these kinds of healthy changes. In that case, it is 

necessary to add medicine to help lower blood pressure. There are many effective 

medications to control high blood pressure, which can help people live longer, healthier 

lives. 

We thank everyone for ongoing participation in the Walkerton Health Study. We hope to 

assess your blood pressure and kidney function in our clinics, which will take place in the 

years 2007 and 2008. Together, we can better understand outcomes from the outbreak, 

and use this information to maximize health in the community. 
69

Irritable Bowel Syndrome

By: Dr. John K. Marshall, MD, MSc, FRCPC 

History and Diagnoses of IBS 

Irritable bowel syndrome (IBS) is a common and frustrating problem, characterized by 

intermittent discomfort in the abdomen and irregular bowel habits (diarrhea, constipation or 

both). Surveys in most Western countries suggest that between 10% and 20% of adults 

suffer from IBS, but not everyone seeks help from their family physician. 

IBS is more common in women than men and usually presents in early adulthood. However 

IBS can appear and affect anyone at any age. Making a diagnosis of IBS can be frustrating 

for both patients and doctors, as there is no single test to prove the diagnosis. Instead, 

doctors look for the right symptom patterns and may do tests to rule out other possibilities. 

IBS is, therefore, a diagnosis of “exclusion”. 

Treatment 

Treatment of IBS is less than perfect, but a number of options exist. First and foremost is 

careful attention to diet and lifestyle to identify “triggers” that induce symptoms or make them 

worse. Triggers can relate to diet (e.g. lactose, fatty foods, spices), stress or any change in 

routine. While not all triggers can be avoided, recognizing and understanding their effects 

on gut function can be helpful and even reassuring. Most people don’t need or want 

medication to treat IBS. For those that do, medications are chosen to ease the most 

troubling symptom(s) of IBS. Unfortunately, current therapy isn’t effective for everyone. 

However, new treatments are being developed to give future IBS patients more options. 

Post-infectious IBS 

Post-infectious IBS is a specific form of IBS where symptoms begin after an episode of 

infectious gastroenteritis. While most people recover fully from such an infection, between 

10% and 30% continue to suffer altered bowel habits (usually diarrhea) and stomach pain 

despite getting rid of the bug. Although doctors have recognized this phenomenon for 

decades, there has been relatively little research to help us understand what happens to 

people with post-infectious IBS. Small studies have suggested that symptoms gradually 

improve in most patients, possibly over years. 

Post-Infectious IBS in Walkerton

Unfortunately, some Walkerton residents became all too familiar with post-infectious IBS 

following the water contamination of 2000. The Walkerton Health Study is underway to 

identify and treat people with health problems related to the outbreak, and to learn more 

about those problems in order to help other people in the future. Among our findings so far 

is that people, who got sick during the outbreak, were three times more likely to have IBS 

than those who stayed well. Young adults, females and people with particularly severe 

bouts of diarrhea were most likely to have post-infectious IBS. And among people who have 

returned to the clinic for their annual visits, many have reported a gradual improvement in 

their bowel habits. 
70

What We Hope to Learn 

As the Walkerton Health Study continues, we hope to learn more about what happens to 

people with post-infectious IBS over time. The current medical thinking is that most will 

return to full health, and that post-infectious IBS does not lead to any other digestive 

problems. We are looking specifically to see whether infectious diarrhea and IBS increase 

the future risk of inflammatory bowel disease (Crohn’s disease and ulcerative colitis). We 

are also looking to see if genes (DNA) can predict who gets sick when water is 

contaminated, and who develops long-term problems. 

All members of the Walkerton Health Study team look forward to learning the answers to 

these important questions, and are grateful to residents who continue to visit the clinic in the 

wake of an awful human tragedy. Your efforts will undoubtedly help other people who face 

similar situations in the future. 

Dr. John Howard, a WEL Gastroenterologist, will be conducting information sessions on 

IBS Tuesday, September 19th at 12:00 noon and 4:00 P.M. 

If you wish to attend, please call (519) 881-1476 to reserve a place. 

Inflammatory Bowel Disease

By John Marshall MD, MSc. FRCPC 

Definition 

Inflammatory bowel disease (IBD) is a chronic medical condition characterized by an 

inflammation in the wall of the digestive tract. Because of its similar name, IBD is often 

confused with IBS (irritable bowel syndrome) but is a very different condition. 

Types of IBD 

IBD has two major forms, Crohn’s disease and ulcerative colitis. In both, the inflamed bowel 

lining can cause abdominal pain, diarrhea and rectal bleeding. However, there are important 

differences between the two. Crohn’s disease can affect any part of the digestive tract “from 

bum to gum”, while ulcerative colitis affects only the large bowel (also called the colon). In 

ulcerative colitis, inflammation is limited to the innermost lining of the bowel. However, 

patients with Crohn’s disease can have inflammation that goes deep into the intestinal lining. 

This can produce tunnels from the intestine to the skin or other organs (called fistulas) and 

infected fluid collections outside the bowel (called abscesses). 

Etiology 

IBD can appear at any age, but most often arises in young adults in their 20s and 30s, with 

men and women affected equally. The cause of IBD is not known, but a number of 

interesting theories have been put forward. It is well known that people can inherit a 

predisposition to the disease from their parents, and it is not unusual for patients with IBD to 

have other affected family members. However environmental factors are also important. For 

example, the “hygiene hypothesis” suggests that IBD develops because we are kept too 

clean as children, and overreact to bacteria or other particles in the digestive tract as adults. 
71

Our intestinal flora (the bacteria that live in our bowels) play a key role in the development of 

IBD, but our understanding of their interaction with the intestine remains limited. 

Prognosis 

Many people with IBD have few symptoms and live normal lives. However, it can be a 

frustrating condition where patients alternate between flares (where symptoms appear) and 

periods of remission, with relatively few symptoms or none at all. Quality of life can suffer, 

and patients can have trouble functioning fully at work or in social situations. 

Treatment 

The treatment of IBD is changing, with the development of new medications and surgical 

techniques. Traditional medications include anti-inflammatories and steroids that turn off or 

reduce inflammation. There is growing interest in the potential role of probiotics and 

prebiotics, which change the mix of bacteria living in the colon. New “biologic” therapies like 

Remicade (infliximab) are costly, but can help patients who don’t respond to other options. 

When medications fail, some patients with IBD undergo surgery to remove affected parts of 

the digestive tract. For patients with ulcerative colitis, removing the colon prevents the 

disease from coming back. However, Crohn’s disease often comes back after surgery in 

other parts of the intestine. 

In Conclusion

In some ways, a diagnosis of IBD can be devastating for young adults more interested 

attending school, beginning their career, or starting a family. However, I often tell patients 

that there has never been a better time to develop this condition. There is exciting research 

underway to understand what causes Crohn’s disease and ulcerative colitis, and there are 

many new novel treatments being studied in clinical trials. The Crohn’s and Colitis 

Foundation of Canada has had huge success in raising funds for research, advocating for 

patients, and providing both education and support to patients and their families. Indeed, I 

encourage everyone to visit their website at www.ccfc.ca. 

Effect of Exposure to Contaminated Water on Pregnancy Complications 

By Dr. Louise Moist, MD, MSc, FRCPC, WEL Investigator 

Shifting Focus 

The Walkerton Health Study is now shifting its focus towards the potential for unrecognized 

long-term health effects after exposure to contaminated water. This gives us the unique 

opportunity to study the complications of pregnancy in women exposed to contaminated 

water compared to women without exposure. 

Preliminary Analysis 

Preliminary analysis of the Walkerton Health Study data indicates that high blood pressure 

during pregnancy was self-reported by 14% of women who conceived after the 

contaminated water outbreak. This is above the reported range in the literature of 5-12%. 

This self-reported increase in high blood pressure highlights the need to confirm the 

incidence, explore potential mechanisms of injury, and document subsequent outcomes in 

both the women who become pregnant and the baby delivered, after exposure to 

contaminated water. 
72

Why? 

The scientific explanation for the increase in blood pressure may be due to the injury from 

the water contaminant (E. coli verotoxin), which decreases the ability of the vessels to dilate 

by a decrease in the synthesis of vasodilatory prostaglandins. Therefore, the initial blood 

pressure drop, which usually is seen in pregnancy, may not occur, and there may be a 

further increase in blood pressure as the pregnancy progresses. 

Ongoing Investigations 

The Walkerton Health Study is collecting health information on over 5000 people who were 

exposed to contaminated water during the outbreak in May 2000. This pregnancy study will 

identify women who became pregnant after exposure to the contaminated water. With their 

permission and in those women only, hospital charts will be reviewed to document a history 

of elevated blood pressure during pregnancy. The rate of pregnancy related high blood 

pressure will be compared to the rate reported in age matched women who were not 

exposed to contaminated water. We will also be collecting information on other factors that 

can influence the development of high blood pressure during pregnancy such as diabetes, 

smoking history and a previous history of high blood pressure. 

This study will involve collaboration with the WEL Investigators of the Walkerton Health 

Study as well as Dr. Robert Gratton, an expert in pregnancy and perinatal outcomes. The 

results of this study are expected after the completion of the 7-year observational study in 

2009. 

Your continued support of the Walkerton Health Study is essential for us to identify longterm health risks to those who drank the contaminated water. 

Reactive Arthritis

By: Dr. Janet Pope MD, MPH, FRCP and 

Dr. Amit X. Garg MD, FRCPC, FACP, WEL Investigator 

Year 5 Focus 

This year, the Walkerton Health Study is focusing on reactive arthritis. In the Year 1 

screening survey, 131 participants indicated that they had a red, hot, swollen joint(s) shortly 

after the water contamination in May of 2000. All were assessed by Dr. John Thompson 

and Dr. N. le Riche, rheumatologists. Upon examination, the vast majority did not have 

reactive arthritis. Those with reactive arthritis were treated and follow-up continued as 

deemed necessary by the rheumatologist. 

In subsequent years, additional questions in the survey identified other participants who may 

have experienced reactive arthritis. 

Reactive Arthritis and Water Contamination 

In many studies, contaminated water has been associated with reactive arthritis. However, 

more common bacteria that cause reactive arthritis are salmonella (such as in food 

poisoning). There are other types of bacteria such as campylobacter (from undercooked 

chicken) and Yersinia that cause inflammation of joints, particularly one or two joints. The 
73

symptoms are usually transient caused by a reaction where the body thinks that it is fighting 

off bacteria, but instead it attacks the joint lining (synovium). 

As many of you are aware, the contaminants in the Walkerton water supply were primarily E. 

coli and campylobacter. Campylobacter and even less so, E. coli, have only rarely been 

associated with reactive arthritis. 

Intervention 

We have received a grant from the Canadian Institute of Health Research to determine: 

• the frequency of reactive arthritis in the affected community 

• and the subsequent precipitation of chronic, reactive, inflammatory arthritis over time. 

We expect to find few cases of ongoing inflammation in joints caused by the contaminated 

water. Of course, other joint complaints are common in the general population, such as 

degenerative arthritis, muscle strains and back pain. Through the great community 

participation in the screening questionnaires, we are hoping to identify and treat people with 

reactive, inflammatory arthritis. To further select those with reactive, inflammatory arthritis, 

an initial assessment will be done by a musculo-skeletal physiotherapist. People with 

positive findings for reactive, inflammatory arthritis will then be offered a consult with Dr. 

Janet Pope, a rheumatologist. 

We will also look at the costs associated with chronic, reactive, inflammatory arthritis. 

However, we are optimistic that the disease burden in the community, from contaminated 

water, causing chronic, reactive, inflammatory arthritis, will be small. However, this 

investigation is important, for it will help the community and the scientific researchers better 

understand chronic, reactive, inflammatory arthritis as it relates to water contamination. 

We thank you for your continued participation in the Walkerton Health Study. 

The Story of another Contaminant in the Water on May 2000

By Marina Salvadori, MD, FRCPC, WEL Investigator 

Camylobacter

When the Walkerton municipal water was contaminated with bacteria in May of 2000, E. coli

O157 became a household name. There were, however, other bacteria in the water and 

some people became sick with bacteria called Campylobacter. Campylobacter is a spiral 

shaped bacteria that can cause disease in humans and in animals. Most people get 

Campylobacter from handling raw poultry or eating raw or undercooked chicken. It only 

takes a very few of these bacteria to make you sick. Even just 500 organisms can make 

someone sick. That can be the amount in one drop of juice from raw chicken. You can also 

get the infection from drinking un-pasteurized milk or drinking contaminated water. 

Campylobacter can live in the intestines of many animals including chickens, cows, pigs, 

sheep, dogs and cats. 

Symptoms 

Most people, who become ill, get diarrhea, cramps, belly pain and fever within 2 to 5 days. 

It is rare to get sick more than 10 days after you have been exposed. You can have no 
74

diarrhea, mild diarrhea or bad diarrhea which may be bloody. Some people get nausea and 

vomiting. The illness typically lasts for about 1 week. Some people, who are infected, never 

have any symptoms at all. The infection is usually diagnosed by sending the stool for 

special cultures in a laboratory. It is very rare to have long term consequences from 

Campylobacter. Some people may get arthritis following Campylobacter and this is called 

reactive arthritis. It usually gets slowly better over about 6 weeks to 2 years. There is also a 

very rare disease that affects the nerves of the body that can begin several weeks after the 

diarrhea. This disease is called Guillain-Barré Syndrome and occurs when your immune 

system attacks your body’s own nerves. This can lead to paralysis that can last several 

weeks. Most people get better from this. As far as we know there were no cases of 

Guillian-Barré Syndrome associated with the Walkerton outbreak. 

Treatment 

Virtually all people affected with Campylobacter recover without any specific therapy. Most 

people should just drink plenty of fluids to keep their body hydrated. Sometimes antibiotics, 

such as erythromycin are used. 

Prevention 

Campylobacter does occur in Ontario, especially in rural populations. Currently there are 

about 30 cases per 100,000 people living in Ontario. The most important ways to avoid 

Campylobacter infection are to drink clean, chlorinated, drinking water, avoid un-pasteurized 

milk and be very careful with food handling practices. In your own kitchen, you should make 

sure all poultry and beef is thoroughly cooked; you should wash your hands with soap after 

handling raw foods and before touching anything else; you should be particularly careful to 

use a separate cutting board for cutting meat and make sure the cutting boards, counter 

tops and utensils are carefully cleaned with soap and hot water. Never be afraid to send 

undercooked poultry back in a restaurant for further cooking. Campylobacter is a reportable 

disease in Ontario and all cases that are cultured in stool are reported to public health for 

investigation. 
75

What really is an E. coli O157:H7?

By Marina Salvadori, MD, FRCPC, WEL Investigator 

Walkerton residents are only too familiar with the term E. coli O157, the bacteria that caused 

most of the illness in May of 2000. Participants of the Walkerton Health Study have been 

interested in learning more about this bacteria. Bacteria, made up of one single cell, are the 

most primitive of life forms. E. coli, or Escherichia coli, are a family of bacteria. They are a 

gram negative rod, which means their shape is oval and they do not stain with a particular 

dye that is routinely used in a microbiology laboratory to identify bacteria. E. coli usually live 

in the stomach and bowels (or gut) of humans and animals. Most cause no harm and are 

part of the “good” bacteria that we need to help us live in normal health. Outside of the gut, 

in the bladder, E. coli are the commonest cause of urinary tract infections. Rarely, they can 

cause diarrhea. As everyone in Walkerton and area knows, E. coli O157 can cause severe, 

bloody diarrhea and hemolytic uremic syndrome (HUS). 

When Discovered 

E. coli have different types of bodies (“O”) and flagellae (or tails, “H”). So E. coli O157:H7 

has the body type of 157 and the tail type of 7. It is unique because it secretes a toxin that 

damages different cells in the human body, particularly the cells that line the blood vessels, 

the kidneys, and the lining of the gut. Since the laboratory can grow E. coli from all stool, 

until the late 1970s people thought that there must be something besides E. coli in the stool 

causing bloody diarrhea and HUS. Then, in the late 1970s, a group of Americans 

discovered that E. coli O157:H7 eats a different type of sugar from other E. coli. With a 

special culture they were able to grow it in the laboratory and show E. coli O157:H7 was a 

cause of bloody diarrhea. In 1982, an outbreak of HUS occurred in Pickering Ontario. 

Doctors at the Hospital for Sick Children in Toronto tested for E. coli O157:H7 in these 

children with HUS. Tests were positive and for the first time 

E. coli O157:H7 was identified as causing HUS. 

Source of Infection 

E. coli O157:H7 normally lives harmlessly in the gut of cattle. It is known to cause 

“hamburger disease” (bloody diarrhea leading in a minority to HUS). When cows are 

slaughtered, fecal material, including E. coli O157:H7, may get on the meat. When it is 

ground up the bacteria spreads through the meat, but cooking kills all the bacteria. 

Inadequately cooked meat gives “hamburger disease”. You can also get this infection from 

eating vegetables, fruit, or water (Walkerton May 2000) that has been contaminated with the 

fecal material from cattle. 

Most Escherichia coli are your friends. We need them to have normal stool, produce 

Vitamin K, and to keep our bodies in balance. E. coli O157:H7 is a very unusual and 

infrequent type of E. coli that is harmful to people. 
76

APPENDIX II - HUS/TTP UPDATE 2008 SYMPOSIUM