ASSESSING THE RISK OF IRRITABLE BOWEL SYNDROME ONE YEAR POST-ACUTE GASTROENTERITIS. A dissertation submitted to the

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2 ASSESSING THE RISK OF IRRITABLE BOWEL SYNDROME ONE YEAR POST-ACUTE GASTROENTERITIS A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Division of Epidemiology and Biostatistics of the Department of Environmental Health of the College of Medicine 2011 by Barbara Kowalcyk B.A., University of Dayton M.A., University of Pittsburgh Committee: Paul Succop, Ph.D. (Committee Chair and Advisor) Arie Havelaar, Ph.D. Craig Hedberg, Ph.D. Stephen Kralovic, M.D., Ph.D.

3 ABSTRACT Introduction: Acute gastroenteritis (GE) is an important cause of morbidity and mortality worldwide, particularly for children. Several studies have associated GE, which may have a foodborne etiology, with the development of irritable bowel syndrome (IBS). Understanding the incidence of GE, and its association with IBS and functional bowel disease (FBD), will improve the clinical management of patients and provide policy makers with better burden of disease estimates. Aims: The aim of this prospective cohort study is to estimate the incidence of GE, IBS and FBD, estimate the relative risk of IBS one year post-ge and explore potential risk factors for IBS among primary care practices in the Netherlands from 1998 to Methods: Data from the Primary Care Network Utrecht (PCNU), a prospective cohort with routine consultation data for more than 60,000 patients annually, were used for the analysis. The annual incidence of GE and IBS consultations were estimated and temporal trends were evaluated. Patients, aged 18 to 70 years, with gastrointestinal infection or diarrhea and at least one year of data recorded in the PCNU electronic databases were included in the GE cohort. Patients with a history of cancer, alcohol abuse, GE symptoms in the prior 12 months, preexisting IBS/FBD diagnosis or abdominal surgery or 5 or more prescriptions associated with IBS or FBD treatment were excluded. Patients consulting for non-ibs related medical reasons, matched by age, gender, consulting practice and time of visit, were randomly selected for the control cohort. The prevalence of IBS during follow-up was compared in the GE and control cohort. Results: In total, 23,451 patients consulted their physician for at least one GE-related event between 1998 and During the same time period, 4,980 patients consulted the PCNU for ii

4 IBS. Temporal trends were fairly consistent across health outcomes with a decreasing trend in incidence from 1998 to 2005, at which point the trend reversed and started to increase. Notably, using a medical registration system that requires a diagnostic code greatly increased the estimated incidence of GE, IBS and FBD. To assess the relative risk of IBS following acute gastroenteritis, 6,173 patients who consulted their physician for at least one GE-related event during the study period and met the inclusion/exclusion criteria were matched to a comparison cohort of 5,967 patients. Patients with GE had an increased risk of IBS (relative risk: 9.71; 95% CI: 6.14, 15.36). Female gender, cramps with illness, healthcare seeking behaviors, consulting practice and year of diagnosis were significantly associated with IBS in GE patients. Similar results were seen for functional bowel disease and when using different definitions for GE. Conclusions: GE and IBS are a significant burden in the Netherlands. Patients diagnosed with acute gastroenteritis in primary care have an increased risk of IBS at one year follow-up compared to their matched controls. Given the importance of understanding disease trends over time and the impact that electronic registration systems can have on the estimated incidences, additional research is needed to determine if recent trends in GE and IBS consultations are due to true increases in disease or are an artefact of the registration system used. Additional studies are also needed to determine the risk of IBS following GE in the general population. iii

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6 ACKNOWLEDGEMENTS I would like to acknowledge and thank the many people who encouraged me and provided invaluable guidance and support over the past 10 years and, in particular, during the pursuit of my doctorate. There are too many to thank individually but I would like to acknowledge a few in particular. To Dr. Stephen Knaebel, for sharing his passion for molecular epidemiology and providing me with a hands-on experience in microbiology. To Drs. Peter Gerner-Schmidt, Robert Tauxe and Patricia Griffin who provided me the invaluable opportunity to see first-hand molecular epidemiology in action during outbreak investigations. To Dr. Tanya Roberts, Caren Wilcox, Dr. Lee-Ann Jaykus and Dr. Glenn Morris, each of whom shared wisdom that helped form my path and inspired me to keep going. I would also like to thank the many faculty, staff and students in the Department of Environmental Health who provided me with wonderful opportunities and a challenging environment that broadened my horizons and taught me so much about the many facets of environmental health. Thanks to Dr. Kim Dietrich, who served on my qualifying exam committee and was so supportive of my efforts. To Dr. Alison Weiss, who served as one of my mentors and provided much-needed feedback on my academic endeavors. To Dr. Susan Pinney, whose advice and guidance have been immensely useful as I embark on completing my first grant and think about future activities. And, a special thank you to Dr. Grace LeMasters, who gave me the opportunity to be a fellow in the MECEH program and provided me with invaluable feedback and advice over the past five years. A special thanks and appreciation to the members of my committee who served as my advisors, mentors and teachers each of you inspired me in many ways and your encouragement and support has meant more to me than you probably realize. Thanks to Dr. iv

7 Stephen Kralovic, who gave me endless encouragement as I struggled to juggle family, career and academic obligations. Thanks to Dr. Craig Hedberg, who so graciously agreed to help me down this path when we first met and whose comments and advice have greatly influenced my journey towards becoming a foodborne disease epidemiologist. Many thanks and appreciation to Arie Havelaar, who provided me with the wonderful opportunity to work internationally with one of the best your vision, comments and critiques were invaluable to me throughout this project. And last, but certainly not least, much thanks and appreciation to Dr. Paul Succop, who has served as my advisor, teacher and mentor your encouragement and support served as a source of strength during the past five years as I faced new challenges and hurdles and was constant reminder that this was achievable. Above all, I would like to thank and acknowledge my family, without whose support none of this would have been possible. To my husband Mike, who has stood beside me throughout my endeavors to improve public health and prevent foodborne disease. Your patience, understanding and support gave me the opportunity, strength and courage to pursue this path I owe much of my success to you. To my father, who encouraged me to go into mathematics and then statistics and never gave up even when I wanted to. To my mother, who has spent countless hours working beside me to improve food safety, encouraged me each step along the way and always made sure things kept going even when I was overwhelmed or too busy to pay attention. Finally, I dedicate this dissertation to my children, Megan, Kevin, Lara and Christopher. To Megan, whose perseverance and ability to overcome adversity amazes me every day you are growing up to be one of the strongest women I know. To Lara, whose sensitivity and unique perspective on life always makes me smile you truly are my sunshine. To Christopher, whose v

8 determination reminds me daily that setting your sights on a goal is always the first step. Finally, to Kevin, who was taken from us way too soon your courage and will to live continues to be an inspiration to me. Each of you is special to me in your own way. You are my life and the driving force for me to do what I do every day. This project was funded, in part, by FDA Grant 1R18FD vi

9 TABLE OF CONTENTS ABSTRACT ACKNOWLEDGEMENTS ii iv CHAPTER 1: INTRODUCTION 10 INTRODUCTION AND OBJECTIVE 10 HYPOTHESIS AND SPECIFIC AIMS 13 SIGNIFICANCE AND RELEVANCE TO PUBLIC HEALTH 13 BACKGROUND 16 OVERVIEW OF THE DISSERTATION 20 IRB APPROVAL 20 CHAPTER 2: EPIDEMIOLOGICAL TRENDS OF ACUTE GASTROENTERITIS, FUNCTIONAL BOWEL DISEASE AND IRRITABLE BOWEL SYNDROME CONSULTATIONS IN THE NETHERLANDS FROM ABSTRACT 21 INTRODUCTION 22 METHODS 24 RESULTS 26 DISCUSSION 32 Table 1. ICPC Codes Selected for GE, IBS and FBD 38 Table 2. Total Patient, Patient-years, Consults by Gender, Age Group and Practice 39 Table 3. PCNU Summary: Patients, Events, Visits for each GE Definition 43 Table 4. PCNU Summary: Patients, Events, Visits for each GE ICPC Code 43 Table 5. Patients and Visits for each definition of GE by Gender, Age Group, Practice, Medical Registration System, Year 44 Table 6. PCNU Summary: Patients, Events, Visits for each Outcome Overall and by ICPC Code 47 Table 7. Patients and Visits for IBS and FBD by Gender, Age Group, Practice, Medical Registration System and Year 48 Table 8. Multivariate Analysis of Association between Exposure and Time of Diagnosis, Age Group, Gender and PCNU Practice (Compared to 1998) 51 Table 9. Multivariate Analysis of Association between Exposure and Time of Diagnosis, Age Group, Gender and PCNU Practice (Compared to Overall Mean) 53 Table 10. Model Building Results (Compared to 1998) 54 Figure 1a. Incidence Rate by Month for each Definition of GE Figure 1b. Incidence Rate by Month for Confirmed GE Figure 1c. Incidence Rate by Month for IBS, FBD (non-ibs) and FBD Figure 2. Mean Incidence Rate by Month for each Health Outcome ( ) Figure 2a. Mean Incidence Rate by Month for GE ( ) vii

10 Figure 2b. Mean Incidence Rate by Month for Confirmed GE ( ) Figure 2c. Mean Incidence Rate by Month for IBS and FBD ( ) Figure 3. Mean Incidence Rate by Month for each Health Outcome ( ) Figure 3a. Mean Incidence Rate by Month for GE ( ) Figure 3b. Mean Incidence Rate by Month for Confirmed GE ( ) Figure 3c. Mean Incidence Rate by Month for IBS and FBD ( ) Figure 4a. Plot of Relative Risk Compared to 1998 by Study Year ( ) for GE Figure 4b. Plot of Relative Risk Compared to 1998 by Study Year ( ) for IBS/FBD Figure 5a. Plot of Relative Risk Compared to 1998 by Study Year ( ) for GE Figure 5b. Plot of Relative Risk Compared to 1998 by Study Year ( ) for IBS/FBD Figure 6a. Plot of Relative Risk Compared to 2006 by Study Year ( ) for GE Figure 6b. Plot of Relative Risk Compared to 2006 by Study Year ( ) for IBS/FBD CHAPTER 3: RELATIVE RISK OF IRRITABLE BOWEL SYNDROME FOLLOWING ACUTE GASTROENTERITIS AND ASSOCIATED RISK FACTORS ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION TABLE 1. ICPC Codes Selected for GE, IBS and Kidney Dysfunction TABLE 2. ICPC Codes Selected for Risk Factors Table 3. Summary of Patients and Events by Inclusion/Exclusion Criteria 86 Table 4. Demographic Characteristics and Co-morbidities for Cases and Matched Controls 87 Table 5. Frequency (%) of Outcomes (Unexposed v. Exposed) for Each Exposure Definition at Each Time Point by Registration System 89 Figure1a. Incidence of FBD over time by GE Definition and Medical Registration System 92 Figure1b. Incidence of IBS over time by GE Definition and Medical Registration System 93 Table 6. Relative Risk (95% CI) of Outcome for Each Exposure Definition at Each Time Point by Registration System 94 Table 7. Relative Risk (95% CI) of Outcome for Each Exposure Definition at each Time Point (Observed) by Registration System 97 Table 8. Significant Risk Factors for Each Outcome Overall and by Time Point and Registration System 100 Table 9. Univariate and Multivariate Odds Ratio (95% CI) for Significant Risk Factors for Outcomes of Interest for All Exposed Patients by Time Point and Exposure Definition 103 Table 10. Descriptive Statistics for Time to Outcome of Interest by GE Definition and Exposure Status 105 Figures 2a-b. Survival Function for IBS following GE Broad for All Patients by Exposure Status and SES 106 Figures 2c-d. Survival Function for IBS following GE Broad for All Patients by Age Group and Exposures 106 viii

11 Figures 2e-f. Survival Function for IBS following GE Broad for All Patients by Concomitant Cramps and Consultation Frequency 107 Figures 2g-h. Survival Function for IBS following GE Broad for All Patients by Concomitant Bloody Stools and History of Dyspepsia 107 Figures 3a-b. Survival Function for FBD following GE Broad for All Patients by Exposure Status and SES 108 Figures 3c-d. Survival Function for FBD following GE Broad for All Patients by Age Group and GE Exposures 108 Figures 3e-f. Survival Function for FBD following GE Broad for All Patients by Consultation Frequency and History of Dyspepsia 109 Figures 3g-h. Survival Function for FBD following GE Broad for All Patients by Concomitant Cramps and Bloody Stools 109 REFERENCES 110 APPENDIX A: ROLE IN THE STUDY 117 ix

12 CHAPTER 1: INTRODUCTION INTRODUCTION AND OBJECTIVE Foodborne illness is a significant public health issue. Globally, diarrheal disease causes an estimated 2 billion illnesses and 2 million deaths each year, with many being attributed to contaminated food and/or water (WHO). While developing countries carry most of the burden, industrialized countries are also greatly affected, with reports that up to 40% suffer a foodborne illness each year (WHO). In the United States, foodborne disease associated with 31 pathogens causes an estimated 48 million illnesses, 128,000 hospitalizations and 3,000 deaths each year (Scallan 2011a; 2011b). In the Netherlands, it was recently estimated that fourteen foodborne pathogens cause 1.8 million illnesses annually with a total burden of 13,500 disability adjusted life years (DALYs) (Havelaar 2011). While several studies have focused on estimating the acute burden of foodborne disease, the long-term burden is not well understood. According to the Food and Drug Administration of the U.S. Department of Health and Human Services, an estimated two to three percent of all foodborne illnesses result in secondary, long-term health complications (Buzby 2001). However, this estimate is based on the incidence of reactive arthritis following foodborne disease and, therefore, likely underestimates the risk of all long-term sequelae. Unfortunately, there is little epidemiologic data on the long-term health outcomes associated with acute foodborne disease and many of these associations have come from case series and small scale studies that have inconsistent follow-up (Roberts 2009). In 1994, the Council for Agricultural Science and Technology issued a report entitled Foodborne Pathogens: Risks and Consequences, which summarized the health outcomes associated with selected foodborne and waterborne pathogens (CAST 1994). Since then, the 10

13 most systematic assessment of sequelae from foodborne disease has come from the Walkerton Health Study, which was initiated following an outbreak in Walkerton, Ontario, Canada in 2000 from municipal water contaminated with E. coli O157:H7 and Campylobacter. Follow-up studies have found an increased risk of post-infectious irritable bowel syndrome, hypertension, renal impairment and self-reported cardiovascular disease among patients with gastroenteritis during the outbreak (Marshall 2010; Clark 2010). In the United States, a 2004 pilot study of the frequency of self-reported complications identified a range of symptoms that may be attributable to gastroenteritis (GE), including rheumatologic symptoms, irritable bowel syndrome (IBS) and hair loss (Rees 2004). Affecting approximately 12% of the global population, irritable bowel syndrome (IBS) is a significant public health issue that has been associated with foodborne disease (WHO, Marshall 2009). IBS is a chronic gastrointestinal disorder with no structural cause that is characterized by episodic abdominal pain and altered bowel habits (Barbara 2009; Halvorson 2006; Thabane 2007). The etiology, pathogenesis and prognosis of IBS are not well understood, diagnosis is difficult and there is no widely accepted treatment (Borgaonkar 2006; DuPont 2008; Wang 2004). Campylobacter, Shigella, Salmonella and E. coli infections have been associated with IBS (McKendrik 1995; Ji 2005; Mearin 2005; Moss-Morris 2006; Spence 2007; Saps 2008; Gradel 2009; Thabane 2010); viral agents have also been associated with IBS symptoms but the short duration often precludes an IBS diagnosis (Marshall 2007). A current conceptual framework for the pathogenesis of post-infectious IBS hypothesizes that exposure to an infectious organism alters the gut flora, increases intestinal permeability and triggers chronic inflammation (Barbara 2009; DuPont 2008; Dunlop 2003; Marshall 2004). Severity of acute gastroenteritis (GE), antibiotic use, age, gender, smoking, education level, psychosocial factors 11

14 and health care seeking behaviors have been associated with increased risk of IBS (Hyams 1996; Gwee 1999; Dunlop 2003; Marshall 2006, 2007; Moss-Morris 2006; Ruigomez 2007; Spence 2007; Nicholl 2008; Thabane 2010, Villani 2010). Studies of the incidence and risk factors of GE and IBS have yielded varied results and few have identified the causal infectious agent(s). Observational research databases, such as population-based public health registries, are ideal for studying long-term and/or rare health events. In some cases, electronic databases of routine health care data (i.e. primary care consultations, hospitalizations) have been used to estimate the incidence of disease. In the Netherlands, such a system was established in 1998 to provide researchers with a cohort of patients. The Primary Care Network Utrecht (PCNU) is a collaboration between the Julius Center of Utrecht University Medical Center and 38 general practitioners working in six primary care centers in the Utrecht area. Routine health care data, including diagnosis, prescriptions and referrals, are recorded for every patient and, starting in 1995, entered into a centralized database. The PCNU database, which is also referred to as the Utrecht GP Research Network, has been used to address other research questions (van de Nadort 2009). Using such a system to estimate the incidence of acute gastroenteritis, the most common manifestation of foodborne disease, and the relative risk of developing sequelae may be a practical method of estimating the long-term burden of foodborne illness. Therefore, this dissertation project was undertaken to assess one of the long-term sequelae associated with foodborne illness using an electronic medical database. Specifically, there were two objectives for this dissertation project. The first objective was to describe the incidence of general practice consultations for GE in the Netherlands over an extended period of time using 12

15 the PCNU electronic databases. The second objective was to estimate the relative risk of IBS in the Dutch population following GE and explore potential risk factors. HYPOTHESIS AND SPECIFIC AIMS The central hypothesis in this dissertation is that IBS is a frequent long-term sequelae of acute gastroenteritis (GE) that represents a significant disease burden. This hypothesis was tested by accomplishing three specific aims: Specific Aim 1: Determine the annual incidence of primary care consultations for GE and IBS in the PCNU from 1998 to 2009 by age and gender. Specific Aim 2: Estimate the relative risk of IBS at one year post-ge in the patients with no history of functional gastrointestinal disorders compared to unexposed individuals. Specific Aim 3: Identify risk factors associated with IBS in patients with a history of GE prior to IBS diagnosis. Factors that will be evaluated include age, gender, education level, bloody stools, abdominal cramps, weight loss, psychosocial factors (depression, anxiety, major life event), high consultation frequency and high prevalence of unexplained symptoms. SIGNIFICANCE AND RELEVANCE TO PUBLIC HEALTH Over the past 60 years, approximately 30% of all emerging infections were caused by pathogens that are commonly transmitted through food (Jones 2008). Preventing pathogenic contamination in the increasingly diverse and global food supply will require significant resources. Limited resources will require a science-based, risk-informed approach to food safety that allocates resources to maximize the public health benefit. A National Academies of Science Institute of Medicine and National Research Council report outlined a conceptual 13

16 approach to food safety risk management that is rooted in strategic planning, public health risk ranking, resource identification and prioritization, intervention and evaluation (NAS 2010). Foodborne illness attribution models and burden of disease estimates are central to the proposed risk-based approach. Further, the report discusses the need for an integrated information infrastructure and identifies public health surveillance, including long-term health outcomes associated with foodborne disease, as a critical component of the risk-based approach. More recently, a Government Accountability Office report also identified the need for a comprehensive, uniform, risk-based approach to food safety (GAO 2011). Understanding the full burden, costs, causes and outcomes of foodborne disease is central to the development of evidence-based medicine, the establishment of public health priorities, the formulation of risk-based public policies and the development of successful strategies and interventions to protect public health. Population-based epidemiologic data are essential to setting public health objectives, defining food safety priorities and evaluating food safety interventions. Recently, there has been a significant move towards evidence-based public health, which uses data and information systematically, engages the community in decision making and applies a program planning framework to make decisions, based on the best available evidence, on the development, implementation, evaluation and dissemination of public health policies, interventions and guidelines (Brownson 2009). As part of the prevention focus of evidencebased public health, it is important to understand the full burden of disease and monitor trends over time. There is significant interest in improving foodborne illness burden of disease estimates both in the US and globally. In 2000, the World Health Assembly identified foodborne disease as a 14

17 global health priority (Stein 2007). Then, in 2006, WHO established a Foodborne Disease Burden Epidemiology Reference Group (FERG) to develop comprehensive foodborne disease estimates from all major causes (Stein 2007; Kuchenmuller 2009). In the United States, the burden of foodborne disease was first estimated in 1998 (Mead 1999). Following methodological improvements, foodborne disease burden estimates were revised in 2010 (Scallan 2011a, 2011b). However, these burden of disease estimates focus on the incidence of illness and death and do not take into account duration or severity of illness. For the past 10 years, the World Health Organization (WHO) has used a global burden of disease concept to report health information using a single summary measure of morbidity, disability and morbidity (Stein 2007). Disability Adjusted Life Years (DALYs) have gained wide-spread acceptance as metrics that account for both the population and individual burden of disease (Havelaar 2007). In the Netherlands, fourteen foodborne pathogens were recently estimated to cause 1.8 million illnesses annually with a total burden of 13,500 DALYs (Havelaar 2011). Further, it was estimated that 21% of the burden was associated with acute illness, 42% with sequelae and 37% with mortality. In the United States, a recent report used five measures of disease burden, including Quality Adjusted Life Years (QALYs), to estimate that 14 foodborne pathogens cause $14.1 billion in cost of illness and a loss of over 61,000 QALYs (Batz 2011). In the Dutch study, IBS was found to be the most frequently occurring sequelae; however IBS was not included, along with reactive arthritis, in the U.S. study due to a lack of data. Many estimates of the burden of foodborne disease are based on estimates of acute illness often GE and sequelae from a variety of sources. As seen in the recent U.S. study, there is 15

18 insufficient data to fully assess the burden of disease. In many cases, the estimates used are from a particular time period and it is assumed that these estimates have not changed over time. In fact, no study has looked at the trends in GE or IBS over an extended period of time. Understanding the epidemiology of and associations between GE and IBS will improve the clinical management of patients, provide policy makers with a better estimate of the burden of disease and lead to a better estimation of the public health benefits of potential preventive strategies. BACKGROUND Incidence of Acute Gastroenteritis (Aim 1) Acute gastroenteritis (GE) and, in particular, diarrheal disease is a leading cause globally of mortality and morbidity. According to the World Health Organization, diarrheal disease causes an estimated 2 billion illnesses annually, with children being disproportionally affected (WHO). While developing countries carry much of this burden, developed countries are affected as well. A 2006 literature review of 33 studies found that the incidence and prevalence estimates for GE in developed countries ranges from 0.1 to 3.5 episodes per person-year (Roy 2006). In the United States, several retrospective population-based cross-sectional telephone surveys have been used to estimate the incidence of GE. A 1993 survey of 1197 members of 462 households in Washington, DC found an annualized incidence of 0.7 episodes per person-year (Akhter 1994). Four years later, in 1997, a national survey of adults found an annualized incidence of 3.2 episodes per person-year (Sandler 2000). From 1996 to 2007, five populationbased telephone surveys were conducted by the Foodborne Diseases Active Surveillance Network (FoodNet) to estimate the incidence of self-reported GE (Roy 2006; Hall 2011). However, due to methodological issues, only data from the last three surveys, which were

19 ( ), 0.54 ( ) and 0.73 ( ) episodes per person-year, were used as estimates for the incidence of GE in the United States in the newly revised burden of disease estimates for foodborne illness in the United States (Roy 2006, Scallan 2010). In the United Kingdom, two prospective population-based studies (IID1 and IID2) used weekly reporting to estimate the incidence of infectious intestinal disease in the community and presenting to general practice (Wheeler 1999, Tam 2011). The first study, conducted in the mid- 1990s, estimated the incidence to be 194 community cases and 33.1 general practice consultations per 1,000 person-years. A decade later, in , the second study estimated the incidence to be 274 community cases and 17.7 general practice consultations per 1,000 person-years. The authors of the second study hypothesized that differences in case definition and the increased popularity telephone health services may have contributed to the increase in community incidence and simultaneous decline in general practice consultations. The authors also noted that incidence estimates obtained using telephone survey methods tend to be two to three times higher than those obtained through prospective methods. Studies in the Netherlands have used all three methods to estimate the incidence of GE. In , a population-based cohort conducted estimated that GE causes 4.5 million cases each year (Sensor 2001). Using weekly reporting cards, the incidence of GE was estimated to be 283 cases per 1,000 person years, representing a significant decrease from the 1991 estimate of 447 cases per 1,000 person years. It is unclear if this decrease is due to an actual decline in the incidence of GE or over/underestimation of the incidence. A national study conducted from 1996 to 1999 in the Netherlands estimated the incidence of GE consultations in general practice to be 7.97 per 1,000 person years, which was slightly less than a comparable study in that estimated 9 cases per 1,000 person years (dewit 2001b). Using 2009 health care usage data, 17

20 the incidence of GE in general practices was more recently estimated to be 13 per 1,000 person years (Havelaar 2011). A recent retrospective study estimated that GE causes 16 million illnesses each year in the Netherlands (Doorduyn 2011). However, the retrospective design of the study and the use of self-reporting likely resulted in an overestimation of the incidence of GE. Relative Risk of IBS following GE (Aim 2) IBS is a broad spectrum disorder that can be debilitating. IBS affects between 10% and 20% of Western populations, causes significant morbidity and places a substantial burden on healthcare systems (Haagsma 2010; Hungin 2003; Thompson 2000). Diagnosis is difficult and largely dependent on the criteria used (Baber 2008; Borgaonkar 2006; Boyce 2000; Walker 2004). Several studies have demonstrated that a significant number of GE patients develop persistent gastrointestinal symptoms which may meet the definition for IBS (Garcia Rodriguez 1999; Neal 2002; Ilnyckyj 2003; Parry 2003a, b; McKeown 2006; Stermer 2006; Marshall 2007). Patients who develop IBS following an episode of acute gastroenteritis (PI-IBS) differ from sporadic IBS patients. PI-IBS is more often associated with diarrhea during GE and the longterm prognosis is slightly better than for unspecified IBS. In the U.S., IBS accounts for 2.4 to 3.5 million physician visits per year and costs an estimated $30 billion (Longstreth 2003). Further, IBS can greatly affect everyday activities, personal relationships, school attendance and work productivity (Hyams 1996; Whitehead 1996; Longstreth 2003; Pare 2006). In the Netherlands, the disease burden of PI-IBS was recently estimated to be 2,300 Disability Adjusted Life Years (DALYs) per year (Haagsma 2010). It was further estimated that 17% of PI-IBS cases resulted from Salmonella, Campylobacter and Shigella infection. 18

21 There is increasing evidence that infectious GE can increase the risk of developing IBS (Halvorson 2006; Thabane 2007). Two recent studies estimated that 10% and 17%, respectively, of IBS patients previously had an episode of acute gastroenteritis (Spiller 2009; Thompson 2000). A military-based case-control study found a significant association between GE and IBS (OR 3.72) (Porter 2011). In a 2006 meta-analysis of eight studies that found a 9.8% median prevalence of IBS in GE patients, GE patients were 7.3 times (95% CI: ) more likely to develop IBS than controls (Halvorson 2006). A more recent meta-analysis of 18 studies found a 10% pooled incidence of IBS and an excess relative risk of 4.86 (95% CI: ) for IBS in patients with intestinal infection than those without (Thabane 2007). However, since only 25% to 30% of patients seek primary care for their IBS symptoms, it is likely that these studies underestimated the incidence of IBS in the population (Thompson 2000). IBS Risk Factors (Aim 3) The etiology of IBS is complex. Studies of IBS following GE have associated severity of GE (duration of diarrhea, presence of blood in stools, abdominal cramps, weight loss), younger age and female gender with increased risk of IBS (Gwee 1996; Neal 1997; Ji 2005; Marshall 2006, 2007; Moss-Morris 2006; Nicholl 2008; Thabane 2010). Anxiety, depression and major life events have also been associated with IBS with some researchers hypothesizing that these disorders prolong gut inflammation and heightened sensory perception (Gwee 1996,1999; Locke 2000; Neal 2002; Dunlop 2003; Moss-Morris 2006; Ruigomez 2007; Tobin 2008). Several studies have found increased health care seeking behaviors in IBS patients but the reasons for this are not well understood (Hyams 1996; Pare 2006;Nicholl 2008). Antibiotic use during and chronic use after GE has also been associated with IBS but it has not been well studied (Ruigomez 2007). One study found that pathogen toxigenicity was an important determinant for 19

22 development of IBS (Thornley 2001). A follow-up study of Salmonella and Campylobacter patients three years post-infection found an association between chronic intestinal disease and single nucleotide polymorphisms in the IFNG gene that controls the expression of a cytokine crucial to the immune response against enteric infections but did not find an association with acute infection, suggesting that patients with chronic intestinal inflammation, such as IBS, may be more susceptible to GE (Doorduyn 2008). OVERVIEW OF THE DISSERTATION This dissertation is in the format of two papers for submission for journal publication (Chapters 2 & 3). The first manuscript for publication (Chapter 2) describes the incidence of general practice consultations for acute gastroenteritis, irritable bowel syndrome and functional bowel disease in the Netherlands from The second manuscript for publication (Chapter 3) describes the relative risk of irritable bowel syndrome and functional bowel disease one year following acute gastroenteritis and associated risk factors. IRB APPROVAL Institutional Review Board approval was requested from the University of Cincinnati on October 13, The study was deemed to not involve human subjects and a final letter of determination was received on October 29, Since patients consent to having their medical records used for research purposes when they join the PCNU, no additional approvals were required in the Netherlands. 20

23 CHAPTER 2: EPIDEMIOLOGICAL TRENDS OF ACUTE GASTROENTERITIS, FUNCTIONAL BOWEL DISEASE AND IRRITABLE BOWEL SYNDROME CONSULTATIONS IN THE NETHERLANDS FROM ABSTRACT Introduction: Acute gastroenteritis (GE) is an important cause of morbidity and mortality worldwide, particularly for children. Several studies have associated GE, which may have a foodborne etiology, with the development of irritable bowel syndrome (IBS) and/or functional bowel disease (FBD). Understanding the incidence of GE, and its association with IBS and FBD, will improve the clinical management of patients and provide policy makers with better burden of disease estimates. Aims: The aim of this study is to estimate the incidence of GE, IBS and FBD among primary care practices in the Netherlands from 1998 to Methods: Data from the Primary Care Network Utrecht (PCNU), a prospective cohort with routine consultation data for more than 60,000 patients annually, were used for the analysis. The annual incidence of GE, IBS and FBD consultations were estimated and temporal trends were evaluated. Results: In total, 23,451 patients consulted their physician for at least one GE-related event between 1998 and During the same time period, 5,924 patients consulted the PCNU for FBD. Significant differences in incidence were seen between men and women, among practices and across age groups. Temporal trends were fairly consistent across all health outcomes with a decreasing trend in incidence from 1998 to 2005, at which point the trend reversed and started to increase. Seasonal variations were also seen. Regardless of the health outcome, using a medical 21

24 registration system that requires a diagnostic code greatly increased the estimated incidence of GE, IBS and FBD. Conclusions: GE, FBD and IBS are a significant burden in the Netherlands. Given the importance of understanding disease trends over time and the impact that electronic registration systems can have on the estimated incidences, additional research is needed to determine if recent trends in GE, IBS and FBD consultations are due to true increases in disease or are an artefact of the registration system used. INTRODUCTION Acute gastroenteritis (GE) is a significant cause of morbidity and mortality worldwide. According to the World Health Organization, diarrheal disease causes an estimated 2 billion illnesses and 1.8 million deaths each year worldwide (WHO). While developing countries carry much of this burden, industrialized countries are also affected with estimates varying depending on the case definition and study design. Infectious agents (viruses, bacteria, parasites) are common causes of GE with contaminated food and/or water frequently being a vehicle for spreading disease. Viral gastroenteritis is most common in winter months while bacterial gastroenteritis is most common in summer months. Regardless of the etiology, GE can cause diarrhea, nausea, vomiting, abdominal cramps and, occasionally, fever. While the disease is usually self-limiting, serious complications can occur. Several studies have associated GE with an increased risk of irritable bowel syndrome (IBS). Affecting an estimated 12% of the global population, IBS falls within the broader category of functional bowel disease (FBD) and is characterized by episodic abdominal pain and altered bowel habits (Barbara 2009; Halvorson 2006; Thabane 2007, 2009). IBS causes significant 22

25 morbidity and can greatly affect quality of life, placing a substantial burden on healthcare systems and society (Haagsma 2010; Hungin 2003; Thompson 2000). Understanding the incidence of GE, IBS and FBD consultations with primary care physicians will help inform foodborne illness burden of disease estimates and prioritization of potential intervention strategies. In the Netherlands, the burden of 14 foodborne pathogens was recently estimated to be 13,500 disability adjusted life years (DAYLYs) (Havelaar 2011). Burden of disease estimates are largely dependent on the methodology used and the data used to inform the estimates. In the Netherlands, population-based cohort studies and studies involving a network of general practitioners were used to estimate the incidence of GE in the 1990 s (dewit 2001). However, since then, no studies have been conducted to update the estimated incidence of GE or validate the results of the original study using a more stable system. Since acute illness represents only a fraction of the burden of foodborne disease, sequelae such as IBS and FBD should also be taken into account in burden of disease estimates. However, no study has examined the incidence of IBS or FBD consultations in the Netherlands. Therefore, the recent burden of disease study in the Netherlands estimated the probability of IBS as a sequelae from foodborne disease using results from a recent meta-analysis (Havelaar 2011). Similarly, the incidence of inflammatory bowel disease (IBD) was estimated using data from Danish registry-based studies. Estimating the incidence of GE and associated sequelae, as well as how the incidence fluctuates over time, is critical to developing burden of disease estimates for foodborne illness. Therefore, the primary purpose of this study is to estimate the incidence of GE, IBS and FBD primary care consultations in the Dutch population and assess trends over time using the electronic databases of the Primary Care Network Utrecht (PCNU). 23

26 METHODS Data Source Data were extracted from the Primary Care Network Utrecht (PCNU) electronic database. Established in 1989 to provide researchers with routine primary care data on a cohort of patients, the PCNU is a collaboration between Julius Center of Utrecht University Medical Center and 38 general practitioners working in six primary care centers in the Utrecht area. Routine health care data, including diagnosis, prescriptions and referrals, are recorded for every patient and, starting in 1995, entered into a centralized database. Diagnoses are coded using the 2 nd Edition International Classification of Primary Care (ICPC) from Wonca International Classification Committee (WICC) (Wonca). Prescribed medications are recorded using the World Health Organization s Anatomical Therapeutic Chemical (ATC) classifications. To date, more than 60,000 patients have been seen annually in the PCNU. From 1998 to 2006, all six practices in the PCNU used the ELIAS registration system. Starting in 2006, practices 1, 3, 4 and 6 began switching to Promedico, a registration system that requires physicians to enter an ICPC code prior to closing out the file. During the same time period, practices 2 and 7 switched to MicroHIS, which is similar to ELIAS and does not require an ICPC code to close the file. Practice 1 used Promedico for less than one year before switching to MicroHis. Since the exact dates for the use of the registration systems were unknown, Practice 1 was excluded from the analyses. Study Cohort The sample population for the study was all patients from the PCNU who were seen between 1998 and 2009, which represents 728,937 patient-years of follow-up. The health outcomes of interest were acute gastroenteritis (GE), functional bowel disease (FBD) and irritable bowel 24

27 syndrome (IBS). ICPC diagnostic codes were used to identify diagnosed subjects and classify the diagnoses as meeting one of four definitions for GE or the definitions for IBS and FBD (Table 1). Consultations that met the health outcome definition and occurred within 30 days of the initial consultation were considered to be part of the same illness episode and were not counted as a new event. Analysis Summary statistics were calculated for socio-demographic characteristics for patients with GE, IBS and FBD. The incidence of GE, IBS and FBD consultations was calculated for each year overall and by practice as the number of incident consultations in a given year divided by the number of patient-years. For incidence plots, the monthly incidence was calculated by dividing the number of incident consultations in a given month by 1/12 th of the total person-years in a given year. The annual incidence of GE, IBS and FBD consultations and 95% confidence intervals were originally estimated using a Poisson regression model adjusting for potential confounders (age, gender, practice). Due to over-dispersion, a negative binomial model was employed to re-estimate the incidence rates. Temporal trends in the incidence of consultations, adjusted for age, gender and practice, from 1998 to 2009 were examined using a multiplicative negative binomial regression model. The independent variable of interest was time, expressed as year of diagnosis and fitted as a continuous variable. Predictors were age group, gender, practice and registration system. Hierarchical models with interaction terms for year with age group, gender and practice were also assessed. However, only the basic model converged for all exposures (Table 10) and only these results were presented. Descriptive statistics and linear regression analysis were used to assess potential season and annual variations in GE, IBS and 25

28 FBD consultations. Statistical analyses were performed using SAS 9.2 for Windows (SAS Institute, Cary, NC). RESULTS Description of data: From 1998 to 2009, the number of patients enrolled in the PCNU ranged from 60,407 to 65,930 per year (Table 2). The majority of patients were under 40 years of age, nearly half were enrolled in one of two practices (3 and 7) and slightly more than half were women. Incidence of GE: During the study period, 23,451 patients had 50,503 consultations for GE in the PCNU (Table 3). The most common diagnostic codes for GE were abdominal pain localized other [D06], gastroenteritis presumed infection [D73] and diarrhea [D11] (Table 4). With the exception of confirmed cases of GE, more women than men consulted the PCNU for GE and about half were under the age of 30 (Table 5). The annual incidence of confirmed GE consultations ranged from 0.77 to 1.15 per 1000 person years; from to for presumed GE; to for symptomatic GE; and to for broad GE (Figure 1). The relative risk of GE, with the exception of confirmed GE, was significantly lower in men than in women, ranging from 0.63 (95% CI: 0.60, 0.65) for broad cases to 0.85 (95% CI: 0.81, 0.89) for presumed cases of GE (Table 8). In the multivariate analysis, significant differences were seen among practices with practices 3, 4 and 6 consistently having a higher relative risk of GE consultation than practice 1 (Table 8). There were no significant differences in the relative risk of GE confirmed between Practices 1, 2 and 7. For all other definitions of GE, practice 2 consistently had a significantly lower relative 26

29 risk of GE consultation than practice 1. Practice 7 had a higher relative risk of GE consultation than practice 1 for symptomatic and broad cases of GE but not for presumed GE. Interestingly, these trends are consistent with the medical registration systems used. Starting in 2006, practices 3, 4 and 6 switched to the Promedico registration system, which requires an ICPC code to be entered before closing the system. During the same time period, practices 2 and 7 switched to MicroHis, a registration system that did not require an ICPC code to be entered. Practice 1 initially switched to Promedico but then switched again to MicroHis. Significant differences were also seen in the multivariate analysis across age groups. The 18 to 30 age group served as the reference in the analysis. For confirmed GE, not significant differences were seen between the reference group and age groups up to age 65. Patients between the ages of 65 and 80 had a significantly lower relative risk of confirmed GE. For all other definitions of GE, children under the age of 18 were about twice as likely to consult the PCNU for GE than the reference group, with the relative risk ranging from 1.50 (95% CI: 1.40, 1.61) for cases meeting the broad definition of GE to 2.40 (95% CI: 2.20, 2.56) for presumed cases. Patients in the 30 to 40, 40 to 50 and 50 to 60 age groups were less likely than the reference group to consult for presumed or symptomatic GE but this was not consistent for broad GE. Patients over the age of 60 were more likely than the reference group to consult for presumed, symptomatic or broad GE. Incidence of IBS and FBD: There were 5,924 patients who consulted the PCNU 13,969 times for FBD (Table 6). The vast majority (72%) of consultations were for IBS. Significantly more women consulted the PCNU for IBS and FBD. Over a third of patients consulting the PNCU for IBS were under the age of 30, compared to less than 10% of patients consulting for FBD. Practices 4, 6 and 7 accounted for over 60% of consulting patients. The incidence of IBS ranged from 8.53 to 15.44, 27

30 and from to for FBD consultations (Figure 2). The relative risk of both IBS and FBD was significantly lower in men than in women, with a relative risk of 0.37 (95% CI:0.34, 0.40) for IBS and 0.42 (95% CI: 0.39, 0.45) for FBD (Table 8). As with GE, significant differences in the incidence of IBS and FBD consultations were seen between the practices in the multivariate analysis. Practices 3, 4 and 6 were significantly more likely to report FBD consultations than practice 1, with the relative risk ranging from 1.40 (95% CI: 1.23, 1.60) for practice 3 to 2.74 (95% CI: 2.43, 3.09) for practice 4 (Table 8). Practice 2 was less likely to report FBD than practice 1, with a relative risk of 0.81 (95% CI: 0.71, 0.93). For IBS, only two of the practices (4 and 6) had a significantly higher relative risk of IBS consultation than practice 1. Practices 2 and 7 had significantly lower relative risk of IBS consultation than practice 1 and practice 3 was not significantly different. Again, these results follow the type of medical registration system used by the various practices. Practices using a registration system that requires entry of an ICPC code generally had a higher relative risk of IBS/FBD than those using a registration system that does not have such a requirement. The only exception was seen in confirmed GE and IBS for Practice 3. Significant differences were also seen in the multivariate analysis across age groups. Again, the 18 to 30 age group served as the reference in the analysis. Children under the age of 18 were significantly less likely to consult the PCNU for IBS or FBD than the reference group. Patients age 60 to 65 and 70 to 80 had a significantly higher relative risk of FBD consultation than the reference group. No significant differences were seen between the other age groups and the reference group. For IBS, patients age 30 to 50, 65 to 70 and over 80 were less likely to consult for IBS, with the relative risks ranging from 0.56 (95% CI: 0.46, 0.67) for the over 80 age group to 0.82 (95% CI: 0.72, 0.94) for the 40 to 50 age group. Only the 60 to 65 age group had a 28

31 higher relative risk of IBS consultation than the reference group (95% CI: 1.05, 1.43). No significant differences were seen for the relative risk of IBS consultation between the reference group and patients aged 50 to 60 or 70 to 80. Temporal analysis of event rates from : Trends in the incidence of GE, IBS and FBD were examined by comparing the risk of outcome in each study year to the baseline year of To account for variation throughout the study period, the analysis was then repeated comparing the risk of outcome in each study year to the overall mean of all study years. Results are presented in Tables 8 and 9 and Figures 4 through 6. No significant differences were seen in the relative risk of confirmed GE from 1999 to 2008 when compared to The relative risk in 2009 was only marginally higher at 1.67 (95% CI: 1.08, 2.58). For presumed, symptomatic and broad cases of GE, no significant differences were seen in the relative risk of GE from 1999 to 2006 when compared to Among presumed cases of GE, the relative risk of GE was significantly higher in 1999 and 2006 onward, with the relative risk increasing as time progressed. Among symptomatic and broad GE cases, the relative risk was significantly higher for 2007 onward when compared to For both IBS and FBD, the relative risk was not significantly different in 1999 and 2000 when compared to From 2001 to 2006, the relative risk of IBS and FBD was significantly lower than Compared to 1998, there were no significant differences in relative risk of IBS from 2007 onward. However, compared to 1998, the relative risk of FBD was significantly higher from 2007 onward. When the analysis was repeated using the overall mean incidence as the reference point, the relative risk of confirmed GE was not significantly different from 1998 to 2004 or from 2006 to In 2005, the relative risk of confirmed GE was significantly lower 29