THE IMPACT OF CLOSTRIDIUM DIFFICILE COLITIS ON FIVE-YEAR HEALTH OUTCOMES OF HOSPITALIZED ULCERATIVE COLITIS PATIENTS

Transcription

1 THE IMPACT OF CLOSTRIDIUM DIFFICILE COLITIS ON FIVE-YEAR HEALTH OUTCOMES OF HOSPITALIZED ULCERATIVE COLITIS PATIENTS by Sanjay K. Murthy A thesis submitted in conformity with the requirements for the Degree of Master s in Science in Clinical Epidemiology and Health Care Research Institute of Health Policy, Management and Evaluation University of Toronto Copyright by Sanjay K. Murthy 2012

2 THE IMPACT OF CLOSTRIDIUM DIFFICILE COLITIS ON FIVE-YEAR HEALTH OUTCOMES OF HOSPITALIZED ULCERATIVE COLITIS PATIENTS Sanjay K. Murthy Master s in Science, Clinical Epidemiology and Health Care Research Institute of Health Policy, Management and Evaluation, University of Toronto 2012 ABSTRACT Clostridium difficile colitis (CDC) is associated with a higher risk of acute death among hospitalized ulcerative colitis (UC) patients. However, the risk of colectomy with CDC in these patients has varied across studies. No study has assessed the long-term health impact of CDC in UC patients. Therefore, the present study evaluated the impact of CDC on five-year health outcomes of hospitalized UC patients based on Ontario health administrative data. No overall association was observed between CDC and five-year risks of colectomy or death in overall cohort. However, patients who were discharged from hospital without undergoing colectomy demonstrated marginally higher five-year risks of colectomy and hospital re-admission. Mortality risk and length of stay during index hospitalization were also higher in patients with CDC. Analysis of a parallel cohort of UC patients derived using a published case definition corroborated most of these results, but demonstrated a higher five-year mortality risk with CDC. ii

3 ACKNOWLEDGEMENTS I would like to thank my supervisor, Dr. Hillary Steinhart, for his guidance and support with this project and throughout my Master s program, as well as for his constant mentorship during my academic training. I would also like to thank my other committee members, Dr. Geoffrey Nguyen, Dr. Jill Tinmouth, Dr. Nick Daneman and Dr. Peter Austin for providing me with valuable insight and suggestions throughout the course of this work. All of the members of my thesis committee have been generous with their time and their intellectual contributions have helped me progress greatly as a clinical researcher. I would like to specially thank Dr. Geoffrey Nguyen for helping me conceive the idea for this project and for his mentorship and collaboration in multiple research projects over the years. I would also like to thank Dr. Peter Austin for contributing extra time towards helping me with complicated statistical analyses. Additionally, I would like to thank Longdi Fu, who has been incredibly helpful in providing me with the necessary data to see this project through to completion. I would also like to thank The University of Toronto Department of Medicine, The Canadian Institutes of Health Research (CIHR), The Canadian Association of Gastroenterology (CAG) and Aptalis Pharma (formerly Axcan Pharma) for providing me with funding to carry out this study. This work was supported by an Eliot Phillipson Clinician-Scientist Training Program Award from the University of Toronto and by a CIHR/CAG/Axcan Fellowship Award. Finally (but certainly not least), I am grateful for the patience and understanding of my wife, Vandana, without whose ongoing support none of this would have been possible. iii

4 TABLE OF CONTENTS Abstract Acknowledgements Table of Contents List of Tables List of Figures List of Appendices ii iii iv vi vii viii CHAPTERS Chapter One: INTRODUCTION Study Background Clostridium Difficile Colitis Discovery of Clostridium Difficile Microbiology of Clostridium Difficile Pathogenicity of Clostridium Difficile Epidemiology of Clostridium Difficile Colitis Clinical Presentation and Diagnosis of Clostridium Difficile Colitis Inflammatory Bowel Disease Epidemiology of Inflammatory Bowel Disease Inflammatory Bowel Disease Pathophysiology and Clinical Presentation Natural History of Inflammatory Bowel Disease Clostridium Difficile Colitis in Inflammatory Bowel Disease Epidemiology of Clostridium Difficile Colitis in Inflammatory Bowel Disease Natural History of Clostridium Difficile Colitis in Inflammatory Bowel Disease Study Rationale and Aims Study Hypothesis 17 Chapter Two: METHODS Summary of Study Methodology Literature Search Strategy Data Sources Study Design and Patients Study Design and Cohort Assembly Excluded Patients 22 iv

5 2.4.3 Comparator Groups Subgroup Analysis Study Outcomes Covariates Sensitivity Analysis Statistical Methods Sample Size Calculation Ethics Review 34 Chapter Three: RESULTS Baseline Characteristics and Adverse Health Outcome Rates in Study Cohort Association of CDC with Five-Year Health Outcomes in Total Cohort Association of CDC with Five-Year Health Outcomes Among Patients Discharged from Hospital Association of CDC with In-Hospital Health Outcomes 39 Chapter Four: DISCUSSION Interpretation of the Primary Study Results Interpretation of Results from the Sensitivity Analyses Study Limitations Issues Related to Study Design and Methods of Confounder Adjustment 75 Chapter Five: SUMMARY AND REMARKS 79 Chapter Six: FUTURE DIRECTIONS AND CHALLENGES 81 REFERENCES 84 v

6 LIST OF TABLES TABLE NUMBER TITLE CHAPTER PAGE 3.1 Baseline Characteristics of Study Patients (Primary Cohort) 3.2 Adjusted Covariate Associations with Five-Year Risks of Colectomy and Death Among Hospitalized UC Patients (Primary Cohort) 3.3 Adjusted Covariate Associations with Five-Year Risks of Colectomy and Death Among Hospitalized UC Patients (Alternate Cohort) 3.4 Adjusted Covariate Associations with Five-Year Risks of Adverse Health Events Among UC Patients Discharged from Hospital Without Undergoing Colectomy (Primary Cohort) 3.5 Adjusted Covariate Associations with Five-Year Risks of Adverse Health Events Among UC Patients Discharged from Hospital Without Undergoing Colectomy (Alternate Cohort) 3.6 Adjusted Covariate Associations with Risks of In- Hospital Colectomy and Death Among Hospitalized UC Patients (Primary Cohort) 3.7 Adjusted Covariate Associations with Risks of In- Hospital Colectomy and Death Among Hospitalized UC Patients (Alternate Cohort) S.1 Baseline Characteristics of Patients Included and Excluded from Sensitivity Analysis based on Alternate Definition for Identifying UC Patients in Health Administrative Data S.2 Pre-Admission Co-morbidities and In-Hospital Complications Among UC Patients Who Died in Hospital Three 42 Three 44 Three 47 Three 49 Three 51 Three 53 Three 55 Appendix One 98 Appendix One 99 vi

7 LIST OF FIGURES FIGURE NUMBER TITLE CHAPTER PAGE 2.1 Schematic diagram of the study timeline Two Flow diagram illustrating patients included and excluded from the primary and alternate cohorts 3.2 Unadjusted and covariate-adjusted colectomy-free and overall survival among hospitalized UC patients based on presence or absence of CDC during index hospitalization Three 41 Three 46 vii

8 LIST OF APPENDICES APPENDIX NUMBER TITLE PAGE One Supplementary Tables 98 viii

9 1 Chapter 1 INTRODUCTION 1.1 Background Clostridium Difficile Discovery of Clostridium Difficile Clostridium difficile was first described by Hall and O Toole in 1935 based on studies of the intestinal flora in newborn infants. 1 Cultures and isolates of this organism were found to cause massive edema in subcutaneous tissues and subsequent death due to respiratory failure when administered to rabbits and guinea pigs. Given the difficulty with isolating this organism, as a result of its slow growth in culture medium, it was originally named Bacillus difficilis. Forty years later, the organism was re-named as Clostridium difficile. Seminal studies in the 1970 s identified C. difficile as the causative agent in the majority of cases of antibioticassociated infectious diarrhea and pseudomembranous colitis. 2, 3 Today, this organism is recognized as an important cause of infectious colitis that is associated with considerable morbidity and mortality among hospitalized patients across North America and Europe Microbiology of Clostridium Difficile Clostridium difficile is an anaerobic, spore-forming, gram-positive bacillus that colonizes the intestinal tract of humans and a number of animals. 9 The human gastrointestinal tract (GIT) is the primary habitat of this organism and transmission between individuals occurs via the fecal-oral route. An important aspect for the survival and transmissibility of this organism is the ability to form heat and chemical-resistant spores during unfavourable

10 2 conditions (dormant state). 10 This property allows the organism to evade detection by the immune system within the GIT and to resist chemical disinfectants used to sanitize the surfaces of counters and appliances in hospitals. C. difficile spores can survive for several years in the GIT. During germination, its outer spore coat develops filamentous projections that attach to the colonic microvilli, facilitating anchorage to the large intestine. 11 Germination of spores and proliferation of vegetative cells are promoted when antibiotic pressure suppresses endogenous gut flora. 12 Under these conditions, C. difficile is able to impart its virulence and cause colitis through secretion of a number of cytotoxins that damage the colonic epithelium and promote a 10, severe inflammatory response Pathogenicity of Clostridium Difficile C. difficile has a predilection for the mucosal surface of the large bowel of humans and other animals, where it causes cytotoxic cell death and inflammation. 9 A number of factors contribute to the pathogenicity of C. difficile, including secretory cytotoxins, cell surface proteins that bind extracellular matrix and host cell membrane domains, collagen proteases and numerous pili that facilitate anchorage to the mucosal surface. The genes responsible for C. difficile s virulence are located within the pathogenicity locus (PaLoc) of the main circular chromosome, and include TcdA ( toxin C. difficile A ), TcdB, TcdC, TcdR and TcdE. 16 TcdA (Toxin A) and TcdB (Toxin B) are the cytotoxins most responsible for host cell damage and death, while the other three toxins regulate production and secretion of these two toxins. TcdE encodes a membrane porin protein that facilitates the release of these toxins from the organism. 14 Toxins A and B are glucosyltransferases that alter intracellular small molecule GTPases. The latter are important regulators of signalling pathways inside host cells. Inactivation of these

11 3 GTPases leads to cytoskeletal disaggregation, inhibition of cell division and membrane trafficking and eventual cell death. 14 TcdA additionally breaks down tight junctions between colonic epithelial cells, allowing entry of TcdB into the colonic mucosa. 17 Furthermore, TcdA has been shown to stimulate release of tumour necrosis factor from activated macrophages as well as induce cytokine production from other inflammatory cells, thereby potentiating the inflammatory response and causing further cell damage. 14 While toxin A was initially believed to be the most important toxin implicated in disease, outbreaks of tcda-/tcdb+ strains have questioned this notion. 18 In a recent study, both toxins were found to be important contributors to the pathogenesis of disease of this organism, either in isolation or in combination. 13 Recent outbreaks of a highly virulent strain of C. difficile in North American and European hospitals have been associated with 16-to-23-fold higher secretion of toxins A and B as compared to the common toxinotype 0 strain of this organism. 15 This strain has been classified by a number of different molecular and biochemical properties, and is referred to as any of BI (based on restriction endonuclease pattern), NAP1 (based on gel electrophoresis separation), 027 (based on ribosomal RNA type in PCR studies) or toxinotype III (based on specific mutations in the pathogenicity locus). An inactivating mutation in tcdc, which regulates the production of tcda and tcdb, is thought to be the mechanism underlying increased production of toxins A and B in this strain. 19, 20 Additionally, the BI/NAP1 strain has been demonstrated to display increased production of another secretory toxin (called binary toxin), to hypersporulate and to have increased resistance to fluoroquinolone antibiotics, relative to other strains. 10, 15 The role of binary toxin in the pathogenesis of C. difficile is still unclear, although in vitro experiments have shown this enzyme to disrupt cell cytoskeleton, leading to excessive fluid loss and eventual cell death. 21

12 4 Once introduced into the colon, C. difficile adheres to the mucus layer via adhesins and then penetrates the mucus with the aid of its flagella and various proteases. The organism subsequently adheres to enterocytes through additional adhesins located on its outer surface coat. In unfavourable conditions, such as in the presence of antibiotics directed against the organism or with reconstitution of host microbial flora, the organism can revert to its spore form for an indefinite period of time. Suppression of host microflora under antibiotic pressure promotes activation of dormant spores. 12 Studies of human gut models have demonstrated that treatment with fluoroquinolones decreases quantities of enterococci, lactobacilli, Bacteroides species and bifidobacteria, thereby promoting the germination of C. difficile spores and proliferation of vegetative cells. 12 Under these conditions, toxin production may also be activated, leading to cytotoxicity and inflammation characteristic of infection with this organism Epidemiology of Clostridium Difficile Colitis While 1 to 3 % of healthy patients in the community and 10 to 30 % of diarrhea-free patients in the hospital setting may be colonized with C. difficile, a much smaller percentage develop C. difficile colitis (CDC) Host and pathogen factors that lead to activation and proliferation of this organism are not well understood, although antibiotic pressure with resultant diminution of host microflora has been consistently shown to be a predisposing factor. 12 It is estimated that CDC is responsible for approximately 3 million cases of diarrhea and colitis annually in the U.S. and is associated with a mortality rate of between 1 and 2.5%. 26 Notably, the mortality rate has been reported to be considerably higher among patients with CDC who are admitted to hospital. 6, 8 Additionally, between 1.8 and 2.6% of patients with CDC

13 5 who are admitted to hospital undergo colectomy for treatment of fulminant or refractory colitis. 27, 28 The mortality rate among such patients is between 30 and 60% Transmission of C. difficile between individuals is thought to occur through passage of spores via the fecal-oral route. Indeed, a number of sources of contamination have been identified in hospital settings, including contact surfaces, health care workers, patients and even hospital air Established risk factors for C. difficile acquisition include older age (particularly over 65 years), antibiotic use (especially clindamycin, penicillins, cephalosporins and fluoroquinolones), 2, 39, extended stays in hospitals or long-term care facilities, 24 intensive care unit admission, 46 gastrointestinal procedures, 47 48, 49 and acid-suppressive medications. There has been a significant rise in the incidence and severity of CDC in hospitals across North America and Europe over the past decade. A review of 1771 cases from the province of Quebec demonstrated that the incidence of CDC increased 4-fold for the entire region and more than 10-fold for persons older than 65 years of age between 1993 and U.S. hospitalbased studies have also demonstrated a two-fold higher incidence of CDC, 80% greater casefatality with CDC and a three-fold rise in the rate of colectomy with CDC in the 2000 s as compared to the 1990 s Moreover, the mortality rate attributable to C. difficile infection during an epidemic of CDC in Quebec hospitals between 2003 and 2004 was reported to be between 6.9% and 16.7%, which was 3-fold greater than the mortality rate among matched hospitalized patients without CDC in one study. 6, 8 The rise in incidence and severity of this infection have been linked to the emergence of the highly virulent BI/NAP1 strain, which has been associated with greater risks of colectomy and death as compared to previous strains of this organism. 5-8, 54, 55 While this strain accounted for less than 0.02% of 6000 typed cases in the U.S. between 1984 and 1993, it was responsible for 96 of 187 (51%) typed cases in eight hospital outbreaks in the U.S. between 2000 and

14 6 Additionally, more than 80% of infected patients during the Quebec epidemic harboured the BI/NAP1 virulent strain and infected patients had a 4-fold higher probability of recent exposure to fluoroquinolones or cephalosporins than uninfected patients. 6 Surprisingly, this strain accounted for just 5% of 389 typed strains from hospitals in 34 European countries in a 2008 European surveillance study Clinical Presentation and Diagnosis of Clostridium Difficile Colitis Clinical disease associated with C. difficile occurs more commonly among patients who have had recent antibiotic exposure, particularly exposure to clindamycin, penicillins, cephalosporins or fluoroquinolones. 57, 58 CDC typically presents as an acute diarrheal illness that can vary in severity from mild colitis associated with minimal abdominal pain and watery diarrhea to fulminant colitis associated with fever, sepsis and multi-organ failure. Patients with fulminant disease may develop ileus and/or toxic megacolon due to penetration of the inflammatory process through the large bowel wall into the smooth muscle layer. Severe complications of this infectious process include toxic megacolon, bowel perforation, and multiorgan failure and death due to overwhelming sepsis. While the infection has a strong 9, 59 predilection for the colon, involvement of the small bowel has also been reported. Antibiotics, including oral vancomycin and/or oral or intravenous metronidazole, along with prompt cessation of other antibiotics that may be potentiating the infection, constitute the mainstay of medical therapy. 35 However, colectomy may be required as definitive therapy in treatment-refractory cases. Severe CDC may give rise to whitish exudates throughout the colon, termed pseudomembranes. These exudates consist of bacterial products, cellular debris, inflammatory cells and mucous, all of which are by-products of a severe inflammatory process. Identification

15 7 of pseudomembranes on endoscopic evaluation is virtually pathognomonic for C. difficile, although alternate diagnoses, including other gastrointestinal infections and inflammatory bowel disease (IBD), must still be considered. 60 The most accurate diagnostic method to identify C. difficile is anaerobic culture of the organism from stools. However, this method may be overly sensitive as it also detects C. difficile that is colonizing the gastrointestinal tract without actually causing infection. It is estimated that 10 to 30% of hospitalized patients are colonized with C. difficile without having active colitis. 7 Additionally, this test can take several days, given the slow growth of C. difficile. The cell cytotoxicity assay is the most accurate test to identify C. difficile infection, based on the 2, ability of C. difficile toxins in the stool of an affected patient to lyse plated cells in vitro. However, this assay is technically demanding and also has a relatively long turnaround time 64, 65 (typically h). As such, rapid testing for the presence of C. difficile toxins A and B in the stool of a patient with unexplained diarrhea, using an enzyme immunoassay (EIA), has become the test of choice in most centres to diagnose CDC. More than 20 commercially available EIA kits exist, with varying performance characteristics. 10 The sensitivity and specificity of these assays range from 31 to 99 % and from 84 to 100 %, respectively, with most assays having a sensitivity greater than 80% and a specificity greater than 95% Notably, given the relatively low prevalence of C. difficile among all patients with diarrhea, the positive predictive values (PPV) of these assays may be considerably lower. 66 Another test that is used in some laboratories to detect C. difficile is the glutamate dehydrogenase (GDH) assay, which capitalizes on the high levels of GDH released by this organism during active infection. While negative predictive values of this assay have been reported to be very high, 64, 69, 70 the lower PPV of this assay has 35, 66 mandated confirmation of a positive GDH test with EIA.

16 8 A newer type of test with a relatively rapid turnaround time and greater sensitivity for detecting C. difficile than previous tests (excluding toxigenic culture) is nucleic acid amplification of part of the C. difficile genome using polymerase chain reaction (PCR). 10 This test is rapidly replacing other tests in many laboratories across North America. Given the high costs of this test, however, some laboratories are using them selectively in combination with EIA and/or GDH testing. 71 Notably, similar to culture assay, this method also detects C. difficile organisms that have colonized the gastrointestinal tract without necessarily causing infection Inflammatory Bowel Disease Epidemiology of Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a chronic idiopathic gastrointestinal disorder that comprises two related, yet pathologically distinct, entities Crohn s disease and ulcerative colitis (UC). Both illnesses typically develop between the 2 nd and 4 th decade of life, but can occur at any age. 72 The incidence and prevalence of these conditions have varied in studies from different regions of the world but have consistently been higher in developed nations, particularly North America, northern Europe and New Zealand. 72 The hygiene hypothesis purports that decreased exposure to pathogenic organisms among children in developed nations, owing to better sanitary conditions, leads to the development of inappropriate immunologic responses and possibly IBD when these individuals are exposed to such pathogens later in life. 73 Synonymous with this concept is the finding that rates of IBD are increasing in developing nations, potentially due to improvements in sanitary conditions along with increased awareness of this disease and improved access to medical care. 72

17 9 From studies spanning the last century, the reported annual incidences of UC in Europe, North America, and Asia-Middle East have ranged from 0.6 to 24.3 per 100,000 person-years, 0 to 19.2 per 100,000 person-years and 0.1 to 6.3 per 100,000 person-years, respectively; the annual incidences of CD in these regions have ranged from 0.3 to 12.7 per 100,000 personyears, 0 to 20.2 per 100,000 person-years and 0.04 to 5.0 person-years, respectively. 72 From prevalence studies, the UC prevalence estimates have ranged from 4.9 to 505 per 100,000 in Europe, 37.5 to per 100,000 in North America and 4.9 to per 100,000 in Asia and the Middle East, and the CD prevalence estimates have ranged from 0.6 to 322 per 100,000 in Europe, and 16.7 to per 100,000 in North America and 0.88 to 67.9 per 100,000 in Asia and the Middle East. 72 Moreover, the overall incidence of both of these conditions has been increasing in all parts of the world, which may reflect a true increase in disease occurrence or improved detection of these conditions due to increased awareness and improved access to health care. 72 The incidence rates for UC and Crohn s disease in Canada have been reported to be 9.9 to 19.5 and 8.8 to 20.2 per 100,000 person-years, respectively, while the prevalence rates of these two conditions are 162 to 249 and 161 to 319 per 100,000, respectively. 74 As such, between 0.3 and 0.6% of the Canadian population has IBD Inflammatory Bowel Disease Pathophysiology and Clinical Presentation Both Crohn s disease and UC are characterized by episodic abdominal pain and variably bloody diarrhea, often with co-existing constitutional symptoms and/or extra-intestinal manifestations, including involvement of the skin, eyes, joints and hepatobiliary system. Both conditions are associated with considerable morbidity and impaired quality of life among affected individuals

18 Crohn s disease can affect any part of the gastrointestinal tract, although more than 90% of patients have isolated involvement of the distal small bowel and/or colon - approximately 30% of these patients have isolated ileal involvement, 30% have isolated colonic involvement and 40% have ileocolonic disease. 79 Additionally, Crohn s disease can affect all layers of the bowel wall, often resulting in complications such as extramural abscess formation, deep ulceration and extension of inflammation into adjacent organs (fistulizing disease), and transmural fibrosis leading to bowel obstruction (fibrostenotic disease). 79, 80 Large areas of unaffected bowel ( skip areas ) flanked by diseased segments is characteristic of this condition. While there is no curative therapy for Crohn s disease, lasting disease remission may be achieved in about 50 to 60% of patients with either localized resection of a diseased segment of bowel or with chronic immunosuppressive therapy Inflammation in ulcerative colitis, on the other hand, is typically confined to the mucosal and submucosal layers of the large bowel and rarely manifests with penetrating or obstructive complications. The disease characteristically involves the rectum and affects a variable extent of colonic mucosa in a continuous ascending fashion. In general, the clinical severity of this condition correlates with the extent of colonic involvement. Large-scale studies have shown that, at the time of diagnosis, close to half of all patients have isolated proctosigmoiditis, twothirds of patients have disease distal to the splenic flexure and 14 to 37% of patients have pancolitis In contrast to Crohn s disease, contiguous colonic involvement without skip areas is characteristic of this condition. Additionally, UC is generally not associated with fistulas or strictures. However, this condition often gives rise to episodes of severe colitis that necessitate hospitalization. Acute, severe colitis may be complicated by the development of toxic megacolon, bowel perforation or massive hemorrhage, any of which may lead to death without 89, 90 prompt definitive therapy. 10

19 11 Definitive therapy in UC typically involves a total proctocolectomy (or simply, colectomy ) with creation of either a neo-rectal pouch using the distal small bowel or a permanent small bowel anastomosis to the abdominal wall, after which a patient may be considered cured of the illness. However, this therapy can be associated with a number of peri-operative and long-term complications, including pouch leaks, chronic or recurrent pouch inflammation, chronic pouch dysfunction and infertility in females. 91, 92 Moreover, the functional, psychological and cosmetic implications of undergoing major abdominal surgery and losing the colon can be traumatizing for many patients. As such, colectomy is typically reserved for patients who develop a serious complication of colitis or as a last effort for patients who have clearly failed medical therapy Natural History of Inflammatory Bowel Disease Both Crohn s disease and UC typically follow a chronic relapsing-remitting pattern of disease symptoms and usually necessitate therapy to treat a disease flare. Population based studies from Scandinavia have demonstrated that only 10 to 12 % of patients have a relapse-free course following initial disease flare over a 10 to 25-year follow-up period. As well, less than 86, % of patients have a continuously active course that does not respond to medical therapy. Probability analyses in these studies have demonstrated that active disease is a significant risk factor for disease relapse in the subsequent year, and, conversely, quiescent disease is a predictor of disease remission in the subsequent year. Both conditions can evolve from relatively mild diseases to more aggressive disease phenotypes that are associated with serious potential complications and/or refractoriness to medical therapy. Crohn s disease presents as isolated inflammatory disease of the small and/or large bowel in more than 80% of patients, but progresses to fistulising/penetrating disease

20 12 and/or fibrostenotic disease, in 50 to 70 % of patients over 20 years from disease onset. 94, 95 The location of the presenting inflammatory disease, however, tends to be stable over time in more than 80% of patients Additionally, almost 80% of patients with Crohn s disease will require surgery at some time in their disease course; 79, to 70% of these patients will require a second surgery by 15 years. 83 UC presents as isolated proctosigmoiditis in close to half of all patients, of whom 50% may progress to more extensive colonic disease and 9% progress to pancolitis. 87 Some patients with UC ultimately require colectomy to treat severe and/or medically-refractory disease and this risk is strongly correlated with the extent and severity of colitis. While patients with isolated proctitis have a 5 to 15 % risk of undergoing colectomy, patients with pancolitis have been shown to have a % risk of incurring this outcome. 84, 87, 100 Hospitalized UC patients with severe colitis are at particularly high risk of requiring colectomy, with reported colectomy rates of 30 to 40% within three months of hospitalization despite treatment with the latest available therapies. 101, 102 Complications of UC that may give rise to the need for colectomy include toxic megacolon and major rectal bleeding, which, in one cohort study of 1116 UC patients, were found to occur in 21% and 25% of patients with pancolitis and 3% and 9.5% of patients with isolated proctitis, respectively. 84 Colonic perforation is the most dreaded acute complication of this condition necessitating colectomy and was associated with 16% mortality in one study. 89 Other important long-term complications of IBD are the development of colorectal cancer (CRC) and death. It has been estimated that patients with chronic UC have between a 7 and 30% absolute risk of developing CRC over a 30 to 40-year period from the time of diagnosis and 2- and 6-fold higher incidence of CRC as compared to an age-adjusted population Reported risk factors for CRC development among UC patients include longer disease duration, extensive colitis, 105 increased disease severity, 107, 108 younger age at diagnosis, 105 family history of CRC, 109, 110 primary sclerosing cholangitis (PSC), 111 and

21 13 decreased use of anti-inflammatory agents. 112, 113 While the risk of CRC in Crohn s disease is less well-defined, studies specifically evaluating patients with colonic Crohn s disease have demonstrated a 4- to 18-fold higher risk of CRC in this population as compared to non-ibd patients. 114, 115 Additionally, these patients are at markedly higher relative risk of developing small bowel adenocarcinoma, although the absolute risk is exceedingly small Most studies have shown that long-term survival rates do not differ overall between UC patients and the general population. 119, 120 However, patients with pancolitis may have a slightly 120, 121 higher mortality risk than non-ibd patients. Mortality risk in patients with Crohn s disease, on the other hand, has been shown to be slightly higher than the general population (standardized mortality ratio ), and has been most often attributable to complications of Crohn s disease in the first few years after diagnosis However, whether the observed higher mortality risk in these patients has been suppressed with the introduction of targeted biologic therapy, which has been associated with improved healing of the bowel lining and improved long-term outcomes in patients with Crohn s disease and UC, awaits further study Clostridium Difficile Colitis in Inflammatory Bowel Disease Epidemiology of Clostridium Difficile Colitis in Inflammatory Bowel Disease IBD has been identified as a strong independent risk factor for C. difficile acquisition. Studies of hospitalized patients have demonstrated that the prevalence of CDC is 2-fold higher among Crohn s disease patients and 4 to 8-fold higher among UC patients as compared to non- IBD patients. 130, 131 Furthermore, the incidence of CDC among IBD patient hospitalizations has increased 2 to 3-fold over the past decade Up to 5% of UC patient hospitalizations are

22 now complicated by CDC Biologic factors that may play a role in C. difficile acquisition among IBD patients have not been elucidated Natural History of Clostridium Difficile Colitis in Inflammatory Bowel Disease In addition to the higher rate of C. difficile acquisition, population-based studies have demonstrated that UC patients have a 4 to 5-fold higher risk of in-hospital mortality in the presence of CDC. 130, 133 As these studies were unable to adjust for baseline differences in UC disease severity or immunosuppressive medication use, or assess for potential misclassification of CDC status, it is uncertain whether the increased mortality risk was entirely attributable to CDC in these studies. However, it is conceivable that infection with C. difficile could have a synergistic effect with underlying chronic colitis, thereby giving rise to a particularly severe colitis that leads to complications such as bowel perforation, toxic megacolon, sepsis, and, ultimately, death. The reported mortality risk among patients with Crohn s disease who acquire C. difficile has been less consistent. A U.K.-based nationwide study reported a 7-fold increased risk of death while a U.S.-based nationwide study reported no increased risk of death among hospitalized Crohn s disease patients with CDC. 130, 133 Notably, the latter study found that colonic involvement was a risk factor for mortality in this setting. 130 The reported colectomy risk associated with CDC among hospitalized UC patients has also been inconsistent across studies. A U.K.-based nationwide study demonstrated a marginally significant 1.5-fold higher risk of colectomy with CDC in UC patients, while a U.S.-based nationwide study actually showed a decreased risk of colectomy among UC patients who had CDC, even after exclusion of patients who were potentially admitted to hospital for elective colectomy. 130, 133 Additionally, two single-centre U.S. studies of hospitalized UC patients did

23 15 not find any difference in the risk of in-hospital colectomy between C. difficile-infected or uninfected patients. 134, 135 However, these studies may have been underpowered to detect associations between CDC and in-hospital health outcomes. Notably, one of these studies did find a marginal statistically significant 2.4-fold higher risk of colectomy at one year following hospitalization in patients with CDC. 134 Overall, the significantly greater risk of C. difficile acquisition and the higher risk of mortality with CDC among hospitalized UC patients is concerning and warrants aggressive preventative care measures on the part of health care workers who manage these patients. Additionally, as more than 500,000 individuals across North America have UC, these findings may have significant implications for hospital care policies and health resource requirements in these patients. 74, 136 Future studies are needed to elucidate modifiable risk factors and therapeutic interventions that may benefit patient outcomes in this setting. 1.2 Study Rationale and Aims While there have been reports of greater in-hospital mortality risk among UC patients infected with C. difficile, no studies have evaluated the long-term impact of CDC on health outcomes in this population. Yet, it is conceivable that CDC could have a sustained impact upon the health of UC patients. One single-centre study recently reported that CDC in hospitalized UC patients was associated with a higher colectomy rate at one year. 134 UC patients who contract CDC may be at higher risk of future episodes of CDC, as these patients may have a greater affinity for C. difficile colonization as compared to non-ibd patients. 23 One study of asymptomatic ambulatory patients in Ireland reported that C. difficile colonization rates are 8.2% and 1.0% among IBD and non-ibd patients, respectively. 23 As such, the C. difficile colonization rate among hospitalized UC patients who contract CDC may be particularly high,

24 16 considering that the colonization rate among asymptomatic hospitalized general medical patients is as high as 30%. 24 Furthermore, it is theoretically possible that C. difficile perpetuates UC disease activity following an acute infection, in predisposed individuals, potentially as a result of abnormal immune responses directed against colonized spores and/or vegetative organisms, although this has not been previously studied. Notably, abnormal and/or exaggerated immune responses to host and pathogenic microbes have been central concepts in the pathogenesis of IBD The notion that an acute gastrointestinal infection could lead to the development or worsening of a chronic gastrointestinal illness has previously been demonstrated for postinfectious irritable bowel syndrome. 144 In addition to elucidating the long-term risks with CDC, the impact of CDC on colectomy risk in UC patients requires clarification, as studies evaluating this association have reported conflicting results. 130, As colectomy risk is generally considered the gold standard for objectifying prognosis among UC patients, investigating the impact of CDC on this outcome is particularly relevant. 145 Therefore, the aim of this study was to evaluate the impact of CDC on five-year colectomy risk among patients hospitalized for ulcerative colitis. Other objectives of the study were to evaluate the influence of CDC on five-year risks of mortality and severe disease recurrence requiring hospitalization, as well as to re-explore the effect of CDC on the risks of colectomy and death during index hospitalization. 1.3 Study Hypothesis The primary study hypothesis was that hospitalized UC patients who are diagnosed with CDC would have a greater five-year colectomy risk as compared to hospitalized UC patients who do not acquire this infection.

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26 18 Chapter 2 METHODS 2.1 Summary of Study Methodology The present study was a population-based retrospective cohort study conducted using Ontario health administrative data. UC patients hospitalized for a primary indication of either UC or CDC between 2002 and 2008 were studied. Patients who were given a diagnosis of CDC during any hospitalization were compared to patients who were not given a hospital diagnosis of CDC throughout the study period. The primary outcome was five-year colectomy risk, while secondary outcomes included five-year risks of mortality and re-hospitalization as well as inhospital risks of colectomy and mortality. Multivariable analyses were conducted to control for relevant confounders. A sensitivity analysis, based on an alternate cohort of UC patients who were identified using previously published criteria, was performed to confirm the validity of all observed associations in the primary analysis. 2.2 Literature Search Strategy Relevant articles pertaining to the present study were obtained through a literature search using the Ovid Medline search engine. The terms ulcerative colitis, Crohn s disease and inflammatory bowel disease were combined using or statements to yield a comprehensive list of articles in this area. Additionally, the terms Clostridium difficile and pseudomembranous colitis were combined using the or statement to yield a comprehensive list of articles relating to this area. These two lists were further combined using an and statement to generate a list of articles specific to studies relating to CDC in IBD. Within this composite set of articles, individual original studies and review articles, as well as reference lists from each article, were surveyed manually for original studies that reported on either epidemiology or prognosis among UC patients. From this lists of studies, only articles that were felt to be

27 19 most relevant to the present study, based on the time period of the original study, the presence of information relevant to the present study and the impact factor of the publishing journal, were selected for supporting evidence. The list of articles derived from the search of Clostridium difficile or pseudomembranous colitis was further combined, using and statements, separately with each of history or discovery, microbiology, pathogenicity or virulence, epidemiology or incidence or prevalence, prognosis or natural history or disease course or surgery or colectomy or proctocolectomy or death or mortality or outcomes, risk factors, and diagnosis or presentation or features or symptoms to yield lists of articles pertinent to each of these diverse aspects of CDC. Similarly, articles of interest pertaining to the various facets of inflammatory bowel disease were identified by combining the search of Crohn s disease or ulcerative colitis or inflammatory bowel disease individually, using and statements, with each of epidemiology or incidence or prevalence, pathophysiology or pathogenesis or pathology, diagnosis or presentation or features or symptoms, and prognosis or natural history or disease course or surgery or colectomy or proctocolectomy or death or mortality or outcomes. Original articles within each of the lists derived from these searches were cross-referenced with citations in relevant review articles to yield a shorter list of the most pertinent articles on the various topics of interest for discussion. Additional studies of interest that were identified through citations in review articles, but that were not identified in the Medline-generated lists, were also selected for discussion. 2.3 Data Sources Data for the present study was acquired from the following Ontario-based population health administrative databases: 1) The Ontario version of the Canadian Institutes for Health Information Discharge Abstract Database (CIHI-DAD), which contains demographic and health information pertaining to all patient hospitalizations throughout Canada (excluding the province of Quebec); 2) The Ontario Health Insurance Plan (OHIP) database, which contains physicians

28 20 claims data pertaining to the majority of physician-patient encounters in Ontario; 3) The Registered Persons Database (RPDB), which contains demographic information and vital status for all Ontario residents; 4) The Ontario Cancer Registry (OCR); and 5) Ontario Census Databases. The CIHI-DAD was the primary data source used in this study. All patient data was accessed through the Institute for Clinical Evaluative Sciences (ICES). Patient information was linked between databases, hospitalizations and physician encounters through unique ICES patient identity codes, providing a comprehensive account of each patient s demographic and clinical profiles and permitting longitudinal outcome assessment. ICES is a non-profit institution based out of Toronto, Canada that stores health information of more than 13 million Ontario residents for the purposes of conducting clinical research and health care policy planning. 2.4 Study Design and Patients Study Design and Cohort Assembly A population-based retrospective cohort study of UC patients hospitalized in Ontario, Canada between March 31, 2002 and March 31, 2008 was conducted. Patients with a Most Responsible Diagnosis (MRD) of either UC (K51.x) or CDC (A04.7) recorded on a hospital discharge abstract corresponding to any hospitalization during the study period were eligible for study, with the stipulation that patients hospitalized for CDC also had a co-morbid diagnosis of UC recorded in their discharge abstract. Patients were included in the study from the time of their first hospitalization during the study period with one of these diagnoses as the MRD. Additionally, patients who were given a co-morbid diagnosis of CDC at any hospitalization during the study period were preferentially studied from the time of hospitalization with this co-

29 21 morbid diagnosis, even if they had been previously hospitalized for UC within the study period. As such, all patients who were given an MRD or co-morbid diagnosis of CDC in hospital throughout the study period were included in the same group and all other patients who were followed from the time of their first UC-related hospitalization within the study period should not have had a CDC-related hospitalization throughout the study period. Patients were assessed for up to five years following index hospitalization for the development of a number of adverse health events, with the final study follow-up date being March 31, 2010 (Figure 1). The MRD in CIHI-DAD corresponds to the acute illness that most profoundly affected a patient s treatment course in hospital or else accounted for the greatest length of hospital stay. A high level of coding accuracy has been demonstrated for the fifty most common MRD s in the Ontario version of the CIHI-DAD, albeit this list did not include UC or CDC. 146 Furthermore, a MRD of UC was demonstrated to have a positive predictive value (PPV) of 79.3%, based on medical record review, for identifying admission to hospital for a UC flare in the Alberta version of the CIHI-DAD specific to the Calgary Health Zone. 147 A co-morbid diagnosis in the CIHI-DAD is one that contributed less importantly to in-hospital treatment or length of stay than the MRD, but nevertheless had a significant impact on a patient s treatment course or clinical outcome during hospitalization. Both pre-admission and post-admission co-morbidity of CDC, based on whether this infection was acquired prior to hospitalization or during hospitalization, respectively, were included in this definition in the present study. Patients who were diagnosed with CDC during a previous hospitalization may have been reported to have CDC as a secondary diagnosis on their hospital discharge abstract such patients were not considered to have CDC in the present study and were excluded from the study if their CDC-related hospitalization occurred within five years prior to the index hospitalization. The chosen start date for patient inception in this study coincided with a transition to diagnostic reporting using the 10 th version of the International Classification of Diseases (ICD-

30 22 10) system in the CIHI-DAD. Fortuitously, this time also coincided fairly closely with reports of emergence of a highly virulent strain of C. difficile (BI/NAP1/027) in North American hospitals, thus permitting evaluation of the impact of CDC in UC patients that is most pertinent to current circumstances. 6, 8, 148 The end date for patient inception was chosen to allow a minimum of two years of observation time for all patients (based on a final follow-up date of March 31, 2010) Excluded Patients Patients were excluded from the study for the following indications: 1) Invalid patient identification number in the CIHI-DAD; 2) Age younger than 18 years, as patterns of care in the pediatric population may differ considerably as compared to the adult population; 3) Elective initial hospital admission within the study period (identified as category L in the Admit Category field in CIHI-DAD), as it was desired to capture patients admitted to hospital with acute colitis; 4) Hospitalization with a MRD or co-morbid diagnosis of CDC within a fiveyear timeframe preceding the date of index hospitalization, in order to limit the study to incident CDC cases; 5) History of partial or total colectomy or proctectomy within a five-year timeframe prior to the date of index hospitalization), as such patients may have had a lesser risk of acquiring CDC and of incurring adverse health outcomes; and 6) Diagnosis of colorectal cancer between five years prior to index hospitalization and the end of the study period, given that these patients would have been at higher risk of incurring colectomy for reasons unrelated to disease activity (Figure 1) Comparator Groups Patients who were given a MRD or co-morbid diagnosis of CDC at any hospitalization during the study period ( UC-CDC group) were compared to those who were not given a

31 hospital discharge diagnosis of CDC during the study period ( UC-noCDC group) on the risk of developing a number of adverse health outcomes over five years following hospitalization Subgroup Analysis Five-year health outcomes were also assessed in a subgroup of patients from the primary cohort who were discharged from hospital without undergoing colectomy, in order to determine the long-term impact of an episode of CDC on the disease course of hospitalized UC patients with potentially less aggressive disease who recover from an acute colitis flare. This analysis was undertaken as it is unknown whether an episode of severe CDC permanently alters the natural history of UC. 2.5 Study Outcomes The primary outcome of the study was the five-year colectomy risk in the primary cohort. Other outcomes included the five-year risk of death in this cohort, as well as the fiveyear risks of colectomy, death, non-elective UC-related hospital re-admission, and non-elective all-cause hospital re-admission among patients who were discharged from hospital without undergoing colectomy. Additionally, risks of colectomy and death, as well as acute care length of hospital stay (LOHS), during the index hospitalization were evaluated. Colectomy outcome was derived from the CIHI-DAD, based on procedure codes corresponding to complete or partial excision of the large intestine or rectum. Death outcome was derived by combining information from the CIHI-DAD and RPDB, to ensure capture of both inpatient and outpatient deaths. All other outcomes were assessed using data in CIHI-DAD. Non-elective indication for hospital re-admission was ascertained through the admit category field in CIHI-DAD.