Alimentary Pharmacology and Therapeutics
Impact of Clostridium difficile colitis on 5-year health outcomes in patients with ulcerative colitis S. K. Murthy*, A. H. Steinhart*,†, J. Tinmouth†,‡,§, P. C. Austin†,§, N. Daneman†,§,¶ & G. C. Nguyen*,†,§
*Mount Sinai Hospital IBD Centre, Department of Medicine, University of Toronto, Toronto, ON, Canada. † Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada. ‡ Division of Gastroenterology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. § Institute for Clinical Evaluative Sciences, Toronto, ON, Canada. ¶ Division of Infectious Diseases, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
Correspondence to: Dr S. K. Murthy, 445–600 University Avenue, Toronto, ON M5G 1X5, Canada. E-mail:
[email protected]
Publication data Submitted 1 May 2012 First decision 30 May 2012 Resubmitted 12 September 2012 Accepted 15 September 2012 EV Pub Online 14 October 2012
SUMMARY Background Clostridium difficile colitis (CDC) is associated with an increased short-term mortality risk in hospitalised ulcerative colitis (UC) patients. We sought to determine whether CDC also impacts long-term risks of adverse health events in this population. Aim To determine whether CDC also impacts long-term risks of adverse health events in this population. Methods A population-based retrospective cohort study was conducted of UC patients hospitalised in Ontario, Canada between 2002 and 2008. Patients with and without CDC were compared on the rates of adverse health events. The primary outcomes were the 5-year adjusted risks of colectomy and death. Results Among 181 patients with CDC and 1835 patients without CDC, the 5-year cumulative colectomy rates were 44% and 33% (P = 0.0052) and the 5-year cumulative mortality rates were 27% and 14% (P < 0.0001) respectively. CDC was associated with a higher adjusted 5-year risk of mortality [adjusted hazard ratio (aHR) 2.40, 95% CI 1.37–4.20], but not of colectomy (aHR 1.18, 95% CI 0.90–1.54). CDC impacted mortality risk both during index hospitalisation (adjusted odds ratio 8.90, 95% CI 2.80–28.3) as well as over 5 years following hospital discharge among patients who recovered from their acute illness (aHR 2.41, 95% CI 1.37–4.22). Colectomy risk was not influenced by CDC in this cohort. Conclusion Clostridium difficile colitis is associated with increased short-term and longterm mortality risks among hospitalised ulcerative colitis patients. As colectomy risk is not similarly impacted by Clostridium difficile colitis, factors predictive of death among C. difficile-infected ulcerative colitis patients require elucidation. Aliment Pharmacol Ther 2012; 36: 1032–1039
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ª 2012 Blackwell Publishing Ltd doi:10.1111/apt.12073
Clostridium difficile colitis in ulcerative colitis INTRODUCTION Clostridium difficile colitis (CDC) is the leading cause of nosocomial infectious diarrhoea and is associated with substantial morbidity and mortality. The past decade has witnessed a rise in the incidence and severity of CDC in hospitals across North America and Europe, largely attributable to the emergence of highly virulent strain of this organism.1, 2 Patients with ulcerative colitis (UC) are at increased risk of acquiring CDC.3–5 The incidence of CDC among UC patients has also been rising in recent years, with CDC now being implicated in up to 5% of UC hospital admissions.3–5 Nationwide studies have further reported that CDC is associated with a 3.8–5.5-fold higher acute mortality risk among hospitalised UC patients.3, 6 The impact of CDC on acute colectomy risk in UC patients has been less consistent across studies.3, 6–8 In addition to increasing short-term health risks, CDC may pose sustained health risks to UC patients. Chronic C. difficile colonisation following an acute infectious episode may increase the risk of future CDC episodes in many patients.9 Moreover, the impact of CDC on UC disease behaviour remains unknown. One study reported that CDC was associated with a greater 1-year colectomy risk in these patients.7 However, no study has assessed the longer term impact of CDC on health outcomes in this population. As UC afflicts more than 500 000 individuals across North America, this could have significant implications for hospital care policy and health resource utilisation in these patients.10, 11 Therefore, we sought to investigate the impact of CDC on 5-year health outcomes among hospitalised UC patients. MATERIALS AND METHODS Data sources Data for this study was acquired primarily from the Ontario version of the Canadian Institutes of Health Information Discharge Abstract Database (CIHI-DAD), which contains demographic and health information pertaining to all patient hospitalisations throughout Ontario. Additional information was obtained from The Ontario Health Insurance Plan (OHIP) database, The Ontario Registered Persons Database (RPDB), The Ontario Cancer Registry (OCR) and Ontario Census Databases. Patient information was linked across hospitalisations and physician encounters and between databases at the Institute for Clinical Evaluative Sciences (ICES), permitting detailed patient profiles and longitudinal health out-
Aliment Pharmacol Ther 2012; 36: 1032-1039 ª 2012 Blackwell Publishing Ltd
come assessments (http://www.ices.on.ca). This study was approved by the ICES Privacy Office.
Patients and study design A retrospective population-based cohort study was conducted of UC patients hospitalised at acute care hospitals in Ontario, Canada, between 31 March 2002 and 31 March 2008. The study start date coincided with the rising incidence of highly virulent C. difficile infectious outbreaks in North American hospitals and also with the onset of diagnostic reporting using ICD-10 codes in CIHI-DAD.1, 2 Patients were eligible for study if they were given a ‘Most Responsible Diagnosis (MRD)’ of UC (K51.x in ICD-10) or else a MRD of CDC (A04.7 in ICD-10) with a co-morbid or secondary diagnosis of UC on a hospital discharge abstract corresponding to any hospitalisation within the study period. The MRD in CIHI-DAD corresponds to the acute illness that most significantly affected a patient’s treatment course or accounted for the greatest length of hospital stay (LOHS). A co-morbid diagnosis is one that contributed significantly to a patient’s in-hospital course, whereas a secondary diagnosis refers to a preadmission co-morbidity that did not complicate a patient’s hospital course. A subgroup of patients who were discharged from hospital without undergoing colectomy was also evaluated, as it remains unknown whether CDC alters long-term disease behaviour specifically among UC patients who recover from their acute illness. Patients were excluded from the study for the following indications: (i) Age younger than 18 years; (ii) Invalid identifying information in CIHI-DAD; (iii) Permanent residence outside of Ontario; (iv) Initial UC-related hospitalisation within the study period for elective indication (based on a specific designation for admission type in CIHI-DAD); (v) Hospitalisation for CDC within the previous 5 years; (vi) History of partial or total colectomy (using a 5-year look-back window), and (vii) Diagnosis of colorectal cancer from 5 years prior to index hospitalisation to the end of the study period. To increase the positive predictive value (PPV) of a UC diagnosis, a published algorithm for identifying UC patients within health administrative data from the province of Manitoba, Canada, was applied to generate the final study cohort.12 This algorithm required that patients had at least five UC-related physician contacts if they were registered with OHIP for 2 or more years or at least three UC-related physician contacts if they were registered with OHIP for less than 2 years (UC-related
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S. K. Murthy et al. hospitalisation counted as a single contact). Physician contacts were identified in the CIHI-DAD and OHIP databases. The sensitivity and specificity of this definition in the original study were 74.4–87.7% and 91.3–93.7% respectively.12 Notably, this definition has not been specifically validated for a hospitalised cohort or within Ontario health administrative data.
Comparator groups Patients who were given a MRD or a co-morbid diagnosis of CDC at any hospitalisation during the study period were evaluated from the time of their first hospitalisation with this diagnosis (‘UC-CDC’ group). These patients were compared with those who were not given a diagnosis of CDC in any hospitalisation during the study period (‘UC-noCDC’ group) on the rates of adverse health events over 5 years following index hospitalisation, with a final follow-up date of 31 March 2010. Outcomes The primary outcomes were the adjusted 5-year risks of colectomy and death. Other outcomes assessed included: (i) The 5-year risks of colectomy, death, non-elective UC-related hospital readmission, and non-elective all-cause hospital readmission, among colectomy-free discharged patients; and (ii) The risks of colectomy and death and the acute care length of hospital stay (LOHS) during index hospitalisation. Covariates The associations between CDC and adverse outcomes were adjusted for the potentially confounding effects of age, gender, weighted Charlson co-morbidity score,13 prior UC-related hospitalisation (using a 5-year lookback window), UC duration (using an 8-year look-back window), hospital teaching status, annual hospital UC admission volumes and year of hospitalisation. LOHS was also adjusted for the effects of in-hospital colectomy and in-hospital death. Prior UC-related hospitalisation and UC duration were used to partially adjust for baseline UC severity. Information on all variables was obtained solely from CIHI-DAD, except for the variable ‘UC duration’ for which both CIHI-DAD and OHIP databases were surveyed. Statistical methods Bivariate comparisons of in-hospital outcomes were conducted using the Chi-squared test (or Fisher’s exact test) for categorical variables and the Wilcoxon ranksum test for interval variables. The Kaplan–Meier 1034
product limit method with log-rank test was used to compare time-to-event outcomes. To evaluate the adjusted effects of CDC on 5-year (longitudinal) and in-hospital (binary) outcomes, while simultaneously accounting for clustering of patients within hospitals, Cox proportional hazards models with robust variance estimates and generalised estimating equation (GEE) methods (to estimate logistic regression models) were used respectively. Negative binomial regression analysis was used to model acute care LOHS. A stepwise modelling approach was used when evaluating death outcome to ensure a minimum 1:10 ratio of covariates to outcome events.14, 15 As such, hospitalisation year was excluded from the analysis of 5-year mortality risk (132 deaths), whereas no additional covariates (aside from CDC status) were included in the analysis of in-hospital mortality risk (13 deaths). Statistical significance was based on a 2-sided type I error rate of 5%. All analyses were performed using SAS 9.1 software (SAS Institute Inc., Cary, NC, USA). Patients were censored at the time of colectomy in the analysis of 5-year mortality risk so that only patients with intact colons who were at risk of experiencing UCrelated adverse events were analysed. In addition, patients who underwent colectomy on the date of rehospitalisation were censored on that date in the analyses of non-elective hospital readmission. Otherwise, patients were censored at the last study follow-up date. Loss to follow-up in this study was assumed to be negligible based on an annual Ontario emigration rate of 0.18% (http://www40.statcan.gc.ca/l01/cst01/demo33b-eng.htm).
RESULTS Patients Of 5743 UC patients who were hospitalised for UC or CDC during the study period, 2016 met entry criteria. Of excluded patients, 2278 did not satisfy the study case definition for UC, 478 were under 18 years of age, 580 were admitted for elective large bowel surgery at index hospitalisation; 155 had undergone prior partial or total colectomy; 130 had been previously hospitalised for CDC within the preceding 5 years; 100 were identified as having prevalent colorectal cancer, 4 were not Ontario residents and 2 had invalid identifying information. In the study cohort, 181 patients (9.0%) were diagnosed with CDC during hospitalisation. Baseline characteristics of study patients are presented in Table 1. Eleven patients had missing information on one or more variables in this study. The cumulative 5-year rates of Aliment Pharmacol Ther 2012; 36: 1032-1039 ª 2012 Blackwell Publishing Ltd
Clostridium difficile colitis in ulcerative colitis Table 1 | Baseline characteristics of study patients
Characteristic
UC-CDC, No. (%) (NTotal = 181)
UC-noCDC, No. (%) (NTotal = 1835)
Age 70 32 (18) 186 (10) Gender F 99 (55) 975 (53) M 82 (45) 860 (47) Charlson co-morbidity score 0 129 (71) 1542 (84) 1 25 (14) 192 (10) 2 27 (15) 101 (6) Previous hospitalisation for UC† No 70 (39) 1626 (89) Yes 111 (61) 209 (11) UC disease duration‡ 2 years 75 (41) 568 (31) >2 years 106 (59) 1267 (69) Annual hospital UC admission volumes (Quintile) 1 (Lowest) 33 (18) 309 (17) 2 28 (16) 332 (18) 3 31 (17) 392 (21) 4 36 (20) 360 (20) 5 (Highest) 53 (29) 442 (24) Hospital type Teaching 113 (62) 1270 (69) Nonteaching 68 (38) 565 (31) Admission year
