of Clostridium difficile infection worsens the prognosis of ulcerative colitis

BACKGROUND: The impact of Clostridium difficile infections among ulcerative colitis (UC) patients is well characterized. However, there is little knowledge regarding the association between C difficile infections and postoperative complications among UC patients. OBJECTIVE: To determine whether C difficile infection is associated with undergoing an emergent colectomy and experiencing postoperative complications. METHODS: The present population-based case-control study identified UC patients admitted to Calgary Health Zone hospitals for a flare between 2000 and 2009. C difficile toxin tests ordered in hospital or 90 days before hospital admission were provided by Calgary Laboratory Services (Calgary, Alberta). Hospital records were reviewed to confirm diagnoses and to extract clinical data. Multivariate logistic regression analyses were performed among individuals tested for C difficile to examine the association between C difficile infection and emergent colectomy and diagnosis of any postoperative complications and, secondarily, an infectious postoperative complication. Estimates were presented as adjusted ORs with 95% CIs. RESULTS: C difficile was tested in 278 (58%) UC patients and 6.1% were positive. C difficile infection was associated with an increased risk for emergent colectomy (adjusted OR 3.39 [95% CI 1.02 to 11.23]). Additionally, a preoperative diagnosis of C difficile was significantly associated with the development of postoperative infectious complications (OR 4.76 [95% CI 1.10 to 20.63]). CONCLUSION: C difficile diagnosis worsened the prognosis of UC by increasing the risk of colectomy and postoperative infectious complications following colectomy. Future studies are needed to explore whether early detection and aggressive management of C difficile infection will improve UC outcomes. de manière significative à l’apparition de complications infectieuses postopéra- toires (RR 4,76 [95 % IC 1,10 à 20,63]). CONCLUSION : Le diagnostic de C difficile aggrave le pronostic de CU, car il accroît le risque de colectomie et les complications infectieuses postopératoires après une colectomie. D’autres études s’imposent pour explorer si le dépistage précoce et la prise en charge dynamique de l’infection à C difficile amélioreront les résultats cliniques de la CU. between C difficile positivity and variables that were indepedently associated with colectomy were tested and included in the model if the likelihood ratio test was statistically significant (ie, P<0.05). Point estimates were presented as adjusted ORs with 95% CIs. development of postoperative complications evaluated.

U lcerative colitis (UC) is characterized by periods of remission followed by periods of disease activity that decrease quality of life.In Western nations, the prevalence of UC has been as high as 500 per 100,000 persons (1), and approximately 15% of UC patients undergo surgical resection of the colon within the first 10 years of diagnosis (2,3).Furthermore, UC patients who undergo colectomy are at increased risk for postoperative morbidity and mortality (4,5).
The increased incidence and severity of Clostridium difficile infections during the past decade (6,7), along with outbreaks of more virulent strains (8), have increased public and practitioner awareness of the importance of this pathogen.While antibiotic exposure is the primary risk factor for C difficile infection, UC has become recognized as an independent risk factor (9,10).C difficile infection risk among UC patients has increased over time, with C difficile prevalence doubling from 26.6 to 51.2 per 1000 discharges from 1998 to 2004 (11).C difficile infection may worsen the prognosis of UC because the infection has been associated with higher morbidity and increased risk for surgery up to one year after diagnosis of infection (11)(12)(13).Consequently, C difficile diagnosis is associated with higher hospital costs among inflammatory bowel disease patients (11).These studies assessed only inpatient C difficile test results and, thus, missed the impact of C difficile infections diagnosed before hospital admission (11,14).
We studied whether C difficile diagnosis in hospital or 90 days before hospital admission among UC patients was associated with an emergent colectomy and, furthermore, the development of postoperative complications.

Data sources
The Data Integration, Measurement and Reporting Hospital Discharge Abstract database was used to capture hospitalizations of UC patients in the Calgary Health Zone (CHZ) in Alberta.The CHZ is a population-based health authority that provides health care to Calgary residents and >20 nearby cities under a public, single-payer system (15).This database includes patients' demographic data, admission and discharge date, and 42 diagnostic and 25 procedural coding fields using the International Classification of Diseases, Ninth and 10th Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM) and the Canadian Classification of Health Intervention (CCI) (4,16).The population-based Calgary Laboratory Services database was used to identify UC patients who underwent stool testing for C difficile.Calgary Laboratory Services confirmed the C difficile infection using a two-step approach: an enzyme immunosorbent assay (EIA) for toxins A and B (TechLab C. difficile TOX A/B II, TechLab Enteric Diagnostics, USA) was used as a screening method; and the stool sample was tested using a second EIA (Triage Clostridium difficile panel, Biosite Diagnostics, USA) if the results of the first EIA were positive.A sample was considered to be C difficile positive if both tests were positive.

Study population
The study population consisted of adults (≥18 years of age) admitted emergently to a CHZ hospital between January 1, 2000 and December 31, 2009 for a UC flare.The approach of identifying the study population was previously validated (16).First, the Data Integration, Measurement and Reporting Hospital Discharge Abstract database was used to identify patients admitted to hospital with a diagnosis of UC (ICD-9-CM 556.X or ICD-10-CA K51.X) in any diagnostic position and a procedural code for colectomy (ICD-9-CM 45.7, 45.8 or CCI 1.NM.87,1.NM.89,1.NM.91,1.NQ.89,1.NQ.90).The colectomy admission was recorded as the index date.Second, from the remaining discharge abstracts, UC patients admitted to hospital for a flare were identified from admissions with a UC code in the primary diagnostic position.Among patients with UC who were admitted to hospital for a flare, but did not undergo a colectomy, all hospital admissions that occurred within the study period (2000 to 2009) were recorded and one admission was randomly selected as the index date (16).Patients who were not tested for C difficile in hospital or within 90 days of hospitalization were not included in the study population.Figure 1 illustrates the inclusion and exclusion criteria that defined the study population.Medical charts of all UC patients identified were reviewed to confirm that the UC patients were admitted to hospital emergently for a UC flare and to collect patients' surgical and medical history relevant to the index admission.

Selection of cases and controls
The primary case definition was undergoing an emergent colectomy during the index admission.Colectomy was defined as emergent if the decision to perform colectomy was made during the admission and after failing to respond to medical management, or because the patient experienced a complication.Controls were the remaining UC patients discharged from hospital without a colectomy after responding to medical management.
The secondary case definition was the development of any postoperative complication and, specifically, an infectious postoperative complication among UC patients who underwent an emergent colectomy.Postoperative complications were defined as an unexpected medical event that occurred between the start of the operation and discharge from the hospital.These complications were classified into seven complication categories including postoperative infection (Appendix 1).Complications were stratified according to severity using the Clavien classification of surgical complications (17).The development of postoperative complications was recorded if the patient experienced at least one complication described under any of the categories graded as Clavien II or higher (ie, requiring medical or surgical intervention or leading to death).C difficile infection was not considered to be a postoperative complication (4).The definition of postoperative complication has been previously validated for UC (16).

Exposure
The primary exposure was a diagnosis of C difficile infection in hospital or 90 days before the index admission.Ninety days before hospital admission was defined a priori to ensure that patients defined as negative for C difficile were not treated for a C difficile infection before hospital admission.A patient was classified as diagnosed with C difficile if at least one test result was positive during the predetermined period.The date of the first positive test was recorded as the index date of infection.C difficile diagnosis was confirmed by medical chart review.Patients were classified as C difficile negative if all test results during the predetermined period were negative.

Covariates
Additional demographic and clinical data extracted from chart review included: age (stratified as 18 to 32, 33 to 47 and ≥48 years, based on the tercile of the cohort); sex; disease extent (left-sided versus pancolitis); disease duration (defined as the interval between UC diagnosis and admission date), length of flare (<2, 2 to 8, >8 weeks); and smoking status (current, ex-smoker, never).Inflammatory bowel disease medications (5-aminosalicylic acid or sulfasalazine, azathioprine, corticosteroids and infliximab) taken at time of admission and/or administered in-hospital were recorded.Patients were classified as having comorbidities (ie, health conditions occurring before hospitalization) if they had at least one of the comorbidities listed in Appendix 2. The definition of comorbidity has been previously validated for UC (16).

Statistical analysis
The associations between the outcome and categorical variables were tested using the Fisher's exact test or the χ 2 test.Continuous variables were expressed as median with interquartile range and compared using the Wilcoxon rank-sum test.Multivariate logistic regression analysis was performed to determine the association between the need for an emergent colectomy and diagnosis of C difficile (defined a priori) after adjusting for other covariates.Age was a priori forced into the regression model.For the other covariates, a backward elimination approach was used to examine independent effects of additional variables on the need for emergent surgery with an entry P value <0.20.Variables were kept in the model if: the two-sided P value was <0.05; or there was evidence of confounding because their removal resulted in a 30% change in the estimate of the primary exposure.The variance inflation factor was used to measure multicollinearity among the independent variables.Multicollinearity was considered to be negligible if the variance inflation factor was <10.Interactions The association between C difficile infection and the development of postoperative complications was also evaluated.Multivariate logistic regression was performed to examine the association between postoperative complications (and then postoperative infection separately) and C difficile diagnosis (defined a priori) after adjusting for other covariates.A backward elimination approach was used to examine the independent effects of variables on the development of postoperative complications (and postoperative infection) using the same procedure as described above.
A sensitivity analysis was performed to determine whether the timing of C difficile diagnosis affected the association with the outcomes.For this, logistic regression models were recalculated with C difficile diagnosis defined as having at least one positive test result in hospital or 14 days before the index admission.Patients who were not tested for C difficile in hospital or 90 days before admission were included in a second sensitivity analysis.Logistic regression models were recalculated for all three outcomes: emergent colectomy, any postoperative complication and infectious complication.
All analyses were performed using STATA version 11 (STATA Corp, USA).The study was approved by the Conjoint Health Research Ethics Board at the University of Calgary (Calgary, Alberta).The present study was conducted in accordance with the strengthening of the reporting of observational studies in epidemiology (STROBE) statement (18).

RESULTS
A total of 278 UC patients met the inclusion criteria.Table 1 summarizes the baseline characteristics of the study population.The indications for an emergent colectomy were bowel complication (n=9), cancer/dysplasia (n=1) and failed medical management in hospital (n=92).C difficile diagnosis was recorded in 11 (11%) UC patients who underwent an emergent colectomy compared with six (3%) patients who responded to medical management (P=0.01).Patients diagnosed with an infection in hospital or up to 90 days before hospitalization had higher odds of undergoing emergent surgery when admitted to hospital (adjusted OR 3.39 [95% CI 1.02 to 11.23]) (Table 2).
Table 1 summarizes the characteristics of the 102 patients who underwent an emergent colectomy and were preoperatively tested for C difficile.The median time from C difficile diagnosis to surgery was 12 days (interquartile range 14 days).At least one postoperative complication was recorded in 30% of UC patients and 20% developed an infectious postoperative complication.Infectious postoperative complications experienced among UC patients with C difficile included: sepsis (n=3), abscess (n=2), urinary tract infection (n=1), pneumonia (n=3) and infected central line (n=1) (Appendix 3).C difficile was diagnosed preoperatively in 24% of patients who experienced an infectious postoperative complication, compared with 7% of UC patients who did not develop an infectious postoperative complication (P=0.046)(Table 1).
Preoperative diagnosis of C difficile was not significantly associated with developing any postoperative complication (adjusted OR 3.16 [95% CI 0.89 to 11.23]) (Table 3).However, individuals diagnosed with C difficile preoperatively had higher odds of developing a new infectious postoperative complication (adjusted OR 4.76 [95% CI 1.10 to 20.63]) (Table 3).
The sensitivity analysis that restricted the exposure definition to only patients tested for C difficile in hospital or 14 days before admission resulted in similar associations between C difficile infection and emergent colectomy (adjusted OR 3.70 [95% CI 1.06 to 12.89]) (Appendix 4), whereas the associations were strengthened for any complication (adjusted OR 6.    (19,20).However, reports describing the impact of C difficile diagnosis on in-hospital and short-term risk of colectomy are inconsistent.Two single-centre studies (21,22) failed to find an association between C difficile and the need for colectomy at index admission or three months following C difficile diagnosis.In addition, a large, nationwide study using in-hospital data reported a negative association between C difficile diagnosis and colectomy, even after taking into consideration patients who were admitted electively (11).The conflicting results between these previous studies and our study may be attributed to methodological differences from our study.Previous studies were potentially limited because of selection bias arising from data collected from tertiary care centres and/or misclassification bias from using administrative databases (23).In contrast, our study was population-based, and used chart reviews to confirm exposures and outcomes.Moreover, previous studies did not account for C difficile testing that occurred before admission to hospital.Furthermore, surgery thresholds may differ among centres (24).Also, different C difficile ribotypes (8,25) and lack of consensus on the treatment of C difficile infections among UC patients may have influenced infection outcomes (26,27).Finally, over time, better surveillance and diagnostic tests along with more aggressive treatment of C difficile infections may account for the differences observed (26)(27)(28)(29)(30).
Several factors may explain the increased risk for postoperative infection among patients with a C difficile infection.First, patients with a C difficile infection may have greater UC disease severity, immunosuppression or systemic toxicity (28).Second, antibiotic exposure before surgery may have increased susceptibility for acquisition of antibiotic-resistant nosocomial infections (29).Finally, C difficile toxin worsens gut permeability (30,31) and promotes bacterial migration, which may have increased the risk for septic complications (32).Our sensitivity analysis that restricted the study population to individuals tested within 14 days of hospital admission or during hospital admission suggested that the timing of C difficile infection influenced postoperative morbidity.
We studied a large population-based cohort of UC patients (16).The diagnosis of UC was confirmed in all cases, which improved the accuracy of our data.Administrative databases may misclassify the diagnosis of UC, colectomy and postoperative complications, thereby influencing the magnitude of risk estimates and the precision of CIs (16).Additionally, we were able to determine the reason for admission (flare versus elective colectomy) and only included individuals admitted as a flare in our analysis.Also, C difficile test results were obtained from a population-based laboratory database that records both inhospital and outpatient testing.Thus, we captured all tests performed on these patients during the study period.Using a centralized laboratory database that captures all C difficile testing is essential because administrative coding of C difficile includes a misclassification error and could miss C difficile diagnosis before admission.Finally, patients were tested for C difficile using a sequential testing approach, which optimized the positive predictive value of detecting diseases with low prevalence.
Several limitations to the present study should be considered.First, we excluded UC patients who were not tested for C difficile in hospital or within 90 days of index admission.Consequently, some UC patients may have been C difficile positive but were never detected.This gives rise to a possible differential misclassification bias in which patients with a more severe form of colitis were more likely to be tested for C difficile, reflecting a population with a more severe form of UC.Second, we were unable to report C difficile incidence rates among UC patients (33).Third, patient information was obtained by reviewing patients' charts, relying on various clinicians for their completeness and accuracy.Due to the retrospective nature of the data, we were not able to control for disease severity by calculating a Mayo score.Additionally, C-reactive protein levels were not reliably measured in all patients during the early study years.Fourth, we were unable to study other patient-related factors, such as antibiotic administration and response, because they were not reliably recorded in the patients' charts.Antibiotic treatment of C difficile (eg, timing and first-line agent) may have influenced disease course.Fifth, approximately 42% of the patients were not tested for C difficile, which may have introduced a selection bias.Previous studies using administrative databases have assumed that a negative code for C difficile is a negative test for C difficile (11).However, our sensitivity analysis demonstrated that individuals not tested for C difficile were also at increased odds for colectomy compared with those who tested negative.Finally, the number of patients with UC who tested positive for C difficile was small, reducing the precision of our findings.Furthermore, the small number of outcomes in the postoperative complications analysis may affect the generalizability of our results.Consequently, our findings should be independently replicated.
C difficile diagnosis was associated with undergoing an emergent colectomy and developing postoperative infectious complications.These findings have important clinical implications.First, physicians should carefully assess for C difficile infection among all UC patients presenting with a flare of disease activity.Second, UC patients with a C difficile infection who undergo a colectomy should be monitored closely and precautions should be taken to prevent infections.Third, increased surveillance for C difficile infections with early identification and aggressive treatment provides potential avenues for improving outcomes among UC patients.Future studies are necessary to assess interventions that may reduce the morbidity of C difficile infections among UC patients, and to determine whether timing of colectomy for UC patients with C difficile infection should be adjusted to minimize postoperative infectious complications.At minimum, these patients require careful surveillance for infections postoperatively.

ACKNOWLEDGEMENTS:
The authors acknowledge the DIMR department for providing data from the CHZ.Dr Kaplan

Figure 1 )
Figure 1) Flow diagram illustrating the inclusion and exclusion criteria for identifying patients admitted with a flare for ulcerative colitis and tested Clostridium difficile (C.difficile) infection in hospital and up to 90 days before admission.DIMR Data Integration, Measurement and Reporting; ICD International Classification of Diseases, Ninth and 10th Revisions

TAble 1 Characteristics of ulcerative colitis (UC) patients admitted to hospital stratified according to flare (medically responsive) and emergent colectomy. emergent colectomy patients were further stratified into development of any postoperative complication and development of infectious complications Characteristics All UC patients (n=278) emergent colectomy patients (n=102)
Data presented as % (n) unless otherwise indicated.*Medicationtaken at admission or in hospitalbetween C difficile positivity and variables that were indepedently associated with colectomy were tested and included in the model if the likelihood ratio test was statistically significant (ie, P<0.05).Point estimates were presented as adjusted ORs with 95% CIs.

TAble 3 logistic regression results for emergent colectomy patients (n=102) experiencing any postoperative complication and infectious postoperative complications with Clostridium difficile diagnosis as primary exposure
DISCUSSIONUC patients diagnosed with C difficile in hospital or 90 days before admission were more likely to undergo an emergent colectomy after controlling for factors such as age, disease extent and corticosteroid use.Additionally, a preoperative diagnosis of C difficile increased the risk for developing an infectious postoperative complication.Consequently, C difficile infection is an important clinical outcome for UC patients admitted to hospital with a flare.UC patients have higher mortality and surgery risk at one and five years following a C difficile diagnosis compared with UC patients without C difficile

Sensitivity analyses: logistic regression results for all ulcerative colitis patients (n=278) who underwent emergent colectomy with Clostridium difficile diagnosis in hospital or 14 days before admission as primary exposure Adjusted OR (95% CI)
is supported through a New Investigator Award from the Canadian Institute of Health Research and a Population Health Investigator Award from Alberta Innovates − Health Solutions.This project was funded by the Alberta Inflammatory Bowel Disease Consortium, which is funded by an AHFMR Interdisciplinary Team Grant.AHFMR is now Alberta Innovates − Health Solutions.Study concept and design: MEN, HWB, GGK.Data acquisition: MEN, MCP, GGK.Analysis and interpretation of the data: MEN, HWB, AF, PLB, LD, RP, SG, GGK.Statistical analysis: MEN.Drafting of the manuscript: MEN, HWB, GGK.Critical revision of the manuscript for important intellectual content: MEN, HWB, KR, JDB, SC, MCP, AF, PLB, LD, RP, SG, GGK.Administrative, technical or material support: HWB, MCP, AF, GGK.Final approval of the manuscript: MEN, HWB, KR, JDB, SC, MCP, AF, PLB, LD, RP, SG, GGK.Gilaad Kaplan: Gilaad Kaplan has served as a speaker for Janssen, Merck, Schering-Plough, Abbott and UCB Pharma.He has participated in advisory board meetings for Jansen, Abbott, Merck, Schering-Plough, Shire and UCB Pharma.Dr Kaplan has received research support from Abbott and Shire.Marie-Claude Proulx: Ms. Proulx has no relevant conflicts of interest.Maria Negron: Dr Negron has no relevant conflicts of interest.Remo Panaccione: Dr Panaccione has served as a speaker, a consultant and an advisory board member for Abbott Laboratories, Merck, Schering-Plough, Shire, Centocor, Elan Pharmaceuticals, and Procter & Gamble.He has served as a consultant and speaker for AstraZeneca.He has served as a consultant and an advisory board member for Ferring and UCB Pharma.He has served as a consultant for Glaxo-Smith Kline and Bristol-Meyers Squibb.He has served as a speaker for Byk Solvay, Axcan, Janssen and Prometheus.He has received research funding from Merck, Schering-Plough, Abbott Laboratories, Elan Pharmaceuticals, Procter & Gamble, Bristol-Meyers Squibb, and Millennium Pharmaceuticals.He has received educational support from Merck, Schering-Plough, Ferring, Axcan and Janssen.Subrata Ghosh: Dr Ghosh has served as a speaker for Merck, Schering-Plough, Centocor, Abbvie, UCB Pharma, Pfizer, Ferring, and Procter & Gamble.He has participated in ad hoc advisory board meetings for Centocor, Abbott, Merck, Schering-Plough, Proctor & Gamble, Shire, UCB Pharma, Pfizer and Millennium.He received research funding from Procter and Gamble, Merck and Schering-Plough.Herman Barkema: Dr Barkema has served as a speaker for Merck, Pfizer and Schering-Plough.Kevin Rioux: Dr Rioux has received research support from Shire and Janssen.Jeroen De Buck: Dr De Buck has no relevant conflicts of interest.Sylvia Checkley: Dr Checkley has no relevant conflicts of interest.Alexandra Frolkis: Ms Frolkis has no relevant conflicts of interest.Paul Beck: Dr Beck has no relevant conflicts of interest.Levinus A Dieleman: Dr Dieleman has served as a speaker and consultant for AbbVie and Janssen.Data FUNDING: CONTRIBUTIONS: DISCLOSURES: presented as n.*Patients may have had ≥1 postoperative complication APPeNDIX 4