Impact of Clostridium difficile infection in patients with ulcerative colitis

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1 Journal of Crohn's and Colitis (2011) 5, available at Impact of Clostridium difficile infection in patients with ulcerative colitis Revital Kariv, Udayakumar Navaneethan, Preethi G.K. Venkatesh, Rocio Lopez, Bo Shen Department of Gastroenterology, Digestive Disease Institute, The Cleveland Clinic, Cleveland, OH, USA Received 24 July 2010; received in revised form 26 September 2010; accepted 27 September 2010 KEYWORDS Clostridium difficile; Colectomy; Ulcerative colitis; Inflammatory bowel disease Abstract Background: Clostridium difficile infection (CDI) is becoming prevalent in general population as well as in patients with inflammatory bowel disease (IBD). Aim: The aim of the study was to identify risk factors for CDI in patients with ulcerative colitis (UC) and to assess outcome of UC in patients following CDI. Methods: UC inpatients or outpatients who had positive results for C. difficile toxins A and B between 2000 and 2006 were identified (N=39) and matched for age and gender to UC patients who were negative C. difficile toxins and had never been diagnosed with CDI (N=39). Records were reviewed for adverse clinical outcome, defined as colectomy within 3 months of C. difficile testing. Conditional logistic regression was used to analyze multivariable association to identify risk factors for CDI and for adverse clinical outcome. Results: A total of 78 subjects were analyzed, 60% were males. Median age was 39. Among 39 patients with CDI, 20 (47.2%) were diagnosed as outpatients, 50% failed treatment with the first antibiotic monotherapy, and 21.2% had recurrent infection. Antibiotic exposure within 30 days prior to C. difficile testing was found to be associated with an increased risk for CDI with an odds ratio of 12.0 (95% CI 1.2, 124.2) Subsequent colectomy within 3 months after CDI diagnosis, was not associated with CDI in both univariable and multivariable analyses. After adjusting for CDI, lack of 5-aminosalicylic acid (ASA) in the treatment regimen was significantly associated with colectomy with an odds ratio of 3.3 (95% CI: 1.2, 9.4). There was no UC- or CDI-associated mortality in this case series. Conclusions: Recent antibiotic exposure was a risk factor for CDI in UC patients. Interestingly, CDI does not seem to adversely affect short-term adverse clinical outcome (colectomy) European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. Abbreviations: 5-ASA, 5-aminosalicylic acid; CDI, Clostridium difficile infection; CD, Crohn's disease; EIA, enzyme immunoassay; IBD, inflammatory bowel disease; IPAA, ileal pouch-anal anastomosis; 6MP, 6-mercaptopurine; NSAIDs, non-steroidal anti-inflammatory drugs; NF-κB, nuclear factor-κb; UC, ulcerative colitis. Corresponding author. Digestive disease Institute-Desk A31, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. Tel.: ; fax: address: shenb@ccf.org (B. Shen) /$ - see front matter 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi: /j.crohns

2 Clostridium difficile and outcome Introduction Clostridium difficile infection (CDI) is the leading identifiable cause of antibiotic-associated diarrhea 1 and is associated with substantial morbidity and mortality. Although a growing body of knowledge on the epidemiology, pathogenesis, risk factors, and management of CDI has been obtained over the last decade, the increased incidence and severity of CDI continue to pose a challenge to the medical community. 3,4 The expected health care costs due to CDI alone are estimated up to 3.2 billion dollars per year in the US. 5 Clearly the impact of CDI on the health care system continues to grow with emergence of community-acquired CDI. 6,7 Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing inflammatory conditions that frequently require long-term medical therapy, periodic hospitalizations, and even surgery. Chronic use of antibiotics, corticosteroids, and immunomodulators has been shown to increase the risk of CDI in IBD patients. 8,9 However, the use of biologic agents did not appear to increase the risk of acquisition of CDI. 10 Recently, two single-center studies and two national inpatient database studies have reported rising rates of CDI among IBD patients and their contributions of increased rates of hospitalizations and mortality. 8,9,11,12 The risk of CDI in IBD appears to persist even after colectomy. For example, small bowel involvement with enteritis can occur due to CDI. 13 CDI has been reported in UC patients with restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). 14,15 Approximately 5% 19% of patients admitted for relapsing IBD were tested positive for C. difficile toxins. 16,17 Studies have been performed to identify the risk factors for CDI in patients with IBD. 8,9,11,12 Patients with UC appear to be at a higher risk for CDI than CD and patients with UC and CDI had a higher mortality and a higher risk for colectomy. 8,9,11,12 Colectomy in UC patients even without CDI has been shown to be associated with higher in-hospital mortality. 18 However, the finding on the impact of CDI on the need for colectomy was inconsistent. A recent study reported a significant inverse relationship between the presence of C. difficile toxins and the need for colectomy during hospitalization. 11 Given the increasing mortality in UC patients with CDI, it was interesting that CDI was not a direct contributing factor for colectomy. There is a clear gap in knowledge. We sought to identify the potential risk factors for CDI infection in UC patients and to assess the outcome of CDI in UC patients defined as colectomy within 3 months of C. difficile testing. 2. Methods 2.1. Patients This was a retrospective, observational case control study of patients who were followed up in the IBD center of the Cleveland Clinic's Digestive disease Institute between the years 2000 and All patients with concurrent diagnosis of UC and CDI were identified from the Cleveland Clinic IBD registry. This historical cohort study was approved by the Institutional Review Board Inclusion and exclusion criteria Both inpatients and outpatients with UC who had positive results for C. difficile toxins A and B were identified from the registry and included for the study. Patients with Crohn's disease or microscopic colitis with co-existing C. difficile infection were excluded. CDI patients without history of IBD or co-existing IBD were also excluded Laboratory test for C. difficile infection Positive C. difficile diagnosis was defined by a positive enzyme immunoassay (EIA) test for stool C. difficile toxins A and/or B and were considered infected if they presented with concomitant symptoms of colitis (i.e., diarrhea, increased stool frequency, rectal bleeding, cramping, and/ or tenesmus). For each case with CDI, a control UC case with a negative stool C. difficile test and no prior history of CDI was matched by age and gender Nosocomial vs. community-acquired CDI Patients were classified into hospitalization related (nosocomial infection) vs. community-acquired CDI. Patients who were tested positive as outpatients or tested positive within 48 h of hospital admission were labeled community-acquired for this analysis Clinical variables Patients' records were reviewed for demographic information, including age, gender, extent of the disease, severity, endoscopic findings, clinical symptoms, multiple laboratory parameters, IBD medications (5-aminosalicylic acids [5-ASA], immunomodulators [azathioprine, 6-mercaptopurine, and methotrexate]), anti-tumor necrosis factor therapy, antibiotics, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), comorbidities, recent antibiotic use or hospital admission. The following clinical parameters were analyzed: anatomic extent of colitis (extensive colitis with involvement proximal to the splenic flexure vs. distal colitis on endoscopy and/or histology); severity of colitis on endoscopy, smoking history, excessive use of alcohol; presence of diabetes, the use of NSAIDs, proton pump inhibitors. Recent antibiotic use was defined by an antibiotic course within 30 days prior to C. difficile testing. Recent surgery or hospital admission was defined by any admission or surgery within 3 months prior to the C. difficile testing. Clinical outcome was defined as subsequent colectomy within 3 months of the index C. difficile testing. All UC patients who tested positive for C. difficile in the setting of colitis symptoms were treated with antibiotics including oral vancomycin, oral rifaximin, or oral or intravenous metronidazole. As patients with UC who developed CDI were less likely to respond to oral metronidazole, oral vancomycin was increasingly used in our practice for the treatment of CDI, particularly those diagnosed after 2005.

3 36 R. Kariv et al Outcome measurements We measured the adverse clinical outcome with the need for colectomy within 3 months of the index C. difficile testing Statistical methods For categorical variables the percentages and corresponding 95% confidence intervals (95% CI) were provided. Univariate comparisons between patients with CDI and UC and only UC groups were performed using t-tests and Wilcoxon's tests (for symmetric and asymmetric data, respectively) for numeric variables, and Chi-square tests for categorical variables (Fisher's Exact Test was used when deemed more appropriate). Cox regression analysis was used to evaluate potential risk factors for CDI. A P-value 0.05 was considered statistically significant. 3. Results A total of 78 were studied, including 39 in the study group with UC and CDI and 39 in the control group with UC without current or history of CDI. The median age was 39 (range 33 55) years. The basic demographic and clinical information is summarized in Table 1. Community-acquired CDI was detected in 47.2% of cases. 50% of patients failed treatment with the first course of mono-antibiotic therapy, and 21.2% had recurrent CDI Risk factors for CDI in patients with ulcerative colitis Table 2 summarizes the demographic and clinical characteristics of UC patients with and without CDI. The clinical and laboratory parameters listed in the table were analyzed. Patients who had UC with superimposed CDI were more likely to have undergone recent surgery or to have had a hospital admission within 3 months prior to C. difficile testing, and were more likely to have been treated with antibiotics within 30 days prior to CDI diagnosis. Compared with patients who did not have a recent surgery or admission, those who did where 3.67 times (95% confidence interval [CI]: 1.02, 13.14) more likely to have CDI. Table 1 Characteristics of C. difficile infection in ulcerative colitis patients (N =39). Factors Number Statistics* Outpatient acquisition of C. difficile % infection Failure of 1st antibiotic course 13 50% Days to cure from C. difficile infection (7, 27.5) History of previous C. difficile % infection Severe diarrhea % Persistent rectal bleeding 23 59% Abdominal pain/cramps % *Statistics presented include Median (Q25, Q75) and %. Table 3 summarizes the multivariate analysis of risk factors associated with CDI in UC patients. Patients who used antibiotics within 30 prior to testing for C. difficile were 12 times more likely to develop CDI than those who did not (odds ratio [OR] = 12.0, 95% confidence interval [CI]: 1.2, 124.2; p=0.037). We did not find significant association between the use of immunosuppressive agents and CDI in UC patients. In our analysis, 13/39 patients who developed CDI were on immunosuppressive medications (i.e., azathioprine, 6-mercaptopurine, methotrexate, infliximab, and/or adalimumab) and 24/39 patients were on corticosteroids in comparison with 7/39 patients on immunosuppressive medications and 20/39 patients on corticosteroids in the 39 UC patients without CDI Outcome of CDI Of the 78 patients with UC, 25 underwent colectomy within 3 months after index C. difficile toxin testing. Twelve patients in the CDI group (48%) had colectomy, while 13 patients in the control group (50.9%) underwent colectomy (P=0.81). Table 4 tabulates the univariate analysis of potential risk factors associated with colectomy. To identify the risk factors associated with colectomy, the multivariable model was studied with inclusion of variables of CDI, use of 5- ASA and age older than 50 years of age. The results are summarized in Table 5. Adjusting for CDI and older age (N50 years), subjects who did not use 5-ASA were 3.3 times more likely to have UC-related surgery (colectomy) within 3 months of C. difficile testing than those treated with 5-ASA (OR = 3.3, 95% CI: 1.2, 9.4; p = 0.03). There was also no reported mortality in the 78 patients in this study. 4. Discussion The present study attempted to assess the risk factors for the development of CDI in UC patients and their adverse outcome defined by colectomy within 3 months of CDI diagnosis. CDI in UC patients was associated with recent surgery or hospital admission and with recent antibiotic use. CDI did not seem to have a negative on clinical outcome of colectomy in UC patients. We speculated that identification of CDI during UC flare up may be beneficial, as some patients with refractory UC might have been due to superimposed CDI and treatment of CDI may help inducing clinical remission of UC. Interestingly, 5-ASA treatment was found to independently protect UC patients from colectomy in our population. CDI has become the leading identifiable infective cause of antibiotic-associated diarrhea in general population. 1 It has increased in incidence, and severity over the years in North America and Europe. 2,4 The epidemiology and natural history of CDI has also changed over the years with increasing reports of the emergence of community-acquired CDI in young, healthy patients. 6,7 The increasing incidence and severity are postulated to be due to a hypervirulent form of C. difficile strain, BI/NAP1/027 that is associated with a more severe disease and a higher mortality. This strain according to a recent CDC report is identified in 38 states throughout the US. 6,7 In clinical practice, we have been encountering

4 Clostridium difficile and outcome 37 Table 2 Factor Univariate comparison of potential factors for C. difficile infection. more CDI in IBD patients recently which led us to investigate their outcome in IBD. C. difficile toxins were speculated to complicate IBD and contribute to relapse of IBD in some patients. 19 With increasing incidence of CDI, superimposed CDI in patients with IBD has been increasingly reported. CDI can even present with enteritis, 13 particularly in patients with IBD who had undergone bowel-diverting surgery or colectomy or as chronic antibiotic refractory pouchitis in patients with IPAA for underlying IBD. 14,15 Recent studies have suggested that in the majority of IBD patients, CDI was contracted outside of the hospital. In a recent study, the median time to development of CDI in non- IBD patients was 4 days in contrast to less than a day with CDI in IBD patients. 8 In another study, 76 79% of patients acquired CDI from the community. 9 A recent study also Table 3 Multivariate analysis of risk factors for C. difficile infection. Reference Odds ratio 95% confidence interval p-value Antibiotics within 30 days prior to CDI Yes vs. No 12.0 (1.2, 124.2) Surgery/admission within 3 months prior to diagnosis of CDI Yes vs. No 1.1 (0.20, 6.05) 0.91 Immunomodulators Yes vs. No 2.9 (0.72, 11.7) 0.13 CDI, Clostridium difficile infection. C. difficile positive (N=39) C. difficile negative (N=39) N Median (25th, 75th) N Median (25th, 75th) Age greater than 50 years % Smoking (ex and active) Alcohol use Proton pump inhibitor use NSAID use Extensive colitis Fulminant colitis Surgery/admission within 3 months prior to diagnosis of CDI Diabetes Other comorbidities* Antibiotics within 30 days prior to CDI ASA Corticosteroids Immunomodulators Biologics Peak white blood cell count (10 9 cells/l) (8.9, 14.7) (6.8, 13.4) 0.49 Lowest albumin (g/l) (2.5, 3.7) (2.5, 4) 0.32 Colon endoscopic score 25 3 (2.0, 3.0) (2.0, 2.5) 0.21 Lowest hemoglobin (g/l) (8.7, 12.8) (9.8, 13.1) ASA, aminosalicylic acid, CDI, Clostridium difficile infection, NSAID non-steroidal anti-inflammatory drug, UC, ulcerative colitis. *Co-morbidities including hypertension, asthma, chronic obstructive pulmonary disease, thromboembolic events and cancer. p-value demonstrated that toxigenic C. difficile was demonstrated more frequently in IBD patients in complete remission with no recent hospitalization or antibiotic exposure (8.2%) than in healthy volunteers (1.0%) and the ribotypes identified were community-acquired highlighting the acquisition of C. difficile in IBD patients. 20 We also observed that 47.2% of patients had acquired the infection outside the hospital. However, the risk of community-acquired CDI was lesser than that reported in other studies. The reason for this difference could be due to referral bias. We also observed that the mode of acquisition, either community acquired or nosocomial did not have any influence on the clinical outcome. Studies have shown that there is increased risk of CDI with use of antibiotics disrupting the bacterial flora, intensive care or prolonged hospital stay and more recently IBD. 8,9,11,12 Multiple studies from tertiary-care institutions as well as large nationwide inpatient databases have demonstrated an increase in incidence and severity of CDI in patients with IBD when compared with general population. 8,9,11,12 In a study of risk factors for CDI in IBD patients, maintenance immunomodulator use and colonic involvement were independently associated with risk of CDI. 9 In addition, 61% of IBD patients who developed CDI had antibiotic exposure up to 2 months prior to development of CDI. 9 A subsequent study also reported that increasing age and colonic involvement were independently associated with CDI in IBD. 8 In our study, we found that use of antibiotics up to 30 days prior to C. difficile testing was independently associated with the development of CDI on both univariate and multivariate analyses. Older age was not associated with CDI. Therefore, the risk factors for the development of CDI did not differ much from the non-ibd population.

5 38 R. Kariv et al. Table 4 Univariate analysis of risk factors for 3-month colectomy. Factor Colectomy (N = 25) No colectomy (N =53) p-value The role of immunomodulator use in the development of CDI was controversial. A recent study reported that 8.2% of patients with IBD were tested positive C. difficile toxins compared with 1.0% in healthy volunteers, and none of the IBD patients with CDI had had any antibiotic or immunosuppressive exposure. 20 These results are in contrast to previous studies which have reported the association of immunomodulator use with CDI in IBD. 8,9 Interestingly, there was no significant association between immunomodulator use and the development of CDI in our study too. Similar observations have been observed in studies of CDI in other patient populations. Immunosuppressive treatment was not associated with mortality or severe colitis compared with matched controls not on any immunosuppressive treatment. 21,22 There was also no association of the use of biologics on the risk of development of CDI, 8 10 which was consistent with the finding in our study. We subsequently studied the clinical outcome defined by colectomy at 3 months following the index C. difficile testing. It was not surprising to note that fulminant colitis was associated with risk of colectomy. However, CDI was not associated with colectomy. Similar observations have been reported from a recent study utilizing the Health Care inpatient care database which reported that the development of CDI was inversely related to the risk of colectomy. 10 Thisobservationinboththe studies is very interesting given the fact that colectomy has been shown to be independently associated with a greater than 2-fold increase in inpatient mortality (incidence rate ratio, 2.4; 95% CI, ). 10 TherecentincreaseinmortalityinIBD patients was thought to be at least partly related to the N Median (25th, 75th) N Median (25th, 75th) Clostridium difficile infection Age greater than 50 years Extensive colitis Fulminant colitis b0.01 Surgery/admission within 3 months prior to diagnosis of CDI Diabetes Other comorbidities Antibiotics within 30 days prior to CDI ASA Corticosteroids Immunomodulators Biologics Peak white blood cell count (10 9 cells/l) (6.9, 14.0) (7.9, 14.5) 0.57 Lowest albumin (g/l) (2.3, 3.7) (2.7, 3.9) 0.22 Colon endoscopic score (2.0, 3.0) (2.0, 3.0) 0.29 Lowest hemoglobin (g/l) (9.1, 11.6) (9.1, 13.4) ASA, aminosalicylic acid; CDI, Clostridium difficile infection; UC, ulcerative colitis. increasing use of colectomy in patients with CDI and IBD. However the opposing relationship of CDI not predisposing to colectomy has suggested that the increased mortality of CDI in IBD may not be entirely related to colectomy. Though colectomy is not a direct marker for disease severity, both our study and the previous study suggest that IBD disease activity or severity might actually be lower among patients with CDI. 10 The lower risk of colectomy with UC CDI may be because of the fact that patients with UC exacerbation due to CDI are much more likely to improve with proper pathogen-directed medical therapy. Thus treating CDI in UC patients may actually prevent the need for colectomy. The increased mortality and length of stay and hospitalization costs reported in multiple studies with CDI in IBD is intriguing. We did not observe any mortality in the group of our patients. However we had not recorded the IBD disease activity and not adjusted for the severity of the disease. This difference in mortality as compared to previous studies cannot be clearly explained. However, as we have discussed, the increased morality in IBD patients with CDI is not related to colectomy. CDI in IBD patients is usually treated with immonomodulators and antibiotics. In a recent multi-center study comparing outcome of hospitalized IBD patients with CDI who were treated with antibiotics (n = 51) or antibiotics and immunomodulators (n=104), primary outcome defined by death or colectomy in 3 months occurred in 12% of patients given the combination treatment vs. none of the patients given antibiotics alone (P=0.01) 23 Combination treatment of immunomodulators and antibiotics was associated with a worse outcome than antibiotic Table 5 Multivariate analysis of risk factors for colectomy. Reference Odds ratio/95% confidence interval p-value 5-ASA use No vs. Yes 3.3 (1.2, 9.4) 0.03 Clostridium difficile infection No vs. Yes 1.4 (0.49, 3.7) 0.55 Age greater than 50 years Yes vs. No 2.5 (0.85, 7.3) ASA aminosalicylic acid.

6 Clostridium difficile and outcome 39 therapy alone. 21 Thus the increased mortality reported in retrospective data base studies may not be entirely related to CDI, but related to treatment with a combination therapy of immunosuppression and antibiotics. 24 Unfortunately, the databases did not have any information on the use of concomitant drugs which could have been interesting to explore. Although the purpose of our article was not to study the antibiotic regimen in CDI, we had used 3 different antibiotics including metronidazole, oral vancomycin, and rifaximin against C. difficile. 50%** failed treatment with the first monoantibiotic course which was similar to a previously published study which reported a 58% failure rate in IBD patients. Similar to previously published reports, vancomycin is being increasingly used in our institution in the management of CDI complicating IBD because of diminishing response to metronidazole. 8,9 TheprotectiveeffectofASAinpreventingcolectomyinUC patients is interesting. ASA has been shown to prevent colorectal cancers in patients with longstanding colitis. 25 ASA has been shown to inhibit leukocyte chemotaxis and production of chemotactic eicosanoids and interleukin-8. 26,27 It has also been shown to inactivate oxygen-derived free radicals protecting the intestinal mucosa from oxidative injury and protects colonic epithelium from injury. 5-ASA has also been shown to induce apoptosis and is an inducer and agonist of peroxisome proliferator-activated receptor and an inhibitor of nuclear factor, all of which result in suppression of inflammation. 28 This anti-inflammatory effect of ASA may be one of the reasons which could explain the protective effect of 5-ASA against colectomy. Further prospective studies employing 5-ASA agents in CDI is required in the future. There were limitations to our study. The study population was recruited from a subspecialty IBD clinic. This might have resulted in referral bias. Also it was a retrospective study of data andwedidnothavecompletedataonthetypeofantibioticused which predisposed to infection nor did we have the information on the typing of C. difficile strain in UC patients. Nonetheless, the current study has several clinical implications. Antibiotic use should be discouraged in UC patients, unless they were tested positive for C. difficile.thisstudyhas broughttosomelightonthefactthatpatientswithibdwho develop CDI do not necessarily require colectomy. In fact, presence of CDI would give an opportunity to treat the infection and prevent colectomy. The protective effect of 5-ASA on the risk of colectomy also needs to be explored. To conclude, CDI in UC patients is associated with recent antibiotic use. Interestingly, CDI does not seem to adversely affect clinical outcome (i.e. need for colectomy) in UC patients and the identification of CDI as a cause for colitis may actually protect patients against colectomy if appropriately treated. Conflict of interest The authors declared no financial conflict of interest. Role of funding source Support was from NIH R03 DK , an American College of Gastroenterology Clinical Research Grant, internal funding was from Cleveland Clinic Digestive Disease Institute. References 1. Asha NJ, Tompkins D, Wilcox MH. Comparative analysis of prevalence, risk factors, and molecular epidemiology of antibiotic-associated diarrhea due to Clostridium difficile, Clostridium perfringens, and Staphylococcus aureus. J Clin Microbiol 2006;44: Bartlett JG, Chang TW, Gurwith M, et al. Antibiotic-associated pseudo membranous colitis due to toxin-producing clostridia. N Engl J Med 1978;298: McDonald LC, Killgore GE, Thompson A, et al. 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