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The Impact of Clostridum Difficile on Surgical Rate Among Ulcerative Colitis Patients: A Systemic Review and Meta‑analysis

There is growing recognition of the impact of Clostridum difficile infection (CDI) on patients with inflammatory bowel disease. Clostridium difficile infection causes greater morbidity and mortality. This study aimed to evaluate the impact of C. difficile on surgical risk among ulcerative colitis (UC) patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ACP Journal Club, DARE, CMR, and HTA. Studies were included if fulfilled the following criteria: (1) Cohort or case–control studies, which involved a comparison group that lacked CDI, (2) Patients were given a primary diagnosis of UC, (3) Comorbidity of CDI was evaluated by enzyme immunoassay of stool for C. difficile toxin A and B or C. difficile stool culture, (4) Studies evaluated surgical rate, and (5) Studies reported an estimate of odds ratio, accompanied by a corresponding measure of uncertainty. Five studies with 2380 patients fulfilled the inclusion criteria. Overall, meta‑analysis showed that UC with CDI patients had a significant higher surgical rate than patients with UC alone. (OR=1.76, 95% CI=1.36–2.28). C. difficile infection increased the surgical rate in UC patients. However, results should be interpreted with caution, given the limitations of this study.


Volume 21, Number 4
Ramadan 1436H July 2015 The Saudi Journal of Gastroenterology

Search strategy
This review was performed according to the standard guidelines for meta-analyses and systematic reviews of observational studies. [13] To find relevant articles for this review, we searched the following databases (from inception to December 2013): MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ACP Journal Club, DARE, CMR, and HTA. The search strategy used free-text words and MeSH terms to increase the sensitivity of the search. The following search terms were used: Inflammatory bowel disease, UC, C. difficile, clinical outcome, colectomy, and surgery. Boolean operators (AND, OR, NOT) were used to narrow and widen the search results. A comprehensive search of reference lists of all review articles and original studies retrieved by this method was performed to identify additional reports. Furthermore, we hand searched abstracts of major gastroenterological meetings, such as the Digestive Disease Week of the American Gastroenterological Association and the World Congress of Gastroenterology. No language restrictions were made. Authors of some identified trials were asked whether they knew of additional studies, including unpublished randomized ones.

Inclusion and exclusion criteria
For inclusion in the systematic review, a study had to meet the following criteria established by the study team: (1) Cohort or case-control studies involved a comparison group that lacked CDI, (2) patients were given a primary diagnosis of UC, (3) diagnosis of CDI was evaluated by enzyme immunoassay of stool for C. difficile toxin A and B or C. difficile stool culture, (4) studies evaluated surgical rate, and (5) studies reported an estimate of relative risk or odds ratio, accompanied by a corresponding measure of uncertainty [ie, 95% confidence interval (CI), standard error, variance, or P value].
Studies were excluded if (1) Age was younger than 18 years, (2) patients had no known history of IBD, (3) outcome of interest was not reported, or (4) incomplete data.

Data extraction
To reduce reporting bias and error in data collection, all papers were examined independently for eligibility by two reviewers (Peng and Shen). Disagreement was resolved by consulting a third reviewer (Ran). Standardized data extraction form created by the study team was used. This form included the authors, location, year of publication, study design, number of CDI-UC patients, number of non-CDI-UC patients, outcome, and the Newcastle-Ottawa Scale.

Statistical analysis
The primary outcome of this analysis was the odds ratio (OR) of surgical rate in CDI-UC versus controls. We calculated the OR with a 95% confidence interval (CI) based on a fixed-effects model using the methods of DerSimonian and Laird. [14] Heterogeneity between the studies was assessed by Chi-square test and the I 2 -statistic. [15] P values <0.05 were considered statistically significant. If significant heterogeneity exists, it would be inappropriate to combine the data for further analysis using a fixed-effects model, whereas the random model was used for calculations. Publication bias was assessed by constructing a funnel plot. Any heterogeneity identified would prompt subgroup analysis in an attempt to explain these findings. Statistical analysis was performed with the software REVMAN X6 from the Cochrane Collaboration.
The characteristics of the included studies are listed in Table 1. Three studies were performed in the United States, and the other two were from Japan and Canada. The patients in the study group were diagnosed as CDI and UC, whereas the patients in the control group were diagnosed as UC alone. The diagnosis of CDI in most studies was according to the following criteria: enzyme immunoassay of stool for C. difficile toxin A and B, C. difficile stool culture, pathological evidence of C. difficile. Two studies [9,36] measured 1-year risks of colectomy between CDI-UC patients and UC patients. One study [10] measured a 5-year outcome of CDI-UC The Saudi Journal of Gastroenterology patients compared with UC patients. One study [11] performed a 3-month impact of C. difficile on UC patients. The other one [12] focused on the 3-year impact of C. difficile on acute UC. Three studies [10,36,37] reported increased surgical risks among CDI-UC patients, whereas another two [11,12] showed that there was no significant difference between CDI-UC and UC patients.
Methodological quality of included studies was evaluated using the Newcastle-Ottawa scale. It uses a "star" rating system to judge quality on the basis of three aspects of the study: Selection of study groups, comparability of study groups, and assessment of the exposure. This scale awards a maximum of 9 stars to each study: up to 4 for selection of participants, 2 for comparability of participants on the basis of the design or analysis, and 3 for ascertainment of exposure. We assigned scores of 0-3, 4-6, and 7-9 for low, moderate and high quality studies, respectively [ Table 1]. All included studies had scores ≥7, which were considered as high quality.

Impact of C. difficile on surgical rate among patients with IBD
Overall, a total of 41% of CDI-UC patients and 31.6% of UC patients had colectomy. The OR of surgical rate in UC-CDI patients compared with controls was 1.76 (95% CI = 1.36-2.28). There was no significant heterogeneity among the examined studies, (P = 0.09) [ Figure 2] so a fixed effect model was used for assessment of the pooled OR. The result showed that C. difficile infection was associated with increased risks of colectomy among UC patients.
Kariv et al. [11] also reported that subjects who did not use 5-ASA were 3.3 times more likely to have UC-related surgery within 3-months of C. difficile testing than those treated with 5-ASA, (95% CI 1.2-9.4, P = 0.03), which to some extent explained the role of immunosuppressants on clinical outcome in patients who were infected with C. difficile. Jodorkovsky et al. [36] found that UC patients with C. difficile infection had significantly higher rates of colectomy in the long-term compared with those not infected, regardless of age and gender, which suggested an association between C. difficile infection and a need for eventual colectomy. Figure 3 shows a funnel plot of studies included in this meta-analysis. On visual inspection, the funnel plot was symmetrical in distribution. So, there was no significant publication bias in this analysis.

DISCUSSION
CDI has become the leading identifiable infective cause of antibiotic-associated diarrhea in general population. [38] Studies have shown that there was increased risk of CDI with use of antibiotics disrupting the bacterial flora, intensive care or prolonged hospital stay and more recently IBD. [5,33] Multiple studies from tertiary-care institutions as well as large nationwide inpatient databases have demonstrated an increase in the incidence and severity of CDI in patients with IBD when compared with general population. In a study of risk factors for CDI in IBD patients, maintenance immunomodulator use and colonic involvement were independently associated with the risk of CDI. In addition, 61% of IBD patients who developed CDI had antibiotic exposure up to 2 months prior to development of CDI. [5] A subsequent study also reported that increasing age and colonic involvement were independently associated with CDI in IBD. [7] One study reported that the use of antibiotics up to 30 days prior to C. difficile testing, was independently associated with the development of CDI. [11] Pathogenicity of C. difficile infection begins with colonization of this Gram-positive anaerobic bacterium. Disruption of the normal intestinal flora allowing C. difficile to flourish is usually associated with antibiotic use and hospitalization. Inflammation may be an additional risk factor that disrupts the normal flora. C. difficile toxins were speculated to complicate IBD and contributed to relapse of IBD in some patients. [39] With increasing incidence of CDI, superimposed CDI in patients with IBD has been increasingly reported. CDI can even present with enteritis, [37] particularly in patients with IBD who had undergone bowel-diverting surgery or colectomy or as chronic antibiotic refractory pouchitis in patients with ileal pouch anal anastomosis for underlying IBD. [40] In our study, we evaluated the association between CDI and surgical rate among UC patients. We found UC-CDI  [12] Japan Cohort UC 55 82 3-year risk of colectomy 8☆ Navaneethan et al., 2011 [9] USA Cohort UC 45 101 1-year risk of colectomy 7☆ Jodorkovsky et al., 2009 [36] USA Cohort UC 47 52 1-year risk of colectomy 7☆ Kariv et al., 2010 [11] USA Case-control UC 39 39 3-month risk of colectomy The Saudi Journal of Gastroenterology patients had statistically significant higher risks of surgery when compared with UC patients (OR = 1.76, 95% CI = 1.36-2.28). There was no statistical significance of heterogeneity among the included studies (P = 0.09).
The explanation could be that UC patients were more susceptible to CDI. In recent years, the reported incidence of CDI has increased, and the OR of acquiring CDI in UC patients was found to be four times as many as in non-IBD patients. [7,33] The exact reason for this phenomenon was unclear. The universal colonic involvement in UC compared with less frequent involvement in CD may contribute to a higher susceptibility to C. difficile infection. [41] Second, C. difficile spores and vegetative organisms in some patients could theoretically alter the natural history of UC by activating abnormal mucosal immune response, or CDI might be a sign reflecting an aggressive form of UC course, which resulted in more ER visits, more hospitalization, escalation of medical treatment and ultimately resulting in colectomy. [9,10] Use of immunosuppressive therapy, in addition to antibiotics, to treat C. difficile in the setting of UC may have also increased the duration or severity of colitis in many individuals. [42] Besides, sicker patients might get CDI. This might play a major role in colectomy because, on endoscopy, it was found that these patients had a significantly active or severe disease when compared with patients without CDI. [9] There were also some limitations to this analysis. First, the number of included studies was small. Second, the unadjusted differences in severity of underlying IBD, comorbidity burden, or antibiotic use between infected and uninfected patients may influence the observed association in this analysis. Possibly, patients with severe manifestations of IBD and more comorbidities were at a greater risk of both acquiring C. difficile infection and worse clinical outcome. However, such information was not available in most of the included studies. Although one study [11] evaluated the role of immunosuppressants on the clinical outcome of UC-CDI patients, more studies are needed to classify whether the use of biologics and immunosuppressants could affect clinical outcome in patients infected with C. difficile. Furthermore, C. difficile exposure status may have been misclassified in a proportion of patients, as a result of both misreporting on hospital discharge abstracts and inadequate stool testing for C. difficile. No studies have evaluated the diagnostic accuracy of CDI among IBD patients. Last but not the least, most of the studies were at an academic center with multiple primary physicians, treatment strategy was subjective and unlikely to be uniform. Specifically, decisions about inpatient therapy and need for surgery is highly individualized. These factors may affect the role of C. difficile in UC patients.
In summary, our analysis suggested an association between C. difficile infection and surgical risks among UC patients. Although no significant heterogeneity was found among the included studies, the number of included studies was small. Therefore, the result should be interpreted with caution and further clinical studies investigating the effect of C. difficile infection on UC patients are warranted. In our analysis, we found CDI increased the surgical rate in UC patients. If it is found that C. difficile does indeed exacerbate UC, this will have profound influence not only on the way we approach C. difficile testing, but also on the way we approach the treatment of UC patients complicated with C. difficile.