Although a considerable number of studies support a substantial increase in incidence, severity, and healthcare costs for Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD), only few evaluate its impact on IBD outcome. Medline and several other electronic databases from January 1993 to October 2013 were searched in order to identify potentially relevant literature. Most of the studies showed that IBD patients with CDI present a greater proportion of worse outcomes than those without CDI. These patients have longer length of hospital stay, higher rates of colectomies, and increased mortality. Patients with ulcerative colitis are more susceptible to CDI and have more severe outcomes than those with Crohn’s disease. However, studies reported variable results in both short- and long-term outcomes. Contrasting results were also found between studies using nationwide data and those reporting from single-center, or between some North-American and European studies. An important limitation of all studies analyzed was their retrospective design. Due to contrasting data often provided by retrospective studies, further prospective multi-center studies are necessary to evaluate CDI impact on IBD outcome. Until then, a rapid diagnosis and adequate therapy of infection are of paramount importance to improve IBD patients’ outcome. The aim of this article is to provide up to date information regarding CDI impact on outcome in IBD patients.

Over the past 15 years, both incidence and severity of Clostridium difficile (C. difficile) infection (CDI) have increased dramatically worldwide[1,2]. In addition to broad-spectrum antibiotic therapy[3,4], other potential risk factors such as advanced age, prolonged hospitalization, immunosuppression, multiple co-morbidities, the use of proton pomp inhibitors, and the occurrence of a hypervirulent strain of C. difficile known as NAP1 (North American pulso-type 1) in some North-American and European areas, have been identified[5-10].

Referring to the same period, several studies clearly demonstrated a significant increase in CDI incidence in patients with inflammatory bowel diseases (IBD)[11-17]. Both ulcerative colitis (UC) and Crohn’s disease (CD) present high-risk for CDI, although patients with UC are more susceptible than those with CD[11,12,15,16]. Overall, IBD patients with CDI show more of the whole range of short- and long-term worst outcomes than those without CDI or with CDI alone[11-13,16-19]. However, studies report variable results concerning mortality and colectomy rates, length of hospital stay, and healthcare costs for IBD patients with CDI[11,13,14,16,18-21].

This review aims to summarize available literature regarding CDI impact on both short- and long-term outcome in adult IBD patients.

A systematic literature search was performed on Medline/PubMed, EMBASE, Scopus, Science Direct, CINAHL, and Web of Science (ISI Web of Knowledge) databases from January 1993 to October 2013 using various combinations of the following key words: “inflammatory bowel disease”, “ulcerative colitis”, “Crohn’s disease” and “Clostridium difficile infection”, “Clostridium difficile-associated diarrhea”, “pseudomembranous colitis”. We included only English written studies carried out on adults, from all geographic regions. A manual search of references from the identified studies was also undertaken to identify any additional studies that may have been missed in the computed-assisted literature search. As our objective was to assess the impact of CDI on IBD patients’ outcome, only studies reporting outcome of IBD patients co-infected with CDI were taken into analysis. The following data were extracted from each study included: length of hospital stay, colectomy rate, mortality, and healthcare costs. In addition, given the increased need for surgical intervention in UC patients with CDI, a short review of Clostridium difficile enteritis and pouchitis has also been made.

Few studies reported on long-term outcomes after an initial episode of CDI in IBD patients (Table 2)[19,21,24,27]. In a retrospective study including 47 patients with UC and CDI and 52 with UC without CDI, Jodorkovsky et al[19] reported that, over the year following the initial infection episode, a significant increase in the number of visits to the emergency room (8 vs 1, P = 0.012) was registered, as well as a higher number of UC-related hospitalizations (58 vs 27, P = 0.001) and a two-fold increase in colectomy rate (44% vs 25%, OR = 2.38, 95%CI: 1.01-5.6; P = 0.04) as compared to UC patients without CDI. Murthy et al[21], in a retrospective cohort study of UC patients with and without CDI, found that CDI was associated with 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). In another retrospective study[24], UC patients with CDI had significantly more UC-related emergency room visits (37 vs 4, P < 0.001) and a higher rate of colectomy (35.6% vs 9%, P < 0.001) than those with UC alone in the year following initial infection. In addition, 55.8% of patients with UC and CDI had an escalation in medical therapy in the year after index infection admission as compared to 12.9% in the previous year (P < 0.0001). In a multivariate analysis for risk factors of colectomy, severe disease on endoscopy (OR = 16.7, 95%CI: 4.1-67.9; P < 0.001) and CDI (OR = 10.0, 95%CI: 2.7-36.3; P < 0.001) were found to be independently associated with colectomy within 1 year. Chiplunker et al[27] in a retrospective, case-control study on 81 patients with IBD comparing disease progression 1 year before and 1 year after the initial infection with C. difficile, found that 46% of patients had more hospitalizations and over a half of them (53%) required an escalation in medical therapy during the year following CDI. No deaths occurred during the 1 year follow-up.

Healthcare costs are higher in IBD patients with CDI than in those with IBD alone due to longer hospital stay, higher number of IBD-related hospitalizations, increased need for surgery, and hospital care charges[13,16]. Nguyen et al[16] found a mean cost increased by 46% and 63% for UC and CD patients, respectively, while Ananthakrishnan et al[13] reported higher increased hospital adjusted expenses of US$ 11406.

The majority of published studies (90%) found by searching Medline and other databases aim to assess CDI incidence in IBD patients, while only 10% of them report on outcome following infection. All studies reporting on outcome in IBD patients with concomitant CDI were retrospective, small single-center cohort studies or large nationwide database studies mostly conducted in North America and Europe. Apart from being retrospective, available studies on outcome have several other limitations such as incomplete information on disease severity, absence of reference to C. difficile diagnosis, antibiotic and immunomodulatory therapy. It should be underlined that most of analyzed studies relate to hospitalized IBD patients in the early 2000s, when enzyme immunoassay of stool for C. difficile toxins A and B has dominated the laboratory diagnosis of CDI, despite its low sensitivity.

Though few in number, studies reporting outcomes associated with CDI in IBD patients most often show that CDI has a negative impact both on short- and long-term IBD outcomes, increasing the need for surgery, morbidity and mortality rates, as well as healthcare costs[11,13,16-18,21,24,27]. Both major forms of IBD are under increasing risk for CDI, although patients with UC are most susceptible to infection and have more severe outcomes[15,16,19]. Short-term outcomes, defined as those measured within 30-90 d of index admission, include length of hospital stay, colectomy and mortality rates. Long-term outcomes, measured at least 1 year following index admission, include emergency room visits, UC-related hospitalizations, escalation in medical therapy, colectomy and mortality rates.

Studies report conflicting results on the length of hospital stay in IBD patients with concomitant CDI: some found similar stays[12,19], others shorter ones[14], while most of them reported longer hospitalization periods than in IBD patients without CDI or with CDI alone[11,13,16,17,21]. Similar or shorter hospitalization periods were reported by single-center studies[12,14,19], while longer stays were found in studies using nationwide databases[13,16,17,21]. Discrepancies between studies may be explained by disease severity and response to medical therapy in IBD patients included in the analyses.

Contrasting results have also been reported with regard to colectomy rates in IBD patients with CDI[11,13,14,17-21,24-26]. Thus, some studies analyzing nationwide data (US NIS HCUP, UK HES) reported high colectomy rates[13,18], while other single-center ones[20,24,25] found CDI to have no negative impact on colectomy rate in UC patients. There are discrepancies in what concerns colectomy rates even between studies using nationwide data in North America[13,18] and Europe[17], probably due to differences in data collection methods and threshold for surgery[23]. In addition, studies analyzing nationwide data for colectomy also include IBD patients admitted for elective surgery, a fact which can contribute to high colectomy rates[23]. Lower risks for colectomy, as reported by single-center North-American[20] and European[14,26] studies, may be partially explained by CDI prompt response to medical therapy, followed by clinical remission of IBD flare, thus preventing surgery[20].

Variable results regarding mortality rate in IBD patients with concomitant CDI are also to be noted[13,14,16-18,21]. High mortality rates reported by some studies using nationwide data[13,16,17] may be accounting for by to the increased use of colectomy in IBD patients with CDI[20], and also by the inclusion of all hospitalized patients who presumably have more severe disease than those from cohort studies[17,23].

Few studies reported long-term outcomes after an initial CDI episode in IBD (UC) patients. Two[19,24] reported an increased number of visits to the emergency room and in UC-related hospitalizations, and higher colectomy rate than in patients with UC alone in the year following initial infection. UC patients with CDI had an escalation in medical therapy 1 year after index admission as compared to the previous year[24,27]. Another study including UC hospitalized patients with and without CDI, found that those with associated CDI had a higher adjusted 5-year risk of mortality, but not of colectomy[21].

We may add that only one study aimed to identify predictive factors for severe outcomes (colectomy, death) associated with CDI in IBD patients[28]. Ananthakrishnan et al[28] in a retrospective study using multi-institutional electronic medical record database from two large referral hospitals over the period 1998-2010, reported a 4.4% colectomy and 15.2% mortality rates during 180-d follow-up of 294 IBD patients with CDI (mostly with UC), and found that among several demographic variables and laboratory parameters, only serum albumin below 3 g/dL, hemoglobin below 9 g/dL, and serum creatinine above 1.5 mg/dL were independent predictors of severe outcomes[28].

Clostridium difficile enteritis usually occurs in IBD patients who have undergone colonic surgery, mainly proctocolectomy[29-31]. C. difficile enteritis is generally rare, although the number of cases reported in literature has recently increased[32]. The predisposition of IBD patients with previous colonic surgery to C. difficile enteritis may be accounted for by the colonization of the neo-terminal ileum with colonic-type bacterial flora[33], and phenotypic changes in the epithelium of pelvic ileoanal pouches[34]. C. difficile enteritis diagnosis and treatment are similar to that for colonic CDI. If some studies reported increased mortality among patients with C. difficile enteritis[35], other ones found low or even no mortality[29].

Clostridium difficile pouchitis has been reported in IBD patients with ileal pouch anal anastomosis (IPAA)[36-38]. Shen et al[36] found that 18.3% of their 115 patients with IPAA had CDI. Morphologic changes in the pouch epithelium secondary to prolonged exposures to fecal stream may favor CDI[34]. In addition, frequent antibiotic treatment for acute or chronic pouchitis is another risk factor for CDI in such patients[36]. Recently, Tyler et al[39] reported that genetic polymorphisms, particularly the NOD2insC risk allele, are associated with increased risk of developing pouch inflammation among patients with UC and IPAA. Treatment with vancomycin, tinidazole, or rifaximin has been used with benefit in many patients[37,38].

IBD patients with CDI are under a higher risk of worse outcomes than those without CDI. Because the available data are often conflicting and obtained from retrospective studies, further prospective multi-center studies are required to evaluate the impact of CDI on IBD outcomes. Until then, to improve patient outcome, clinicians should have a high index of suspicion for CDI in all IBD patients presenting with a disease flare in order to rapidly establish diagnosis and prompt treatment of infection.