Paralleling the rising burden of CDI in the general population, recent years have witnessed a dramatic increase in CDI in patients with IBD. Recently, two single-center studies and two national inpatient database studies have reported a rising rate of CDI among IBD patients and their contributions of increased rates of hospitalization and mortality[9-12]. In a retrospective study of all confirmed CDI patients from a tertiary care center over a 7 years period, there was a doubling in the CDI rate in CD patients (9.5 to 22.3/1000 admissions) and tripling in UC patients (18.4 to 57.6/1000 admissions)[9]. A similar increase in the rate of CDI in IBD patients from 1.8% in 2004 to 4.6% in 2005 was observed in a subsequent study from a different tertiary-care center[10]. Furthermore, both studies identified that IBD patients, in particular those with UC, were at a disproportionately higher risk for acquiring CDI than non-IBD patients. In a large study utilizing the Healthcare Cost and Utilization Project Nationwide Inpatient Sample inpatient care database in the US, hospitalized patients with concurrent CDI and IBD had a 4 times greater mortality than those admitted to hospital for IBD or CDI alone[11]. In a subsequent study utilizing the same National Inpatient Sample database to study the temporal pattern of CDI, the prevalence of CDI among UC patients (37.3 per 1000) was higher than that among CD patients (10.9 per 1000), non-IBD gastrointestinal (GI) patients (4.8 per 1000), and general medicine patients (4.5 per 1000). In addition the incidence of CDI among UC patients almost doubled (26.6 per 1000 to 51.2 per 1000) over the 7-year period. CDI was independently associated with a greater mortality among patients with UC, but not CD[12].

Superimposed infections of pathogenic bacteria or viruses may contribute to exacerbation of IBD. Concurrent CDI is one of them. In a Scandinavian study in 1983, only 5% of patients admitted for a flare had CDI which would make routine screening not cost-effective[28]. However recent studies reported that approximately 5%-19% of newly-admitted patients for relapsing IBD tested positive for C. difficile toxins[29,30]. Similar to the adult population, pediatric IBD patients also seem to be susceptible to CDI as a recent Italian study identified C. difficile toxins in 24.7% of patients with diarrhea or abdominal pain[31]. C. difficile carriage status was studied with stool culture and molecular microbiological methods in IBD patients in clinical remission with no recent hospitalization or antibiotic exposure[32]. Toxigenic C. difficile was demonstrated more frequently in IBD patients (8.2%) than in healthy volunteers (1.0%). However, none of these patients developed CDI after a 6 mo follow-up and all the ribotypes identified were community-acquired, highlighting the acquisition of C. difficile in IBD patients even in remission from a wide variety of community sources[32]. The clinical relevance and significance of this community-acquired C. difficile carriage is interesting and its effect on the outcome of IBD has not been studied.

Environmental exposure continues to be the most common route of acquisition of CDI. Recent hospitalization increases the risk for nosocomial acquisition of CDI, the most common setting for the infection. Antibiotic-resistant C. difficile spores survive in hospital environment and can be isolated on toilets, bedrails, floors, telephones, call buttons, stethoscopes, and the hands of healthcare workers[19-21]. Sharing a room with an infected patient also increases the risk of infection[19].

Interestingly in a majority of IBD patients, CDI seems to often be contracted outside of the hospital. In a recent study, the median time to development of CDI in non-IBD patients was 4 d in contrast to less than a day with CDI in IBD patients[9]. In another study, 76%-79% of patients acquired CDI from the community[10]. 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[32]. In a case-control study from our institution, we also observed that 47.2% of patients had acquired the infection outside the hospital[33].

Almost any antibiotic has been associated with the development of CDI. The risk of CDI varies depending on the type of antibiotic, frequency, duration, route of antibiotic use, and the use of concurrent medications[34-37]. However, even a short-term use of prophylactic antibiotics can cause CDI[38]. The most common implicated antibiotics associated with CDI till recently were ampicillin, amoxicillin, cephalosporins, and clindamycin[34-37]. However, with widespread use, fluoroquinolones have become one of the common predisposing factors for CDI[38-41]. The exact mechanism of antibiotic-associated CDI in IBD is unclear. In addition, frequency of antibiotic exposure in relation to CDI risk in IBD has been highly variable. Antibiotic use prior to 3 mo before the development of CDI was seen in only 40% of IBD patients compared with 69% in the non-IBD population in a study[42]. A separate study showed that 61% of IBD patients with antibiotic exposure developed C. difficile[10]. In a cohort study, 57.2% of patients acquiring a CDI received antibiotics in the previous 6 mo[8]. In our recent study, antibiotic exposure within 30 d prior to C. difficile testing was found to be associated with an increased risk for CDI with odds ratio of 12.0 [95% confidence interval (95% CI): 1.2-124.2][33].

Immunosuppression is also proposed as another risk factor for the development of C. difficile infection. Cancer chemotherapy, particularly methotrexate[43] or patients with organ transplantation on immunosuppression appear to be at risk. The role of immunomodulators in the development of CDI is controversial. Previously studies have reported the association of immunomodulators with CDI in IBD[9,10]. However, in the studies from our institution and others suggest that immunosuppressive treatment was not associated with the risk of CDI[33,44,45].

The relationship of the use of corticosteroids to the risk of CDI has been studied in IBD patients. In a large cohort study of IBD patients, corticosteroid use with or without simultaneous use of other immunomodulating drugs was associated with a 3-fold increase in the risk of CDI (relative risk = 3.38, 95% CI: 1.88-6.10)[8]. Even in the absence of other immunomodulating drugs, the risk increased 2.5 fold in patients using corticosteroids[8]. Corticosteroids have also been shown to increase the risk of CDI relapse in solid organ transplant patients[44]; however corticosteroids and their risk of association to CDI have not been studied in IBD patients.

The use of biologics, specifically infliximab to the risk of CDI was studied in IBD patients and there appears to be no association of the use of biologics on the risk of development of CDI[8].

The normal bacterial flora in the bowel is an important natural defense and inhibits the growth of C. difficile[46]. In addition, the gastric acid barrier is a host mechanism to protect against ingested microorganisms[47]. The use of proton pump inhibitors and the risk for CDI is a subject of controversy, as published results of studies have been conflicting. Some initial studies demonstrated a higher risk of development of CDI with proton pump inhibitor therapy but this finding has not been consistently demonstrated[42,48].

Similar to the non-IBD populations, increasing age has been proposed as a risk factor for CDI in the IBD population[49-51]. IBD patients with CDI, however, were younger than the corresponding non-IBD population who developed CDI. In addition to immunosuppressive medication, host immunity, particularly the humoral arm, may play a role in determining susceptibility to CDI[52]. Thus serum and intestinal secretory antitoxin antibodies may afford protection and may be associated with mild colitis or carriage, while patients with deficient response develop severe or recurrent CDI[52]. Recurrent CDI is also suggested to be because of alterations in the fecal microbiota with markedly decreased diversity as demonstrated by phylogenetic analysis of 16S rRNA-encoding gene sequences[53].

IBD itself has been shown to be a specific risk factor for the development of CDI, particularly in those with colonic involvement[9,11,54]. Patients with UC appear to be at a higher risk for the development of CDI than CD and the presence of colonic disease conferred 3-fold greater risk (odds ratio = 3.12, 95% CI: 1.28-5.12) for CDI[11]. Similarly CD patients with colonic involvement seem to be at a greater risk for CDI than those with isolated small bowel disease[11]. The risk of CDI in relation to disease activity is unclear. A recent study suggested that patients with a greater disease activity may be at a higher risk for CDI[31]. However, in the population based study by Nguyen et al[12], the inverse association between CDI and colectomy rate led to the suggestion that IBD patients with CDI have lesser disease activity, although there was no information on the disease activity. Similarly, in our recent study we did not find any difference in the endoscopic disease activity in UC patients with and without CDI[33].

Patients with CDI are at risk for complications including toxic megacolon, colonic perforation, and peritonitis with sepsis. Patients with IBD are similarly at risk for these complications. Single-center and nationwide studies have studied the outcome of CDI in patients with IBD. The results have been highly variable with some studies reporting shorter stay in patients with CDI in IBD than those in non-IBD patients[42], and some studies showing similar lengths of stay[55], while other studies highlighting increased hospitalization duration and costs[10].

The colectomy rate in CDI is an important measurement of short-term outcome in CDI. 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: 1.8-3.2)[56]. However studies have reported varying rates of colectomy for CDI in the setting of IBD. In a large study utilizing the Health Care inpatient care database, the development of CDI was inversely related to the risk of colectomy[11]. Similarly a subsequent study reported low rates for colectomy after CDI (1 of 15 patients)[42]. In our recent study with colectomy at 3 mo following CDI infection being the end point, we did not find CDI as a risk factor[33]. In a single-center case-control study, the rate of emergent colectomy in their CDI-UC population was 23% with the indication being toxic complications (4 of 11) or medically refractory disease (7 of 11) compared to 13.4% in the C. difficile-negative IBD population[55]. However, it is interesting that 7/11 patients had medically refractory disease and may be C. difficile was a colonizer. Also there was no statistically significant difference in the short-term risk of colectomy at 1 mo[55]. In another study, underlying IBD was associated with 6 fold greater risk of bowel surgery compared with patients with CDI without underlying IBD[10]. We believe that the lower risk of colectomy with UC-CDI in most studies may be due to the fact that patients with UC exacerbation resulting from CDI are much more likely to improve with proper pathogen-directed medical therapy. Therefore, treating CDI in UC patients may actually prevent the need for colectomy in the short term (Figure 1).

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Figure 1 Toxic megacolon in a 27-year-old patient with Clostridium difficile infection who had underlying ulcerative colitis, resulting in emergent subtotal colectomy. Arrow indicate dilated colon.

There are limited studies available investigating the long-term outcome of CDI in patients with IBD. In a recent retrospective case control study, UC-CDI patients had worse clinical outcome than UC patients without CDI, with a follow-up of up to a year after CDI[55]. On the other hand, the study did not discriminate between recurrent CDI vs worse IBD disease activity because of the retrospective nature and study design. However, C. difficile-positive patients had significantly more UC-related hospitalizations (58 hospitalizations vs 27 hospitalizations) and emergency room visits in the year following initial admission (8 visits vs 1 visit). Also, up to a year following the index admission, patients with CDI had significantly higher rates of colectomy compared to C. difficile-negative patients (44.6% vs 25%). In a case-control study comparing the disease course for 1 year before and 1 year after the initial infection in 87 patients with IBD with C. difficile, colectomy occurred in only 10.3% of patients (9/87) following CDI[57]. While 8% had fewer hospitalizations in the year following infection, 41.3% of patients (36/87) followed for a year after CDI had no difference in the number of hospitalizations. However, 46% of patients (40/87) had more hospitalizations in the year following CDI (range 1-9 hospitalizations)[57]. Also 53% (46/87) of IBD patients with CDI required an escalation in their IBD medical therapy including initiation of biologic therapy (26%; 23/87), dose escalation of current biologic (8%; 7/87), escalation or initiation of azathioprine/6-MP (11.5%; 10/87) or methotrexate (7%; 6/87)[57]. Both these studies are limited by their retrospective nature and it is unclear whether underlying IBD severity was responsible for this outcome or whether C. difficile produces certain immunological changes that leads to a worse long term clinical outcome. Table 1 summarized both the short and long term outcome of CDI in IBD.

Plain radiography is usually normal in patients with CDI, unless they have complications like ileus or toxic megacolon or perforation. CT imaging is useful in the diagnosis of severe or fulminant CDI and the characteristic features include colonic-wall thickening, pericolonic stranding, the “accordion sign”, and the “double-halo sign”[63]. The accordion sign is seen with oral contrast and shows the high attenuation in the colonic lumen alternating with a low attenuation inflamed mucosa, while the double-halo sign is seen with intravenous contrast[63]. The presence of these signs in the right clinical setting may suggest a diagnosis of CDI.

Lower endoscopic visualization forms an important part in the evaluation of patients with CDI in IBD. Isolated CDI produces the classic endoscopic appearance of pseudomembrane formation which is described in 50% of patients[64,65]. However in patients with underlying IBD, classic endoscopic or histologic features of pseudomembranes are conspicuously absent, making it hard to diagnose CDI in patients with worsening diarrhea[10,42]. In fact, recently published studies from Milwaukee and Belgium did not identify pseudomembranes in any of the IBD patients with CDI who underwent endoscopic evaluation[10,42]. However endoscopy may be useful to assess disease activity of IBD and also to rule out other secondary causes of diarrhea including concurrent cytomegalovirus infection[66].

The classic histologic picture in CDI is the presence of pseudomembranes. Pseudomembrane formation is caused by sloughing and necrosis of the mucosa with ulceration secondary to inflammation. Pseudomembranes are actually characteristic ‘‘volcano’’ lesions with focal ulceration with inflammation composed of polymorphonuclear leukocytes, fibrin, chronic inflammatory cells, and epithelial debris[66]. In patients with IBD, pseudomembranes are not commonly present, CDI tends to produce a nonspecific mucopus; erythema and friability are commonly encountered endoscopic findings[10].

These assays are based on the detection of toxins A and/or B using either a monoclonal antibody or a polyclonal antiserum that recognizes the specific toxin. The ELISA test is inexpensive and the results are available within 2-6 h. The most widely used ELISAs for detection of both toxins A and B in stool are somewhat less sensitive (70%-90%) than the cell cytotoxicity assay (see below). Up to 30% of tests may be falsely negative in comparison to the cell cytotoxicity assay or culture[67,68]. They do, however, demonstrate excellent specificity (99%)[68,69]. The lower sensitivity of these tests can be improved by performing ELISAs on 2 or 3 specimens rather than on 1 specimen, which increases the diagnostic yield by 5%-10%[70]. In IBD patients, the diagnostic yield of ELISA testing may be much lower. Four sequential stool samples were shown to increase the diagnostic yield to 92%[42].

Latex agglutination assay is based on the glutamate dehydrogenase (GDH) enzyme produced by C. difficile. The sensitivity of these tests approached almost 96%-100% in a recent study[71]. However, certain other organisms can also produce GDH and also the positivity indicates only the presence of the organism, rather than in vivo production of C. difficile toxins. It is not recommended for routine clinical use.

Cell cytotoxicity assay is the gold standard test for diagnosis of CDI. It detects as little as 10 picograms of toxin and it is the most sensitive available test for detection of toxin B[72-75]. It is based on the principle that the toxins in the stool exert a cytopathic effect characterized by cell rounding which can be demonstrated in tissue culture. The high sensitivity (94%-100%) and specificity (99%) of the cytotoxicity assay is its major advantage. Disadvantages are its relatively high technical expertise and the 24-48 h needed to complete the assay[76].

Stool culture is seldom used for routine diagnosis because of labor intensiveness, long turnaround time (24-48 h) and a low specificity. The in vivo production of toxins can be seen in hospitalized patients who are asymptomatic carriers. It fails to differentiate toxin-producing from nontoxigenic strains. However, because culture permits molecular typing of the organisms, it is essential for monitoring molecular epidemiology and antibiotic susceptibility[72]. We do not recommend its routine use in the diagnosis of CDI in clinical practice.

Polymerase chain reaction (PCR) based primers for the detection of genes for toxins A and is highly sensitive and specific for the diagnosis of CDI[77,78]. Culture of the organisms may be required for PCR, which makes the process more technically demanding and challenging. A study based on the nested PCR assay reported a 99% concordance with the cytotoxicity assay and a sensitivity of 96.3% and a specificity of 100%[78].

Small intestinal C. difficile has increasingly been reported. The spectrum of CDI has definitely expanded with small bowel involvement (Figure 2)[99]. They are more frequently reported in patients with IBD who have undergone total colectomy or some form of gastrointestinal surgery[13]. The most common presentation is increased ileostomy output with associated dehydration. In patients with small bowel CDI, the risk factors seem to be slightly different. Antibiotic use and IBD predispose to small bowel CDI similar to CDI of the colon. Prior surgeries of the colon/colectomy, and host factors including advanced age, immunocompromised state are proposed as additional risk factors for small bowel CDI[100]. More than 90% of patients reported in the literature had gastrointestinal surgery of the colon.

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Figure 2 Recurrent Clostridium difficile enteritis in neoterminal ileum in a 36-year-old patient with diverting ileostomy for ileal pouch who had a preoperative diagnosis ulcerative colitis. Arrows: Enteritis due to Clostridium difficile infection and dilated loops of small bowel.

The reason for the predisposition of patients who undergo colonic surgery to small bowel CDI is not clear although multiple hypotheses are proposed. Firstly, changes occur in the small-bowel bacterial flora resembling colonic flora and after colectomy this may make it susceptible to overgrowth with C. difficile, particularly with concomitant antibiotic use[101]. This is based on the fact that the neoterminal ileum is colonized by colonic-type bacterial flora after ileocolonic resection[102]. Prolonged exposures to fecal stream may make the small bowel mucosa undergo metaplastic changes, as seen in patients with IPAA[103]. This notion was further supported by the fact that similar changes may occur in patients with end ileostomy and the long latent period between the surgery and the infection supports this. Changes occur in the ileostomy flora resembling the fecal flora[104]. In patients who develop infection in the immediate post operative period, a majority of patients had CDI of the colon prior to surgery which leads to the hypothesis that in those patients CDI of the small bowel may be secondary to migration of C. difficile into the small bowel after surgery. CDI is a toxin-mediated disease process. Although receptors for C. difficile toxins are typically on colonic epithelium, the receptors for toxin B is ubiquitous and may be present on small bowel epithelium which could mediate diarrhea in the immediate post operative period in the absence of colonic phenotype changes[105]. Secondly, colonization of the small bowel occurs because the protective mechanisms are compromised by colonic resection surgeries. The mechanical action of the ileocecal valve may be lost because of surgery[106]. In addition, continued peristalsis in the small bowel also inhibits colonization of the small bowel with C. difficile[106]. Therefore, surgeries involving only the left side of the colon with preservation of the ileocecal valve do not seem to increase the risk of CDI of the small bowel, highlighting the importance of the ileocecal valve in preventing colonization.

Initial studies highlighted that infection of the small bowel with C. difficile was associated with an increased mortality[13]. The increased permeability of the small intestinal mucosa was hypothesized to be due to result in profound sepsis[107]. However, recent studies showed a favorable prognosis. In fact, two large recent case series reported no mortality[100,108]. This may be probably secondary to increased awareness of the problem and early intervention.

The treatment of small bowel CDI is controversial and stratification of the disease severity as CDI of the colon could be used to initiate appropriate management plan. In a series of 11 patients, more than 50% responded to metronidazole alone[108]. In another series, all six patients were treated with a combination of metronidazole and vancomycin[100]. Thus similar to colonic CDI, oral vancomycin may be a first-line agent for severe CDI, while in mild to moderate disease, metronidazole may be used. However in patients who do not improve within 72 h of initiation of treatment with metronidazole, vancomycin needs to substituted instead of metronidazole.

CDI has been reported in patients with IPAA[14,15,109,110]. CDI in IPAA can either present with asymptomatic colonization or with chronic antibiotic-refractory pouchitis or occasionally with fatal outcome. As the majority of patients have a history of short- or long- term exposure to antibiotics, CDI should be excluded in pouch patients with persistent symptoms with or without endoscopic findings of pouchitis or other pouch disorders.

In patients with IPAA, the epithelium of pelvic pouches undergoes morphologic changes facilitating fecal flora establishment[109]. These histologic adaptive changes include villus atrophy, Paneth cell hyperplasia, and a partial transition to colonic mucin phenotype without complete metaplasia[103]. In a recent study of 115 patients with IPAA, 21 (18.3%) were tested positive for C. difficile toxin A or B[14]. Three of those patients had chronic antibiotic-refractory pouchitis and all 3 patients had clinical remission and disappearance of C. difficile toxin from the stool with anti-C. difficile treatment with rifaximin or tinidazole. Three additional patients with other pouch-associated disorders also symptomatically improved with treatment of CDI. We also recently reported a patient who developed CDI of the pouch and neoterminal ileum immediately after ileostomy closure with a fatal outcome[111]. Fulminant outcomes of CDI of the pouch have also been described recently in a case report[112]. Similar to IBD patients with CDI who do not have the classic endoscopic or histologic features of pseudomembranes[10,42], superimposed CDI in pouch patients hardly have endoscopic or histologic features of pseudomembranes which makes the diagnosis challenging.

The treatment of CDI in IPAA is empiric at this point. There are no published prospective trials. The traditional drugs used in the management of CDI are metronidazole and vancomycin. Previous studies suggest that metronidazole may be not completely protective against CDI of the pouch, as the bacterial infection can develop while the patients had been still on metronidazole[109,110]. Therefore, in patients with C. difficile-associated pouchitis, metronidazole may not be considered as the first-line agent. Based on our own experience and limited published literature, rifaximin, tinidazole, or vancomycin have been used with satisfactory results[14,110].

Diversion colitis is common in segments of the colorectum after surgical diversion of the fecal stream, which may persist indefinitely unless the excluded segment is reanastomosed[113]. Patients with diverted bowel appear not immune to the development of CDI in the excluded downstream bowel segment. There has been a case report in which, following subtotal colectomy and end-ileostomy for medically refractory disease, a UC patient subsequently developed severe CDI in the rectal remnant (Hartmann pouch) and the patient responded to metronidazole suppositories[110].