Clostridium difficile is a Gram-positive anaerobe described as early as 1935 as being a member of the intestinal flora in neonates. It was not until 1978 that it was first described in association with antibiotic-associated pseudomembranous colitis (PMC). C difficile infection (CDI) is now the predominant cause of PMC and an important cause of health care–associated diarrhea. The last 2 decades have witnessed several shifts in its epidemiology. In addition to the nearly worldwide increase in its incidence, it has been increasingly recognized as an important cause of diarrhea in the community setting in individuals not previously considered at high risk, including in children, adults with no recent antibiotic or health care exposure, pregnant women, and, more recently, individuals with underlying inflammatory bowel diseases (IBD). The similarity in clinical presentation between CDI and an IBD flare but divergent treatment paradigms with directed antibiotic therapy in the case of CDI and escalation of immunosuppression in an IBD flare makes it important for the treating clinician to have a high index of suspicion for CDI in patients with IBD. This review attempts to summarize the changes in CDI epidemiology over the last 2 decades, its growing impact on patients with IBD, diagnostic algorithms, and treatment modalities.
Burden of C Difficile Infection
There has been a dramatic increase in the occurrence of CDI among hospitals in the United States with a doubling of incidence from 31 in 100,000 population in 1996 to 61 in 100,000 population in 2003. There were an estimated 348,950 hospitalizations in 2008. Studies from other regions such as Quebec, reveal an even steeper increase, with the incidence reaching 156 in 100,000 population in 2003. During the same period, the proportion of patients with severe or complicated CDI also doubled from 7% to 18% with a corresponding increase in mortality. The prevalence of community-acquired CDI (CA-CDI) remains lower than that in hospital-based studies but still significant at 7 to 46 cases per 100,000 population. Data from the United Kingdom mandatory reporting and surveillance showed a reduction in CDI incidence by 54% between 2007 and 2010; such a decrease has not yet been shown in the other cohorts.
Paralleling the increase in the non-IBD population, there has been a similar increase in CDI among patients with IBD. In a study utilizing a national hospitalization database, Ananthakrishnan and coworkers found an increase in the rate of CDI among patients hospitalized with ulcerative colitis (UC) from 24 in 1000 to 39 in 1000 with a significant but less steep increase among patients with Crohn disease (CD; 8 in 1000 to 12 in 1000) from 1998 to 2004. Data from 2007 show that the incidence has continued to increase. An earlier study by Rodemann and colleagues found a similar rate of increase at their tertiary referral center between 1998 and 2004. Specifically, among patients presenting with a disease flare, early reports suggested between 5% and 18% of patients may have superimposed CDI ; more recent reports have identified rates as high as 47% among adults and 25% to 60% among children.
Pathogenesis and Variant Strains of C Difficile
C difficile is a spore-forming anaerobe that exerts its effect through the formation of toxins, the 2 key toxins being toxins A and B, encoded by the genes tcdA and tcdB, respectively. These cytotoxins act by causing glycosylation of the rho and ras proteins essential for maintaining cytoskeletal integrity. The resultant disruption of the tight junctions leads to loss of epithelial integrity and the consequent watery diarrhea associated with CDI. Initial research suggested toxin A to be the key toxin, and, indeed, early-generation enzyme-linked immunosorbent assay tests for diagnosis of CDI detected toxin A alone. Subsequent human and animal data suggest that toxin B was the dominant toxin ; strains that produced toxin A alone but not toxin B were not pathogenic in animal models of CDI. Approximately 10% to 15% of human CDI may be caused by C difficile strains producing toxin B alone. A third toxin, the binary toxin, encoded at a distinct locus, has been associated with an increased production of toxins A and B. Scanning electron microscopy studies suggest that this binary toxin may be more pathogenic by facilitating adhesion of the clostridia to the intestinal epithelium by enabling actin polymerization and redistribution of microtubules.
Several variant strains of C difficile have been described, some of them “hypervirulent” with an association with severe disease. The most prominent of such strains is the BI/NAP1/027 strain that was first identified to be responsible for an epidemic of CDI in Quebec, Canada. This strain has been identified subsequently in several other countries and in association with other regional outbreaks, some of them leading to fatality. The BI/NAP1/027 strain produces binary toxin and may have greater adherence to intestinal epithelium. The exact prevalence of this strain in the IBD population is not known, but estimates from other countries have attributed between 25% to 50% of all CDI to this strain, including a majority of the hospital isolates, although others have arrived at a lower estimate. A similar prevalence can be estimated to occur in patients with IBD. A second variant strain, the ribotype 078 strain, was initially identified in the Netherlands and has been associated with severe disease. This strain may be responsible for 8% to 10% of all hospital-acquired CDI.
Pathogenesis and Variant Strains of C Difficile
C difficile is a spore-forming anaerobe that exerts its effect through the formation of toxins, the 2 key toxins being toxins A and B, encoded by the genes tcdA and tcdB, respectively. These cytotoxins act by causing glycosylation of the rho and ras proteins essential for maintaining cytoskeletal integrity. The resultant disruption of the tight junctions leads to loss of epithelial integrity and the consequent watery diarrhea associated with CDI. Initial research suggested toxin A to be the key toxin, and, indeed, early-generation enzyme-linked immunosorbent assay tests for diagnosis of CDI detected toxin A alone. Subsequent human and animal data suggest that toxin B was the dominant toxin ; strains that produced toxin A alone but not toxin B were not pathogenic in animal models of CDI. Approximately 10% to 15% of human CDI may be caused by C difficile strains producing toxin B alone. A third toxin, the binary toxin, encoded at a distinct locus, has been associated with an increased production of toxins A and B. Scanning electron microscopy studies suggest that this binary toxin may be more pathogenic by facilitating adhesion of the clostridia to the intestinal epithelium by enabling actin polymerization and redistribution of microtubules.
Several variant strains of C difficile have been described, some of them “hypervirulent” with an association with severe disease. The most prominent of such strains is the BI/NAP1/027 strain that was first identified to be responsible for an epidemic of CDI in Quebec, Canada. This strain has been identified subsequently in several other countries and in association with other regional outbreaks, some of them leading to fatality. The BI/NAP1/027 strain produces binary toxin and may have greater adherence to intestinal epithelium. The exact prevalence of this strain in the IBD population is not known, but estimates from other countries have attributed between 25% to 50% of all CDI to this strain, including a majority of the hospital isolates, although others have arrived at a lower estimate. A similar prevalence can be estimated to occur in patients with IBD. A second variant strain, the ribotype 078 strain, was initially identified in the Netherlands and has been associated with severe disease. This strain may be responsible for 8% to 10% of all hospital-acquired CDI.
Risk Factors for CDI
General Risk Factors
Broad-spectrum antibiotic use and health care contact are well recognized as key risk factors for CDI. Historically, as many as 65% to 95% of patients with CDI reported recent use of antibiotics. The spectrum of agents associated with CDI spans all antibiotic classes with the risk being greater for broad-spectrum antibiotics and those that lead to greater disruption of the intestinal flora. Clindamycin, cephalosporins, and fluoroquinolones are associated with the greatest excess risk for CDI. Given their widespread use, up to one-third of CDI may be attributable to fluoroquinolone use with a small proportion being attributable to cephalosporins (10%) and clindamycin. The emergence of the BI/NAP/027 appears to be, in part, selected by wide spread use of fluoroquinolones, as the strain is resistant to this class of antibiotics.
Antibiotic use and health care contact are less common risk factors in patients with IBD with between 40% and 60% of IBD patients not reporting recent use of antibiotics. Although the majority of CDI-IBD cases have been nosocomially acquired, a sizeable minority of patients acquire CDI outside the health care setting. Thus, lack of traditional risk factors should not preclude considering CDI in the differential diagnosis of patients presenting with an IBD flare. Both age and comorbidity increase risk of CDI. Proton-pump inhibitor use or gastric acid suppression has been variably reported as a risk factor for CDI in non-IBD cohorts but appears to be uncommon in patients with IBD.
In addition to these extrinsic factors, host immune response plays a key role in CDI pathogenesis. Individuals who are able to mount a strong antitoxin antibody response are more likely to remain asymptomatic or colonized with C difficile, whereas those with lower levels of antitoxin antibody are more likely to develop symptomatic disease.
IBD-Specific Risk Factors
Several IBD-specific factors increase the risk for CDI, the most important being immunosuppression. Maintenance immunosuppression confers a 2-fold increase in the risk for CDI (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.28–5.12). Colonic disease is also a risk factor for CDI (OR, 3.12; 95% CI, 1.28–5.12) with several studies reporting higher rates of CDI in those with UC compared with those with CD. Severity and extent of colonic inflammation may also modulate CDI risk with a greater risk of CDI in patients with pancolitis compared with those with limited distal disease.
Clinical Features
The clinical symptoms associated with CDI are often indistinguishable from an IBD flare and include diarrhea, sometimes watery, with or without the presence of overt bleeding. There may be associated abdominal pain, cramping, or tenesmus. Physical examination may find abdominal tenderness; rebound or guarding is a sign of severe colitis. Fever and leukocytosis are seen with both CDI and an IBD flare. Markers of severe CDI include renal dysfunction, markedly elevated white blood cell count, or an increased serum lactate level. Diarrhea may not be universally seen in severe disease, as 20% of patients may have concomitant ileus. Radiologic evaluation is useful to establish ileus and also aids in the diagnosis of toxic megacolon in patients with severe disease. Although a plain x-ray may suffice in many patients, a computed tomography scan is more sensitive for early disease. None of these features are specific for C difficile and may not aid in differentiating CDI from an IBD flare. However, patients with previously known limited or distal colonic disease now showing pancolonic thickening should raise suspicion for superimposed CDI. The classic colonoscopic appearance of CDI is the pseudomembrane, which histologically comprises exudates and debris on a base of mucosal denudation (“volcano” lesion). However, this finding has been found uncommonly in patients with underlying IBD. In a multicenter study of hospitalized CDI-IBD patients, Ben-Horin and colleagues identified pseudomembranes in 12 of 93 patients (13%) who underwent a lower endoscopy; the only factor independently associated with pseudomembranes was the presence of fever. Nevertheless, in patients who do not yield a positive diagnosis using noninvasive stool testing, a limited sigmoidoscopy allows to (1) evaluate for the presence or absence of pseudomembranes; (2) assess for the endoscopic severity of disease, including presence of deep ulcers, which has prognostic significance; (3) to obtain biopsies to rule out cytomegalovirus infection; and (4) to obtain stool aspirate for C difficile testing.
Impact of C Difficile Infection on Course of IBD
Single-center and multicenter studies have consistently demonstrated the significant adverse impact of CDI on patients with IBD. Compared with non-IBD controls, patients with IBD in whom CDI developed have 4-fold greater mortality and are 6 times more likely to require bowel surgery. They also had a substantially longer hospital stay and an excess $11,406 in adjusted hospitalization charges. Compared with those with IBD alone, patients with both CDI and IBD had 6-fold greater in-hospital mortality and a 2-fold increase in emergency gastrointestinal surgery or colectomy. Between 20% and 45% of IBD patients hospitalized with CDI may require colectomy, with the common indications being refractory disease or toxic complications. Ananthakrishnan and colleagues examined temporal changes in the excess morbidity associated with CDI in patients with IBD and found that there was a nonsignificant increase in the excess mortality risk associated with CDI between 1998 and 2007 ( P = .15) but the odds of colectomy compared with non-CDI controls significantly increased over the same time period ( P = .03).
There are few reports examining if CDI has an impact on the natural history of disease beyond the acute episode. Jodorkovsky and coworkers found a higher rate of UC-related emergency room visits or hospitalizations 1 year after the initial episode of CDI with a 2-fold increase in the rate of colectomy. Jen and colleagues, using data from the National Health Service in England found a nearly 6-fold excess mortality at 30 days and 365 days after the initial hospitalization for CDI. Chiplunker and colleagues identified a mean increase in 0.89 hospitalizations per patient in the year after CDI with more than half the patients requiring escalation of maintenance therapy for their IBD (one-quarter of the CDI-IBD cohort required new initiation or escalation of biologic therapy).
Special Situations Related to CDI in IBD Patients
Healthy Carriage
Not all patients with C difficile have overt infection. Between 1% and 4% of healthy adults may be colonized with C difficile with a much higher rate among neonates (hypothesized to be because of a lack of intestinal epithelial receptors for C difficile toxin). In a study by Clayton and coworkers, the rate of asymptomatic carriage in adults with IBD on aminosalicylate therapy was greater (8%) than that among healthy volunteers; whether the same extends to patients on immunosuppression is unclear.
Pouchitis
Patients with an ileal pouch anal anastomosis frequently require antibiotics for treatment of acute ileal pouch anal anastomosis, predisposing them to the development of CDI. In one series of 115 patients with IPAA, C difficile toxin was identified in 21 patients (19%). Risk factors for CDI of the pouch included male sex and prior history of left-sided colitis. Thus, a diagnosis of CDI should be entertained in patients with refractory or recurrent pouchitis, particularly if unresponsive to standard antibiotic therapy.
Enteritis
Patients with a colectomy and ileostomy are not excluded from risk of CDI and can get C difficile enteritis. Lundeen and colleagues reported a series of 6 patients with C difficile enteritis who presented with high-volume ileostomy output, fever, and ileus. All patients in this series responded to a combination of metronidazole and vancomycin although the morbidity and mortality rate have been high in other case series. CDI can also involve segments of diverted bowel; such infection responds to topical vancomycin.
Diagnosis of C Difficile Infection
The diagnosis of CDI depends on demonstrating the toxin or a toxigenic strain in the diarrheal stool of the suspected patient. Testing formed stool samples has limited value and should be avoided. The most commonly used test is the enzyme immunoassay (EIA) directed against both toxins A and B ( Table 1 ). The performance of this test has varied widely in different settings with an estimated sensitivity of 63% to 94% and a specificity of 75% to 100%. More relevant measures of test performance in the clinical setting are the positive (PPV) and negative predictive values (NPV). At low CDI prevalence, the PPV for a single stool EIA is low at 52% to 70% with a high NPV. The performance improves at higher CDI prevalence, however, with a still substantial rate of false-negative test resuts. Testing repeat stool samples has yielded few additional cases in the non-IBD population and may not be cost effective. Nevertheless, in the right clinical setting, testing multiple samples may improve the yield; such a practice has been adopted in some patients with IBD. In those with a high index of suspicion, one might consider repeating with a different diagnostic test. Another recently available test is the real-time polymerase chain reaction that detects the toxigenic genes. This test has a significantly greater sensitivity and specificity than the EIA with a similar turnaround time. Its performance specifically in the IBD population has not been determined.
| Test | Comment |
|---|---|
| Diagnostic tests | |
| EIA – Toxin A or EIA Toxin A/B | Relatively inexpensive, fast turnaround time, suboptimal sensitivity |
| Polymerase chain reaction – Toxin B gene | Rapid, sensitive |
| Cell culture cytotoxicity assay | Sensitive, relatively long turnaround time, technically complex |
| Anaerobic culture | Sensitive, relatively long turnaround time |
| Supportive tests | |
| Fecal leukocytes | Not specific, cannot differentiate between CDI and IBD flare |
| White blood cell count, serum creatinine, serum albumin | Useful in assessing severity of disease, no role in diagnosis |
| Plain abdominal x-ray | Can detect toxic megacolon or free perforation. Less sensitive to demonstrate colitis. Cannot differentiate CDI from IBD flare. |
| Computed tomography abdomen | Sensitive in demonstrating colitis. Cannot differentiate CDI from IBD flare. Can detect toxic megacolon or free perforation. |
| Sigmoidoscopy/colonoscopy | May demonstrate pseudomembranes (uncommon in IBD patients). Allows for assessment of severity of disease and to obtain biopsies to rule out cytomegalovirus infection. |
The gold standard for the diagnosis of CDI is the toxigenic culture or the cell-culture cytotoxicity assay, a 2-step test consisting of culturing C difficile from diarrheal stool followed by demonstration of the toxin-mediated cytopathic effect after 24 to 48 hours of inoculation. A simpler test with a high NPV is the EIA against the C difficile common antigen (glutamate dehydrogenase). The PPV of this test is low and requires that a positive test be followed by a second, confirmatory antitoxin EIA. However, a negative test result has a high NPV in ruling out CDI and can avoid the need for the more expensive antitoxin EIA. Such a 2-step testing strategy has been proposed but has not yet been widely adopted.
Treatment of C Difficile Infection
General measures in the treatment of all patients with CDI include cessation of the offending antibiotic, if possible, or switching to an agent with a narrower spectrum of action ( Table 2 ). Such measures have been successful in the treatment of a small proportion of patients with mild CDI ; however, specific directed therapy against CDI is required in the majority of patients with IBD. Specific trials for the treatment of IBD patients with CDI are lacking; management algorithms for such patients are extrapolated from the non-IBD patients. Other general measures include avoiding antimotility drugs or agents with anticholinergic activity.
| Clinical Scenario | Treatment Option |
|---|---|
| Initial episode, mild | ☐ Oral metronidazole 500 mg every 8 hours or 250 mg every 6 hours ☐ Continue current immunosuppression |
| Initial episode, severe | ☐ Oral vancomycin 250–500 mg every 6 hours ☐ Consider adding intravenous metronidazole 500 mg every 8 hours in patients with ileus or severe disease ☐ Other potential adjunctive therapies include tigecycline, fidaxomicin, intravenous immunoglobulin, fecal bacteriotherapy |
| Recurrent episode | ☐ Prolonged course of oral vancomycin with gradual taper over 4–6 weeks ☐ Two-week course of oral vancomycin followed by 4–6 weeks of rifaximin 200–400 mg every 8 hours ☐ Fidaxomicin 200 mg (oral) twice a day ☐ Other potential therapies include fecal bacteriotherapy and intravenous immunoglobulin |
| Refractory disease | ☐ Oral vancomycin 500 mg every 6 hours AND intravenous metronidazole 500 mg every 8 hours ☐ Consider supplementing oral vancomycin with vancomycin retention enemas ☐ Early surgical consultation |
Choice of First-Line Therapy
Until recently, oral vancomycin was the only agent approved by the US Food and Drug Administration for the treatment of CDI. Fidaxomicin, a first-in-class macrocyclic antibiotic has also recently received US Food and Drug Administration approval for the treatment of CDI. Metronidazole remains most commonly used and is typically given at a dose of 500 mg orally every 8 hours or 250 mg every 6 hours. Oral vancomycin may be used in doses ranging from 125 to 500 mg every 6 hours with comparable efficacy among the different dosing regimens. Intravenous vancomycin has no effect against C difficile owing to poor luminal concentration. The duration of treatment with either antibiotic is 10 to 14 days. The ratio of colonic luminal concentration to minimum inhibitory concentration for C difficile is higher for vancomycin than metronidazole, although both agents achieve luminal concentration well above the minimum inhibitory concentration. Metronidazole is less expensive than vancomycin but may also not be tolerated because of metallic taste, gastrointestinal side effects, and risk of neuropathy with long-term use. Vancomycin has the theoretical risk of increasing the spread of vancomycin-resistant enterococci. The high cost of oral vancomycin ($300–$600 per course compared with $20 for metronidazole) may be offset by the oral administration of the generic intravenous formulation for hospitalized patients (estimated cost $45). Early randomized trials from the 1980s and 1990s showed comparable efficacy of both metronidazole and vancomycin. However, more recent data have raised concern regarding lower treatment efficacy and a higher recurrence rate with metronidazole. In a landmark trial, Zar and colleagues compared the efficacy of both drugs stratified by severity of CDI. Severe CDI was defined by the presence of pseudomembranes, intensive care unit admission, or any 2 of the following: fever, leukocytosis, hypoalbuminemia, or age greater than 60 years. For mild disease, both metronidazole and vancomycin had similar efficacy (98% vs 90%, P = .36). However, vancomycin had significantly greater clinical cure rates in those with severe disease (97% vs 76%, P = .02). A second trial comparing the 2 agents also included a third arm consisting of tolevamer, a binding resin. Similar to the Zar trial, vancomycin was similar to metronidazole for mild or moderate disease but more efficacious in those with severe disease. There are no similar studies evaluating drug efficacy stratified by disease severity in patients with IBD. Given the greater morbidity and mortality noted with CDI in patients with IBD, it is reasonable to infer IBD patients requiring hospitalization for CDI as having “severe” disease and using oral vancomycin as the first line in such patients. In patients with milder IBD or ambulatory patients, oral metronidazole may be an appropriate first-line option.
A recent study published in abstract form compared the performance of oral vancomycin, metronidazole, or combination therapy with both metronidazole and vancomycin in the treatment of CDI. Although the study did not comment on rates of clinical cure, the rate of recurrent CDI was greater in those who received vancomycin alone compared with the 2 other groups. However, the nonrandom allocation of treatment, lack of treatment efficacy as a primary endpoint, and potential confounding by disease severity limits the generalizability of those results. Nevertheless, a combination of intravenous metronidazole and oral vancomycin may have a role in the treatment of patients with severe CDI and ileus who may not achieve adequate colonic luminal concentration of vancomycin.
Two recent phase 3 trials compared the efficacy of vancomycin (125 mg 4 times daily) with that of fidaxomicin, a novel macrocyclic antibiotic (200 mg twice daily) over a 10-day treatment period. In this noninferiority trial comprising 629 patients, the rate of clinical cure was similar in both treatment groups (88% fidaxomicin vs 86% vancomycin). However, the rate of recurrent CDI was significantly lower in the fidaxomicin arm (15%) compared with the vancomycin arm (25%), an effect likely caused by less disruption of the intestinal flora by fidaxomicin. However, this advantage was not seen in patients infected with the BI/NAP/027 strain. Experience with this antibiotic in patients with IBD is limited; however, it promises to be an effective alternative, particularly in patients with recurrent disease or those at high risk for recurrence. Other agents that have shown efficacy in the treatment of CDI include rifaximin (90% efficacy in a single open-label trial), teicoplanin (not available in the United States), nitazoxanide, fusidic acid, bacitracin, and binding resins, such as cholestyramine and colestipol. Data on the efficacy of these agents in IBD patients is lacking.
Immunosuppression in Patients with CDI
One challenge in the treatment of CDI in patients with IBD is the management of immunosuppression. It is well recognized that immunosuppression increases risk of CDI and may predispose to adverse outcomes. However, symptoms of a disease flare are indistinguishable from that of CDI, and, in many cases, the 2 may coexist. A multicenter study by Ben-Horin and coworkers examined the outcomes of CDI-IBD patients treated with antibiotics (AB) alone compared with those who received antibiotics in combination with immunomodulator (AB-IM) therapy. The composite primary endpoint of death, colectomy, toxic megacolon, or respiratory failure was more common in the AB-IM cohort; treatment with 2 or 3 immunomodulators substantially increased the likelihood of the primary outcome (OR, 17; 95% CI, 3–91). As evidenced by the wide confidence interval, the number of patients in each subgroup was small. Moreover, the nonrandom allocation to treatment arms raises concern regarding confounding by severity. Extrapolating data from opportunistic infections, it is reasonable to conclude that one must avoid escalation of immunosuppression in the setting of untreated CDI. In particular, the dose of steroids should be minimized where possible. However, in a significant proportion of the cases, it may be necessary to avoid combination treatment with both antibiotics and immunosuppressive agents.
Management of Refractory Disease and the Role of Surgery
Despite optimal medical therapy, a significant proportion of patients with CDI-IBD remain refractory. An inflamed colon may increase luminal concentration of intravenous metronidazole, which is a useful adjunct to oral vancomycin in those with severe colitis or coexisting ileus). Vancomycin can also be administered via a nasoenteric tube or directly into the colon through a retention enema. Careful rectal administration of 500 mg of vancomycin mixed in 100 mL of saline every 4 to 12 hours through a Foley catheter placed in the rectum (after insufflation of the balloon) has been effective in some patients. Tigecycline is an alternate intravenous antibiotic (50 mg twice daily) that has been used in patients with severe disease with good efficacy. Small case series have reported successful treatment of severe or recurrent CDI with the use of intravenous immunoglobulin (single dose of 150–400 mg/kg). Rates of failure with this therapy remain high, reflecting the severity of disease in this cohort.
Early surgical consultation is essential in patients with refractory or severe CDI, as late surgery has been associated with substantial morbidity and mortality. Factors predicting severe disease requiring surgery include marked leukocytosis (>15,000/mm 3 ), elevated serum lactate level, or underlying IBD. The treatment of choice is a subtotal colectomy with end-ileostomy. Segmental resection or hemicolectomy is associated with a high mortality and is not preferred. A recent study published in abstract form described 34 patients with severe CDI (non-IBD) who underwent a temporary loop ileostomy with intraoperative lavage with 8 L of PEG-3350/electrolyte solution and intracolonic administration of vancomycin, 500 mg every 8 hours. The mortality rate in this cohort was 21% (compared with 47% in historical controls) with 24 of 27 survivors retaining their colon (and 10 of 18 having their ileostomy reversed at 6 months).
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