Pouchitis Following Ileal Pouch Anal Anastomosis

Risk Factors 

Demographic features such as age and race, as well as the surgical technique used, does not appear to have a predisposing effect on the occurrence of pouchitis.17 Extraintestinal manifestations (EIMs) of UC, specifically ankylosing spondylitis and iritis, have been associated with an increased risk of pouchitis.18 Lohmuller and coworkers reported that, if EIMs were present before an IPAA, pouchitis occurred in 39% of patients and 53% of patients when EIMs were present after the IPAA compared with 26 or 25%, respectively, of patients with no EIMs used as controls.16 Primary sclerosing cholangitis (PSC) occurs in approximately 5% of patients with UC and is a significant predisposing factor for pouchitis with a cumulative risk factor of 79% at 10 years compared with 45.5% of adults with UC without PSC.10

The interleukin-1 receptor antagonist gene (IL-1ra) allele 2 has been implicated as a genetic marker for a predisposition to pouchitis. Interleukin-1 is an important proinflammatory cytokine that is competitively inhibited from binding to the IL-1 receptor by IL-1ra, which does not induce signal transduction.19 Individuals carrying the IL1-ra allele 2 gene have an associated decrease level of IL-1ra resulting in a relative disequilibria of IL-1/IL-1ra thus resulting in an increase in IL-1 receptor activation. Carter and coworkers showed that 57% of patients with an IPAA following colectomy for UC developed pouchitis with a median interval of 18 months following surgery and 72% of patients with pouchitis carried the allele 2 compared with 45% who did not carry allele 2.20 In contrast, Aisenberg and coworkers reported that carriage of IL-1ra allele 2 was negatively associated with pouchitis.21 These contradictory findings may be due to how pouchitis was defined and the size of the study population.

The presence of antineutrophil cytoplasmic antibodies with a perinuclear staining pattern (pANCA) has been shown to be associated with UC in about 60% of patients but the evidence for the predictive value of pANCA for pouchitis is controversial.17, 22, 23 For example, in a study of 95 patients with UC and serum collected at the time of colectomy, pouchitis occurred in 34% with a median follow-up of 32 months.24 Pouchitis occurred in 42% of those who had pANCA, which was significantly higher compared with 20% who were pANCA negative. When the pANCA titers were stratified into high, medium, and low levels, the cumulative risk of developing chronic pouchitis was 57% for those patients with a high pANCA titer, which was a significantly higher risk than for those patients with medium, low, or absent levels of pANCA. There was no correlation between the three categories of pANCA titers and acute pouchitis.24 In contrast, Aisenberg and coworkers reported that, of 102 patients with UC and IPAA, pouchitis occurred in 49% within 5 years and the prevalence of pANCA was 54% in sera collected following IPAA surgery.21 Neither the presence of pANCA nor the titer of pANCA correlated with pouchitis, though only one patient had a high pANCA titer.21 At this time, pANCA titers measured before or after colectomy can not be considered to be reliable predictors of a risk for pouchitis.

Treatment 

An alteration in the microflora of the fecal content of the ileoanal pouch without specific pathogens being identified has been implicated in the occurrence of pouchitis and has been supported by the successful treatment of pouchitis with antibiotics. There is no correlation between fecal bacterial concentrations and histologic evidence of acute inflammation, although anaerobic bacterial overgrowth is associated with villous atrophy and chronic inflammation of the ileoanal pouch, possibly increasing the susceptibility of clinically evident pouchitis.4, 8, 25 Very few randomized, controlled trials have been reported to validate various therapies.

Metronidazole and ciprofloxacin are the two most commonly used antibiotics to treat pouchitis. In a placebo-controlled, crossover study of 11 patients with active chronic pouchitis there was a 73% response rate to metronidazole compared with 9% of patients given placebo.26 Hurst and coworkers showed that 79% of 52 patients with acute pouchitis responded to treatment with metronidazole, 250 mg three times daily for 7 days, in a noncontrolled, nonrandomized study.27 Another noncontrolled study showed that 11 of 52 patients who did not respond to metronidazole were given ciprofloxacin, 500 mg twice daily, and had a response rate of 73%.28 A randomized trial of 16 patients compared treatment of acute pouchitis with either metronidazole or ciprofloxacin for 2 weeks and showed both drugs reduced PDAI scores but the ciprofloxacin group had a greater reduction of the PDAI score than with metronidazole and with no side effects compared with 33% rate of side effects with metronidazole.29 Adverse side effects of metronidazole include nausea, dyspepsia, metallic taste, abdominal pain, and peripheral neuropathy. A combination of ciprofloxacin, 500 mg twice daily with rifaximin, 1 g twice daily (not available in the US), had a response rate of 88.8% (complete remission or clinical improvement) in patients with chronic or refractory pouchitis.30 Anecdotal evidence suggests that patients with chronic pouchitis may have a sustained remission with a combination of metronidazole and ciprofloxacin, a rotating schedule of antibiotics, or a single dose of metronidazole or ciprofloxacin every 2 or 3 days.

Based on the presumption that pouchitis may be related to an alteration in the intestinal microflora, probiotics have been used to promote a healthy microenvironment and possibly suppress potential pathogenic organisms. Probiotics are live, nonpathogenic organisms, usually bacteria that are normally found in the human intestine. Commercially available preparations include varying quantities of bacteria such as lactobacilli, bifidobacteria, streptococci, Escherichia coli Nissle 1917, and Clostridium butyricum, or yeast such as Saccharomyces boulardii either alone or in combination.31, 32

The beneficial effect of probiotics in the treatment of pouchitis was demonstrated in a placebo-controlled, prospective study of 40 patients with chronic relapsing pouchitis who, following antibiotic therapy, were randomized to receive placebo or 6 g daily of VSL#3® (VSL Pharmaceuticals, Inc., Ft. Lauderdale, FL) for 9 months.33 VSL#3® contains 300 billion viable bacteria per gram of four strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus, and L. delbrueckii subsp. Bulgaricus), three strains of Bifidobacterium (B. longum, B. breve, and B. infantis), and one strain of Streptococcus salivarius subsp. Thermophilus. The relapse rate was 15% in the probiotic-treated group of 20 patients and 100% in the 20 patients given placebo; thus, there was a sustained remission of 85% with probiotic treatment during the 9-month follow-up.33 These encouraging results were extended in another study of 36 patients with recurrent or refractory pouchitis in which 20 patients received 6 g of VSL#3® daily and 16 patients received placebo and were evaluated at 2 and 12 months after randomization.34 Again, remission was maintained for 1 year in 85% of the probiotic-treated group compared with 6% given placebo.34 In an effort to prevent the first episode of pouchitis following IPAA, 20 patients received 9 g of VSL#3® daily and 20 patients were treated with placebo for 1 year.35 Pouchitis occurred in 10% of the probiotic-treated group compared with 40% of those given placebo; thus, VSL#3® appeared to be effective in prophylaxis of acute pouchitis.35 The mechanism by which VSL#3® may be beneficial is unknown but significantly lower levels of mRNA expression of IL-1β, IL-8, and interferon-γ have been found in ileal pouch mucosal biopsies from VSL#3®-treated patients compared with placebo controls, suggesting a modulator effect of the mucosal immune response.36

Other probiotic preparations have been used to prevent the first episode of pouchitis or prevent recurrence. Patients having had IPAA at least 1 year before study were given 108 colony forming units each of lactobacilli and bifidobacteriae in Cultura (TINE Dairies BA, Oslo, Norway) daily for 4 weeks and had a significant decrease in some symptoms as recorded in their diary but not when the answers were obtained by interview.37 Grosselink and coworkers reported that the occurrence of a first episode of pouchitis was significantly less frequent in patients treated daily with 1 to 2 × 1010 Lactobacillus rhamnosus GG in Vifit (Mona, Woerden, The Netherlands) compared with patients who did not receive the probiotic with a cumulative risk of 7% compared with 29%, respectively, at 3 years.38 The control group in this study consisted of patients with IPAA surgery between 1989 and 1996 compared with the probiotic treatment group with surgery between 1996 and 2001.39

Probiotics appear to be effective in preventing the first episode of pouchitis and maintaining remission in chronic pouchitis. Which strains of bacteria or yeast are most effective and at what dose to administer remains to be elucidated.

Quality of Life 

Several tools to measure health-related quality of life (HR QoL) have been used to consistently show that patients with an IPAA have a QoL that is comparable to the general population.14, 17, 40, 41 Patients with a functioning IPAA have reported significantly lower energy levels but otherwise no difference in their HR QoL compared with healthy controls, whereas patients with pouch failure leading to pouch excision had lower QoL scores for physical and social function, energy, and physical role function than either the healthy control population or the patients with a functioning IPAA.14 Shen and coworkers assessed HR QoL in patients with inflammatory conditions of IPAA including Crohn’s disease, pouchitis, and cuffitis, as well as noninflammatory IPS, which has normal mucosa and clinical features of irritable bowel syndrome.42 Patients in all groups had significantly worse QoL scores measured by Cleveland Global QoL and irritable bowel syndrome QoL (IBS QoL) and the IBS QoL scores were significantly worse in the patients with IPS than the pouchitis group.42

Häuser and coworkers reported that patients with UC and IPAA had lower mental and physical HR QoL than the general German population but 94% of 61 patients judged their global HR QoL as slightly better, better, or very much better than before they had an IPAA.41 Extraintestinal manifestation (48%), surgical complications of IPAA, and anxiety had a greater negative effect on HP QoL than pouchitis defined by a PDAI score ≥7.41 A prospective study of 20 patients with IPAA for UC measured HR QoL with Time Trade-Off, Short-Form 36, and Rating Form of IBD Patient Concerns before surgery and 1, 6, and 12 months after takedown of the ileostomy.40 There was a significant improvement in all HR QoL measures after IPAA and the Time Trade-Off scores were significantly improved by 1 month after surgery.40 Hahnloser and coworkers have updated an ongoing, very long-term, prospective assessment of 409 patient 15 years after IPAA for UC and showed no change in social activities, sports, traveling, recreational activities, and family relationships.43 Work was unaffected in 83%. Sexual activity was mildly restricted in 16 and 17%, and severely restricted in 2 and 4% by 10 and 15 years after IPAA, respectively.43

Less information is available regarding the QoL of pediatric patients following an IPAA. Wewer and coworkers recently reported that 27 children and adolescents with a median age of 15 years and median of 3.7 years following IPAA answered a questionnaire assessing overall satisfaction, stool habits, pouch function, and pouchitis.13 Although the questionnaire has not been validated, the results showed that, of those patients who answered, they had a median of six daytime bowel movements and one bowel movement at night. Of the 27 patients, 63% were completely satisfied with the IPAA, 33% were fairly satisfied, and 85% would advise others to have the same operation.13

Overall, it appears that several factors such as EIM, anxiety, pouchitis, and pouch failure negatively impact the HR QoL of patients with IPAA. However the vast majority of patients of all ages with UC requiring surgical treatment have an improved QoL after an IPAA and it is a QoL similar to the general population.