Portal de Periódicos da CAPES

Clinical management of pouchitis

2004; Elsevier BV; Volume: 127; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2004.10.011

1528-0012

William J. Sandborn, Darrell S. Pardi,

Inflammatory Bowel Disease

A 31-year-old man who had an ileoanal J pouch with a hand sewn anastomosis 6 months ago for ulcerative colitis presents with a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort. Up to 25% of patients with ulcerative colitis eventually require colectomy, and the majority of these patients have an ileoanal pouch created. Pouchitis is an idiopathic chronic inflammatory disease, which may occur in the ileal pouch.1Mahadevan U. Sandborn W.J. Diagnosis and management of pouchitis.Gastroenterology. 2003; 124: 1636-1650Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar It is expected that the total number of patients with pouchitis in the United States will eventually reach 30,000–45,000 persons (prevalence of 12–18/100,000 persons).2Sandborn W.J. Pouchitis. Kluwer Academic Publishers, Lancaster, UK1997Google Scholar Pouchitis is therefore emerging as an important third form of inflammatory bowel disease. The differential diagnosis for conditions leading to symptoms of pouch dysfunction is shown in Table 1.3Sagar P.M. Pemberton J.H. Ileo-anal pouch function and dysfunction.Dig Dis. 1997; 15: 172-188Crossref PubMed Scopus (39) Google Scholar The most common cause of pouch dysfunction is pouchitis. The diagnosis of pouchitis is suggested by variable clinical symptoms of increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency and tenesmus, incontinence, and fever. A clinical diagnosis of pouchitis should be confirmed by endoscopy and mucosal biopsy of the pouch.1Mahadevan U. Sandborn W.J. Diagnosis and management of pouchitis.Gastroenterology. 2003; 124: 1636-1650Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Endoscopic examination shows inflammatory changes, which may include mucosal edema, granularity, contact bleeding, loss of vascular pattern, hemorrhage, and ulceration.4Di Febo G. Miglioli M. Lauri A. Biasco G. Paganelli G.M. Poggioli G. Gozzetti G. Barbara L. Endoscopic assessment of acute inflammation of the ileal reservoir after restorative ileo-anal anastomosis.Gastrointest Endosc. 1990; 36: 6-9Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 5Moskowitz R.L. Shepherd N.A. Nicholls R.J. An assessment of inflammation in the reservoir after restorative proctocolectomy with ileoanal ileal reservoir.Int J Colorectal Dis. 1986; 1: 167-174Crossref PubMed Scopus (332) Google Scholar Histologic examination shows acute inflammation, including neutrophil infiltration and mucosal ulceration, superimposed on a background of chronic inflammation, including villous atrophy, crypt hyperplasia, and chronic inflammatory cell infiltration.5Moskowitz R.L. Shepherd N.A. Nicholls R.J. An assessment of inflammation in the reservoir after restorative proctocolectomy with ileoanal ileal reservoir.Int J Colorectal Dis. 1986; 1: 167-174Crossref PubMed Scopus (332) Google Scholar, 6Shepherd N.A. Jass J.R. Duval I. Moskowitz R.L. Nicholls R.J. Morson B.C. Restorative proctocolectomy with ileal reservoir pathological and histochemical study of mucosal biopsy specimens.J Clin Pathol. 1987; 40: 601-607Crossref PubMed Scopus (271) Google Scholar Endoscopic examination of the neoterminal ileum above the ileal pouch should be normal. Patients with pouchitis can be classified according to disease activity, symptom duration, and disease pattern.2Sandborn W.J. Pouchitis. Kluwer Academic Publishers, Lancaster, UK1997Google Scholar Disease activity can be classified as the following: remission (no active pouchitis), mildly to moderately active (increased stool frequency, urgency, infrequent incontinence), or severely active (hospitalization for dehydration, frequent incontinence). Symptom duration can be classified as the following: acute (<4 weeks) or chronic (≥4 weeks). Finally, the disease pattern can be classified as the following: infrequent (1–2 acute episodes), relapsing (≥3 acute episodes), or continuous. The cumulative risk of having 1 or more episodes of pouchitis reaches nearly 50% by 5 years.7Penna C. Dozois R. Tremaine W. Sandborn W. LaRusso N. Schleck C. Ilstrup D. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis.Gut. 1996; 38: 234-239Crossref PubMed Scopus (440) Google Scholar, 8Svaninger G. Nordgren S. Oresland T. Hulten L. Incidence and characteristics of pouchitis in the Kock continent ileostomy and the pelvic pouch.Scand J Gastroenterol. 1993; 28: 695-700Crossref PubMed Scopus (104) Google Scholar The majority of these episodes of pouchitis are acute pouchitis (either infrequent or relapsing pattern), with approximately 5% of patients developing chronic pouchitis.7Penna C. Dozois R. Tremaine W. Sandborn W. LaRusso N. Schleck C. Ilstrup D. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis.Gut. 1996; 38: 234-239Crossref PubMed Scopus (440) Google ScholarTable 1Etiology, Primary Symptoms, Diagnosis, and Treatment of Ileoanal Pouch DysfunctionEtiologyPrimary symptomsDiagnosisTreatmentPouchitisIncreased stool frequencyPouch endoscopy with biopsyAntibioticsCrohn’s diseaseIncreased stool frequencyPouch endoscopy with biopsyAntibioticsAbdominal pain and bloatingSmall bowel x-rayCorticosteroidsPerianal or pouch vaginal fistulasPouchogramBudesonidePelvic MRIAzathioprine6-mercaptopurineMethotrexateInfliximabSpecific infectionIncreased stool frequencyBiopsy for CMVGancyclovirCMVStool for C difficileMetronidazoleC difficileVancomycinPrimary decreased pouch complianceIncreased stool frequencyPouchogramDietExam under anesthesisAnti-diarrheal therapyDecreased pouch compliance secondary to pelvic sepsisIncreased stool frequencyPelvic MRIAntibioticsPouchogramDrainageExam under anesthesisDiversionIrritable pouch syndromeIncreased stool frequencyDiagnosis of exclusion (negative endoscopy, pouchogram, small bowel x-ray)AntispasmodicsAbdominal pain and bloatingAnti-diarrheal therapyFiberCuffitisFecal bleedingPouch/cuff endoscopy with biopsyFecal urgencyTopical mesalamineStrictured anastomosisDifficulty evacuatingPhysical examinationExam under anesthesia with dilationLong efferent limb (S pouch, lateral pouch)Difficulty evacuatingHistorySurgical shortening of spout or pouch revisionPouchogramDecreased pouch emptyingDifficulty evacuatingPouchogramCatheterizationNuclear scintographic emptying studyTap water enemasPelvic floor dysfunctionDifficulty evacuatingAnorectal manometryBiofeedbackPouch strictureDifficulty evacuatingPouch endoscopyExam under anesthesia with dilationIschemic Crohn’s diseasePouchogramTorsionSmall bowel x-rayEndoscopic balloon dilationMesenteric angiogram (rarely indicated)StricturoplastyPouch excisionAdhesionsAbdominal pain and bloatingSmall bowel x-rayExploratory laparotomy with lysis of adhesions Open table in a new tab Other causes of pouch dysfunction include Crohn’s disease, specific infection of the pouch, decreased pouch compliance, irritable pouch syndrome, cuffitis, strictured anastomosis, long efferent limb, decreased pouch emptying, pelvic floor dysfunction, pouch stricture, and adhesions. Approximately 5% of patients with ulcerative colitis who undergo colectomy with ileoanal pouch will eventually have a change in diagnosis to Crohn’s disease.9Hyman N.H. Fazio V.W. Tuckson W.B. Lavery I.C. Consequences of ileal pouch-anal anastomosis for Crohn’s colitis.Dis Colon Rectum. 1991; 34: 653-657Crossref PubMed Scopus (175) Google Scholar, 10Sagar P.M. Dozois R.R. Wolff B.G. Long-term results of ileal pouch-anal anastomosis in patients with Crohn’s disease.Dis Colon Rectum. 1996; 39: 893-898Crossref PubMed Scopus (197) Google Scholar This diagnosis is suspected when the pouch endoscopy shows prepouch ileitis or the patient develops perianal or pouch vaginal fistulas (pouch fistulas should be further evaluated with pelvic MRI and or examination under anesthesia). Infection of the ileoanal pouch with cytomegalovirus (CMV) or Clostridium difficile (C difficile) occur rarely and should be suspected when patients who have endoscopic findings consistent with pouchitis fail to respond to antibiotic therapy.11Munoz-Juarez M. Pemberton J.H. Sandborn W.J. Tremaine W.J. Dozois R.R. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis report of two cases.Dis Colon Rectum. 1999; 42: 117-120Crossref PubMed Scopus (89) Google Scholar, 12Mann S.D. Pitt J. Springall R.G. Thillainayagam A.V. Clostridium difficile infection—an unusual cause of refractory pouchitis report of a case.Dis Colon Rectum. 2003; 46: 267-270Crossref PubMed Scopus (77) Google Scholar The diagnoses of CMV pouchitis or C difficile pouchitis are made by pouch biopsy and stool studies. Decreased pouch compliance typically occurs in patients with previous or ongoing pelvic sepsis and can be diagnosed by digital examination and pelvic MRI.3Sagar P.M. Pemberton J.H. Ileo-anal pouch function and dysfunction.Dig Dis. 1997; 15: 172-188Crossref PubMed Scopus (39) Google Scholar Irritable pouch syndrome is diagnosed in patients with symptoms of pouchitis who have a negative pouch endoscopy.13Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Brzezinski A. Soffer E.E. Remzi F.H. Bevins C.L. Fazio V.W. Irritable pouch syndrome a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis.Am J Gastroenterol. 2002; 97: 877-972Crossref Google Scholar Cuffitis is inflammation of the rectal cuff in patients with a stapled ileoanal pouch; it is diagnosed with endoscopy.14Shen B. Lashner B.A. Bennett A.E. Remzi F.H. Brzezinski A. Achkar J.P. Bast J. Bambrick M.L. Fazio V.W. Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis.Am J Gastroenterol. 2004; 99: 1527-1531Crossref PubMed Scopus (137) Google Scholar Ileoanal anastomotic stricture is diagnosed by digital examination.15Prudhomme M. Dozois R.R. Godlewski G. Mathison S. Fabbro-Peray P. Anal canal strictures after ileal pouch-anal anastomosis.Dis Colon Rectum. 2003; 46: 20-23Crossref PubMed Scopus (83) Google Scholar A functionally obstructed, long efferent limb should be suspected in patients with S pouches or lateral pouches who have obstructive symptoms and is diagnosed by pouchogram. Decreased pouch emptying, pelvic floor dysfunction, and pouch stricture should be considered in patients with bloating symptoms and difficulty evacuating. These conditions are diagnosed by pouchogram, nuclear scintigraphic emptying study, and anorectal manometry.3Sagar P.M. Pemberton J.H. Ileo-anal pouch function and dysfunction.Dig Dis. 1997; 15: 172-188Crossref PubMed Scopus (39) Google Scholar There are few cases in the literature of C difficile enteritis of the ileoanal pouch and no reported cases of bacterial enteric pathogens (bacterial or parasitic). For this reason, there is no utility in ordering these tests in patients presenting for the first time with symptoms of ileoanal pouch dysfunction. Flexible sigmoidoscopy is a useful test in identifying inflammation of the prepouch ileum (which would suggest Crohn’s disease), inflammation of the ileoanal pouch (which would suggest the possibilities of Crohn’s disease, pouchitis, and rarely ischemia and specific infection of the pouch with CMV), and inflammation of the rectal cuff in a patient with a stapled J pouch (which means that 1–2 cm of rectum remains distal to the pouch-anal anastomosis). At a patient’s first endoscopic evaluation for ileoanal pouch dysfunction, biopsies of the pouch for histology should be performed to help establish a diagnosis (see below). Once a diagnosis of pouchitis is established, then repeated biopsies of the ileoanal pouch at the time of future endoscopies are not routinely required. In patients with a stapled J pouch, the rectal cuff should be examined for endoscopic findings of inflammation, which would indicate cuffitis. It should be noted that patients can have both pouchitis and cuffitis simultaneously. The prepouch ileum should be biopsied only if there are apthous ulcers or other endoscopic findings of inflammation to confirm a diagnosis of Crohn’s disease. The finding of inflammation of the pouch seen at endoscopy is nonspecific. Thus, we recommend that biopsy of the pouch be performed at the time of the initial endoscopy to help establish a diagnosis because histology can be helpful in distinguishing among Crohn’s disease, pouchitis, CMV pouchitis, and ischemia. We typically biopsy the pouch, even if the mucosa appears normal at endoscopy because some patients with mildly symptomatic pouchitis may have clear evidence of active acute pouchitis on biopsy with minimal endoscopic findings. Finally, for patients with a stapled ileoanal J pouch, the rectal cuff should be biopsied yearly for dysplasia. For patients with ileoanal pouch dysfunction and evidence of cuffitis at endoscopy, the endoscopic diagnosis of cuffitis can be confirmed with cuff biopsies. Pelvic MRI should be performed if the patient has perianal fistulas or vaginal drainage or pain in the pelvic or perianal region to delineate fistula anatomy and to identify absesses and pelvic sepsis. Perianal and vaginal fistulas may arise from the pouch, which is more consistent with Crohn’s disease, or from the anastomosis itself, which is more compatible with a technical complication from the surgery. Perianal Crohn’s disease may have associated perianal or pelvic abscesses, and an anastomotic fistula may be associated with peripouch pelvic sepsis. A pelvic MRI is not necessary if a patient does not have fistulas or prominent symptoms of pelvic or perianal pain. Pouchogram contrast x-ray is useful in evaluating for Crohn’s disease, a pouch stricture, decreased pouch compliance, a strictured anastomosis, a long efferent limb, and decreased pouch emptying. Crohn’s disease will manifest as fistulas arising from the pouch or stricturing of the pouch seen on pouchogram. Other causes of pouch structuring that can be seen with pouchogram include ischemic damage to the pouch and torsion or kinking of the pouch because of adhesions or surgical misadventure. Decreased pouch compliance (which usually occurs as a result of scarring from prior or ongoing pelvic sepsis) will show a small contracted pouch on pouchgram. Patients with an S pouch or lateral pouch have an efferent limb referred to as a spout. The spout can become elongated and intermittently kink, leading to functional obstruction of the outlet of the pouch. Pouchogram x-ray can be useful in delineating the pouch anatomy and identifying an elongated spout. Some patients will develop decreased pouch emptying, either because the pouch is too large or because possibly because of damage to enteric nerves during pouch construction. A nuclear medicine scintigraphic pouch-emptying study can be used to measure quantitatively the pouch emptying. The typical clinical presentation is difficulty with pouch evacuation. Patients with reduced pouch emptying may benefit from pouch irrigation and possibly pouch reconstruction. A scintigraphic pouch-emptying study is not necessary in a patient who does not complain of difficulty evacuating the pouch. Anorectal manometry can be useful in diagnosing pelvic floor dysfunction. The typical clinical presentation is pelvic pain and difficulty with pouch evacuation. Such patients may benefit from biofeedback therapy. Anorectal manometry is not necessary in a patient who does not complain of significant pelvic pain or difficulty evacuating the pouch. In the past, it was common to make an empiric diagnosis of pouchits in patients with an ileoanal pouch and increased stool frequency. The empiric diagnosis was followed by empiric therapy with antibiotics. This strategy often leads to an incorrect diagnosis of pouchitis in patients who actually have Crohn’s disease, anastomotic stricture, cuffitis, irritable pouch syndrome, and other causes of pouch dysfunction. Because pouchitis tends to reoccur in many patients, it is important to make an accurate diagnosis initially. Thus, empiric therapy is not appropriate in a patient with new onset pouch dysfunction. Once a diagnosis of pouchitis has been established by endoscopy and confirmed by biopsy, it may be reasonable to treat symptomatic relapse with empiric antibiotics, reserving repeat endoscopy for patients who fail to respond to antibiotic therapy. The patient in the case outlined above has a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort. The most likely cause of these symptoms is pouchitis, which is diagnosed by pouch endoscopy with biopsy. Therefore, the recommended management strategy to evaluate this patient with pouch dysfunction is pouch endoscopy with biopsy. Biopsy of the pouch should be performed not only to establish a diagnosis of pouchitis but to exclude other causes of pouch dysfunction. If this management strategy does not lead to a diagnosis, then pouchogram x-ray would be a reasonable next diagnostic step. The patient underwent endoscopy of the ileoanal pouch. An adult gastroscope was used rather than a flexible sigmoidoscope because of its smaller diameter (which allows easier passage across the ileoanal anastomosis) and greater flexibility (which allows easier passage into the prepouch ileum to evaluate for Crohn’s disease). The prepouch ileum had a normal endoscopic appearance. The pouch itself showed patchy friability with multiple apthous ulcers. Biopsies showed acute and chronic inflammation, mucosal ulceration, and villous atrophy. Based on the clinical history and these endoscopic and histologic findings, the patient was diagnosed with acute pouchitis. Specific treatments for pouchitis are outlined in Table 2. Clinical experience has demonstrated that most patients with pouchitis who are empirically treated with metronidazole or ciprofloxacin experience clinical improvement.16Hurst R.D. Molinari M. Chung T.P. Rubin M. Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy.Arch Surg. 1996; 131: 497-502Crossref PubMed Scopus (238) Google Scholar A few small clinical trials have confirmed these observations.17McLeod R.S. Taylor D.W. Cohen Z. Cullen J.B. Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir.Lancet. 1986; 1: 726-728Abstract PubMed Scopus (76) Google Scholar, 18Madden M.V. McIntyre A.S. Nicholls R.J. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis.Dig Dis Sci. 1994; 39: 1193-1196Crossref PubMed Scopus (259) Google Scholar, 19Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Remzi F.H. Brzezinski A. Bevins C.L. Bambrick M.L. Seidner D.L. Fazio V.W. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.Inflamm Bowel Dis. 2001; 7: 301-305Crossref PubMed Scopus (288) Google Scholar, 20Sambuelli A. Boerr L. Negreira S. Gil A. Camartino G. Huernos S. Kogan Z. Cabanne A. Graziano A. Peredo H. Doldan I. Gonzalez O. Sugai E. Lumi M. Bai J.C. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial.Aliment Pharmacol Ther. 2002; 16: 27-34Crossref PubMed Scopus (133) Google Scholar Madden et al treated 13 patients with active chronic pouchitis in a crossover trial of oral metronidazole 400 mg, 3 times daily or placebo for 14 days.18Madden M.V. McIntyre A.S. Nicholls R.J. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis.Dig Dis Sci. 1994; 39: 1193-1196Crossref PubMed Scopus (259) Google Scholar Metronidazole reduced the (mean ± SD) daily stool frequency from 10.0 ± 2.8 to 9.0 ± 5.2, whereas placebo-treated patients had an increase in mean daily stool frequency from 8.9 ± 2.5 up to 10.7 ± 4.1 (P < .05). A second randomized controlled trial by Shen et al compared 2 weeks of treatment with metronidazole 20 mg/kg per day to ciprofloxacin 1000 mg/day in patients with acute pouchitis.19Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Remzi F.H. Brzezinski A. Bevins C.L. Bambrick M.L. Seidner D.L. Fazio V.W. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.Inflamm Bowel Dis. 2001; 7: 301-305Crossref PubMed Scopus (288) Google Scholar Both drugs significantly reduced the pouchitis disease activity index score (0–18 point score), but ciprofloxacin had a greater reduction in overall pouchitis disease activity index score (6.9 ± 1.2 vs. 3.8 ± 1.7, respectively, P = .002), symptom score (2.4 ± 0.9 vs. 1.3 ± 0.9, respectively, P = .03), and endoscopic score (3.6 ± 1.3 vs. 1.9 ± 1.5, respectively, P = .03) vs. metronidazole. A third randomized controlled trial comparing metronidazole 1000 mg/day and budesonide enemas 2 mg/day is described below.20Sambuelli A. Boerr L. Negreira S. Gil A. Camartino G. Huernos S. Kogan Z. Cabanne A. Graziano A. Peredo H. Doldan I. Gonzalez O. Sugai E. Lumi M. Bai J.C. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial.Aliment Pharmacol Ther. 2002; 16: 27-34Crossref PubMed Scopus (133) Google Scholar The most commonly used antibiotic for pouchitis is metronidazole.16Hurst R.D. Molinari M. Chung T.P. Rubin M. Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy.Arch Surg. 1996; 131: 497-502Crossref PubMed Scopus (238) Google Scholar, 17McLeod R.S. Taylor D.W. Cohen Z. Cullen J.B. Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir.Lancet. 1986; 1: 726-728Abstract PubMed Scopus (76) Google Scholar, 18Madden M.V. McIntyre A.S. Nicholls R.J. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis.Dig Dis Sci. 1994; 39: 1193-1196Crossref PubMed Scopus (259) Google Scholar, 19Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Remzi F.H. Brzezinski A. Bevins C.L. Bambrick M.L. Seidner D.L. Fazio V.W. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.Inflamm Bowel Dis. 2001; 7: 301-305Crossref PubMed Scopus (288) Google Scholar, 20Sambuelli A. Boerr L. Negreira S. Gil A. Camartino G. Huernos S. Kogan Z. Cabanne A. Graziano A. Peredo H. Doldan I. Gonzalez O. Sugai E. Lumi M. Bai J.C. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial.Aliment Pharmacol Ther. 2002; 16: 27-34Crossref PubMed Scopus (133) Google Scholar The main alternative to metronidazole is ciprofloxacin.16Hurst R.D. Molinari M. Chung T.P. Rubin M. Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy.Arch Surg. 1996; 131: 497-502Crossref PubMed Scopus (238) Google Scholar, 19Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Remzi F.H. Brzezinski A. Bevins C.L. Bambrick M.L. Seidner D.L. Fazio V.W. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.Inflamm Bowel Dis. 2001; 7: 301-305Crossref PubMed Scopus (288) Google Scholar Most patients with pouchitis will have symptomatic improvement after 1 or 2 days of therapy with metronidazole at doses of 750–1500 mg/day. Patients with a clinical course of relapsing or chronic pouchitis may need continuous maintenance treatment with metronidazole at doses ranging from 250 mg every third day up to 750 mg/day. Adverse effects occurred in 33%–55% of patients during metronidazole treatment, including nausea, vomiting, abdominal discomfort, headache, and skin rash.18Madden M.V. McIntyre A.S. Nicholls R.J. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis.Dig Dis Sci. 1994; 39: 1193-1196Crossref PubMed Scopus (259) Google Scholar, 19Shen B. Achkar J.P. Lashner B.A. Ormsby A.H. Remzi F.H. Brzezinski A. Bevins C.L. Bambrick M.L. Seidner D.L. Fazio V.W. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.Inflamm Bowel Dis. 2001; 7: 301-305Crossref PubMed Scopus (288) Google Scholar, 20Sambuelli A. Boerr L. Negreira S. Gil A. Camartino G. Huernos S. Kogan Z. Cabanne A. Graziano A. Peredo H. Doldan I. Gonzalez O. Sugai E. Lumi M. Bai J.C. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial.Aliment Pharmacol Ther. 2002; 16: 27-34Crossref PubMed Scopus (133) Google ScholarTable 2Treatments Reported to be Beneficial for PouchitisClass exampleAntibioticsMetronidazoleCiprofloxacinAmoxicillin/clavulanic acidErythromycinTetracyclineRifaximin + tetracyclineMetronidazole + ciprofloxacinProbiotic bacteriaLactobacilli, Bifidobacteria, S thermophilusE coli Nissle 19175-AminosalicylatesMesalamine enemasSulfasalazineOral mesalamineCorticosteroidsConventional corticosteroid enemasBudesonide suppositoriesBudesonide enemasOral corticosteroidsImmune modifier agentsCyclosporin enemasAzathioprine, 6-mercaptopurineInfliximabNutritional agentsSCFA enemas or suppositoriesGlutamine suppositoriesDietary fiber (pectin, methylcellulose, inulin)Oxygen radical inhibitorsAllopurinolAntidiarrheal/antimicrobialBismuth carbomer enemasBismuth subsalicylateNOTE. Modified with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636–1650.SCFA, short chain fatty acid. Open table in a new tab NOTE. Modified with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636–1650. SCFA, short chain fatty acid. Recent studies have demonstrated that altering pouch bacterial contents by administering probiotic bacteria can be an effective therapeutic strategy. Three controlled trials have been performed.21Gionchetti P. Rizzello F. Venturi A. Brigidi P. Matteuzzi D. Bazzocchi G. Poggioli G. Miglioli M. Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 305-309Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 22Mimura T. Rizzello F. Helwig U. Poggioli G. Schreiber S. Talbot I.C. Nicholls R.J. Gionchetti P. Campieri M. Kamm M.A. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.Gut. 2004; 53: 108-114Crossref PubMed Scopus (780) Google Scholar, 23Gionchetti P. Rizzello F. Helwig U. Venturi A. Lammers K.M. Brigidi P. Vitali B. Poggioli G. Miglioli M. Campieri M. Prophylaxis of pouchitis onset with probiotic therapy a double-blind, placebo-controlled trial.Gastroenterology. 2003; 124: 1202-1209Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar Gionchetti et al randomized 40 patients with chronic pouchitis in remission (after induction therapy with antibiotics) to treatment with either an oral probiotic preparation (2, 3-gram bags of VSL-3, each containing 300 billion viable lyophilized bacteria per gram) or placebo for 9 months.21Gionchetti P. Rizzello F. Venturi A. Brigidi P. Matteuzzi D. Bazzocchi G. Poggioli G. Miglioli M. Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 305-309Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar The VSL-3 preparation contained viable lyophilized bacteria including the following: 4 strains of lactobacilli (L acidophilus, L delbrueckii subsp. bulgaricus, L plantarum, L casei), 3 strains of bifidobacteria (B infantis, B longum, B breve), and 1 strain of Streptococcus salivarius subsp. thermophilus. At 9 months, the relapse rate was 15% in the VSL-3 group and 100% in the placebo group (P < .01). In a second controlled trial, 36 patients with recurrent or refractory pouchitis were treated with antibiotics and then randomized to maintenance therapy with VSL-3 or placebo for 1 year. The relapse rates were 10% in the VSL-3 group and 94% in the placebo group, P < .0001.22Mimura T. Rizzello F. Helwig U. Poggioli G. Schreiber S. Talbot I.C. Nicholls R.J. Gionchetti P. Campieri M. Kamm M.A. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.Gut. 2004; 53: 108-114Crossref PubMed Scopus (780) Google Scholar In a controlled trial, patients undergoing colectomy and ileoanal pouch were randomized to prophylactic therapy with VSL-3 or placebo for 1 year.23Gionchetti P. Rizzello F. Helwig U. Venturi A. Lammers K.M. Brigidi P. Vitali B. Poggioli G. Miglioli M. Campieri M. Prophylaxis of pouchitis onset with probiotic therapy a double-blind, placebo-controlled trial.Gastroenterology. 2003; 124: 1202-1209Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar The rate of developing pouchitis during the first year was 10% in the VSL-3 group and 40% in the placebo group, P < .05. Of interest, the VSL-3 appeared to reduce the mean stool frequency of asymptomatic patients as well. Uncontrolled studies have reported that oral and rectal corticosteroids may be clinically beneficial in patients with active pouchitis.24Shepherd N.A. Hulten L. Tytgat G.N. Nicholls R.J. Nasmyth D.G. Hill M.J. Fernandez F. Gertner D.J. Rampton D.S. Owen R.W. Kmist W.A. Keighley M.R.B. O’Connell P.R. Kumar D. Williams N.S. Pouchitis.Int J Colorectal Dis. 1989; 4: 205-229Crossref PubMed Scopus (149) Google Scholar, 25Tytgat G.N. van Deventer S.J. Pouchitis.Int J Colorectal Dis. 1988; 3: 226-228Crossref PubMed Scopus (71) Google Scholar, 26Scott A.D. Phillips R.K. Ileitis and pouchitis after colectomy for ulcerative colitis.Br J Surg. 1989; 76: 668-669Crossref PubMed Scopus (57) Google Scholar A randomized, placebo controlled trial of 2 mg budesonide enemas vs. metronidazole showed similar efficacy for budesonide and metronidazole.20Sambuelli A. Boerr L. Negreira S. Gil A. Camartino G. Huernos S. Kogan Z. Cabanne A. Graziano A. Peredo H. Doldan I. Gonzalez O. Sugai E. Lumi M. Bai J.C. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial.Aliment Pharmacol Ther. 2002; 16: 27-34Crossref PubMed Scopus (133) Google Scholar Twenty-six patients with acute pouchitis were randomized to either budesonide enemas or oral metronidazole 500 mg twice daily for 6 weeks. Fifty-eight percent of budesonide patients and 50% of metronidazole patients improved. Fifty-seven percent of metronidazole patients had adverse events vs. only 25% of budesonide patients. Unpublished clinical experience suggests that oral, controlled-release budesonide 9 mg/day is also of clinical benefit for pouchitis. An algorithm of the approach to treatment of pouchitis is shown in Figure 1. Patients with acute pouchitis are treated with metronidazole or ciprofloxacin. Patients who experience frequent relapses of pouchitis and patients with chronic pouchitis will require long-term maintenance therapy with antibiotics or probiotics. In practice, we would institute maintenance therapy for patients who relapse at least 3 times within 1 year or within 1 month of discontinuation of antibiotics. Among patients receiving maintenance antibiotics who develop loss of clinical benefit after prolonged treatment, rotation of 3 or 4 antibiotics in 1-week intervals may be beneficial. Those patients who do not respond to metronidazole or other antibiotics can be treated with rectal or oral budesonide. Other treatment options may include rectal therapy with mesalamine enemas or suppositories and oral therapy with sulfasalazine or mesalamine, rectal or oral steroids, and possibly azathioprine or 6-mercaptopurine, or infliximab. Some patients may require combination therapy with multiple agents. There is little evidence to support therapy with short-chain fatty acid enemas, glutamine suppositories, inulin, or allopurinol. A minority of patients will be unresponsive to all medical therapy. These patients should be referred to a colorectal surgeon for consideration of permanent ileostomy with pouch exclusion or excision. The evidence-based treatment options for this patient include metronidazole, ciprofloxacin, and budesonide. Although there is more overall experience with metronidazole, we prefer ciprofloxacin because it has a more favorable toxicity profile. In this patient, we would use ciprofloxacin 500 mg orally twice daily for 14 days and then discontinue therapy. Patients with pouch dysfunction should be evaluated with ileoanal pouch endoscopy and biopsy before a diagnosis of pouchitis is made. Small controlled trials have reported superior efficacy of metronidazole compared with placebo and similar efficacy for metronidazole compared with both ciprofloxacin and budesonide enemas for active chronic pouchitis. Three somewhat larger placebo-controlled trials reported that probiotic bacteria are effective for maintaining remission in patients with chronic pouchitis and for preventing the onset of pouchitis after colectomy with ileoanal pouch. Some patients with chronic pouchitis require maintenance therapy with antibiotics or probiotics, and some will require permanent ileostomy with pouch exclusion or excision.