Pouchitis: What Every Gastroenterologist Needs to … What Every Gastroenterologist Needs to Know...

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1538–1549

Pouchitis: What Every Gastroenterologist Needs to Know

BO SHEN

Department of Gastroenterology/Hepatology, Digestive Disease Institute, The Cleveland Clinic Foundation, Cleveland, Ohio

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Pouchitis is the most common complication among pa-tients with ulcerative colitis who have undergone restor-ative proctocolectomy with ileal pouch–anal anastomosis.Pouchitis is actually a spectrum of diseases that vary inetiology, pathogenesis, phenotype, and clinical course. Al-though initial acute episodes typically respond to antibiotictherapy, patients can become dependent on antibiotics ordevelop refractory disease. Many factors contribute to thecourse of refractory pouchitis, such as the use of nonsteroi-dal anti-inflammatory drugs, infection with Clostridium dif-ficile, pouch ischemia, or concurrent immune-mediated dis-orders. Identification of these secondary factors can helpdirect therapy.

Keywords: Ileal Pouch; Pouchitis; Restorative Proctocolectomy;Ulcerative Colitis.

The past decade has witnessed a rapid process in the med-ical treatment for ulcerative colitis (UC), particularly the

vailability and a wide use of anti–tumor necrosis factor (TNF)iological agents.1 Although the medical community has antic-

pated that the advance in pharmaceutical therapy may have anmpact on the disease course of UC, by reducing the need forolectomy,2 the long-term efficacy of the biological agents is

still unclear. On the other hand, restorative proctocolectomywith ileal pouch–anal anastomosis (IPAA) has become the sur-gical treatment of choice for the majority of patients with UC orfamilial adenomatous polyposis (FAP) who require colectomy.

Over the years, various forms of the ileal pouch configura-tion have been developed, ranging from Kock pouch (alsoknown as K or continent ileostomy), S pouch, to W or J pouches(Figure 1). One pouch configuration may offer technical advan-tages over the other. For example, UC patients with a poor analsphincter function may elect to have a K pouch after colectomy.Obese UC patients with a short mesentery may be chosen tohave an S pouch after colectomy because this particular pouchconfiguration offers an additional 2 to 2.5 cm of small bowel, asan efferent limb, to reach the anal canal. The W pouch, whichwas designed in the 1980s, largely has been abandoned becauseof its frequent complications. The choice between the variousforms of ileal pouches depends on the following: (1) indicationfor colectomy (colitis-associated neoplasia vs refractory UC); (2)mucosectomy vs no mucosectomy; and (3) technical feasibility(body mass index, length of mesentery, and pathology of theanal canal or rectal stump). Currently, the most commonlyperformed ones are J and S pouches.

The pouch procedure has been shown to improve patients’health-related quality of life significantly and to reduce the risk
for colitis-associated neoplasia. On the other hand, various
complications from the pouch surgery have been reported,ranging from procedure-associated leaks, strictures, sinuses, orfistulae, to pouchitis, cuffitis, and de novo Crohn’s disease(CD)-like conditions of the pouch and irritable pouch syn-drome (IPS).

Pouchitis is the most common complication in UC patientswith IPAA, with a reported cumulative prevalence ranging from23% to 46%,3– 6 and an annual incidence up to 40%.7 Oralantibiotic therapy has been the mainstay treatment for patientswith pouchitis based on the current theory that the inflamma-tion at the ileal pouch reservoir results from or is triggered bythe alteration in the composition of microbiota. However, wehave encountered an increasing number of patients withpouchitis who initially responded to antibiotic therapy anddeveloped refractory disease later on. The management ofchronic antibiotic-refractory pouchitis (CARP) has been chal-lenging and, in fact, chronic pouchitis is one of the mostcommon causes for pouch failure, defined as permanent diver-sion, pouch excision, or complete pouch revision.8

Etiology and PathogenesisMounting evidence suggests that gut microbiota play a

key role in the initiation and disease progression of pouchitis.The contribution of gut microbiota to the pathogenesis ofpouchitis may be 2-fold: the alteration in commensal bacteria(ie, dysbiosis)9 –12 and the emergence of pathogenic bacteria,fungi, or viruses (such as Clostridium difficile13). The role of

acterial diversity or dysbiosis in the pathogenesis of pouchitiss not entirely clear, as it is in the field of inflammatory bowelisease (IBD).14 The construction of the ileal reservoir leads ton altered bowel anatomy that can promote fecal stasis andolonic metaplasia in the pouch body from the original ilealucosa, creating an environment favorable to the development

f inflammation. It is intriguing that certain bacterial species,uch as Bacteriodaceae species and Clostridiaceae species, werehown to be associated with inflammation of the pouch mu-osa, whereas others, such as Enterococcaceae species, may haven active role in maintaining immunologic homeostasis in the

Abbreviations used in this paper: CARD15, caspase recruitmentdomain family, member 15; CARP, chronic antibiotic-refractorypouchitis; CD, Crohn’s disease; CDI, Clostridium difficile infection;CMV, cytomegalovirus; FAP, familial adenomatous polyposis; IBD, in-flammatory bowel disease; IL, interleukin; IPAA, ileal pouch-anal anas-tomosis; IPS, irritable pouch syndrome; NOD2, nucleotide-binding oli-gomerization domain containing 2; NSAID, nonsteroidal anti-inflammatory drug; PSC, primary sclerosing cholangitis; TNF, tumornecrosis factor; UC, ulcerative colitis.

© 2013 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2013.03.033

http://dx.doi.org/10.1016/j.cgh.2013.03.033

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December 2013 POUCHITIS 1539

pouch mucosa.15 Unfortunately, even with the state-of-the-artmolecular microbiology technology, no individual species orphylotypes have been shown consistently to be related specifi-cally to pouchitis.12,16 Potential candidate bacterial species re-ated to pouchitis may include Lachnospiraceae, Incertae Sedis XIV,nd Clostridial cluster IV.17

Pathogen-associated pouchitis can occur in a subset of pa-tients. C difficile infection (CDI) is common in symptomaticpatients with IPAA, with either enzyme immunoassay (EIA)13 orpolymerase chain reaction (PCR)18-based assays. Patients who

ere positive for C difficile after IPAA had a wide spectrum oflinical presentations, ranging from being asymptomatic carri-rs (with colonization) to those with fatal outcomes.19 Otherathogens have been reported to be associated with episodes ofctive pouchitis, including C perfringens,9 Campylobacter spe-ies,20 group D streptococci (Enterococcus species),21 hemolytictrains of E coli,22 and cytomegalovirus (CMV)23,24 infection.hese pathogenic microbes detected in pouchitis patients with

ystemic symptoms may contribute to disease episodes or beesponsible for a refractory course to conventional antibioticherapy.

The alteration in both innate and adaptive mucosal immu-ity in the noninflamed pouch and pouchitis has been studiedxtensively.25–30 Different bacterial species may exert different

impacts on innate and adaptive mucosal immune function.15,31

Fecal stasis, the increased microbial load, and constant expo-sure to lumen contents might collectively cause adaptive mor-phologic alterations in the pouch mucosa that mimic colonicmetaplasia.32 Colonic metaplasia seems to be associated withdysbiosis, particularly the presence of sulfate-reducing bacte-ria.33 Alterations in mucin glycoproteins, similar to those seenin UC, also occur in pouchitis.34 Altered glycoproteins are moreusceptible than the native molecules to enzymatic degradationy microbiota with the breach of mucosal barrier function.35 An

ncreased permeability of the gastrointestinal mucosa to micro-iota was observed in the ileal pouch.25 Aberrant expression of

Toll-like receptors have been found in the ileal pouches ofpatients with and without pouchitis.31,36,37 Antimicrobial pep-ides produced by intestinal Paneth cells and other gut epithe-ial cells are important components of innate immunity in the

Figure 1. Configurations andanatomy of various ileal pouches.

astrointestinal tract.38 – 40 The expression of Paneth-cell–

specific human defensin-5 is increased in both inflamed andnoninflamed pouches compared with that in the normal termi-nal ileum.41,42 The findings suggest that innate mucosal immu-

ity actively is involved in both normal adaptation to fecaltasis/bacterial overload and the development of pouchitis.

Adaptive mucosal immunity also has been studied inouchitis for the past 2 decades. There was an increased pro-

iferation of immature plasma cells in pouchitis.29,30,43 Thereas also an increased production of proinflammatory media-

ors/cytokines, such as TNF,44 – 47 cell adhesion molecules,48

platelet-activating factor,49 lipoxygenase products of arachi-onic acids,50,51 vascular endothelial growth factor,51 and pro-

nflammatory neuropeptides.45,52–54 UC pouches were shown tohave higher levels of proinflammatory cytokines than that ofFAP pouches.55 Imbalance between proinflammatory (such asnterleukin [IL]-8) and immunoregulatory (such as IL-10) cyto-ines may contribute to the inflammatory process of pouchi-is.47 However, the abnormalities in adaptive mucosal immunity

probably reflect activation of a nonspecific inflammatory cas-cade or pathway.45 Nonetheless, the up-regulation of the pro-inflammatory mediators may provide therapeutic targets, par-ticularly in CARP.

Risk FactorsIn addition to gut microbiota and mucosal immunity,

genetic, vascular, and luminal factors (such as nonsteroidalanti-inflammatory drugs [NSAIDs]) are likely to contribute tothe initiation, exacerbation, and progression of pouchitis.Pouchitis almost exclusively occurs in patients with restorativeproctocolectomy with underlying IBD and rarely in those withFAP, suggesting the contribution of genetic and/systemic fac-tors to its pathogenesis. Immunogenetic studies showed thatgenetic polymorphisms such as those of IL-1–receptor antago-nist,56 nucleotide-binding oligomerization domain containing

/caspase recruitment domain family, member 15 (NOD2/ARD15),57,58 or a combined carriership of Toll-like receptor-1237C and CD14-260T alleles,59 were associated with the risk

for chronic pouchitis. Mutations of NOD2/CARD15 and
TNFSF15 also were shown to be related to severe pouchitis.60

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1540 BO SHEN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 12

Gastrointestinal, systemic, or environmental risk factors re-ported to be associated with pouchitis include extensive UC,61,62

the presence of backwash ileitis,61,63 precolectomy thrombocy-tosis,64 the presence of concurrent primary sclerosing cholan-

itis (PSC)63,65,66 or other immune-mediated disorders,67 being aonsmoker,62,68 the regular use of NSAIDs,62,66 and ischemia.69

Systemic immune reactions to bacterial antigens as well ashost’s self-tissue also have been studied in pouchitis. Reportedpouchitis-related serology markers include perinuclear antineu-trophil cytoplasmic antibodies,6,63,70,71 anti-CBir1 flagellin,6

IgG4,72 and microsomal antibodies.73

It should be pointed out that pouchitis represents a diseasespectrum from an acute antibiotic-responsive form to a chronicantibiotic-refractory phenotype. Different phenotypes of pouchitismay reflect the same disease process at different stages or differentdisease processes with various etiopathogenetic pathways. Assuch, acute and chronic pouchitis may be associated withdifferent risk factors.62 For example, smoking was associated

ith acute pouchitis,6 whereas extraintestinal manifesta-tions,6 preoperative thrombocytosis, a long duration ofPAA,6 and postoperative surgery-related complications,74

were reported to be associated with chronic pouchitis. Smok-ing appears to be a protective factor against the developmentof chronic pouchitis.75 Patients with CARP, not acutepouchitis, were reported to be associated with concurrentautoimmune disorders.67

Diagnosis and Differential DiagnosisThe diagnosis of pouchitis is not always straightfor-

ward because of the lack of specific symptoms and signs. Pa-tients with healthy pouches are expected to have 4 to 7 softbowel movements a day, with continence. Patients with pouchi-tis can have a wide range of clinical presentations, ranging fromincreased stool frequency, urgency, abdominal cramps, nighttime seepage, to incontinence. These symptoms, however, arenot specific and they can be present in other inflammatory andnoninflammatory disorders of the pouch. Furthermore, theseverity of subjective symptoms does not correlate with theobjective degree of objective inflammation on endoscopy or onhistology.76,77 Therefore, the diagnosis of pouchitis should notbe dependent solely on the symptom assessment. To complicatethe matter further, the diagnosis of pouchitis may resemblehitting a moving target because the disease process of pouchitisand other pouch disorders may not be static. For example, apatient who has typical acute antibiotic-responsive pouchitis asan initial presentation may later develop CD of the pouch.Therefore, a combined assessment of symptoms, endoscopicfeatures, and histologic features is advocated for the diagnosisand differential diagnosis of pouchitis.76,78 Several diagnosticinstruments have been proposed for the diagnosis of pouchitisand grading of severity. Among them is the 18-point PouchitisDisease Activity Index consisting of symptom, endoscopy, andhistology subscores,78 which has been the most commonly used,mainly as a research tool. The endoscopy is the most accurate tograde the degree of inflammation.

Differential diagnosis. Various inflammatory andfunctional disorders of the pouch share similar clinical presen-tations with pouchitis. Among them are IPS, cuffitis, CD of thepouch, and fecal incontinence from anal sphincter damage. IPS,by definition, is featured with clinical symptoms of diarrhea,
cramps, and urgency, in the absence of endoscopic or histologic s
inflammation of the pouch. Currently, IPS is a diagnosis ofexclusion, although evaluation with a barostat examinationyields evidence of visceral hypersensitivity in patients.79 Cuffitis,which is considered a variant of ulcerative proctitis, typicallycauses urgency and blood in stools. De novo CD of the pouchcan occur in patients with a preoperative diagnosis of UC. It has3 phenotypes: inflammatory, fibrostenotic, and fistulizing.Pouch body inflammation can be a part of CD.

Endoscopic evaluation. It is important to correctlyidentify the landmarks of J, S, and K pouches during endo-scopic and radiographic evaluation. The characteristic land-marks include the afferent limb, pouch inlet, the tip of J (in Jpouch), efferent limb (which are different between J and Spouches), and the pouch outlet (the anal transitional zone orrectal cuff for J and S pouches or the nipple valve for a K pouch)(Figure 1).

Pouchoscopy is the most valuable tool for the diagnosis anddifferential diagnosis of pouchitis. A careful pouchoscopyshould include the evaluation of the earlier-described land-marks, including the afferent limb, pouch inlet, the tip of the J,pouch body, anastomosis, and anal transitional zone or cuff(Figure 2A). Sedated or nonsedated pouchoscopy provides themost valuable information on the configuration and distensi-bility of the pouch body, severity, extent, or distribution ofmucosal inflammation (Figures 2 and 3), and the presence ofconcurrent backwash ileitis, cuffitis, or inflammatory polyps.The presence of a mucosal ridge, inflammatory polyps (Figure2D), poorly distensible or pouch body (Figure 2B), or the loss ofthe “owls’ eye” configuration of a J pouch (Figure 2A),80 sug-gests chronic inflammation. Immune-mediated pouchitis, suchas those associated with PSC or autoimmune disorders, andIgG4-associated pouchitis, often has concurrent long segmentinflammation at the afferent limb in addition to diffuse pouchi-tis (Figure 3B and C). Asymmetric distribution of inflammationin the pouch body may be a sign of ischemic pouchitis. Typi-cally, inflammation in ischemic pouchitis is present only at thedistal half to quarter of the pouch body or at one limb of thepouch body, sparing the rest of the pouch, with a sharp demar-cation of inflamed and noninflamed parts of pouch body (Fig-ure 2C).69

Pouchoscopy is also a major modality for the diagnosis ofCD of the pouch and surgery-related complications (such asstricture, fistula, sinus [Figure 3D], and prolapse).81 Patients

ith CD of the pouch typically have segmental inflammation ofhe pouch body and/or afferent limb, strictures at the pouchnlet or afferent limb, the presence of complex perianal fistulasr pouch-vaginal fistulas with an internal fistular orifice at thenal canal (rather than at the dentate line for cryptoglandularstula or at the anastomosis for surgical leak).

Abdominal/pelvic imaging. Abdominal imaging isn important part of the evaluation for the diagnosis andifferential diagnosis of ileal pouch disorders. Pouchitis can beresent alone or with other concurrent inflammatory or me-hanical/structural complications (such as stricture, sinus, orstula). In fact, pouch inflammation can be a part of CD. Aater-soluble contrast pouchogram often is used to delineate

he pouch shape and anatomy and the presence of luminalngulation, stricture, sinus, or fistula. Computed tomographynterography or magnetic resonance imaging enterography isseful for the evaluation of the location, number, and degree of
trictures, the presence of an abscess, or the presence of inflam-

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mation of the pouch as well as the proximal small bowel.Contrast pelvic magnetic resonance imaging with fistula proto-col is valuable for the evaluation of the anatomy and abnor-malities around the pouch body and anal transitional zone,such as fistula, sinus, abscess, and presacral sinus-associatedosteomyelitis. Anorectal ultrasound often is useful in the de-tection of anal sphincter injury, sinus, or fistula. In addition,examination under anesthesia in the operating room may beneeded in complex pouch disorders (Figure 4).81

Histologic evaluation. Histology may have a limitedrole in grading acute or chronic inflammation of the pouchbecause it does not correlate with the more robust endoscopyscoring system. However, histologic evaluation provides valu-able information on special features, such as granulomas, viralinclusion bodies (for CMV infection), pyloric gland metaplasia(a sign of chronic mucosal inflammation),82 and dysplasia, andthe presence of excessive crypt apoptosis (a sign of autoimmuneenteritis)83 or IgG4-expressing plasma cells in the laminapropria.84

Laboratory evaluation. Laboratory testing is oftennecessary as a part of the evaluation for patients with pouchdisorders, particularly in those with chronic pouchitis. Patientswith healthy or diseased pouches often have iron-deficiencyanemia85 and/or a low vitamin D level.86,87 Pouch patients witha cholestatic picture on the liver function panel, such as anincrease of alkaline phosphatase, should be investigated for the

Figure 2. Normal pouch andpouchitis of various etiologies onendoscopy. (A) Normal pouchwith an owls’ eye configuration,reflecting a widely openedpouch inlet and the tip of a J. (B)Chronic pouchitis with ulcersand a stiff pouch. (C) Pouchitiswith an ischemic pattern, with in-flammation at the afferent limbside, and normal mucosa at theefferent limb side of the J pouch,with sharp demarcation of in-flammation and noninflamedparts along the suture line. (D) Alarge pouch inflammatory polypresulting from chronic mucosalinflammation.

presence of PSC. In patients with persistent symptoms, a stool

test for CDI should be performed.88 For the majority of patientswith a repeated or chronic exposure to antibiotics, CDI hasbeen a growing problem.13 For patients with systemic symp-oms, such as chills, fever, and night sweats, a fecal assay forther intestinal pathogens (such as Campylobacter species) and alood or tissue assay for CMV or Epstein–Barr virus infectionay be needed.In patients with chronic pouchitis, fecal coliform culture and

ensitivity testing could help to identify effective antibioticgents.89 For patients with CARP, other etiologies need to be

evaluated; in particular, one must look for the components ofautoimmunity. The serology panel may include celiac tests,antinuclear antigens, serum IgG4 level,72 and antimicrosomal

ntibodies.73 Fecal assays of lactoferrin90 –92 and calprotectin93

have been investigated for the diagnosis and differential diag-nosis of pouchitis. They may have some value in the assessmentof treatment outcome (eg, mucosal healing). Genetic testingand IBD serology have been shown to provide useful informa-tion on the pathogenesis and prognosis of pouch disorders andIBD. However, the role of current available genetic and sero-logic profiles in the diagnosis and differential diagnosis ofpouchitis is limited.

Classification and Disease CoursePouchitis represents a disease spectrum, with ranging

pathogenetic pathways, clinical presentations, and disease
courses. Clinically, the treatment for different phenotypes of

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pouchitis is not the same. Initial episodes of pouchitis in themajority of patients respond favorably to therapy with oralbroad-spectrum antibiotics such as metronidazole, cipro-floxacin,94 and tinidazole. According to the duration of

Figure 4. Diagnostic algorithmor recurrent pouchitis. ANA, an-inuclear antibody; LFT, liver
unction test.
ouch-related symptoms, pouchitis can be classified intocute (�4 wk) and chronic (�4 wk) forms. Based on theesponse to and frequency of antibiotic therapy, pouchitisan be categorized into antibiotic-responsive, antibiotic-

Figure 3. Pouchitis of variousetiologies on endoscopy. (A)Chronic pouchitis with concur-rent distal pouch sinus (arrow).(B and C) Diffuse pouchitis andenteritis with a similar mucosapattern in a patient with PSC. (D)Chronic pouchitis with C difficileinfection.

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dependent, and antibiotic-refractory phenotypes. Based onthe etiology, pouchitis also can be divided into idiopathicand secondary (such as NSAID-induced, ischemia-related,and CMV-associated) entities. Sometimes, the terminologycombining the earlier-described features is used to charac-terize certain types of pouchitis, such as chronic antibiotic-refractory pouchitis (CARP).

The timing of the initial onset of pouchitis may suggestits etiology. In our anecdotal experience, pouchitis, whichoccurs immediately after ileostomy closure, may result fromprocedure-associated complications, such as ischemia oranastomotic leaks. On the other hand, the late initial onsetof pouchitis (ie, onset occurring years after pouch construc-tion), can be related to systemic or local factors, such asexcessive weight gain.95

The natural history of pouchitis may follow the diseasecourse of IBD, progressing from an acute disease of bacterialetiology to a chronic disease with persistent inflammation fromdysregulated immunity. For example, acute, antibiotic-respon-sive pouchitis may evolve into CARP. The disease course variesbetween affected individuals. Approximately 40% of patientswith acute pouchitis who have a single episode responding toantibiotic therapy may never have recurrence.96 However, re-lapse of pouchitis or recurrent pouchitis is common; however,in this study, the remaining 60% had at least one subsequentrelapse. It is estimated that 5% to 19% of patients with acutepouchitis develop refractory pouchitis or a frequently relapsingform of the disease.97–99 CARP is one of the common causes forpouch failure, resulting in permanent diversion or pouch exci-sion.

ManagementPouchitis patients often benefit from low-carbohydrate

and/or low-fiber diets. Its rationale is the presence of small-bowel bacterial overgrowth from the lack of valve function at

able 1. Controlled Trials in Pouchitis

Study Study design N Indication

adden et al,105

1994RCT 13 Treatment of chronic

pouchitis

Gionchetti et al,111

2000RCT, placebo-

controlled40 Secondary prophylaxis o

relapsing pouchitis

Shen et al,200194

RCT 16 Treatment of acute antiresponsive pouchitis

ionchetti et al,7

2003RCT, placebo-

controlled40 Primary prophylaxis of

pouchitis

Mimura et al,112

2004RCT, placebo-

controlled36 Secondary prophylaxis o

relapsing pouchitis

Isaacs et al,104

2007RCT, placebo-

controlled18 Treatment of active pou

PDAI, Pouchitis Disease Activity Index (range, 0–18 points); RCT, ranaVSL#3 contains 4 strains of Lactobacillus (L casei, L plantarum,

ifidobacterium (B longum, B breve, and B infantis), and 1 strain of

the junction between the afferent limb and pouch body. An

elemental diet has been shown to help relieve symptoms ofchronic pouchitis.100 Antidiarrheal agents can be used for thereatment of frequent and/or loose/watery bowel movements.

Primary prophylaxis of initial episodes of pou-hitis. Primary prophylaxis of the initial episodes of pouchitisfter ileostomy closure, using probiotic or antibiotic agents, haseen investigated. In a randomized trial of a probiotic agent,alled VSL#3 (containing Lactobacillus species, Bifidobacterium

species, Streptococcus salivarius species, and Thermophilus species)Sigma-Tau Pharmaceuticals, Inc, Gaithersburg, MD), 2 of 20atients (10%) in the study group and 8 of 20 (40%) in thelacebo group developed pouchitis within 12 months of ileos-omy closure.7 The administration of Lactobacillus rhamnosus GGlso was shown to be effective in the primary prophylaxis.101,102

A small, randomized, placebo-controlled trial of oral tinidazolealso showed some efficacy in preventing initial episodes ofpouchitis.103

Treatment of acute pouchitis. Patients with initialepisodes of acute pouchitis typically respond to antibiotic ther-apy. In patients who experience pouchitis symptoms immedi-ately after pouch construction and ileostomy closure and donot respond to the antibiotic therapy, surgery-associated com-plications, such as pouch anastomotic leaks or sinus, should besuspected. There are few published randomized placebo-controlled trials on the treatment of or on the secondary pre-vention of pouchitis (Table 1). Metronidazole, ciprofloxacin,tinidazole, and rifaximin104 commonly have been used in thereatment of acute pouchitis in clinical practice. The first-lineherapy includes a 14-day course of metronidazole (15–20 mg/g/d) or ciprofloxacin (1 g/d).94,105,106 An open-label trial ofombination therapy using ciprofloxacin and metronidazole for

weeks was shown to be effective in treating pouchitis andackwash ileitis in patients with or without concomitantSC.107 Other antibiotic or nonantibiotic agents also have been

investigated and shown to be effective in some patients in small

Agent Duration Outcome

Metronidazole 1.4g/d vs placebo

1 wk 2 in stool frequency, morein study group than inplacebo

Probioticsa 6 g/dvs placebo

9 mo Relapse in 15% of studygroup; 100% in placebo(P � .001)

Ciprofloxacin 1 g/dvs metronidazole20 mg/kg/d

2 wk 2 in PDAI score:ciprofloxacin �6.7;metronidazole �5.9


12 mo Pouchitis in 10% of the studygroup; 40% in placebo(P � .05)


Up to 1 y Relapse in 15% of the studygroup; 94% in placebo(P � .0001)

Rifaximin 1.2 g/dvs placebo

4 wk Remission in 25% of thestudy group; 0% in control(P � .206)

ized, controlled trial.cidophilus, and L delbrueckii subspecies bulgaricus), 3 strains oftococcus salivarius subspecies thermophilus.

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case studies, including amoxicillin-clavulanic acid and a carbon

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microsphere agent.108 Diffuse pouchitis can be associated withackwash ileitis, particularly in patients with concurrent PSC,hich can be treated with oral budesonide.109 High-dose VSL#3

was reported to be effective for treating mild pouchitis.110

Secondary prophylaxis of subsequent episodesof pouchitis. Relapse of pouchitis or recurrent pouchitis iscommon after the treatment and resolution of the initial treat-ment.96 An estimated 5% to 19% of patients with acute pouchi-tis develop treatment-refractory or a frequently relapsing formof the disease.97�99 Randomized placebo-controlled trials haveshown that VSL#3 was effective for maintaining antibiotic-induced remission in patients with relapsing pouchitis.111,112 Inthe first randomized controlled trial from Bologna, Italy, VSL#3was given at a dose of 6 g/d as maintenance therapy afterremission had been induced by oral ciprofloxacin (1 g/d) andrifaximin (2 g/d). During this 9-month trial conducted in 40patients, 15% of patients in the probiotic group relapsed, com-pared with 100% of patients in the placebo group.111 Similaresults were reported in another randomized controlled trial ofSL#3 from St Mark’s Hospital in London, in which 29 of 36articipants also were from Bologna, Italy.112 In postmarketing,pen-label studies, the response rate to VSL#3 was not as highs in the randomized controlled trials. In a study of 31 patientsith antibiotic-dependent pouchitis, who received VSL#3 asaintenance therapy after induction of remission using 2eeks of treatment with ciprofloxacin, 25 patients (81%) had

topped taking the probiotic at 8 months because of the lack offficacy or the development of adverse effects.113 Similar resultsith 13% efficacy were reported in a separate open-label trial of

his agent.114 The discrepancy in the reported efficacy amonghe published or presented studies may be owing to the dietarytructure of the study populations, inclusion criteria, and dos-ge of the probiotic agents. Other options for maintenanceherapy for antibiotic-dependent pouchitis could be rifaxi-

in,115 and oral or topical mesalamine.116

Treatment of chronic antibiotic-refractory pou-chitis. Patients with CARP, by definition, do not respond toconventional antibiotic therapy. The treatment of CARP has beenchallenging. The commonly used broad-spectrum antibiotics, suchas ciprofloxacin and metronidazole, do not target any specificbacterial agents. Therefore, fecal bacterial culture and sensitiveassay have been recommended to identify suitable antibiotics.89

Secondary factors that are associated with an antibiotic-refrac-tory course should be identified and managed. These factorsinclude NSAID use, concurrent pouch surgery–related mechan-ical complications (such as ischemia,69 stricture, fistula, andsinus), CDI, CMV infection, and the presence of immune-mediated disorders (eg, PSC and celiac disease).67

Treatment options for CARP include a prolonged course ofcombined antibiotic therapy, such as 4 weeks of a combinationof ciprofloxacin (1 g/d) with rifaximin (2 g/d),117,118 metronida-ole (1 g/d),119 or tinidazole (1–1.5 g/d).116 In small case series,orticosteroids (including topical or oral budesonide109,120), im-unosuppressive agents, or even infliximab121 or adali-umab122 have been studied for the treatment of CARP with

some efficacy. The efficacy of those agents suggests the role ofimmune-mediated processes in the disease initiation, relapse,and progression of CARP. Newly described autoimmunepouchitis83 and IgG4-associated pouchitis84 also may be evalu-

ted. The treatment for immune-medicated pouchitis is empiric
t this point and treatment options include corticosteroids, u
immunomodulators, or anti-TNF biologics. It should bepointed out that there is a great overlap in pharmaceuticaltherapy between the treatment of CARP and CD of the pouch.For example, a long-term single or dual antibiotic therapy ortopically active corticosteroid (budesonide) has been used forboth CARP and CD of the pouch. Although immunomodulatoror anti-TNF biological therapy commonly is used in treatingthe fistulizing form of CD of the pouch,123,124 those agents are

ot applied routinely in CARP. For fibrostenotic CD of theouch, medical therapy often is combined with endoscopicreatment.125

Chronic pouchitis may be associated with concurrent mechan-ical or structural disorders of the pouch, such as strictures andanastomotic sinus. For example, pouch outlet obstruction (such asanastomotic stricture), can be associated with pouchitis, presum-ably owing to bacteria overload from prolonged fecal stasis. Therelease of the obstruction, often along with concurrent antibiotictherapy, may promote the resolution of pouchitis.125

Treatment of C difficile pouchitis. CDI poses aunique problem for patients with ileal pouches. Fecal C difficiletoxins should be tested routinely in patients with antibiotic-dependent or antibiotic-refractory pouchitis. Pouch patientswith a positive stool test for C difficile toxins may have a differ-ent clinical presentation, ranging from being an asymptomaticcarrier to having fulminant pouchitis/enteritis.19 With anemerging prevalence and severity of CDI in patients with orwithout IBD (including those with ileal pouches), it has beenrecommended that oral vancomycin be considered as the first-line therapy in severe infection requiring hospitalization.126

Oral or intravenous metronidazole traditionally has been con-sidered the first-line therapy for CDI. However, its efficacyspecifically in the IBD or pouch population with CDI is un-known. Failure rates of metronidazole before the emergence ofthe epidemic C difficile BI/NAP1/027 strain were 16%, but moreecently reported failure rates have been alarmingly high at5%.127,128 In pouch patients with or without CDI, a vast ma-

ority were exposed to, and were on, oral metronidazole ther-py.13,18 Therefore, I recommend that for patients with CARP orevere pouchitis and CDI, which can be fulminant and lethal,19

oral vancomycin may be considered as the first-line therapy.The recommended dose of oral vancomycin is 125 to 250 mgfour times daily for 4 weeks. For patients with mild acutepouchitis, without prior or concurrent exposure to metronida-zole, oral metronidazole may be used as the first-line therapy.Oral fidoxamicin 200 mg twice a day for 10 to 14 days or fecalmicrobiota transplantation (personal unpublished data) may bean alternative for refractory or recurrent CDI.

Prospective View and RecommendationsIt is obvious that microbiota play a critical role in the

pathogenesis of pouchitis. In fact, all currently published ran-domized controlled trials in pouchitis are regarding the efficacyof antibiotics or probiotics (Table 1). On the other hand, theinvestigation of the role of gut microbiota in the etiopathogen-esis of pouchitis has been difficult because 90% of gut bacteriaare not culturable.129 Molecular microbiology techniques forhe qualitative and quantitative measurement of microbiota arexpensive and labor-intensive, particularly for the identificationf the individual responsible bacteria. There are great variations

n the composition of gut microbiota among healthy individ-
als, not mentioning the difference among healthy and dis-


eased individuals. Therefore, the interpretation of the microbi-ota profile in cross-sectional studies comparing healthy anddiseased pouches can be difficult. Furthermore, the commonlyused broad-spectrum antibiotic agents are not targeted for anyspecific bacteria species. We hope that those agents can helprestore the normal balance between good and bad bacteria inthe pouch. It is common that patients with antibiotic-respon-sive pouchitis later develop antibiotic dependency or resistance.

We speculate that the persistent alteration of gut microbiotaor dysbiosis, despite intermittent or chronic antibiotic therapyor probiotic therapy, consistently induces an abnormal mucosalimmune response, leading to chronic pouchitis or CARP. Pa-tients with genetic susceptibility (such as those with a NOD2/CARD15 mutation) and/or systemic immune-mediated disor-ders (such as PSC, IgG4-associated systemic disorders) may beparticularly vulnerable to the development of CARP. A molec-ular classification of pouchitis, with a combined assay of im-munogenetic, serologic, and clinical markers, would be invalu-able for the identification of etiopathogenesis, diagnosis,treatment stratification, and prognosis prediction.

It has become clear that we should take a 3-dimensional viewof pouchitis. Pouchitis represents a disease spectrum with var-ious pathogenetic pathways, clinical presentations, and diseasecourses ranging from acute antibiotic-response types to chronicantibiotic-refractory phenotypes. For each individual patient,on the other hand, the diagnosis of pouchitis or other pouchdisorders can be a moving target. Therefore, patients with IPAAshould be monitored closely. Pouchoscopy is the best way tomonitor the disease status of the pouch, to grade the degree ofinflammation, and to identify structural abnormalities. Patientswith minimal symptoms but with endoscopic inflammationstill should be treated to minimize smoldering inflammationcausing chronic “stiff” pouch with transmural inflammation,which can result in pouch failure.130 More importantly, differ-ent treatment strategies should be applied to treat differentphenotypes of pouchitis at different stages.

Diagnosis (Figure 4) and treatment (Figure 5) algorithms are

Figure 5. Treatment algorithmfor pouchitis.

proposed based on published studies as well as my own expe-

rience in the subspecialty Pouch Center at the ClevelandClinic.131 If a patient has symptoms of increased bowel fre-quency, watery stools, or urgency, antidiarrheal agents can beused first. If the symptoms do not get better in 1 to 2 days, thepatient should be evaluated and in some cases treated empiri-cally with antibiotics. Pouchoscopy, the diagnostic test ofchoice, needs to be performed, along with laboratory evalua-tion. In most cases, the combined evaluation of endoscopy,histology, and laboratory testing often provides clues for trig-gering, or etiologic factors for, the flare-up. For patients withdiffuse pouchitis and diffuse enteritis of the afferent limb,immune-mediated pouchitis/enteritis may be considered. Forpatients with pouch inflammation that is distributed asymmet-rically and has a sharp demarcation of inflamed and nonin-flamed parts of the pouch body, ischemic pouchitis is a possi-bility (Figure 4). Often, pouchoscopy may show clues ofstructural abnormalities, such as strictures, fistulas, and si-nuses. If CD of the pouch is suspected, abdominal and pelvicimaging or examination under anesthesia often is needed.

The treatment of antibiotic-responsive pouchitis is straightfor-ward. The prognosis of pouchitis is determined by the frequency ofthe need for antibiotic therapy (antibiotic-dependent pouchitis)and the development of the refractory disease course (CARP). Aprolonged course of dual antibiotic therapy may help induceremission in patients with CARP. Oral or topical mesalamineagents and a topically active corticosteroid agent (budesonide) arethe preferred first-line drugs for immune-mediated pouchitis/enteritis. Back-up agents may include 6-mercaptopurine/azathio-prine, methotrexate, tacrolimus, or anti-TNF agents (Figure 5).

In summary, the diagnosis and management of pouchitis andthe identification of its etiologic or triggering factors can be chal-lenging. Pouchitis represents a disease spectrum, ranging from anacute antibiotic-responsive form to a chronic antibiotic-refractoryphenotype, with different disease mechanisms and prognoses. Acombined evaluation of pouchoscopy, histology, and laboratorytesting may help classify disease phenotypes and stratify their
management.


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Reprint requestsAddress requests for reprints to: Bo Shen, MD, AGAF, Department of

Gastroenterology/Hepatology Desk A31, The Cleveland Clinic Founda-tion, 9500 Euclid Avenue, Cleveland, Ohio 44195. e-mail: [email protected]; fax: (216) 444-6305.

Conflicts of interestThe author discloses the following: Bo Shen has received honoraria

from Aptalis, Abbott, and Prometheus Lab.

mailto:[email protected]

mailto:[email protected]

GASTROENTEROLOGY ARTICLE OF THE WEEK Jan 16, 2014

Shein B. Pouchitis: What every gastroenterologist needs to know. Clin Gastroenterol Hepatol 2013;11:1538-1549. 1. Treatment strategies for pouchitis include a. vancomycin 125mg tid b. metronidazole 15-20 mg/kg; 14 days c. ciprofloxacin 500mg bid; 14 days d. rifaximin 1.2g/day, 4 weeks e. budesonide for PSC related backwash ileitis 2. Laboratory evaluation of patients with CARP should include a. IgG4 levels b. ANA c. IgM levels d. CMV DNA PCR e. Liver enzymes f. TTG antibodies True or False 3. Patients with a pouch complaining of diarrhea, cramps, urgency and having a normal endoscopic exam of the pouch have mild pouchitis 4. After an initial episode of pouchitis that responds to antibiotics, recurrence occurs in up to 60% of patients. 5. The presence of fistulae or perianal disease suggests recurrent Crohn’s disease 6. Pouchitis is as likely to develop in patients undergoing IPAA for UC as those undergoing IPAA for familial adenomatous polyposis coli. 7. VSL#3 may be effective in secondary prophylaxis of pouchitis 8. Asymmetric distribution of inflammation in the pouch may indicate ischemia 9. Patients with healthy pouches should have no more than 2 stools a day 10. Histology will provide an accurate assessment of the severity of the pouchitis 11. Vancomycin 125mg qid is recommended for the treatment of c. difficile pouchitis 12. Pouchitis presenting very soon after pouch creation is more likely secondary to procedure-associated complications such as ischemia 13. All patients with an ileal pouch are at risk for cuffitis

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