3.1. Background Information

Pouchitis as a disease was first described by Kock et al. in 1977 as a nonspecific inflammatory condition affecting the ileal pouch of patients that underwent proctocolectomy, commonly presenting as increased stool frequency, urgency, incontinence, and pelvic discomfort [5]. Proctocolectomy with IPAA is the ideal approach for patients with familial adenomatous polyposis (FAP) and UC with dysplasia or refractory to medical management [6]. The most common complication of patients with UC post-IPAA surgery is pouchitis, with one study reporting it occurs in up to 59% of patients [7]. Most patients respond positively to antibiotics, but 5%–19% of cases develop chronic or relapsing symptoms [8]. Pouchitis as a disease does not have an official classification yet; however, it can be categorized by disease course and by response to treatment. Acute pouchitis lasts for ≤ 4 weeks, while chronic cases should last > 4 weeks. In terms of recurrence, we can broadly group pouchitis as infrequent (< 3 episodes/year), relapsing (1–3 episodes/year), and continuous. Cases can either be antibiotic-responsive, meaning the resolution of symptoms in < 2 weeks with monotherapy, antibiotic-dependent (i.e., requiring maintenance therapy to achieve remission), and antibiotic-refractory (i.e., not responding to standard therapy) [6]. CARP refers to cases that fail a 4-week monotherapy (metronidazole or ciprofloxacin) and require extensive prolonged therapy consisting of ≥ 2 antibiotics, ASA, corticosteroids, or oral immunomodulators [8].

It is also speculated that genetic susceptibility plays a role in the development of pouchitis. Genetic polymorphism of interleukin-1 receptor antagonists and NOD2/CARD15 has been linked with a higher risk of developing acute or chronic pouchitis, according to immunogenetic studies [9, 10].

Most cases of pouchitis are labeled as idiopathic, as its etiology and pathogenesis are not fully understood. Pouchitis with known etiologies are categorized as “secondary pouchitis” [3]. It is important to thoroughly investigate patients with CARP in search of secondary etiologies. Around 20%–30% of cases of CARP have identifiable secondary causes [8]. They may be attributed to intestinal dysbiosis or fecal stasis inducing bacterial overgrowth; causative agents such as C. difficile, Candida, or CMV; use of nonsteroidal anti-inflammatory drugs (NSAIDs); ischemia; or inflammatory conditions such as Crohn’s or UC recurrence [11, 12]. Due to the high success rate of antibiotic treatment on pouchitis, bacterial pouchitis is the most accepted common etiology.

3.2. Typical Presentation and Diagnosis

People with pouchitis have variable clinical presentations. Pouchitis can be suspected in patients with abdominal cramps accompanied by increased stool frequency, urgency, day- or night-time fecal incontinence or seepage, or tenesmus [6]. However, symptoms are insufficient in conclusively diagnosing pouchitis, as its nonspecific presentation resembles other inflammatory conditions such as Crohn’s disease, cuffitis, and irritable pouch syndrome (IPS), to name a few; thus, one must employ laboratory and endoscopic investigation including biopsy for histological assessment [8].

The most well-recognized diagnostic tool for the assessment of pouch inflammation is the Pouchitis Disease Activity Index (PDAI), which takes into account symptoms, endoscopy findings, and histology (all scored from 0 to 6 points). Pouchitis can be diagnosed when the score is greater or equal to 7 [1]. However, the PDAI is not specific enough as other inflammatory conditions can elevate the score (Crohn’s, UC, IPS, etc.). Nonetheless, a study reported that 25% of the cases with clinical symptoms of pouchitis but a PDAI score below 7 failed to respond to empiric antibiotic therapy, and so they classified them as having IPS [13].

A careful history should be investigated; rectal bleeding is uncommon to pouchitis, and it points to other disorders (i.e., IPS and cuffitis). The use of NSAIDs should also be investigated as it has been theorized to cause inflammatory flares by exacerbating colonic injury while hindering healing [8].

Laboratory studies should include a complete blood panel, a basic metabolic panel, and liver functional tests. Elevated alkaline phosphatase and/or bilirubin levels can point the secondary etiology to primary sclerosing cholangitis (PSC), a condition with a reported association to pouchitis [14]. Stool studies should include C. difficile toxin, especially in cases of increased stool frequency. When coupled with systemic symptoms such as fever and chills, additional testing should include stool cultures (for Salmonella, Shigella, Yersinia, and Campylobacter) and E. coli O157:H7 specific testing [6]. Although not routinely obtained, celiac serology can be collected during initial evaluation [2]. In case of low total IgA or identification of anti-TTG IgA antibodies, IgG TTG and IgG deamidated gliadin peptides (DGPs) should be obtained. If their results are suspicious of celiac disease, an intestinal biopsy is needed for confirmation.

Endoscopic evaluation of the afferent limb and the proximal and distal pouch is the most important step for proper diagnosis, and pouch biopsy should always be performed (gross findings alone are nonspecific). This is especially true in cases of CARP, as an offending agent should be ruled out. Endoscopic findings can include diffuse erythema with or without edema, granularity, friability, bleeding, mucous exudates, erosions, and ulcerations [6]. If endoscopic findings are indicative of Crohn’s, they should be correlated with histology and further imaging (i.e., bowel follow-through X-ray or computed tomography) [13].

Histology can present acute or chronic inflammation with infiltration of polymorphonuclear leukocytes, crypt abscesses, and ulceration. Although this has limited specificity and pouchitis grading ability, it can provide useful pathogenic features such as granulomas, dysplasia, inclusion bodies (indicating CMV), or ischemia [6]. In our case, histopathological studies yielded lymphocytic infiltration with villous atrophy, indicative of celiac disease.

To the best of our knowledge, very few cases of CARP have been associated with celiac disease, with only one case similarly describing de novo celiac development post-IPAA surgery [4, 15].

The diversity in clinical presentation, disease course, and histopathology of pouchitis makes it a diagnostic challenge.

3.3. Treatment and Management

Antibiotics are the mainstay in the treatment of both acute and chronic pouchitis, and probiotics have a role in maintenance to prevent relapse. The first-line therapy is oral metronidazole 250 mg 3 times daily for 1 week or oral ciprofloxacin 500 mg twice daily for 1 week; ciprofloxacin has been shown to reduce the PDAI score and symptoms more than metronidazole [13]. For chronic antibiotic-dependent cases, maintenance therapy is indicated, with rifaximin at 200 mg OD being widely used to achieve remission for extended durations [16]. In a randomized controlled trial, a multistrain high potency probiotic preparation given for 9 months maintained remission in 85% percent of the group compared to 0% in the placebo group [17].

In CARP patients with no evidence of secondary causes (PSC, celiac disease, Crohn’s, etc.), antibiotic combination therapy might be necessary. Rifaximin at 1 g twice daily with ciprofloxacin 500 g twice daily each for 15 days was tested by Gionchetti et al. and proved effective [11]. In case of failure of combined antibiotic treatment, immunogenic CARP can be suspected. Therapy is then shifted to rectal mesalamine 1 g OD for 4 weeks (initial therapy), and then hydrocortisone suppository OD for 2 weeks [18].

Pouchitis patients found to have celiac disease must adhere to a life-long gluten-free diet, barring wheat, barley, and rye from their food products [19]. Regular monitoring for micronutrient deficiencies is recommended as a follow-up with their dietician, especially iron, folic acid, vitamin B12, and vitamin D [19].