One of the most pursued areas of inflammatory bowel disease research is the influence of variations of gene loci on the development of IBD. As cytokines play a major role in the inflammatory pathway that lead to disease manifestations, many studies have focused on the role of cytokines such as interleukin (IL)-1 alpha, beta, and receptor antagonist (RA) in the etiology of IBD. IL-1 alpha and beta are proinflammatory cytokines, whereas IL-1RA is the natural inhibitor of these cytokines. Genetic polymorphisms that lead to a reduction in the ratio of IL-1 alpha and beta to IL-1RA will potentially lead to increased and/or chronic inflammation [20].

It is also possible that an imbalance in the ratio of IL-1 alpha and beta to IL-1RA may influence the initiation of inflammation leading to pouchitis in patients status post IPAA. In 2001, Carter et al. reported that patients that developed pouchitis had a higher IL-1RN*2 carrier rate as compared to patients that did not have the particular allele, 72% versus 45%, respectively [7]. IL-1RN*2 represents a polymorphism in the IL-1 gene cluster that has been associated with a change in the ratio of IL-1 alpha and beta to IL-1RA and the development of UC. This finding suggests patients with UC that carry this allele may have an increased tendency of developing pouchitis after IPAA.

More recent studies have identified other genetic polymorphisms and cell membrane receptors that are associated with pouchitis. The NOD2/CARD15 mutations have been shown to be associated with the development of pouchitis and, in some instances, a more severe manifestation of the disease [21–23]. These mutations are associated with several markers of disease severity in pediatric CD [24]. It is therefore highly probable that these patients may actually have CD involving the pouch.

Intestinal epithelial expression of the innate Toll-like receptors (TLRs) 2, 4, and 5 is activated by bacterial peptidoglycan, lipopolysaccharides, and flagellin and leads to a complex downstream cascade of inflammatory signaling mediated by NF-κB. These TLRs have shown to be upregulated in patients with pouchitis [25]. Lammers et al. showed that patients who possess Toll-like receptor (TLR) 9-1237C and CD14-260 T alleles have a higher risk of developing chronic or relapsing pouchitis [26]. Alterations in tight junction claudin-1 and claudin-2 expression in biopsies of patients with pouchitis also indicate increased barrier dysfunction as a result of the inflammation [27].

A novel concept of immunoglobulin G4 (IgG4)-associated pouchitis has been described [28, 29]. Seril et al. demonstrated a high prevalence of IgG4-expressing plasma cells in the pouch of patients with chronic antibiotic-refractory pouchitis (CARP). Patients with CARP were also more likely to have autoimmune thyroid disease, primary sclerosing cholangitis (PSC), and serum microsomal antibodies suggestive of an autoimmune-mediated pouchitis [30]. Future studies are needed to further investigate the role of IgG4 in the etiology, pathogenesis, and prognosis of patients with pouchitis.

The favorable response of the majority of acute episodes of pouchitis to antibiotic therapy and more recently to administration of probiotics suggests that bacterial populations are important etiological factors in the development of pouchitis. Pouchitis also rarely occurs until after takedown of the ileostomy with resultant resumption of fecal flow to the neoileum pouch. However, to date, no single microbial factor has been identified as the causative factor. Fecal stasis in the pouch may also be a contributing factor. A study of rats who received IPAA after colectomy had longer fecal retention and higher rates of inflammation in the pouch compared to rats who underwent straight ileorectal anastomosis [31]. As in patients with IBD prior to IPAA, 16 S ribosomal RNA sequencing has demonstrated altered microbial diversity in patients with pouchitis at multiple taxonomic levels with an increase in Fusobacteria and Enterobacteriaceae and a decrease in Bacteroidetes [32–34].

Other studies have looked at the role of serological markers, such as antibodies to bacteria fragments, in the pathogenesis of inflammatory bowel disease and also pouchitis. Serological markers such as anti-Saccharomyces cerevisiae antibodies (ASCA) have been found to be associated with postoperative fistula formation after restorative proctocolectomy (RPC) [35]. Antibodies to OmpC, an outer membrane porin from E. coli and I2 (antigen to Pseudomonas fluorescens), were found to be predictive of postoperative continuous inflammation of the pouch [36]. In 2001, Fleshner et al. studied the relationship between pouchitis and serum perinuclear antineutrophil cytoplasmic antibody (pANCA) in a prospective study. They did not find an overall significant difference in the occurrence of pouchitis in the pANCA-positive versus pANCA-negative groups. They did, however, demonstrate a significant relationship between the development of chronic pouchitis in patients with a high level of pANCA (>100 EU/ml) as compared to patients with a medium level (40–100 EU/ml), low level (<40 EU/ml), or undetectable level of pANCA [10]. A more recent study investigating the impact of preoperative pANCA and anti-CBir1 flagellin on the development of acute or chronic pouchitis showed that both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA. Anti-CBir1 increases the incidence of acute pouchitis only in patients who have low-level pANCA expression and increases the incidence of chronic pouchitis in patients who have high-level pANCA expression [37]. These findings are suggestive of a pathogenic immune response to bacterial antigens.

Infection with Clostridium difficile has been increasingly recognized as a problematic cause of diarrhea in IBD patients with both pre- and postcolectomy with IPAA. C. difficile as a cause of pathogen-associated pouchitis is diagnosed in up to 10% of adults with increased risk in patients with recent hospitalization, receiving antibiotics, and males [38, 39]. When possible, PCR testing for C. difficile toxin B is more sensitive than enzyme immunoassay though neither is specific, and clinical context needs to be considered for patients who may be colonized [40]. Evaluation with either endoscopy or fecal calprotectin helps to establish inflammation in the setting of symptoms in patients positive for C. difficile. As many of the patients have already been on metronidazole, consider vancomycin as the first-line treatment. Recurrent or persistent C. difficile may also require fecal microbial transplant to eradicate [41].

During pouchoscopy, if the pattern of inflammation is isolated to specific limb or wall of the pouch, ischemia should be considered as an etiology of the pouchitis. Ischemia can arise from tension on the pouch when it is pulled into the pelvis during surgery, either from torsion of the pouch when attached to the cuff or by leaving a long cuff resulting in a mobile base for the pouch to rotate on. Ischemia can also occur from decreased tissue perfusion as a vasculitic component of the underlying disease [42]. Ischemic pouchitis can be evaluated under fluoroscopy and by a surgeon for tension-induced ischemia which may require revision. If there is no evidence of tension on the pouch, a more global ischemic process may be the cause. Ischemia has been proposed as a contributing factor in intestinal inflammation after the observation that IBD patients improved after treatment with hyperbaric oxygen therapy (HBOT). A 1994 study demonstrated improvement in 8 of 10 patients with perianal CD, 5 of which had complete resolution [43]. A follow-up study showed decreased levels of IL-1, IL-6, and TNF-α in these patients after HBOT [44]. A 2014 review by Dulai et al. evaluated 17 studies in which HBOT was administered for either UC or CD (including perianal disease) with varying protocols of which 86% responded (n = 613, 8924 treatments). The most common complication from treatment was middle ear barotrauma and tympanic membrane perforation (1.5% patients, 0.1% of all treatments) [45]. A recent case report of a patient with chronic antibiotic refractory pouchitis had significant improvement in symptoms after treatment with HBOT [46]. More studies including randomized controlled trials should be completed to further evaluate such a therapeutic endeavor.

Undiagnosed CD can present clinically as chronic pouchitis following IPAA. In adults, a 2008 study by Melmed et al. reported 16/238 (7%) patients who underwent IPAA for UC or IBD-U were later diagnosed as having CD with significant risk factors of family history of CD and/or presence of serum ASCA-IgA. Four of these patients (25%) failed medical management and had a diverting ileostomy [47]. A 2012 study by Coukos et al. also demonstrated association of ASCA-IgA, ASCA-IgG, and anti-CBir1 flagellin in the development of CD of the pouch or fistula in patients with UC after IPAA [48]. In pediatrics, Wewer et al. reported approximately a 6% detection rate for CD in 30 patients aged 7–17 years status post IPAA with a median follow-up of 3.7 years [4]. Ozdemir et al. reviewed the outcomes of 361 pediatric patients who underwent IPAA over a 27-year period and found 18 patients (5%) to be later diagnosed with CD [14]. In a more recent 2016 single-center study follow-up of 74 pediatric patients (15–30 years later) after IPAA, Shannon et al. reported 28% were ultimately diagnosed as having CD, of which 40% required take down of the pouch for pouch failure [15]. The most common manifestations of CD noted for patients status post IPAA are fistulizing disease of the pouch and pre-pouch ileitis.

The presence of extraintestinal manifestations related to inflammatory bowel disease has been studied as possible predictors of the development and severity of pouchitis. Lohmuller et al. looked at extraintestinal manifestations such as erythema nodosum, arthritis, and uveitis to determine a relationship. Their group found that pouchitis occurred in 39% of patients with preoperative extraintestinal manifestations as compared to 26% of UC patients with no preoperative extraintestinal manifestations (p < 0.001). They also found an increased risk of pouchitis if postoperative extraintestinal manifestations were diagnosed [8].

Multiple groups have specifically analyzed the relationship between primary sclerosing cholangitis (PSC) and the development of pouchitis. Penna et al. found that pouchitis occurred in 63% of the patients with PSC, while pouchitis only occurred in 32% of the patients without this particular extraintestinal manifestation (p < 0.001). This group also reported an increased frequency of chronic pouchitis in patients with PSC versus patients without this disease, 60% and 15%, respectively (p < 0.001) [9]. In 2005, a study by Gorgun et al. refuted this claim. This group reported a higher overall mortality for patients with PSC status post IPAA; however, they did not find a statistically significant relationship between chronic pouchitis and UC in patients with preoperative PSC [49]. A review of the available literature by Rahman et al. concluded that pouchitis appears to be more common in the subset of patients that have both UC and PSC [50]. Shen et al. also demonstrated that concurrent PSC appears to be associated with a significant pre-pouch ileitis on endoscopy and histology in patients with IPAA [51].

After IPAA a region of colonic columnar mucosa remains unless a mucosectomy is performed [52]. It has been shown that patients have markedly better pouch function when mucosectomy is not performed, and this is the preferred treatment modality in the absence of dysplasia. As a result, a “cuff” remains above the anal transitional zone (Fig. 44.2). The length of the cuff is dependent on the type of IPAA performed. After a stapled IPAA, the preferred method by adult colorectal surgeons, a region of 1.5–2 cm of diseased mucosa, remains. A hand-sewn IPAA has traditionally been performed by pediatric surgeons and leaves a variably smaller cuff region. Neither method is superior to the other as far as complication rate, but the stapled IPAA may offer improved nocturnal continence with higher resting and squeeze pressures of the pouch demonstrated by anorectal manometry [53].

As expected, remaining diseased columnar mucosa can develop inflammation, a term coined “cuffitis.” Patient symptoms include anal pain or discomfort, bleeding, discharge, or diarrhea and endoscopic features typical of colitis in the cuff region (erythema, friability, ulceration). Thompson-Fawcett et al. biopsied the cuff of 113 patients after stapled IPAA and found 13% had evidence of acute inflammation, most of which was mild and 9% were symptomatic [54]. Wu et al. followed 120 patients with cuffitis (12.9%) from their registry of 931 pouch patients over a median of 4 years and found no difference in the demographics, risk factors, and extent or severity of disease compared to controls without cuffitis. Of these patients, 33% responded to topical 5-ASA/steroid therapy, 18% relapsed after initial response to 5-ASA/steroid therapy, and 48% did not respond to topical therapy and required immunotherapy. Sixteen patients (13%) with cuffitis ultimately had failure of the pouch due to CD of the pouch, refractory cuffitis, or surgical complications (fistula, sinus) requiring diversion or pouch reconstruction [55]. As a small segment of colonic mucosa remains in situ, the risk for dysplasia remains equally present in the cuff as in the pouch [56].

It has previously been established that cigarette smoking is associated with a reduction in the risk of developing UC. In 1996, Merrett et al. also described a link between smoking and a reduction in the incidence of pouchitis in patients after IPAA. Their study documented that 18/72 (25%) nonsmokers were diagnosed with pouchitis, while 1/17 smokers (5%) were diagnosed with pouchitis. The reason for these findings is unclear, but may be related to the effect of smoking on gut mucosal permeability [57]. Fleshner et al. performed a multivariate analysis of clinical factors associated with pouchitis after IPAA. He showed that smoking and the use of steroids prior to colectomy were associated with acute pouchitis, while smoking in of itself appeared to protect against the development of chronic pouchitis [58].