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 pro-inflammatory 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 [18].

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 with patients that did not have the particular allele, 72% vs. 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 that 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 cytokine receptors that are associated with pouchitis. The NOD2/CARD 15 mutations have been shown to be associated with the development of pouchitis, and in some instances, a more severe manifestation of the disease [19, 20]. These mutations are associated with several markers of disease severity in pediatric CD [21]. It is therefore highly probable that these patients may actually have CD involving the pouch. Lammers et al. showed that patients who possess Toll-like receptor 9-1237C and CD14-260T alleles have a higher risk for developing chronic or relapsing pouchitis [22].

A novel concept of IgG4-associated pouchitis has been described. A total of 124 patients with symptomatic ileal pouches who were followed in a subspecialty Pouchitis Clinic had serum IgG4 levels measured. Eight percent of these patients had elevated serum IgG4 and half of those with elevated levels had chronic antibiotic refractory pouchitis [23]. Bo Shen et al. also described a patient diagnosed with chronic pouchitis who had persistent elevation of IgG4 level in the serum and associated lymphoplasmacytic infiltrates with abundant IgG4 positive plasma cells on mucosal biopsies of the pouch [24]. The presence of an elevated serum IgG4 level in this group of patients was not associated with the diagnosis of autoimmune pancreatitis. Elevation of serum IgG4 is considered to be one of the biomarkers of autoimmune pancreatitis. Future studies are needed to further investigate the role of IgG4 in the etiology, pathogenesis, and prognosis of patients with pouchitis.

The 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. However, to date, no single microbial factor has been identified as the causative factor. In 2004, Gosselink et al. reported an increase in aerobic bacteria and pathogenic bacteria such as Clostridium perfringens and hemolytic strains of Escherichia coli in stool collected from patients during episodes of acute pouchitis [25]. The significance of these particular pathogens is yet to be determined. 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 have been found to be associated with postoperative fistula formation after restorative protocolectomy [26]. Antibodies to OmpC an outer membrane porin from E. Coli and I2 (antigen to Pseudomanas fluorescens) were found to be predictive of postoperative continuous inflammation of the pouch [27]. These findings are suggestive of a pathogenic immune response to bacterial antigens.

It has been proposed that ischemia plays a role in the etiology of pouchitis. Several studies have examined the relationship between mucosal pH as a marker of ischemia and the development of pouchitis. The results of these studies are mixed and show no definitive relationship. Other studies have investigated the relationship between anastomotic narrowing and ischemia. No direct relationship has been demonstrated between tension at the anastomotic site leading to ischemia and the subsequent development of pouchitis [13].

Undiagnosed CD can present clinically as chronic pouchitis following IPAA. In his retrospective study of 151 pediatric patients who underwent IPAA for presumed underlying UC, Alexander et al. reported that 15% of the patients were ultimately diagnosed with CD [15]. Wewer et al. reported approximately a 6% detection rate for CD in pediatric patients aged 7–17 years of age status-post IPAA [4]. The most common manifestations of CD noted for patients status-post IPAA are pouch fistulizing disease and prepouch ileitis.

The presence of extraintestinal manifestations related to inflammatory bowel disease has been studied as 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. They also found an increased association with 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. This group also reported an increased frequency of chronic pouchitis in patients with PSC vs. patients without this disease, 60% and 15%, respectively [9]. In 2005, a study by Gorgun et al. refuted this claim. This group reported a higher overall mortality for patients with PSC status-IPAA; however, they did not find a statistically significant relationship between chronic pouchitis and UC in patients with preoperative PSC [28]. 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 [29]. Bo Shen et al. also demonstrated that concurrent PSC appears to be associated with a significant prepouch ileitis on endoscopy and histology in patients with IPAA [30].

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 [31]. 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 [32].

It has been shown that serum perinuclear antineutrophil cytoplasmic antibody (pANCA) is associated with a diagnosis of UC; therefore, it is a natural progression to investigate whether serum pANCA has any effect on the diagnosis of pouchitis in patients after IPAA. Retrospective studies have shown mixed results in determining whether there is a direct relationship between pANCA and pouchitis. In 2001, Fleshner et al. studied the relationship between pouchitis and pANCA in a prospective study. They did not find an overall significant difference in the occurrence of pouchitis in the pANCA positive vs. 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 [33].

The first episode of pouchitis occurs most often in the first 6 months after closure of the loop ileostomy, however it can occur at any time after IPAA is performed [11]. To accurately make a diagnosis, a combination of clinical symptoms, endoscopic findings, and histologic findings need to be obtained. In practice, a presumptive diagnosis of pouchitis is often made on clinical symptoms alone. The proper diagnosis of pouchitis has been a source of debate in the literature. Several groups advocate that diagnosing pouchitis on clinical symptoms alone leads to overdiagnosis of this disease. Pouchoscopy still remains the main tool for establishing a diagnosis and also for evaluating for other differential diagnosis in suspected cases of pouchitis [34].

The clinical presentation of pouchitis typically includes a combination of increased stool frequency, abdominal cramping, hematochezia, bowel incontinence, and/or low grade fever. Endoscopic findings involve assessing the severity of inflammation of the pouch mucosa. Signs of inflammation include erythema, edema, granularity, mucosal ulceration, and friability. The distal and posterior portions of the pouch are most often affected and should routinely be biopsied. In addition, if inflammation of the neo-terminal ileum is visualized, this finding is suggestive of CD. Cheifetz et al. suggest that single aphthous lesion in the terminal ileum does not confirm the diagnosis, rather the presence of serpiginous ulcers are more suggestive [35]. Histology of the pouch is graded on an ABC scale. Type A mucosa is described as normal mucosa or mild villous atrophy with no or minimal inflammation. Type B mucosa is described as transient atrophy with temporary moderate to severe inflammation followed by normalization of the architecture. Type C mucosa is described as persistent atrophy with severe inflammation [36]. Type B and C mucosa are most often found in pouchitis. When a diagnosis of pouchitis is made, evidence of acute and/or chronic inflammation is typically present on biopsy samples. Chronic lymphocytic infiltrate, crypt hyperplasia, crypt abscesses, and fibromuscular obliteration of the lamina propria are specific findings that aid in the diagnosis [37].

Histologic evaluation is also invaluable in identifying some of the other secondary causes of pouchitis such as pathogens like cytomegalovirus (CMV) or Candida, ischemia, mucosal prolapse, granulomas, and dysplasia [38]. Other laboratory tests such as stool studies for Clostridium difficile infection may be important especially in patients with chronic antibiotic refractory pouchitis [38]. Inflammatory markers in the serum may be useful noninvasive adjuncts in evaluation of patients with suspected pouchitis. Studies evaluating the erythrocyte sedimentation rate as a marker of pouchitis have shown, despite its role as a nonspecific marker of inflammation, that it correlates with the Pouchitis Disease Activity Index (PDAI) and episodes of pouchitis [39, 40]. Elevation of the serum C-reactive protein is a nonspecific marker of inflammation, but this was also found to correlate with the PDAI score and the presence of endoscopic inflammation in the pouch and afferent limb [34, 39]. Fecal inflammatory markers usually are reflective of the presence of intestinal inflammation. The fecal pyruvate kinase, calprotectin, and lactoferrin levels have been found to correlate with pouchitis and PDAI scores in a number of studies [41–43]. The fecal markers could serve as potential adjunctive tests in the initial evaluation of patients with pouchitis but their role in the overall management of these patients still needs to be clearly elucidated.

Several scales for grading pouchitis have been developed over the last two decades. The most commonly used and referenced scales include the PDAI (Sandborn, et al.), Moskowitz Criteria (Moskowitz, et al.), and The Heidelberg Pouchitis Activity Score (Heuschen et al.). Tables 39.2 and 39.3 detail the PDAI and the Moskowitz Criteria.

The classification of pouchitis can be made based upon several different factors. Severity varies from remission to severely active. Duration varies from acute (less than 4 weeks) to chronic (more than 4 weeks). Frequency varies from infrequent to continuous. Pouchitis can also be graded according to response to therapy. Response to therapy is described as antibiotic-responsive, antibiotic-dependent, or antibiotic-resistant (refractory) [44]. Table 39.4 outlines the classification of pouchitis based on different factors. In addition, it must be considered that not all patients status-post IPAA with symptoms of diarrhea and abdominal pain will truly have pouchitis. Other disease entities that may present similarly to pouchitis include Irritable Pouch Syndrome, cuffitis, stenosis of the pouch, CD, celiac disease, and infectious bowel disease (most often secondary to C. difficile or CMV).