There are no randomized clinical trials of medical therapy for indeterminate colitis. In fact, patients with IC are generally excluded from clinical trials. Therefore, little is known about the response of these patients to conventional medical therapies. It is frequently assumed that because many patients with indeterminate colitis will eventually be diagnosed with either CD or UC, any therapy that is effective in both diseases may be useful for the treatment of IC as well. Burakoff advocates that the approach to medical treatment should be based on the anatomic distribution of disease and the severity of relapse [33].

Anecdotal experience suggests that patients with IC often respond to steroids, salicylates (oral and topical), and immunosuppressives such as 6-mercaptopurine and azathioprine; however, no data exist on the response rate of patients with IC compared to that of patients with CD or UC. Black et al. reported the results of an open label trial of infliximab in the treatment of medically refractory indeterminate colitis. Of 20 patients treated with infliximab, 14 (70 %) had a complete response, 2 (10%) had a partial response, and 4 (20%) had no response. Of note, half of the enrolled patients were ultimately diagnosed with CD, though the response rate was no different in these patients compared to those who retained a diagnosis of IC [34]. Therefore, although limited studies and no controlled trials prove that patients with IC respond to conventional IBD therapies, we believe that a high percentage of these patients will respond to medical therapy and agree with Burakoff that therapy should be based on both anatomic location and disease severity.

Several studies have examined the surgical outcomes and complications of patients with indeterminate colitis following total proctocolectomy (TPC) and ileal pouch-anal anastomosis (IPAA); however, there are no reports on the natural history of children with IC who underwent these operative procedures. Although these studies are all limited by their retrospective design, we will summarize and interpret their major findings in the remainder of this section.

Yu et al. retrospectively studied 1,437 adult patients with chronic UC and 82 patients with IC between 1981 and 1995. Median follow-up time was 6.9 years following IPAA. By 10 years following IPAA, patients with IC compared to those with UC had significantly more episodes of pelvic sepsis (17 vs. 7%; p  <  0.01), pouch fistula (31 vs. 9%; p  <  0.01), and pouch failure (27 vs. 11%; p  <  0.01). In this study, there were no significant differences in the rate of pouchitis between the two groups. Importantly, 15% of the IC patients had their diagnosis changed to CD during follow-up, compared to only 2% of those originally diagnosed with UC (p  <  0.01). When the patients re-classified as CD were removed from analysis, patients with persistent IC did not have significantly different outcomes when compared to patients with chronic UC. Therefore, in this study it appears that the higher rate of surgical complications is limited to the subgroup of patients who were ultimately diagnosed with Crohn disease [35].

In another study, McIntyre et al. compared the outcomes of 71 adult IC patients and 1,232 UC patients following IPAA. Mean follow-up was 56 months for the IC group and 60 months for the UC group. The number of bowel movements and incontinence rates were similar in both groups; however, failure rate was higher in the IC group compared to the UC group (19 vs. 8%) [36].

A third study retrospectively compared complication rates in 140 adult patients with IC and 231 UC patients matched for age, sex, method of anastomosis, presence of defunctioning stoma, and length of follow-up. The IC patients were more likely to develop minor perianal fistulae and pelvic abscess, but not anastomotic leak or major fistulae. There were no significant differences in the rate of pouch failure. As in previous studies, the proportion of patients who were diagnosed with CD following surgery was greater in IC patients than the UC controls. The same authors also compared 115 IC patients with 1399 UC controls in a prospective analysis and found no significant differences in functional outcomes, quality of life, or satisfaction with IPAA surgery [37].

More recent studies support that there is no significant difference in rate of pouchitis following IPAA in patients with UC and IC. Murrell et al. showed that the incidence of acute and chronic pouchitis and the development of de novo CD were not statistically different between UC and IC patients. That study also demonstrated that the long-term outcome following IPAA was equivalent between patients with UC and IC [38].

Taken together, these studies suggest that postsurgical complications such as pouch failure, fistula, and pelvic sepsis may be higher in adult IC patients undergoing TPC and IPAA when compared to UC patients; however, these studies suggest that the higher complication rate may be limited to the subset of patients who ultimately receive a diagnosis of Crohn disease. Arrossi et al. examined the significance of preexisting terminal ileum inflammation in IC and UC patients and how this influenced outcomes from TPC and IPAA. That study demonstrated that the severity of terminal ileal inflammation had no significant correlation with clinical outcomes following TPC and IPAA in patients with UC and IC. It went on to suggest that since surgical outcomes were the same, backwash ileitis should not be used as a criterion for classification of IC when assessing if a patient is a candidate for TPC and IPAA [39]. These studies underscore the importance of complete presurgical evaluation, as proper classification prior to surgery may lead to improved risk assessment.

Regardless of the complication rates, several of these studies have demonstrated that IC and UC patients have similar functional status, satisfaction, and quality of life following surgical treatment, and therefore, patients with IC should not be precluded from undergoing colectomy and restorative IPAA. Additional data concerning the natural history of children with IC following surgery are desperately needed before any generalizations can be made about pediatric patients with indeterminate colitis, particularly in very young children who may be at higher risk of Crohn disease when compared to older children and adults.

To address the questions, inconsistencies, and controversies in the diagnosis and classification of pediatric inflammatory bowel disease, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn and Colitis Foundation of America jointly organized a working group of pediatric gastroenterologists and GI pathologists in 2003 and 2007. The goals of this working group were to establish an agreed upon set of definitions and phenotypes, and to develop an algorithm that would improve inter-observer agreement in the diagnosis and classification of CD, UC, and IC.

Although the working group was unable to find enough data in the literature to state a definition of IC, they put forth several general recommendations. First, the group suggested that clinicians try to avoid overuse of the diagnosis of IC, and specifically stated that the following criteria do not preclude a diagnosis of UC in children with colitis: backwash ileitis, rectal sparing, histologic patchiness, periappendiceal inflammation, and gastritis. The committee also recommended that for patients diagnosed with IC based on symptoms highly atypical for UC such as ileal aphthae, backwash ileitis in a patient with left-sided colitis, profound growth failure, large oral aphthae, or absolute rectal sparing, clinicians should precisely specify the reason(s) for this diagnosis rather than UC or CD. The committee further recommended patients given a provisional diagnosis of IC undergo additional endoscopic and radiographic evaluation after 1 year or during the next disease exacerbation to try to establish a definitive diagnosis, while acknowledging that partially treated disease may have a patchy distribution [1].

Patients with indeterminate colitis are a heterogeneous group, and controversy exists regarding the diagnostic criteria for this condition. Marked variability in the usage of this term among physicians has resulted in widespread differences in the prevalence of this condition and has limited our understanding of the natural history. Additionally, patients with IC are often excluded from clinical trials, further limiting our understanding of both the clinical course and response to therapy, and this lack of evidence is particularly problematic in the pediatric population. We conclude that efforts should be made to standardize diagnostic criteria and to prospectively characterize the clinical course and response to therapy by a combination of observational and randomized studies. In the meantime, we believe that indeterminate colitis represents a mixture of patients with UC, patients with CD, and patients in whom, after several years of follow-up and re-evaluation, the diagnosis remains “indeterminate.” It appears that pediatric patients with IC are ultimately evenly divided between reclassification as UC or CD; however, very young children may more commonly have a final diagnosis of CD. We advocate medical treatment with agents that are effective in both CD and UC (i.e., steroids, salicylates, immunomodulators, and infliximab), with specific therapies chosen based on disease location, severity, and estimation of risk for recurrence. Although IC patients who undergo surgical therapy such as colectomy and IPAA may be at higher risk of postoperative complications, they appear to have similar functional outcomes. As such, surgical therapy should not be withheld from IC patients with refractory disease, once an attempt has been made to re-classify their disease status.