In establishing a diagnosis of IC , it is essential to exclude other causes of colitis such as infections ( Clostridium difficile, Yersinia, Mycobacterium tuberculosis, Entamoeba histolytica, E. coli 0157:B7 or other verocytotoxin-producing strains, drugs (nonsteroidal anti-inflammatory drugs, NSAIDS), Behçet’s, malignancy, vasculitis , and certain immunologic disorders. Immune deficiency disorders which may include chronic intestinal inflammation are: chronic granulomatous disease, Wiskott–Aldrich syndrome, common variable immunodeficiency disease (CVID), immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and glycogenosis type 1b [2, 20, 21] .

Geboes and Van Eyken published an in-depth description of the histologic features observed in normal intestinal mucosa as well as the changes seen in patients with IBD [22]. Focal or diffuse plasmacytosis at the base of the mucosa and crypt architectural changes are strong predictors of IBD. However, it is important to recognize that these findings develop during the course of IBD. Thus, while basal plasmacytosis was seen within 15 days of the onset of IBD, crypt distortion was observed at 16–30 days in only 25 % of patients but increased to 75 % after 4 months. In comparison to adults, children < 10 years of age with new-onset UC show less crypt architectural changes and more rectal sparing than older patients. In addition, 4–8 % the initial biopsies were within the normal range. The authors suggested that the presence of basal lymphoplasmacytosis, seen in 58 % of cases, should lead to suspicion of underlying IBD. It in this group of children and adults with short history of disease onset, mild basal lymphoplasmatocytosis and no or minimal crypt architecture abnormalities that the term “IBD-U” has been proposed [12, 22, 23] .

Patients with IBD-U clearly have IBD but the definitive features of UC or CD are absent. IBD-U may also be appropriate for cases of PSC where rectal sparing and patchy or focal inflammation are also more frequently observed [12]. Riddell stated that to differentiate IC lesions from CD lesions in resected specimens, submucosal and subserosal lymphoid aggregates away from areas of ulceration, non-necrotizing granulomas and skip areas should be absent. This is particularly true where there is nonspecific ileal involvement or gastritis with negative stains for H. pylori [24].

In cases of fulminant colitis, overlapping features between UC and CD (relative rectal sparing, focal inflammation or deep fissuring ulceration) result in a diagnosis of IC in approximately 10–15 % of patients [7, 22]. It is also important to recognize that some medications, such as corticosteroids or aminosalicylic acid (ASA) preparations, may change the diffuse histologic appearance in UC to a more focal appearance [6, 17]. Thus, slides from the original or pretreatment colonoscopy should be reviewed when considering a diagnosis of IC [23, 24].

Although histologic criteria would appear to allow differentiation between CD and UC, in 2002, Farmer et al. documented disparity among pathologists reviewing cases of colonic IBD [25] The diagnosis of gastrointestinal pathologists differed from that of the referring institution in 45 % of surgical specimens and 54 % of biopsy specimens. Of 70 cases initially diagnosed with UC, 30 (43 %) were changed to CD or IC; in contrast, 17 % of cases initially diagnosed with CD were changed to UC or IC .

The performance of upper gastrointestinal endoscopy with biopsies (esophagogastroduodenoscopy, EGD) identifies some patients with CD whose colonoscopy biopsies are indeterminate [12, 19]. Kundhal et al. reported that while diffuse nonspecific gastritis occurred with similar frequency in children with either CD and UC (92 vs. 75 %), focal antral gastritis was significantly more common in CD than UC (52 vs. 8 %) [26]. The authors defined focal inflammation as “localized inflammation of the gastric pits, glands, or foveolae by mononuclear and polymorphonuclear leukocytes bordering directly on uninflamed mucosa.” This is similar to the statements previously published by Riddell [24]. However, a recent assessment of focal enhancing gastritis (FEG) in 262 pediatric patients showed that while FEG was highly associated with IBD, it did not reliably distinguish between UC and CD [27]. Granulomas in the stomach or duodenum provide evidence confirming the diagnosis of CD even in endoscopically normal-appearing mucosa [24]. Hence, performing an EGD should be part of the initial evaluation of pediatric patients for IBD .

We evaluated the role of p-ANCA and anti-Saccharomyces cerevesiae (ASCA) to determine whether we could identify UC and CD in pediatric patients previously diagnosed as IC [5]. While p-ANCA was positive in 68 % of those favoring UC, and ASCA positive in 37 % of those favoring CD, 86 % of our patients with IC were both p-ANCA and ASCA negative.

Joossens et al. correlated serologic markers with prospective follow-up evaluation in 97 adult patients initially diagnosed with IC [8]. After a mean follow-up of 6 years, 32 % of the adult patients with IC were reclassified as having UC or CD, half of whom were positive for p-ANCA or ASCA. However, almost half of the patients with IC (48.5 %) remained p-ANCA/ASCA negative and continue to have characteristics of IC even 10 years after the initial diagnosis [8].

Recently, Sura et al. utilized serology (pANCA, ASCA, and anti-OmpC) in 117 adult patients with IC and reassessed their disease type at 1 year [28]. P-ANCA identified 78 % of patients who subsequently were diagnosed with UC compared with only 18 % sensitivity for ASCA to predict a subsequent diagnosis of CD.