It is now recognized that our current culture methods are capable of identifying only a small subset of microorganisms that inhabit the intestine, and we cannot reliably culture all pathogens from a stool sample. In addition, a small number of documented cases of infectious colitis last longer than 30 days [5, 6]. Therefore, not every patient with bloody diarrhea and negative stool cultures has inflammatory bowel disease as the cause of their colitis. Epidemiologists utilize strict criteria (e.g., bloody diarrhea for over 6 weeks, or greater than two episodes of colitis within a 6-month period) to determine if a patient has ulcerative colitis [7, 8]. However, the practicing clinician does not wish to wait 6 weeks or longer to determine whether or not to treat the patient for IBD. Thus, in children with bloody diarrhea and negative stool cultures, performance of colonoscopy with random biopsies for histology early in the course of suspected IBD is important. Certain clinical and laboratory parameters (including chronic history of gastrointestinal complaints, growth failure, perianal tags, abnormal liver function tests, family history of IBD, and iron deficiency anemia) strengthen the argument for early colonoscopy in the individual patient. In contrast, other findings (fever, positive fecal leukocytes or calprotectin) can be seen in both IBD and infection [9]. It is also important to remember that a patient may have laboratory finding suggestive of infection, and also have new onset IBD. The new, ultrasensitive C. difficile PCR test has been particularly problematic in this regard, as the test is so sensitive it may not be able to differentiate between C. difficile colonization and C. difficile infection in the IBD patient [10].

Studies suggest that colonoscopy with careful examination of biopsy samples will allow differentiation between ASLC and IBD. In a cohort of 114 adults with acute colitis of less than 5 days duration, Mantzaris et al. performed colonoscopy at disease onset and subsequent flexible sigmoidoscopies at 1, 3, 6, and 18–24 months after initial illness. At 12 months after the onset of illness, a total colonoscopy was performed. Ultimately 68 patients were diagnosed with ASLC, and 46 patients were diagnosed with IBD (42 UC, 4 Crohn ileocolitis). Patients with UC had a significantly higher prevalence of diffuse erythema (100% vs. 25%), granularity (100% vs. 8%), and friability (100% vs. 12%) than patients with ASLC; in contrast, patients with self-limited colitis had a significantly higher prevalence of patchy erythema and microaphthoid lesion [11]. Histologic features identified reported in chronic inflammatory bowel disease but not in ASLC include: basal plasmacytosis, basal lymphoid aggregates, crypt branching, crypt atrophy, and the presence of Paneth cells in the left colon [6, 11–13]. Other findings, such as focal crypt destruction or superficial aphthous lesions, do not reliably differentiate between ASLC and IBD [14]. In one pediatric study, 8 of 29 patients with focal active colitis (cryptitis with an adjacent increase in lamina propria macrophages and T lymphocytes) were ultimately diagnosed with Crohn disease [15]. In another more recent study of focal active colitis in 90 adults, medications (NSAIDs) and infection were the most common causes, but 15% of patients who initially presented with focal active colitis on biopsy went on to develop IBD [16].

In summary, in a patient with bloody diarrhea and negative stool cultures, the performance of colonoscopy with random biopsies throughout the colon may provide the clinician and pathologist with evidence that proves or disproves the diagnosis of inflammatory bowel disease. Endoscopic findings suggesting IBD include erythema, granularity, and friability, and histologic evidence supporting an IBD diagnosis include crypt distortion, crypt branching, and basal lymphoplasmacytic infiltrate. While the patient with focal active colitis on biopsy has a 15–25% chance of developing IBD over time, this histologic finding alone is not enough to make a diagnosis.

The role of barium radiography in differentiating between CD and UC is well established, and most of the initial epidemiologic studies that classified these two diseases utilized the findings on barium radiography to assist in the differentiation of these two conditions. In Crohn disease of the ileum, the terminal ileum, ileocecal valve, and cecum demonstrate various degrees of narrowing, ulceration, and stenosis [54]. In contrast, in UC with backwash ileitis the terminal ileum has a granular appearance, the ileocecal valve is wide open, and the cecum is normal caliber. Some authors have questioned the utility of barium radiography in otherwise healthy patients with a normal ileoscopy, it is unclear how often the findings of a barium study change the diagnosis [54].

While at one time, experts recommended that all children with IBD undergo an upper GI with small bowel follow through at the time of initial diagnosis, newer imaging modalities are currently replacing the barium meal at many centers. The expertise and the use of non-barium imaging modalities (ultrasound, nuclear medicine, computed tomography, and MRI studies) in the differentiation of CD from UC vary greatly from center to center. All of these modalities have been utilized in the diagnosis of IBD patients, with good results [19, 55–57]. However, the benefits in diagnosis must be weighed against the study’s cost and the radiation exposure to the patient [58].

The most appealing of these newer modalities is MRI, because MRI generally provides reasonable quality images without exposure to radiation. Of the above modalities, MRI scan of the bowel offers the potential benefit of accurate anatomic localization without radiation. Recent studies suggest that MRI can differentiate between CD of the ileum and backwash ileitis by evaluating bowel wall thickness of the ileum [19, 56]. A prospective study in children comparing MRI to CT scan suggested comparable sensitivity and specificity for detecting small bowel findings such as bowel wall thickening, mesenteric inflammation, fistula, and abscess [59]. However, in this clinician’s experience, MRI is highly operator dependent, and nonspecific abnormalities such as “jejunal enhancement” may mislead the radiologist and clinician. Thus, I recommended not changing a patient’s diagnosis from UC to Crohn disease simply on the basis of a jejunal MRI finding alone. To have pancolonic “UC-like disease” and true jejunal inflammation is extremely rare. If an MRI demonstrates a nonspecific abnormality in the mid small bowel, such a finding should be confirmed by some sort of other modality (either another type of imaging study or enteroscopy).

A number of serum markers of variable sensitivity and specificity are currently available as a “diagnostic panel for inflammatory bowel disease.” Serology is discussed in greater detail elsewhere in this book (Chap. 18). The utility of serology in differentiating between CD and UC is highly controversial, and there remains doubt if this test has utility in routine clinical pediatric practice [60, 61]. The anti neutrophil cytoplasmic antibody (pANCA) is identified in approximately 75% of patients with ulcerative colitis, and up to 20% of patients with Crohn disease [62–64]. In contrast, antibodies to Saccharomyces cerevisiae antibody (ASCA) are present in 40–80% of patients with Crohn disease, are rarely if ever seen in UC, and are preferentially associated with ileocecal Crohn disease.

As previously discussed, the current gold standard for diagnosis of CD and UC is based on endoscopy and histology, not on serology. However, there is increasing evidence, that serologic markers may be predictive of pouch complications, including Crohn disease of the pouch. Coukos et al. identified two markers (ASCA and CBir) as predictive of the risk of pouchitis, pouch fistulae, or need for pouch takedown [65]. In a second study, Melmed et al. identified family history of Crohn disease and positive ASCA serology as risk factors for development of Crohn disease of the pouch [66]. Therefore, while we do not routinely obtain serologic markers in most straightforward cases of IBD, we do consider them in children with severe colitis that may be facing surgery.