Even in case of chronic digestive manifestations, an infectious disease remains the most frequent differential diagnosis to be considered [2, 17]. It is therefore important to collect stools for bacterial culture and parasitic pathogens at the initial evaluation of a patient with suspected IBD. Contrary to acute presentation, an antimicrobial treatment is generally not considered until laboratory tests have confirmed a specific infectious disease. Depending on the pathogen, the part of the gut involved and the symptoms may vary, leading to consideration of either CD or UC (Table 17.2).

Infection with Yersinia enterocolitica is usually associated with a mild illness in children [18], but subacute and chronic ileitis or ileocolitis have been reported [18, 19]. This can also be associated with erythema nodosum and polyarthritis. Endoscopic features include aphthoid lesions of the cecum and ileum with round or oval elevations with ulcerations. The ulcers are mostly uniform in size and shape, in contrast to CD [20]. US examination or magnetic resonance enterography (MRE) show mucosal thickening and nodular pattern of the terminal ileum and colon that can mimic CD, but also enlarged mesenteric lymph nodes [21]. In contrast to CD, fistula formation and fibrotic stenosis are not observed. Stool or biopsy sample cultures may require a specific enrichment medium, are time-consuming, and not always positive. The diagnosis can be made by serology, showing an increase (or a very high titer) of antibody in two successive sera. However, serology also has false-positives (antigenic cross-reaction with other bacteria), and false-negatives (serology is specific for only three serotypes: Yersinia enterocolitica 03 and 09, and Yersinia pseudotuberculosis).

Infection with enteropathogenic and enteroaggregative Escherichia coli (EPEC, EAEC) may be responsible for chronic diarrhea in children, especially when they live or travel in developing countries [22, 23].

Infection with Clostridium difficile leads to digestive disease ranging from self-limited diarrheal syndrome, to severe pseudomembranous colitis. Sometimes, sustained symptoms lead to consideration of the possibility of IBD. Clostridium difficile infection must be sought in children receiving antibiotics, especially beta-lactams, although it may occur without prior antibiotic therapy. Rectosigmoidoscopy, performed with care and minimal insufflation, reveals the presence of typical yellow-white pseudomembranes in approximately one-third of patients [24], and infection is confirmed by the presence of the toxin A or B in stool or by polymerase chain reaction. Nevertheless, Clostridium difficile infection can occasionally occur in patients with UC or CD, even without the use of antibiotics [25, 26], and stool toxin positivity has been reported in 5–25% of IBD patients with relapse, mostly after antibiotic exposure [24, 26]. Clinical symptoms are quite similar in both diseases, and it is recommended that stool assay for Clostridium difficile be obtained in children with IBD during acute relapses [24].

Giardia intestinalis infection can be associated with chronic diarrhea, abdominal pain, and weight loss [27], which may occasionally lead one to consider the possibility of IBD. Giardia is found in most countries in the world, the prevalence being highest in developing countries. Trophozoites or cysts of Giardia intestinalis can be found in fresh stool specimens or rectal biopsies. In some cases, it may be necessary to examine duodenal aspirations or biopsies. Jejunal morphology may be normal, although partial or even total villous atrophy has been reported [28, 29]. Failure to eradicate giardiasis can be due to hypogammaglobulinemia or deficit in secretory IgA.

Entamoeba histolytica infection occurs mostly in developing countries. Infection may be asymptomatic, or lead to a dysenteric syndrome. Demonstration of Entamoeba histolytica trophozoites and cysts in stools remains the mainstay of diagnosis. Chronic amoebic colitis could lead to clinical, radiological, and endoscopic findings that can be indistinguishable from those of IBD [30, 31]. However this differentiation is important because amoebiasis can become fulminant if the patient is treated with immunosuppressive agents for presumed IBD [32]. In these chronic manifestations, the parasite can be difficult to find in stool samples or in rectal biopsies, even using a concentration technique. The presence of high titers of antibodies in the serum may then be helpful in the diagnosis of chronic amoebiasis.

Intestinal tuberculosis remains a challenging diagnosis in developing countries, because treatments used for CD may adversely affect tuberculosis [33]. Intestinal tuberculosis involves the ileocecal region more frequently, isolated colonic location being present in only 10–25% of cases. Symptoms can be very similar to those of CD; these include diarrhea, abdominal pain, fever, weight loss, abdominal mass of the right iliac fossa, and even suppurative perineal lesions. The presence of intramural swelling, mesenteric thickness, stricture or fistula on US examination, or MRI can be encountered in both diseases [34], although the absence or minimal asymmetric thickening of colonic wall and the presence of enlarged necrotic lymph nodes favor the diagnosis of tuberculosis [35–38]. Nodules, ulcers, and strictures can be seen at ileocolonoscopy, or possibly at enteroscopy in the case of isolated jejunal lesions [39–42], but these lesions can be indistinguishable from those of CD. Usually, intestinal tuberculosis has less than four segments involved, a patulous ileocecal valve, transverse ulcers (longitudinal in CD), and more scars [43]. The characteristics of histological lesions may also be helpful, needing to perform multiple biopsies [44]: in tuberculosis, granuloma are typically bigger, often confluent, located beneath the ulcerations, and absent in noninflamed mucosa, and half of them contain caseum. Tuberculin skin test is positive in only 70–80% of patients with intestinal tuberculosis. The diagnosis may be facilitated by the presence of active pulmonary tuberculosis (but, this is only present in 20% of cases), or ascites, or large lymphadenopathy on imaging [35, 36]. Unfortunately, acid-alcohol resistant bacilli are very rarely present on direct examination of intestinal biopsies, and culture is positive in only 40% of cases. PCR for Mycobacterium tuberculosis on intestinal biopsies is better, showing an accuracy of >80% for the diagnosis of intestinal tuberculosis [45, 46]. Amplification of insertion element IS6110 that is specific for M. tuberculosis in the fecal samples [47] and the Quantiferon-TB gold, a blood test using an interferon-γ-release assay, look to be promising tools [48, 49], but their diagnostic value for the diagnosis of intestinal tuberculosis remains to be evaluated. In cases of persistent doubt, empiric treatment with antituberculosis drugs has been proposed in countries where the prevalence of tuberculosis is high, reconsidering diagnosis of CD if the patient’s condition does not improve [50]. Nevertheless, this approach is not recommended by others who advise to make every effort to reach an accurate diagnosis before starting specific therapy [33].

Primary intestinal infection with cytomegalovirus (CMV) can occur in immunocompromised children, but it is exceptional in immunocompetent children [51]. Endoscopy reveals ulcerative and hemorrhagic colitis, and histological examination of the biopsy will confirm the infection with CMV by finding typical intranuclear inclusions in the colonic mucosa, associated with immunostaining with a specific antibody. PCR of colonic tissue can also be used to detect viral DNA in the colon, although the significance of a positive result remains unclear in the absence of histological features of CMV disease. The role of this virus in exacerbations of IBD remains under debate: is it only an opportunistic agent present in inflamed tissues, or active infection which really worsens colonic lesions? [52, 53]. CMV colitis is rare in CD or mild-moderate UC [53]. In patients with severe and/or refractory UC, local reactivation of CMV can be detected in inflamed colonic tissue in about 30% of cases, but does not influence the outcome in most studies [53]. Nevertheless, treatment with ganciclovir has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies [54]. It is recommended to test for CMV reactivation via PCR and/or immunochemistry on colonic biopsies in all patients with severe colitis refractory to immunosuppressive therapy and treat with ganciclovir when CMV is detected [52, 55, 56].

Celiac disease is easily recognized in the classic mode of presentation of children who present with chronic diarrhea, anorexia, failure to thrive, and abdominal distension. Presentation is often less typical in older children who complain of abdominal pain, chronic diarrhea, anorexia, short stature, or iron-resistant anemia, symptoms that may also suggest IBD. In this situation, laboratory investigations should include specific antibodies against tissue transglutaminase, endomysium, or deamidated gliadin peptides. If these antibodies are positive, the diagnosis of celiac disease will be further confirmed by duodenal biopsy showing villous atrophy with increased number of intraepithelial lymphocytes [57].

Eosinophilic gastroenteropathy is a rare condition characterized by infiltration of the gastrointestinal tract with eosinophils [58]. Most common symptoms are vomiting, abdominal pain, and growth failure. Diarrhea associated with rectal bleeding is present in 23% of cases, especially in infants, and symptoms of protein-losing enteropathy are present in 33–100% of cases [59, 60]. Endoscopic examination may show nodularity, erythema, friability, erosions, and ulcerations in the upper digestive tract and/or in the colon [9, 59, 61]. The diagnosis is strongly suggested by a context of food allergy or the association with hypereosinophilia in the blood, which is present in 70–100% of cases [59, 61]. The presence of excessive eosinophils in the digestive mucosa will confirm the diagnosis, although it may also be encountered in CD. Gastric biopsies may demonstrate eosinophilic gastroenteropathy more consistently, most patients having more than 10 eosinophils per high-power field in the antral or duodenal mucosa [59, 62]. Allergic skin tests or serum-specific IgE against main food allergens are useful to guide dietary recommendations.

The importance of the intestine as an immune barrier is highlighted by the proximity of gut-associated lymphoid tissue to the luminal surface of the gastrointestinal tract, an external environment which is rich in microbial pathogens and dietary antigens. Significant gastrointestinal disorders leading to chronic diarrhea, malabsorption, and failure-to-thrive are frequently present in primary or acquired immunodeficiency diseases [63]. In the recent years, a significant number of monogenic diseases, affecting the epithelial barrier, the inflammatory response, or the immune response, have been recognized as the cause of IBD-like manifestations (Table 17.4). These diseases should be sought after, especially in cases of very early (<6 years) or even infantile (<2 years) onset symptoms, and often present with a distinct phenotype, that is, indeterminate pancolitis or severe ulcerative or fistulizing perineal disease [64]. Although the frontier between these monogenic diseases (currently being discovered) and classic IBD is vague, the precise characterization of the genetic defect is of importance because therapeutic options may be different in some cases, like bone marrow transplantation, for example. This emphasizes the importance of a close collaboration between pediatric gastroenterologists, immunologists, and specialists in immunodeficiency syndromes for early efficient medical care and for active research to discover involved genes.

The most frequent manifestations of immunodeficiency syndromes are recurrent, persistent, and severe or unusual infections [65]. Disturbance of the immune system in the gut may also lead to autoimmune diseases, excessive production of IgE, or malignancies [66, 67].

Immunodeficient patients may present with chronic nonspecific enterocolitis, characterized at small bowel biopsy by subtotal villous atrophy with acute and chronic inflammatory cell infiltration of the lamina propria [65, 68–79]. This chronic nonspecific enteropathy is not responsive to a gluten-free diet and occurs in several immunodeficiency disorders, affecting humoral response (X-linked agammaglobulinemia, IgA deficiency, common variable immunodeficiency), T-cell function (Wiskott-Aldrich syndrome, acquired immunodeficiency syndrome), or both (combined immunodeficiency). In some cases, strictures of the intestine may develop [68–71]. In these patients, it is important to rule out infection with opportunistic bacteria or parasites, and also with more common pathogens, such as rotavirus, adenovirus, picornavirus [65]. In rare patients, the cause of the chronic enterocolitis is a disease affecting the epithelial barrier (Table 17.4).

Enterocolitis that resembles CD is mostly associated with neutropenia or defects of phagocytic function. Patients with chronic granulomatous disease may present with chronic colitis, perirectal abscesses and fistulae, and antral narrowing [72, 73]. The similarity with CD also includes endoscopic appearance, radiographic abnormalities, and even histological features showing granulomata and giant cells in the digestive mucosa. Nevertheless, a paucity of neutrophils, an increased number of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris suggest chronic granulomatous disease [74]. Patients with leukocyte adhesion molecule deficiency, a rare disorder of phagocytic function, also present with oral and perineal involvement that may be mistaken for CD. These manifestations include stomatitis with pharyngitis, gingivitis with periodontitis, ischiorectal abscesses, and distal ileocolitis [75]. Other disorders of neutrophils, such as congenital neutropenia, glycogen storage disease type 1b, and the Hermansky-Pudlak syndrome [76], are responsible for CD-like enterocolitis. The same presentation may be caused by T-cell or B-cell defects, IgA deficiency, and acquired immunodeficiency syndrome [63, 77].