Although IBD can occur at any age, up to 25 % of patients develop symptoms during childhood and adolescence [1, 2]. Some epidemiological studies from USA and Europe have shown a steady inrise in the overall mean annual incidence of pediatric IBD around the world, that seems to be primarily due to an increase in the incidence of CD [1, 2, 6]. CD is unequally distributed all over the world, with highest rates occurring in Western and Northern countries, and with a decreasing gradient from North to South and from West to East [7–11]. The worldwide highest prevalence of pediatric IBD is reported from the Canadian Ontario region, with approximately 56 IBD patients for 100,000 inhabitants [8]. Epidemiological observations from this area, using health administrative data, have indicated an increasing incidence of pediatric CD from 9.5 in 1994 to 11.4 in 2005 per 100,000, with unchanged incidence rates for pediatric ulcerative colitis (UC; 4.1–4.2) [9]. In Europe, a recent study based on the registry of chronic inflammatory intestine diseases in North-West pf France (EPIMAD) indicated a mean annual incidence rate of 2.6 for pediatric CD [11]. The largest population-based study of incidence of pediatric IBD in the USA was reported from Wisconsin, estimating an yearly incidence of IBD of 7.05 per 100,000, the incidence of CD being 4.56, that is, more than twice the rate of UC (2.14) and a prevalence of 48–71 per 100,000 [12]. A recent study estimating the prevalence of IBD in the USA using a large, multistate sample, reported a prevalence of CD in children of 43/100,000 [13]. Factors contributing to the evident increase in the global incidence could be a greater case ascertainment, the widening case definition, earlier onset in predisposed individuals, and greater access to health care; however, there is a wide agreement that the rising incidence of pediatric IBD is due to a real increase in the number of affected children [14]. It has been postulated that the “Westernization” of different societies accounts for the progressive rise in the incidence of the disease also in previously low-incidence areas, including Japan [15], other Asian countries [16], and some Eastern European countries [17] .

Pediatric IBD present specific phenotypic and demographic differences when compared with adult-onset disease. While CD and UC occur with equal distribution in adults [18], it has been reported that in childhood CD is more frequently diagnosed than UC [19, 20]; moreover, while in adults there is an equal male to female ratio (or a mild female predominance), all pediatric IBD cohort studies or registries indicate a male predominance [20]. In pediatric CD, most patients have an extensive disease, ileocolonic or colonic, and distinction of UC from colonic CD may be not uncommonly challenging [21]. As recently confirmed by EPIMAD registry, children with CD are more likely to have upper gastrointestinal involvement than their adult peers [11]. Moreover, disease severity seems to differentiate pediatric-onset CD: children often present an inflammatory or nonstricturing, nonpenetrating disease, while complicated disease is fairly unusual at presentation. However, even with treatment, many data demonstrate that inflammatory CD progresses to stricturing and penetrating disease in several children [11, 20]. Adult disease begins more often with stricturing or penetrating disease, with a lower trend of disease progression than pediatric-onset disease .

The most accepted hypothesis for the pathogenesis of CD is that the interaction between luminal contents (i.e., the intestinal microbiota) and the mucosa leads to a dysregulated inflammation in a genetically predisposed host. Several microorganisms have been considered as potential causative agents for CD, including Mycobacterium paratuberculosis, Listeria monocytogenes, novel Burkholderiales, Escherichia coli [22, 23]. Recently, strains of adherent-invasive E. coli (AIEC), capable of adhering to and invading epithelium, and to replicate in macrophages, have been described in adults and children with CD [24, 25]. Nevertheless, there are no strong data to support a role for any of these microorganisms as the causative factor in the etiology of IBD. Some of the most interesting findings in the pathogenesis of IBD come from genetics. The importance of genetics in CD was strongly suggested by family, twin, and phenotype concordance studies. Monozygotic twins exhibit phenotypic concordance in 50–70 % of CD patients, and their relative risk of developing CD is 800-fold greater compared to the general population [26]. Recently, the discovery of several susceptibility genes has further supported the importance of genetic predisposition in CD [27]. After the pivotal study of Hugot et al. in 2001, who discovered the association of variants of the NOD2 gene with ileal CD [28], and the discovery of the correlation between variants of interleukin ( IL)23 receptor gene and both CD and UC in 2006 [29], the number of IBD genetic associations discovered has dramatically increased. More susceptibility loci have been quickly identified, such as autophagy genes, ATG16L1 and IRGM [30]. In the past decade, the implementation of genome-wide association studies (GWAS) has significantly advanced our knowledge on the importance of genetic susceptibility in IBD [31, 32]. To date, the GWAS performed have identified more than 70 risk-conferring loci for CD [31]. GWAS have revealed a substantial overlap in genetic risk loci between CD and UC. However, some genes are quite different for CD or UC, clearly denoting the genetic heterogeneity of the two forms of IBD, each one of them showing distinctive and shared genetic associations. For instance, NOD2, autophagy genes, and ITLN1 are unique for CD [31]. Despite the discovery of a massive number of susceptibility genes for IBD, we are still far from understanding the mechanism by which such genetic variants cause the intestinal inflammation . The challenge for basic IBD researchers is now to identify how genetic abnormalities influence pro-inflammatory pathways, providing information that could directly improve the clinical management. A number of pro-inflammatory pathways have been elucidated, in some cases enabling the development of specific interventions. For instance, NOD2 gene-defected patients have an impaired ability to recognize and process bacterial products, and this may lead to an inappropriately innate immune response. Some CD patients with variants of the autophagy genes ( ATG16L1 and IRGM) have a defective capacity to process cell degradation products, as well as bacteria, and therefore an insufficient ability to eliminate pro-inflammatory factors [33]. One of the most important discoveries in the field of genetics of pediatric IBD is the recent identification of impaired IL10 signaling in some forms of very-early-onset (within the first months of life) CD [34]. The common characteristics of these patients are a very early onset of an aggressive CD colitis, treatment-resistant, with perianal involvement. This form of CD is due to homozygous mutations in either IL10RA or IL10RB, which encode subunits of the IL10 receptor, or for IL10 itself [35]. One could speculate that this form of IBD with a monogenetic inheritance could identify a subset of patients with a “more” Mendelian transmission, opening new horizons of research and also expectations to understand the definite mechanisms underlying these diseases.

CD is characterized by a transmural inflammation that can occur anywhere in the gastrointestinal tract, from mouth to anus. While the terminal ileum is the most common site of CD, about 60 % of children have an extensive ileocolonic involvement and 20–30 % an isolated colonic disease [18]. CD typically presents in any age group with a constellation of abdominal pain, diarrhea, weight loss, and poor appetite; however, short stature and predominant perianal disease are further significant presenting features in pediatric CD. Impairment of linear growth and associated delay in sexual development can occur before the onset of intestinal symptoms and can dominate the clinical presentation [36]. Growth failure is a unique characteristic of pediatric-onset CD: It is defined as linear growth at or < 2 standard deviations (SD) below the mean for age, or decreased growth velocity, and can occur in 15–20 % of children with CD [37]. The onset of growth failure is usually insidious, and any child or adolescent with impairment of the linear growth should have an appropriate initial diagnostic evaluation for IBD [18]. The presence of growth and pubertal delay is a key factor in the management of pediatric IBD . Maintaining adequate nutrition, minimizing inflammation, and maximizing corticosteroid-free treatment remain a crucial part of managing the potential growth stunting effects of active IBD, most specifically of small bowel CD. During the clinical course of CD, growth failure has been reported in up to 40 % of children with CD and a final height below the fifth percentile is reported in 7–30 % of patients with pediatric-onset CD [38, 39]. Growth failure in CD originates from different factors, such as malnutrition with decreased intake, increased gastrointestinal losses, malabsorption, and medication effects. All these components can certainly impact an individual’s nutritional state. In addition, it is now widely agreed that inflammation process per se may directly inhibit linear growth and play a major role in the etiology of growth retardation [40]. Inflammatory mediators such as IL-6 and TNF-α are crucial factors in reducing plasmatic levels of insulin-like growth factor 1 (IGF-1), the peripheral mediator of the growth hormone [41]. In fact, impressive catch-up growth can be observed as soon as remission of intestinal inflammation is achieved. It is essential that height, weight, pubertal staging, and bone age are accurately and regularly measured and recorded in young patients with CD. Nutritional supplementation and need for “catch-up” growth should be an important part of the evaluation of a pediatric CD patient. Delay of pubertal onset is also common in active pediatric CD, and also the duration of puberty can be impaired. Active or relapsing disease during the years following the onset of puberty may slow or even arrest the progression of puberty. Moreover, pubertal delay affects estrogen and androgen levels, which are important for normal bone mineralization, contributing to the development of osteoporosis and osteopenia [42]. Inducing and maintaining disease remission before and during the pubertal years is thus crucial in order to ensure the attainment of final predicted height, avoiding a missed pubertal growth spurt.

There is no gold standard single test allowing a definite diagnosis of CD . It is the combination of family and personal history, physical examination, and subsequent laboratory, imaging, and endoscopic assessment that leads to the correct diagnosis. Nevertheless, a subset of 10–15 % of children with IBD confined to the colon receive an initial diagnosis of inflammatory bowel disease unclassified (IBD-U), and they will be subcategorized only during follow-up [18]. The first diagnostic issue is whether the presenting symptoms are related to CD. In the presence of classic clinical presentation, differentiating CD from other diseases with initial similar symptoms may be relatively simple [43]. However, in a child with bloody diarrhea and infectious etiologies , like Salmonella, Yersinia, Shigella, E. coli, etc., must be excluded. It is also important to evaluate and rule out vasculitides (such as Henoch–Schönlein purpura, and hemolytic–uremic syndrome) or allergic colitis. An abdominal pain mimicking CD may be determined by other conditions, such as intestinal lymphoma, ovarian cyst, appendicitis , or intussusception . Figure 28.2 shows the suggested diagnostic workup of children or adolescents with suspected IBD .

The current goals of treatment of pediatric CD are to induce and maintain a prolonged remission, minimizing drug toxicity. At long term, they should include preventing relapses, optimizing growth and pubertal development, and improving quality of life. Modern expectations of CD therapy call also upon the concept of mucosal healing, and, eventually, of deep remission (i.e., clinical remission, biomarker remission, and mucosal healing) [68]. The introduction of these outcomes may be the best way to alter the natural course of these diseases by preventing disability and bowel damage [69]. This may be of clinical relevance in children with CD, given the long-term consequences of early-onset aggressive disease presentation. Pediatric CD therapy employs many of the same treatment regimens as their adult counterparts. There are only a few well-designed clinical trials performed in children, therefore much of the evidence given is based on adult data. Conventional therapy is based on the escalation of drugs, from those with a better safety profile but a lower efficacy (antibiotics, mesalazine, sulfasalazine) to those with improved efficacy but a greater risk of side effects (steroids, immunomodulators, biologicals, surgery). This “step-up” approach is applied in most cases of pediatric IBD (Fig. 28.3). The advantages of “step-up” management are mainly to reserve more toxic drugs for those patients with a demonstrable “need” for more intensive therapy [70]. However, potential disadvantages include the observation that conventional therapies have not altered the disease course towards disease complications (strictures and fistulae) or the need for surgical procedures. Hence, pediatric gastroenterologists are moving towards an “early aggressive” approach, with the aim of changing the natural history of the disease [70]. So far, there are no definite proper criteria to select which patients will certainly benefit from an early aggressive approach [71]. The knowledge of these genetic, laboratory, or clinical markers will be the challenge in pediatric IBD research.