Disease location is not fixed over time. In a recent report from Scotland, at diagnosis extensive disease including the ileum, colon, and upper GI tract (disease location characterized as L3  +  L4 by the Montreal classification [8]) was found in 31% of children [9]. However, among a subgroup of 149 children with less extensive disease at diagnosis who were followed at least 2 years after diagnosis, extension of CD was noted in 39% [9].

Disease behavior also evolves over time. At initial diagnosis, the vast majority of children have an inflammatory disease phenotype. However, as time goes on, an increasing proportion expresses a changing phenotype, characterized as either stricturing or penetrating. This has been documented clearly in data derived from the pooled observations from three ­multicenter North American pediatric IBD registries [10]. Among 796 children followed prospectively from diagnosis, 96 (12%) presented with a stricturing or penetrating CD ­phenotype. Among the 700 who had an inflammatory ­phenotype at presentation, 140 (20%) developed stricturing or penetrating disease after a mean of 32 months of follow-up [10], a finding strikingly similar to the 24% rate of complicated CD behavior described after 4 years in a pediatric study from Scotland [9]. Similar observations over extended periods of time have been reported in population-based studies in adults from both France [11] and New Zealand [12] (Fig. 7.2). In the latter study, a comparison of 630 subjects with adult-onset ­disease and 85 children diagnosed before age 17 years revealed no difference in the rate of progression from inflammatory to either stricturing or penetrating disease phenotype [12].

Racial differences may affect the frequency of complicated CD, as a study from Baltimore has demonstrated more frequent stricturing and penetrating disease in black children compared to white children seen in the same university-based practice [13]. The risk for phenotypic change may also be associated with the presence of specific genetic allelic variants. For instance, patients with NOD2/CARD15 variants appear to be at increased risk for fibro-stenosing complications [14, 15], while those with abnormalities in the IBD5 gene may be more likely to develop perianal fistulae [16]. Children at risk for stricturing or internal penetrating complications have also been shown to be more likely to have increased immune responses to microbial antigens, characterized by the presence of high titer antibodies such as anti-ompC and anti-I2 [10, 17].

For a significant subgroup of children with Crohn disease, growth impairment is an important characteristic of the disease’s natural history. While acute weight loss commonly is present in children with both ulcerative colitis and Crohn disease, impairment in linear growth is primarily a problem in the latter condition. At the time of initial diagnosis, about a third of children with Crohn disease has already dropped two or more major growth channels from their preillness growth percentiles [18, 19]. More dramatically, 88% have delayed height velocity at diagnosis [20]. Over time, periods of significantly impaired growth can be seen in about 60% of children and adolescents [19]. While catch-up growth is often possible, 7–35% of children diagnosed during the 1970s and 1980s had final adult heights that were significantly shorter than expected [19]. As a group, young adults who develop Crohn disease as children have adult heights skewed towards the lowest percentiles. In reports from both Chicago and New York, ∼50% of young adults with childhood onset Crohn disease have final adult heights less than the 10% for the general population, and ∼25% have adult heights less than the 5% [18, 19]. While therapies including enteral nutrition [21] and infliximab [22, 23] have improved growth in the short to medium term, current therapies have not yet been demonstrated to provide a long term reversal of growth impairment.

An important characteristic of Crohn disease in children as well as adults is the tendency to develop corticosteroid dependence. Population-based studies in adults from both Olmsted County, MN [24] and Copenhagen County, Denmark [25] demonstrate similar findings. These studies document that acute response to corticosteroid therapy in adults with Crohn disease is reasonably good (complete remission in 48–58%, partial remission in 26–32%, and no response in 12–20%). However, long-term response is less optimal, with rates of corticosteroid dependence of 28–36% at 1 year [24, 25].

A similar risk for corticosteroid dependence is evident in children. As in adults, acute response to a course of corticosteroids is good. In data derived from a multicenter North American observational registry, among newly diagnosed children with moderate-severe Crohn disease activity treated with corticosteroids, 60% have a complete and 24% a partial clinical response by 3 months after initiation of treatment [26]. However, despite concomitant use of immunomodulators in many of these children, 31% are corticosteroid dependent at 1 year. In fact, without infliximab, only 46% of the children in this study maintained a corticosteroid free remission to 1 year following an initial course of corticosteroids [26].

The need for surgery represents another important aspect of the natural history of Crohn disease in children. Table 7.1 summarizes published rates for surgery in children from a variety of different countries. Data from Denmark estimate a mean yearly operation rate of approximately 13%. The cumulative probability of surgery in this Danish cohort at 20 years was estimated to be 47% [5]. A more recent multicenter pediatric experience from the USA estimates the cumulative incidence of surgery to be 6% at 1 year, 17% at 5 years, and 28% at 10 years after diagnosis [31]. Similarly, a pediatric study from Scotland noted resection rates of 20% at 5 years and 34% at 10 years [9]. The presence of variant NOD2/CARD15 alleles appears to increase the risk for surgery, presumably due to the known association of these genetic polymorphisms with the development of fibrostenotic ileal disease [14, 15]. The presence of anti-Saccharomyces cerevisiae antibodies also appears to be associated with increased risk for surgery [10, 31].

The effect of immunomodulatory therapy on the need for surgery remains an open question. An analysis from France evaluated a series of successive 5-year adult CD cohorts [32]. Although there was a significant increase in the use of immunomodulatory therapy over time, there was no associated change in the rate of surgery [32]. By contrast, multivariate analysis from a similar series of 5-year adult CD cohorts from the United Kingdom identified the early use of thiopurines (within 3 months of diagnosis) to be associated with a marked reduction in the rate of surgery [33].

The benefit of infliximab therapy in decreasing surgical rates is equally unclear. In a Spanish retrospective assessment of infliximab therapy used in a “step-up” fashion, no significant decrease in surgical rates could be identified in patients receiving infliximab compared to those not receiving the treatment [34]. However, other studies reach the opposite conclusion. For instance, in a study utilizing data from a combined Danish and Czech collaboration, surgical rates in adults 40 months after starting infliximab were 20–23% in infliximab responders compared to 76% in nonresponders [35]. Similar findings in children have been reported, with surgical rates 50 months after starting infliximab of 10% in patients maintained on the biologic compared to 70% in infliximab failures [36].

Although there are little hard data published to document clinical experience, following surgery, the natural history of Crohn disease is to recur both endoscopically and symptomatically. In retrospective adult studies, symptomatic recurrence of Crohn disease following so-called curative resection (complete resection of all visibly evident disease) is reported to be 20–30% within the first year after surgery, with increasing likelihood in each subsequent year [37]. One or more additional surgeries are required in 15–45% of adults within 3 years, 26–65% in 10 years, and 33–82% in 15 years [25]. Controlled trials document severe endoscopic recurrence after placebo treatment in 43–79% of adult subjects by 1 year after surgery and in 42–85% of subjects after 2 years [38–43].

In children, the overall rate of clinical recurrence is estimated to be 50% at 5 years after initial resection [29]. However, the site and extent of preoperative Crohn disease can affect the recurrence free interval, such that it is estimated that 50% of children with extensive ileocolitis recur within 1 year, compared to a 50% recurrence rate after 5 years in children with ileocecal disease, and a 50% recurrence rate after 6 years if preoperative disease is confined to the small bowel [29]. Additional risk factors for postoperative recurrence in children are summarized in Table 7.2.

Whether children with Crohn disease are at increased risk for malignancy over their lifetime is unknown. No data derived from a population with childhood onset Crohn disease have been reported. Studies in adults, however, suggest that Crohn disease patients do have an excess of malignancies compared to the general population. In a population-based cohort from the Uppsala region of Sweden, there was an increased relative risk of colorectal cancer of 2.5 (95% confidence interval 1.3–4.3) in patients with Crohn disease [46]. Duration of illness and gender did not affect risk, but those subjects with colonic disease had a greater risk of colorectal disease than those with only small bowel involvement. Of note, however, among those subjects with any colonic involvement diagnosed with Crohn disease before the age of 30 years, the relative risk of colorectal cancer increased to 20.9 (95% Confidence interval 6.8–48.7) [45]. By contrast, a similar population-based study from Denmark identified a relative risk of colorectal cancer of only 1.1 (95% confidence interval 0.6–1.9), and no risk differences were noted in different subgroups of patients [47]. A similar modest increase in colorectal cancer risk (1.9; 95% confidence interval 0.7–4.1) was found in a population-based study from Olmsted County, MN [48].