In the last several years, inflammatory bowel disease (IBD) has been extensively characterized, resulting in efficient (but not harmless) therapies such as with anti-cytokine biologicals. In spite of this remarkable progress, the pathogenesis is still confusing, but on a higher level, and a therapy to control or, better, to cure this chronic inflammation is still a long way off. The complexity of IBD is especially challenging in children—is the pathogenesis, genetics (CARD15, tumor necrosis factor-α 308 A) (1,2), immunology, diagnosis and therapy of IBD not heterogeneous enough? Even in its clinical presentation, IBD heterogeneity is broader than previously known. Although children with IBD have been studied more systematically, with the establishment of registries, it has become obvious that younger children seem to present with special features (3,4).
In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Ruemmele et al. (5) analyse the data of 10 infants with onset of IBD in the first year of life, adding a small but important stone to the mosaic of IBD. Compared with older IBD patients, there was a predominance of colonic involvement (with rectal bleeding) in all patients. Furthermore, but not surprisingly, this patient group required (1) more aggressive therapeutic efforts to achieve remission, (2) parenteral nutrition, (3) the application of steroids, azathioprine and cyclosporine medication, (4) more surgical interventions, and (5) had more relapses. The authors carefully looked for pathogenetic factors such as bacterial infections, use of antibiotics before disease onset and breastfeeding among others, but the study group was too small to find any significant data about them. The average duration of breastfeeding was 2 months in the patients in the Ruemmele et al. study. These factors need to be readdressed in larger cohorts. Because of the progression of the clinical manifestations and the extent of therapy, the long-term treatment of infants with IBD onset is of great concern. A follow-up of 2.5 years for the reported patients is short. There is special interest in the long-term follow-up of disease with onset in the first year of life. Another aspect of follow-up is important considering that 2 of the 10 patients presented with a milder course: Such patients must receive diagnostic reevaluation during follow-up to confirm IBD or to exclude other causes of bowel inflammation such as food allergy. The high number of patients with indeterminate colitis (6 of the 10 patients in the present study) is an additional reason for a careful reevaluation in the follow-up.
What is the challenge in diagnosing IBD in infants? The differential diagnosis of IBD is broader the younger the child is and includes not only allergic and infectious disorders but also rare genetic defects such as autoimmune enteropathy, septic granulomatosis, glycogenosis 1b, carbohydrate-deficient glycoprotein and Hermansky-Pudlak syndrome. Moreover, the pediatric gastroenterologist must be aware of congenital anomalies, including fistula in ano. The assessment of the small bowel is of diagnostic as well as therapeutic relevance in IBD. Because small bowel followthrough and abdominal CT are stressful, cause high exposure to radiation, and are not sensitive, especially for infants, the pediatric gastroenterologist faces a diagnostic dilemma.
The report of Ruemmele et al. is of great relevance not only because they describe a new phenomenon but also because it opens a new door to the pathogenetic understanding of IBD. The genetic influence(s), which is few according to the concordance rates (10% for ulcerative colitis and 37% for Crohn disease), should be stronger in the infant age group. Therefore, genetic analysis such as CARD15 and other more likely candidates with predominant colonic disease is promising. Alternatively, environmental (as well as genetic) factors involved in the pathogeneis of IBD are of special interest in infancy, a period characterized by maturation of the mucosal immune system and predominance of the TH2 cytokine profile (6). Because the TH2 immune reaction is present in patients with ulcerative colitis, the observation of colonic involvement in all of the patients studied by Ruemmele et al. is not surprising. The dynamics of immune maturation may be also expressed by the relative large number of patients (6 of 10) with indeterminate colitis. A provocative question is whether patients with disease onset in the first year have a chance in the follow-up to generate secondary tolerance or spontaneous immune suppression. This may not be excluded considering the potential of the young immune system and that 2 of the 10 patients of the study group presented with a milder course.
Another interesting aspect of infants with IBD as presented by Ruemmele et al. includes the bacterial flora, which colonized the newborn bowel and propagated the maturation of the immune system including an immune balance (TH1 = TH2 = TH3/Tr1) (7,8), but bacterial colonization is also a requirement for the development of IBD. A molecular analysis of the bacterial colonization (dependent on antibiotic therapy) will allow further insights into this pathogenetic factor. Parameters of the mucosal immune system other than bacterial flora and cytokines, which are under sensitive regulation during infancy, include epithelial barrier function, permeability and immunoglobulin A responses, all of which need to be evaluated in the described patient group.
Therapy and prevention of complications seem to be the most challenging part of treating infants with IBD. The efficacies and side effects of established therapies must be carefully evaluated in this patient group. Special attention should be paid to prebiotics and probiotics (9), whose potential benefits in the interaction between establishment of bacterial colonization and maturation of the mucosal immune system are hard to predict.
Taken together, infants with IBD offer special aspects of IBD, which may be essential for our understanding of this disease. These additional insights into the pathogenesis of IBD may justify our (disenchanted) hope to have reached the “end of the beginning” (10).
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