D. Knafelz

Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register (1996-2003).

Background: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. Methods: In 1996 an IBD register of disease onset was established on a national scale. Results: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohns disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996–2003 an increase of IBD incidence from 0.89 to 1.39/105 inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. Conclusions The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD.

Clinical role of calprotectin assay in determining histological relapses in children affected by inflammatory bowel diseases

Background: Inflammatory bowel diseases (IBD) are characterized by periods of remission with recurrent episodes of symptom exacerbation because of acute intestinal inflammation, which is correctly evaluated by endoscopy with biopsy sampling. However, many surrogate markers of intestinal inflammation, including fecal calprotectin (FC), are detected as potential predictors of mucosal inflammation in IBD patients. The aim of our study was to retrospectively assess the clinical efficacy of the calprotectin assay in determining histological relapses of pediatric IBD patients. Methods: We retrospectively reviewed the histological examinations, clinical records, and FC values of patients who had undergone colonoscopy at our hospital over an 8‐year period, from December 31, 1998, to December 31, 2006. Only patients with a first histological examination showing a quiescent IBD who submitted to a second histological examination during the next 3 years were selected. Results: Seventy‐three IBD patients, all with a first biopsy showing a quiescent IBD, were studied; at the second histological examination, 32 presented with relapse and 41 presented with remission. Relapsed patients showed significantly increased FC levels compared with nonrelapsed patients. A FC value of 275 &mgr;g/g achieved sensitivity and negative predictive value of 97% and specificity and positive predictive value of 85% in predicting histological relapse. Conclusions: FC seems to be a direct measure of intestinal inflammation and therefore a good marker of the risk of histological relapse in pediatric IBD patients. The application of this test in clinical practice may enable the avoidance of invasive tests as well as targeting treatment.

Relationship between CARD15, SLC22A4/5, and DLG5 polymorphisms and early-onset inflammatory bowel diseases: An Italian multicentric study

BACKGROUND Inflammatory bowel disease (IBD) has been associated with several polymorphisms in genes likely involved in innate immune responses and integrity of epithelial mucosal barrier. A major role in adult Crohns disease (CD) has been defined for 3 polymorphisms in the CARD15 gene, whereas variants in the SLC22A4, SLC22A5, and DLG5 genes could have a minor contribution to IBD susceptibility. METHODS We analyzed a panel of 6 polymorphisms within these genes in 227 Italian early-onset IBD patients (134 CD, 93 ulcerative colitis [UC]; age at diagnosis <or=18 years) and 166 unaffected control subjects. RESULTS Each CARD15 variant was found to be independently associated with CD. After the genotypes at the 3 polymorphisms were combined, 37.3% patients carried at least 1 variant compared with 9.2% control subjects (odds ratio, 5.87; 95% CI 3.11-11.1; P < 0.001). The combined frequency of CARD15 variants was also higher in UC children compared with control subjects (14% vs 9.2%), but this difference was not significant. However, CARD15 variants were associated with earlier onset of UC, and the mutation rate was significantly higher in UC patients with onset at or before 6 years of age compared with control subjects (27.6% vs 9.2%) (odds ratio = 3.76; 95% CI 1.42-9.94; P = 0.01). CARD15 variants also were associated with ileal CD involvement and a higher rate of extraintestinal manifestations in UC. Allele and genotype frequencies at SLC22A and DLG5 polymorphisms were not significantly different between cases and controls. CONCLUSIONS Our results demonstrate that in the Italian population, the major CARD15 polymorphisms are associated with susceptibility to early-onset CD and with ileal involvement and suggest a previously unreported association with very early-onset, severe UC.

Mast cell-nerve interactions in children with functional dyspepsia.

Background and Aims: Functional dyspepsia in childhood is commonly triggered by food allergen in sensitised individuals. We investigated the topography of eosinophils and mast cells in gastric antral lamina propria, the interaction of mast cell products with mucosal nerve fibres, and changes in gastric antral muscle slow wave activity in children with atopy and non–atopy-related functional dyspepsia. Patients and Methods: Open label study of gastric mucosal cows milk challenge in 10 atopic and 6 nonatopic children (ages 2–12 years) investigated consecutively with gastroscopy for functional dyspepsia. Simultaneous surface electrogastrography and milk challenge were undertaken and laser scanning fluorescence microscopy used to examine the association of mast cell tryptase with mucosal nerves in the gastric mucosa before and after challenge. Results: Eosinophils and mast cells within the lamina propria were increased in number in children with atopic functional dyspepsia and degranulated rapidly after cows milk challenge in the atopic group. For degranulating eosinophils, median = 13.0% (interquartile range = 3.7–31.0) premilk versus 32.0% (12.0–42.0) after milk biopsies (P < 0.05); for degranulating mast cells, 5.35% (2.7–10.9) premilk biopsies versus 18.75% (12.9–22.1) after milk biopsies (P < 0.05). No such differences were seen in nonatopic patients. Mast cells were closely associated with mucosal nerve fibres and released tryptase, which colocalised with proteinase-activated receptors on mucosal nerve fibres. The gastric antral slow wave became abnormal within 2 minutes of antigen challenge in atopics with an increase in dominant frequency instability coefficient (P < 0.005), decrease in 3 cycles per minute myoelectrical activity (P < 0.01), and increase in bradygastria (P < 0.01). Conclusions: Early-onset neuroimmune interactions induced by cows milk in the gastric mucosa of atopic children are associated with rapid disturbance of gastric myoelectrical activity and dyspeptic symptoms.

Long-term treatment with autologous red blood cells loaded with dexamethasone 21-phosphate in pediatric patients affected by steroid-dependent Crohn disease.

Background: Inflammatory bowel disease (IBD) present in childhood in 15% to 25% of cases. The aim of therapy in children is not only to guarantee normal growth but also to prevent relapse and to maintain remission. Steroids are effective to induce remission; however, resistance, dependency, and irreversible side effects can develop. The aim of this study was to determine whether treatment with repeated infusions of autologous red blood cells (RBCs) loaded with dexamethasone 21-phosphate (Dex 21-P) is safe and allows maintenance of long-term remission in children with steroid-dependent Crohn disease (CD). Patients and Methods: Eighteen consecutive pediatric patients who met the inclusion criteria were admitted to the study. Infusions of autologous RBCs loaded with Dex 21-P were performed every 4 weeks; the mean duration of treatment was 24 months. At the beginning of treatment and after 6, 12, and 24 months, we performed clinical evaluation according to the Pediatric Crohn Disease Activity Index (pCDAI). Assessment of body mass indexamethasone and bone mineral density by means of computerized bone mineralometry-dual energy x-ray absorptiometry, endoscopic evaluation, and hematic morning cortisol determination were also performed. Results: During treatment, the mean pCDAI significantly decreased (P < 0.05); 78% of patients discontinued steroids. Determination of morning cortisol showed suppression only on the first day after infusion, followed by normalization of values. Endoscopic findings showed remission in 44% of patients. None of the patients experienced serious side effects. Conclusions: These data suggest that repeated infusions of RBCs loaded with Dex 21-P can be safe and useful to maintain long-term remission in pediatric patients with moderately active CD.

Diagnostic Work-up of Inflammatory Bowel Disease in Children: The Role of Calprotectin Assay

Background: Some reports highlight the potential application of fecal calprotectin as a direct biomarker of intestinal inflammation and, therefore, as support in choosing candidates for endoscopy. The value of 100 &mgr;g/g was recently assumed as the best cutoff for this assay. The purpose of this study was to assess the diagnostic precision of the fecal calprotectin assay, compared to histology, as a stool‐screening biomarker for inflammatory bowel disease (IBD) among a group of prospectively identified patients referred for recurrent abdominal pain and altered bowel habits. Methods: Between 1999 and 2007 we prospectively evaluated the calprotectin assay in a cohort of patients with recurrent abdominal pain and altered bowel habits associated or not with other symptoms suggestive of IBD. All patients suspected of IBD, according to Rome and Porto criteria, provided stool specimens for the calprotectin assay and subsequently underwent endoscopic procedures. Results: Compared to histology, the cutoff of 100 &mgr;g/g reached a sensitivity and specificity of 100% and 68%, respectively, and a likelihood ratio (LR) of 3.1. The cutoff value of 160 &mgr;g/g, however, in our series produced the best joint estimate of sensitivity and specificity: 100% and 80%, respectively, with an LR of 5. Conclusions: In pediatric patients with recurrent abdominal pain and changes in stool habits, a positive calprotectin assay is closely associated with IBD; its systematic employment, therefore, seems to improve the process of endoscopy referral. This test, simple and inexpensive, could be included in the first noninvasive phase of an IBD diagnostic work‐up. (Inflamm Bowel Dis 2010)

The clinical implications of thalidomide in inflammatory bowel diseases

Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFα agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD.

Transition of gastroenterological patients from paediatric to adult care: A position statement by the Italian Societies of Gastroenterology

In 2013, four Italian Gastroenterological Societies (the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition, the Italian Society of Hospital Gastroenterologists and Endoscopists, the Italian Society of Endoscopy, and the Italian Society of Gastroenterology) formed a joint panel of experts with the aim of preparing an official statement on transition medicine in Gastroenterology. The transition of adolescents from paediatric to adult care is a crucial moment in managing chronic diseases such as celiac disease, inflammatory bowel disease, liver disease and liver transplantation. Improved medical treatment and availability of new drugs and surgical techniques have improved the prognosis of many paediatric disorders, prolonging survival, thus making the transition to adulthood possible and necessary. An inappropriate transition or the incomplete transmission of data from the paediatrician to the adult Gastroenterologist can dramatically decrease compliance to treatment and prognosis of a young patient, particularly in the case of severe disorders. For these reasons, the Italian gastroenterological societies decided to develop an official shared transition protocol. The resulting document discusses the factors influencing the transition process and highlights the main points to accomplish to optimize compliance and prognosis of gastroenterological patients during the difficult transition from childhood to adolescence and adulthood.

Chronic pancreatitis as presentation of Crohn's disease in a child.

It is reported that a pancreatic disease may precede the diagnosis of inflammatory bowel disease (IBD) both in children and in adults. Idiopathic chronic pancreatitis, however, occasionally co-exists with the IBD, mainly at pediatric age. We report a case of a patient who progressively developed the features of a chronic pancreatitis, before the diagnosis of Crohns Disease (CD). Ten months after the onset of the first episode of pancreatitis the patient developed bloody diarrhea, mucus stools and biochemical findings of inflammation. The colonoscopy revealed a diffuse colitis without involvement of the last loop and the gastroscopy showed inflammation of the iuxta-papillary area. The histological findings confirmed the diagnosis of CD that involved the colon and the duodenum. In conclusion, in children the idiopathic chronic pancreatitis may be an unusual presentation of CD. Thus, if other known cause of chronic pancreatitis are not found, a not invasive work up to exclude the IBD should be warranted. An early coincidental diagnosis of the IBD may delay the progression of the pancreatic disease.

Clinical outcome and safety of periodic infliximab therapy in children and adolescents with Crohn's disease

To the Editor: We have read with great interest the recent paper by Lien et al. (1) on growth and safety in term infants fed reduced-protein formula with added bovine alpha-lactalbumin. At the end of the Discussion section the authors state the following: “this current study is the first to reduce total protein concentration in infant formula by the use of a new whey fractionation method.” However, in September 2002 (2) we published a study in which reduced protein formulas were studied in term infants and compared with infants fed conventional formula or breast milk. In this study the bovine alphalactalbumin proportion in the reduced protein formula was also increased by a protein fractionation process involving bovine whey proteins. Surprisingly, the authors of the current study (1) have not made any reference to our study although it was published in the same Journal. The two formulas (EF experimental formula and CF control formula) used in the present study (1) had a total protein concentration of 14.4 g/L and 15.1 g/L, respectively. The difference of 0.7 g/L is very small and it would be interesting to know the batch-to-batch variation in protein concentration in the two formulas. The protein/energy ratio of the formulas is not reported, but assuming an energy density of 67 kcal/100 ml the difference in protein content per 100 kcal would be only 0.1 g (2.15 and 2.25 g/100 kcal). It would also be nice to know the non-protein nitrogen content of the formulas used. Did reduced protein formula really decrease true protein intake in the EF feeding group? Mean protein intakes in the infants were not presented.