C. Talbotec

The efficacy of exclusive nutritional therapy in paediatric Crohn’s disease, comparing fractionated oral vs. continuous enteral feeding

Backgroundu2002 Nutritional therapy has an established role as induction therapy in paediatric Crohn’s disease. However, compliance is the main difficulty and may be greatly influenced by the administration route.

Phenotypic Characterization of Very Early-onset IBD Due to Mutations in the IL10, IL10 Receptor Alpha or Beta Gene: A Survey of the GENIUS Working Group.

Objective:Early-onset inflammatory bowel disease starting within the first months of life could be due to a particular genetic defect. We set up the GENetically determined ImmUne-mediated enteropathieS (GENIUS) network and collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution. Design:Ten patients with early-onset inflammatory bowel disease with confirmed mutations in IL10, IL10RA, or IL10RB genes were characterized on clinical, endoscopic–histological, immunobiological, and radiological findings. Functional assays to confirm defective responses to IL10 were performed on peripheral blood mononuclear cells. Results:A functional defect in IL10 signaling was confirmed in all IL10R patients tested. Disease started with severe diarrhea within the first 12 weeks in all patients. All infants showed Crohns disease–like ulcerations limited to the colon with marked perianal inflammation (fissures, abscess, and fistula); disease progression to the small bowel occurred in only 1 patient. Four of the 10 patients had granulomata on histology, and all patients showed Crohns disease–like mesenteric infiltration on imaging. Disease pattern was indistinguishable between IL10R alpha or beta chain or IL10 defects; autoimmunity was not observed. Mutations in IL10 were more frequently associated with bacterial and viral infections. Patients responded partially to treatment with steroids or anti–tumor necrosis factor drugs, whereas hematopoietic stem cell transplantation proved efficacious. Conclusion:The importance of the IL10 pathway within the colonic mucosa is highlighted by the development of severe colitis within a few weeks in infants with mutations in IL10, IL10RA, or IL10RB. Immunosuppression failed to correct the defect in this pathway, which seems to be a key to controlling inflammation in the colon.

Development of Crohn disease during anti-TNF-α therapy in a child with juvenile idiopathic arthritis

Tumour necrosis factor alpha (TNF) is believed to play a key role in initiating and amplifying the inflammatory reaction in the intestinal mucosa of patients with Crohn disease (1–3). High levels of TNFare secreted by lamina propria T lymphocytes and monocytes in patients with CD, and abundant TNFis even detectable in the stools (3–5). TNFis a transmembrane protein with an intracellular tail. Once cleaved by a metalloproteinase, soluble TNFis secreted (6). Based on the role of TNFin experimental colitis and the high levels of TNFfound in the mucosa during active disease, therapeutic strategies have been developed to block TNF activity. In fact, neutralizing anti-TNF antibodies have proved to be highly effective in otherwise treatmentresistant CD (7–9). The hypothesis that the beneficial effect of anti– TNFantibodies is a result of neutralization of soluble TNFwas recently questioned. For instance, long-term remissions which sometimes occur after one single injection of infliximab cannot be explained solely by the neutralization of soluble TNF, given the pharmacodynamics of this antibody. Furthermore, different types of anti-TNF molecules with high affinity to soluble TNFare more or less effective in treating patients with CD(3). We report a boy with juvenile idiopathic arthritis (JIA) who experienced CD while taking anti-TNF medication (etanercept) for his arthritis and who had a severe relapse of his intestinal/perianal disease during a second treatment course with etanercept. This child is highly responsive to anti-TNF treatment with infliximab, indicating that a more profound immunoregulatory effect than simple TNF neutralization is needed to down-regulate the mucosal inflammation in CD. CASE REPORT

Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.

Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73xa0%) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21xa0%) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (pxa0<xa010−4) and, for half of them, with choanal atresia (pxa0<xa010−4). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (pxa0=xa00.032) with milder PN dependency to weaning in some cases. Finally, four patients (7xa0%) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

Assessment and outcome of children with intestinal failure referred for intestinal transplantation

BACKGROUND & AIMSnChronic intestinal failure (CIF) requires long term parenteral nutrition (PN) and, in some patients, intestinal transplantation (ITx). Indications and timing for ITx remain poorly defined. In the present study we aimed to analyze causes and outcome of children with CIF.nnnMETHODSn118 consecutive patients referred to our institution were assessed by a multidisciplinary team and four different categories were defined retrospectively based on their clinical course: Group 1: patients with reversible intestinal failure; group 2: patients unsuitable for ITx, group 3: patients listed for ITx; group 4: patients stable under PN. Analysis involved comparison between groups for nutritional status, central venous catheter (CVC) related complications, liver disease, and outcome after transplantation by using non parametric tests, Mann-Whitney tests, Kruskal-Wallis, Wilcoxon signed rank tests and chi square distribution for percentage.nnnRESULTSn118 children (72 boys) with a median age of 15 months at referral (2 months-16 years) were assessed. Etiology of IF was short bowel syndrome [n = 47], intractable diarrhea of infancy [n = 37], total intestinal aganglionosis [n = 18], and chronic intestinal pseudoobstruction [n = 17]. Most patients (89.8%) were totally PN dependent, with 48 children (40.7%) on home-PN prior to admission. Nutritional status was poor with a median body weight at -1.5 z-score (ranges: -5 to +2.5) and median length at -2.0 z-score (ranges: -5.5 to +2.3). The mean number of CVC inserted per patient was 5.2 (range 1-20) and the mean number of CRS per patient was 5.5 (median: 5; range 0-12) Fifty-five patients (46.6%) had thrombosis of ≥2 main venous axis. At admission 34.7% of patients had elevated bilirubin (≥50 μmol/l), and 19.5% had platelets <100,000/ml, and 15% had both. Liver biopsy performed in 79 children was normal (n = 4), or showed F1 or F2 fibrosis (n = 29), bridging fibrosis F3 (n = 20), or cirrhosis (n = 26). Group 1 included 10 children finally weaned from PN (7-years survival: 100%). Group 2 included 12 children with severe liver disease and associated disorders unsuitable for transplantation (7-years survival: 16.6%). Group 3 included 66 patients (56%) who were listed for small bowel or liver-small bowel transplantation, 62/66 have been transplanted (7 years survival: 74.6%). Factors influencing outcome after liver-ITx were body weight (p < .004), length (p < .001), pre-Tx bilirubin plasma level (p < .001) and thrombosis (p < .01) for isolated ITx, Group 4 included 30 children (25.4%) with irreversible IF considered as potential candidates for isolated ITx. Four children were lost from follow up and 3 died within 2 years (survival 88.5%). Among potential candidates, the following parameters improved significantly during the first 12 months of follow up: Body weight (p.0001), length (p < .0001) and bilirubin (p < .0001).nnnCONCLUSIONSnmany patients had a poor nutritional status with severe complications especially liver disease. PN related complications were the most relevant indication for ITx, but also a negative predictor for outcome. Early patient referral for Tx-assessment might help to identify and separate children with irreversible IF from children with transient IF or uncomplicated long-term PN, allowing to adapt a patient-based treatment strategy including or not ITx.

Tolerance and efficacy of azathioprine in pediatric Crohn's disease

Background: Thiopurines are considered first‐line immunomodulators for the prevention of relapse in moderate to severe pediatric Crohns disease (CD). Early introduction of thiopurines was shown in a pediatric trial to maintain steroid‐free remission in 90% of patients for 18 months. In the present study we analyzed the tolerance and efficacy of azathioprine (AZA) to maintain remission in a homogenous single‐center observational cohort of children with CD. Methods: In all, 105 pediatric CD patients (male/female 68/37) were retrospectively evaluated for the efficacy of AZA (doses 1.4–4 mg/kg) to maintain remission at 6, 12, 18, and 24 months of follow‐up. Overall, 93 children were included with active disease (pediatric Crohns disease activity index [PCDAI] >30), steroid/enteral‐nutrition dependency, or postileocecal resection. Remission was defined as PCDAI ≤10 without steroids. Patients requiring antitumor necrosis factor (TNF) medication, other immunomodulators, or surgery were considered to experience a relapse. Results: Based on PCDAI, steroid‐free remission was achieved in 56/93 (60.2%), 37/93 (39.8%), 31/93 (33.3%), and 29/93 (31.2%) at visits month (M)6, M12, M18, and M24, respectively. Within the first 4 weeks, AZA was stopped in 10/93 patients due to adverse reactions (pancreatitis, nausea, vomiting, skin reactions, general weakness), or not introduced due to low thiopurine methyl transferase (TPMT) activity (n = 3). No neutropenia occurred in patients with normal TPMT activity. Three infectious episodes were documented requiring temporary AZA suspension. Conclusions: AZA is efficacious in maintaining remission in pediatric CD patients, but to a lesser extent than previously suggested. The majority of patients who are in steroid‐free remission at 12 months remained in prolonged remission. Overall tolerance of AZA was excellent. Inflamm Bowel Dis 2011

Pediatric ulcerative colitis associated with autoimmune diseases: A distinct form of inflammatory bowel disease?

Background: The pathogenesis of inflammatory bowel disease (IBD) is multifactorial, with some patients presenting additional autoimmune symptoms. Inflammatory colitis associated with autoimmune (AI) liver disease appears to have clinical features different from those of “classical” ulcerative colitis (CUC). The aim of this study was to describe these features, in order to differentiate a subgroup of colitis associated with autoimmunity (CAI) from CUC. Methods: Twenty‐eight consecutive children with inflammatory colitis associated with primary sclerosing cholangitis (PSC), celiac disease, or AI hepatitis were compared with a matched control group of 27 children with isolated UC. Clinical course, histology, as well as inflammatory profile in the colonic mucosa based on real‐time polymerase chain reaction (PCR) were analyzed. Results: In CAI the main digestive symptoms at disease onset were abdominal pain (12/28) and bloody strings in the stool (12/28), along with a high prevalence of autoimmune diseases in relatives, as compared with bloody diarrhea in the CUC group (26/27). At diagnosis, pancolitis was seen in 18/28 CAI patients compared with 8/27 in UC. In CAI, the pathological findings were different from CUC: 1) major lesions predominantly located in the right colon; 2) pseudo‐villous appearance of the mucosa, and strong infiltration with eosinophils; 3) mild glandular lesions; and 4) differing inflammatory infiltrate with reduced FOXP3, interleukin (IL)‐2, and thymic stromal lymphopoietin (TSLP) levels. Evolution in CAI was less aggressive, requiring less corticosteroids/immunomodulators. Conclusions: Precise clinical, histological, and molecular analyses reveal marked differences between patients with CUC and those with associated AI phenomena, supporting the hypothesis of a distinct AI presentation of IBD. (Inflamm Bowel Dis 2012)

Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.

BACKGROUNDnInflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD.nnnOBJECTIVEnWe thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency.nnnMETHODSnWe performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, axa0condition we named enteropathy-lymphocytopenia-alopecia. Thexa0candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patients biopsy specimen were analyzed.nnnRESULTSnWe identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway.nnnCONCLUSIONSnWe show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of bothxa0epithelial cells and lymphocytes cooperatively causes IBD.

Prepubertal Growth in Children with Long-Term Parenteral Nutrition

In children who depend on long-term parenteral nutrition (PN), a major goal is to obtain optimal growth. The aim of this retrospective study was to analyze growth in children on long-term cyclic nocturnal home PN, over at least 8 years before puberty. Nine boys and 7 girls were studied. Their mean age at the time of study was 11 years with a mean PN duration of 10.5 (8.6–16.4) years. Diseases were short bowel syndrome (5), intractable diarrhea (4), chronic intestinal pseudo-obstruction (4) and long segment Hirschsprung’s disease (3). In each child, periods of at least 2 years were analyzed: either periods of regular growth (R: height gain >50th percentile), or slow growth (S: height gain ≤25th percentile). Results were expressed as mean ± SD. Comparisons were performed using either Student’s test for unpaired data or Wilcoxon’s test for paired data. PN provided a mean of 224 ± 80 mg nitrogen/kg/day and 43 ± 14 kcal/kg/day equivalent to 50% of recommended supplies. At the time of study, the population presented with weight (W) = –0.7 ± 0.8 SD and height (H) = –1.5 ± 1.3 SD. The difference between W and expected W for H (W/H) was significant (p < 0.002). W/H ratio was 105 ± 11%. For the total PN duration, weight gain was +0.2 ± 1.5 SD and height loss was –0.75 ± 1.4 SD. An excess weight gain occurred in parallel with the deflection of height gain. Of the 16 children, regular prepubertal growth was achieved in 4 only. The other 12 showed alternate periods of R and S. In 8 of them, 26.5 years of R and 33.5 years of S were compared, each child being his own control. PN nitrogen and energy supplies were significantly higher during R periods than during S periods. In the absence of any disease or treatment explaining the failure to thrive, inadequate PN supplies, especially in terms of nitrogen supply, are thought to be responsible for a negative nitrogen balance and slowed growth. In case of any deflection away from the individual growth curve, it is recommended to adjust the PN supply early, especially nitrogen supply.

Anastomotic ulcerations after intestinal resection in infancy.

Objective: Anastomotic ulceration (AU) is a rare complication after intestinal resection and anastomosis, described mostly in children. The main symptom is occult bleeding, leading to iron-deficiency anemia, which is life threatening. Methods: The present survey reports a series of patients with AU after intestinal resection in infancy, focusing on predictive factors, medical and surgical treatment options, and long-term outcomes. Eleven patients (7 boys) born between 1983 and 2005 with AU after an intestinal resection and anastomosis in infancy were included in this retrospective review. Results: The diagnosis of AU was often delayed for several years. No predictive factor (including the primary disease, the length of the remnant bowel, and the loss of the ileocaecal valve) could be identified. Numerous treatment options, including antibiotics and anti-inflammatory drugs, proved to be ineffective to induce prolonged remission. Even after surgical resection, relapses were observed in 5/7 children. Conclusions: The mechanism leading to AU remains unknown. Contrary to previous reports with limited follow-up, no medical or surgical treatment could prevent recurrences. Because relapses may occur several years after treatment, long-term follow-up is needed.