Ron Shaoul

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Pediatric Crohn's Disease and Growth Retardation: The Role of Genotype, Phenotype, and Disease Severity

Background. Delayed growth is a well-established feature of pediatric Crohns disease. Several factors have been shown to affect growth, including disease location, severity, and treatment. The recently discovered NOD2 gene has been correlated to ileal location of Crohns disease and subsequently could affect growth through the resulting phenotype or as an independent risk factor. The aim of our study was to determine if growth retardation is affected by genotype independently of disease location or severity. Methods. Genotyping for 3 NOD2 single-nucleotide polymorphisms was performed in 93 patients with detailed growth records. Parameters including disease location, disease severity, and NOD 2 genotype and their effect on z scores for height and weight at disease onset and during follow-up were analyzed. Results. NOD2 mutations were correlated with ileal location but not with disease severity or growth retardation. Ileal involvement was significantly associated with height retardation at disease onset and the lowest z score during follow-up. Use of steroids affected weight but not height. Regression models for growth variables revealed that the strongest association with impaired growth is with disease severity (weight- and height-failure odds ratios: 6.17 and 4.52, respectively). Conclusions. Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure.

A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease

Objectives Budesonide has been found effective in patients with mild and moderate Crohn disease and has been found to cause fewer side effects than prednisone. The use of oral budesonide has not been prospectively evaluated in children with Crohn disease. Therefore, the authors initiated a trial to compare remission and tolerance to budesonide and prednisone in children with mild or moderately active Crohn disease. Methods A prospective randomized open controlled 12-week trial was carried out comparing pH modified release budesonide, 9 mg, versus prednisone, 40 mg, in children with active mild to moderate pediatric Crohn disease. Results Thirty-three patients (20 boys and 13 girls; mean age, 14.3 years) enrolled and completed the study. The groups treated with budesonide and prednisone did not differ by age, onset of disease, location of disease, or disease activity. The remission rate at 12 weeks was 47% in the budesonide treatment group and 50% in the prednisone treatment group. Side effects occurred in 32% and 71% of patients treated with budesonide and prednisone, respectively (P < 0.05). Severity of cosmetic side effects was significantly lower in patients treated with budesonide (P < 0.01). Conclusions Remission rates for Crohn disease with budesonide and prednisone treatment in this study were similar. Pediatric patients treated with budesonide had significantly fewer side effects than patients treated with prednisone. Budesonide should be considered an alternative to prednisone in pediatric patients with mild to moderate disease activity.

Colonic expression of MUC2, MUC5AC, and TFF1 in inflammatory bowel disease in children

Background: The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD. Results: Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell–like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation. Conclusion: The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.

Morbidity of Overweight (≥85th Percentile) in the First 2 Years of Life

OBJECTIVES. Our hypothesis was that morbidity related to overweight/obesity is already evident in infants and young toddlers. The major objectives of this study were (1) to assess the prevalence of overweight in a sample of hospitalized infants and (2) to assess the prevalence of morbidity in overweight infants in a community-based sample. METHODS. The hospital admission study population included 2139 infants, ≤24 months of age, who were admitted for any reason to the pediatric department at the Bnai Zion Medical Center in 2004–2005. For the community-based sample, we identified overweight infants (≥85th weight-for-height percentile in ≥2 measurements, ≥3 months apart), ≤24 months of age, in 8 mother and child health care facilities in the Haifa subdistrict of Israel. Parents of infants were interviewed by using a structured questionnaire. RESULTS. We found that overweight infants (85th to 94th percentiles) had fewer admissions and fewer repeated admissions than expected. Infants of ≥95th percentile had more admissions than expected, as well as a larger number of repeated admissions. In the second part of the study, we found that rates of developmental delays (mainly delayed gross motor skills) and snoring were significantly higher in infants of ≥85th percentile. In addition, although the results were not statistically significant, infants with overweight suffered more frequently from breathing problems, such as asthma and stridor. When the mothers were asked to assess whether their child was overweight, only 31.6% of mothers of overweight children thought that the child was overweight. CONCLUSIONS. The high admission rates for infants of ≥95th percentile and the high incidence rates of respiratory morbidity, snoring, and delayed gross motor skills in overweight infants support our hypothesis regarding early morbidity associated with overweight.

A polymorphism in the TNF-alpha promoter gene is associated with pediatric onset and colonic location of Crohn's disease.

OBJECTIVES:Studies suggest that pediatric onset of Crohns disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-α expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-α function may influence variability of disease location and AOO of CD.METHODS:We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-α promoter region.RESULTS:Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-κB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p = 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p = 0.008) and positively associated with isolated colitis (OR = 2.16, p = 0.008, OR = 2.12, p = 0.03 corrected) and familial disease (p = 0.004).CONCLUSIONS:Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-κB in TNF-α promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.

TNF promoter polymorphisms and modulation of growth retardation and disease severity in pediatric Crohn's disease.

OBJECTIVES:Delayed growth is common in pediatric Crohns disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being the presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia, and weight loss are all manifestations of circulating TNF-alpha, which is elevated in CD. The ability to secrete TNF-alpha may be affected by polymorphisms in the TNF-alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset CD are affected by TNF promoter genotype.METHODS:Genotyping for TNF-alpha and NOD2/CARD15 single nucleotide polymorphisms was performed in 87 patients with detailed growth records. Parameters including disease location and disease severity were recorded, and the effect of these polymorphisms on Z-scores for height and weight at disease onset and during follow-up were analyzed.RESULTS:Lower age of onset was linked to more height retardation, while the presence of colonic disease and the absence of ileal disease were more likely to predict the absence of growth retardation. The presence of two polymorphisms thought to decrease circulating TNF-alpha was associated with higher mean Z-scores for height and a trend toward less growth retardation. Two other polymorphisms were modestly associated with disease severity.CONCLUSION:Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.

Infant feeding patterns in the first 6 months: an assessment in full-term infants.

Background: The infant formula market has grown significantly and offers a wide range of products for the different stages of healthy infant growth. Healthy infants often go through a series of unnecessary changes of formulas. The present study aimed to identify the factors leading to switches to alternative formulas. We studied the feeding patterns in the first 6 months of babies born at term, particularly changes in infant formulas. We also investigated the reasons for choosing the first formula, infant formula changes, the addition of formulas to supplement breast-feeding, and various aspects related to formula thickening. Patients and Methods: Two hundred parents of babies ages 6 to 18 months were interviewed. The interviews included a detailed questionnaire and were conducted in child and maternal health care centers. Results: Forty-seven percent of these infants underwent changes in their formula in the first 6 months of life, most of which (67%) were to another cows milk–based formula. The main reasons for switching a formula were regurgitation or vomiting (24%) followed by restlessness (18%). Lower z scores at birth and a higher Δz2 (z score at the time of the questionnaire minus z score at birth) were associated with significantly more formula changes. The impact of pediatricians and other health care professionals on the choice of infant nutrition was surprisingly negligible. Conclusions: The most common reason for switching a formula was concern regarding common infantile symptoms or behavior patterns perceived by parents to be related to formula intolerance. The decision to switch formula was usually made by the parents without consulting a health professional.

Comparison of outcomes parameters for induction of remission in new onset pediatric Crohn's disease: Evaluation of the porto IBD group "growth relapse and outcomes with therapy" (GROWTH CD) study

Background:Robust evaluation of induction therapies using both clinical and inflammatory outcomes in pediatric Crohns disease (CD) are sparse. We attempted to evaluate clinical, inflammatory, and composite outcomes of induction of remission therapies (normal C reactive protein [CRP] remission) in a large pediatric prospective multicenter study. Methods:Patients enrolled at diagnosis into the growth relapse and outcomes with therapy in Crohns disease study were evaluated for disease activity, CRP, and fecal calprotectin at 8, 12 and 52 weeks after starting treatment. The primary endpoint was week-12 steroid-free remission defined by pediatric Crohns disease activity index and CRP <0.5 mg/dL. The protocol required tapering off corticosteroids by week 11. Results:We analyzed 222 patients (mean age, 12.9 ± 3.2 yr) main evaluated treatment options included: 5-ASA (n = 29), exclusive enteral nutrition (n = 43), and corticosteroids (n = 114). Clinical remission at week 12 was achieved in 155 (73%) patients; both exclusive enteral nutrition and steroids were associated with normal CRP remission at week 12, although in a post hoc subgroup analysis exclusive enteral nutrition was superior in mild-to-moderate disease for this outcome. Among those in steroid-free remission in week 12, normal CRP predicted 1-year sustained remission (86% for normal CRP versus 61% for elevated CRP; P = 0.02). Baseline severity and early immunomodulation were similar in both groups. Conclusions:Normal CRP steroid-free remission at week 12 was impacted by type of induction therapy, but not by early immunomodulation. It was associated with more corticosteroids-free remission at week 52 and a trend for less relapses.

NOD2/CARD15 mutations and presence of granulomas in pediatric and adult Crohn's disease

Objectives:The etiology and mechanism leading to granuloma formation in patients with Crohn’s disease (CD) are presently unknown. The first susceptibility gene to be identified as a risk factor for CD is the NOD2/CARD15 gene on Chromosome 16. Mutations in NOD2 could affect the intracellular response to bacterial products and may eventually lead to granuloma formation. The association between NOD2 and granulomas has not been previously explored. We evaluated a possible association between NOD2 mutations and granuloma formation, and compared the prevalence of granulomas in both pediatric and adult cohorts. Methods:Patients were consecutively recruited through pediatric gastroenterology and adult gastroenterology programs. Patients were eligible if CD was confirmed, and they had undergone full colonoscopy with biopsy and/or surgical resection. Patients underwent genotyping for NOD2 disease-associated mutations. Results:A total of 230 patients were enrolled into the study, of whom 169 patients met all inclusion/exclusion criteria (Group 1, 77 patients [age range 1–16 years]; Group 2, 92 patients [age range 17–68 years]). Surgical resection was performed more often in adults (P < 0.005), and gastroscopy was performed more frequently in children (P < 0.001). Granulomas were found in 34% of the patients studied. The prevalence of granulomas did not differ by age, age group, or gender. A disease-associated NOD2 mutation was found in 37.8% of patients. Granulomas were found in 39% of patients with NOD2 mutations compared with 31% of those without NOD 2 mutations (difference was not significant). In addition, no difference was noted for the specific mutations. Conclusions:We did not find any correlation between NOD2 mutations and granuloma formation. The cause of granulomas in CD remains elusive.