Avi Pacht

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.

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.

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.

A Novel Algorithm for the Diagnosis of Celiac Disease and a Comprehensive Review of Celiac Disease Diagnostics

There is an urgent clinical need for a better laboratory celiac disease diagnosis with both less false positive results and minimal underdetection. The aim of the present study was to evaluate the performance and diagnostic accuracy of different assays in an outpatient population setting for the diagnosis for celiac disease (CD) in order to design an optimal algorithm. We used 15 different ELISA assays to assess 47 blood samples of newly diagnosed children (positive biopsy results) and 52 samples from age- and sex-matched children with negative biopsy results for CD. Scoring criteria were established for grading the assays performance and characteristics. The combined gliadin and tTG assays exhibited the best sensitivity (100%). The addition of other assays to the CeliCheck neo-epitopes assay improved specificity so that the final algorithm had 100% sensitivity, 96.2% specificity, and 98.1% accuracy. The clinical demand for both maximal sensitivity and maximal specificity cannot be achieved with a single test. Using a combination of a sensitive assay together with specific assays improved celiac disease detection rates, with an acceptable number of false positive results. This model, however, needs to be confirmed prospectively in both children and adults.

A new algorithm for the diagnosis of celiac disease

Celiac disease (CD) affects at least 1% of the Western population but remains largely unrecognized. In our laboratory, we utilize a novel algorithm to diagnose pediatric CD that offers both high sensitivity and high specificity for diagnosis in an outpatient setting. The aim of the present study was to challenge this algorithm and to test its performance in children and adults suspected of having CD. Using a three-assay algorithm, screening with the most sensitive tissue transglutaminase (tTG) complexed with deamidated gliadin peptide neoepitope immunoglobulin A (IgA)+IgG assay and confirming with the two specific tTG IgA and tTG IgA+IgG assays, we examined the serological results from 112 children aged 0–17 years old and 60 adults in comparison to their respective biopsy results. The algorithm performance was calculated by statistical analysis. The use of the new algorithm enabled us to diagnose CD with 98% sensitivity, 93% specificity and 95% accuracy in the pediatric group and 94% sensitivity, 92% specificity and 93% accuracy in the total population studied. The false-negative cases in the adult group were attributed to previous adherence to a gluten-free diet, and the single false-negative result in a young child became a true positive after 6 months. We have also monitored three celiac patients before and after diagnosis and found that the algorithm may be suitable for disease monitoring. The newly proposed three-assay algorithm for celiac detection is very reliable in both children and adults. Due to the high performance of this assay, the further need for confirmatory intestinal biopsies will be reassessed.

Challenging our serological algorithm for celiac disease (CD) diagnosis by the ESPGHAN guidelines.

*Corresponding author: Mira Barak, PhD, Central Laboratory of Haifa and Western Galilee, Clalit Health Services, Hataasia 47, Nesher 20300, Haifa, Israel, Phone: +972-4-209093, Fax: +972-4-209094, E-mail: miraba@clalit.org.il Orit Rozenberg, Paul Froom, Maya Grinberg, Dina Reginashvili and Clara Henig: Central Laboratory of Haifa and Western Galilee, Clalit Health Services, Haifa, Israel Avi Pacht: Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, Haifa, Israel Aaron Lerner: Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, Haifa, Israel; and B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

The significance of isolated elevation of serum aminotransferases in infants and young children

Introduction: The aim of this study was to assess the clinical significance and prognosis of a prolonged isolated elevation of serum aminotransferases without cholestasis (>3 months) in infants and young children, investigated for a variety of conditions, and to determine a protocol for their follow-up and investigation. Methods: A combined prospective-retrospective analysis of apparently healthy babies and young children with isolated elevation of serum aminotransferases of at least 1.5 times above the norm for age which persisted for at least 3 months and whose creatine phosphokinase (CK), gamma glutamyltransferase (GGT), alkaline phosphatase and bilirubin levels remained normal throughout the study duration. The children underwent the following investigations: abdominal ultrasound and infectious, metabolic and/or immunological investigation depending on the duration of the abnormality. Results: Six children were eliminated following the finding of positive cytomegalovirus (CMV) antigen in the urine. 72 children were investigated (47 males and 25 females). The duration of serum aminotransferases elevation was 3–36 months (average 12.4, median 11.5 months). The initial, maximal and final alanine aminotransferase (ALT) values were 85.5, 140.5 and 39.8 IU/l, respectively. Of seven children who had liver biopsies performed, three (42.8%) were suspected of having a glycogen storage disease which was not confirmed enzymatically. Four biopsies revealed non-specific histological changes. Conclusions: Isolated elevation of serum aminotransferases in healthy looking young children is mostly a benign condition that usually resolves within a year. If no pathology is found during routine investigation, these children can be followed conservatively. Liver biopsy does not contribute much to the diagnosis and is probably unnecessary.

Remifentanil versus fentanyl for esophagogastroduodenoscopy in children.

Objectives: We compared sedation by propofol combined with either fentanyl or remifentanil in pediatric outpatients undergoing diagnostic esophagogastroduodenoscopy. Patients and Methods: Forty-two children scheduled for esophagogastroduodenoscopy in our institution were randomly assigned to receive 2 mg/kg propofol plus either 1 μg/kg bolus of fentanyl (group F; n = 20) or 0.5 μg/kg bolus of remifentanil (group R; n = 22). Cardiorespiratory parameters, sedation level, adverse effects related to the drugs and/or to the procedure, ease of performance for the endoscopist, and time to awakening were analyzed. Results: There were no clinically significant changes in hemodynamics. Apnea periods >20 seconds and decreases in SaO2 <90% occurred more frequently in group R (31.8% vs 0%, P < 0.01, and 27.3% vs 5.0%, P > 0.05, respectively). Children in group R had significantly shorter average time to awakening: 9.5 ± 5.6 vs 16.5 ± 10.5 minutes (P = 0.01), and received a significantly lower total dose of propofol (P = 0.034). Adverse effects within the first 24 hours postprocedure occurred less frequently in group R (P = 0.03). Conclusions: Remifentanil in combination with propofol provides good analgesic and sedative effects, which were shorter lasting compared with fentanyl-based sedation, and caused fewer delayed adverse effects. The use of remifentanil was associated with respiratory depression, emphasizing the need for experienced anesthesiologists.

The neurologic profile of children and adolescents with inflammatory bowel disease.

In recent years, there has been an increasing incidence of inflammatory bowel disease in children and adolescents. Neurologic involvement has been mainly reported in adults, and information in pediatrics is based primarily on individual case reports. In this study, we explored the prevalence and spectrum of neurologic manifestations of 50 children with inflammatory bowel disease in comparison to healthy controls. Based on clinical reports and neurologic evaluation, 34 patients (68%) exhibited neurologic manifestations compared with 10 children (23.8%) in the control group (P < .001). The main symptoms associated with inflammatory bowel disease in comparison to the control subjects were headache: 46% vs 3% (P < 0.001), dizziness: 26% vs none (P < .001), hypotonia: 10% vs none (P = .06), attention-deficit hyperactivity disorder (ADHD): 28% vs 7.1% (P < .001), tics and sensory complaints: 16% vs 2.4% (P = .036). Seizures and neuropsychiatric disorders were less characteristic. A larger-scale prospective study is required to further clarify this association.