David M. Israel

Serum Immune Responses Predict Rapid Disease Progression among Children with Crohn's Disease: Immune Responses Predict Disease Progression

BACKGROUND AND AIM:Crohns disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in pediatric CD patients.METHODS:Sera were collected from 196 pediatric CD cases and tested for immune responses: anti-I2, anti-outer membrane protein C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), and anti-Saccharomyces-cerevisiae (ASCA) using ELISA. Associations between immune responses and clinical phenotype were evaluated.RESULTS:Fifty-eight patients (28%) developed internal penetrating and/or stricturing (IP/S) disease after a median follow-up of 18 months. Both anti-OmpC (p < 0.0006) and anti-I2 (p < 0.003) were associated with IP/S disease. The frequency of IP/S disease increased with increasing number of immune responses (p trend = 0.002). The odds of developing IP/S disease were highest in patients positive for all four immune responses (OR (95% CI): 11 (1.5–80.4); p= 0.03). Pediatric CD patients positive for ≥1 immune response progressed to IP/S disease sooner after diagnosis as compared to those negative for all immune responses (p < 0.03).CONCLUSIONS:The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients.

A randomized trial of yoga for adolescents with irritable bowel syndrome

BACKGROUND Adolescents with irritable bowel syndrome (IBS) frequently experience interference with everyday activities. Mind-body approaches such as yoga have been recommended as interventions for patients with IBS. Despite promising results among adult samples, there have been limited studies exploring the efficacy of yoga with pediatric patients. OBJECTIVE To conduct a preliminary randomized study of yoga as treatment for adolescents with IBS. METHODS Twenty-five adolescents aged 11 to 18 years with IBS were randomly assigned to either a yoga or wait list control group. Before the intervention, both groups completed questionnaires assessing gastrointestinal symptoms, pain, functional disability, coping, anxiety and depression. The yoga intervention consisted of a 1 h instructional session, demonstration and practice, followed by four weeks of daily home practice guided by a video. After four weeks, adolescents repeated the baseline questionnaires. The wait list control group then received the yoga intervention and four weeks later completed an additional set of questionnaires. RESULTS Adolescents in the yoga group reported lower levels of functional disability, less use of emotion-focused avoidance and lower anxiety following the intervention than adolescents in the control group. When the pre- and postintervention data for the two groups were combined, adolescents had significantly lower scores for gastrointestinal symptoms and emotion-focused avoidance following the yoga intervention. Adolescents found the yoga to be helpful and indicated they would continue to use it to manage their IBS. CONCLUSIONS Yoga holds promise as an intervention for adolescents with IBS.

Gastric polyps and nodules in children receiving long-term omeprazole therapy.

Objective Multiple gastric polyps have been reported to occur in adults receiving omeprazole therapy. There are little published data in children. We report our experience in monitoring the gross and histologic appearance of the stomach in children receiving long-term omeprazole therapy. Methods This was a retrospective review of the charts of children who received omeprazole for more than 6 months for reflux esophagitis between 1989 and 1998. All patients had repeated endoscopic examinations until healing of the esophagitis was confirmed and then annually thereafter. At endoscopy, gastric mucosal swellings were classified as polyps or nodules based on histology. Results Thirty-one children had long-term endoscopic follow-up while receiving omeprazole. Seven of 31 children had gastric polyps and/or nodules, noted between 10 and 48 months (mean = 28 months) of omeprazole therapy. Four had nodules only, one had a sessile hyperplastic polyp, and two had both a polyp (one hyperplastic and one fundic gland polyp) and nodules. All lesions were found in the gastric body. Nodules in four of the six children disappeared spontaneously while the children continued to receive omeprazole. The polyps persisted. There were no dysplastic changes in the gastric mucosa or polyps in any of the patients. There were no significant differences between the 7 children with and the 24 without polyps/nodules with respect to age, gastrin concentrations, or dose and duration of omeprazole therapy. Conclusions Gastric polyps and nodules may be found in children receiving long-term omeprazole therapy. The gastric changes in our patients were benign during the mean observation period of 31 months.

Esophageal Crohn disease in children: a clinical spectrum.

BackgroundThe incidence of esophageal Crohn disease (ECD) in adults ranges from 0.2% to 11.2% and in children is up to 43%. The aim of the study was to determine the clinical and endoscopic spectrum of ECD and its prevalence in our patient population. MethodsChart review of children with Crohn disease (CD). Esophageal Crohn disease was defined by accepted endoscopic and/or histologic findings. Results210 children with CD were identified; 27 of those children had ECD. Nine children presented with specific upper GI symptoms; dysphagia, heartburn, nausea, vomiting, and odynophagia. Esophagoscopy in children with upper gastrointestinal symptoms revealed deep ulcers (n = 2), aphthous ulcers (n = l), erosions (n = l), edematous nodules, (n = l) and normal mucosa (n = 4). In asymptomatic children aphthous ulcers (n = 5), erosions (n = 3), deep ulcers (n = 3), and normal looking mucosa (n = 7) were seen. Twenty children also had gastric lesions, 3 children had duodenal lesions, and 3 children had both duodenal and gastric involvement. All 27 children had evidence of ileo-colonic or colonic disease. Acid suppressive medications were given only to children with upper GI symptoms and endoscopic esophageal lesions. The mean duration of follow-up from diagnosis of CD was 3.02 years (range 2 months—11.7 years). At last follow-up review, 7 children were receiving acid suppression and no children were receiving steroids. There were no complications related to ECD. ConclusionThe prevalence of endoscopic ECD is 7.6% but as many as 17.6% of our patient population had histologic evidence of ECD. The clinical and endoscopic spectrum of ECD are highly variable and poorly correlate with each other.

Omeprazole maintenance therapy for gastroesophageal reflux disease after failure of fundoplication.

Background Recurrence of gastroesophageal reflux (GER) in children after failed fundoplication poses a therapeutic challenge. The authors report the experience with long-term omeprazole for children with severe GER after failed fundoplication. Methods The authors reviewed the charts of all children who were treated with omeprazole for GER subsequent to failed fundoplication from 1990 to 1999. All underwent endoscopic and clinical assessment of the treatment at baseline, at 3–5 months, at 6–9 months, and annually. Results Eighteen children presented with GER, after a total of 27 fundoplications. Ten had corrected esophageal atresia, 6 had neurologica impairment, and 2 had hiatal hernia. The mean age of presentation of children with recurrence of GER was 7.8 years, and symptoms of GER occurred 4.9 years (range, 0.6–13) after last fundoplication. Fifteen patients had a mean follow-up of 4.4 years for omeprazole. Ten patients had grade III/IV esophagitis and 5 had grade II esophagitis at presentation after fundoplication. Marked improvement was noted in symptoms of GER and severity of esophagitis while taking omeprazole. Remission of esophagitis was maintained while the patient was taking omeprazole and none had further surgery. There was no recurrence of peptic strictures in eight of nine children on omeprazole, after initial esophageal dilatations. Except for benign gastric polyps in three patients, no clinical adverse effects were observed. Conclusions Omeprazole is an effective long-term drug for gastroesophageal reflux disease after failed fundoplication in children. Omeprazole was well-tolerated by all children and should be tried before subsequent surgical intervention.

Effect of long-term omeprazole treatment on antral G and D cells in children

Background Long-term omeprazole therapy is associated with hypergastrinemia. In the antrum, gastrin secretion from G cells is inhibited in a paracrine manner by somatostatin secreted from D cells. Omeprazole may alter the ratio of G to D cells; however, there are limited data concerning such an effect in humans and none in children. The authors studied the effect of long-term omeprazole therapy on antral G- and D-cell numbers in children. Methods Six children received omeprazole for 4 to 7 years for erosive reflux esophagitis. Endoscopic antral biopsy specimens obtained at baseline and at 1, 4, and 7 years of omeprazole administration were immunostained to assess G and D cell numbers per antral gland. The G- and D-cell numbers were also assessed in an age-matched control group consisting of 24 healthy children from six different age groups. Results The mean G-cell number per unit area showed a significant increase at 4 years (85 ± 5.7 years) and at 7 years (89 ± 6.8 years) on omeprazole compared with baseline (56 ± 4.8 years) (P < 0.01). D-cell numbers did not change. The ratio of G to D cells increased progressively, and the change from baseline was significant at 7 years taking omeprazole (P < 0.02). In the control group, G- and D-cell numbers did not differ significantly within the six age groups. Conclusions Long-term omeprazole therapy is associated with a significant increase in G-cell numbers and in the ratio of G to D cells in children. These changes reflect the effect of omeprazole because there was no change in these parameters in the age-matched control group.

Mucopolysaccharidosis type VII (Sly syndrome) presenting as neonatal cholestasis with hepatosplenomegaly.

Mucopolysaccharidosis type VII (Sly syndrome), a rare lysosomal storage disorder caused by deficiency of the enzyme -glucuronidase, was first reported in 1973 in a two year old boy with hepatosplenomegaly, skeletal abnormalities and moderate mental retardation (1). MPS type VII is unusual amongst the MPS syndromes in that it can manifest clinically in the newborn period often in association with hydrops fetalis, however transient functional liver abnormalities have also been described. We report a neonate with MPS type VII who presented with significant cholestatic jaundice and hepatosplenomegaly and provide a review of the literature.

Acute Onset of Generalized Pruritic Rash in a Toddler

Case Report A 15-year-old boy with Down syndrome (DS) presented with a 12-month history of multiple, asymptomatic papules on the extensor aspect of the limbs and buttocks. The mother and patient denied any scratching. A 1-month trial of Tetracycline 250 mg BD had no effect, and a combination of betamethasone valerate and fusidic acid (Fucibet , Leo Pharm, Princes Risborough, Buckinghamshire, UK) was unhelpful. No relevant family history was known. Examination revealed multiple 5 to 10 mm erythematous papules and nodules with central keratin plugs on the upper and lower limbs and buttocks, some occurring in a linear fashion (Figs. 1 and 2). Folliculitis was evident on the buttocks and to a minor degree on the thighs. Laboratory investigations were all normal or negative including full blood count, renal and liver function, bone profile, glucose, inflammatory markers, thyroid function, antinuclear antibody (ANA), complement, and immunoglobulins. Skin swabs revealed no growth. Skin biopsies from the arm and thigh showed similar features (Figs. 3 and 4).

Concomitant Therapy with Immunomodulator Enhances Infliximab Durability in Pediatric Inflammatory Bowel Disease

Background: Data on long-term durability of infliximab (IFX) and outcomes of concomitant therapy with immunomodulator in pediatric inflammatory bowel disease are limited. Methods: Children with inflammatory bowel disease who received IFX ± immunomodulator were retrospectively reviewed. Predictors of induction response were assessed using a binary logistic regression model and long-term outcomes evaluated by Cox proportional hazards model. Propensity score matching examined long-term efficacy of concomitant therapy in patients with Crohns disease (CD). Results: Among 148 patients (113 CD, 35 ulcerative colitis; median age at IFX initiation 14.09 years [interquartile range 12.16–15.65]), 91% experienced response to induction therapy; patients with CD were more likely to respond (95% versus 77%, odds ratio = 2.63, 95% confidence interval, 1.01–6.85, P = 0.048). Despite dose optimization, secondary loss of response occurred at a rate of 9.01% and 8.33% per year for patients with CD and ulcerative colitis, respectively. A Cox proportional hazards model showed that concomitant therapy >6 months significantly lowered the risk of secondary loss of response in CD (hazard ratio = 0.39, 95% confidence interval, 0.17–0.88, P = 0.025). The same trend was observed in ulcerative colitis but did not reach significance. A higher proportion of patients on IFX monotherapy stopped IFX because of loss of response or infusion reactions (55% versus 21%, P < 0.001). Propensity score analysis of patients with CD showed significantly higher steroid-free remission rates for concomitant versus monotherapy at 1 year (78% versus 54%, P = 0.020) and 2 years (68% versus 46%, P = 0.044), and durability of response (P = 0.022). Conclusions: These data demonstrate sustained efficacy of IFX in a cohort of pediatric patients with inflammatory bowel disease with durability of response enhanced by concomitant therapy.