Steven J. Steiner

Comparison of Oral Prednisone and Topical Fluticasone in the Treatment of Eosinophilic Esophagitis: A Randomized Trial in Children

BACKGROUND & AIMS Although eosinophilic esophagitis is recognized increasingly, outcome data guiding therapy are limited. We conducted a prospective randomized trial comparing oral prednisone (P) and swallowed fluticasone (F) for histologic and clinical response. METHODS Patients were randomized to receive P or F for 4 weeks, followed by an 8-week weaning protocol. Esophageal histology was evaluated at baseline and after 4 weeks of therapy. Clinical assessments were performed at weeks 0, 4, 12, 18, and 24. RESULTS Eighty patients with eosinophilic esophagitis were enrolled: 40 in the P arm and 40 in the F arm. Histologic improvement was seen in 30 of 32 P and 34 of 36 F patients, with a greater degree of histologic improvement in the P group. All P and 35 of 36 F patients were free of presenting symptom(s) at week 4. Symptom relapse was seen in 45% of patients by week 24. Kaplan-Meier analysis showed no difference between P and F with regard to relapse rate (P = .7399). No significant difference in time to relapse was found between groups (P = .2529). Systemic adverse effects were noted in 40% of the P arm, whereas esophageal candidal overgrowth was seen in 15% of the F arm. CONCLUSIONS Systemic and topical corticosteroids were effective in achieving initial histologic and clinical improvement. P resulted in a greater degree of histologic improvement, without evidence of an associated clinical advantage over F in terms of symptom resolution, relapse rates, or time to relapse. Symptom relapse was common to both groups upon therapy discontinuation, highlighting the need for maintenance treatment protocols.

Correlation between number of eosinophils and reflux index on same day esophageal biopsy and 24 hour esophageal pH monitoring.

OBJECTIVE:The presence of eosinophils on esophageal biopsy is a marker of esophagitis in children. Eosinophilic inflammation without evidence of gastroesophageal reflux has led to the new diagnosis of eosinophilic, or allergic, esophagitis. The aim of this study was to correlate the number of eosinophils with the reflux index on same day esophageal biopsy and 24 h esophageal pH monitoring.METHODS:A retrospective analysis of data collected from children who underwent same day endoscopy with esophageal biopsies and 24 h esophageal pH monitoring over a 3-yr period was performed. The patients were divided into five groups: Group 1: 0 eosinophils/hpf and no histologic change, Group 2: 0 eosinophils/hpf but histologic changes, Group 3: 1–5 eosinophils/hpf, Group 4: 6–20 eosinophils/hpf, and Group 5: >20 eosinophils/hpf. Reflux indices were analyzed within each group.RESULTS:A total of 305 patients met the inclusion criteria. The mean reflux indices ± standard error within each group were Group 1 (n = 171): 2.14 ± 0.18%, Group 2 (n = 40): 3.93 ± 1.24%, Group 3 (n = 42): 5.96 ± 1.53%, Group 4 (n = 21): 4.18 ± 1.27%, and Group 5 (n = 31): 2.02 ± 0.53%. The mean reflux index in Group 3 was significantly greater than Groups 1 and 5.CONCLUSIONS:The presence of denser infiltrates of eosinophils does not correlate with increased gastroesophageal reflux. The finding of more than 20 eosinophils/hpf is likely associated with a normal reflux index and a nonacid-related cause of esophagitis.

White specks in the esophageal mucosa: an endoscopic manifestation of non-reflux eosinophilic esophagitis in children☆

BACKGROUND White specks in the esophageal mucosa have been observed in children with eosinophilic esophagitis. The aim of this study was to determine the relationship between white specks in the esophageal mucosa and allergic (non-reflux) eosinophilic esophagitis. METHODS Endoscopic data, pH probe results, and histopathology reports for children with esophageal endoscopic abnormalities seen during a 17-month period were reviewed. Eosinophilic esophagitis was grouped according to the number of eosinophils per high power field (non-allergic, <15 eosinophils/high power field; allergic, > or =15 eosinophils/high power field). RESULTS Of 1041 endoscopies performed during the study period, 153 revealed evidence of eosinophilic esophagitis. Of these 153, 61 had fewer than 15 eosinophils/high power field and 92 had 15 or more eosinophils/high power field. At 31 of the 153 procedures, white specks were noted in the esophageal mucosa. The sensitivity of white specks in the esophageal mucosa for allergic eosinophilic esophagitis was only 30%, but the specificity was 95%. pH probe testing was performed in 21 patients with white specks and was normal in all. CONCLUSIONS This report describes a new endoscopic finding associated with allergic eosinophilic esophagitis in children. Eosinophilic esophagitis tends to be severe when white specks are present (> or =15 eosinophils/high power field) and is not associated with pathologic gastroesophageal reflux, as demonstrated by pH probe testing.

Severity of basal cell hyperplasia differs in reflux versus eosinophilic esophagitis.

Objectives: Basal cell hyperplasia of the esophageal epithelium is a frequent finding in children with histological evidence of esophagitis. The aim of this study was to compare the severity of basal cell hyperplasia in gastroesophageal reflux vs eosinophilic esophagitis. Methods: A cohort of pediatric patients who underwent same-day endoscopy with esophageal biopsy and 24-hour esophageal pH monitoring was divided into groups based on endoscopic and pH monitoring findings. Basal cell hyperplasia was defined as normal (≤25% of esophageal epithelial height), mild (26%-50%), moderate (51%-75%) or severe (>75%). The severity of basal cell hyperplasia in patients with abnormal pH monitoring studies, both with and without endoscopic abnormalities of the esophagus, was compared with the severity in patients with eosinophilic esophagitis. Results: Twenty-seven children with abnormal pH monitoring were identified. Of these 27 children, 11 had endoscopic findings consistent with reflux esophagitis. Thirty patients with eosinophilic esophagitis were identified. Patients with eosinophilic esophagitis had significantly increased severity (P < 0.001) of basal cell hyperplasia (87% severe, 3% moderate, 3% mild, 7%, normal) than patients with abnormal esophageal pH monitoring alone (11% severe, 4% moderate, 15% mild, 70% normal) or in combination with endoscopic abnormalities (18% severe, 9% moderate, 18% mild, 55% normal). Conclusions: Basal cell hyperplasia is more severe in children with eosinophilic esophagitis than in those with reflux esophagitis. The finding of basal cell hyperplasia is a powerful clue into the underlying etiology of pediatric esophagitis and, along with epithelial eosinophil count, can be used as information to guide therapy.

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

BACKGROUND Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohns disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohns disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohns disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the models specificity improved to 71%. INTERPRETATION Our findings support the usefulness of risk stratification of paediatric patients with Crohns disease at diagnosis, and selection of anti-TNFα therapy. FUNDING Crohns and Colitis Foundation of America, Cincinnati Childrens Hospital Research Foundation Digestive Health Center.

Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children

Background and Aims: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. Subjects and Methods: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. Results: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ± 4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ± 4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls’ 1-time measurement. Conclusions: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.

Ileocecal histoplasmosis simulating Crohn disease in a patient with hyperimmunoglobulin E syndrome.

We describe a 14-year-old girl with hyperimmunoglobulin E (Job) syndrome who presented with fatigue, abdominal pain, fever, and weight loss. Endoscopic examination of the terminal ileum revealed ulceration, edema, and erythema. Histopathologic findings of the terminal ileum demonstrated intracellular yeast forms compatible with Histoplasma capsulatum. The patient was treated with oral itraconazole and had a rapid and complete response.

Accuracy and tolerability of the Bravo catheter-free pH capsule in patients between the ages of 4 and 18 years

Objective: The aim of this study was to determine if the Bravo pH capsule is comparable to the nasally placed pH catheter in terms of pH-metry, safety, and tolerability in children. Methods: Ten patients each in the age ranges of 4 to 6 years, 7 to 10 years, and >10 years were tested simultaneously with the catheter and the capsule. Six each were tested with the catheter alone or the capsule alone. Subjects recorded adverse events and graded tolerance (in terms of activity, appetite, and satisfaction) on a scale of 1 to 5, with a score of 5 indicating that the device was well tolerated. A 24-hour reflux index and 24- and 48-hour reflux indices were generated from the catheter and capsule, respectively. Student t test, Mann-Whitney U test, and Fisher exact test were used to compare reflux index, tolerability, and adverse events between the catheter and capsule. Results: Sixty-six patients 4 to 16 years of age (mean, 9.4 years) were enrolled. There was no statistically significant difference between the mean reflux indices (RIs) obtained simultaneously with the catheter and capsule in all patients combined on day 1 (P = 0.0665). There was a significant difference between day 2 and days 1 and 2 combined with the capsule versus the catheter (P = 0.007 and P = 0.0107); however, a discordant result of normal RI on day 1 and pathological RI on day 2 was seen in only 1 patient. The capsule was better tolerated than the catheter in terms of appetite (P = 0.029), activity (P = 0.001), and satisfaction (P = 0.003). There were no significant complications. Conclusions: The Bravo pH capsule was as accurate and safe and better tolerated than the conventional pH catheter in children 4 years of age and older.

Protein and energy metabolism response to the initial dose of infliximab in Children with Crohn's disease

Background Tumor necrosis factor‐&agr; (TNF‐&agr;) may contribute to the alterations in protein and energy metabolism present in children with Crohns disease (CD), who frequently suffer from growth disturbance. We hypothesized that anti‐TNF‐&agr; therapy would reduce protein losses, due to decreased proteolysis and increased protein synthesis, and that anti‐TNF‐&agr; therapy would decrease resting energy expenditure. Methods Children with active CD underwent metabolic assessment immediately before and 2 weeks following initial infliximab infusion. Using the stable isotopes [d5] phenylalanine and [1–13C] leucine, 2 independent measures of protein metabolism were determined during fasting and in response to parenteral nutrition. Energy expenditure, determined by indirect calorimetry, was measured in fasting and parenterally fed states. Results Fifteen children completed the study. Following infliximab therapy, significant reductions in proteolysis (P < 0.05) were noted in the fasting state (8%–11%) and during parenteral nutrition infusion (10%–12%). Phenylalanine utilization for protein synthesis decreased significantly (8%–13%) following infliximab (P < 0.05). Protein balance was not significantly altered. No significant changes in energy expenditure were observed following infliximab in fasting or parenterally fed states. Supplementation with parenteral nutrition resulted in significantly decreased proteolysis (8%–21%; P < 0.05), increased protein synthesis (37%–45%; P < 0.01), and improved protein balance (P < 0.01) compared to the fasting state. Conclusions Following the initial infliximab infusion in children with CD, proteolysis and protein synthesis were significantly reduced in the fasting and parenterally fed states. Supplementation with parenteral nutrition resulted in significant improvements in protein metabolism compared to the fasting state both before and after infliximab therapy. (Inflamm Bowel Dis 2007)

Serum levels of α1-antitrypsin predict phenotypic expression of the α1-antitrypsin gene

We conducted a retrospective analysis to determine if both α1-antitrypsin serum level and phenotype need be studied when evaluating children for α1-AT deficiency. We collected data from patients less than 19 years old who had both serum α1-AT level and phenotype determined over a 9-year period (January 1992–December 2000). Eighty-eight patients were identified and 15 had the PiZZ phenotype. The serum α1-AT level was below normal (normal 85–215 mg/dl) in all 15 PiZZ patients. Seventy-two of 73 non-PiZZ patients had normal or above normal serum levels. The sensitivity of the serum α1-AT level was 100%, and the specificity was 99%. The serum α1-AT level had a positive predictive value of 94% and a negative predictive value of 100%. We conclude that serum α1-AT levels are highly predictive of the PiZZ phenotype. Determination of the serum α1-AT level alone should be the initial test when evaluating for α1-AT deficiency.