Ranjan Dohil

Oral Viscous Budesonide Is Effective in Children With Eosinophilic Esophagitis in a Randomized, Placebo-Controlled Trial

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is caused by immunologic reactions to ingested/inhaled allergens. The diagnosis is considered if >or=15 eosinophils per high-powered field (eos/hpf) are detected in mucosal biopsies. Placebo-controlled studies have not been conducted to evaluate the safety and efficacy of oral viscous budesonide (OVB). METHODS Children with EoE were randomly assigned to groups that were given OVB (n=15) or placebo (n=9). Patients<5 feet and >or=5 feet tall received 1 mg and 2 mg OVB daily, respectively. All patients received lansoprazole. Duration of treatment was 3 months, followed by repeat endoscopy and biopsies. Patients were classified as responders if their peak eosinophil counts were <or=6 eos/hpf, partial responders were 7-19 eos/hpf, and nonresponders were >or=20 eos/hpf. Baseline and post-treatment symptoms and endoscopic and histologic features were scored. RESULTS Thirteen (86.7%) children given OVB (P<.0001) and none who received placebo (P=.3) were classified as responders. Mean pre-/post-treatment peak eosinophil counts were 66.7 and 4.8 eos/hpf, respectively, in the group given OVB (P<.0001); they were 83.9 and 65.6 eos/hpf, respectively, in the group given placebo (P=.3). In the group given OVB, there were significant reductions from baseline values in proximal (P=.002), mid (P=.0003), and distal (P=.001) esophageal eosinophilia. After OVB therapy, compared with baseline, the mean symptom (P=.0007), endoscopy (P=.0005), and histology scores improved (P=.0035) significantly. CONCLUSIONS OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.

Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids

Background:  Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown.

Oral Viscous Budesonide: A Potential New Therapy for Eosinophilic Esophagitis in Children

BACKGROUND:Eosinophilic esophagitis (EE) is a disorder characterized typically by pan-esophageal eosinophilia. We evaluate a palatable, long-acting topical corticosteroid preparation for the treatment of EE.STUDY DESIGN:This is a retrospective analysis of symptoms, endoscopic and histologic findings, efficacy, and safety of treatment in children with EE receiving oral viscous budesonide. Response to therapy was determined histologically by the number of eos/hpf. Patients were classified by histology into responders (0–7 eos/hpf), partial responders (8–23 eos/hpf), and nonresponders (≥24 eos/hpf). A symptom score (max. 14) and an EE endoscopy score (max. 8) were used to compare data.RESULTS:In 20 children (mean age 5.5 yr, median age 4.1 yr) the mean highest eosinophil count was 87 eos/hpf (range 30–170) before and 7 eos/hpf (range 0–50, P < 0.0001) after therapy. There were 16 (80%) responders, 1 partial responder, and 3 nonresponders. Commonest pretreatment symptoms were nausea, vomiting, pain, and heartburn. The mean symptom score fell from 4.4 to 0.8 (P < 0.0001) and the mean endoscopy score from 3.6 to 0.8 (P < 0.0001). No significant adverse events were reported. Morning cortisol levels were within normal limits.CONCLUSIONS:Topical viscous budesonide is a safe and effective therapy for EE in young children.

Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction

BACKGROUND Increased numbers of mast cells are present in the esophageal epithelium in patients with eosinophilic esophagitis (EE). However, mast cell infiltration into the esophageal lamina propria (LP) and smooth muscle (SM) and the effects of their products on SM function has not been determined. OBJECTIVE We investigated mast cell localization and characterization in esophageal SM, the functional significance of mast cell TGF-β1 expression to contraction of human esophageal smooth muscle (HESM) cells in vitro, and the effect of topical corticosteroids on the number of tryptase-positive (MC(T)) and chymase-positive (MC(C)) mast cells in patients with EE. METHODS MC(T)- and MC(C)-positive mast cell numbers were quantitated in the epithelium, the LP before and after topical corticosteroid therapy, and the muscularis mucosa in patients with EE and control subjects by using immunohistology. Double immunofluorescence was used to assess mast cell production of TGF-β1. The ability of TGF-β1 to influence HESM cell contractility was assessed in vitro. RESULTS In the SM in patients with EE, significantly increased numbers of MC(T)- and TGF-β1-positive cells (but only low levels of eosinophils) were detected compared with those seen in control subjects. MC(T) expressed TGF-β1, which increased the contractility of cultured primary HESM cells in vitro. Topical corticosteroid therapy in patients with EE significantly reduced epithelial MC(T) numbers but not LP tryptase-chymase-positive mast cell numbers. CONCLUSIONS MC(T) numbers, rather than eosinophil numbers, are increased in the SM in patients with EE, express TGF-β1, and increase the contractility of HESM cells in vitro. As such, mast cells localized to SM in patients with EE might modulate esophageal contractility.

Distinguishing eosinophilic esophagitis in pediatric patients: clinical, endoscopic, and histologic features of an emerging disorder.

Goals To determine the clinical, endoscopic, and histologic criteria that distinguish children with eosinophilic esophagitis (EE) from those with non-EE diagnoses. Background EE is a disease of escalating incidence. Distinguishing children with EE from those with non-EE diagnosis can be difficult before endoscopy. Study A retrospective case-control study was performed for children with any degree of esophageal eosinophilic inflammation who underwent esophageal biopsy at Childrens Hospital San Diego from January 1998 to December 2002. A database containing children who met histologic criteria for EE and an equivalent number of children who had milder esophageal eosinophilia (non-EE patients) was created to compare the 2 groups. Results The number of EE cases increased from 15 in 1998 to 35 in 2002. EE patients were predominantly school-aged boys; 5 of 102 were suspected to have EE before biopsy. Although EE and non-EE patients complained of vomiting and abdominal pain at equivalent rates, EE patients were 3 times more likely to complain of dysphagia [odds ratio (OR)=3.11, 95% confidence interval (CI) 1.55-6.65] and twice as likely to have stricture formation (OR=2.43, 95% CI 0.72-11.75). On endoscopy, patients with EE were 19-times more likely than non-EE patients to have endoscopic abnormalities (OR=19, 95% CI 9.0-45.88). Histologically, EE patients were more likely to have basal zone hyperplasia and degranulated eosinophils (OR=45 and 157, respectively). Conclusions We demonstrate that school-aged children, particularly boys, who complain of dysphagia should raise the index of suspicion for EE. We also suggest that EE-associated strictures are more common than peptic strictures in children.

A symptom scoring tool for identifying pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation.

BACKGROUND Eosinophilic esophagitis (EE) is an increasingly recognized allergic disease entity that is difficult to distinguish clinically from other causes of esophagitis, especially gastroesophageal reflux disease (GERD). To our knowledge, there are no prospectively analyzed or validated symptom scoring tools for pediatric patients with EE and no prospective evaluation correlating symptoms with tissue inflammation. OBJECTIVES To prospectively analyze a symptom scoring tools ability to distinguish pediatric patients with EE from those with GERD and from control patients with and without allergies and to correlate symptoms with tissue inflammation. METHODS A prospective study of a symptom scoring tool given to patients with EE (n = 35 not receiving EE targeted therapy), patients with GERD (n = 27 not undergoing acid suppression), allergic control patients (n = 24), and nonallergic control patients (n = 14) at an academic pediatric hospital. Histology and endoscopy scores were correlated with symptom complaints. RESULTS The total symptom score was higher among patients with EE (mean, 6.51; 95% confidence interval [CI], 5.50-7.53) and GERD (mean, 5.44; 95% CI, 4.64-6.25) than in allergic (mean, 0.92; 95% CI, 0.28-1.55) and nonallergic (mean, 1.00; 95% CI, 0.40-1.60) patients (P < .001). Patients with EE and GERD complained of more nausea/vomiting, abdominal pain, heartburn/regurgitation, and nocturnal awakening than control groups (P < .001). Only dysphagia (mean, 0.9 [95% CI, 0.7-1.2] in EE patients vs 0.4 [95% CI, 0.2-0.7] in GERD patients) and anorexia/early satiety (mean, 1.4 [95% CI, 1.2-1.6] in EE patients vs 0.8 [95% CI, 0.5-1.1] in GERD patients) discriminate EE from GERD (P < .01). These symptoms also correlated with the severity of histologic and endoscopic findings (P < .05). CONCLUSION Dysphagia and anorexia/early satiety identify pediatric patients with EE and correlate symptoms with tissue inflammation.

Dysfunction of the longitudinal muscles of the oesophagus in eosinophilic oesophagitis

Background: Oesophageal motility, as measured by manometry, is normal in the majority of patients with eosinophilic oesophagitis (EO). However, manometry measures only the circular muscle function of the oesophagus. The goal of the present study was to assess circular and longitudinal muscle function during peristalsis in patients with EO. Methods: Ultrasound imaging and manometry were simultaneously acquired during swallow-induced peristalsis in patients with EO and controls to measure the longitudinal muscle and circular muscle contraction, respectively. A probe with an ultrasound transducer was positioned 2 cm and then 10 cm above the lower oesophageal sphincter and five, 5 ml water swallows were recorded before and after edrophonium. Results: There is no difference in the incidence of swallow-induced peristalsis and manometric pressures (a marker of circular muscle contraction) between controls and patients with EO. However, changes in the muscle thickness (a marker of longitudinal muscle contraction) are markedly diminished in patients with EO, at both 2 and 10 cm above the lower oesophageal sphincter. The longitudinal muscle response to edrophonium is markedly blunted in patients with EO. Normal subjects demonstrate synchrony between the circular and longitudinal muscle contraction during peristalsis that is affected by edrophonium. On the other hand, patients with EO demonstrate mild asynchrony of circular and longitudinal muscle contraction during swallow-induced contractions that is not altered by edrophonium. Conclusions: In patients with EO, there is selective dysfunction of the longitudinal muscle contraction during peristalsis. It is proposed that the longitudinal muscle dysfunction in EO may contribute to dysphagia.

Anti–IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis

BACKGROUND Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking, and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with prominent mast cell infiltration. OBJECTIVE We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in biopsy specimens from pediatric patients with EoE from a previous randomized anti-IL-5 trial. METHODS A subanalysis was completed for children treated with 0.55, 2.5, or 10 mg/kg mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess the numbers of eosinophils, tryptase-positive mast cells, IL-9(+) cells, and mast cell-eosinophil couplets before and after treatment. RESULTS Forty-three biopsy specimens had adequate tissue for paired analysis. Forty percent of subjects responded to anti-IL-5 (defined as <15 eosinophils per high-power field [hpf] after mepolizumab therapy), and 77% of all subjects had decreased numbers of mast cells after anti-IL-5. In responders epithelial mast cell numbers decreased from 62 to 19 per hpf (P < .001), were significantly lower than in nonresponders after therapy (P < .05), and correlated with eosinophil numbers (r = 0.75, P < .0001). Mast cells and eosinophils were found in couplets before therapy, and these were significantly decreased only in responders after anti-IL-5 (P < .001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9(+) cell numbers decreased from 102 to 71 per hpf (P < .001) after anti-IL-5. CONCLUSIONS Pediatric patients with EoE had significantly fewer mast cells, IL-9(+) cells, and mast cell-eosinophil couplets in the esophageal epithelium after anti-IL-5 therapy. Because eosinophils were one source of IL-9, they might support esophageal mastocytosis.

The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine

OBJECTIVES Cysteamine prevents organ damage in children with cystinosis, but may cause gastrointestinal (GI) symptoms. In this study we evaluated the nature of GI disease, and the value of omeprazole in controlling GI symptoms in these children. STUDY DESIGN Upper GI disease was evaluated with endoscopy, gastrin levels, and acid secretion studies after oral administration of cysteamine, before and after 16 weeks of therapy with omeprazole. A symptom score was devised. RESULTS Eleven children (mean age, 5.7 years) were studied. After cysteamine ingestion, before and after omeprazole therapy, the mean maximum acid output was significantly higher than the mean basal acid output. The maximum acid output was measured within 60 minutes of cysteamine ingestion and was reduced by omeprazole therapy (P<.01). The mean peak gastrin level was 30 minutes postcysteamine and was higher than baseline (P<.01). The initial mean symptom score (maximum score, 14) was 6.9 and fell to 0.7 (P<.0001) after 16 weeks of omeprazole therapy. At endoscopy, two children had diffuse gastric nodularity, and nearly all had cystine crystal deposits. CONCLUSIONS GI symptoms in children with cystinosis receiving cysteamine are often acid-mediated and improve with omeprazole. Cystine crystals were detected in the GI tract and may signify inadequate treatment with cysteamine.

Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis

Author(s): Doherty, Taylor A; Baum, Rachel; Newbury, Robert O; Yang, Tom; Dohil, Ranjan; Aquino, Melissa; Doshi, Ashmi; Walford, Hannah H; Kurten, Richard C; Broide, David H; Aceves, Seema