Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.

BACKGROUND & AIMS: We evaluated the efficacy and safety of high-dose swallowed fluticasone propionate (FP) and dose reduction in patients with eosinophilic esophagitis (EoE) and analyzed esophageal transcriptomes to identify mechanisms. METHODS: We conducted a randomized, multisite, double-blind, placebo-controlled trial of daily 1760 mcg FP in participants age 3-30 years with active EoE. Twenty-eight participants received FP, and 14 participants received placebo. After 3 months, participants given FP who were in complete remission (CR) received 880 mcg FP daily, and participants in the FP or placebo groups who were not in CR continued or started, respectively, 1760 mcg FP daily for 3 additional months. The primary end point was histologic evidence for CR. Secondary end points were partial remission (PR), symptoms, compliance, esophageal gene expression, esophageal eosinophil count, and the relationship between clinical features and FP responsiveness. RESULTS: After 3 months, 65% of subjects given FP and no subjects given placebo were in CR (P = .0001); 12% of those given FP and 8% of those given placebo were in PR. In the FP group, 73% of subjects remained in CR, and 20% were in PR after the daily dose was reduced by 50%. Extending FP therapy in FP-resistant participants did not induce remission. FP decreased heartburn severity (P = .041). Compliance, age, sex, atopic status, or anthropomorphic features were not associated with response to FP. Gene expression patterns in esophageal tissues of FP responders were similar to those of patients without EoE; there was evidence for heterogeneous steroid signaling in subjects who did not respond to FP and preliminary evidence for transcripts predictive of FP responsiveness. CONCLUSIONS: Daily administration of a high dose of FP induces histologic remission in 65%-77% of patients with EoE after 3 months. A 50% dose reduction remained effective in 73%-93% of patients who initially responded to FP. Nonresponders had evidence of steroid resistance; histologic and molecular markers may predict resistance. Clinicaltrials.gov number: NCT00426283.

Long-term outcomes in pediatric-onset esophageal eosinophilia.

BACKGROUND: Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis (CE). OBJECTIVE: Characterization of long-term clinical outcomes in patients with pediatric EoE is needed. METHODS: From histologic review of 3817 pediatric esophageal biopsy specimens from 1982-1999, we conducted a nested case-control study of patients with retrospectively identified histologic eosinophilic esophagitis (rEoE) and CE, as well as an age-matched control cohort. Participants were asked to complete validated health-related outcome questionnaires. RESULTS: At an average of 15 years after initial endoscopy, both cohorts (42/198 patients with rEoE and 67/468 patients with CE, as well as 100 age-matched control subjects) completed questionnaires. Compared with control subjects, quality of life was significantly decreased among patients with rEoE (P < .001) and patients with CE (P < .001). Rates of dysphagia (patients with rEoE, 49%; patients with CE, 37%; control subjects, 6%) and food impaction (patients with rEoE, 40%; patients with CE, 14%; control subjects, 3%) were significantly increased in the rEoE cohort compared with those seen in control subjects (P < .001 and P < .001, respectively). Increased esophageal eosinophil counts (odds ratio [OR], 1.6; 95% CI, 1.1-2.5; P < .05) during childhood were predictive of dysphagia during early adulthood. Food allergy (OR, 2.7; 95% CI, 1.2-6.0; P < .01), allergic rhinitis (OR, 3.5; 95% CI, 1.8-6.8; P < .001), and asthma (OR, 2.1; 95% CI, 1.04-4.3; P = .04) were associated with dysphagia. Food impaction was more common among patients with reported food allergy than among those without (OR, 3.1; 95% CI, 1.2-7.8; P = .02). CONCLUSIONS: Esophageal eosinophilia is associated with reduced quality of life and persistent symptoms 15 years after presentation. Increased esophageal eosinophil counts and the occurrence of food allergy and atopy in childhood increase the rate of dysphagia in young adulthood.

A striking local esophageal cytokine expression profile in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. OBJECTIVE: Early studies have suggested that esophageal eosinophilia occurs in association with T(H)2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized. METHODS: A human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays were used to quantify cytokine mRNA in esophageal biopsies and blood samples. RESULTS: Esophageal transcripts of numerous chemokines (eg, chemokine [C-C motif] ligand [CCL] 1, CCL1, CCL23, CCL26 [eotaxin-3], chemokine [C-X-C motif] ligand [CXCL] 1, and CXCL2), cytokines (eg, IL13 and ATP-binding cassette, subfamily F, member 1), and cytokine receptors (eg, IL5 receptor, alpha) were induced at least 4-fold in individuals with EE. Analysis of esophageal biopsies (n = 288) revealed that eotaxin-3 mRNA level alone had 89% sensitivity for distinguishing individuals with and without EE. The presence of allergy was associated with significantly increased esophageal expression of IL4 and IL5 mRNA in patients with active EE. We identified 8 cytokines (IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40 ligand, IL-1α, and IL-17) whose blood levels retrospectively distinguished 12 patients without EE from 13 patients with EE with 100% specificity and 100% sensitivity. When applied to a blind, prospectively recruited group of 36 patients, the cytokine panel scoring system had a 79% positive predictive value, 68% negative predictive value, 61% sensitivity, and 83% specificity for identifying EE. CONCLUSION: Evidence is presented that IL13 and IL5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive T(H)2 immunity in regulating eotaxin-3-driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines.

Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999.

BACKGROUND: Eosinophilic esophagitis (EE) is now a commonly encountered disorder that was rarely diagnosed a decade ago. OBJECTIVE: We aimed to determine the epidemiologic and histologic features of retrospective pediatric esophageal eosinophilia before the first case of EE at our institution was recognized. METHODS: Esophageal biopsy specimens obtained between 1982 and 1999 with reflux esophagitis were re-examined and reorganized into 2 groups based on peak esophageal eosinophil number (<15 eosinophils per high-powered field [hpf] and > or =15 eosinophils/hpf). The epidemiology and histology of the entire cohort and a population-based cohort were evaluated. RESULTS: Eight hundred seven biopsy specimens from 666 patients were re-examined; 198 patients had 15 eosinophils/hpf or greater. Among a population-based cohort of patients with 15 eosinophils/hpf or greater, there was a modest increase in incidence (P < .001; incidence rate ratio, 1.18; 95% CI, 1.09-1.28). After correcting for a 40-fold increase in the number of endoscopies during this time period, the proportion of biopsy specimens with 15 eosinophils/hpf or greater did not change (0.08 in 1982 vs 0.08 in 1996 [peak]; P = .9; incidence rate ratio, 1.02; 95% CI, 0.73-1.44). Patients who had as few as 5 eosinophils/hpf were more likely to have persistent esophageal eosinophilia on repeat esophagogastroduodenoscopy, evidence of basal layer hyperplasia, and lamina propria fibrosis compared with patients with less than 5 eosinophils/hpf (P < .001). CONCLUSIONS: Esophageal eosinophilia at levels consistent with EE was present among 30% of patients given diagnoses of reflux esophagitis, and the incidence of esophageal eosinophilia did not change over time. Patients with 5 eosinophils/hpf or greater had evidence of other histologic abnormalities and were likely to have persistent esophageal eosinophilia.