A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
ABSTRACT: Phenotypes of eosinophilic esophagitis (EoE) are not well-characterized.To describe clinical features of patients with EoE with predefined phenotypes, determine predictors of these phenotypes, and make inferences about the natural history of EoE.Retrospective study.Tertiary-care center.Incident EoE cases from 2001 to 2011 that met consensus diagnostic guidelines.Review of records.Endoscopic phenotypes, including fibrostenotic, inflammatory, or mixed. Other groups of clinical characteristics examined included atopy, level of esophageal eosinophilia, and age of symptom onset. Multinomial logistic regression assessed predictors of phenotype status.Of 379 cases of EoE identified, there were no significant phenotypic differences by atopic status or level of eosinophilia. Those with the inflammatory phenotype were more likely to be younger than those with mixed or fibrostenotic (13 vs 29 vs 39 years, respectively; P < .001) and less likely to have dysphagia, food impaction, and esophageal dilation (P < .001 for all). The mean symptom length before diagnosis was shorter for inflammatory (5 vs 8 vs 8 years; P = .02). After multivariate analysis, age and dysphagia independently predicted phenotype. The odds ratio (OR) for fibrostenosis for each 10-year increase in age was 2.1 (95% CI, 1.7-2.7). The OR for dysphagia was 7.0 (95% CI, 2.6-18.6).Retrospective, single-center study.In this large EoE cohort, the likelihood of fibrostenotic disease increased markedly with age. For every 10-year increase in age, the odds of having a fibrostenotic EoE phenotype more than doubled. This association suggests that the natural history of EoE is a progression from an inflammatory to a fibrostenotic disease.
Project description:<h4>Objectives</h4>Eosinophilic esophagitis (EoE) is a chronic inflammatory condition that causes esophageal remodeling and stricture formation. We compared the clinical course of symptoms, endoscopic findings, histology, and changes in phenotype over time in EoE patients with inflammatory and fibrostenotic phenotypes.<h4>Methods</h4>Data were obtained from EoE patients from three medical centers and followed prospectively. Endoscopic features and histology from index and follow-up endoscopies were recorded. Behavior was classified as inflammatory if endoscopic findings demonstrated furrows or white plaques and as fibrostenotic if endoscopic findings included fixed rings or strictures.<h4>Results</h4>Two hundred and fifty-six EoE patients were included in the analysis. The mean age was 32±18 years, 25% of patients were <18 years, 89% of patients were Caucasians, and 74% of patients were male. The mean duration of symptoms before diagnosis was 6.8±7.2 years with a follow-up of 1.7±1.9 years (maximum follow-up of 12 years). Fifty-four percent of patients presented with fibrostenotic EoE, whereas 46% presented with inflammatory EoE. Patients with inflammatory disease were younger than those with fibrostenotic disease (24±19 vs. 39±15 years, P<0.001). Patients with fibrostenotic disease had a longer duration of symptoms than those with inflammatory disease (8.1±7.7 vs. 5.3±6.3 years, P=0.002). Over the study period, 47 (18%) had remission of inflammatory EoE, 68 (27%) continued to have inflammatory disease, 74 (29%) continued to have fibrostenotic disease, 65 (25%) fibrostenotic patients had regression of fibrosis, and 2 patients (1%) progressed from inflammatory disease to fibrostenotic disease. Patients who had regression from their fibrostenosis were more likely than patients who continued to demonstrate fibrostenosis to have a decrease in proximal (54% vs. 32%, P<0.001) and distal (70% vs. 38%, P<0.001) eosinophilia.<h4>Conclusions</h4>Most EoE patients maintained their phenotype or had an improvement with <1% progressing from inflammatory to fibrostenosis. This suggests that early therapeutic strategies aimed at controlling inflammation may interrupt, decrease, or prevent the remodeling fibrosis in EoE.
Project description:OPINION STATEMENT:New developments in eosinophilic esophagitis (EoE) pathogenesis are shaping our current therapeutic and management strategies. EoE is a chronic allergic inflammatory disease with progression to fibrostenotic disease. The disease warrants early diagnosis and long-term maintenance therapy. The diagnosis of EoE should be based on the concept of an allergy-mediated disease with esophageal dysfunction and esophageal eosinophilia. Recent findings suggest that proton pump inhibitor (PPI)-responsive esophageal eosinophilia (PPI-REE) is likely a continuum of EoE or a similar T-helper 2 (Th2)-mediated allergic process. PPIs have therapeutic properties that can benefit both gastroesophageal reflux disease (GERD) and EoE. Therefore, PPIs should be considered not a diagnostic tool but, rather, a therapeutic option for EoE. If patients are PPI nonresponsive, then dietary therapy or steroid therapy should be considered. Dilation can be reserved as adjuvant therapy for severe fibrostenotic lesions.
Project description:BACKGROUND:Eosinophilic esophagitis (EoE) is increasingly common, but data on phenotypic aspects are still incomplete. OBJECTIVES:To describe the clinical, endoscopic, and histopathologic features of a large number of children and adults with EoE across the United States. METHODS:This was a multisite single visit registry enrolling subjects aged 6 months to 65 years with EoE. Participants provided responses regarding their medical history, with verification of the diagnosis and history by the study teams. RESULTS:A total of 705 subjects were analyzed (median [interquartile range] age at enrollment 11.2 [6.7-17.7] years, 68.2% male, 87.9% whites). Of these, 67 subjects had concurrent gastrointestinal eosinophilia, with gastric mucosa most common. An age- and race-dependent time gap was present between symptom onset and time of diagnosis (adults and whites with longer gap). Food allergy and atopic dermatitis were associated with a decrease in this gap. Symptoms varied with age (more dysphagia and food impaction in adults) and with race (more vomiting in non-whites). Esophageal rings and strictures at diagnosis were more common in adults, although esophageal eosinophilia was comparable among age groups. Concomitant allergic disease (91%), infectious/immunologic disorders (44%), neurodevelopmental disorders (30%), and failure to thrive (21%) were common. Depression/anxiety increased with age. EoE was reported in 3% of parents and 4.5% of siblings. CONCLUSIONS:Gastrointestinal eosinophilia is present in approximately 10% of patients with EoE; the symptom-diagnosis time gap is influenced by age, race, food allergy, and atopic dermatitis; symptoms vary with race; concurrent infectious/immunologic disorders and mental health disorders are common; and the level of esophageal eosinophils is comparable in patients with and without fibrostenotic features.
Project description:Eosinophilic esophagitis (EoE) is difficult to distinguish from gastroesophageal reflux (GERD) and other causes of dysphagia. We assessed the utility of a set of clinical and endoscopic features for predicting EoE without obtaining esophageal biopsies.We prospectively enrolled consecutive adults undergoing outpatient upper endoscopy at the University of North Carolina from July 2011 through December 2013. Incident cases of EoE were diagnosed per consensus guidelines. Non-EoE controls had either GERD- or dysphagia-predominant symptoms. A predictive model containing clinical and endoscopic, but no histological, data was assessed. Receiver operator characteristic curves were constructed and the area under the curve (AUC) was calculated.A total of 81 EoE cases (mean age 38 years; 60% male; 93% white; 141 eosinophils per high-power field (eos/hpf)) and 144 controls (mean age 52, 38% male; 82% white; 3 eos/hpf) were enrolled. A combination of clinical (age, sex, dysphagia, food allergy) and endoscopic (rings, furrows, plaques, hiatal hernia) features was highly predictive of EoE. The AUC was 0.944, with sensitivity, specificity, and accuracy of 84, 97, and 92%. Similar values were seen after limiting controls to those with only reflux or dysphagia or to those with esophageal eosinophilia not due to EoE.We validated a set of clinical and endoscopic features to predict EoE with a high degree of accuracy and allow identification of those at very low risk of disease. Use of these predictors at the point-of-care will avoid the effort and expense of low-yield histological examinations for EoE.
Project description:There are few data exploring modifiable risk factors for eosinophilic esophagitis (EoE). We aimed to determine if smoking, alcohol consumption, and nonsteroidal anti-inflammatory drug (NSAID) use were risk factors for EoE, and to assess their impact on EoE phenotypes and treatment outcomes. We performed a case-control study analyzing data collected from a prospective cohort of adults undergoing upper endoscopy for symptoms of esophageal dysfunction. Incident EoE cases were diagnosed via consensus guidelines. Exposure data were collected via standardized patient questionnaire. Follow-up assessments for cases were made after treatment, with histologic response defined as <15 eosinophils per high-power field (eos/hpf). Exposures were compared between EoE cases and controls, among EoE cases with and without fibrostenosis, and among EoE responders and nonresponders. A total of 115 cases and 225 controls were analyzed. Cases were less likely to have ever smoked cigarettes (23% vs. 47%, P < 0.001) or currently use NSAIDs (17% vs. 40%, P < 0.001) compared to controls. These relations persisted after multivariate analysis. Although alcohol use was more common among cases (75% vs. 51%, P < 0.001), the effect was abrogated after multivariate analysis. Smoking, alcohol, and NSAID use were not associated with the fibrostenotic phenotype. There was a trend toward improved histologic response among EoE patients concomitantly using NSAIDs (87% vs. 63%, P = 0.08; aOR 6.97 (95% CI: 0.81-60.3). In conclusion, NSAID and smoking were inversely associated with EoE compared to endoscopy-based controls. Alcohol use was more prevalent in the EoE cases, although not an independent risk factor. Concomitant NSAID use may improve treatment response and is worthy of future study.
Project description:BACKGROUND AND AIMS:Subepithelial fibrosis in eosinophilic esophagitis (EoE) can be detected only in esophageal biopsy specimens with adequate amounts of lamina propria (LP). We investigated how often pediatric esophageal biopsy specimens contain adequate LP, and whether esophageal eosinophilia influences the acquisition rates. METHODS:We evaluated 284 esophageal biopsy specimens from 39 patients with EoE, and 87 biopsy specimens from 32 patients without esophageal eosinophilia or other esophageal abnormalities for the presence of adequate LP and fibrosis. RESULTS:On a per biopsy specimen basis, there was no significant difference in the rate of procuring adequate amounts of LP between patients with EoE and patients without esophageal eosinophilia (43% vs 31%, P = .14). Eighty-five percent of patients with EoE had fibrosis. Fibrosis in patients with EoE was patchy and more likely to be detected in the middle or distal esophagus (odds ratio, 19.93; 95% confidence interval, 4.12-91.52). Among patients with fibrosis, the probability of its detection reached >95% with 7 middle-distal esophageal biopsy specimens. Most children with newly diagnosed EoE already had subepithelial fibrosis despite exhibiting only inflammatory endoscopic features. CONCLUSIONS:Most individual esophageal biopsy specimens in children are inadequate for assessing subepithelial fibrosis, and the rates of procuring adequate LP per biopsy specimen are similar in patients with and without EoE. To reliably detect fibrosis in patients with EoE, at least 7 biopsy specimens should be taken from the middle-distal esophagus. The finding of fibrosis in children with newly diagnosed EoE and only inflammatory endoscopic features suggests that fibrosis can occur early in this disease.
Project description:BACKGROUND:The management of eosinophilic esophagitis (EoE) relies on the severity of esophageal eosinophilia, yet there is poor evidence of its prediction of esophageal fibrotic remodeling and subsequent complications such as dysphagia, food impactions, or strictures. Functional luminal imaging planimetry (FLIP) has had limited use in pediatric patients to evaluate esophageal tissue mechanics. We aimed to standardize the FLIP technique and to measure esophageal compliance in children with EoE in comparison to controls. METHODS:Subjects were enrolled into a prospective observational study and had FLIP performed at the time of endoscopy. We calculated esophageal distensibility and compliance for the total and segmental esophagus independently (ie, proximal, middle, and distal esophageal segments). We evaluated esophageal biopsies for eosinophilia and epithelial remodeling, calculated endoscopy scores, and documented patient symptoms. RESULTS:We enrolled 11 EoE and 12 controls subjects, aged 5 to 18 years old. While EoE subjects had lower esophageal compliance (P?=?0.004) than controls, the difference in distensibility did not reach significance (P?=?0.151). Epithelial remodeling severity was more strongly correlated with compliance than with distensibility. Epithelial remodeling scores ?2 had a significant association with lower compliance both segmentally and in the entire esophagus (P?=?0.029), but not with distensibility. Compliance measures were more sensitive in detecting subjects with remodeling score ?2 than distensibility (79% vs 64%). CONCLUSIONS:Compliance is a more sensitive measure of esophageal epithelial remodeling in children compared to distensibility, and a more appropriate measure of esophageal tissue mechanics. Standardized placement of the FLIP catheter is important to accurately assess esophageal compliance.
Project description:Eosinophilic esophagitis (EoE) is a recently recognized upper gastrointestinal allergic disorder characterized by esophageal dysfunction (e.g., dysphagia) and esophageal eosinophilia of ?15 eosinophils/high-power field in patients who have persistent esophagitis even on proton pump inhibitor (PPI) therapy. The histologic method is the gold standard of EoE diagnosis. However, EoE clinical symptoms do not always correlate with histology, and the histologic method has sensitivity and specificity issues due to the patchiness of EoE and the subjective nature of the method. The "EoE transcriptome" was initially discovered in 2006, which led to the invention of the EoE diagnostic panel (EDP). In addition to providing a definitive EoE diagnosis with high accuracy, the EDP has been useful in elucidating several key elements about the disease including the efficacy of specific drugs such as swallowed glucocorticoids and anti-IL-13 humanized antibody therapy, the relationship between EoE and PPI-responsive esophageal eosinophilia, and predicting the disease course and responsiveness to therapy. The EDP's long-term potential arises from its plasticity to incorporate new genes and uncover novel disease pathogenesis. We expect that the EDP will be increasingly helpful for personalized medicine approaches and improved diagnostics and disease monitoring.
Project description:Eosinophilic esophagitis (EoE) is thought to be more common among males and Caucasians, but little is known about the disease presentation among patients with different genders or racial backgrounds. The objective of this study was to determine the clinical, endoscopic, and histologic characteristics of patients with EoE of different genders or racial backgrounds.We conducted a retrospective study of the University of North Carolina EoE clinicopathologic database between January 2000 and December 2008. Cases of EoE were defined per 2007 consensus guidelines and stratified by race and gender for comparison.In all, 208 incident EoE cases were identified (76% males, mean age 26 years, 82% Caucasian, and 12% African American). Caucasians were older at diagnosis than African Americans (27.1 vs. 19.0?years, P=0.05), less likely to present with failure-to-thrive (9 vs. 30%, P=0.002), and more likely to have esophageal rings (41 vs. 12%, P=0.005). These findings persisted after stratification by age. A higher proportion of males were diagnosed under the age of 18 as compared with females (48 vs. 64%, P=0.05). Males were more likely to report dysphagia and food impaction as symptoms (71 vs. 53%, P=0.02 and 35 vs. 20%, P=0.05, respectively), and these findings also persisted after stratification by age. The remainder of clinical, endoscopic, and histologic features did not differ by either race or gender.While age and dysphagia differed by gender and race among EoE patients, the majority of symptoms and findings were not different across groups, even after stratification by age. Clinicians should maintain a high index of suspicion for EoE, regardless of race or gender, and obtain esophageal biopsies to confirm the diagnosis.
Project description:BACKGROUND:Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. OBJECTIVE:We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. METHODS:LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. RESULTS:Gene ontology and pathway analyses linked TNF-? and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-?-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-? stimulates epithelial LOX expression through activation of nuclear factor ?B and TGF-?-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. CONCLUSIONS:There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-? secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.