Novel Minimally Invasive Assessment of Gastronintestinal Inflammation in Food Allergy

Eosinophilic esophagitis (EE) is an increasingly recognized gastrointestinal disease that accounts for ~50% of pediatric and adult cases of dysphagia and food impaction. Long-term consequences of chronic eosinophilic inflammation in EE include esophageal remodeling, with subepithelial fibrosis, and esophageal narrowing and strictures, thus emphasizing the importance of this disease. Translational studies show that >90% of EE patients respond to dietary interventions, supporting a role for humoral (IgE) and/or cell-mediated food allergy. The role of IgE-mediated mast cell (or basophil) responses in initiating the esophageal inflammatory cascade remains uncertain since RAST testing alone shows poor specificity for identifying the offending food allergen(s), whereas SPTs remain the best available test to identify relevant food allergens. Standard of care for EE includes initial endoscopy with biopsy for obtaining esophageal tissue to determine the numbers of eosinophils, =15/hpf being diagnostic. No serological or stool analyses to date provide durable findings that correlate with histological evidence of disease progression vs. remission. The role of repeated endoscopy and biopsy is under debate, since the cost-benefit ratio is unknown and entails risks. <P> We hypothesize and present preliminary results that the Enterotest,(tm) a string-based test first used for detection of intestinal Giardia, can be used to assess esophageal inflammation at the protein and mRNA levels (termed the Esophageal String Test or EST). <P> The project's objectives are to: (1) test the efficacy of the EST as a novel, minimally invasive, inexpensive, sensitive and specific method for measuring esophageal inflammation in EE patients, particularly tissue eosinophilia, cytokine and chemokine profiles, and levels of CD23, FceRI and tryptase, and (2) use the EST to monitor disease status following nutritional or corticosteroid treatments. <P> We propose two integrated hypotheses that: (1) luminal inflammatory mediators detected using EST correlate with mucosal inflammation as determined by esophageal biopsy in patients with EE, and (2) the EST can be used as a minimally invasive clinical assessment of esophageal inflammation for disease management. <P> Aim 1 will characterize the inflammatory response in the esophageal luminal microenvironment of EE patients using the EST, performing measurements of specific eosinophil-expressed inflammatory mediators (eosinophil granule proteins), to determine their associations with the histopathologic features of EE disease. <P> Aim 2 will determine the impact of treatment on the esophageal inflammatory response in EE patients comparing quantitative measurements of plasma, esophageal mucosa (biopsy) and luminal (EST) CD23, FceRI, tryptase, Th1 and Th2 cytokines, eotaxin-3, and eosinophil granule protein biomarkers to correlate changes with treatment-induced responses. <P> These studies will begin to validate the EST as a minimally invasive diagnostic tool for monitoring esophageal inflammation in EE, the participation of CD23/FceRI/IgE, and the efficacy of using the EST to determine histopathologic responses to treatment in lieu of repeated endoscopies and biopsies. <P>PUBLIC HEALTH RELEVANCE: Food allergic diseases (including eosinophilic gastrointestinal diseases such as eosinophilic esophagitis) currently afflict an estimated 4-6% of the United States population. Care of patients with esophageal allergies is limited because of the need for initial and repeated endoscopies and biopsies for diagnosis and evaluation of the effectiveness of treatment in terms of disease remission or progression. This application focuses on studies validating a novel method, the Esophageal String Test, for analyzing esophageal inflammation through the use of minimally invasive existing technology, the Enterotest(tm), and using this novel test to evaluate the effects of treatment on esophageal inflammation and the participation of IgE-mediated pathways in the pathogenesis of eosinophilic esophagitis. Results from these studies will improve the quality of life for patients with food allergies and eosinophilic esophagitis by limiting the number of invasive endoscopy with biopsy procedures required for their care, and by increasing overall understanding of the pathogenesis of eosinophilic esophagitis and other food allergic gastrointestinal diseases.