Evaluation of long-term course in children with eosinophilic esophagitis reveals distinct histologic patterns and clinical characteristics.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic and increasingly prevalent antigen-driven disease. There is a paucity of information on long-term course in children. OBJECTIVE: We sought to understand the longitudinal trajectory of pediatric EoE during routine clinical care. METHODS: We prospectively enrolled children into an EoE database and reviewed their medical and pathologic records over 13 years. RESULTS: From 2011 to 2015, 146 children with EoE seen for their first visit at our center had 2 or more years of follow-up and 3 or more endoscopies over an average follow-up period of 5.13 years (range, 2-13 years). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with less than 15 eosinophils/high-power field (hpf) for greater than 75% of their follow-up period were termed continuous responders (CRs). Children with waxing and waning inflammation of less than 15 eosinophils/hpf for less than 75% but 25% or more of the follow-up period were termed intermittent responders (IRs). Nonresponders (NRs) were defined as having less than 15 eosinophils/hpf for less than 25% of their follow-up. Fifty-nine (40%) of 146 patients were CRs, 65 (45%) of 146 were IRs, and 22 (15%) of 146 were NRs. CRs differed from IRs and NRs on the parameter of male/female ratio (1:1 in CRs, 4:1 in IRs, and 6:1 in NRs; P < .001) and in their initial response to any therapy, including proton pump inhibitors (P < .001). Endoscopic severity correlated with esophageal eosinophilia (r = 0.73, P < .001). On multivariate analysis, female sex and initial therapeutic response to medications or elimination diet were associated with long-term control of esophageal eosinophilia. CONCLUSIONS: Long-term pediatric EoE followed 3 different longitudinal trajectories of inflammation. The long-term histologic groups differed significantly in biological sex and initial therapeutic response.

The TGFß1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFß1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFß1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE. METHODS: Genotype at TGFß1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype. RESULTS: The TGFß1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFß1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGFß1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling. CONCLUSIONS: Our data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

MMPs-2 and -14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated disease in children and adults associated with substantial esophageal remodeling and fibrosis. The expression of the remodeling-associated matrix metalloproteinases (MMPs) has not been previously detailed in EoE. METHODS: MMP-2 and -14 expression and cellular localization were assessed using real-time quantitative polymerase chain reaction and immunohistochemistry/immunofluorescence in EoE fibroblasts, active and inactive pediatric EoE biopsies, and nondiseased control biopsies. The effect of transforming growth factor (TGF)-ß1 treatment on MMP-2 expression in cultured esophageal epithelial (HET1A) cells was analyzed. RESULTS: MMP-2 and -14 mRNA were expressed in EoE fibroblasts and biopsies. Proliferating epithelial cells produced MMP-14 more abundantly in EoE than in controls (P < 0.001) and the degree of epithelial MMP-14 expression correlated positively with basal zone hyperplasia (r = 0.65, P = 0.002). EoE lamina propria had higher numbers of MMP-2- and -14-positive cells (906 ±â€Š167 and 701 ±â€Š93 cells/mm²) as compared with controls (258 ±â€Š93 cells/mm², P < 0.01 and 232 ±â€Š54 cells/mm², P < 0.01), and MMP-14 expression correlated with the severity of fibrosis. Following therapy with topical corticosteroids, MMP-14 and -2 were significantly diminished (P < 0.01). TGF-ß1 increased the expression and secretion of MMP-2 from esophageal epithelial HET1A cells. CONCLUSIONS: MMP-2 and -14 are elevated in pediatric patients with EoE and significantly decrease following topical corticosteroid therapy. TGF-ß1 increases MMP-2 in esophageal epithelial cells. This alludes to previously unappreciated role for MMPs in EoE-associated esophageal remodeling and a potential positive feedback loop via TGF-ß1.