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BACKGROUND: Eosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need in EG for more precise diagnostic tools. OBJECTIVE: We aimed to develop tissue- and blood-based diagnostic platforms for EG. METHODS: Patients with EG and non-EG controls were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. The EGDP(18) scores were derived from the expression of 18 highly dysregulated genes and Blood EG scores from dysregulated cytokines/chemokine levels. RESULTS: Gastric biopsies and blood samples from 185 subjects (EG 74, non-EG 111) were analyzed. The EGDP a) identified patients with active EG (P < .0001, AUC ≥0.95); b) effectively monitored disease activity in longitudinal samples (P = .0078); c) highly correlated in same-patient samples (antrum vs. body, r = 0.85, P < .0001); and d) inversely correlated with gastric peak eosinophil levels (r = −0.83, P < .0001), periglandular circumferential collars (r = − 0.73, P < .0001), and endoscopic nodularity (r = −0.45, P < .0001). For blood-based platforms, eotaxin-3, TARC, IL-5, and TSLP levels were significantly increased. Blood EG scores a) distinguished patients with EG from non-EG controls (P < .0001, AUC ≥0.91); b) correlated with gastric eosinophil levels (plasma r = 0.72, P = .0002; serum r = 0.54, P = .0015); and c) inversely correlated with EGDP(18) scores (plasma r = −0.64, P = .0015; serum r = −0.46, P = .0084). Plasma eotaxin-3 strongly associated with gastric CCL26 expression (r = 0.81, P < .0001). CONCLUSION: We developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and tools for this emerging rare disease.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, increasingly prevalent antigen driven disease. There is a paucity of information on long-term course in children. OBJECTIVE: 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 pathology records over 13 years. RESULTS: From 2011 to 2015, 146 EoE children seen for their first visit at our center had ≥2 years of follow up and ≥3 endoscopies over an average follow up time of 5.13 years (range 2–13). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with 75% of their follow up time were termed “continuous responders” (CR). Children with waxing and waning inflammation of

BACKGROUND: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency,with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. OBJECTIVE: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. METHODS: A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. RESULTS: The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt(ft) mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. CONCLUSION: In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. Acommon SNP in MATT has an association with AD in human subjects.

Background Allergen-specific IgG 4 (sIgG 4 ) antibodies are often associated with tolerance, but sIgG 4 antibodies to causally relevant foods have been reported recently in adults with eosinophilic esophagitis (EoE). Prevalence and levels of food sIgG 4 are not well established in the general pediatric population. Objective We sought to investigate serum food sIgG 4 with component diagnostics in children with EoE and children from an unselected birth cohort and to explore the effects of sex, age, and milk consumption on sIgG 4 levels. Methods Sera from 71 pediatric patients with EoE and 210 early adolescent children from an unselected birth cohort (Project Viva) were assayed for sIgG 4 and specific IgE (sIgE) to major cow's milk (CM) proteins (α-lactalbumin, β-lactoglobulin, and caseins) and to wheat, soy, egg, and peanut proteins. Results In the EoE cohort high-titer sIgG 4 (≥10 μg/mL) to CM proteins was more common than in control sera and achieved odds ratios for EoE ranging from 5.5 to 8.4. sIgE levels to CM proteins were mostly 4 IU/mL or less in patients with EoE, such that sIgG 4 /sIgE ratios were often 10,000 or greater. When adjusted for age and milk consumption, high-titer sIgG 4 to CM proteins was strongly associated with EoE, with an odds ratio of greater than 20 to all 3 CM proteins in boys. Conclusions sIgG 4 to CM proteins are common and high titer in children with EoE. Although it is not clear that this response is pathogenic, sIgG 4 levels imply that these antibodies are an important feature of the local immune response that gives rise to EoE.

M O N D A Y 631 A Predictive Score for the Presence of Eosinophils in the Esophagus Margaret Redmond, MD, Jean Brown, MD, Dale Rhoda, Wei Wang, John Russo, MD, Thomas Platts-Mills, MD, PhD, FAAAAI, FRS, Elizabeth Erwin, MD; Nationwide Children’s Hospital, Columbus, OH, University of South Florida, Tampa, FL, University of Virginia, Charlottesville, VA. RATIONALE: Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis that weighs heavily on having >15 eosinophils per high power field (hpf) on esophageal biopsy. Our objective was to define clinical features that could be used to predict the diagnosis of EoE reducing the need for esophageal biopsy. METHODS: We reviewed 442 medical records for pediatric patients having esophageal biopsy. Using data on demographics, symptoms, and laboratory results, we performed multivariate logistic regression using complete data from 360 charts. RESULTS: We found that there were four independent predictors for the presence of any eosinophils on esophageal biopsyfemale gender [odds ratio (OR) 0.45, p50.004], having food stuck (OR 6.0, P50.001), the absence of diarrhea (OR 0.40, p50.003), and weighted peripheral blood eosinophil count. Using these parameters for the group of patients we studied, sensitivity and specificity for having eosinophils in the esophagus were 0.18 and 0.97 respectively. The area under the ROC curve was 0.72. For 60 patients, serum specific IgE to foods was available. By univariate analysis, specific IgE to milk >0.35 IU/ml, was associated with EoE (OR 5.7, p50.008). Only having peripheral blood eosinophil count >600/mm3 seemed to have a slight effect on having low eosinophils compared with >15 eos/hpf (OR 3.5, p50.05). CONCLUSIONS: The high specificity we found suggests that in patients with a negative biopsy result, our test model is likely to be negative. There was little clinical evidence in our model to support a distinction between low esophageal eosinophils and >15 eosinophils/hpf.

Nasal polyps (NPs) are characterized by eosinophilic inflammation, which is generally considered sensitive to corticosteroid treatment.We evaluated levels of neutrophilia in NPs and investigated whether increased neutrophilia in polyp tissue affected the response to corticosteroid treatment.We studied 3 independent cross-sectional groups of patients with NPs. Levels of infiltration by different types of inflammatory cells were determined by using immunohistochemical analyses and compared with those seen in control nasal tissues from subjects without NPs. Levels of inflammatory mediators were measured by using real-time PCR, ELISA, and FlowCytomix analyses. Patients with NPs received oral corticosteroid therapy (30 mg of prednisone once daily for 7 days); clinical parameters of efficacy were associated with NP phenotypes.Among patients with NPs, 76.5% had an eosinophilic phenotype, 46.0% had a neutrophilic phenotype, and 35.8% had a mixed phenotype (indicated by double staining). Overall, patients' symptoms improved after corticosteroid treatment; numbers of eosinophils and levels of their mediators (IL-4 and IL-5), but not numbers of neutrophils or levels of their mediators (IL-8 and interferon-inducible protein 10), were reduced (P.05). After corticosteroid treatment, patients with the nonneutrophilic phenotype (neutrophil negative) had significantly greater reductions in bilateral polyp size scores, nasal congestion scores, total nasal symptom scores, and nasal resistance than patients with the neutrophilic phenotype (neutrophil positive, P.05).There are different phenotypes of NPs based on the type of immune cell infiltrate and cytokines produced (eosinophilic or neutrophilic). Patients with the neutrophilic phenotype have less response to treatment with corticosteroids based on symptom scores.