Background Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. Objective Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness following withdrawal of OIT. Methods We conducted a pilot clinical trial of peanut OIT at two U.S. centers. Subjects aged 1–16 were recruited and treated for up to five years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg peanut protein/day. Blood was collected at multiple time points. Clinical endpoints were measured with 5000 mg double-blinded, placebo-controlled food challenges once specific criteria were met. Results Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. 12/24 (50%) successfully passed a challenge one month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin tests as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2, and lower ratios of peanut-specific:total IgE, compared to subjects not passing. There were no differences in peanut IgG4 levels or functional activity at end-of-study. Conclusions This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated up to five years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin tests and lower allergen-specific IgE levels were predictive of successful outcome.

Background Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly-diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. Objective To test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy. Methods We enrolled 40 children aged 9–36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block-randomized 1:1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/day in a double-blinded fashion. The primary endpoint, sustained unresponsiveness at four weeks after stopping E-OIT (4-SU), was assessed by DBPCFC either upon achieving four pre-specified criteria, or after three maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared to 154 matched standard-care controls. Results Of 40 consented subjects, three (7.5%) did not qualify. Overall, 29/37 (78%) in the intent-to-treat analysis achieved 4-SU (300 mg arm, 17/20 [85%]; 3000 mg, 12/17 [71%], p=0.43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29/32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgEs significantly increased (RR 19.42 [95%CI 8.7 – 43.7], p<0.001). Allergic side effects during E-OIT were common but all were mild-moderate. Conclusion At both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

Objectives Esophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases and determine the frequency and predictors of requiring multiple dilations. Methods We conducted a retrospective cohort study in the University of North Carolina EoE clinicopathological database from 2002-2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, total number of dilations) and complications. Patients with EoE who had undergone dilation were compared to those who did not and also stratified by whether they required single or multiple dilations. Results Of 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms prior to diagnosis (11.1 vs. 5.4 yrs, p<0.001). 95 patients (58%) required >1 dilation (417 dilations total, mean of 4.4 ± 4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58%, or 95/164) required a second dilation. Of these individuals, 75% required dilation within 1 year. Conclusions Dilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms prior to diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within one year. These findings can be used to counsel patients with fibrostenotic complications of EoE.

Background and aims Some patients with eosinophilic esophagitis (EoE) have an extremely narrowed esophagus, but the characteristics of this group have not been extensively described. We aimed to characterize the narrow-caliber phenotype of EoE, determine associated risk factors, and identify differences in treatment response in this sub-group of patients. Methods This retrospective cohort study from 2001 to 2014 included subjects with a new diagnosis of EoE per consensus guidelines. Demographic, endoscopic, histologic, and treatment response data were extracted from medical records. An “extreme narrow-caliber esophagus” was defined when the neonatal endoscope was required to traverse the esophagus due to inability to pass an adult endoscope. Cases with and without the extreme narrow-caliber esophagus were compared. Multivariable logistical regression was performed to assess treatment outcomes. Results Of 513 patients with EoE, 46 (9%) had an extreme narrow-caliber esophagus. These cases were older (33 vs 22 years; p<0.01), had longer symptom duration (11 vs 3 years; p<0.01), more dysphagia (98% vs 66%; p<0.01), and food impactions (53% vs 31%; p<0.01). Dilation was more common with extreme narrowing (69% vs 17%; p<0.01). Narrow-caliber patients were more refractory to steroid treatment, with lower symptom (56% vs 85%), endoscopic (52% vs 76%), and histologic (33% vs 63%) responses (p<0.01 for all), and these differences persisted after multivariate analysis. Conclusion The extreme narrow-caliber esophagus is a more treatment-resistant sub-phenotype of EoE and is characterized by longer symptom duration and requirement for multiple dilations. Recognition at diagnosis of EoE can provide important prognostic information.

The authors investigated whether different types of aggression relate to the A779C tryptophan hydroxylase (TPH) polymorphism and to serotonergic activity in volunteers. A factor analysis of the Buss-Durkee Hostility Inventory yielded 2 factors representing Neurotic Hostility (NH) and Aggressive Hostility (AH). The authors used a neuroendocrine challenge with Citalopram in 48 volunteers and increased cortisol concentrations only in those with high levels of AH. Finally, an association study with 58 volunteers revealed that the A779C TPH polymorphism significantly relates to AH, with the highest aggression levels for the genotype AA and the lowest aggression levels for the genotype CC, but not to NH. Results are discussed with respect to inconsistent findings in the literature, which may be explained by this distinction of types of aggression.

Background: Oral and sublingual immunotherapies for peanut allergy have demonstrated efficacy in small clinical trials; however, mechanisms and biomarkers correlating with clinical outcomes remain elusive. Previous studies have demonstrated a role for IgG in post-OIT plasma in the suppression of IgE-mediated mast cell reactions. Objective: The aim of this study was to characterize the role that peanut oral and sublingual immunotherapy-induced plasma factors play in the inhibition of ex vivo basophil activation and whether inhibitory activity is associated with clinical outcomes. Methods: Plasma samples from subjects on placebo, peanut oral immunotherapy (OIT) or peanut sublingual immunotherapy (SLIT), and IgG-depleted plasma or the IgG fraction were incubated with sensitized basophils, and the inhibition of basophil activation following stimulation with peanut extract was measured. Basophil inhibition results were compared between the two routes of immunotherapy, time on treatment and clinical outcomes. Results: Plasma from subjects after 12 months of active peanut OIT, but not placebo, inhibits basophil activation ex vivo. Depletion of IgG abrogated the blocking effect of OIT plasma, while the IgG fraction substantially blocked basophil activation. Basophils are inhibited to a similar extent by undiluted OIT and SLIT plasma; however, diluted OIT plasma from the time of desensitization challenge inhibited basophils more than diluted SLIT plasma from time of desensitization challenge.Plasma from subjects who experienced sustained unresponsiveness following OIT inhibited basophils to a greater extent than plasma from subjects who were desensitized, but this was not true for SLIT. Conclusions and ClinicalRelevance: Peanut immunotherapy induces IgG-dependent functional changes in plasma that are associated with OIT but not SLIT clinical outcomes. Understanding the mechanisms of peanut OIT and SLIT may help derive informative biomarkers. K E Y W O R D S basophil activation, food allergy, IgG, immunoglobulin, immunotherapy, peanut allergy

Goals To characterize patients who suffer perforation in the context of EoE and to identify predictors of perforation Background Esophageal perforation is a serious complication of eosinophilic esophagitis (EoE). Methods We conducted a retrospective cohort study of the UNC EoE clinicopathologic database from 2001–2014. Subjects were included if they had an incident diagnosis of EoE and met consensus guidelines, including non-response to a PPI trial. Patients with EoE who had suffered perforation at any point during their course were identified, and compared to EoE cases without perforation. Multiple logistic regression was performed to determine predictors of perforation. Results Out of 511 subjects with EoE, 10 (2.0%) had experienced an esophageal perforation. While those who perforated tended to have a longer duration of symptoms prior to diagnosis (11.4 vs. 7.0 years, p=0.13), a history of food impaction (OR 14.9; 95% CI 1.7–129.2) and the presence of a focal stricture (OR 4.6; 1.1–19.7) were the only factors independently associated with perforation. Most perforations (80%) occurred after a prolonged food bolus impaction, and only half of individuals (5/10) carried a diagnosis of EoE at the time of perforation; none occurred after dilation. Six patients (60%) were treated with non-operative management, and four (40%) required surgical repair. Conclusion Esophageal perforation is a rare but serious complication of eosinophilic esophagitis, occurring in approximately 2% of cases. Most episodes are due to food bolus impaction or strictures, suggesting that patients with fibrostenotic disease due to longer duration of symptoms are at increased risk.

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