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.

New Findings r What is the central question of this study? Acetaminophen (paracetamol) is an analgesic and antipyretic, which has been shown to improve self-paced cycling performance through a reduction in pain. We sought to ascertain whether acetaminophen could improve time to exhaustion during exercise in the heat through its antipyretic action. r What is the main finding and its importance? An acute dose of acetaminophen allowed participants to cycle significantly longer in hot conditions by a mean of 4 min (+17%). This was accompanied by significantly lower core, skin and body temperature, and participants found the exercise less of a thermal strain. These findings suggest that acetaminophen may reduce the thermal challenge of exercise in hot conditions. Acetaminophen (paracetamol) is a commonly used over-the-counter analgesic and antipyretic and has previously been shown to improve exercise performance through a reduction in perceived pain. This study sought to establish whether its antipyretic action may also improve exercise capacity in the heat by moderating the increase in core temperature. On separate days, 11 recreationally active participants completed two experimental time-to-exhaustion trials on a cycle ergometer in hot conditions (30 • C, 50% relative humidity) after ingesting a placebo control or an oral dose of acetaminophen in a randomized, double-blind design. Following acetaminophen ingestion, participants cycled for a significantly longer period of time (acetaminophen, 23 ± 15 min versus placebo, 19 ± 13 min; P = 0.005; 95% confidence interval = 90-379 s), and this was accompanied by significantly lower core (−0.15 • C), skin (−0.47 • C) and body temperatures (0.19 • C; P < 0.05). In the acetaminophen condition, participants also reported significantly lower ratings of thermal sensation (−0.39; P = 0.015), but no significant change in heart rate was observed (P > 0.05). This is the first study to demonstrate that an acute dose of acetaminophen can improve cycling capacity in hot conditions, and that this may be due to the observed reduction in core, skin and body temperature and the subjective perception of thermal comfort. These findings suggest that acetaminophen may reduce the thermoregulatory strain elicited from exercise, thus improving time to exhaustion.

Background In a previously reported CoFAR study, 55 subjects with egg allergy underwent randomized, placebo-controlled egg oral immunotherapy (eOIT). Active treatment induced desensitization in most and sustained unresponsiveness (SU) in a smaller subset. We hypothesized that component-resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU in OIT subjects. Methods Longitudinal samples for 51 egg-allergic subjects (37 active, 14 placebo) were available. Egg white- (EW), ovalbumin- (OVA), and ovomucoid (OVM)-specific levels of IgA, IgA1, and IgA2 were quantified by ELISA. IgE and IgG4 to these antigens were quantified using ImmunoCAP®. Clinical responders achieved SU to egg; all others were considered non-responders. Between-group comparisons were made amongst active and placebo, as well as responders and non-responders. Results No placebo subjects achieved responder status. Through month 48, among the 37 active subjects, baseline IgE-OVM was lower in responders (median 3.97 kU/L, n=19) than non-responders (10.9 kU/L, n=18, p=0.010). Logistic regression analysis revealed lower baseline IgE-EW (p = 0.038), IgE-OVM (p = 0.032) and a higher IgG4:IgE-OVM ratio (p=0.013) were associated with clinical response. Relative increases in IgG4-EW, IgA-EW and IgA2-EW were greater in responders (p= 0.024, 0.024, 0.029, respectively). Ratios of IgG4:IgE, IgA:IgE, IgA2:IgE for EW and IgA:IgE for OVA were significantly elevated among responders (p = 0.004, 0.009, 0.028, 0.008, respectively). Conclusions Increased IgG4-EW, IgA-EW and IgA2-EW during eOIT are associated with clinical response to eOIT. Lower pre-treatment IgE-EW and IgE-OVM are also associated with SU. Future studies are needed to evaluate and validate these potential biomarkers.

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RATIONALE: Eosinophilic Esophagitis (EoE) has been etiologically associated with egg, milk, and wheat allergy. Non-traditional allergens are being increasingly identified in EoE. We aimed to identify sensitization patterns to aeroallergens and food, and associations with pan-allergens, in an EoE population. METHODS: A case-series analysis of skin test results from 66 EoE patients meeting IRB/study criteria was performed. Associations between sensitization to pan-allergens, profilin/PR-10 and sensitization to aeroallergens and foods were determined via Chi-square tests. Entomophilous plant extracts (Locust; profilin, Alfalfa; PR-10, and non-native Ailanthus; profilin) were used as pan-allergen markers. RESULTS: 73 % of our EoE patients (aged 2-73 years; mean 5 16 years; 56% male) were sensitized to both aeroallergens and food. 18% were sensitized solely to aeroallergens and 1.5% solely sensitized to food. 86.4 % patients were pansensitized (> 3 aeroallergens). Overall, patients were sensitized to an average of 20.4 (SD514.9) aeroallergens and 6.3 (SD56.5) foods. Sensitization to egg (12/60, 20%), milk (8/62, 13%) and wheat (4/58, 7%) was less than anticipated, and sensitization to unique, pan-allergen containing foods: mustard (14/36, 39%), sunflower (15/25, 60%), garlic (12/45, 27%), and corn (12/46, 26%) was observed. Sensitization to unusual foods, along with legumes and tree nuts, was significantly associated with sensitization to PR-10 (p<0.05) and profilin pan-allergen markers (p<0.05). CONCLUSIONS: Novel findings in our EoE population included: 86.4% of patients were pansensitized to aeroallergens and increased sensitization to unique foods was associated with sensitization to pan-allergens. Increased research into pan-allergen sensitization and cross reactivity to food maybe warranted in highly aeroallergen-pansensitized EoE patients.

Several promising minimally invasive biomarkers for EoE have emerged; however, few are able to differentiate EoE from other atopic diseases.

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.