Faculty Bibliography

BACKGROUND:Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE:This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS:Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS:At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS:After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

Rationale: Although IgE-mediated food allergies affect 7.6% of children and 9% of adults in the United States, there is limited information on the prevalence and characteristics of allergic reactions to food during travel. Understanding the reactions that occur during travel will provide at-risk passengers and carriers with the necessary information to create measures to prevent and manage these emergencies.
Method(s): We analyzed two patient registry surveys on allergic history and allergic reactions established by Food Allergy Research and Education (FARE) using SPSS.
Result(s): Out of 4956 survey respondents who described the location of their allergic reactions to foods, 86 (1.7%) reported reactions during travel. Of these, 18.6% (n=16) occurred on an airplane/in-flight, and 81.4% (n=70) were reported while commuting/in-transit. Overall, the most common sites of reported reactions were home (17.2%, n=2270) and dining out (7.4%, n=976). There were no statistically significant differences between those reporting travel-related reactions and non-travel-related reactions with regards to concomitant asthma, eczema, allergic rhinitis, drug allergy, or eosinophilic esophagitis. There was no difference in self-reported severity of the reaction and epinephrine use during the reaction. However, those reporting travel-related reactions were significantly more likely to report a lifetime history of anaphylaxis (p=0.04). Peanut and tree nuts were the most commonly identified food allergen for both travel-related reactions and non-travel-related reactions.
Conclusion(s): Allergic reactions during travel were rare in these surveys and were reported more frequently during commuting than on airplanes/in-flight. Individuals reporting travel reactions were more likely to report a lifetime history of anaphylaxis.
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BACKGROUND:Excessive production of IgE plays a major role in the pathology of food allergy. In an attempt to identify anti-IgE natural products, Arctium Lappa was one of the most effective herbs among approximately 300 screened medicinal herbs. However, little is known about its anti-IgE compounds. OBJECTIVE:To identify compounds from Arctium Lappa for targeted therapy on IgE production and explore their underlying mechanisms. METHODS:Liquid-liquid extraction and column chromatographic methods were used to purify the compounds. IgE inhibitory effects were determined on IgE producing human myeloma U266 cells, peanut-allergic murine model, and PBMCs from food-allergic patients. Genes involved in IgE inhibition in PBMCs were studied by RNA sequencing. RESULTS:The main compounds isolated were identified as arctiin and arctigenin. Both compounds significantly inhibited IgE production in U266 cells, with arctigenin the most potent (IC50=5.09μg/mL). Arctigenin (at a dose of 13.3 mg/kg) markedly reduced peanut-specific IgE levels, blocked hypothermia and histamine release in a peanut-allergic mouse model. Arctigenin also significantly reduced IgE production and Th2 cytokines (IL5, IL13) by PBMCs. We found 479 differentially expressed genes in PBMCs with arctigenin treatment (p<0.001 and fold-change ≥1.5), involving 24 gene ontology terms (p<0.001, FDR <0.05); cell division was the most significant. Eleven genes including UBE2C and BCL6 were validated by qPCR. CONCLUSION/CONCLUSIONS:Arctigenin markedly inhibited IgE production in U266 cells, peanut allergic murine model and PBMCs from allergic patients by down-regulating cell division, cell cycle-related genes and up-regulating anti-inflammatory factors.

BACKGROUND:For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. METHODS:We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. FINDINGS/RESULTS:Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. INTERPRETATION/CONCLUSIONS:In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. FUNDING/BACKGROUND:National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

Few patients with food allergy are "highly allergic," meaning they always have severe reactions and always react to very small amounts of allergen. Standard medical approaches for allergy management have focused on the safety and lifestyle modifications this group truly needs, but consequently families with food allergy are typically advised to strictly avoid any exposure to their implicated allergens. Most food-allergic subjects are actually not reactive to very low doses, and many never experience severe reactions. There are also notable conditions where a different care plan is already commonly offered: patients with pollen-related food allergy syndrome, with food-associated exercise-induced anaphylaxis, and with resolving or mild milk or egg allergy might be advised to ingest the allergens in specific circumstances with detailed instructions. Because oral immunotherapy and allergy prevention by early exposure have emphasized alternatives to strict avoidance, there is increasing interest in prospects to forego strict avoidance in those with food allergy. For patients with a high threshold of reactivity (low-dose tolerant, high-dose mildly reactive), there may be options such as allowing the ingestion of products with precautionary allergen labels, allowing dietary indiscretions with small amounts of the allergen, or even encouraging ingestion of subthreshold amounts with therapeutic intent. These practices have not been extensively studied and could be considered controversial. If these approaches are considered, shared decision making is needed in discussing them with patients and families. This review considers the potential approaches to those who are "not highly allergic": the risks, benefits, shared decision making, and research needs.

Since the World Allergy Organization (WAO) Diagnosis and Rationale against Cow's Milk Allergy (DRACMA) Guidelines were published 10 years ago, new evidence has accumulated about the diagnosis, therapy, and specific immunotherapy for cow's milk allergy (CMA). For this reason, WAO has felt the need to update the guidelines. We introduce here this update. The new DRACMA guidelines aim to comprehensively address the guidance on diagnosis and therapy of both IgE non-IgE-mediated forms of cow's milk allergy in children and adults. They will be divided into 18 chapters, each of which will be dedicated to an aspect. The focus will be on the meta-analyzes and recommendations that will be expressed for the 3 most relevant clinical aspects: (a) the diagnostic identification of the condition; (b) the choice of the replacement formula in case of CMA in infancy when the mother is not able to breastfeed, and (c) the use of specific immunotherapy for cow's milk protein allergy.
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BACKGROUND:Understanding about patient-reported biphasic food-related allergic reactions currently remains sparse. OBJECTIVE:To characterize patient-reported biphasic food-related allergic reactions among a national food allergy registry. METHODS:We utilized two Patient Registry surveys established by Food Allergy Research & Education (FARE). Variables were described with proportions and 95% confidence intervals; unadjusted results were stratified by respondent type. Multivariable logistic regression evaluated the adjusted odds of reporting a biphasic reaction. RESULTS:The incidence of reported biphasic reactions was 16.4% (CI: 15.3-17.7). 12.8% (CI: 12.5-14.3) of parent/guardian respondents and 21.8% (CI: 19.7-23.8) of self-respondents indicated a biphasic reaction during their most recent food-allergic reaction. Among respondents with a mild initial reaction, 7.4% reported a biphasic reaction compared with 30% with a very severe initial reaction. When the initial reaction was mild, 69.6% of parent/guardian respondents (CI: 47.2 - 85.4) and 52.0% of self-respondents (CI: 38.0 - 35.7) with a biphasic reaction reported a mild secondary reaction. When the initial reaction was very severe, 36.3% of parent/guardian respondents (CI: 26.4 - 47.5) and 42.9% of self-respondents (CI: 31.1 - 55.5) with a biphasic reaction reported a very severe secondary reaction. Female gender, Black/African-American race, reaction age 5-12 and 26-66 years, initial moderate, severe, or very severe reaction, and one or more annual reactions were associated with increased odds of a biphasic reaction. CONCLUSION/CONCLUSIONS:This study characterizes the incidence of patient-reported biphasic reactions and provides valuable information on probable severity of a biphasic food-related allergic reaction. Further research is necessary to understand the epidemiology of food-related biphasic reactions.

BACKGROUND:Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy diagnosed via history and/or an oral food challenge (OFC). OBJECTIVE:To determine allergists' approach to FPIES OFCs. METHODS:A web-based survey was e-mailed to 1100 randomly selected American Academy of Allergy, Asthma and Immunology members. RESULTS:A total of 132 individuals responded (12% response rate). A total of 95.5% (n = 105) of respondents perform OFCs in their practice, but only 58.7% (n = 71) perform FPIES OFCs. The median number of FPIES OFCs in children was reported as 3 per year (range, 0-76); all but 1 respondent (2.5%) had not performed any FPIES OFCs in adults. The most common FPIES OFC foods were cow's milk, rice, lightly cooked egg, oat, soy, baked milk, and baked egg. The decision to offer FPIES OFCs was based on the severity of past reactions, the patient and family's desire, and the patient's age. FPIES OFCs were most commonly performed in an outpatient setting, with placement of peripheral intravenous access depending on the severity of past reactions and with a serving appropriate for age divided into 3 equal portions administered over 30 minutes. There was significant variability in the approach to conducting FPIES OFCs. Most respondents (87.4%, n = 127) indicated that specific guidelines for performing FPIES OFCs would be helpful. CONCLUSIONS:Our study highlights the discordance in allergists' practices performing OFCs for IgE-mediated food allergy compared with FPIES. The lack of universal agreement on the optimal way to perform OFCs in FPIES demonstrates the need for future studies to develop a standardized protocol for FPIES OFCs.