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Epinephrine is the first-line treatment for severe allergic reactions, and rapid treatment is associated with lower rates of hospitalization and death. Current treatment options (epinephrine auto-injectors and manual intramuscular injection) are considered cumbersome, and most patients/caregivers fail to use them, even during severe reactions. An intranasal epinephrine delivery device, neffy , has been designed to provide an additional option for patients/caregivers. We sought to assess the comparative pharmacokinetics and pharmacodynamics of neffy 2.0 mg, EpiPen 0.3 mg, and manual intramuscular injection 0.3 mg. This was a phase 1, randomized, 6-treatment, 6-period, 2-part crossover study in 59 healthy subjects. Pharmacokinetic and pharmacodynamic parameters following single and repeat doses of epinephrine were assessed before dosing and at various postdose intervals. The pharmacokinetic profile of neffy was bracketed by approved injection products, with a mean peak plasma level of 481 pg/mL, which fell between EpiPen (753 pg/mL) and epinephrine manual intramuscular injection (339 pg/mL). When dosed both once and twice, neffy resulted in more pronounced increases in pharmacodynamic parameters relative to EpiPen or manual injection. neffy 's pharmacokinetic profile was bracketed by approved injection products, with pharmacodynamic responses that were comparable to or better than approved injection products. neffy is expected to be a safe and effective option, particularly for patients/caregivers who are reluctant to carry and use injection devices. [ABSTRACT FROM AUTHOR]

[Display omitted] Food protein–induced enterocolitis syndrome (FPIES) is a non–IgE-mediated food allergy with a typical onset in infancy. Its symptoms are distinct from those of IgE-mediated food allergies and include severe repetitive vomiting, lethargy, and pallor. FPIES reactions are associated with T H 17 cytokines and a systemic innate immune activation; however, the link between immune activation and symptoms is poorly understood. Our aim was to use an untargeted metabolomics approach to identify novel pathways associated with FPIES reactions. Serum samples were obtained before, during, and after oral food challenge (OFC) (10 subjects with FPIES and 10 asymptomatic subjects), and they were analyzed by untargeted metabolomics. Two-way ANOVA with false discovery rate adjustment was used for analysis of metabolites. Stomach and duodenal biopsy specimens from non-FPIES donors were stimulated with adenosine in vitro and serotonin measured by immunoassay. The levels of a total of 34 metabolites, including inosine and urate of the purine signaling pathway, were increased during OFCs performed on the patients with symptomatic FPIES compared with the levels found for asymptomatic subjects. Expression of the purine receptors P2RX7 and P2RY10 and the ectonucleotidase CD73 in peripheral blood was significantly reduced after OFC of the patients with FPIES. The level of the serotonin metabolite 5-hydroxyindoleacetate was significantly elevated after reaction. Adenosine stimulation of gastric and duodenal biopsy specimens from FPIES-free donors induced a significant release of serotonin, suggesting a link between purinergic pathway activation and serotonin release. Activation of the purinergic pathway during FPIES reactions provides a possible mechanism connecting inflammation and vomiting by triggering serotonin release from gastric and duodenal mucosa. [ABSTRACT FROM AUTHOR]

Food protein-induced enterocolitis syndrome (FPIES) is a non IgE-mediated gastrointestinal food allergy that presents with delayed vomiting after ingestion primarily in infants. While the pathophysiology of FPIES is poorly understood, the clinical presentation of acute FPEIS reactions has been well characterized. The first International Consensus Guidelines for the Diagnosis and Management of Food Protein-induced Enterocolitis Syndrome were published in 2017 and reviewed epidemiology, clinical presentation and prognosis of acute and chronic FPIES. The workgroup outlined clinical phenotypes, proposed diagnostic criteria, and made recommendations on management. This article summarizes the guidelines and adds recent updates. FPIES is gaining recognition, however there continues to be delays in diagnosis and misdiagnosis due to overlap of symptoms with over conditions, lack of a diagnostic test and because some of the common trigger foods are not thought of as allergenic. More research into disease mechanisms and factors influencing differences between populations is needed. [ABSTRACT FROM AUTHOR]

Tolerance development is an important clinical outcome for infants with cow's milk allergy. 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. 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. 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). 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Shellfish allergy is a long-lasting disorder usually persisting throughout life. Despite its high prevalence, there is limited information about allergenic shrimp proteins. Objective: Characterization of shrimp allergens. Methods: Fifty-two adults and children with a history of immediate allergic reactions to shrimp and elevated serum IgE to shrimp were selected for this study. Tryptic digests from a 20-kd IgE-binding protein were analyzed by LC-MS/MS, identifying the protein as a sarcoplasmic-calcium-binding protein. cDNA encoding sarcoplasmic calcium-binding protein (SCP) from a shrimp cDNA library (Litopenaeus vannamei) was amplified by PCR, cloned into an expression vector, and sequenced. Recombinant SCP was tested with patients'' sera. ELISA inhibition experiments determined the fraction of total shrimp IgE recognizing SCP. A functional assay with a rat basophilic leukemia cell line was used to determine the capacity for mediator release induced by SCP. Results: Immunoblotting demonstrated IgE binding by 31 of 52 (59.6%) of the sera to a 20-kd shrimp protein. The protein was identified as a SCP. Amplified cDNA encoding SCP was isolated and sequenced. Open reading frame translation provided the complete amino acid sequence of shrimp SCP. Recombinant SCP was recognized by serum IgE from 20 of 52 (38.4%) subjects, of whom 17 of 20 (85%) were children. ELISA inhibition of pooled sera IgE reactivity to BS extract using recombinant SCP was significant (as high as 79%). For some subjects, mediator release induced by recombinant SCP was higher than that induced by recombinant tropomyosin. Conclusion: We have identified and cloned a new shrimp allergen, Lit v 4.0101, an SCP, which appears to be of particular importance in the pediatric population. [Copyright &y& Elsevier]

Background: About 70% of children with milk allergy tolerate extensively heated milk (HM) products and outgrow their allergy earlier than those who react to HM. Objective: To test the hypothesis that HM-tolerant children have a higher precursor frequency of adaptive allergen-specific regulatory T (Treg) cells. Methods: Allergic, HM-tolerant, outgrown, or control subjects were defined by oral food challenge. PBMCs were cultured with purified caseins and controls for 7 days, and proliferating CD25+CD27+ Treg cells were identified by flow cytometry. Proliferating cells were also characterized for their expression of FoxP3, CTLA 4, CD45RO, and CD127. Allergen-specific Treg cell origin and function were assessed by depletion of CD25hi cells before culture. Results: There was a higher percentage (median [25th% to 75th%], 16.85% [7.1-31.7]) of proliferating allergen-specific CD25+CD27+ T cells from cultures of HM-tolerant subjects (n = 18) than subjects with allergy (n = 8; 4.91% [2.6-7.5]; P < .01). Control subjects with no history of milk allergy (n = 7) also had low percentages of these cells (2.9% [2.4-6.0]), whereas outgrown subjects (n = 7) had intermediate percentages (9.0% [2.7-16.4]). There were no significant differences between the patient groups in the frequency of polyclonal Treg cells or allergen-specific effector T cells. Allergen-specific Treg cells were found to be FoxP3+CD25hiCD27+, cytotoxic T lymphocyte–associated antigen 4+, CD45RO+CD127− and were derived from circulating CD25hi T cells. Depletion of the CD25hi cells before in vitro culture significantly enhanced allergen-specific effector T-cell expansion. Conclusion: A higher frequency of milk allergen-specific Treg cells correlates with a phenotype of mild clinical disease and favorable prognosis. [Copyright &y& Elsevier]

Background: Prior studies have suggested that heated egg might be tolerated by some children with egg allergy. Objective: We sought to confirm tolerance of heated egg in a subset of children with egg allergy, to evaluate clinical and immunologic predictors of heated egg tolerance, to characterize immunologic changes associated with continued ingestion of heated egg, and to determine whether a diet incorporating heated egg is well tolerated. Methods: Subjects with documented IgE-mediated egg allergy underwent physician-supervised oral food challenges to extensively heated egg (in the form of a muffin and a waffle), with tolerant subjects also undergoing regular egg challenges (in a form of scrambled egg or French toast). Heated egg–tolerant subjects incorporated heated egg into their diets. Skin prick test wheal diameters and egg white, ovalbumin, and ovomucoid IgE levels, as well as ovalbumin and ovomucoid IgG4 levels, were measured at baseline for all subjects and at 3, 6, and 12 months for those tolerant of heated egg. Results: Sixty-four of 117 subjects tolerated heated egg, 23 tolerated regular egg, and 27 reacted to heated egg. Heated egg–reactive subjects had larger skin test wheals and greater egg white–specific, ovalbumin-specific, and ovomucoid-specific IgE levels compared with heated egg– and egg-tolerant subjects. Continued ingestion of heated egg was associated with decreased skin test wheal diameters and ovalbumin-specific IgE levels and increased ovalbumin-specific and ovomucoid-specific IgG4 levels. Conclusions: The majority of subjects with egg allergy were tolerant of heated egg. Continued ingestion of heated egg was well tolerated and associated with immunologic changes that paralleled the changes observed with the development of clinical tolerance to regular egg. [Copyright &y& Elsevier]

Background: Cow''s milk allergy is the most common childhood food allergy. Previously we noted that children who outgrew their milk allergy had milk-specific IgE antibodies primarily directed against conformational epitopes; those with persistent milk allergy also had IgE antibodies directed against specific sequential epitopes. Objective: Because high temperature largely destroys conformational epitopes, we hypothesized that some children with milk allergy would tolerate extensively heated (baked) milk products. Methods: Children with milk allergy were challenged with heated milk products; heated milk–tolerant subjects were subsequently challenged with unheated milk. Heated milk–tolerant, unheated milk–reactive subjects ingested heated milk products for 3 months and were then re-evaluated. Immune responses were assessed in all subjects; growth and intestinal permeability were followed in heated milk–tolerant subjects. Results: One hundred children (mean age, 7.5 years; range, 2.1-17.3 years) underwent heated milk challenges. Sixty-eight subjects tolerated extensively heated milk only, 23 reacted to heated milk, and 9 tolerated both heated and unheated milk. Heated milk–reactive subjects had significantly larger skin prick test wheals and higher milk-specific and casein-specific IgE levels than other groups. At 3 months, subjects ingesting heated milk products had significantly smaller skin prick test wheals and higher casein-IgG4 compared with baseline; other immunologic parameters, growth, and intestinal permeability were not significantly different. Heated milk–reactive subjects had more severe symptoms during heated milk challenge than heated milk–tolerant subjects experienced during their unheated milk challenge. Conclusion: The majority (75%) of children with milk allergy tolerate heated milk. [Copyright &y& Elsevier]

Background: Food allergy is the most common cause of anaphylaxis outside the hospital setting. Objective: We sought to determine the rate, circumstances, and risk factors for repeated doses of epinephrine in the treatment of food-induced anaphylaxis in children. Methods: Anonymous questionnaires were distributed to families of children with food allergies during allergy outpatient visits to a food allergy referral center. Demographic information, allergy and reaction history, and details regarding the last 2 anaphylactic reactions requiring epinephrine were collected. Results: A total of 413 questionnaires were analyzed. Seventy-eight children (median, 4.5 years of age; range, 0.5-17.5 years) reported 95 reactions for which epinephrine was administered. Two doses were administered in 12 (13%) and 3 doses in an additional 6 (6%) reactions treated with epinephrine. Peanut, tree nuts, and cow''s milk were responsible for >75% of reactions requiring epinephrine. Patients receiving multiple doses of epinephrine more often had asthma (P = .027) than children receiving a single dose. The amount of food ingested or a delay in the initial administration of epinephrine were not risk factors for receiving multiple doses. The second dose of epinephrine was administered by a health care professional in 94% of reactions. Conclusion: In this referral population of children and adolescents with multiple food allergies, 19% of food-induced anaphylactic reactions were treated with more than 1 dose of epinephrine. Prospective studies are necessary to identify risk factors for severe anaphylaxis and to establish rational guidelines for prescribing multiple epinephrine autoinjectors for children with food allergy. [Copyright &y& Elsevier]

Background & Aims: Secreted immunoglobulins play an integral role in host defense at mucosal surfaces, and recent evidence shows that IgG can participate in antigen sampling from the intestinal lumen. We examined whether IgE also could facilitate transepithelial antigen sampling. Methods: Stool samples from food-allergic patients undergoing oral food challenge were analyzed for CD23 and food-specific IgE. CD23 isoform expression on primary human intestinal epithelial cells (IEC) was analyzed by polymerase chain reaction. The role of CD23 isoforms in transcytosis of antigen and IgE–antigen complexes was assessed using polarized human T84 cells retrovirally transfected with CD23a or CD23b. Results: CD23 was expressed constitutively on IECs, and food-allergic patients had increased levels of soluble CD23 and food-specific IgE in the stool after challenge. CD23a, but not CD23b, was expressed by primary human IECs. We show in transcytosis assays that CD23a, but not CD23b, acts as a bidirectional transporter of IgE. In addition, specific IgE facilitated the uptake of antigen from the apical surface of an epithelial monolayer by diverting antigen from delivery to lysosomes. Finally, delivery of antigen–IgE complexes across the epithelial barrier could induce the degranulation of rat basophil leukemia cells transfected with the human high-affinity IgE receptor. Conclusions: These studies show that CD23a is expressed normally on human IECs, and in the presence of IgE can function as an antigen-sampling mechanism capable of activating subepithelial mast cells. IgE may serve as a secretory immunoglobulin that in concert with CD23 participates in food-induced pathophysiology of the gastrointestinal tract. [Copyright &y& Elsevier]

Background: Levels of IgE antibody to egg white of greater than 7 kIU/L are highly predictive of clinical reactivity to egg, and lower levels often require evaluation with oral food challenge (OFC) to establish definitive diagnosis. OFCs have inherent risks, and diagnostic criteria indicating high likelihood of passing would be clinically useful. Objective: We sought to determine whether the size of the skin prick test (SPT) to egg white adds diagnostic utility for children with low egg white–specific IgE antibody levels. Methods: A retrospective analysis of clinical history, egg white–specific IgE antibody levels, SPT responses, and egg OFC outcomes was performed. Results: Children who passed (n = 29) egg OFCs and those who failed (n = 45) did not differ significantly in age, clinical characteristics, or egg white–specific IgE levels. There were, however, significant differences between both egg white SPT wheal response size and egg/histamine SPT wheal index. Children who failed egg OFCs had a median wheal of 5.0 mm; those who passed had a median wheal of 3.0 mm (P = .003). Children who failed egg OFCs had a median egg/histamine index of 1.00; those who passed had a median index of 0.71 (P = .001). For egg white–specific IgE levels of less than 2.5 kIU/L, an SPT wheal of 3 mm or an egg/histamine index of 0.65 was associated with a 50% chance of passing. Conclusion: In children with low egg white–specific IgE levels, those with smaller SPT wheal responses to egg were more likely to pass an egg OFC than those with larger wheal responses. The size of the egg white SPT response might provide additional information to determine the timing of egg OFC. Clinical implications: The size of the egg white SPT wheal response might provide the clinician with additional information to determine the timing of egg OFC in children with low egg white–specific IgE antibody levels. [Copyright &y& Elsevier]

Food protein–induced enterocolitis syndrome (FPIES) is a non–IgE-mediated food allergy characterized by profuse vomiting within hours of ingestion of the causative food. We have previously reported that FPIES is associated with systemic innate immune activation in the absence of a detectable antigen-specific antibody or T-cell response. The mechanism of specific food recognition by the immune system remains unclear. Our aim was to identify immune mechanisms underlying FPIES reactions by proteomic and flow cytometric analysis of peripheral blood. Children with a history of FPIES underwent supervised oral food challenge. Blood samples were taken at baseline, at symptom onset, and 4 hours after symptom onset. We analyzed samples from 23 children (11 reactors and 12 outgrown). A total of 184 protein markers were analyzed by proximity ligation assay and verified by multiplex immunoassay. Analysis of cell subset activation was performed by mass cytometry and spectral cytometry. Symptomatic FPIES challenge results were associated with significant elevation of levels of cytokines and chemokines, including IL-17 family markers (IL-17A, IL-22, IL-17C, and CCL20) and T-cell activation (IL-2), and innate inflammatory markers (IL-8, oncostatin M, leukemia inhibitory factor, TNF-α, IL-10, and IL-6). The level of the mucosal damage marker regenerating family member 1 alpha (REG1A) was also significantly increased. These biomarkers were not increased in asymptomatic challenges or IgE-mediated allergy. The level of phospho-STAT3 was significantly elevated in myeloid and T cells after challenge in individuals with symptoms. Mass cytometry indicated preferential activation of nonconventional T-cell populations, including γδ T cells and CD3+CD4–CD8–CD161+ cells; however, the potential sources of IL-17 in PBMCs were primarily CD4+ T H 17 cells. These results demonstrate a unique IL-17 signature and activation of innate lymphocytes in FPIES. [ABSTRACT FROM AUTHOR]