Identification of cow milk epitopes to characterize and quantify disease-specific T cells in allergic children.

BACKGROUND: Cow milk (CM) allergy is the most prevalent food allergy in young children in the United States and Great Britain. Current diagnostic tests are either unreliable (IgE test and skin prick test) or resource-intensive with risks (food challenges). OBJECTIVE: We sought to determine whether allergen-specific T cells in CM-allergic (CMA) patients have a distinct quality and/or quantity that could potentially be used as a diagnostic marker. METHODS: Using PBMCs from 147 food-allergic pediatric subjects, we mapped T-cell responses to a set of reactive epitopes in CM that we compiled in a peptide pool. This pool induced cytokine responses in in vitro cultured cells distinguishing subjects with CMA from subjects without CMA. We further used the pool to isolate and characterize antigen-specific CD4 memory T cells using flow cytometry and single-cell RNA/TCR sequencing assays. RESULTS: We detected significant changes in the transcriptional program and clonality of CM antigen-specific (CM+) T cells elicited by the pool in subjects with CMA versus subjects without CMA ex vivo. CM+ T cells from subjects with CMA had increased percentages of FOXP3+ cells over FOXP3- cells. FOXP3+ cells are often equated with regulatory T cells that have suppressive activity, but CM+ FOXP3+ cells from subjects with CMA showed significant expression of interferon-responsive genes and dysregulated chemokine receptor expression compared with subjects without CMA, suggesting that these are not conventional regulatory T cells. The CM+ FOXP3+ cells were also more clonally expanded than the FOXP3- population. We were further able to use surface markers (CD25, CD127, and CCR7) in combination with our peptide pool stimulation to quantify these CM+ FOXP3+ cells by a simple flow-cytometry assay. We show increased percentages of CM+ CD127-CD25+ cells from subjects with CMA in an independent cohort, which could be used for diagnostic purposes. Looking specifically for TH2 cells normally associated with allergic diseases, we found a small population of clonally expanded CM+ cells that were significantly increased in subjects with CMA and that had high expression of TH2 cytokines and pathogenic TH2/T follicular helper markers. CONCLUSIONS: Overall, these findings suggest that there are several differences in the phenotypes of CM+ T cells with CM allergy and that the increase in CM+ FOXP3+ cells is a potential diagnostic marker of an allergic state. Such markers have promising applications in monitoring natural disease outgrowth and/or the efficacy of immunotherapy that will need to be validated in future studies.

Factors Affecting Delayed Gastric Emptying and Long-Term Outcomes of Children With Gastric Emptying.

OBJECTIVES: Our study attempted to identify what factors best predict for delayed gastric emptying (DGE) and whether children respond to treatment. METHODS: Children aged between 0 and 18 were included who had a gastric emptying scintigraphy (GES) study performed between 2009 and 2018. Baseline clinical details were recorded from clinic visit records regarding symptoms, medication, and past medical history. Results were analyzed using multivariate regression analysis and coefficient analysis. Children were followed up at 2 years to assess their symptoms and medication usage. RESULTS: Two hundred and eighty-five children were included in the study of which 174 demonstrated DGE. All children had symptoms prior to GES, the most common symptom being that of vomiting and reflux symptoms which were present in over 90% of patients; other common symptoms like abdominal pain and nausea were seen commonly in around 30%. A genetic disorder and prior surgery were more common in children with DGE but there was no difference in presenting symptoms between normal and DGE groups. Regression analysis showed prior surgery and particularly prior abdominal surgery predicted for DGE and additionally predicted for those with highly DGE. Improvement in symptoms and reduction in medication usage was seen after 2 years. CONCLUSIONS: This study provides one of the largest data sets looking at DGE in children. Prior surgery was found to be a key factor in predicting for highly DGE. Symptoms and medication usage did significantly reduce substantially after 2 years.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

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.

BSACI 2021 guideline for the management of egg allergy.

This guideline advises on the management of patients with egg allergy. Most commonly egg allergy presents in infancy, with a prevalence of approximately 2% in children and 0.1% in adults. A clear clinical history will confirm the diagnosis in most cases. Investigation by measuring egg-specific IgE (by skin prick testing or specific IgE assay) is useful in moderate-severe cases or where there is diagnostic uncertainty. Following an acute allergic reaction, egg avoidance advice should be provided. Egg allergy usually resolves, and reintroduction can be achieved at home if reactions have been mild and there is no asthma. Patients with a history of severe reactions or asthma should have reintroduction guided by a specialist. All children with egg allergy should receive the MMR vaccine. Most adults and children with egg allergy can receive the influenza vaccine in primary care, unless they have had anaphylaxis to egg requiring intensive care support. Yellow Fever vaccines should only be considered in egg-allergic patients under the guidance of an allergy specialist. This guideline was prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and is intended for allergists and others with a special interest in allergy. The recommendations are evidence based. Where evidence was lacking, consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, diagnosis, treatment, prognosis and co-morbid associations.

Fifteen-minute consultation: The EATERS method for the diagnosis of food allergies.

The EATERS mnemonic is a novel method for taking an allergy focused clinical history. It provides a degree of certainty for diagnosing food allergy and can be used in both IgE and non IgE mediated reactions. EATERS will allow health care professionals to use their existing clinical skills to interpret the history of an allergic reaction, and by doing so will help to make sense of allergy test results.

Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence.

BACKGROUND: Filaggrin is an epidermal protein that has a role in skin barrier function. Filaggrin loss-of-function (FLG-LOF) mutations are a significant risk factor for eczema and atopy, but their association with food allergy (FA) is less clear. OBJECTIVE: We explored the longitudinal relationship between 3 common FLG-LOF mutations and FA using the Isle of Wight birth cohort. METHODS: FA diagnosis was based on recognized allergic reactions within 4 hours after exposure to known food allergens. Food allergen sensitization (FAS) was identified by using skin prick tests conducted between 1 and 18 years of age to a range of food allergens. Three FLG mutations were genotyped in 1150 (79%) of 1456 children. The temporal relationships between FA, FAS, and eczema in children with FLG mutations were explored by using path analysis with total, direct, and indirect effect models. RESULTS: There was a significant total effect of FLG-LOF mutations on the risk of FA in later childhood at the ages of 10 (odds ratio, 31.46; 95% CI, 2.86 to >100) and 18 (odds ratio, 4.25; 95% CI, 1.55-11.61) years. Path analysis showed that there was no direct effect of FLG-LOF mutations on FA at any age; however, an indirect effect was found on FA at all ages through eczema and FAS in the earlier years. CONCLUSION: FLG-LOF mutations are associated with FA in older children through eczema and FAS during early childhood. Our results highlight a biologically plausible pathway, which suggests that skin barrier function is important in the development and persistence of FA.

Highly accurate prediction of food challenge outcome using routinely available clinical data.

BACKGROUND: Serum specific IgE or skin prick tests are less useful at levels below accepted decision points. OBJECTIVES: We sought to develop and validate a model to predict food challenge outcome by using routinely collected data in a diverse sample of children considered suitable for food challenge. METHODS: The proto-algorithm was generated by using a limited data set from 1 service (phase 1). We retrospectively applied, evaluated, and modified the initial model by using an extended data set in another center (phase 2). Finally, we prospectively validated the model in a blind study in a further group of children undergoing food challenge for peanut, milk, or egg in the second center (phase 3). Allergen-specific models were developed for peanut, egg, and milk. RESULTS: Phase 1 (N = 429) identified 5 clinical factors associated with diagnosis of food allergy by food challenge. In phase 2 (N = 289), we examined the predictive ability of 6 clinical factors: skin prick test, serum specific IgE, total IgE minus serum specific IgE, symptoms, sex, and age. In phase 3 (N = 70), 97% of cases were accurately predicted as positive and 94% as negative. Our model showed an advantage in clinical prediction compared with serum specific IgE only, skin prick test only, and serum specific IgE and skin prick test (92% accuracy vs 57%, and 81%, respectively). CONCLUSION: Our findings have implications for the improved delivery of food allergy-related health care, enhanced food allergy-related quality of life, and economized use of health service resources by decreasing the number of food challenges performed.

Increased intake of oily fish in pregnancy: effects on neonatal immune responses and on clinical outcomes in infants at 6 mo.

BACKGROUND: Long-chain n-3 PUFAs found in oily fish may have a role in lowering the risk of allergic disease. OBJECTIVE: The objective was to assess whether an increased intake of oily fish in pregnancy modifies neonatal immune responses and early markers of atopy. DESIGN: Women (n = 123) were randomly assigned to continue their habitual diet, which was low in oily fish, or to consume 2 portions of salmon per week (providing 3.45 g EPA plus DHA) from 20 wk gestation until delivery. In umbilical cord blood samples (n = 101), we measured n-3 fatty acids, IgE concentrations, and immunologic responses. Infants were clinically evaluated at age 6 mo (n = 86). RESULTS: Cord blood mononuclear cell (CBMC) production of interleukin (IL)-2, IL-4, IL-5, IL-10, and tumor necrosis factor-α in response to phytohemagglutinin (PHA) and of IL-2 in response to Dermatophagoides pteronyssinus allergen 1 (Derp1) was lower in the salmon group (all P ≤ 0.03). In the subgroup of CBMCs in which an allergic phenotype was confirmed in the mother or father, IL-10 production in response to Toll-like receptor 2, 3, and 4 agonists, ovalbumin, salmon parvalbumin, or Derp1 and prostaglandin E(2) production in response to lipopolysaccharide or PHA was lower in the salmon group (all P ≤ 0.045). Total IgE at birth and total IgE, incidence and severity of atopic dermatitis, and skin-prick-test positivity at 6 mo of age were not different between the 2 groups. CONCLUSION: Oily fish intervention in pregnancy modifies neonatal immune responses but may not affect markers of infant atopy assessed at 6 mo of age. This trial is registered at clinicaltrials.gov as NCT00801502.

Can the Brighton Collaboration case definitions be used to improve the quality of Adverse Event Following Immunization (AEFI) reporting? Anaphylaxis as a case study.

The Brighton Collaboration (BC) was established in 2000 with the aim of developing globally accepted standardized case definitions for adverse events following immunizations (AEFI) as well as guidelines for the collection, analysis and presentation of surveillance data. Some of the BC case definitions are complex and this may limit their application for use in post-marketing vaccine surveillance. Barriers to the application of the BC case definitions include an incomplete description of an adverse event and inconsistencies in reporter use of adverse event terms. We have taken the BC case definition for anaphylaxis and developed a clinical checklist and glossary of terms used in the case definition. It is anticipated that these resources can be used at a community level by AEFI reporters. If used, these resources could improve the quality of adverse event reports which would facilitate the application of the BC case definition at a regional and/or national level.