Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Basophil activation test as predictor of severity and threshold of allergic reactions to egg.

BACKGROUND: Identifying patients at risk of severe allergic reactions and/or low threshold of reactivity is very important, particularly for staple foods like egg. METHODS: One hundred and fifty children underwent double-blind placebo-controlled food challenge (DBPCFC) to baked egg (BE), skin prick testing and blood collection for serology and basophil activation test (BAT). Patients who passed BE DBPCFC underwent loosely cooked egg (LCE) DBPCFC. Severity of allergic reactions was classified following Practall guidelines and threshold dose was determined during DBPCFC. RESULTS: Sixty out of 150 (40%) children reacted to BE and 16 out of 77 (21%) to LCE on DBPCFC. Considering DBPCFC to BE, 23 children (38%) had severe reactions and 33 (55%) reacted to 0.13 g or less of egg protein (low threshold group). Two children (2 out of 16 = 12%) had severe reactions to LCE. Demographic, clinical and most immunological features were not significantly different between severe/non-severe BE reactors or low/high threshold groups. Severe BE reactors had higher ovomucoid-sIgE (p = .009) and higher BAT to BE (p = .001). Patients with lower threshold to BE had higher IgE-specific activity (p = .027) and BAT to egg (p = .007) but lower severity score (p = .008). Optimal cut-offs for ovomucoid-sIgE had 100% sensitivity, 35% specificity and 60% accuracy and for BAT 76% sensitivity, 74% specificity and 75% accuracy to identify BE severe reactors. Optimal cut-offs for specific activity had 70% sensitivity, 68% specificity and 69% accuracy and for BAT 70% sensitivity, 72% specificity and 71% accuracy to identify low threshold patients. CONCLUSIONS: BAT was the best biomarker to predict severity and threshold of allergic reactions to BE and can be useful when making decisions about management of egg allergy.

Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy.

The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta-analyses were undertaken for food-test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double-blind placebo-controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2-sIgE had 92%, Cor a 14-sIgE 95%, Ana o 3-sIgE 94%, casein-sIgE 93%, ovomucoid-sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.

Partial Egg Consumption Modifies the Diagnostic Performance of Allergy Tests to Predict Outcome of Double-Blind Placebo-Controlled Food Challenges to Egg.

BACKGROUND: Many children are consuming some egg when they are diagnosed with egg allergy. We hypothesized that egg consumption could modify the diagnostic performance of allergy tests. OBJECTIVE: To stratify diagnostic performance of tests according to egg consumption status. METHODS: The BAT2 study (NCT03309488) participants underwent oral food challenge (OFC), food-frequency questionnaires, skin prick test (SPT), specific immunoglobulin E (sIgE) and specific immunoglobulin G4 (sIgG4) and basophil activation test (BAT). RESULTS: At study entry, 45% of participants reported partial egg consumption ("consumers") and 55% were avoiding egg strictly ("avoiders"). Avoiders had larger SPT (P < .001), higher BAT to egg (P < .001), sIgE to egg white (EW; P = .001) and to ovalbumin (OVA; P = .001), but not to ovomucoid (P = .231). Consumers had higher levels of sIgG4 to all egg allergens (P < .001) than avoiders. In consumers, the test with the best diagnostic performance was BAT (area under the curve [AUC] = .912) followed by SPT to raw egg (AUC = 0.805), EW-sIgE (AUC = 0.738), and OVA-sIgE (AUC = 0.732). In avoiders, the best tests were BAT (AUC = 0.834) and EW-sIgE (AUC = 0.833) followed by OVA-sIgE (AUC = 0.793) and SPT to EW (AUC=0.789). Using 100% sensitivity and 100% specificity cut-offs, the proportion of patients requiring OFC were 33% for BAT, 53% for SPT to raw egg, 61% for OVA-sIgE, and 73% for EW-sIgE for consumers; and 73% for BAT, 79% for EW-sIgE, and 93% for SPT to EW for avoiders. CONCLUSIONS: The diagnostic performance of tests is influenced by the immunomodulatory effect of egg consumption. BAT is the most reliable test and reduced the need for OFC, particularly in partial egg consumers.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Diagnostic utility of allergy tests to predict baked egg and lightly cooked egg allergies compared to double-blind placebo-controlled food challenges.

BACKGROUND: Double-blind placebo-controlled food challenges (DBPCFC) are the gold-standard to diagnose food allergy. However, they can cause allergic reactions of unpredictable severity. We assessed accuracy of current and new diagnostic tests compared to DBPCFC to baked egg (BE) and to lightly cooked egg (LCE). METHODS: Children aged 6 months to 15 years were assessed for possible egg allergy as part of the BAT2 study (NCT03309488). They underwent clinical assessment, skin prick test (SPT), specific IgE (sIgE) and basophil activation test (BAT). The results of the tests were compared with DBPCFC outcomes to both BE and LCE. RESULTS: A total of 150 children underwent DBPCFC to BE, 60 (40%) reacted to and 85 (57%) tolerated BE and 5 (3%) had inconclusive oral food challenges (OFC). Seventy-seven children tolerant to BE had DBPCFC to LCE and 16 reacted. The test within each modality with the best diagnostic performance for BE allergy was as follows: SPT to egg white (EW) (AUC = 0.726), sIgE to EW (AUC = 0.776) and BAT to egg (AUC = 0.783). BAT (AUC = 0.867) was the best test in the younger than 2 years age group. Applying 100% sensitivity and 100% specificity cut-offs, followed by OFC, resulted in 100% diagnostic accuracy. BAT enabled the greatest reduction in OFC (41%). Using sIgE followed by BAT allowed to reduce the number of BATs performed by about 30% without significantly increasing the number of OFC. CONCLUSIONS: The best diagnostic test was BAT to egg in terms of diagnostic accuracy and reduction in number of OFC. Using sIgE to EW followed by BAT required fewer BATs with sustained OFC reduction and diagnostic accuracy.