BACKGROUND: Cow\'s milk and egg allergy affect approximately 1.9% and 0.9% of children, respectively. Dietary advancement therapies (DATs), including milk (ML) and egg (EL) ladders, and baked milk (BM-OIT) and baked egg (BE-OIT) oral immunotherapy, are potential therapeutic options for these patients.
OBJECTIVE: To perform systematic review and meta-analysis of the safety and efficacy of DATs in children with IgE-mediated milk or egg allergy.
METHODS: A systematic literature review was conducted, exploring 22 potential outcomes, with meta-analysis performed where ≥3 studies reported data. The GRADE approach was used to determine the certainty of evidence for each outcome, and the Johanna Briggs Institute tools were used for determining risk of bias.
RESULTS: Twenty-nine studies met inclusion criteria among 9946 titles screened. Tolerance occurred in 69% of EL, 58% of ML, 49% of BE-OIT, and 29% of BM-OIT patients. All-severity allergic reactions occurred in 21% of EL, 25% of ML, 20% of BE-OIT, and 61% of BM-OIT patients, with epinephrine use in 3% of EL, 2% of ML, and 9% of BM-OIT patients. At-home reactions occurred in 19% of BE-OIT and 10% of BM-OIT patients. Discontinuation occurred in 14% of EL, 17% of ML, 17% of BE-OIT, and 20% of BM-OIT patients. The mean time to BE egg and BE-OIT tolerance was 13.25 months (4 studies) and 19.1 months (3 studies). Certainty of evidence was very low, and risk of bias high. Study heterogeneity was high, attributable to multiple factors.
CONCLUSIONS: There is very low certainty of evidence supporting DAT safety and efficacy. We cannot conclude that DAT accelerates tolerance development.

Identifying patients at risk of severe allergic reactions and/or low threshold of reactivity is very important, particularly for staple foods like egg.
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.
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.
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.

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).
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.
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.
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.

Dietary advancement therapies (DATs) constitute a continuum spanning extensively heated item ingestion, progressive milk or egg ladders, and oral immunotherapy (OIT). These represent an evolution in food allergy management from strict avoidance to an active therapy that may modulate the immune system to develop tolerance to particular forms of the allergen. Many egg or milk individuals are tolerant to baked egg or milk at baseline, and regular consumption (at home ingestion) of baked milk or egg is a safe process with potential quality of life and immunologic benefit. Milk and egg ladders, developed for non-IgE mediated allergy, are increasingly being adapted to IgE-mediated allergy as a potentially safe at-home option for gradual dietary advancement. However, data are limited regarding how safe and effective these approaches are or what patient is best suited for which DAT. It is also unclear whether extensively heated allergen consumption and ladders are susceptible to the same patient-specific factors that affect day-to-day tolerance and safety in OIT. Several recent events involving near-fatal or fatal reactions to milk or egg products (all among patients with asthma) have highlighted that DATs are not risk-free, and that physician guidance in these therapies is essential. Such guidance may include obtaining informed consent before starting any DAT and instituting the same safe dosing rules for OIT across any form of DAT. This rostrum discusses practical concerns about the safety of DAT, and considerations regarding how clinicians can maximize patient protection while defining the safety and efficacy of real-world implementation of these concepts.