Background: The majority of egg-allergic children outgrow hypersensitivity against heated egg and then raw egg over time. The roles of ovomucoid (OVM)- and ovalbumin (OVA)-specific IgD in children who naturally outgrow egg allergy are uncertain. We investigated whether specific IgD to egg white (EW), OVM, and OVA correlate with allergen-specific IgE and can predict the development of immune tolerance to egg allergens. Methods: The tolerated doses of cooked egg white, which were determined by oral food challenge and/or an episode of accidental ingestion and corresponding specific IgE, IgG4 and IgD levels were evaluated in 57 children with egg allergy and 23 non-egg allergic children. Results: Patients avoiding all forms of egg had lower EW-, OVM-, and OVA-specific IgD and IgG4 than those partially avoiding egg, those that had outgrown egg allergy, and non-egg allergic children. The ratio of OVM-specific IgD to OVA-specific IgD increased depending on the ingestible amounts of boiled EW, whereas the ratio of OVM-specific IgG4 to OVA-specific IgG4 did not change. Receiver operating curve analysis revealed that the ratio of OVM-specific IgE to OVM-IgD was the best index to discriminate intolerant from tolerant egg-allergic patients. Conclusion: The production of OVM-specific IgD differs from OVM-specific IgG4 as children naturally outgrow egg allergy. The ratio of OVM-specific IgE to OVM-specific D is useful in distinguishing egg-sensitized patients with clinically reactive egg allergy from those who naturally outgrow egg allergy.

Letter to EditorTo the EditorEgg-allergic children have higher ovomucoid (OVM)-specific IgD (sIgD) levels compared to the atopic controls.1 Within the egg-allergic group, children with higher levels of OVM-sIgD have a decreased risk of anaphylactic reactions. Ovalbumin (OVA)-sIgD increases in egg-allergic children desensitized by oral immunotherapy (OIT) but not in children unresponsive to OIT or with sustained unresponsiveness to OVA challenge.2 The natural development of tolerance and the acquisition of sustained unresponsiveness by OIT in egg-allergic children are associated with an increase in OVM-specific IgG4 (sIgG4) levels and a decrease in OVM-specific IgE (sIgE) levels.3 To elucidate the potential role of IgD in the outgrowing of egg allergy, we analyzed levels of egg white (EW)-, OVM-, and OVA-sIgD and sIgG4 in sera from 57 egg-allergic children (28 avoided all forms of egg in the diet (complete avoidance of egg: CAE), 18 were able to ingest at least 1/32 cooked whole egg but not one cooked whole egg (partial avoidance of egg: PAE), and 11 outgrew egg allergy (OGE)) and 23 healthy non-egg allergic children (non-egg allergy: NEA) (Table S1). The study was approved by The Research Ethics Committee of University of Fukui (#20110052), and written informed consent was obtained from the parent or guardians.EW-, and OVM-sIgE levels measured using ImmunoCAP (Thermo-Fisher Inc., MA) were higher in the CAE group, followed by the PAE, OGE, and NEA groups (Fig 1, Fig S1). The CAE group exhibited lower serum levels of EW- and OVA-sIgD compared to the NEA group and the PAE group, respectively, and had the lowest OVM-sIgD serum levels among all groups, suggesting that OVM-sIgD levels are associated with outgrowing egg allergy. We observed the lowest serum levels of EW-, OVA-, and OVM-sIgG4 in the CAE group, followed by the PAE and OGE groups. The ratio of OVM-sIgD to OVA-sIgD increased as children outgrew egg allergy, whereas the ratio of OVM-sIgG4 to OVA-sIgG4 did not change. Thus, the production of OVM-sIgD differs from OVM-sIgG4 as children naturally outgrow egg allergy.High-affinity, but not low-affinity, IgE is known to cause anaphylaxis.4 High-affinity IgE is derived from memory IgG1+ B cells, whereas low-affinity IgE is derived from naïve IgM+IgD+ B cells. Considering class switching pathways, switching direction from IgM to IgD, and from IgG1 to IgE or IgG4, elevated OVM-sIgD levels might be associated with low-affinity OVM-sIgE levels as children outgrow egg allergy, resulting in hypo-responsiveness to OVM.A recent study found that OVM-sIgE avidity was more effective at differentiating clinically reactive egg-allergic patients from those tolerant of heated egg compared to EW-sIgE.5 The ratio of OVM-sIgE to OVM-sIgD or sIgG4 in the CAE group was significantly higher compared to the PAE, OGE, and NEA groups (Fig 2). Receiver operating analysis revealed that the ratio of OVM-sIgE to OVM-sIgD discriminated non-tolerant from partially-tolerant egg-allergic patients with the largest area under the curve (AUC = 0.965) compared with levels of OVM-sIgE or the ratio of OVM-sIgE to OVM-sIgG4. The optimal cutoff for the ratio of OVM-sIgE to OVM-sIgD had 86.5% sensitivity and 96.4% specificity to identify high-risk subjects (Table S2).There are several limitations to this study. First, there was a small number of patients. Second, all children were only challenged with heated egg and were instructed to avoid egg of any form if they tested positive with less than 1/32 cooked whole egg. Finally, there was a lack of trajectory of sIgD levels during natural tolerance development.In conclusion, the ratio of OVM-sIgE to OVM-sIgD is a useful marker to identify high-risk egg-allergic patients capable of ingesting a low-dose of cooked whole egg who might be a good candidate for low-dose OIT.