Does Appropriate Timing for Early Introduction Differ Between Hen's Eggs and Nuts?

The prevalence of common food allergies varies considerably across geographical regions [1]. In Japan, the most common food allergy in infants is hen's egg, followed by cow's milk, and nuts were the third in 2021 [2]. Eczema is a major risk factor for food allergy [3]; so eczema children were high risk populations for food allergy. Various trials have reported that early introduction of allergenic foods such as peanuts, eggs and milk can prevent food allergies [4]. However, the best timing of allergenic food introduction is unclear. Previous studies reported differences in sensitisation by antigen and age [5-7]. However, data on temporal disparities in sensitisation patterns for hen's egg, peanut and nuts based on age are lacking for children under 2 years of age with eczema. The aim of this study was to elucidate the temporal disparities in patterns of sensitisation to nuts (almond, walnut, cashew and hazelnut) compared to the patterns of sensitisation to other common allergens (peanut, egg white, house dust mite [HDM], Japanese cedar and Malassezia) during infancy among infants with eczema. This was a retrospective cohort study using the electronic medical records of children who sought medical attention between June 2013 and June 2023 in the National Center for Child Health and Development. We extracted the data on blood test results, including total and specific IgE levels as well as TARC levels using the following screening criteria: [1] presence of a disease code for atopic dermatitis, [2] history of steroid prescriptions, [3] history of allergy centre visits and [4] requirement that the individual was younger than 2 years of age at the time of allergy testing. Blood samples were analysed by SRL, in Tokyo, Japan and IgE levels were measured using ImmunoCAP assays (Thermo Fischer Scientific, Waltham, MA, USA). IgE sensitisation was defined as an IgE level ≥0.35 IU/mL. Ethics approval for this study was granted by the Ethics Committee of the National Center for Child Health and Development (reference no. 2023-083). Informed consent was obtained in the form of opt-out on the website. The number of infants was 2426. A total of 32,912 IgE tests were conducted, and the detailed results for each test are provided in Table S1. Figure 1 illustrates the sensitisation status to specific allergens at different age groups: every 3-month age groups. Throughout the entire study period, the sensitisation rate was consistently lower for nuts, peanut, HDM and Japanese cedar than for egg white. The onset of sensitisation to egg white was observed before 3 months of age, whereas the onset of sensitisation to nuts, peanut and HDM was observed in older age groups. Regarding the timing of peak sensitisation rates, the sensitisation rates were highest for all nuts and peanuts allergens, in the 18- to 21-month age group. The sensitisation rates for walnut, cashew, almond, hazelnut and peanut were 25.2%, 41.6%, 54.9%, 46.4% and 52.3%, respectively, in these age groups:18- to 21-month age group. Conversely, the highest rate of sensitisation to egg white was in the 15- to 18-month age group, reaching 93.2%. Notably, although the rate of sensitisation varied between tree nuts and peanut, there was an overall trend of increase in the rate of sensitisation starting around 15 months of age. In contrast, a sensitisation rate of >50% was observed for egg white starting at 3–6 months of age. This is the first investigation examining month of age-specific sensitisation status to tree nuts and peanut in infants with eczema, who are at higher risk populations. Additional information about study findings are available in the following the repository (https://doi.org/10.5281/zenodo.11355934). Our analyses revealed that the onset of sensitisation to egg white and other foods (walnut, cashew, almond, hazelnut and peanut) exhibited an age lag, and the rate of sensitisation to nuts was notably lower than that to egg white during infancy. Furthermore, sensitisation to nuts rapidly increased from 15 months of age. In Iran, the rate of sensitisation to nuts was 5% in children younger than 1 year of age, which increased to 17.7% by 2 years of age [6] In Turkey, the rates of sensitisation were 14.0%, 8.7%, 8.0% and 3.8% for hazelnut, walnut, cashew and almond, respectively, in children up to 2 years of age whereas the rate of sensitisation to egg white was 49.7% [7]. These differences suggest the potential role of environmental antigen levels. In the present study, the rate of HDM sensitisation was lower and onset was later than that of egg white. We previously showed environmental allergen levels in the dust of households, the egg white allergen level was higher than that of HDM [8]. The introducing nuts by 6 months of age might be a safe strategy to reduce the incidence of food allergy. On the contrary, nuts pose challenges for consumption during the initial phases of weaning due to their texture. If delaying nut consumption slightly does not cause harm, it could ease the burden on both caregivers and infants. We are planning to initiate a RCT to explore the differences in the preventive effects of walnut allergy based on the timing of walnut consumption initiation (WISH-J study). This study has some limitations. This study was a retrospective observational and non-interventional study. In the present study, we are elucidating temporal disparities in sensitisation patterns between hen's egg and nuts in infants with eczema. The current study focusing on the onset of sensitisation in children at high risk for nut allergy provides pivotal, valuable insights for the development of strategies to mitigate the increasing incidence of nut allergy. S.H. and K.Y.-H. conceived the idea of the study. S.H. drafted the original manuscript. M.S.-A., T.F., Y.O. and K.Y.-H. supervised the conduct of this study. K.Y.-H. reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the final version of the manuscript to be published. We thank to all the physicians who collected blood samples to measure IgE titers. Informed consent was obtained in the form of an opt-out on the website. Ethics approval for this study was granted by the Ethics Committee of the National Center for Child Health and Development (reference no. 2023-083). The authors declare no conflicts of interest. Currently, individual participant data sharing is unavailable because the IRB permission is not yet obtained under the Ethical Guidelines for Medical and Biological Research Involving Human Subjects and Personal Information Protection Commission, Japan. The individual participant data sharing will be available after the IRB permission is granted. Any data queries can be emailed to the Primary Investigator Kiwako Yamamoto-Hanada at [email protected]. Table. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.