The prevalence of immunoglobulin (Ig) E–mediated food allergy in children has increased remarkably worldwide in recent decades, placing a substantial burden on patients, their caregivers, and health care systems. The results of food allergy epidemiologic studies vary by study method, such as whether the diagnosis is based on an oral food challenge (OFC), a clinician’s history taking, or self-reported questionnaires, but it is apparent that the prevalence of IgE-mediated food allergy in children is increasing despite variations in research designs [1]. Large-scale population-based studies in Australia reported that the prevalence of food allergy exceeded 10% in infants and was 4%–5% in older children [2,3]. According to a cross-sectional population-based survey in the United States, the prevalence of IgE-mediated food allergy in children was 7.6%.4) In a Korean birth cohort study, the prevalence of immediate-type food allergy was 5.3% among infants [5]. Potentially life-threatening food-induced anaphylaxis is of greater importance, especially in younger individuals, in whom a sharp increase has been observed compared to older individuals. The annual admission rates due to foodinduced anaphylaxis in Australia increased 9-fold between 1998–1999 and 2018–2019, with the highest rates in those younger than 1 year of age [6]. According to a national big data analysis in Korea, the prevalence of all-cause anaphylaxis increased 1.7-fold from 2010 to 2014 and was greatest in the 0–2 years age group, in which food-induced anaphylaxis was most frequent [7].

Allergies to peanuts, tree nuts, and seafood tend to persist, whereas those to cow’s milk, hen’s eggs, wheat, and soy are typically outgrown during the preschool years. However, some studies suggested that the resolution timing of these food allergies may now be delayed compared with past decades [8,9]. Food allergy patients and/or their caregivers often experience a significant decrease in quality of life, especially if they experience severe symptoms, have multiple food allergies, or have allergies to staple foods that are more difficult to avoid, such as cow’s milk, hen’s eggs, or wheat [10,11]. Therefore, it is important for clinicians to equip themselves with current knowledge about the natural course of food allergy to guide elimination diets as well as to evaluate food allergy resolution at appropriate timing during follow-up. This review discusses the natural course of major IgE-mediated food allergies in children.

Our understanding remains poor about why some food allergies outgrow earlier versus persist longer. Tolerance to food allergens is driven mainly by antigen-presenting cells within the gut lamina propria by the promotion of T-cell differentiation. CX3CR1⁺ dendritic cells directly uptake antigens from the intestinal lumen and have greater inflammatory potential, whereas CD103⁺CX3CR1⁻ dendritic cells have tolerogenic properties [12]. Goblet cell-associated antigen passages deliver antigens to CD103⁺CX3CR1⁻ dendritic cells and, therefore, are associated with oral tolerance induction [13]. Migratory CD103⁺ dendritic cells from the lamina propria in the mesenteric lymph nodes can promote the development of gut-homing regulatory T cells through multiple mechanisms involving transforming growth factor-β (TGF-β), retinoic acid, transmembrane proteins, and enzymes involved in tryptophan catabolism [14-16].

Regulatory T cells, especially Foxp3⁺ regulatory T cells characterized by CD25 expression, play an essential role in oral tolerance. Foxp3 knockout mice developed multi-organ allergic inflammatory responses, whereas adoptive transfer of regulatory T cells could suppress anaphylaxis in a food allergy animal model [17,18]. Higher numbers of milk-specific CD4⁺CD25⁺ T regulatory cells were associated with the development of oral tolerance to cow’s milk [19,20]. Regulatory T cells can also produce several inhibitory cytokines, such as interleukin (IL)–10 and TGF-β. Interleukin (IL)-10 suppresses Th2 immune reactions and allergic inflammation by reducing IgE production and promoting allergen-specific IgG4 responses. Children who developed natural tolerance to hen’s eggs or peanuts had considerably increased IL-10 levels expressed by CD4⁺ T regulatory, CD25⁺ CD127^lo, and Foxp3⁺ cells [21,22].

Immunosuppressive regulatory B cells regulate the immune responses by suppressing effector T cells via the production of suppressor cytokines such as IL-10 and TGF-β [23]. Also, IL-10-secreting regulatory B cells produce IgG4, a non-inflammatory isotype that prevents IgE-mediated mast cell and basophil degranulation [24].

Numerous studies have shown that IgE-mediated allergies to cow’s milk, hen’s eggs, wheat, and soy are more likely to resolve in childhood, while allergies to peanuts, tree nuts, and seafood tend to persist [25-30]. However, the majority of studies on the natural course of food allergy were inherently limited by their design because population-based prospective studies using OFC at predetermined intervals are almost impossible to perform. Many past studies were retrospective analyses that included both OFC and medical history for assessing tolerance, whereas recent studies in Australia released longitudinal population-level challenge-based results of the natural course of food allergy in children [3,26,29]. The factors believed to affect the tolerance development or persistence of food allergy include symptom severity on ingestion, age at diagnosis, comorbid allergic diseases, and various immune-related markers that will be described later [31]. As the current status and results of studies related to the natural course of food allergy vary widely by the food in question, large-scale recent studies are mainly described in the text, while other various research results including Korean data for each major food allergy are listed in Tables 1 and 2 for the reference for each major food allergen.

Evidence of markers predicting the resolution or persistency of food allergy remains insufficient today. Factors associated with the timing of food allergy resolution include age at diagnosis, comorbid allergic diseases and their severity, symptom severity on ingestion, skin prick test (SPT) reaction size, foodspecific IgE levels, rate of change of food-specific IgE levels or SPT reaction sizes, ratio of specific IgE to IgG4, diet, gut microbiome, and interventions such as oral immunotherapy (Fig. 1). The degree of sensitization to the specific food by serum-specific IgE levels or SPT is among few tools that can be repeatedly performed in the actual clinical setting to monitor the natural course of food allergy. Diagnostic cutoff levels for predicting the persistency of food allergy have been suggested by numerous studies, but the results varied widely by age, region, and study design bearing considerable limits when applied in clinical practice [48-51].

The extensive research results related to specific IgE for predicting OFC outcomes at specific time points are not covered in detail in this article, as they refer more to the diagnosis of food allergy. This review mainly examined and summarized the findings related to predicting persistent food allergy in studies that prospectively or retrospectively followed the natural course of food allergy over time (Table 3). Studies showed that the persistence of food allergy was considerably associated with the baseline, peak (highest at all ages), and/or time point food-specific IgE levels. The resolution rates of cow’s milk allergy by 10 years was 87% with a peak cow’s milk-specific IgE <2 kU_A/L and 5% with a peak level of ≥50 kU_A/L [25].

Component-resolved data in some foods may provide additional information to enable a more precise diagnosis as well as for persistence predictions of food allergy. High levels of ovomucoid- and casein-specific IgE were associated with persistent hen’s egg and cow’s milk allergies, respectively, but specific cutoff levels for ovomucoid- or casein-specific IgE for predicting persistent food allergy have not been reported to date [35,52]. High IgE levels to gliadins were correlated with persistent wheat allergy and the development of asthma in children [53]. Other components such as Ara h 2 and Ara h 6 from peanut, Jug r 1 from walnut, Cor a 9 and Cor a 14 from hazelnut, and Ana o 3 from cashew nut have been studied for their useful value in diagnosing food allergy, but the role of these components with regard to the natural course of food allergy should be further investigated [54-57].

Diet and the gut microbiome also influence the persistence of food allergy by influencing mucosal immune tolerance [58]. It was recently suggested that regular consumption of the food in the form of reduced allergenicity, such as baked products containing egg and/or milk, or at an amount that does not induce symptoms, may improve the prognosis of food allergy [59]. Certain strains such as Bifidobacterium longum and Bacteroides fragilis can induce intestinal regulatory T cells, possibly by pattern-recognition receptor activation on dendritic cells [60]. Metabolites such as short-chain fatty acids produced by bacteria after the digestion of dietary fibers play an important role in enhancing the regulatory activity of dendritic cells, leading to the induction of regulatory T cells and IL-10-secreting T cells [61].

It is imperative for clinicians to aptly guide the timing of food allergy resolution assessments using appropriate parameters. As the course of food allergy can vary substantially depending on food type, patient age, and test results, clinicians would have to integrate all available information to evaluate the patient’s food allergy resolution status. By incorporating the results of various studies (Table 3), Santos et al. recently suggested an approach to assessing food allergy resolution: for cow’s milk and hen’s egg, a baseline specific IgE <2 kU_A/L, >50% decrease in specific IgE levels over >12 months, and specific IgE <3 kU_A/L (cow’s milk) or <2 kU_A/L (hen’s egg) at other time points were associated with likely resolution; for peanuts, a baseline specific IgE <2 kU_A/L and other time point-specific IgE <2 kU_A/L (if reaction) or <5 kU_A/L (if no reaction) were associated with likely resolution; and for tree nuts, a baseline specific IgE <2 kU_A/L was associated with likely resolution, whereas an SPT reaction size ≥13 mm and/or specific IgE ≥5 kU_A/L at other time points were associated with likely persistence [62]. When considering OFC for the assessment of food allergy resolution, clinicians should consider multifaceted factors such as patent age, the importance of the food in the diet, previous history of reactions, potential for risk, comorbidities especially severe atopic dermatitis, uncontrolled asthma, or eosinophilic gastrointestinal diseases, and patient and family preferences (Fig. 2).

The current leading treatment for modifying the natural course of food allergy is oral immunotherapy, an allergen-specific approach based on progressive incremental ingestion of the food allergen doses until a daily maintenance dosage is reached to achieve desensitization. Although oral immunotherapy still requires some attention, such as adverse events occurring not rarely during the treatment and achievement of continued tolerance, its implementation is gradually expanding worldwide and studies proving its efficacy are abounding [63-65]. Epicutaneous immunotherapy has been actively studied, particularly for peanut allergy, and has shown safe and modest treatment responses, especially in younger children [66]. In cases of severe or multiple food allergies, studies of allergen-specific immunotherapy combined with biologics such as omalizumab have been reported, enabling faster dose escalation and lower rates of adverse reactions during immunotherapy [67,68]. The purpose of allergenspecific immunotherapy in food allergy may be sufficient tolerance induction in some patients or the increase of the tolerated dose to improve quality of life in others, which will not be discussed in detail here. Other than immunotherapy, aspects that may affect the natural course of food allergy are diet, gutmicrobial modulation, skin barrier management, psychological state, and other environmental factors, which are outlined in Fig. 3.

To provide the optimal treatment to patients with food allergy and help improve their quality of life, it is essential that clinicians understand the natural course of individual food allergies. At this point, it remains unclear why some children outgrow their food allergy and others do not. Past studies of the natural course of food allergy are heterogeneous and bear limitations in terms of study design, but lately, population-based prospective data are becoming available. Based on the various factors associated with food allergy persistence, health care practitioners should offer relevant information to patients and their caregivers and conduct relevant assessments to evaluate food allergy resolution at appropriate timing. Using therapeutic tools including allergen-specific immunotherapy, gut-microbial modulation, and other potential therapeutics to be developed, we may be able to alter the course of food allergy in the future.