An Update on the Most Effective Methods for Preventing the Risk of Developing Food Allergies in Children: A Literature Review

Abstract

Food allergy is a major health concern, particularly among children, and is characterized by its rising predominance worldwide. Food allergies are known to reduce the quality of life of children and parents as they induce constant stress and anxiety. To combat this, there needs to be a deeper understanding of the most optimal methods of prevention available. Throughout several years, there have been many approaches introduced to target food allergies, some of which include late vs. early introduction, avoidance, immunotherapy, and breastfeeding. However, there has always been an ongoing debate about the methods which are the most effective in reducing the risk of developing food allergies in children. At present, early introduction shows the most promising results for reducing the risk of food allergy development. However, despite promising preliminary research, there needs to be more focus on long-term and diverse clinical trials to develop more personalized and effective interventions that improve patient outcomes and quality of life. This comprehensive review provides a detailed analysis and outline on various methods for reducing the risk of developing food allergies in children. It explores various prevention approaches such as avoidance, immunotherapy, early introduction, and breastfeeding.

Keywords: food allergies, children, prevention, breastfeeding, early introduction, immunotherapy, avoidance

Introduction & Background

A food allergy is defined as a hypersensitive immune response to food. Once exposed to a certain type of food, an individual may have an allergic reaction leading to symptoms varying from urticaria to anaphylaxis [1]. These allergic reactions most often occur on the skin, respiratory airways, and mucous membranes [2].

A food allergy develops when a person comes into contact with a protein in food called an allergen. Once this contact occurs, the immune system makes a type of antibody against the allergen called immunoglobulin E (IgE) antibodies [3]. These IgE antibodies will attach to two types of immune cells, mast cells and basophils, and will circulate throughout the body in the bloodstream. When the person comes into contact with the same allergen again, the IgE antibodies will bind to the allergen and cause an immune response [3, 4]. The immune response will lead to symptoms such as skin rashes, angioedema, diarrhea, runny or blocked nose, and wheezing or coughing [5].

These types of adverse reactions can have a significant impact on the quality of life of both the child and the parents. It can lead to the unnecessary restriction and elimination of important food, causing nutritional deficiencies for the child. The fear of experiencing an allergic reaction can also cause ongoing stress and anxiety [6].

The prevalence of allergies can vary depending on geography and age. For instance, western countries such as the United States, Australia, and parts of Europe have higher rates of food allergies. In these countries food allergies are estimated to affect 10% of the population, particularly among younger children [7]. Globally, food allergies are estimated to affect around 4% of children and 1% of adults, however, this figure rises to around 8% for children and 4% for adults in western countries [6, 7, 8, 9]. For example, Australia has the highest rate of food allergies worldwide, with the prevalence being more than 10% in children 12 months of age [7, 9]. In the United States, around 8% of children have food allergies, with around 40% of allergic children experiencing anaphylaxis from specific food allergens [10].

As the prevalence of food allergies in children continues to gradually rise, it is important to understand the most optimal prevention methods available. Avoidance continues to be the most traditional way to prevent allergies, however, it is known to negatively impact growth and development in children. Likewise, breastfeeding is the clinical gold standard for infant feeding and nutrition and can help with the prevention of food allergies. However, an on-going debate about the efficacy of this method has delayed the output of concrete recommendations. Immunotherapy can be divided into allergen-specific and allergen-nonspecific. This method continues to show upside potential as more clinical studies continue to be conducted. Lastly, early introduction of allergenic foods continues to be the most promising approach. Introducing foods to young children has shown positive results in reducing the risk of food allergies in children.

This review aims to provide an evidence-based update on the most effective methods for reducing the risk of developing allergies in children. By examining approaches such as dietary avoidance, early introduction, breastfeeding, and immunotherapy, the review will provide a deeper understanding of prevention options available to healthcare providers and parents. It will not only enhance scientific knowledge but be beneficial for parents seeking to decrease the risk of allergic reactions in their children.

Review

Avoidance

One of the most common and traditional ways to reduce the risk of food allergies is to avoid them. This involves identifying and steering away from known allergens and allergy-causing foods [3]. To identify allergens, the recommended strategies include a skin prick test, allergen-specific serum IgE, and oral food challenges [11].

Once identified, individuals with food allergies can implement many steps in their daily life to prevent the occurrence of an allergic reaction. Individuals can read nutritional labels thoroughly before purchasing any food and be aware of any possible cross-contamination during food preparation [12]. Parents and caregivers can also utilize practical avoidance strategies to navigate allergy management effectively. These strategies include using allergen-free recipes, minimizing food outside the house, using meal services which outline ingredients used in food preparation such as The Good Kitchen and HelloFresh, and apps such as Allergy Force which help navigate allergy management more easily [12].

Although avoidance is known to be the cornerstone for food allergy management, it is associated with a variety of other adverse effects such as nutrient deficiency and mental health problems [13, 14]. Due to food restriction and elimination, many children experience nutritional deficiency, impacting their growth and development [3, 14]. A study investigating the relationship between diet and growth in children found that children with two or more food allergies were shorter, based on height-for-age percentiles [15]. Additionally, Hobbs et al. conducted a retrospective chart review to investigate the impact of food allergies on growth in children. The study results showed that children with food allergies had significantly lower weight for length (WFL) and body mass index (BMI) ratios compared to healthy controls. The study also reported that compared to children with 1 or 2 food allergies, children with 2 or more food allergies had significantly lower mean weight (55.3% vs 69.2%) and height (62.2% vs 74.8%) percentiles [15].

Fear of allergic reactions also causes stress, anxiety, and depression in parents and children. A study conducted on 10-16-year-olds, showed that individuals with food allergies recorded more symptoms of anxiety and depression [16]. Another study conducted by Birdi et al. reported that parents of children with food allergies experienced more anxiety and depression [17].

There are many alternatives to common food allergens that can help allergic children obtain the necessary nutrients needed for optimal growth. For instance, alternatives for cow milk include coconut milk, almond milk, plant-based milk, and yogurt. There are also alternatives to eggs such as flax-seed, chia-seed eggs, and silken tofu. Alternatives for peanuts include sunflower seed butter, soynut butter, and coconut butter [18, 19]. Although these alternatives exist, there needs to be an increased focus on other prevention methods that provide a greater level of certainty for parents and their children.

Breastfeeding

Breastfeeding is another method that has been investigated in being able to reduce the risk of developing food allergies in children. Breast milk is known to be beneficial for a child as it provides constant exposure to the mother’s immune system. Through breastfeeding a child is able to receive nutrients for growth and development. The child also receives immunoglobulins, cytokines, and other immunomodulatory factors for immune protection and defense [20].

One way breastfeeding helps build a strong immune system is through the development of a healthy and selective gut microbiome [20]. Breast milk contains natural prebiotics called human milk oligosaccharides (HMOs). HMOs are sugar chains that exhibit anti-inflammatory properties, support the maturation of the gastrointestinal immune system, and interact with dendritic cells to modulate immune responses and enhance immune tolerance [20]. Most importantly, HMOs play a key role in influencing the composition of the infant gut microbiome. During breastfeeding, the infant’s gut microbiome feeds primarily off HMOs. Since HMOs are resistant to digestive enzymes they can reach the colon leading to selective advantage of beneficial bacterial species such as bifidobacterium, Bacteroides, and lactobacilli [20, 21]. The role of these bacterial species is to help develop the child’s immune system to tolerate different substances without causing an adverse reaction [22, 23].

The overall composition of the gut microbiome in breast-fed children is different from that of non-breast-fed children. A study conducted by Kourosh et al. reported that children with food allergies had a significantly different gut microbiome than control subjects [20]. This factor is predicted to help in reducing the risk of developing food allergies later in life. It is worth noting that implementing antibiotic therapy during pregnancy is associated with a decrease in the microbial diversity of bacteria in breast milk, impacting the immunity for the child [21].

During breastfeeding, the child is also exposed to small amounts of allergens present in breast milk. These allergens can act as a method of early introduction for the child. The allergens exposed to the child can vary depending on the mother’s diet [22]. Tracy et al. found that mothers who consumed peanuts while breastfeeding in combination with introducing peanuts to their children by 12 months led to 1.7% of children becoming sensitized to peanuts by the age of seven [23]. It is recommended that breastfeeding should be combined with early introduction of solid foods at four to six months of age for the most optimal results in protecting against food allergies [22].

Although breastfeeding is currently recommended as the primary prevention for allergic diseases, many studies have yielded mixed results. A review conducted by Odijk et al. reported that breastfeeding is associated with reducing the risk of cow milk allergy in high-risk infants [24]. Similarly, a study conducted by Verhasselt et al. found that breastfed children had a fourfold reduction in prevalence of IgE-mediated egg allergy [25]. In contrast, the most recent systematic review and meta-analysis conducted by Lodge et al. found no statistically significant association between breastfeeding alone and the development of food allergies [20, 26)]. Many researchers believe that the contradicting evidence in results is due to variations in human milk composition, genetic differences between children, and differences in methodological approaches [26]. For instance, some studies relied on parents reporting symptoms or diagnoses, which is not always accurate or reliable.

Due to conflicting results and the lack of evidence on whether breastfeeding can be used as an effective method in reducing the risk of food allergies in children, more research is needed to better understand the role of breastfeeding in allergy prevention.

Table 1. Summary of studies that have investigated the relationship between breastfeeding and the development of food allergies in children

Allergen-Specific Immunotherapy

Allergen immunotherapy (AIT) is a method designed to lessen the severity of food-induced allergic reactions. It works by gradually administering small, increasing amounts of allergens to an allergic individual [27, 28]. The ultimate goal of AIT is to desensitize the individual to the food allergens allowing them to consume a normal serving of the food. AIT includes three different routes of administration: oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) [28, 29].

Oral Immunotherapy (OIT)

OIT involves a mixture of the food allergen into a vehicle which is then consumed through an oral route by the allergic individual [30]. Dosages of the mixture will be gradually increased until the individual is able to tolerate the usual dose [28]. The entire procedure includes three different phases: the initial escalation phase, a dose build-up phase, and a maintenance phase [30].

A study conducted by Blumchen et al. reported a 60% success rate for passing an oral food challenge for 23 children on a 500 mg peanut protein dose for 9 weeks [31]. In 2011, the first multicenter, randomized, double-blind, placebo-controlled study conducted by Varshney et al. showed that 16 patients receiving OIT were able to tolerate a maximum dose of 5 g of peanut protein compared to the placebo group [32]. Additionally, in 2012, Staden et al. reported that of the 45 children treated with either egg or milk OIT, 9 were able to build a complete tolerance and 7 were able to build a partial tolerance [30]. However, OIT patients experience more adverse reactions compared to SLIT and EPIT due to more dosage use [28, 33]. These reactions are mostly mild, such as itching of the oropharynx, rash, and mild abdominal pain, with around 2.7% of patients developing eosinophilic esophagitis [33, 34].

Sublingual Immunotherapy (SLIT)

SLIT involves the use of food allergen extracts that are placed under the tongue. Generally, the dosage of SLIT is lower than OIT and the rate of desensitization is also reduced compared to OIT [28]. The efficacy of SLIT was first seen in a multicenter, randomized, double-blind, placebo-controlled study conducted by Fleischer et al. The results of this study showed that of the 40 peanut-allergic participants, 70% of them were able to achieve a 10-fold or more increase in the reaction-triggering threshold [29]. Another double-blind placebo-controlled study conducted by Kim et al showed successful results of SLIT for peanut allergies in children. In this study, 18 children between ages 1 to 11 with confirmed peanut allergy were evaluated. The results showed that after 12 months of SLIT, the treatment group safely ingested 20 times more peanut protein than the placebo group, exhibiting increased tolerance by treated participants [35]. Patients after SLIT also experience mild reactions, mainly itching of the oropharynx (7-40% of patients) [33].

Epicutaneous Immunotherapy (EPIT)

EPIT involves an allergic individual receiving an allergen-containing patch that is applied to the skin. Through this patch, the food allergen is absorbed by dendritic cells [28]. EPIT has shown promising results in a recent phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted by Greenhawt et al. The trial results showed that using EPIT for 12 months was helpful in desensitizing children 1 to 3 years of age from peanut allergies compared to placebo [36]. However, patients in the intervention group experienced adverse effects such as erythema (98.0% of patients), pruritus (94.7%), and site swelling (72.5%) [36]. Furthermore, an exploratory clinical pilot study examined the safety and efficacy of milk protein-containing patches in children with severe milk allergies. Results showed that amongst the 8 children that enrolled, 4 showed improvement in their ability to handle milk proteins after using the patch for 8-48 weeks [37]. Adverse events for EPIT patients are least common compared to OIT and SLIT, with mild reactions such as site swelling observed on patch sites in more than 90% of patients, and non-patch site reactions observed in <20% of patients [33]. Although there is substantial evidence for the effectiveness of EPIT on peanut allergies, larger studies need to be conducted for its efficacy on other food allergies.

Overall, AIT continues to show promising efficacy in reducing the risk of developing allergies. Researchers are optimistic about this method of prevention and are hoping to formulate other combination therapies with AIT [37]. However, more studies are needed to fully understand why certain adverse reactions are occurring during these treatments. This is important as minimizing these adverse reactions can further improve treatment outcome and patient quality of life.

Table 2. Summary of studies which have investigated the association between the three AIT methods: OIT, SLIT, and EPIT, and the development of food allergies

Allergen Nonspecific Immunotherapy

For individuals with multiple food allergies, allergen nonspecific immunotherapy may be a better option. This type of immunotherapy targets multiple parts of the immune system such as cytokines, toll-like receptors, IgE antibodies, probiotics, and genes [28]. 

Anti-Cytokine Therapy 

Anti-cytokine therapy has gained traction due to evidence showing that cytokine signaling is associated with inflammatory responses. It is suggested that food allergies can be prevented by blocking this cytokine signaling through blocking agents [28]. This type of therapy has shown promising preliminary results in mouse models. For instance, a study using a mouse model found that administering Lactococcus Lactis transfected to release interleukin (IL)-10, helped protect against food-induced anaphylaxis [28, 38]. A phase two placebo-controlled clinical trial with a small population of adults has also shown efficacy in protecting against peanut allergy. This clinical trial used a newly produced anti-IL-33 antibody as a blocking agent [26, 39]. It is important to note that this type of therapy has not been tested for reducing the risk of food allergies in children.

Toll-Like Receptors (TLRs)

Toll-like receptors (TLR) are a class of receptors that are present in immune cells such as dendritic cells and macrophages [28]. In humans, there are ten functional TLRs (TLR1-10). Investigators have shown increased interest in targeting these receptors to produce a strong Th1, nonallergic, response [40]. TLRs can be stimulated in two different ways: through microbial particles such as lipopolysaccharides and specific TLR agonists [28, 40]. An agonist that has been investigated in a murine model is the TLR9 agonist, an immune modulatory oligonucleotide (IMO) [28, 41]. The results from this model showed that IMOs are able to alter peanut-induced Th2 allergic immune responses to Th1 nonallergic immune responses. This led to a reduction in inflammation and anaphylaxis [41]. It is also important to note that this method has not been tested in humans.

Anti-IgE Therapy

Anti-IgE therapy is another form of allergen nonspecific immunotherapy. This type of therapy targets IgE antibodies to prevent allergic reactions and primarily applies the use of the medication Omalizumab (Xolair) [28]. Omalizumab is an anti-IgE humanized monoclonal antibody that binds to IgE and prevents it from releasing pro-inflammatory mediators [42, 43]. An open-label study conducted by Savage et al reported that after 6 months of treatment, the median cumulative eliciting dose of peanut protein significantly increased from 80 mg to 6500 mg for 14 participants allergic to peanuts [42, 44]. Additionally, a recent single-center, single-arm, real-life, retrospective observational study reported that in 15 pediatric patients, after 4 months of Omalizumab treatment, all patients had an increase in the threshold for all foods tested [42, 45]. 

Investigators also wanted to test the efficacy of Omalizumab in combination with OIT. To investigate this, a double-blind, placebo-controlled trial involving 57 subjects from age 7 to 32 years with cow milk allergy was conducted. The participants were given Omalizumab for 4 months along with the continued treatment of OIT to achieve a maintenance dose. The results showed that the group treated with Omalizumab showed fewer adverse reactions requiring epinephrine compared to the placebo group [28, 46]. The results from this trial were confirmed in a case series involving 14 children with egg and cow milk allergies. This investigation showed the children were able to tolerate OIT treatment more effectively when treated with Omalizumab as a pretreatment for OIT [28, 46]. 

Probiotics 

Probiotics in the treatment of food allergies are based on introducing health-promoting microorganisms into the gastrointestinal tract. Since gut microbiome composition and function are known to be one of the factors that control immune tolerance, targeting it through the use of probiotics has caught the attention of many investigators [47]. This approach may be more effective in addressing the altered gut microbiota in allergic children. These children often show reduced levels of beneficial gut bacteria including but not limited to Bifidobacterium, Faecalibacterium, Akkermansia, and Lachnospira, with higher levels of harmful bacteria such as Staphylococcus aureus and Enterobacteriaceae [48]. 

In recent years, there has been increasing amounts of evidence that shows the benefits of using probiotics to combat food allergies. A clinical trial of probiotic supplementation with Lactobacillus GG (LGG), combined with hydrolyzed casein formula in milk-allergic children, showed an increased rate of milk tolerance after 1, 6, and 12 months, compared to the control group [28, 49]. Zhang et al in a meta-analysis also reported that administering a combination of prenatal and postnatal probiotics helped reduce the risk of food sensitization [50]. Tang et al. conducted a double-blind, randomized, placebo-controlled trial involving 62 children with peanut allergies. The children were given either a placebo or Lactobacillus rhamnosus probiotic (2×10^10 CFU) with peanut OIT daily for 6 months. Results showed that 89.7% of children in the treatment group were desensitized to peanut allergies compared to 7.1% of children from the placebo group [50, 51]. It is important to note that the optimal strains, dosages, timing, and duration of probiotic administration remain unknown [50].

Although the use of probiotics has shown promising results, medical experts from organizations such as the American Academy of Pediatrics, the European Academy of Allergy and Clinical Immunology, and the World Allergy Organization (WAO) do not recommend probiotics as a primary prevention method for allergies, but it is favored for pregnant/lactating women and infants with a family history of allergies and allergic diseases [50]. The hesitancy is due to an association of probiotic supplementation with adverse reactions such as heart aches and problems with brain function. There have also been reports of serious infections related to probiotic supplementation in immunocompromised individuals [50]. The lack of evidence supporting a specific probiotic strain also adds to the hesitancy as administration guidelines remain unclear. Thus, more research needs to be conducted to understand the best probiotic strains, dosage, timing, and duration for allergy prevention [50].

Gene Therapy

Gene therapy to reduce the risk of food allergies involves using adeno-associated virus (AAV) vectors. It is postulated that AAV is able to prevent allergic reactions through the consistent release of anti-human IgE.  Researchers have tested this idea on a humanized mouse model of peanut allergy and found that AAV effectively prevented food-induced anaphylaxis through sustained and continuous release of anti-human IgE [28, 52]. 

Table 3. Summary of studies which have investigated the effectiveness of allergen-nonspecific immunotherapy in reducing the risk of developing food allergies

Early Introduction

Early introduction refers to the practice of introducing allergenic foods into an infant’s diet at a young age. Once these foods are introduced to a child, it helps the immune system recognize these substances as harmless, thereby reducing the risk in the development of allergies [53]. It is recommended that early introduction should be implemented to infants ages 4 to 6 months for the most optimal results in preventing the development of food allergies [54]. Infants can be introduced to many allergenic foods such as peanuts, eggs, milk, soy, tree nuts, and fish/shellfish [55]. Many health organizations have now started to shift their focus from strict avoidance of food allergens to early introduction as evidence has shown it to be effective in reducing the risk of developing food allergies, especially in high-risk children.

Evidence for the Early Introduction of Peanuts

Two studies that showed groundbreaking results in early introduction are the Learning Early About Peanut Allergy (LEAP) study and the Enquiring About Tolerance (EAT) study. The LEAP study investigated whether introducing peanut-containing foods to infants at high risk for peanut allergy could prevent the development of the allergy. The results showed that early introduction of peanuts significantly reduced the prevalence of peanut allergies by 81% among high-risk infants aged 4 to 11 months [56, 57]. The EAT study investigated the impact of introducing multiple allergenic foods (peanut, egg, cow’s milk, sesame, and wheat) to infants 3 months of age alongside breastfeeding. The results showed that early introduction showed a significant reduction in the prevalence of food allergies compared to the standard introduction group [55, 57, 58].

Evidence for the Early Introduction of Eggs

The Solids Timing for Allergy Reduction (STAR) trial also presented results in support towards the benefits of early introduction. This trial was a double-blind, randomized controlled trial where infants were introduced to 1 teaspoon of raw, pasteurized egg powder or rice powder daily from 4 to 8 months of age. The results showed that infants who were introduced to the food had a reduced risk of developing egg allergy [55, 59]. Another study which investigated the early introduction of eggs was the Prevention of Egg Allergy with Tiny Amount Intake (PETIT) study. The results from this study showed that of the 47 participants who received heated egg powder, only 4 of them developed an egg allergy compared to 18 in the placebo group [55, 60].

Evidence for the Early Introduction of Cow Milk

Studies that investigated the early introduction of cow milk to infants include the Strategy for Prevention of Milk Allergy by Daily Ingestion of Infant Formula in Early Infancy (SPADE) study and the Preventing Atopic Dermatitis and ALLergies (PreventADALL) study. The SPADE study found that infants who were randomized to cow milk at 1 to 2 months of age had a significantly lower rate of cow milk allergy [55, 61]. Similarly, the PreventADALL study reported that early introduction of cow milk to infants resulted in an overall reduced prevalence of food allergy [55, 62].

Early introduction continues to be one of the most promising methods available in reducing the risk of developing allergies in children. The substantial evidence available helps show the effectiveness of this method. It is important to note that there are gaps and limitations such as the unclarity of including infants from diverse demographic and ethnic backgrounds and targeting only high-risk infants limits the applicability of the finding on the general population of infants. However, the evidence recommends that early introduction of peanuts, cooked eggs, and other allergenic foods should not be delayed [55].

Table 4. Summary of studies which have investigated the effectiveness of early introduction in reducing the risk of developing food allergies in children

Conclusion

To conclude, as the prevalence of food allergies continues to gradually rise, it is of utmost importance to analyze the different prevention methods available. This review has provided an in-depth analysis on prevention methods such as avoidance, breastfeeding, immunotherapy, and early introduction.

Based on current evidence, early introduction of allergenic foods continues to be the most effective method in reducing the risk of developing allergies in children. Research has shown that introducing allergenic foods to children between 4 to 6 months of age is the most optimal time period to prevent the risk of developing food allergies. For best results, parents should progressively introduce solid allergenic food within 4 to 6 months of life. Additionally, parents should introduce food in a smooth consistency based on the infant’s ability to chew. For high-risk infants or infants with severe food allergies, medical counseling is needed before early food introduction to reduce the risk of reaction upon ingestion [53].

Avoidance also remains at the center of food allergy management, however, due to the negative impact on overall health researchers are now moving away from this method. Implementing allergen-specific and allergen-nonspecific immunotherapy can also be an effective strategy for preventing food allergies, however, there still needs to be more robust evidence on these methods. Lastly, although breastfeeding is known to provide numerous benefits for infants, due to the lack of statistically significant evidence of the relationship between breastfeeding and food allergies, it cannot be recommended with confidence. However, combining breastfeeding with the early introduction of food allergens by including some of the food allergens in the mother’s diet during breastfeeding may provide benefits.

Further investigation on this topic needs to be conducted. The focus should be on exploring the impact of these prevention methods on children. There is also a need for studies involving more diverse populations to ensure the prevention method is effective across different ethnic, geographic, and socioeconomic groups. More long-term studies are also required to assess the impact of these prevention methods over time. Future research needs to explore effective implementation strategies for these prevention methods in a real-world setting, such as examining potential barriers for parents and healthcare providers to adopt these strategies. Lastly, more comprehensive guidelines need to be integrated with the available evidence on these prevention methods. Guidelines should be tailored to individual risk factors and family preferences.

References

1. Barni S, Liccioli G, Sarti L, Giovannini M, Novembre E, Mori F. Immunoglobulin E (IgE)-Mediated Food Allergy in Children: Epidemiology, Pathogenesis, Diagnosis, Prevention, and Management. Medicina. 2020;56(3):111. doi:https://doi.org/10.3390/medicina56030111
2. Institute for Quality and Efficiency in Health Care. Allergies: Overview. Nih.gov. Published July 13, 2017. https://www.ncbi.nlm.nih.gov/books/NBK447112/
3. Calvani M, Anania C, Caffarelli C, et al. Food allergy: an updated review on pathogenesis, diagnosis, prevention and management. Acta Bio Medica : Atenei Parmensis. 2020;91(Suppl 11):e2020012. doi:https://doi.org/10.23750/abm.v91i11-S.10316
4. Anvari S, Miller J, Yeh CY, Davis CM. IgE-Mediated Food Allergy. Clinical Reviews in Allergy & Immunology. 2018;57(2):244-260. doi:https://doi.org/10.1007/s12016-018-8710-3
5. Seth D, Poowutikul P, Pansare M, Kamat D. Food Allergy: A Review. Pediatric Annals. 2020;49(1):e50-e58. doi:https://doi.org/10.3928/19382359-20191206-01
6. Elghoudi A, Narchi H. Food allergy in children—the current status and the way forward. World Journal of Clinical Pediatrics. 2022;11(3):253-269. doi:https://doi.org/10.5409/wjcp.v11.i3.253
7. Loh W, Tang M. The Epidemiology of Food Allergy in the Global Context. International Journal of Environmental Research and Public Health. 2018;15(9):2043. doi:https://doi.org/10.3390/ijerph15092043
8. Warren CM, Jiang J, Gupta RS. Epidemiology and Burden of Food Allergy. Current Allergy and Asthma Reports. 2020;20(2). doi:https://doi.org/10.1007/s11882-020-0898-7
9. Osborne NJ, Koplin JJ, Martin PE, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. Journal of Allergy and Clinical Immunology. 2011;127(3):668-676.e2. doi:https://doi.org/10.1016/j.jaci.2011.01.039
10. Gupta RS, Warren CM, Smith BM, et al. The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States. Pediatrics. 2018;142(6). doi:https://doi.org/10.1542/peds.2018-1235
11. Oriel RC, Wang J. Diagnosis and Management of Food Allergy. Immunology and Allergy Clinics of North America. 2021;41(4):571-585. doi:https://doi.org/10.1016/j.iac.2021.07.012
12. Schauberger EM, Singh AM. Food allergy management. Journal of Food Allergy. 2020;2(1):59-63. doi:https://doi.org/10.2500/jfa.2020.2.200021
13. Leone L, Mazzocchi A, Maffeis L, De Cosmi V, Agostoni C. Nutritional management of food allergies: Prevention and treatment. Frontiers in Allergy. 2023;3. doi:https://doi.org/10.3389/falgy.2022.1083669
14. Feng C, Kim JH. Beyond Avoidance: the Psychosocial Impact of Food Allergies. Clinical Reviews in Allergy & Immunology. 2018;57(1):74-82. doi:https://doi.org/10.1007/s12016-018-8708-x
15. Hobbs CB, Skinner AC, Burks AW, Vickery BP. Food Allergies Affect Growth in Children. The journal of allergy and clinical immunology In practice. 2015;3(1):133-134.e1. doi:https://doi.org/10.1016/j.jaip.2014.11.004
16. Shanahan L, Zucker N, Copeland WE, Costello EJ, Angold A. Are children and adolescents with food allergies at increased risk for psychopathology? Journal of Psychosomatic Research. 2014;77(6):468-473. doi:https://doi.org/10.1016/j.jpsychores.2014.10.005
17. Birdi G, Cooke R, Knibb R. Quality of Life, Stress, and Mental Health in Parents of Children with Parentally Diagnosed Food Allergy Compared to Medically Diagnosed and Healthy Controls. Journal of Allergy. 2016;2016:1-7. doi:https://doi.org/10.1155/2016/1497375
18. Ooi cAmi, cToshiya Iiba, Takano cKosuke. Ingredient substitute recommendation for allergy-safe cooking based on food context. IEEE xplore. Published online August 1, 2015. doi:https://doi.org/10.1109/pacrim.2015.7334878
19. Carla Da Silva. Food Substitutes for Common Allergies. Food Allergy Canada. Published July 16, 2014. Accessed August 12, 2024. https://foodallergycanada.ca/food-substitutes-for-common-allergies/
20. Järvinen KM, Martin H, Oyoshi MK. Immunomodulatory effects of breast milk on food allergy. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2019;123(2):133-143. doi:https://doi.org/10.1016/j.anai.2019.04.022
21. Cukrowska B, Bierła JB, Zakrzewska M, Klukowski M, Maciorkowska E. The Relationship between the Infant Gut Microbiota and Allergy. The Role of Bifidobacterium breve and Prebiotic Oligosaccharides in the Activation of Anti-Allergic Mechanisms in Early Life. Nutrients. 2020;12(4). doi:https://doi.org/10.3390/nu12040946
22. Zoi Koukou, Eleftheria Papadopoulou, Eleftherios Panteris, et al. The Effect of Breastfeeding on Food Allergies in Newborns and Infants. Children (Basel). 2023;10(6):1046-1046. doi:https://doi.org/10.3390/children10061046
23. Pitt TJ, Becker AB, Chan-Yeung M, et al. Reduced risk of peanut sensitization following exposure through breast-feeding and early peanut introduction. Journal of Allergy and Clinical Immunology. 2018;141(2):620-625.e1. doi:https://doi.org/10.1016/j.jaci.2017.06.024
24. Odijk J, Kull I, Borres MP, et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966-2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy. 2003;58(9):833-843. doi:https://doi.org/10.1034/j.1398-9995.2003.00264.x
25. Verhasselt V, Genuneit J, Metcalfe JR, et al. Ovalbumin in breastmilk is associated with a decreased risk of IgE-mediated egg allergy in children. Allergy. 2020;75(6):1463-1466. doi:10.1111/all.14142
26. Nuzzi G, Di Cicco ME, Peroni DG. Breastfeeding and Allergic Diseases: What’s New? Children. 2021;8(5):330. doi:https://doi.org/10.3390/children8050330
27. Nurmatov U, Dhami S, Arasi S, et al. Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis. Allergy. 2017;72(8):1133-1147. doi:https://doi.org/10.1111/all.13124
28. Licari A, Manti S, Marseglia A, et al. Food Allergies: Current and Future Treatments. Medicina. 2019;55(5):120. doi:https://doi.org/10.3390/medicina55050120
29. Nicolaides RE, Parrish CP, Bird JA. Food Allergy Immunotherapy with Adjuvants. Immunology and Allergy Clinics of North America. 2020;40(1):149-173. doi:https://doi.org/10.1016/j.iac.2019.09.004
30. Wood R. Oral Immunotherapy for Food Allergy. Journal of Investigational Allergology and Clinical Immunology. 2017;27(3):151-159. doi:https://doi.org/10.18176/jiaci.0143
31. Blumchen K, Ulbricht H, Staden U, et al. Oral peanut immunotherapy in children with peanut anaphylaxis. The Journal of Allergy and Clinical Immunology. 2010;126(1):83-91.e1. doi:https://doi.org/10.1016/j.jaci.2010.04.030
32. Varshney P, Jones SM, Scurlock AM, et al. A randomized controlled study of peanut oral immunotherapy: Clinical desensitization and modulation of the allergic response. Journal of Allergy and Clinical Immunology. 2011;127(3):654-660. doi:https://doi.org/10.1016/j.jaci.2010.12.1111
33. Pajno GB, Fernandez-Rivas M, Arasi S, et al. EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy. Allergy. 2017;73(4):799-815. doi:https://doi.org/10.1111/all.13319
34. Muraro A, Tropeano A, Giovannini M. Allergen immunotherapy for food allergy: Evidence and outlook. Allergologie select. 2022;6(01):285-292. doi:https://doi.org/10.5414/alx02319e
35. Kim EH, Bird JA, Kulis M, et al. Sublingual immunotherapy for peanut allergy: Clinical and immunologic evidence of desensitization. Journal of Allergy and Clinical Immunology. 2011;127(3):640-646.e1. doi:https://doi.org/10.1016/j.jaci.2010.12.1083
36. Greenhawt M, Sindher SB, Wang J, et al. Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy. The New England Journal of Medicine. 2023;388(19):1755-1766. doi:https://doi.org/10.1056/nejmoa2212895
37. Pierre-Louis Hervé, Dioszeghy V, Matthews K, Bee KJ, Campbell DE, Sampson HA. Recent advances in epicutaneous immunotherapy and potential applications in food allergy. Frontiers in allergy. 2023;4. doi:https://doi.org/10.3389/falgy.2023.1290003
38. Frossard CP, Steidler L, Eigenmann PA. Oral administration of an IL-10-secreting Lactococcus lactis strain prevents food-induced IgE sensitization. J Allergy Clin Immunol. 2007;119(4):952-959. doi:10.1016/j.jaci.2006.12.615
39. Chinthrajah S, Cao S, Liu C, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight. 2019;4(22):e131347. Published 2019 Nov 14. doi:10.1172/jci.insight.131347
40. Jorge Losada Méndez, Palomares F, Gómez F, et al. Immunomodulatory Response of Toll-like Receptor Ligand–Peptide Conjugates in Food Allergy. ACS Chemical Biology. 2021;16(11):2651-2664. doi:https://doi.org/10.1021/acschembio.1c00765
41. Zhu FG, Kandimalla ER, Yu D, Agrawal S. Oral administration of a synthetic agonist of Toll-like receptor 9 potently modulates peanut-induced allergy in mice. Journal of Allergy and Clinical Immunology. 2007;120(3):631-637. doi:https://doi.org/10.1016/j.jaci.2007.05.015
42. Arasi S, Maurizio Mennini, Cafarotti A, Fiocchi A. Omalizumab as monotherapy for food allergy. Current Opinion in Allergy and Clinical Immunology. 2021;21(3):286-291. doi:https://doi.org/10.1097/aci.0000000000000744
43. Kumar C, Zito PM. Omalizumab. PubMed. Published 2021. https://www.ncbi.nlm.nih.gov/books/NBK545183/
44. Savage JH, Courneya JP, Sterba PM, Macglashan DW, Saini SS, Wood RA. Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy. J Allergy Clin Immunol. 2012;130(5):1123-1129.e2. doi:10.1016/j.jaci.2012.05.039
45. Fiocchi A, Artesani MC, Riccardi C, et al. Impact of Omalizumab on Food Allergy in Patients Treated for Asthma: A Real-Life Study. J Allergy Clin Immunol Pract. 2019;7(6):1901-1909.e5. doi:10.1016/j.jaip.2019.01.023
46. Wood RA, Kim JS, Lindblad R, et al. A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow’s milk allergy. J Allergy Clin Immunol. 2016;137(4):1103-1110.e11. doi:10.1016/j.jaci.2015.10.005
47. Carucci L, Coppola S, Rosilenia Carandente, Roberto Berni Canani. Targeting Food Allergy with Probiotics. Advances in experimental medicine and biology. Published online January 1, 2024:79-93. doi:https://doi.org/10.1007/978-3-031-58572-2_5
48. Lopez-Santamarina A, Gonzalez EG, Lamas A, Mondragon A del C, Regal P, Miranda JM. Probiotics as a Possible Strategy for the Prevention and Treatment of Allergies. A Narrative Review. Foods. 2021;10(4):701. doi:https://doi.org/10.3390/foods10040701
49. Ribeiro JF, Pedrosa C. Probiotics, prebiotics and food allergy. European annals of allergy and clinical immunology. 2023;(online first). doi:https://doi.org/10.23822/eurannaci.1764-1489.319
50. Wang HT, Anvari S, Anagnostou K. The Role of Probiotics in Preventing Allergic Disease. Children. 2019;6(2). doi:https://doi.org/10.3390/children6020024
51. Tang MLK, Ponsonby AL, Orsini F, et al. Administration of a probiotic with peanut oral immunotherapy: A randomized trial. Journal of Allergy and Clinical Immunology. 2015;135(3):737-744.e8. doi:https://doi.org/10.1016/j.jaci.2014.11.034
52. Pagovich OE, Wang B, Chiuchiolo MJ, et al. Anti-hIgE gene therapy of peanut-induced anaphylaxis in a humanized murine model of peanut allergy. Journal of Allergy and Clinical Immunology. 2016;138(6):1652-1662.e7. doi:https://doi.org/10.1016/j.jaci.2016.03.053
53. Comberiati P, Costagliola G, D’Elios S, Peroni D. Prevention of Food Allergy: The Significance of Early Introduction. Medicina. 2019;55(7):323. doi:https://doi.org/10.3390/medicina55070323
54. Trogen B, Jacobs S, Nowak-Wegrzyn A. Early Introduction of Allergenic Foods and the Prevention of Food Allergy. Nutrients. 2022;14(13):2565. doi:https://doi.org/10.3390/nu14132565
55. Venter C, Smith PK, Fleischer DM. Food allergy prevention: Where are we in 2023? Asia Pacific Allergy. 2023;13(1):15-27. doi:https://doi.org/10.5415/apallergy.0000000000000001
56. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. The New England journal of medicine. 2015;372(9):803-813. doi:https://doi.org/10.1056/NEJMoa1414850
57. Kakieu Djossi S, Khedr A, Neupane B, Proskuriakova E, Jada K, Mostafa JA. Food Allergy Prevention: Early Versus Late Introduction of Food Allergens in Children. Cureus. Published online January 9, 2022. doi:https://doi.org/10.7759/cureus.21046
58. Perkin MR, Logan K, Tseng A, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. N Engl J Med. 2016;374(18):1733-1743. doi:10.1056/NEJMoa1514210
59. Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: A randomized controlled trial. Journal of Allergy and Clinical Immunology. 2013;132(2):387-392.e1. doi:https://doi.org/10.1016/j.jaci.2013.05.002
60. Natsume O, Kabashima S, Nakazato J, et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. The Lancet. 2017;389(10066):276-286. doi:https://doi.org/10.1016/s0140-6736(16)31418-0
61. Sakihara T, Otsuji K, Arakaki Y, Hamada K, Sugiura S, Ito K. Randomized trial of early infant formula introduction to prevent cow’s milk allergy. Journal of Allergy and Clinical Immunology. Published online September 2020. doi:https://doi.org/10.1016/j.jaci.2020.08.021
62. Skjerven HO, Lie A, Vettukattil R, et al. Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial. The Lancet. 2022;399(10344):2398-2411. doi:https://doi.org/10.1016/s0140-6736(22)00687-0