Is AIT The Future of Treating Food Allergies in Children?

Milk, eggs, fish, shellfish, wheat, soy, peanuts, and tree nuts – an unconventional grocery list or one of the main triggers of a child’s food allergy?

Food allergies in children remains a growing public health issue. They are thought to affect about 8% of children in the US with around 42% of them exhibiting severe allergic symptoms.¹ Food allergies are estimated to be responsible for approximately 30,000 emergency department visits in the USA per year. ² The heterogenous clinical presentation of food allergies in children can range from mild urticaria to life threatening anaphylaxis.³ In order to determine the presence of a food allergy, the World Allergy Organization identifies skin testing as the first line diagnostic tool, while the European Academy of Allergy and Clinical Immunology (EAACI) guidelines identify serum IgE and oral food challenges as further methods for IgE food allergy diagnosis.^4,5

Once a food allergy has been identified, there are few methods of management.  Currently on an individual level, managing food allergens in children remains rather unsophisticated. It typically involves meticulous and careful avoidance of the allergen and possession of emergency medicine such an epinephrine autoinjector. On a community level, approaches to help combat and support allergy management include guidelines followed by schools and restaurants, as well as cooperation with parents. While these measures are indispensable to foster a safe, environment for children with food allergies, they continue to leave much room for error. For example, in a prospective Canadian cohort study of 1941 children with peanut allergies, 567 accidental exposures to peanut allergens occurred in 429 children over 4589 patient-years, yielding an annual incidence rate of 12.4%.⁶ As these accidental exposures can range in their allergic response, those with severe life-threatening reactions are forced to rely on emergency medication in possession. This becomes challenging if those around the child do not know how to administer the epinephrine autoinjector. Moreover, a retrospective study for food triggered allergic reactions presenting to a pediatric emergency department concluded that epinephrine autoinjectors are frequently not available during accidental reactions.⁷ While this underscores the importance for both increased patient and community knowledge on how to respond in these situations, it also places emphasis on the role of human error in these treatment methods.  While it is possible that these treatment methods for children will become obsolete with the development of spontaneous tolerance over time, food allergies due peanuts, tree nuts and fish tend to persist.⁸

Allergen immunotherapy (AIT) provides hope for children with food allergies. The aim of AIT therapy is to achieve a mild or unchanged allergic reaction when the dose of allergen increased.⁹ Studies assessing the effectiveness of AIT therefore usually directly assess clinical desensitization or immunological tolerance in the context of clinical outcomes, such as the severity of the allergic symptoms, as well as in terms of immunological parameters such as skin prick testing and serum levels of immunological biomarkers. The mechanism of AIT relies on an early mast cell and basophil induction for degranulation, T_reg cells and peripheral T-cell tolerance to antigens and suppression of effector cells and inflammatory responses during allergen AIT.¹⁰ Therefore, assessing immunological biomarkers before and after the AIT protocol can provide additional insight into the immunological changes occurring. Despite this, while some immunological parameters such as serum IgE and IgG levels would perhaps be expected to decrease, they often do not show direct correlation to clinical improvement.¹⁰ For this reason, they are usually only assessed in conjunction with clinical outcomes. While AIT is common in pollen and insect venom allergies, it has yet to become common practice in the treatment of food allergies.¹¹ The Food and Drug Administration has approved Palforzia, an oral immunotherapy (OIT) designed to help reduce the risk of severe allergic reactions in children with peanut allergy.¹² It can be initiated in children aged 4-17 with a confirmed diagnosis of peanut allergies and consists of three distinct phases that lead up to a daily maintenance dose.¹² In order to assess effectiveness, a randomized double-blind placebo controlled study showed that 67.2% of Palforzia recipients tolerated a 600 mg dose of peanut protein, compared to 4.0% of placebo recipients.¹² Palforzia approval has paved the way for further innovations and research within AIT for food allergies. In fact, a systematic review undertaken by the EAACI assessing 1259 patients further confirmed that AIT can be effective in improving reactivity in children with food allergies.¹¹ On the other hand, other studies still assert more research on the ability to induce immunological tolerance, as well as the risks of adverse reactions are needed for it to be recommended in clinical practice. ^13,14 

Therefore, while AIT shows great potential, some flaws need to be addressed. Research in AIT can be difficult to conduct safely, ethically and logistically, due to the risk of adverse events resulting from the treatment, long treatment periods and variability in allergen immunotherapy protocols. ¹⁴ For example, Grzeskowiak et. al calculated that among 27 controlled and non-controlled studies, adverse events led to treatment failure in 1 in 15 subjects.¹⁵ AIT is associated with both an increased risk of systematic adverse reactions like anaphylaxis and local adverse reactions like urticaria.¹¹ While studies continue to support effectiveness of allergen immunotherapy in achieving clinical desensitization in food allergenic children, study protocol related factors should be continuously reevaluated to improve safety. Some studies even suggest that co-administration with oral histamines or probiotics are associated with improved treatment outcomes. ¹⁵ Addressing such concerns will be crucial to its future implementation. AIT seemed to be cost effective in the context of allergic rhinitis using the National Institute for Health and Care Excellence cost-effectiveness threshold of £20,000 per quality-adjusted life-year. ¹⁶ While this is promising, different health economic analyses assessing AIT in food allergies were unable to produce sufficient conclusion on the cost effectiveness, as there were no eligible studies assessing the cost effectiveness in that context.^11,16 The deficit in knowledge of certain aspects of AIT, such as the cost effectiveness, makes it difficult for it to become more commonplace.

In response to these challenges, new solutions to make AIT research and clinical trials safer have been identified.¹⁷ For example, a review assessing AIT in the context of precision medicine suggested using biomarkers associated with systems and network medicine, as well as a clinical decision support system for data.¹⁸ Moreover, in most AIT studies, adverse effects that required epinephrine autoinjectors became extremely infrequent once subjects reached the long term phase.¹⁸ With this in mind, protocol related factors such as the elimination of a rush phase, aiming for lower target maintenance dose and the usage of co-treatments such as omalizumab were determined to be factors that could improve the safety and efficacy of OIT trials. ^18,19 Another important parameter to safely assess the functionality of the immunotherapy is defining an eliciting dose. An eliciting dose is the lowest amount of food that exhibits allergic symptoms, which can be often difficult to determine in infants and toddlers.²⁰  With the implementation of these improvements, it is likely that AIT research can be conducted in a safer, most efficient manner.