By Karishma Sira, Biological Sciences ‘21

Author’s Note: This review was originally written for my UWP104F class in Winter Quarter 2021. While environmental allergies are well known to the public, many people are unaware of the social, mental, financial, and most importantly, physical costs of food allergies. I highly benefited from getting treated for food allergies through immunotherapy, so I want to make these methods more known. I want to raise awareness on the available non-avoidant treatments catered to food allergy sufferers and inform readers that these methods are important developments happening in the world of food allergy immunotherapy. This article will also explain the basic mechanisms of immunotherapy, the differences between each delivery method, the relative effectiveness of these methods, and the risks and benefits of each method. These factors should all be considered when recommending a specific method to an allergic individual.  

Food allergies are becoming an increasingly common global health crisis. The various consequences of living with food allergies reduces the quality of life for those affected [1]. Aside from the immediate dangers of severe allergic reactions, there is a significant amount of social restrictions and anxiety involved. Dealing with food allergies costs American individuals and families 25 billion dollars annually [2]. Avoidance diets are the most common way to treat food allergies, but they are statistically unsustainable: 75% of peanut-allergic children get accidentally exposed to peanuts by the time they are 5 years old [1]. As a result, allergy immunotherapy is an important developing preventative treatment that can allow individuals to consume allergens to improve quality of life. 

There are three main emerging treatments: oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT). All three use different delivery methods to introduce the patient to allergens to achieve desensitization. The different delivery methods may contribute to the different levels of success observed between them.

The guiding principle of food allergy immunotherapy, regardless of delivery method, is to induce a state of prolonged desensitization–defined as an increase in tolerance threshold–to an allergen [3]. This may be achieved by maintaining consumption of allergen over time through doses tailored to the patient’s observed tolerance threshold. Tolerance thresholds are determined with food challenges, where the patient consumes allergens until they experience notable allergic symptoms [4]. Desensitization may be gradually achieved through increases in dosage [3, 4]. Allergen doses slowly increase over time as the patient’s tolerance increases. Administering the allergen this way is thought to familiarize the body with it so that the immune response to the allergen gradually becomes less severe over time [5]. 

Generally, the immune response to allergens is mediated by allergy-specific antibodies called Immunoglobulin E (IgE). Once a food allergen has been ingested and detected by the immune system, IgE activates immune cells that cause inflammation and other allergy symptoms. Immunotherapy attempts to change the immune response so that allergens stimulate non-allergy specific antibodies like Immunoglobulin G (IgG) [5]. IgG antibodies produce a normal immune response to foreign bodies like infections and viruses. Training the body to respond with IgG prevents the allergic response, eliminating adverse allergic symptoms. 

Immunotherapy aims to create a state of long term desensitization known as sustained unresponsiveness (SU). By achieving SU, patients are more likely to retain tolerance even after they stop taking the regular, repeated doses of allergen. Patients with SU can often freely be in the presence of their allergens or even consume them [3, 4]. SU is not considered a “cure” of allergies. Immunotherapy simply aims to change the Immunoglobulin E-mediated allergic response to a less drastic response that has little to no effect on quality of life [1]. SU is less commonly achieved than desensitization across all delivery methods, with only a small subset of patients reaching SU after years of therapy [6]. Nonetheless, SU remains the ideal end goal for all patients [3]. 

Delivery Methods

Across all studies cited in this literature review, delivery methods vary in efficacy depending on the food allergen being treated. Discussing the efficacy of each method for individual food allergens would thus require extensive examination and comparison of many individual studies. This level of specificity is not necessary to explain or compare the efficacies of the three immunotherapies. The duration and safety of each treatment seems to widely vary based on the particular allergic response, tolerance threshold, and specific allergens of an individual. Despite these differences, however, much of the research yields consistent results in the overall relative efficacy of each method. As such, this review will describe a general consensus about the effectiveness of each delivery method across many studies. 

Delivery Method #1 – Oral Immunotherapy

The first food allergy immunotherapy delivery method, which has recently received Food and Drug Administration (FDA) approval for peanut allergen [7] is oral immunotherapy (OIT). In OIT, the patient ingests allergen protein often in powder form and mixed with other non-allergenic food [5].

OIT has yielded the most promising clinical results out of all immunotherapy delivery methods [5]. Most patients treated with OIT have reached desensitization, though SU is less commonly observed [3]. Adverse allergic reactions are reasonably likely to occur during OIT, though most reactions are mild. All reactions can be promptly addressed within a clinical or hospital setting. Despite this, individuals with severe and fast-acting allergic reactions (e.g. anaphylaxis) may still face risks to their physical well-being [3, 6]. As of now, only an OIT treatment, known as PalforziaⓇ, for peanut allergen has been approved by the FDA out of all potential immunotherapies. At this point in time, it has passed clinical trials and requires additional risk assessments, education, and patient counseling for use [7]. 

Adjuvant medications–used in combination with a treatment to enhance or modify its effects are being examined as additional safety measures to make OIT safer. Omalizumab is a monoclonal antibody, an antibody cloned from existing antibodies that can be taken as medicine to assist immune functions. Omalizumab selectively binds to IgE, which occupies IgE enough to suppress the allergic response [8]. Omalizumab appears to have no bearing on the effectiveness of the desensitization process [3]. However, it has been shown to speed up the process and decrease incidence of adverse allergic reactions.  For common allergens like milk and peanut, little to no adverse reactions were observed when Omalizumab was administered to subjects [8]. However, further research and clinical trials with larger sample sizes and a wider array of allergens must be conducted before Omalizumab can be universally used as a safety protocol for food allergy immunotherapy [8].

Delivery Method #2 – Sublingual Immunotherapy

The second delivery method is sublingual immunotherapy (SLIT). SLIT requires that liquid or dissolvable extracts of allergens be regularly administered under the tongue, held there for a time, and then swallowed [5]. Using this method, the allergen can be mainly taken into the body by way of antigen presenting cells in the sublingual mucosa found under the tongue. This route avoids enzymes encountered during gastric digestion that might change the structure of the allergen protein. This is useful in ensuring that the immune system becomes fully desensitized to the correct allergen [6]. 

One advantage of SLIT is its safety; adverse allergic reactions and anaphylaxis are not commonly observed [5, 6]. Additionally, using SLIT before OIT is highlighted as a potential benefit. Patients who experience adverse reactions with OIT generally are advised to use SLIT as a stepping stone treatment. This lets them build enough desensitization to make OIT a more viable option, as they experience less side effects [5].

Delivery Method #3 – Epicutaneous Immunotherapy

The third delivery method in food allergy immunotherapy is epicutaneous immunotherapy (EPIT). Immune cells in the skin called Langerhans cells help introduce the allergen to the body when dermal patches are applied to the skin [5, 9]. Patches are kept on for increasingly longer durations and replaced as instructed by a physician until the patient is mostly unresponsive to the allergen. At this point, patches must still be worn to maintain results, but need only be replaced every 24 hours [2]. 

Using this route to absorb allergens successfully prevents entry to vasculature, which is thought to limit severe systemic allergic reactions and only results in mild, cutaneous reactions [1, 9]. Similar to SLIT, this makes EPIT’s safety profile better than OIT’s. Additionally, EPIT does not place restrictions on the patient’s lifestyle and does not require close clinical observation like OIT or SLIT [2]. 

Comparing Delivery Methods

As mentioned earlier, OIT is largely considered the most effective of the three immunotherapies described. Most patients are successfully desensitized and SU, though still infrequent, it occurs more often than other methods [3, 5]. 

SLIT has shown modest levels of desensitization, but is overall considered less effective than OIT, showing less immunologic changes over time [6]. It does not appear to confer high levels of SU [5]. It is unknown whether this is attributed to the fact that most patients appear to struggle with completing the recommended duration of treatment [9]. 

EPIT also demonstrates levels of desensitization comparable to SLIT, with 28-50% of patients showing tolerance to their allergen on average [1, 2]. SU has not been well documented in either EPIT or SLIT [1], which seems to be the main reason why they do not have FDA approval [2]. 

Conclusions

Preventative food allergy immunotherapy has been a developing area of study due to a global increase in food allergy incidence [5]. Three prominent immunotherapy delivery methods have emerged with differing efficacies and safety profiles.

OIT is widely considered the most clinically efficient and promising delivery method, since it consistently produces desensitization [5]. SLIT shows less consistent desensitization [6] and maintaining treatment is difficult for patients. EPIT shows similar results to SLIT [9]. While SU is not commonly achieved, it is more common in OIT [1, 3], which may explain why the only FDA-approved food allergy immunotherapy is OIT for peanut allergen [7]. 

The safety and convenience of each method may also affect patient choice. OIT may be the most effective and quick-acting, but it also runs the largest risk of adverse reactions, which warrants close clinical attention during treatment [3, 6]. In contrast, SLIT does not seem to cause many adverse reactions and is encouraged as a stepping stone treatment for patients that would like to move on to OIT once more tolerance to their allergen is built up. This practice seems to make OIT much safer [5] along with the use of medications like Omalizulab [8]. EPIT is also safer than OIT but has the added advantage of being a convenient and low maintenance treatment [5, 9]. At maintenance, dermal patches used for EPIT only need to be replaced every 24 hours, no clinical observation is required, and there are no restrictions placed on the patient’s lifestyle [2]. 

As allergies become more common across the globe, more children struggle to adhere to avoidance diets and become vulnerable to accidental exposure to allergens [1]. Immunotherapy methods have developed in the hopes of increasing the quality of life of these food allergic individuals [1]. Future research may be able to improve on the observed effects and safety of immunotherapy. Ultimately, any progress will be able to help food allergy sufferers improve their quality of life. 

References:

1. Costa, C., Coimbra, A., Vítor, A., Aguiar, R., Ferreira, A. L., & Todo-Bom, A. (2020). Food allergy – From food avoidance to active treatment. Scandinavian journal of immunology, 91(1), e12824. doi:10.1111/sji.12824
2. Kim, E. H., & Burks, A. W. (2020). Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy. Allergy, 75(6), 1337–1346. doi:10.1111/all.14220
3. Wood R. A. (2017). Oral Immunotherapy for Food Allergy. Journal of investigational allergology & clinical immunology, 27(3), 151–159. doi:10.18
4. Marcucci, F., Isidori, C., Argentiero, A., Neglia, C., & Esposito, S. (2020). Therapeutic perspectives in food allergy. Journal of translational medicine, 18(1), 302. doi:10.1186/s12967-020-02466-x
5. Burks, A. W., Sampson, H. A., Plaut, M., Lack, G., & Akdis, C. A. (2018). Treatment for food allergy. The Journal of allergy and clinical immunology, 141(1), 1–9. doi:10.1016/j.jaci.2017.11.004
6. Scurlock A. M. (2018). Oral and Sublingual Immunotherapy for Treatment of IgE-Mediated Food Allergy. Clinical reviews in allergy & immunology, 55(2), 139–152. doi:10.1007/s12016-018-8677-0
7. Caccomo, S. (2021). FDA approves first drug for treatment of peanut allergy for children. U.S. Food and Drug Administration. <https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children>. 
8. Dantzer, J. A., & Wood, R. A. (2018). The use of omalizumab in allergen immunotherapy. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 48(3), 232–240. doi:10.1111/cea.13084
9. Reisacher, W. R., & Davison, W. (2017). Immunotherapy for food allergy. Current opinion in otolaryngology & head and neck surgery, 25(3), 235–241. doi:10.1097/MOO.0000000000000353