Food Allergy and Anaphylactic Shock

 Food-induced anaphylaxis is a serious allergic reaction that can rapidly cause death in otherwise healthy individuals. It is estimated that 0.1% to 5% of children in the United States have a prescription for epinephrine, and food-induced reactions account for 30-50% of anaphylaxis reaction cases (1). Food allergy related anaphylaxis is much more common in children, with the estimated prevalence of food allergies being 8% in children under 18. The prevalence of food allergies worldwide is 1-10%, and in the U.S., there are about 90,000 food-related emergency department visits occur each year (2). This presents a major problem for our population, and not much is currently known about the treatment of anaphylaxis. The optimal way to manage anaphylaxis currently is avoidance of the cause of the food-induced anaphylaxis and immediate use of emergency medications upon exposure to the allergen (3). Exploring the mechanisms of how anaphylactic reactions are induced, and what factors play into their occurrence may help us to find better treatment options for patients with food allergies.

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The symptoms related to anaphylactic reactions are characterized by airway constriction, inflammation, and typical IgE-mediated responses. Inflammatory mediators such as mast cells and basophils act to regulate the inflammatory response when a foreign particle invades. This inflammatory response can activate phagocytic cells including neutrophils, eosinophils and macrophages. These cells are attracted to the foreign particle, and they act to ingest it and remove it from circulation. Natural killer cells (NK cells) are involved in the innate immune response. NK cells recognize cells under stress or invasion from foreign substances and bind to them. They are capable of inducing apoptosis (programmed cell death) in the stressed cells and the pathogens they contain. Complement proteins and cytokines also play a major role in the induction of allergic reaction. These molecules can induce different processes of the immune system. For example, pro-inflammatory cytokines can stimulate the inflammatory process. These responses happen when antigen-presenting cells like dendritic cells present antigens (food allergen) to a TH₂ cell. This cell releases cytokines like IL-4 and IL-13, which stimulate B cell class-switching to IgE antibodies (2). Activation of mast cells with specific IgE bound to their surface is the main event that occurs during allergic reaction. The IgE isotype has the lowest concentration in circulation and it is unable to fix complement, but its concentrations are elevated in those with allergic diseases. When IgE is elevated and secreted, it binds to its high affinity FcεRI on basophils. Upon this binding, it sensitizes mast cells and other effector cells to release mediators in response to subsequent encounters with that specific antigen or with cross-reactive antigens (4).

It is currently known that mast cells are the principal effector cells in IgE-mediated allergic reaction, but there is evidence to show that basophils and other cells of the innate immune system also play a major role in anaphylaxis and acute food allergy symptoms. Food induced allergic reactions are typically characterized as immediate, reproducible, and readily diagnosed by looking for IgE antibodies binding to their high-affinity receptor known as FcεRI that is expressed on mast cells and basophils. When an antigen binds to the IgE antibody-receptor complex, this induces the release of preformed mediators including histamine, tryptase, and some cytokines. Histamine is one of the mediators that is released by mast cells and basophils, and is thought to be the major reason for most of the characteristics and results from anaphylaxis reactions. With this being said, current medications that inhibit histamine are not sufficient to reverse anaphylaxis, suggesting that other mediators play a large role in the mechanism of anaphylaxis. Platelet-activating factor has emerged as one of these important mediators. PAF is released by mast cells and macrophages during anaphylaxis. Higher levels of PAF and lower levels of its metabolizing enzyme correlate with the severity of anaphylactic shock. It is shown that PAF has been proven to be a major contributor to anaphylactic reactions because blockage of PAF when combined with the use of antihistamines eliminates all signs of anaphylaxis (1). This is a great example of how exploring the mechanism of a mediator for allergic reaction can help us to understand how it occurs and how we might be able to treat it.

In people without allergies, food molecules are ignored by the immune system and deemed to be harmless. In other people, an exaggerated adaptive immune response is mounted against a harmless molecule. When there is an exaggerated and inappropriate immune reaction involving allergens, it is termed a type 1 hypersensitivity reaction. In someone with an allergy, their mast cells and other cell types already have antigen-specific IgE bound to FcεRI. Upon re-exposure to the original antigen, there is cross-linking of adjacent FcεRI-bound IgE, and this results in the aggregation of surface FcεRI. If this aggregation of surface FcεRI is strong enough and for long enough, it induces mast cells and basophils to initiate a series of signaling events. These events lead to the signal for the release of cytokines and other mediators. The mediators released shortly after antigen and IgE-induced mast cell degranulation initiate a hypersensitivity, or early phase reaction. This response is characterized by increased vascular permeability, contraction of the airways, and enhanced secretion of mucus, which can result in reduced airflow and wheezing (4). Results of a study done on patients with allergies in the U.K. showed that of all food-related allergic reactions that resulted in difficulty breathing, 86% of reactions led to respiratory arrest (3). In a systemic response, this can result in anaphylaxis, a strong immune response that can quickly result in death if not treated (4).

Anaphylaxis reactions are immediate and unpredictable, which is why they can be difficult to manage and treat. Some reactions can progress so fast that no treatment can be given before respiratory or cardiac arrest occurs (3). This leads us to believe that the best treatment for allergies is avoidance of the allergen itself, but there are many problems with this solution. Avoidance of allergens places a constant responsibility on patients and caregivers, and leaves patients vulnerable to unintentional ingestion of the allergen, and subsequent induction of anaphylaxis. So, what if we could get rid of the allergy completely? This is what is being studied through the use of oral immunotherapy.

Oral immunotherapy, also known as oral desensitization, is a method of inducing the body’s immune system to tolerate a food that causes an allergic overreaction (5). The way desensitization works is through the suppression of certain immune responses. There are various pathways through which T regulatory cells act on cells of the immune system, leading to the suppression of effector cell function. The presumed mechanism of action for oral immunotherapy is through allergen activation of dendritic cells in the gut, resulting in effector cell modulation (5). Clinical trials have shown that oral immunotherapy can effectively desensitize many individuals without major morbidity or mortality. In a double-blind, randomized, placebo-controlled study, 55 children, 5-11 years of age with allergies to egg received oral immunotherapy. The results of the study showed that oral immunotherapy could desensitize a high proportion of the children with egg allergies. After 10 months of therapy, 55% of the children who received oral immunotherapy were considered to be desensitized (6).

The overall goal of allergen immunotherapy is to produce a state of immune tolerance, a long-term loss of allergic activity even after the discontinuation of therapy. This allows for desensitization to be more easily achieved, meaning that the amount of food that must be ingested to trigger an allergic reaction is increased during the therapy. But this type of therapy raises other important questions, like how long will this desensitization last? And do patients eventually achieve complete tolerance of an allergen? For people with food allergies, the development of an allergic versus a healthy immune response seems to be the balance between T regulatory cells and disease-promoting TH₂. Based on this, a permanent tolerance to the food should be expected, meaning that the food could be ingested without signs of allergic reaction, even after long periods lacking exposure to the allergen. With that being said, the term desensitization refers to a reversible state after exposure to incremental doses of the allergen, rendering the effector cells less reactive. The problem here is that once administration of the allergen is discontinued, the reactivity of the body to the antigen returns (5). Currently, there is not enough evidence to support the fact that desensitization is working towards a state of complete and permanent oral tolerance. The details and duration of immunotherapy must be taken into consideration when trying to determine if it will achieve a state of tolerance. Some studies show that overall, patients who regularly consume at-home doses of the allergens are able to maintain desensitization. This may indicate that immunotherapy must be maintained in order for the individual to be deemed “tolerant” of the allergen.

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With oral immunotherapy looking like a great way to combat food allergies, we must also look at the adverse effects involved in this therapy, and weigh the risks with the benefits. The occurrence of adverse effects during oral immunotherapy is reported very frequently. Some studies report that 100% of patients experience adverse reactions. A large peanut oral immunotherapy study looked at the reactions of its participants throughout all phases of therapy. It was concluded that the frequency and severity of reactions were the greatest during the initial days upon introduction to the allergen, while there were the least adverse reactions during the later phases of at-home dosing. It is also important to note that severe systemic side effects, including anaphylactic reactions, were reported independent of the dosing schedule, and at all points in the trial (5). This should make us wonder, even though oral immunotherapy has many potential benefits, including the possibility of eventual complete tolerance, is it safe?

While oral immunotherapy has risks associated with its use, the risks of exposure to the allergy itself may outweigh the risks of the therapy. Avoidance of the allergen may not be sufficient for a patient with severe systemic reactions because of the risk of accidental exposure. In these patients, the introduction of effective tolerance would present a life-saving treatment. With this being said, more information is urgently needed about appropriate patients for the therapy, and the risk factors associated with the more serious side effects. However, oral immunotherapy continues to be an area of research for allergists and immunologists because of these risk factors and concerns for safety. Understanding the mechanisms involved in allergic reaction can help us to derive better treatment options to improve the quality of life for patients with food allergies. Recently, anti-IgE monoclonal antibody, known as Omalizumab, was used in combination with the use of oral immunotherapy in patients with severe food allergies, and this was able to enhance the safety and effectiveness of the oral immunotherapy (5). This leads us to believe that there are many factors involved in how allergic reactions are conducted, so there may be multiple ways we need to treat them.

Exploring the mechanisms by which anaphylactic reactions are induced, and what factors play into their occurrence may help us to find better treatment options for patients with food allergies. With different factors such as effector cells, cytokines, and antibodies all playing a role in the propagation of an allergic reaction, there may be different targets for treatment. Oral immunotherapy appears to be a promising area of research that provides hope and optimism for patients with food allergies. With the goal of improving the quality of life of patients and family members, it represents a promising treatment option for the future.

Citations

1. Cianferoni A, Murano A. Food-induced anaphylaxis. Immunol Allergy Clin North Am. 2012 Feb; 32(1): 165-95.
2. Hussey-Freeland DM, Minogue HF, Nadeau KC. Advances in food allergy oral immunotherapy: towards tolerance. Curr Opin Immunol. 2016 Oct; 42: 119-23.
3. Pumphrey, RSH. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000; 30: 1144-50.
4. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012 May 4; 18(5): 693-704.
5. Pajno GB, Cox L, Caminiti L, et al. Oral immunotherapy for treatment of immunoglobulin e-mediated food allergy: the transition to clinical practice. Pediatr Allergy Immunol Pulmonol. 2014 Jun 1; 27(2): 42-50.
6. Burks AW, Jones SM, Wood RA, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012 Jul 19; 367: 233-43.