Role of Biologics in Anaphylaxis Care

Anaphylaxis is a medical emergency, and perioperative anaphylaxis (POA), which carries a higher risk of fatality compared to other forms of anaphylaxis, occurs at a rate of 15.3 per 100,000 cases. Research indicates that antibiotics and neuromuscular blocking agents (NMBAs) are among the more frequent triggers (Immunol Allergy Clin North Am 2022;42:145-59; Ann Allergy Asthma Immunol 2024;132:124-76). Compared to other forms of anaphylaxis, POA carries a higher risk of fatality, especially in patients with factors like male gender, hypertension, heart disease, and emergency surgeries (J Allergy Clin Immunol Pract 2024;12:1603-4; Anaesthesia 2009;64:199-211). Other substances that can cause similar reactions, through often non-IgE-mediated pathways, include dyes, antiseptics, colloids (gelatins), and iodinated contrast agents (Clin Rev Allergy Immunol 2022;62:383-99). Despite substantial progress in understanding POA, there are significant challenges that could impair early recognition and intervention. These challenges include the use of multiple agents simultaneously or in succession, patients’ inability to report early symptoms, and lack of immediately available reliable and valid skin and blood testing for some agents.

Understanding the underlying immunobiology of anaphylaxis creates opportunities to improve diagnostic modalities and explore new therapeutics. A common theme in anaphylaxis is the degranulation of mast cells, and to a lesser extent, basophils, leading to sudden onset of multiorgan involvement that could progress rapidly. In most patients, anaphylaxis is caused by IgE-mediated immediate hypersensitivity reactions in a presensitized individual. The antigen-specific IgE binds to the FcεRI¹, resulting in cross linking of these receptors on the surface of the mast cell and leading to the release of various mediators, including histamine, proteases, tryptase, and other inflammatory mediators such as prostaglandins and leukotrienes (Immunol Allergy Clin North Am 2022;42:145-59; J Allergy Clin Immunol 2017;140:335-48). Non-IgE-mediated mechanisms, such as immune complexes, complement, IgG antibodies, and others that have not been fully elucidated, are responsible for a significant portion of perioperative hypersensitivity reactions. Following the release of mast cell-driven chemicals, interaction with histamine and other receptors leads to dilation of blood vessels, release of fluid into tissues resulting in pruritic hives and swelling, and a drop in blood pressure, as well as bronchoconstriction (J Allergy Clin Immunol 2017;140:335-48). Early recognition of these symptoms followed by prompt intervention is paramount for patient survival. In this brief review, we present the role of the recently available biologics in anaphylaxis care.

Since anaphylaxis is a life-threatening condition, prevention of its occurrence in patients with known triggers may result from biologics. Biologics are therapeutic products (organic molecules) derived from living organisms or that contain components of living organisms that act on specific targets to modulate the immune system (by their action on a protein or a receptor as their therapeutic target), resulting in the prevention and treatment of various allergic reactions and inflammatory and autoimmune diseases (Current Allergy and Asthma Reports 2023;23:1-11). These products are typically large, complex molecules, often proteins, produced using biotechnological methods like recombinant DNA technology. They work to prevent anaphylaxis mainly by targeting specific pathways involved in the allergic reaction. Until recently, prevention of recurrence of an anaphylactic episode was limited to avoiding the trigger when identified and desensitization techniques for amenable IgE reactions caused by some agents if repeat exposure is required. However, biologics have shown recently to be effective as a preventative therapeutic modality (Curr Opin Allergy Clin Immunol 2021;21:455-64). Thus, in recent years, the strategy for managing anaphylaxis has evolved from a primarily defensive approach to a more proactive one (J Allergy Clin Immunol 2020;145:1082-1123). Rather than solely focusing on avoiding allergens (e.g., certain foods, drugs), the emphasis has shifted toward understanding how these allergens can be safely consumed or used, whether accidentally or as part of a deliberate dietary plan and patient care (J Allergy Clin Immunol 2020;145:1082-1123; Curr Opin Allergy Clin Immunol 2021;21:261-2). This change in perspective has generated growing interest in the potential role of biologic agents in anaphylaxis treatment, as they could significantly transform the management of affected patients.

While biologics can help control the underlying immune responses that cause anaphylaxis, they are usually reserved for cases where traditional treatments are not effective or for people who have chronic conditions that predispose them to frequent anaphylactic reactions, such as food allergies, frequent accidental reactions, and severe asthma. It is important to note that the availability of biologics for anaphylaxis is limited and they are not a substitute for emergency treatments, like avoidance of the allergic trigger, unless as a part of an immunotherapy plan, and epinephrine, which is the immediate treatment for anaphylactic reactions (Current Allergy and Asthma Reports 2023;23:1-11). However, this may change with time, as with an increase in experience with these biologics.

Patients with a known risk of anaphylaxis are always advised to carry an epinephrine autoinjector (such as an EpiPen) and to seek emergency medical attention in the event of an allergic reaction. Biologics may be considered as adjunctive therapy to improve management and reduce the frequency or severity of allergic episodes triggered by accidental exposure to the allergic trigger in certain individuals. The following are some modes of action by which biologics can help prevent anaphylaxis (Curr Opin Allergy Clin Immunol 2021;21:455-64)

1. Targeting IgE: IgE antibodies play a pivotal role in the allergic response, including anaphylaxis. Omalizumab (Xolair) is a biologic that specifically binds to IgE and prevents it from attaching to mast cells and basophils. This reduces the release of histamine and other inflammatory mediators that cause the symptoms of anaphylaxis.
2. Interfering with immune cells: Some biologics are designed to target and modulate the function of immune cells such as T-cells or eosinophils that contribute to the allergic response. By decreasing the activity or number of these cells, biologics can reduce the overall allergic response.
3. Blocking immune signaling pathways: Biologics such as monoclonal antibodies can block specific cytokines, which are signaling proteins like interleukins that contribute to the inflammation associated with allergies. By inhibiting these pathways, biologics can reduce inflammation and the severity of allergic reactions.
4. Desensitization: In certain cases, biologics may be used as part of a desensitization process, helping the immune system to tolerate the allergen and thus prevent severe reactions.

Most studied biologics

Omalizumab is a humanized IgG₂ monoclonal antibody that binds to circulating IgE at the FcεRI binding site, the high-affinity receptor for the Fc region of IgE, thereby stopping it from binding to the FcεRI antibody on mast cells and preventing mast cell degranulation (J Allergy Clin Immunol 2019;143:923-6.e1). Additionally, it inhibits the Th₂-mediated response and suppresses the immune response typically associated with Th₂ cells², which are a subset of T-helper cells. The Th₂ response is involved in the body’s immune reaction, particularly in promoting the production of antibodies (especially IgE) and activating eosinophils. This pathway is often associated with allergic reactions and asthma. By inhibiting the Th₂-mediated response, the substance or mechanism in question can reduce allergic inflammation and hypersensitivity reactions, which are driven by this pathway. This inhibition can be beneficial in treating conditions like asthma, allergies, and other immune system disorders where Th₂ responses are exaggerated by blocking IgE binding to its receptors on dendritic cells (Allergy 2009;64:1728-36). Omalizumab is currently FDA approved for treating certain Th₂-mediated diseases such as asthma, chronic idiopathic urticaria, and nasal polyps (Curr Opin Allergy Clin Immunol 2021;21:455-64). It has an acceptable safety profile; however, anaphylaxis was reported in 0.09% of patients, and the first few doses therefore are usually given under medical supervision (J Allergy Clin Immunol 2007;120:1373-7).

Omalizumab has also shown efficacy for preventing anaphylaxis in various scenarios, and its use for these purposes has been recently FDA-approved. Oral immunotherapy (OIT) is a procedure used to manage food allergies by gradually desensitizing patients to food they are allergic to. The goal is to protect affected individuals from anaphylaxis in case of accidental exposure. OIT is currently FDA-approved for peanut allergies and is being investigated for other food allergies. Adjunctive treatment with omalizumab has been shown to increase tolerance to accelerated OIT by reducing adverse events (Curr Opin Allergy Clin Immunol 2021;21:455-64; J Allergy Clin Immunol 2016;137:1103-10.e11). Other studies have demonstrated increased allergen threshold and decreased symptomatic accidental exposures to food in children with food allergy and who are taking omalizumab for other causes. Therefore, omalizumab is currently approved by the FDA for treatment of food allergy (J Allergy Clin Immunol Pract 2019;7:1901-9.e5). However, avoidance of the culprit food must be continued unless it’s part of an oral immunotherapy plan.

Omalizumab has shown efficacy in improving tolerance to venom immunotherapy in patients with mastocytosis, as well as reducing the frequency of anaphylactic episodes in patients with idiopathic anaphylaxis (Allergol Select 2021;5:128-32; J Allergy Clin Immunol 2007;119:1550-1; Ann Allergy Asthma Immunol 2009;102:257-8). Dupilumab is a monoclonal antibody that binds the alpha chain of the IL-4 receptor, thereby blocking the downstream signal triggering by two vital Th₂ cytokines (IL-4 and IL-13) and subsequently reducing Th₂ allergic inflammation (Clin Exp Allergy 2020;50:5-14). Dupilumab is widely used for treatment of asthma, eczema, eosinophilic esophagitis, and nasal polyps (Allergy 2021;76:2621-4; JAMA Dermatol 2020;156:44-56; Allergy 2022;77:1231-44). There are several ongoing studies that investigate the efficacy and safety of dupilumab for treatment of food-induced anaphylactic reactions in the setting of oral immunotherapy and atopic dermatitis, with most showing favorable results (J Investig Allergol Clin Immunol 2022;32:97-115).

Other biologics have been recently investigated for their potential in treatment of food allergy (Curr Opin Allergy Clin Immunol 2021;21:455-64). For example: Etokimab, an (IL)-33 antagonist, has led to improved tolerance to peanuts in some children with peanut allergy. This result was combined by a reduction in Th₂ cytokines (JCI Insight 2019;4: e131347).

Anaphylaxis is a life-threatening illness that needs to be promptly recognized and managed. The use of biologics marks a significant advancement in the proactive management of anaphylaxis. While they are not yet a replacement for traditional emergency treatments like epinephrine, biologics hold great promise in reducing the incidence and severity of anaphylactic reactions, particularly in patients with chronic conditions or repeated exposure risks. Several biologics have shown promise in managing and preventing severe allergic reactions, and they are currently undergoing extensive research. Although their use is still limited by factors such as cost and the need for additional validation, biologics represent a significant step forward in reducing the morbidity and mortality associated with anaphylactic reactions, especially in perioperative settings. While one of these medications has already been approved for the prevention of food-induced anaphylaxis, other indications may be on the path to approval and could potentially help reduce the morbidity, health care costs, and mortality associated with anaphylactic reactions, especially perioperative anaphylaxis. The drawbacks of these agents currently are cost, need for additional validation, and anaphylaxis to the biologic itself (Current Allergy and Asthma Reports 2023;23:1-11).