Update on Anaphylaxis

IN THE LAST decade, the number of cases of anaphylaxis has dramatically escalated in the United States. According to an article titled “Trends in Emergency Care for Anaphylaxis,” between 2008 and 2016, emergency department visits for anaphylaxis increased 1.9-fold among adults and 3.2-fold among children.¹ The U.S. Food and Drug Administration (FDA) estimates food-induced anaphylaxis results in 30,000 emergency room visits, 2,000 hospitalizations and 150 deaths each year.² And, while eliminating anaphylaxis is unlikely despite studies to determine its triggers, researchers are pursuing methods of reducing the risk posed by this allergic reaction.

What Is Anaphylaxis?

Anaphylaxis is an extreme, sometimes life-threatening allergic reaction to an antigen such as food (milk, eggs, fish, shellfish, tree nuts, peanuts, wheat or soybeans), drugs (penicillin, aspirin, ibuprofen or anesthesia), insect bites (bees, wasps, hornets, yellow jackets or fire ants) or latex (disposable gloves, intravenous tubes, syringes, adhesive tapes or catheters) to which the body has become hypersensitive. Food allergy is the most common culprit of anaphylaxis.

When a severe, life-threatening reaction to an allergen occurs, symptoms usually present within five minutes to two hours after contact with the allergen. Symptoms generally affect two or more of these body systems:³

• Skin: hives, swelling (face, lips, tongue), itching, warmth, redness

• Respiratory: coughing, wheezing, shortness of breath, chest pain/tightness, throat tightness, hoarse voice, nasal congestion or hay fever-like symptoms (runny itchy nose and watery eyes, sneezing), trouble swallowing

• Gastrointestinal: nausea, pain/cramps, vomiting, diarrhea

• Cardiovascular: paler than normal skin color/blue color, weak pulse, passing out, dizziness or light-headedness, shock

• Other: anxiety, sense of doom (the feeling that something bad is about to happen), headache, uterine cramps, metallic taste

Allergic reactions among people vary from mild to severe to anaphylactic, and people may not react the same way twice. Reactions typically follow a uniphasic course (peaking within 30 minutes to one hour after symptoms appear and resolving either spontaneously or with treatment within the next 30 minutes to one hour). However, 20 percent will be biphasic (having a recurrence of anaphylaxis after appropriate treatment). When a biphasic reaction occurs, the second phase usually occurs after an asymptomatic period of one hour to eight hours, but there may be a 24-hour delay. Protracted anaphylaxis (a recurrence of anaphylactic symptoms several hours after successful treatment in the absence of a new exposure to a triggering antigen) may persist beyond 24 hours.⁴ In rare cases, anaphylaxis can be fatal.

Diagnostic Criteria

Symptoms of anaphylaxis vary and can be difficult to recognize. People who experience one of three of the following conditions may be having an anaphylactic reaction: symptoms within minutes to several hours after coming into contact with an allergen, two or more of the typical symptoms of anaphylaxis and a drop in blood pressure.

Allergies can be diagnosed by an allergist or an immunologist with a skin prick test, an oral food challenge (OFC), an OFC with naked milk and egg products, and/or specific IgE (sIgE) testing and allergen-specific IgG testing. Test results can differentiate between a sensitivity and a true allergy.⁵

Causes of Food Allergies

According to the National Institute of Allergy and Infectious Diseases (NIAID), food allergies develop when a person consumes or comes into contact with an allergen, and the immune system makes an antibody called immunoglobulin E (IgE), which circulates through the blood and attaches to immune cells called mast cells and basophils. While this initial exposure does not cause an allergic reaction, subsequent contact with the same allergen may allow previously created IgE antibodies to recognize it, which can then launch an immune response that can result in a severe allergic reaction. However, some people make IgE antibodies against certain foods without developing an allergy, while others still may develop only a mild allergy compared to those who experience severe reactions.⁶

In the United States and other parts of the developed world, food allergy has been growing in prevalence.⁷ According to a recent survey, more than 10 percent of U.S. adults (more than 26 million people) are estimated to have a food allergy.⁸

Risk Factors for Anaphylaxis

Certain people are more at risk for food allergies than others. Risk factors include:³

• Age: Food allergy is more common in young children than in older children or adults.

• Family history: A person is more likely to have a food allergy if his or her parent or sibling has one.

• Another food allergy: An individual who has a food allergy is at greater risk for developing another.

• Related medical conditions: A person’s risk is increased if he or she has an allergic disease such as asthma, eczema or hay fever.

Although a severe or fatal anaphylactic reaction can happen at any age, teenagers and young adults with food allergies are at highest risk of fatal food-induced anaphylaxis. And, individuals with food allergies who also have asthma may be at increased risk for severe or fatal food allergy reactions.⁹

Food allergy typically occurs with comorbid conditions. For instance, food-allergic children are two times to four times more likely than those without food allergies to have related conditions such as asthma (4.0-fold), atopic dermatitis (2.4-fold) and/or respiratory allergies (3.6-fold).⁵

Treating Anaphylaxis

Current prevailing treatments for anaphylaxis are to prevent it by avoiding triggers and to administer epinephrine as soon as symptoms present if an anaphylactic reaction occurs. Doctors also strongly recommend patients who have experienced an anaphylactic reaction be transferred to a hospital for further treatment, including observation for biphasic or protracted anaphylaxis.

While there is no cure for food allergy or anaphylaxis, some experimental immunotherapies might decrease symptoms in people with food allergies, thereby reducing the risk or severity of a reaction.

According to Food Allergy Research and Education (FARE), the world’s largest private funder of food allergy research, which has invested more than $90 million to study allergic reactions and discover life-changing treatments, three types of immunotherapy to treat food allergies have made significant progress in human clinical trials:

1) Oral immunotherapy in which the allergen is eaten;

2) Sublingual immunotherapy in which the allergen is placed under the tongue; and

3) Epicutaneous immunotherapy in which the allergen in a dermal patch is applied to the skin.

A fourth type of immunotherapy, subcutaneous immunotherapy (SCIT), has made less progress in clinical trials, but, more recently, new efforts are underway to develop safer SCIT methods.¹⁰

Ongoing Research

Nurry Hong, FARE’s chief of strategy and innovation, explains the current research landscape for anaphylaxis: “There are many ways to potentially prevent the onset of severe anaphylaxis, including food allergy. The two primary approaches being tried can be generally segmented into two buckets. Bucket one is to disrupt the specific mechanisms that are involved in causing an anaphylactic reaction. And, bucket two is to modulate the body’s immune system to try and regulate the underlying causes that lead to an IgE-mediated condition.

“There is a growing drug pipeline in bucket one disrupting the mechanisms of anaphylaxis. The leader is Xolair (omalizumab), which is an anti-IgE molecule already on the market and approved for asthma and urticaria. Xolair is being developed now for food allergy. The success of Xolair is creating a growing pipeline of alternative ways of inhibiting IgE. Essentially, there is interest to develop a better drug profile than Xolair. Researchers are looking at both IgE and non-IgE mechanisms. In the latter category, the emerging targets are various receptors on mast cells that may inhibit their function, as well as various mechanisms that have been used in other diseases, including cancer. Siglecs [sialic acid-binding immunoglobulin-type lectins] are a popular type of receptor on mast cells being targeted, but there are other cell types and receptors also being researched.

“In bucket two, in modulating the body’s immune system, there is a lot of activity going on within atopic disease. There is a common underlying immune response in all of these conditions (Th2 response), which share some similar characteristics. Based on our knowledge across these diseases, there is a growing pipeline trying to treat these conditions with either monotherapy or combination drug therapies. The classes of therapies include immunotherapy, biologics, microbiome-based therapeutics and various small molecule drugs.

“There are many targets that are emerging. Immunotherapy has been available for many years, but is just emerging as an FDA-regulated therapy for food allergy. Biologics targeting various immune-regulating cytokines are another big class emerging (anti-IL-4, IL-13, IL-5, IL-33, IL-25 and TSLP, among others). Researchers are also trying to identify ways to ‘upregulate’ the immune system so the body can defend and retrain itself to the antigen to be nonresponsive. Microbiome plays a role in this latter category, as do other novel targets being explored.”

Scientists are in the very early stages of conducting novel research on receptors being investigated for their ability to inhibit histamine release. Preliminary research shows certain receptors inhibit the rapid release of inflammatory mediators such as histamine, prostaglandins, leukotrienes, tryptase and cytokines, which could potentially reduce the risk and severity of anaphylactic reactions.

Recent research also shows engagement of a mast cell inhibitory receptor can block human mast cell allergic activation and protect mice from anaphylaxis. Anti-siglec-8 antibodies are in clinical trials for various diseases, including mast cell diseases. Following are results of several recent research projects on the receptors siglec-3 and siglec-8 and the enzyme Bruton’s tyrosine kinase (BTK):

• According to a recent study conducted on siglec-3, scientists demonstrated liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days. The results demonstrated the potential of exploiting CD33 to desensitize mast cells to provide a therapeutic window for administering allergen immunotherapy without triggering anaphylaxis.¹¹

• In another recent study conducted on siglec-8 (AK002), results showed AK002 selectively evokes potent apoptotic and antibody-dependent cellular cytotoxicity activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition.¹²

• In a study on potential applications of BTK inhibitors for the prevention of allergic reactions, the scientists explain that BTK is an enzyme located downstream of FcεRI and is essential for FcεRI-mediated activation of mast cells and basophils. According to the scientists, the importance of BTK in mediating systemic allergic responses is demonstrated by earlier studies showing BTK-deficient mice have impaired anaphylaxis in a model of passive cutaneous anaphylaxis.¹³

• Research shows drugs that target the BTK enzyme are very effective at blocking anaphylaxis. Currently, there are two FDA-approved BTK inhibitors for use in humans — ibrutinib and dasatinib — that are used to treat cancer. There are also three other BTK inhibitors in development — acalabrutinib, zanubrutinib and PRN1008 — currently in clinical trials.¹³

• A study on the potential applications of BTK inhibitors for the prevention of allergic reactions provided encouragement for the concept that BTK inhibitors can inhibit or reduce the severity of anaphylactic reactions.¹³

Future Outlook

Although scientists might not discover a cure or preventive therapy for anaphylaxis or food allergy, they are optimistic they will discover therapies in the future that will reduce the risk or severity of anaphylaxis.

“We are very hopeful that there will be many more options to treat conditions with IgE-mediated anaphylaxis both to stop the specific mechanisms involved but also to better retrain the immune system to be less desensitized,” says Hong. “We believe the future will require many different mechanisms and combinations of therapies to treat all patients. There will not be one solution that works for all, or at least that would not be a realistic expectation. Our hope is that immunotherapy for food allergy continues to proliferate, providing an option to achieve a baseline of protection.

“Xolair or other anti-IgE therapies should get approved in the next wave of innovations for food allergy (they are already available for other diseases), along with various biologics targeting key immune functions like IL-4. We believe there is a way to improve on therapy where some patients may be able to achieve relearned tolerance or effectively are nonreactive for sustained periods of time. The research is starting to emerge to potentially make treatment much more effective than what is available today.

“However, we still have a lot to learn about IgE-mediated anaphylaxis. The known mechanisms and targets are only the beginning, and we will elucidate even more targeted approaches to safely stopping anaphylaxis in the future.”

Looking ahead, researchers will continue the pursuit of preventive therapy for anaphylaxis, as well as its major cause: food allergy. Lowering the risk and decreasing the severity of anaphylaxis would greatly reduce the high numbers of emergency room visits, hospitalizations and deaths that occur each year from this life-threatening condition.