X. IMMUNOGLOBULIN E (IgE) AND ANAPHYLAXIS

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1 X. IMMUNOGLOBULIN E (IgE) AND ANAPHYLAXIS Definitions Immunoglobulin E (IgE) is one of the major mediators of allergic conditions such as hives, seasonal allergy, asthma and anaphylaxis. All of these allergic reactions involve the binding of IgE antibodies to surface receptors on a variety of cells. On first exposure to an allergic trigger, specific IgE antibodies form against that antigen and are bound to receptor sites on the cell surface. On subsequent exposures, the allergic trigger causes the establishment of chemical links between the IgE molecules (known as cross-linking), resulting in a single, strong network of molecules. The cross-linking leads to activation and degranulation (release of granules) of the mast cell or basophil (white blood cells with abundant granules). 235 This process of cross-linking, activation and degranulation stimulates the release of histamine and other potentially toxic products that elicit the familiar signs and symptoms of an allergic reaction. 235,236 Since histamine receptors are present in many sites in the body including the skin, gastrointestinal tract, hart, vascular bed, and bronchial smooth muscle, any or all of these areas may be affected. Reactions include the wheal and flare eruptions of the skin that are characteristic of hives, sneezing, runny nose and irritation of the eyelids associated with seasonal allergy and the dermal, respiratory, cardiovascular and gastrointestinal signs and symptoms that are the clinical manifestations of anaphylaxis. 236 The clinical definition of anaphylaxis is an immediate systemic reaction caused by rapid, IgEmediated immune release of potent mediators from tissue mast cells and peripheral blood basophils. 237 In contrast, anaphylactoid reactions are immediate systemic reactions that mimic anaphylaxis but are not caused by IgE-mediated responses. 237 Identifying IgE Antibodies as a Diagnostic Tool The first step in determining the cause of an anaphylactic episode is taking a careful history of exposure immediately before the onset of the reaction, and testing for IgE antibodies to the suspected allergen. 237,238 Currently such tests can identify several, but not all, causes of anaphylaxis including foods, penicillin, insulin and insect venom. 237 While testing for IgE antibodies can be used as a diagnostic tool, the test is not completely foolproof. A recent review paper stresses the need for further diagnostic tools in laboratory tests as not all allergic subjects exhibit clinical reactivity. 239 For example, when symptoms begin soon after eating a particular food, the cause of the episode may be easy to determine. However, in many patients, determining the precise cause can be more difficult. The laboratory evaluation of patients with a food-induced anaphylactic reaction should focus on determining whether or not the person has specific IgE antibodies to the food in question. This can be done by way of prick or puncture skin testing. A negative prick/puncture skin test is an excellent indicator of a non-ige-mediated reaction to the suspected food. A positive prick skin test does not necessarily mean that the food has caused the reaction, but if the patient also has a history of anaphylaxis to that food, the positive test is a good indicator of allergic reactivity. While the successful prediction of an allergic reaction or level of severity of a particular reaction is not possible at this point in time, current IgE research may help elucidate patient-food relationships. For example, the relationship between the number of binding sites on a patient s IgE antibodies and the antibodies subsequent reaction to a food protein may provide a clue as to how severe a reaction may be

2 IgE antibody testing can be useful in diagnosing insect sting allergy, another common cause of anaphylactic reactions. In diagnosing insect sting allergy, it is important to differentiate systemic reactions, in which the classic signs of anaphylaxis are present, from large local reactions and toxic reactions. In large local reactions, signs and symptoms, including swelling, occur around the sting site. Toxic reactions, which develop after multiple stings, may resemble anaphylaxis, but are mediated by chemicals in the venom itself rather than by IgE. Anaphylaxis after a single sting calls for evaluation by venom skin testing to determine what insect has caused the reaction and the individual s sensitivity. 237 Conversely, allergic reactivity to drugs cannot be determined by IgE antibody testing. 239 Non-IgE Anaphylaxis While there is abundant evidence on the role of IgE in both anaphylaxis and asthma, other data suggest that anaphylaxis may occur in the total absence of IgE. Oettgen and colleagues have concluded that non-ige pathways for anaphylactic hypersensitivity exist in mice, based on their research with genetically modified mice that make no IgE but produce other types of immunoglobulin. Despite the IgE deficiency, the mutant mice became anaphylactic when exposed to antigens and displayed abnormally fast heartbeat (tachycardia) and pulmonary function changes similar to those seen in anaphylactic mice that lack the genetic mutation. 240 IgE Research Despite the emergence of new information about the IgE response, complete understanding of this topic remains elusive. The situation is further complicated by the challenges of applying knowledge gained through the use of animal models and experimental models to the human condition. For example, while the work by Oettgen in genetically altered mice (described above) raises interesting questions about the role of IgE in anaphylaxis, whether it will hold true in humans is still unknown. In addition to trying to better understand the function of IgE, scientists are testing Hu-901, or anti-ige, as an antibody to reduce or prevent the IgE response in allergic conditions. 241,242 However, safety concerns have yet to be successfully addressed, and the impact of anti-ige therapy on patients at risk for anaphylaxis remains to be seen. The emerging data show that the IgE response is more complex than previously suspected. Continuing research in this area should help fill in the gaps in existing knowledge of IgE induction and regulation and may provide new treatment options in the future. Prevention and Treatment Despite all that has been learned about anaphylaxis, cures for severe allergies remain unavailable and patients at risk for anaphylaxis must remain vigilant about avoiding allergic triggers. They must become educated about their allergens and how to avoid them, whether the culprit is food, latex, medication or insect venom. The allergic person s family, friends, teachers and colleagues should also know about and understand the ramifications of the allergy so that they can aid in the prevention of anaphylaxis and be ready to assist if an emergency arises. Many experts suggest wearing a medical alert bracelet or necklace that can provide valuable, life-saving information in a crisis. Being prepared in case of an emergency is critical because accidents do happen and anaphylaxis develops quickly. This means learning about symptoms and taking them very seriously. All persons at risk for anaphylaxis should carry self-injectable epinephrine 50

3 (adrenaline), preferably in a form that is easy to use and quickly administered in a crisis situation. 243 Emergency Treatment of Anaphylactic Reactions Epinephrine, otherwise known as adrenaline, is the first-line standard of care for treating anaphylaxis. 244, 245 The immediate injection of epinephrine is essential. 245 Waiting for the paramedics or ER staff to administer epinephrine may greatly increase the chance of death because anaphylaxis can kill within minutes. The sooner a patient receives epinephrine, the greater the likelihood of surviving an attack of anaphylaxis. Most anaphylactic deaths have occurred when epinephrine was either not used or not used in time. 244 Side effects of epinephrine may include palpitations, tachycardia (an abnormally fast heartbeat), sweating, nausea and vomiting, and respiratory difficulty. 246 Cardiac arrhythmias may follow administration of epinephrine. Patients should be carefully instructed by a physician about the circumstances under which this life-saving medication should be used. Many physicians also recommend taking antihistamines such as diphenhydramine to relieve the symptoms of allergic reactions, but antihistamines in no way substitute for epinephrine. Only epinephrine can halt the potentially deadly effects of anaphylaxis. 244 Studies have shown that intramuscular injections of epinephrine are preferable to subcutaneous injections for the treatment of anaphylaxis since the body absorbs epinephrine faster via the intramuscular route, allowing the medication to take effect more quickly during allergic emergencies, when timing is critical. 247,248 The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology recommend that people with life-threatening allergies carry an injectable form of epinephrine (adrenaline) such as EpiPen (epinephrine) Auto-Injectors with them at all times. 243,244 It is a good idea not only to carry epinephrine injectors, but also to keep them readily accessible at home, work, school or anywhere else one spends much time. Highly allergic individuals should consult with their doctors about carrying two epinephrine autoinjectors, as some reactions are so severe they require two doses of epinephrine. In one study, more than 35% of patients needed more than one dose to manage the reaction. 249 Professional emergency care should be sought immediately in the event of anaphylaxis. Even if self-injectable epinephrine is administered, its effects last only 10 to 20 minutes. Anaphylaxis can escalate rapidly to cause suffocation or a fatal drop in blood pressure. As a result, people experiencing anaphylaxis may need emergency respiratory or cardiac care, or even to be resuscitated if they stop breathing altogether. More commonly, patients will need professional care to determine whether additional epinephrine, steroids, antihistamines, or other treatment is required. Follow-up is also important because of the possibility of delayed or biphasic reactions. Patients should remain under medical supervision for eight hours or longer after an episode of anaphylaxis occurs, and after they go home, they should continue to exercise vigilance. 250 Studies have shown that 18 to 28% of people suffering an anaphylactic reaction experienced a recurrence within 24 to 48 hours after the initial reaction and required further medical treatment, 51

4 including additional epinephrine. 251, 252 Therefore it is essential that anyone who experiences anaphylaxis should be equipped with enough self-injectable epinephrine to treat additional episodes if necessary, whether they are secondary reactions or result from future exposures to anaphylactic triggers. Patients should also ask their physicians whether antihistamines should be carried, in addition to epinephrine. Indication EpiPen and EpiPen Jr (0.3 and 0.15 mg epinephrine) Auto-Injectors are indicated for emergency treatment of allergic reactions (anaphylaxis) for people with a history of an anaphylactic reaction. Important Safety Information EpiPen Auto-Injectors should be used with extreme caution in people who have heart disease. Side effects of EpiPen Auto-Injectors may include fast or irregular heartbeat, nausea, and breathing difficulty. Certain side effects may be increased if EpiPen Auto-Injectors are used while taking tricyclic antidepressants or MAOIs. The EpiPen and EpiPen Jr Auto-Injectors are designed as emergency supportive therapy only and are not a replacement or substitute for immediate medical or hospital care. In case of accidental injection, please seek immediate medical treatment. Please see accompanying full Prescribing Information or visit EpiPen is a registered trademark of Dey, L.P. Dey, L.P All rights reserved. Printed in the USA for USA residents only. 2/08 G /009 References 235 Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg. 2003;97: Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Middleton E, ed. Allergy: principles and practice. 5t ed. St. Louis: Mosby, 1998: Nicklas et al, Joint Council of Allergy, Asthma & Immunology. Anaphylaxis. J Allergy Clin Immunol. 1998;101(No.6, Pt 2):S465-S528. S Bochner BS, Lichtenstein LM. Current Concepts: Anaphylaxis. N Engl J Med. 1991;324(25): Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the Definition and Management of Anaphylaxis: Summary Report. J Allergy Clin Immunol. 2005;115: Oettgen HC, Martin TR, Wynshaw-Boris A, et al. Active anaphylaxis in IgE-deficient mice. Nature. 1994;370(6488): Van Neerven RJ, van Roomen CP, Thomas WR, et al. Humanized anti-ige mabhu-901 prevents the activation of allergen-specific T cells. Int Arch Allergy Immunol. 2001;124(1-3): Chehade M. IgE and non-ige-mediated food allergy: treatment in Curr Opin Allergy Clin Immunol. 2007;7(3): American Academy of Allergy Asthma & Immunology. Allergic Conditions: Epinephrine American Academy of Allergy and Immunology. Position statement: The use of epinephrine in the treatment of anaphylaxis. J Allergy Clin Immunol. 1994;94:

5 245 Merck Research Laboratories. Disorders due to hypersensitivity. In: The Merck Manual, 16 th ed.1992: Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr versus EpiPen in young children weighing 15 to 30 kg at risk for anaphylaxis. J Allergy Clin Immunol. 2002;109(1): Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998;101: Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108(5): Korenblat PE, Lundie MJ, Dankner RE, et al. A retrospective study of the administration of epinephrine for anaphylaxis indicating need for more than one dose ACCP Meeting Abstract # Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005;95(3): Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78: Brazil E, MacNamara AF. Not so immediate hypersensitivity the danger of biphasic anaphylactic reactions. J Accid Emerg Med. 1998;15: