2001 DEY B9-508-00 7/01.

2001 DEY B /01

Anaphylaxis: Screen, Educate, and Protect to Improve Patient Outcomes
Anaphylaxis is a potentially fatal allergic reaction that can occur anywhere and at any age. It is associated with exposure to many substances, including foods, insect venoms, drugs, and latex. To improve patient outcomes, it is imperative that all health care professionals be aware of the associated risk factors, be able to rapidly identify the signs and symptoms, and be prepared to effectively screen, educate, and protect patients at risk. 2001 DEY B /01

Definition of Anaphylaxis
Systemic allergic reaction Affects body as a whole Multiple organ systems may be involved Onset generally acute Manifestations vary from mild to fatal Anaphylaxis is a severe systemic allergic reaction: it is a response to an allergen that generally affects the body as a whole. While some anaphylactic reactions involve one organ system, such as the respiratory tract, other reactions may affect multiple systems simultaneously (including the cardiovascular and gastrointestinal systems). An anaphylactic event is generally acute in onset, but depends upon individual patient sensitivity, the dose, and the route of administration of the allergen. Most reactions begin within an hour of exposure to the allergen. Some individuals experience symptoms within seconds, while others demonstrate symptoms hours after exposure. In general, it is believed that more severe reactions are more rapid in onset. The manifestations of anaphylaxis can range from relatively mild symptoms, involving only the skin, to life-threatening reactions, involving the respiratory and cardiovascular systems. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC.

Myth: Anaphylaxis Is Rare
REALITY: Anaphylaxis is underreported Incidence seems to be increasing Up to 41 million Americans at risk (Neugut AI et al, 2001) 63,000 new cases per year (Yocum MW et al, 1999) 5% of adults may have a history of anaphylaxis (various surveys) For 30 years, epidemiologic data regarding the incidence of anaphylaxis from all causes have been limited. This has resulted in the perception by many clinicians that anaphylaxis is rare. Although estimates of its occurrence are difficult to determine, specialists agree that the incidence of anaphylaxis is underreported and appears to be increasing. A recently published study indicates that as many as 41 million individuals in the United States are at risk; however, cases may go unreported as many affected individuals fail to inform their physicians about prior reactions. Confusion about the definition of anaphylaxis may also lead to underreporting, and mild reactions, involving hives and occurring without other manifestations, are not always recorded as anaphylaxis. More severe symptoms may be misdiagnosed as acute asthma or other respiratory emergencies. An epidemiologic study conducted by Yocum et al at the Mayo Clinic identified an average annual incidence rate of 21 per 100,000 person-years. If this is projected as a national average, then approximately 63,000 new cases of anaphylaxis would be reported each year in the United States. While there have been few reports of the overall prevalence of anaphylaxis, it has been estimated that 5% of adults may have a history of anaphylactic reactions. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Neugut AI, et al. Anaphylaxis in the United States. An investigation into its epidemiology. Arch Intern Med 2001;161:15–21. Yocum MW, et al. Epidemiology of anaphylaxis in Olmsted County: a population-based study. J Allergy Clin Immunol 1999;104:452–456.

Pathogenesis of Anaphylaxis
IgE-mediated (Type I hypersensitivity) Sensitization stage Subsequent anaphylactic response Most anaphylactic episodes are mediated by IgE antibodies; these are also known as Type I hypersensitivity reactions. Prior to the anaphylactic event, a sensitization stage must occur, during which the affected individual is first exposed to the allergen. This exposure results in subsequent production of specific IgE antibodies. A repeat exposure to the same allergen results in the development of the signs and symptoms of anaphylaxis. Berkow R, ed. The Merck Manual of Medical Information: Home Edition. Whitehouse Station, NJ: Merck & Co, Inc; 1997.

Sensitization Stage  Antigen (allergen) exposure  Plasma cells
produce IgE antibodies against the allergen Plasma cell IgE This slide presents the steps occurring in the sensitization stage. The initial meeting with the allergen produces no symptoms, but sensitizes the individual to future exposures. In this stage, the individual is exposed to a normally harmless substance, such as peanuts or shellfish, that the body perceives as an allergen. IgE antibodies, produced by plasma cells in response to this exposure, attach to tissue mast cells and peripheral blood basophils of the body’s immune system. At this point, sensitization is complete. Berkow R, ed. The Merck Manual of Medical Information: Home Edition. Whitehouse Station, NJ: Merck & Co, Inc; 1997. Marieb E. Nonspecific body defenses and immunity. In: Human Anatomy & Physiology. 4th ed. Menlo Park, Calif: Addison Wesley Longman, Inc; 1998:758–797. Mast cell with fixed IgE antibodies  IgE antibodies attach to mast cells and basophils Granules containing histamine

Anaphylactic Reaction
 More of same allergen invades body Antigen • • • • • • • • • • • • • •  Allergen combines with IgE attached to mast cells and basophils, which triggers degranulation and release of histamine and other chemical mediators • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Mast cell granules release contents after antigen binds with IgE antibodies • • • • • • • • • • • • • • • • . • • • • • • • • • During subsequent encounters with the same allergen, the allergen cross-links to adjacent IgE molecules on the surface of the mast cells and basophils. This induces an enzymatic cascade that causes the mast cells and basophils to degranulate, releasing a flood of histamine and other bioactive mediators, such as prostaglandins and various cytokines. Together, these chemicals induce the inflammatory response, producing increased vascular permeability, vasodilation, smooth muscle contraction, and myocardial depression, which are responsible for the clinical manifestations of hives, edema, bronchospasm, and shock. Marieb E. Nonspecific body defenses and immunity. In: Human Anatomy & Physiology. 4th ed. Menlo Park, Calif: Addison Wesley Longman, Inc; 1998:758–797. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Histamine and other mediators •

Common Causes of IgE-mediated Anaphylaxis
Foods Insect venoms Latex Medications Immunotherapy Insect venom Inhalant allergens Allergens causing IgE-mediated anaphylaxis are primarily proteins. Proteins present in foods, insect venoms, and latex are the most common causes of anaphylaxis occurring by this mechanism. Virtually any medication can cause anaphylaxis. The most common drug allergens, which occur as haptens, are the beta-lactam antibiotics and the sulfonamides, but many other drugs can cause severe allergic reactions. Because immunotherapy involves exposure to an allergen, it has the potential to trigger anaphylaxis; the occurrence, however, is low. For patients undergoing venom immunotherapy, the incidence of allergic reactions is approximately %; these are mostly mild and tend to occur early in treatment. More severe reactions are much less common (2%–5%). Immunotherapy injections for asthma and other nonvenom allergies have resulted in at least 47 deaths over the past 40 years. While it is important to remember that fatal anaphylaxis can occur in these patients, this extremely low risk is far outweighed by the benefits of immunotherapy. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Valentine MD. Anaphylaxis and stinging insect hypersensitivity. JAMA 1992;268:2830–2833. Cook RP, et al. The safety of allergen immunotherapy: a literature review. Ear Nose Throat J 1998;77:378–379,383–388.

Anaphylactoid Reactions
Non–IgE-mediated Complement-mediated Anaphylatoxins, eg, blood products Direct stimulation eg, radiocontrast media Mechanism unknown Exercise NSAIDs Anaphylactoid reactions resemble anaphylaxis clinically, but are unique in that they are not mediated by IgE and may occur upon initial exposure to an allergen. Despite these differences, it has become common practice to use the term anaphylaxis to describe either clinical syndrome. Although IgE antibodies are not involved here, the mast cell can be induced to react by other mechanisms. These include activation of the complement system or direct stimulation of mast cells and basophils to produce a sudden, massive release of histamine and other mediators. Anaphylactoid reactions following the administration of blood products occur as a result of immune complex formation and activation of the complement system. As by-products of an activated complement system, the protein fragments C3a and C5a act as anaphylatoxins because of their ability to trigger the release of mediators from mast cells and basophils. Although the exact mechanism of direct stimulation of mast cells and basophils is unclear, exposure to various agents may result in mast cell degranulation and symptoms of anaphylaxis. Agents such as radiocontrast media, opioids, and neuromuscular blocking agents have been associated with these direct effects. Other causes, for which the mechanism is unknown, include NSAIDs and exercise. Again, reactions to these triggers do not require prior exposure, although patients with a history of reactions to radiocontrast media demonstrate a markedly increased risk of anaphylaxis upon subsequent exposure. The incidence of reactions to aspirin and other NSAIDs is approximately 1%, although aspirin intolerance may be present in up to 20% of asthmatics. The occurrence of exercise-induced anaphylaxis is intermittent and unpredictable; however, episodes tend to decrease or stabilize over time. These reactions may be associated with the ingestion of certain foods prior to or after exercise. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC. Atkinson TP, et al. Anaphylaxis. Med Clin North Am 1992;76:841–855. Wyatt R. Anaphylaxis. How to recognize, treat, and prevent potentially fatal attacks. Postgrad Med 1996;100:87–99.

Myth: The Cause of Anaphylaxis is Always Obvious
REALITY: Idiopathic anaphylaxis is common Triggers may be hidden Foods Latex Patient may not recall details of exposure, clinical course Often, the cause of an anaphylactic reaction is obvious. In some cases, however, no specific etiology can be determined, even after repeated episodes and extensive investigation. This is referred to as idiopathic anaphylaxis. In the case of food and latex allergies, the trigger may be easily hidden. Food product labels may use ingredient names confusing to consumers (eg, whey for milk protein). In addition, accidental cross-contamination of production lines may occur. Many individuals may be unaware that latex is present in the elastic of undergarments, in erasers, balloons, and any of 40,000 other common household items. And finally, many patients simply may not recall the details of prior exposures. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC.

Clinical Manifestations of Anaphylaxis
Skin: Flushing, pruritus, urticaria, angioedema Upper respiratory: Congestion, rhinorrhea Lower respiratory: Bronchospasm, throat or chest tightness, hoarseness, wheezing, shortness of breath, cough The clinical manifestations of anaphylaxis are the result of the effects of mast cell mediators on 1 or more of the 4 major organ systems involved in a reaction: the skin, the respiratory tract, the gastrointestinal tract, and the cardiovascular system. These organ systems are rich in mast cells and are highly sensitive to the effects of mast cell mediators. The cutaneous manifestations of flushing, pruritus, urticaria, and angioedema are seen in the majority of cases of anaphylaxis. Flushing and pruritus are often the first signs observed, later progressing to include hives and angioedema. In the upper respiratory tract, edema of the larynx, epiglottis, and surrounding tissues can cause severe and even fatal obstruction. Swelling of the lips and tongue may be severe enough to impair ventilation. The symptoms of rhinitis (eg, pruritus, watery discharge from the nose and eyes) are common. In the lower respiratory tract, bronchospasm may be associated with chest or throat tightness, hoarseness, shortness of breath, cough, and wheezing, especially in patients with underlying reactive airways disease. In fact, there is evidence that patients with asthma may be at highest risk of fatal food-induced anaphylaxis because of their increased risk of lower airway complications. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC.

Gastrointestinal tract: Oral pruritus Cramps, nausea, vomiting, diarrhea Cardiovascular system: Tachycardia, bradycardia, hypotension/shock, arrhythmias, ischemia, chest pain Gastrointestinal symptoms occur most commonly in food-induced anaphylaxis, but can occur with other causes as well. Oral pruritus is often the first symptom observed in patients experiencing food-induced anaphylaxis. Abdominal cramping is also common, but nausea, vomiting, and diarrhea are frequently observed as well. The cardiovascular effects of anaphylaxis may be profound. Typically, tachycardia is present, occurring as a compensatory response to a decreased intravascular volume. However, bradycardia may also develop as a result of increased vagal activity or in patients with atrial conduction defects or those taking beta blockers. Hypotension and hypotensive shock occur as a result of peripheral vasodilation, increased capillary permeability, and intravascular volume losses. In addition, ECG changes may be observed, including arrhythmias and evidence of ischemia, and patients may complain of chest pain. Bochner BS. Anaphylaxis. N Engl J Med 1991;324:1785–1790.

Signs/symptoms Incidence (%) Urticaria and angioedema Upper airway edema* Dyspnea and wheezing Flush* Dizziness, syncope, and hypotension Gastrointestinal symptoms Rhinitis* Headache* Substernal pain* Itch without rash* Seizure* *Symptom or sign not reported in all four series 88 56 47 46 33 30 16 15 6 4.5 1.5 This table summarizes the presenting signs and symptoms documented in 4 studies involving 743 patients with anaphylaxis. The most common symptoms were urticaria and angioedema, occurring in 88% of patients. The next most common manifestations were respiratory symptoms, such as upper airway edema, dyspnea, and wheezing. Cardiovascular symptoms of dizziness, syncope, and hypotension, were less common, but it is important to remember that cardiovascular collapse may occur abruptly, without the prior development of skin or respiratory manifestations. Other symptoms of rhinitis, headache, substernal pain, and pruritus without rash were less commonly observed. Lieberman P. Distinguishing anaphylaxis from other serious disorders. J Respir Dis 1995;16:411–420.

Myth: Anaphylaxis Always Presents with Cutaneous Manifestations
REALITY: Approximately 10%-20% of anaphylaxis cases will not present with hives or other cutaneous manifestations 80% of food-induced, fatal anaphylaxis cases were not associated with cutaneous signs or symptoms It is commonly believed that all cases of anaphylaxis present with cutaneous manifestations, such as hives or mucocutaneous swelling. But in fact, as previously mentioned, up to 20% of anaphylactic episodes may not involve these signs and symptoms on presentation for emergency care. Moreover, a survey of children with food-induced anaphylaxis showed that 80% of fatal reactions were not associated with cutaneous manifestations, but rather involved initial gastrointestinal complaints of abdominal cramping and vomiting. This is important, as many of the most severe cases of anaphylaxis may go unrecognized by emergency personnel, resulting in inappropriate treatment and adverse health outcomes. Wood RA. Common myths about anaphylaxis. Food Allergy News. 2000;9:1–11. Sampson HA, et al. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380–384.

Clinical Course of Anaphylaxis
Uniphasic Biphasic Recurrence up to 8 hours later Protracted Hours to days The clinical course of anaphylaxis is variable, and depends on patient sensitivity and dose and route of administration of the allergen. We are most familiar with the uniphasic type of anaphylactic reaction, whose onset occurs in seconds to under an hour following allergen exposure and resolves within 4 hours with appropriate treatment. However, up to 20% of cases exhibit a biphasic pattern, in which recurrence of symptoms, or the appearance of new signs and symptoms, is observed several hours after the initial onset of the reaction. Signs and symptoms experienced during the recurrent phase may be similar, or worse than, those associated with the initial reaction. Since life-threatening manifestations may recur, careful monitoring is critical. The American Academy of Allergy Asthma and Immunology currently recommends that patients experiencing anaphylaxis be observed in a hospital for at least 4 hours after the initial symptoms subside. In still other individuals, a protracted syndrome may occur, lasting from hours to days in duration. Given these variations in clinical course, it is important that clinicians be particularly vigilant in these cases, as death can occur virtually at any time during this period. AAAAI Board of Directors. Position statement.Anaphylaxis in schools and other childcare settings. J Allergy Clin Immunol 1998;102:173–176. Stark BJ, et al. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986;78:76–83.

Myth: Prior Episodes Predict Future Reactions
REALITY: No predictable pattern Severity depends on: Sensitivity of the individual Dose of the allergen Another widely held belief is that the severity of previous anaphylactic reactions will predict future episodes or that each consecutive episode will become progressively more severe. To be accurate, there is no predictable pattern with regard to the severity of future anaphylactic reactions. The severity of any reaction depends on the individual’s degree of hypersensitivity and the dose of the allergen, neither of which is constant or predictable. In addition, a patient’s response to a particular allergen may be exacerbated by poorly controlled asthma, exercise, or the consumption of alcohol. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Anaphylaxis Fatalities
Estimated 500–1000 deaths annually 1% risk Risk factors: Failure to administer epinephrine immediately Beta blocker, ?ACEI therapy Asthma Cardiac disease Rapid IV allergen Data regarding fatalities associated with anaphylactic reactions are limited. It is estimated, however, that between 500 and 1000 individuals die of anaphylaxis each year, and that the risk of death in those who experience such a reaction approximates 1%. It is clear that the risk for an increased severity of anaphylaxis or death may be related to alterations in the body’s homeostatic mechanisms, as in patients receiving beta blockers, ACE inhibitors, or in the presence of underlying adrenal insufficiency. Beta blocking drugs or the presence of asthma may worsen the airway response to treatment and complicate resuscitative efforts. Moreover, epinephrine administration in the face of beta blocker treatment may lead to unopposed -adrenergic effects and significant hypertension. Preexisting cardiac disease or the rapid intravenous infusion of an allergen may also be responsible for poor outcomes. Importantly, the failure to administer epinephrine immediately after the onset of anaphylactic symptoms has been shown to be an independent risk factor contributing to fatal outcomes. Miller RL. Epidemiology of anaphylaxis. Presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC. Bocher BS. Anaphylaxis. N Engl J Med 1991:324:1785–1790.

Food-induced Anaphylaxis: Incidence
35%–55% of anaphylaxis is caused by food allergy 6%–8% of children have food allergy 1%–2% of adults have food allergy Incidence is increasing Accidental food exposures are common and unpredictable Food allergy is the most common cause of anaphylaxis, accounting for 35% to 55% of cases. The prevalence of food allergy is highest in the first year of life. Overall, 6% to 8% of young children display food allergy in population studies employing oral food challenges. The greater susceptibility of young infants is believed to be the result of immunologic immaturity and, to some extent, immaturity of the gut. Introducing solid foods to an infant’s diet after 4 months of age has been shown to prevent some food allergy. As children mature, the prevalence of food allergy declines. Oral food challenge studies in adults have indicated that 1% to 2% are affected by food allergies. It appears that, for both children and adults, the incidence of food allergy and anaphylaxis is increasing. More children are demonstrating peanut allergy, possibly due to early exposure through breast milk, as well as many environmental factors. More adults are reporting allergic reactions to foods, possibly due to a greater exposure to processed and foreign foods. The incidence of food-related anaphylaxis is underreported for several reasons. First, anaphylaxis is not reportable by the CDC. In addition, many patients fail to recognize a particular food as the stimulus for a reaction, and, if the reaction was mild, may have self-medicated with over-the-counter antihistamines and never consulted a physician. If the patient did seek emergency medical care, there is a good chance that follow-up with a primary care physician or an allergist was never scheduled. Kemp SF, et al. Anaphylaxis. A review of 266 cases. Arch Intern Med 1995; 155:1749–54. Pumphrey RSH, et al. The clinical spectrum of anaphylaxis in northwest England. Clin Exp Allergy 1996; 26:1364–1370. Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 1987;79:683–688.

Food-induced Anaphylaxis: Common Triggers
Children and adults (usually not outgrown): Peanuts Tree nuts Shellfish Fish Additional triggers in children (commonly outgrown): Milk Egg Soy Wheat Food-induced anaphylaxis is caused by exposure to specific food proteins (but not carbohydrates or fats). Lifelong sensitivity to peanuts, tree nuts, shellfish, and fish account for 80% to 90% of life-threatening anaphylactic reactions. Reactions resulting from lifelong triggers tend to be more severe in their presentation. Additional triggers include milk, egg, soy, and wheat. Fortunately, at least 85% of children outgrow their sensitivity to these foods. Of interest, certain foods such as bananas, avocado, chestnuts, kiwi, and stone fruit (B-A-C-K-S) display a cross-sensitivity in latex-allergic individuals. Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 1987;79:683–688. Bock SA, et al. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr 1990;117:561–567. Ahlroth M, et al. Cross-reacting allergens in natural rubber latex and avocado. J Allergy Clin Immunol 1995;96:167–173. Alenius H, et al. Crossreactivity between allergens in natural rubber latex and banana studied by immunoblot inhibition. Clin Exp Allergy 1996;26:341–348.

Food-induced Anaphylaxis: Common Symptoms
Oropharynx: Oral pruritus, swelling of lips and tongue, throat tightening GI: Crampy abdominal pain, nausea, vomiting, diarrhea Cutaneous: Urticaria, angioedema Respiratory: Shortness of breath, stridor, cough, wheezing Following exposure to food triggers, initial symptoms may be limited to the oropharynx, and include sensations of tingling or itching of the mouth, swelling of the lips or tongue, and throat tightness. As one might expect, the GI tract is prominently involved; crampy abdominal pain is most common, but nausea, vomiting, and diarrhea are also frequently observed. Further spread of the antigen through the blood results in effects on the skin (urticaria, angioedema) and the respiratory system (shortness of breath, stridor, cough, and wheezing). In the most severe cases, the cardiovascular system is involved, as evidenced by hypotension and cardiovascular collapse. As with other causes of anaphylaxis, food-induced reactions are often not associated with cutaneous symptoms. Indeed, studies have shown that 80% (or more) of patients experiencing fatal food-induced anaphylaxis had no evidence of skin involvement. Sampson HA, et al. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380–384. Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC. Yuninger JW, et al. Fatal food-induced anaphylaxis. JAMA 1988;260:1450–1452.

Food-induced Anaphylaxis: Fatal Reactions
Fatal reactions are on the rise ~150 deaths per year Usually caused by a known allergy Patients at risk: Peanut and tree nut allergy Asthma Prior anaphylaxis Failure to treat promptly w/epinephrine Many cases exhibit biphasic reaction Of significant concern is the increase in reports of fatal food anaphylaxis. Approximately 150 individuals in the United States die each year from these events, a number believed to be underestimated due to the exclusion of those who die before reaching a hospital or sudden deaths attributed to other causes. Death is usually caused by a known food allergen ingested away from home and the failure to administer epinephrine promptly. This may be due to a delayed recognition of the seriousness of the reaction and a “wait and see” approach during an insidious progression of symptoms to a severe and irreversible level. Individuals at great risk for a fatal reaction include those with asthma, a prior anaphylactic history, and those who deny symptoms and therefore delay treatment with epinephrine. In one study (Sampson et al) many cases of fatal food-induced anaphylaxis occurred in a biphasic clinical pattern. In these, mild oral and gastrointestinal symptoms occurred within 30 minutes of food ingestion. These symptoms resolved, only to be followed 1–2 hours later by severe respiratory symptoms and hypotension. Due to the potential for this presentation, it is critical that patients with food-induced anaphylaxis presenting for emergency care be closely observed for a minimum of 4 hours following their recovery from the initial event. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides Sampson HA, et al. Fatal and near-fatal anaphylactic reactions to food in children. N Engl J Med 1992;327:380–384. Yuninger JW, et al. Fatal food-induced anaphylaxis. JAMA 1988;260:1450–1452.

Fatal Food-induced Anaphylaxis (Bock SA, et al. JACI 2001;107:191–193)
32 cases of fatal anaphylaxis Adolescents or young adults Peanuts, tree nuts caused >90% of Rxn 20 of 21 with complete history had asthma Most did not have epinephrine available This recent study by Bock and colleagues presents the characteristics of 32 episodes of fatal anaphylaxis reported to a national registry established by the American Academy of Allergy, Asthma, and Immunology. Most patients involved were adolescents or young adults with known allergies to peanuts or tree nuts. All but 1 of 21 patients with complete information had asthma at the time of death. Most of the reactions took place away from home, and only a few patients (n=4) had epinephrine available for administration at the time of their reaction. Bock SA, et al. Fatalities due to anaphylactic reactions to food. J Allergy Clin Immunol 2001;107:191–193.

Food-induced Anaphylaxis: Prevention
I. AVOID ALLERGENS Learn to read product labels Identify alternative names for ingredients Find “hidden” ingredients Avoid high-risk foods (eg, baked goods) Avoid sharing food, utensils, or food containers Minute amounts can be life-threatening Provide educational materials FAAN- ( Strict adherence to prevention guidelines is key to reducing the risk for future anaphylactic episodes. Avoidance of foods that trigger allergic reactions may be achieved by educating patients regarding food labels and ingredient terminology. This requires an awareness of alternative names for certain ingredients, eg, whey for milk protein or natural flavor for cow’s milk. Patients and their families, friends, and teachers must be alert to changes in product labeling and cautious of unknown ingredients to avoid potentially serious and unexpected reactions. Labels must be thoroughly examined for the presence of “hidden” ingredients (eg, peanut butter in spaghetti sauce). Peanut-allergic patients must be educated to avoid certain high-risk foods, such as baked goods and Asian dishes, which may be prepared with nut-based ingredients. Children should be reminded frequently not to trade or share food, food utensils, or food containers. Even minute amounts of certain foods, such as peanuts, can be life-threatening when ingested by an allergic individual. Children may experience a skin rash or an upset stomach simply as a result of exposure to residual peanut butter or milk on tables wiped clean of visible material. It is important to provide educational materials to patients on how to avoid food allergens. The Food Allergy & Anaphylaxis Network has educational materials geared towards patients regarding food allergies. Their website address is provided. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Food-induced Anaphylaxis: Prevention
II. RISK MANAGEMENT Complete avoidance is impossible Must always be prepared to treat a reaction Have an emergency action plan Keep EpiPen or EpiPen Jr on hand at all times Train caregivers and teachers on EpiPen use Wear MedicAlert bracelet Another important component of anaphylaxis prevention is risk management. Understanding that complete avoidance is impossible due to hidden ingredients or accidental exposure, it is important that family, friends, and teachers be aware of a child’s allergic history and the potential ramifications associated with an exposure. Guardians and caregivers must always be prepared to treat a reaction. An emergency plan should be in place in the home, at school, at day care, and during sports activities. Since the immediate administration of epinephrine may save a life, an EpiPen or EpiPen Jr auto-injector should be readily available. Teachers and other caregivers should be instructed on the proper use of the EpiPen unit, as well as the importance of rapidly transporting the patient to a health care facility for emergency medical care. Patients should be urged to wear a MedicAlert bracelet in the event that they are unable to communicate the nature of their symtoms and suspected cause. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. EpiPen is a registered trademark of EM Industries, used with permission by Dey, L.P., Napa Calif. MedicAlert  is a registered trademark of MedicAlert Foundation, Turlock, Calif.

Venom-induced Anaphylaxis: Incidence
0.5%–5% (13 million) Americans are sensitive to one or more insect venoms Incidence is underestimated Incidence increasing due to fire ants and Africanized bees Incidence rising due to more outdoor activities At least 40–100 deaths per year Systemic reactions to insect stings are a major medical problem. Population studies indicate that the incidence of systemic reactions from stinging insects of the Hymenoptera order ranges from 0.5% to 5%, meaning that up to 13 million Americans are sensitive to the venom of stinging insects. Many of these patients have reactions severe enough to warrant emergency care or hospital admission. The actual incidence of these reactions is likely to be much higher, since reactions to insect stings are not reportable by the CDC, and few individuals report the event to their primary care physician or allergist. The incidence is also believed to be rising due to a recent influx of fire ants and, possibly, as a result of the presence of Africanized bees in southern Texas. The incidence is also likely rising as a result of a greater interest in outdoor activities, such as gardening, hiking, camping, and bicycling in the rural countryside. It is estimated that approximately 40–100 deaths occur each year as a result of anaphylaxis due to insect stings, but again, since these are often unrecognized and rarely reported, this incidence is likely to be significantly underestimated. Anaphylaxis can occur in any age group, but most deaths due to insect sting anaphylaxis occur in adults. Valentine MD. Anaphylaxis and stinging insect hypersensitivity. JAMA 1992;268: Golden DBK, et al. Epidemiology of insect venom sensitivity. JAMA 1989;262: Wyatt R. Anaphylaxis: how to recognize, treat, and prevent potentially fatal attacks. Postgrad Med 1996;100:87-99.

Venom-induced Anaphylaxis: Common Culprits
Hymenoptera Bees Wasps Yellow jackets Hornets Fire ants Geographical Honeybees, yellow jackets most common in East, Midwest, and West regions of US Wasps, fire ants most common in Southwest and Gulf Coast The protein component of insect venom is responsible for the symptoms associated with anaphylaxis. Insects most commonly associated with triggering severe allergic reactions are members of the Hymenoptera order. These include bees, wasps, yellow jackets, hornets, and fire ants. These key culprits can be further delineated by the geographic location in which they reside. Honeybees and yellow jackets account for most of the systemic sting reactions reported in the eastern, midwestern, and western United States. Wasps and fire ants cause most of the reactions in the southwestern and Gulf Coast regions of the country. As a result of warmer weather conditions, the fire ant has become an increasingly prevalent pest and common cause of venom-associated reactions. Known for their aggressive behavior, fire ants attack in swarms, stinging their victims up to 7 or 8 times. These insects pose a serious health risk to susceptible humans and animals. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Venom-induced Reactions: Common Symptoms
Normal: Local pain, erythema, mild swelling Large local: Extended swelling, erythema Anaphylaxis: Usual onset within 15–20 minutes Cutaneous: urticaria, flushing, angioedema Respiratory: dyspnea, stridor Cardiovascular: hypotension, dizziness, loss of consciousness 30%–60% of patients will experience a systemic reaction with subsequent stings Normally, an insect sting produces local pain, redness, and mild swelling. Insect stings always are accompanied by pain, which differentiates stings from insect bites. This reaction usually subsides within 1 to 2 hours. Large local reactions are more pronounced and involve swelling that extends from the sting site over a large area. Symptoms usually peak at 48 hours and may last up to 1 week. If severe, such reactions may be accompanied by fatigue and nausea. Symptoms of venom-induced anaphylaxis vary from patient to patient and are typical of anaphylaxis triggered by other causes. The most common symptoms are cutaneous, including urticaria, flushing, and angioedema. Additionally, respiratory (upper airway edema) and cardiovascular events (shock) can be fatal. In most patients, symptoms occur within 15 to 20 minutes. Among patients who have experienced venom-induced anaphylaxis and not undergone venom immunotherapy, the risk of a systemic reaction (of equal or lesser severity) from future stings ranges between 30% and 60%. Reisman RE. Clinical aspects of Hymenoptera allergy. In: Levine MI, Lockey RF, eds. Monograph on Insect Allergy. Pittsburgh, Pa: Dave Lambert Associates; 1995:39–42.

Venom-induced Anaphylaxis: Prevention
Avoidance Measures What to do What not to do Have professionals Use scented products remove hives or nests Wear bright colors Wear white, smooth- finish clothes, ankle- Go barefoot high shoes Drink from open cans Keep outdoor areas free when contents are not of garbage visible Similar to the management of other causes of anaphylaxis, protection against future anaphylactic episodes requires both avoidance measures and risk management strategies. Avoidance is the primary preventive measure for patients who have had an allergic reaction to an insect sting. However, accidents are never planned and not all stings can be prevented. For example, Hymenoptera that fly may be very difficult to avoid and are not eliminated by the use of insect repellants. It is therefore very important to utilize these recommended avoidance measures in conjunction with risk management strategies, in particular, the immediate availability of an EpiPen/ EpiPenJr auto-injector. Patients should be instructed to minimize their exposure to insects by having professionals remove any hives or nests; wearing white, smooth-finish clothes; covering as much of the body as possible; and keeping outdoor areas free of food refuse and garbage. Additionally, patients should avoid scented products, such as perfumes, shampoos, or lotions, and should avoid wearing bright colors, which attract insects. Shoes should be worn at all times. And finally, patients should be strongly advised to avoid drink containers that do not allow visibility of their contents, to decrease the likelihood of a sting to the tongue or throat by a hidden insect. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Buckingham RB, Levine MI. Protective measures against insect stings and bites. In: Levine MI, Lockey RF, eds. Monograph on Insect Allergy. Pittsburgh, Pa:: Dave Lambert Associates; 1995:93–98. Hutcheson PS, et al. Lack of preventive measures given to patients with stinging insect anaphylaxis in hospital emergency rooms. Ann Allergy 1990;64:306–307.

Venom-induced Anaphylaxis: Prevention
Risk Management Keep EpiPen or EpiPen Jr on hand at all times Educate and train on EpiPen use Develop emergency action plan Wear a MedicAlert bracelet Consult an allergist to determine need for venom immunotherapy Because insect stings cannot be completely avoided, all patients at risk for anaphylactic reactions should have an EpiPen or EpiPen Jr auto-injector immediately accessible for administration. In fact, multiple EpiPen units should be available in Scout first aid kits and in schools and other public facilities. Emergency personnel training must emphasize the need for prescribing multiple EpiPen or EpiPen Jr units and scheduling follow-up care for patients at risk. Patients and their families must be educated about the significance of prompt treatment and trained about the appropriate use of the EpiPen auto-injector. Patients must be counseled on the importance of seeking medical attention promptly, even if the symptoms appear mild initially. It must be emphasized to family members and teachers that a “wait and see” approach only delays appropriate life-saving care and portends a poor outcome. Additionally, an emergency action plan must be developed and shared with all who are in close contact with the affected individual. This plan should emphasize the need for immediate epinephrine administration and a call for emergency assistance and transport to a health care facility for further management, which may include antihistamines, corticosteroids, intravenous fluids, and oxygen. Patients should wear a MedicAlert bracelet to facilitate rapid treatment if the patient is unconscious. To further decrease their risk, individuals at risk should be appropriately followed up by scheduling a consultation with an allergist to determine the need for venom immunotherapy. Hutcheson PS, et al. Lack of preventive measures given to patients with stinging insect anaphylaxis in hospital emergency rooms. Ann Allergy 1990;64:306–307. AAAAI Board of Directors. The use of epinephrine in the treatment of anaphylaxis. J Allergy Clin Immunol 1994;94:666–668.

Venom-induced Anaphylaxis: Immunotherapy
Medical criteria Hx of any systemic reaction in adults Hx of life-threatening reaction in children Positive venom skin test 97% effective Can be discontinued in most after 3–5 years; 10% risk of systemic reaction to subsequent stings Unlike individuals susceptible to anaphylaxis triggered by food, latex, or medications, those allergic to insect venom have the option of undergoing immunotherapy. Venom immunotherapy is medically indicated in any adult with a history of a systemic reaction to an insect sting, and in children who have had life-threatening sting reactions. A positive skin test response to one or more insect venoms is also required before immunotherapy is initiated. Venom immunotherapy has been shown to be 97% effective in providing protection against future systemic reactions related to insect stings. This is in contrast to the 30% to 60% risk for the development of a similar reaction that may occur in susceptible individuals not receiving immunotherapy. Most patients are able to discontinue venom immunotherapy after 3 to 5 years, although longer treatment may be recommended for patients experiencing more severe sting reactions. It must be remembered that, even after discontinuing venom immunotherapy, patients have a 10% risk of developing a systemic reaction to subsequent stings, although these reactions are generally mild. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Hunt KJ, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med. 1978;299:157–161. Nicklas RA, et al. Anaphylaxis: insect stings and bites. J Allergy Clin Immunol 1998;101: S493–S495.

Venom-induced Anaphylaxis: Immunotherapy
Risk of anaphylaxis 10%-15% of patients experience systemic reactions during early weeks of treatment Sx generally occur within 20 minutes Patients at risk: asthma, prior reactions, beta blocker or ACEI therapy Immunotherapy is generally well tolerated, with approximately 10%-15% of patients experiencing treatment-related systemic reactions. These reactions are generally mild and tend to occur in the first few weeks of treatment. The incidence of systemic reactions is much lower during maintenance therapy. Reactions typically occur within 20 minutes of immunotherapy administration, and range from symptoms of rhinitis or hives to chest tightness and throat swelling to loss of consciousness. Patients at greatest risk for systemic reactions related to immunotherapy include those with steroid-dependent asthma, a prior history of systemic reactions to immunotherapy, increased allergy sensitivity during diagnostic testing, and those receiving beta blocker or ACE inhibitor treatment. Valentine MD. Anaphylaxis and stinging insect hypersensitivity. JAMA 1992;268:2830–2833. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Immunotherapy-induced Anaphylaxis
Risk management Trained physician, equipped facility Epinephrine immediately available Monitor closely for 20–30 minutes Consider supply of EpiPen for those at high risk To ensure patient safety, immunotherapy must be performed only by a physician specifically trained in immunotherapy and anaphylaxis management and in facilities equipped to handle potential complications. Epinephrine should be immediately available during all immunotherapy sessions. It is also recommended that patients be closely monitored for at least 20 minutes following immunotherapy, a period during which allergic reactions may be expected to occur. This time may be extended to 30–45 minutes for high-risk patients. As insurance, physicians should consider prescribing EpiPen for patients with a significant risk for a systemic reaction following treatment. AAAAI Board of Directors. Guidelines to minimize the risk from systemic reactions caused by immunotherapy with allergenic extracts. Position Statement #25. Available at:

Latex-induced Anaphylaxis: Incidence
1%–6% of US population (up to 16 million) affected 8%–17% incidence among health care workers Repeated exposure leads to a higher risk Incidence has increased since mid 1980s Latex gloves, especially powdered gloves Latex allergy has been recognized as a medical problem with increasing frequency since the mid-1980s when surgical glove use rose dramatically to protect the health care work force against bloodborne pathogens. Recent reports indicate that latex allergy affects between 1% and 6% of the general population, or as many as 16 million Americans. Among health care workers, this figure rises to between 8% and 17%, involving up to 935,000 medical personnel. It is well known that repeated exposure increases the risk of developing latex sensitivity. Thus, those who have chronic medical conditions (eg, congenital urinary tract problems, spina bifida) that involve repeated, ongoing exposure to latex are at higher risk for developing anaphylaxis. For example, it has been reported that as many as 67% of children with spina bifida exhibit some degree of latex sensitivity. The incidence of latex allergy is increasing, largely due to the substantial rise in the use of powdered latex gloves among health care workers, custodians, sanitation workers, and food service staff. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Latex-induced Anaphylaxis: Triggers
Proteins in natural rubber latex Component of ~40,000 commonly used items Rubber bands Elastic (undergarments) Hospital and dental equipment Latex-dipped products are biggest culprits Balloons, gloves, bandages, hot water bottles Latex-induced anaphylaxis occurs in response to the proteins present in natural rubber latex. Synthetic latex rarely causes allergic reactions. Natural rubber latex is a component of an estimated 40,000 common items, including rubber bands, elastic (eg, in undergarments), and hospital and dental equipment. Latex-dipped products, such as balloons, gloves, condoms, diaphragms, Koosh balls, bandages, baby bottle nipples, hot water bottles, pacifiers, and rubber toys are common culprits in triggering allergic reactions. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Reactions to Latex Irritant contact dermatitis
Dry, itchy, irritated hands Allergic contact dermatitis Delayed hypersensitivity Latex allergy Immediate hypersensitivity Sx: hives, itching, sneezing, rhinitis, dyspnea, cough, wheezing Greatest risk with mucosal contact Three types of reactions may occur in individuals exposed to latex-containing products. It is important to distinguish between them so that anaphylactic reactions can be recognized and treated promptly. Irritant contact dermatitis is the most common reaction to latex; this involves the development of dry, itchy, irritated areas on the skin, usually the hands. It is caused by exposure to gloves and glove powder, workplace chemicals, and frequent handwashing. Irritant contact dermatitis is not considered a true allergy. Allergic contact dermatitis is a delayed hypersensitivity reaction resulting from exposure to chemicals added to latex during harvesting, processing, or manufacturing. The skin reaction resembles that caused by poison ivy, occurring 24 to 48 hours after contact. It may progress to oozing skin blisters or spread away from the area of initial contact. Latex allergy is an immediate hypersensitivity reaction of potentially greater severity than the 2 previously described conditions. Prior sensitization to proteins in the latex results in symptoms that range from mild (skin redness, hives, or itching) to moderate (rhinitis symptoms) to severe (wheezing, dyspnea). The greatest risk for these reactions is associated with mucosal contact. U.S. Department of Health and Human Services. Preventing allergic reactions to natural rubber latex in the workplace. DHHS (NIOSH) Publication No ; August 1998.

Latex-induced Anaphylaxis: Prevention
I. AVOIDANCE Use latex-free products Alert employer/health care providers, schools about need for latex-free products and equipment Wear MedicAlert bracelet Awareness of cross-sensitivity with foods: To be most effective, prevention requires the utilization of both avoidance measures and risk management strategies. Patients with a history of prior allergic reactions to latex should use latex-free products in the home and workplace. Because latex is a component of many household items, it may be difficult to avoid completely. However, as health care facilities, manufacturers, and others recognize the significant increase in reactions to latex, latex substitutes—or, at least powder-free, low-protein latex products—are becoming more readily available. Latex-sensitive individuals should alert their employers and health care providers of their history so that latex-free products can be utilized and serious anaphylactic reactions avoided. These individuals should be encouraged to wear a MedicAlert bracelet to communicate the need for medical assistance in the event of life-threatening symptoms. And finally, patients need to be educated regarding the potential cross-sensitivity between latex allergy and sensitivity to certain foods, including banana, avocado, chestnuts, kiwi, and stone fruit. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000. Banana Avocado Chestnuts Kiwi Stone fruit Others

Latex-induced Anaphylaxis: Prevention
II. RISK MANAGEMENT Prescribe EpiPen® or EpiPen® Jr Accidental exposure Patients at risk Educate re: EpiPen® use Develop emergency action plan Understanding that allergic reactions cannot be completely avoided, risk management strategies must be implemented. Patients with a history of latex sensitivity or those at high risk (eg, patients with spina bifida, congenital urologic abnormalities, multiple surgeries) should have an EpiPen auto-injector readily available for administration at the first onset of symptoms. Patients must be educated regarding when and how to administer EpiPen, as well as the need to develop and share an emergency action plan in the case of an anaphylactic episode. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Other Causes of Anaphylactic and Anaphylactoid Reactions
Drugs Antibiotics Chemotherapeutic agents Aspirin, NSAIDs Biologicals (vaccines, monoclonal antibodies) Radiocontrast media Exercise Idiopathic Many drugs have been implicated in the development of severe allergic reactions in hospitalized patients and as the primary reason for hospital admission. These include antibiotics (beta-lactams, sulfonamides, vancomycin, ciprofloxacin, tetracyclines, nitrofurantoin), chemotherapeutic agents (vincristine, methotrexate, fluorouracil), aspirin and other nonsteroidal anti-inflammatory drugs, and biologicals, such as vaccines and monoclonal antibodies. It has been estimated that 1 in 2700 hospitalized patients experiences drug-induced anaphylaxis. A recent meta-analysis of serious and fatal drug reactions indicates that, in the United States, as many as 500,000 hospital admissions per year may be associated with serious drug-related allergic reactions. Penicillin is the most frequent drug-related cause of anaphylaxis, accounting for 75% of anaphylactic deaths in the United States. Radiocontrast media (RCM) are used in more than 10 million procedures annually in the United States. Anaphylactoid reactions are estimated to occur in 0.22% to 1% of patients exposed. Patients with a history of such reactions have a 16% to 44% risk of reaction upon re-exposure. This risk may be reduced with pretreatment or the use of lower osmolality agents. Exercise-induced anaphylaxis may be associated with food or medication (aspirin, NSAIDs) ingestion prior to physical exertion, and may be associated with a higher incidence of familial atopic disorders. In a substantial percentage of cases, no cause for anaphylaxis can be identified. In a retrospective review of 266 cases referred to a private allergy practice, Kemp and colleagues classified 37% (or 98 patients) as having anaphylaxis of an idiopathic etiology. Porter J, et al. Drug-induced anaphylaxis, convulsions, and extrapyramidal symptoms. Lancet 1977;1:587. Lazarou J, et al. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. Nicklas RA, et al. Anaphylaxis. J Allergy Clin Immunol 1998;101(suppl):S465–S528. Kemp SF, et al. Anaphylaxis. A review of 266 cases. Arch Intern Med 1995;155:1749–1754.

Diagnosing Anaphylaxis
Based on clinical presentation, exposure Hx Cutaneous, respiratory Sx most common Some cases may be difficult to diagnose Vasovagal syncope Scombroid poisoning Systemic mastocytosis In some cases, a definitive diagnosis of anaphylaxis can be made on the basis of clinical manifestations and evidence for a temporal exposure to a specific allergen. In general, the existence of airway compromise, hypotension, gastrointestinal symptoms, and generalized cutaneous reactions, alone or in combination, are essential to this diagnosis. The onset of symptoms is typically immediate, but in food allergies, can be delayed up to 1 to 2 hours after exposure. Cutaneous and respiratory manifestations are most common in patients with anaphylaxis, but there may be a few important exceptions. In 2 studies of fatal, food-induced anaphylactic reactions, at least 80% of patients presented without skin manifestations. This is an important point, as the diagnosis of anaphylaxis is most often overlooked in cases in which no cutaneous manifestations are observed. Similarly, cardiovascular collapse with shock may occur immediately without respiratory or cutaneous symptoms. In other cases, anaphylaxis may be difficult to diagnose. Some conditions (such as those listed here) may share some clinical features of anaphylaxis, such as loss of consciousness and hypotension (as in vasovagal syncope) or generalized urticaria (seen in scombroid fish poisoning or systemic mastocytosis). These syndromes must be ruled out before a definitive diagnosis can be made. Bochner BS. Anaphylaxis. N Engl J Med 1991;324:1785–1790. Yunginger JW, et al. Fatal food-induced anaphylaxis. JAMA 1988;260:1450–1452. Sampson HA, et al. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380–384.

Careful history to identify possible causes Can be confirmed by serum tryptase Specific for mast cell degranulation Remains elevated for up to 6 hours Other labs to rule out other diagnoses Refer to allergist for specific testing The physician must obtain a careful history to identify potential causes for the anaphylactic event. The diagnosis of anaphylaxis may be confirmed by the presence of elevated plasma concentrations of the enzyme tryptase, which is specific for mast cell degranulation. Tryptase may be a useful marker, as it remains elevated for up to 6 hours following an anaphylactic episode and is stable in refrigerated serum, so that an assay may be performed in a previously obtained sample. Other laboratory data should be obtained as indicated to differentiate between anaphylaxis and other similarly presenting conditions. Once anaphylaxis is diagnosed and treated, referral to an allergist is recommended so that allergy testing can be done to confirm the specific cause and provide specific information about treatment and prevention. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides Wood RA. Identifying patients at risk for serious allergic reactions: an introduction to anaphylaxis. Abstract presented at: Anaphylaxis: Safely Managing Your Patients at Risk for Severe Allergic Reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC.

Allergists can identify specific causes by: Skin tests/RAST Foods Insect venoms Drugs Challenge tests NSAIDs Exercise Allergists routinely perform skin tests or RASTS (radioallergosorbent tests) to identify the cause of a previous allergic reaction due to foods, insect venoms or drugs, and guide further management. A wheal response indicates the presence of specific IgE antibodies to the allergen tested, and identifies a specific trigger in a given patient. Challenge testing may also be indicated. This involves a supervised exposure to suspected foods, drugs, or exercise by an allergist. In these situations, emergency medications (including epinephrine) and supportive care measures must be readily accessible since direct exposure may result in anaphylaxis.

Treatment of Anaphylaxis
Immediate treatment with epinephrine imperative No contraindications in anaphylaxis Failure or delay associated with fatalities IM may produce more rapid, higher peak levels vs SC Must be available at all times Antihistamine (oral or parenteral; if oral, use liquid or chewable tablet) Call 911; proceed to Emergency Room Treatment must begin immediately following the onset of symptoms, as it is well known that the reaction can rapidly progress within minutes to a life-threatening event. Epinephrine is the pharmacologic treatment of choice for an acute anaphylactic reaction. While there is reluctance by some to administer epinephrine, there are no contraindications to its use for a life-threatening allergic event. In fact, there is clear evidence that failing to use epinephrine, or delaying its use, may contribute to fatal outcomes associated with this serious disorder. Standard references recommend that epinephrine be administered by either the subcutaneous or intramuscular routes. A recent prospective randomized study has demonstrated, however, that peak drug concentrations may be higher and attained more rapidly by the intramuscular route. An antihistamine, usually diphenhydramine, also should be administered immediately. Although antihistamines do not have any life-saving effects and should not be considered a substitute for epinephrine, they can help reduce symptoms more quickly and potentially shorten the course of the reaction. When given orally, it is best if they are given as a liquid or chewable (or rapidly dissolving) tablet for quicker absorption. Following administration of epinephrine, a patient should be instructed to call 911 and proceed to an emergency room for follow-up medical care. Medical personnel should be told that a dose of epinephrine has been given. Bochner BS, et al. Anaphylaxis. N Engl J Med 1991;324:1785–1790. Yunginger JW, et al. Fatal food-induced anaphylaxis. JAMA 1988;260:1450–1452. Simons FER, et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33–37.

EpiPen/EpiPen Jr: Directions for Use
All patients at risk should be instructed as to the proper administration of EpiPen/EpiPen Jr before the need for its use arises. Detailed instructions for self-administration (contained in each auto-injector package) should be carefully reviewed with the patient. In addition, a training device (known as the EpiPen Trainer) that simulates the auto-injection process without actual drug delivery is available. Using the EpiPen Trainer, patients should practice self-administration under the supervision of a physician (or a trained assistant) until an appropriate administration technique and a satisfactory comfort level are assured. To prepare the EpiPen/EpiPen Jr for use, grasp the auto-injector with the hand (forming a fist around the unit) with the black tip facing downward. Immediately before use, remove the gray activation cap with the other hand, being careful not to touch the black tip, where the needle is located, at any time. EpiPen/EpiPen Jr package instructions. Napa, Calif: Dey, L.P., December 2000.

After uncapping the auto-injector, place the black tip near the fleshy outer portion of the thigh. Instruct the patient that it is not necessary to remove any clothing; the EpiPen/EpiPen Jr auto-injector is designed to work effectively through clothing. Remind the patient not to touch the black tip of the auto-injector at any time. EpiPen/EpiPen Jr package instructions. Napa, Calif: Dey, L.P., December 2000.

With a quick motion, swing out and jab firmly into the outer thigh, so that the injector is at a 90 degree angle to the thigh. Hold firmly in the thigh for several seconds. During this time, a spring-activated mechanism is released, and a dose of epinephrine is administered. When practicing with the trainer, a “click” indicates that the device worked properly. Remove the unit and massage the injection site for an additional few seconds. Once administration is complete, the patient should check the black tip of the auto-injector. If the needle is exposed, a dose of epinephrine was injected. If not, the above steps should be repeated. Inform the patient that most of the liquid (90%) stays in the auto-injector after the dose is administered and cannot be reused. To avoid an accidental needle stick, the needle of the fired unit should be bent back against a hard surface. Carefully return the auto-injector to its carrying tube (NEEDLE FIRST) without replacing the gray safety cap. Recap the carrying tube and bring it to the emergency care facility for proper disposal. Patients should be instructed to go immediately to the nearest Emergency Room for further medical attention. Medical personnel should be told that a dose of epinephrine has been given and should dispose of the auto-injector properly. Patients should be reminded to store their EpiPen/EpiPen Jr in a dark place at room temperature; prolonged temperature extremes (refrigeration or car glove box, trunk) should be avoided for optimal functioning of the auto-injector. Patients should check the EpiPen/EpiPen Jr monthly for expiration date and discoloration. If the unit has expired or the drug solution appears brown, the unit should be discarded and replaced immediately. EpiPen/EpiPen Jr package instructions. Napa, Calif: Dey, L.P., December 2000.

Myth: Epinephrine is Dangerous
REALITY: Risks of anaphylaxis far outweigh risks of epinephrine administration Minimal cardiovascular effects in children (Simons et al, 1998) Caution when administering epinephrine in elderly patients or those with known cardiac disease Misconceptions about epinephrine administration have resulted in delayed treatment and unfortunate outcomes. Some believe that epinephrine is too unsafe, as a result of its adverse cardiovascular effects. These effects, which include hypertension, tachycardia, arrhythmias, and myocardial ischemia may be related to excessive -and -agonist activity associated with rapid intravenous infusion of moderate to high doses of epinephrine. The reality is that the danger of untreated anaphylaxis far outweighs the risks of epinephrine for the vast majority of patients, particularly when usual doses are administered by the subcutaneous or intramuscular routes. A study by Simons et al reported no serious adverse effects in pediatric patients receiving epinephrine by these routes. Increases in blood pressure and heart rate were observed, but were mild and transient and could not be correlated with serum epinephrine concentrations. Particular caution should be exercised, however, when epinephrine is administered to elderly patients or those with pre-exisitng cardiac conditions. Barach EM, et al. Epinephrine for treatment of anaphylactic shock. JAMA 1984;251:2118–2122. AAAAI Board of Directors. The use of epinephrine in the treatment of anaphylaxis. J Allergy Clin Immunol 1994;94:666–668. Simons FER et al. Epinephrine absorption in children with a history of anaphylaxis. J Clin Allergy Immunol 1998;101:33-37.

Treatment of Anaphylaxis
Additional measures may include Corticosteroids Supplemental O2; airway maintenance IV fluids, vasopressor therapy Repeat epinephrine if Sx persist or increase after minutes Repeat antihistamine ± H2 blocker if Sx persist Observe for a minimum 4 hours Arrange follow-up care, provide EpiPen® Rx and education After an immediate injection of epinephrine, the patient must be transported to an emergency care facility for follow-up care. Due to the potential for a protracted or biphasic reaction, all patients should remain in the Emergency Department for observation for at least 4 hours. Corticosteroids may be helpful in preventing prolonged or biphasic reactions and should be administered in all severe cases. If the initial reaction persists or escalates despite the initial dose of epinephrine, the dose may be repeated after minutes. One study showed that 35% of patients required more than 1 dose of epinephrine to effectively manage an anaphylactic reaction. Basic supportive measures, such as oxygen and maintenance of airway patency, may be required. Intravenous fluids or vasopressor therapy may be administered for hypotension. Patients receiving beta blocker therapy may be unresponsive to the vasopressor effects of epinephrine; in these cases, intravenous glucagon may reverse hypotension. An additional dose of antihistamine should be given if symptoms persist and an H2 blocker such as cimetidine also may be helpful in reversing the histamine-induced component of anaphylactic hypotension. Finally, follow-up care must be arranged prior to discharge. The patient should be referred to an allergist if they have not seen one previously. If this was a first reaction, the patient should be provided with an EpiPen prescription and instructions regarding its use. The Emergency Room physician should make sure that patients who had previously been prescribed an EpiPen have a current prescription. Broadbent JB. Anaphylaxis: safely managing your patients at risk for severe allergic reactions. Postgraduate Institute for Medicine; October 8, 1999; Washington, DC. Lieberman P. Anaphylaxis: guidelines for prevention and management. J Respir Dis 1995;16:456–462. Korenblat P, et al. A retrospective study of epinephrine administration for anaphylaxis:how many doses are needed? Allergy Asthma Proc 1999;20:383–386.

Myth: Anaphylaxis is Reported
REALITY: Most individuals do not inform their personal physician of an anaphylactic reaction either at the time of the reaction or during routine exams Given the life-threatening severity of anaphylaxis, it may be assumed that patients will seek medical care and inform their primary care physician of the event. However, this is often not the case. The reality is that patients treated in the Emergency Department frequently do not seek follow-up care or referral with an allergist. Therefore, it is important to screen patients through careful questioning about their medical history to determine the need for preventive measures. Dey, L.P. Anaphylaxis Myths & Realities. Slide presentation. Based on the work of David B.K. Golden, MD, Johns Hopkins University School of Medicine.

Risk Management for Anaphylaxis
SCREEN Atopy 10% of children with asthma have food allergy 30%–40% of children with atopic dermatitis have food allergy Previous reactions 75% will have more than one 57% will have three or more Any individual may be at risk for anaphylaxis at some time, despite the absence of obvious risk factors. However, some individuals are at greater risk than others, and must be identified with effective screening tools and counseled regarding their risk for anaphylaxis. Screening measures must be adopted to identify atopic patients and those who are predisposed to develop allergic rhinitis, asthma, atopic dermatitis, or food allergy. Atopic children (and adults) have an increased risk of developing food-induced anaphylaxis. Reports have shown that 10% of children with asthma and 37% with atopic dermatitis demonstrate food allergy. These patients (or their parents) must be carefully interviewed to determine if previous allergic reactions have occurred. Those with positive responses may be at increased risk for future reactions. Of those who have experienced an anaphylactic reaction, 75% will experience another and 57% will have 3 or more. (Dey has a useful screening tool available to assist physicians in asking the appropriate questions.) It is also important to emphasize that patients with asthma, adrenal insufficiency, or those taking beta blocker or ACEI therapies may be at risk for a more severe reaction or death following allergen exposure. Lieberman P. Distinguishing anaphylaxis from other serious disorders. J Respir Dis 1995;16:411–420. Sampson HA. Food allergy. In: Primer on Allergic and Immunologic Diseases. JAMA 1997; 278:1888–1894. Dey, L.P. Fact file on anaphylaxis: acute allergic reactions to food, medication, insect stings, latex. Napa, Calif: Dey, L.P.; 2000.

Screening Patients at Risk
Did you ever have a severe allergic reaction: To any food? To any medicine? To an insect sting? To latex? That caused breathing trouble? Severe hives and swelling? Severe vomiting or diarrhea? Dizziness? That required you to go to the hospital? Physicians must carefully screen their patients to identify those at risk for anaphylaxis. Detailed information about food, medication, latex, and stinging insect exposures in the hours before the episode should be obtained. The questions shown in this slide are examples from an intake form provided by a practicing allergist. A positive answer to any question requires further probing regarding the details of the event, eg, suspected cause, duration of symptoms, treatment received, and the presence of underlying diseases such as asthma. Source: Intake Tool. Developed by David B.K. Golden, MD, Associate Professor of Medicine at the Johns Hopkins University School of Medicine; Baltimore, Md. Dey, LP. Napa, Calif., 2000.

SCREEN, Educate, and Protect
Patients at Risk Effective screening is critical in identifying patients for whom EpiPen/EpiPen Jr should be prescribed. The patient screener pictured on this slide is available from Dey, L.P. It includes pertinent information describing the usual causes of anaphylaxis, related symptoms, and potential consequences if such events are not immediately treated with epinephrine. This screening tool may be used to assist parents (or patients) in quickly and easily documenting important symptoms and associated situations indicating a high risk for anaphylaxis. It is hoped that positive responses will encourage affected individuals to seek medical assistance and obtain multiple units of EpiPen/EpiPen Jr to reduce the risk of death or near-death related to these events. Anaphylaxis Screening Tool. Napa, Calif:Dey, L.P., 2001.

EDUCATE Teach avoidance measures “Accidents are never planned” Stress importance of: Always having a current EpiPen on hand Immediate treatment Emphasize the need for follow-up care Once patients at risk have been identified, they should be educated about anaphylaxis and appropriate avoidance measures. Physicians must emphasize that avoidance measures are not 100% effective in preventing future episodes. Accidental exposure can and will occur; therefore, patients need to be prepared. Stress the importance of always having a current EpiPen on hand. Stress that the expiry date of unit should be checked regularly (and enroll the unit in the free reminder program offered by Dey; enrollment forms are included in every package). Stress the need for immediate administration at the onset of symptoms. Provide training on the administration of an EpiPen unit using the EpiPen Trainer. To facilitate appropriate management, it may be optimal to supply some patients at risk with multiple units of EpiPen, particularly patients with severe prior reactions. Explain the importance of follow-up care, including prompt transport to the nearest emergency care facility and referral to an allergist for further treatment. Also, emphasize the patient’s responsibility in reporting the details of any reaction to his/her primary care physician or allergist.

* EpiPen® 2-Pak was launched in April 2001
As stated earlier, it may be optimal to supply some patients at risk with multiple units of EpiPen, particularly: a) patients with severe prior reactions; b) patients who live, work, or play 15 minutes from medical attention; and c) patients living in areas where epinephrine is not automatically carried on ambulances (true in 38 states). EpiPen 2-Pak  offers two auto-injectors and a Trainer in every carton. * EpiPen® 2-Pak was launched in April 2001

EDUCATE: Draft an Emergency Plan Provide specific instructions on when to administer EpiPen or EpiPen Jr Call for help (911); transport patient to emergency care facility Stay calm; keep patient warm Specify directions for antihistamine use Report EpiPen administration Establishing an emergency plan involves identifying specific steps that parents and other caregivers can take to facilitate prompt treatment of an anaphylactic episode. This emergency plan is particularly useful in reducing associated fears, allowing prompt action to potentially save a life. As indicated, EpiPen® or EpiPen® Jr should be administered (through the clothing if necessary) immediately at the onset of symptoms. Since the severity of symptoms can quickly escalate to life-threatening, the importance of this intervention cannot be overstated. A caregiver should subsequently call for help (911, physician, parents) and the patient should be quickly transported to an emergency care facility for further treatment and observation. The patient should be kept warm and reassured that help is on the way. Specific guidelines for the administration of antihistamines should be provided; these drugs should never be considered a substitute for epinephrine in this situation. Patients and caregivers should be instructed to bring used EpiPen auto-injectors with them to the Emergency Department to communicate any medication use prior to their arrival.

Screen, Educate, and Protect
Emergency Health Care Plan ALLERGY TO:_____________________________________________________________ Child’s Name:___________________________D.O.B:____________Teacher:___________________ Asthmatic Yes (High risk for severe reaction) No Signs of an allergic reaction include: Systems: Symptoms: MOUTH itching & swelling of the lips, tongue, or mouth THROAT* itching and/or a sense of tightness in the throat, hoarseness, and hacking cough SKIN hives, itchy rash, and/or swelling about the face or extremities GUT nausea, abdominal cramps, vomiting, and/or diarrhea LUNG* shortness of breath, repetitive coughing, and/or wheezing HEART* “thready” pulse, “passing-out” The severity of symptoms can quickly change! *All above symptoms can potentially progress to a life- threatening situation! ACTION: 1. If ingestion is suspected give________________________________________________ medication/dose/route and_____________________________________________________immediately! 2. CALL RESCUE SQUAD:_________________________________________________ 3. CALL: Mother__________________ Father___________________ or emergency contacts 4. CALL: Dr.____________________________ at ____________________________ DO NOT HESITATE TO ADMINISTER MEDICATION OR CALL RESCUE SQUAD EVEN IF PARENTS OR DOCTOR CANNOT BE REACHED! ________________________ _______ _______________________M.D. _______ Parent Signature Date Doctor’s Signature Date For children with multiple food allergies, use one form for each food. Place Child’s Picture Here Because severe anaphylactic reactions often occur outside the home, it is important that an emergency action plan be readily available for each patient at risk. This plan should identify specific symptoms of an allergic reaction and outline specific actions to be taken in the event of symptom development. This includes medications to be administered and appropriate calls for emergency transport and parental notification. This plan should be reviewed and signed by all caregivers trained in the management of anaphylaxis, including the patient’s physician, parents, teachers, and scout leaders. All included individuals should be trained in when and how to administer epinephrine, and to assist in ensuring that an adequate supply of EpiPen/EpiPen Jr is available in the case of an emergency situation. AAAAI Board of Directors. Position statement: Anaphylaxis in schools and other childcare settings. J Allergy Clin Immunol 1999;102: EMERGENCY CONTACTS TRAINED STAFF MEMBERS 1.__________________________________ Relation:________________Phone:________ 1._________________________Room______ 2.__________________________________ 2._________________________Room______ 3.__________________________________ 3._________________________Room______ AAAAI Board of Directors. Position statement: Anaphylaxis in schools and other childcare settings. J Allergy Clin Immunol 1999;102: Reprinted with permission.

Myth: Anaphylaxis is Easy to Avoid If You Know What You are Allergic To
REALITY: Most cases of anaphylaxis are due to accidental exposures It seems logical that anaphylaxis can be avoided simply by avoiding known allergens. However, most cases of anaphylaxis occur due to accidental exposures. Clinical studies have found repeatedly that, even when patients attempt strict avoidance of a known allergen, their efforts are rarely 100% successful. Hidden food ingredients can lead to fatal anaphylaxis. Even minute amounts of allergen, such as food particles that become airborne during cooking, can cause an allergic response. Other allergen sources, such as latex or flying Hymenoptera, may be similarly difficult to avoid. It is much more common to have a reaction to a hidden ingredient to which there is a known allergy than to experience an allergic reaction to a previously tolerated food. Wood RA. Common myths about anaphylaxis. Food Allergy News. 2000;9:1–11. Sampson H, et al. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380–384. Bock SA, et al. The natural history of peanut allergy. J Allergy Clin Immunol. 1989;83:900–904. AAAAI Board of Directors. Position statement.Anaphylaxis in schools and other childcare settings. J Allergy Clin Immunol 1998;102:173–176. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides

PROTECT: Prescribe self-injectable EpiPen Teach patient proper use of EpiPen Educate family, friends, teachers, caregivers Because complete avoidance is impossible, and the failure to administer epinephrine immediately may prove fatal, an EpiPen® / EpiPen® Jr (epinephrine) auto-injector should be prescribed for all patients at risk. In fact, physicians should prescribe multiple units so that patients may have immediate access to life-saving medication wherever they may be. Teach the patient how to use the EpiPen appropriately, using the EpiPen Trainer so he/she may be prepared in the event of an anaphylactic episode. All patients, regardless of whether they are capable of epinephrine self-administration, may still require the help of others because the severity of the reaction may interfere with their attempts at self-administration. Thus, patients should work with family members, friends, and other caregivers so they know how to use EpiPen and can assist in an emergency situation. Anaphylaxis Committee, AAAAI. Anaphylaxis. Teaching Slides AAAAI Board of Directors. Anaphylaxis in schools and other childcare settings [position statement]. J Allergy Clin Immunol 1998;102:173–176.

Screen, educate, and protect
Anaphylaxis Screen, educate, and protect + Immediate treatment = Saved lives Anaphylaxis is a serious health problem of increasing prevalence. Although hundreds of deaths due to anaphylaxis occur annually, we must recognize that we as clinicians have the tools to prevent these fatal outcomes. Prevention must include avoidance measures and risk management strategies to be most effective. With appropriate education and the availability of epinephrine, anaphylactic reactions should rarely have a fatal outcome, particularly if patients at risk are identified We must conscientiously screen, educate, and protect our patients with these available tools. Prescribing multiple units of EpiPen is recommended for patients at risk so that immediate treatment can be instituted wherever the patient may be.

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