eMedicine Specialties > Allergy and Immunology > Major Allergic Diseases

Anaphylaxis

Stephen F Kemp, MD, FACP, Professor of Medicine, Associate Professor of Pediatrics, Director of Allergy and Immunology Fellowship Program, Departments of Medicine and Pediatrics, Associate Director of Division of Clinical Immunology and Allergy, Department of Medicine, University of Mississippi Medical Center; Consultant in Allergy and Immunology, Medical Service, G V (Sonny) Montgomery Veterans Affairs Medical Center
G William Palmer, MD, Consulting Staff, Shoreline Allergy and Asthma Associates

Updated: Apr 29, 2009

Introduction

Background

Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea anemone toxin caused a dog's death. They named this response anaphylaxis, which is derived from the Greek words a - (against) and – phylaxis (immunity, protection).

Anaphylaxis is an acute multiorgan system reaction, potentially fatal, caused by the release of chemical mediators from mast cells and basophils.^1,2 The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems.

Anaphylaxis has no universally accepted clinical definition. The traditional nomenclature for anaphylaxis reserves the term anaphylactic for IgE-dependent reactions and the term anaphylactoid for IgE-independent events, which are clinically indistinguishable. The World Allergy Organization, which is an international umbrella organization representing more than 70 national and regional professional societies dedicated to allergy and clinical immunology, has recommended replacing this terminology with immunologic (IgE-mediated and non-IgE-mediated [eg, IgG and immune complex complement-mediated]) and non-immunologic anaphylaxis.³

Clinically, anaphylaxis is considered likely to be present if any 1 of the 3 following criteria is satisfied within minutes to hours:

• Acute symptoms involving skin, mucosal surface, or both, and at least one of the following: respiratory compromise, hypotension, or end-organ dysfunction
• Two or more of the following occur rapidly after exposure to a likely allergen: hypotension, respiratory compromise, persistent gastrointestinal symptoms, or involvement of skin or mucosal surface
• Hypotension develops after exposure to an allergen known to cause symptoms for that patient: age-specific low blood pressure or decline of systolic blood pressure of more than 30% compared to baseline

In clinical practice, however, delaying treatment until the development of symptoms affecting multiple organs is risky, since the ultimate severity of anaphylaxis is difficult to predict from its outset.

Pathophysiology

When mast cells and basophils degranulate, whether by IgE- or non–IgE-mediated mechanisms, preformed histamine and newly generated leukotrienes, prostaglandins, and platelet activating factor (PAF) are released. The physiologic responses to these mediators include smooth muscle spasm in the respiratory and gastrointestinal tract, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings.

These physiologic events lead to some or all of the classic symptoms of anaphylaxis: flushing; urticaria/angioedema; pruritus; bronchospasm; laryngeal edema; abdominal cramping with nausea, vomiting, and diarrhea; and feeling of impending doom. Concomitant signs and symptoms can include rhinorrhea, dysphonia, metallic taste, uterine cramps, light-headedness, and headache. Hypotension, cardiac arrhythmias, syncope, and shock can result from intravascular volume loss, vasodilation, and myocardial dysfunction. Increased vascular permeability can produce a shift of 35% of vascular volume to the extravascular space within 10 minutes.

Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines. These mediators can activate the kallikrein-kinin contact system, the complement cascade, and coagulation pathways. The development and severity of anaphylaxis also depend on the responsiveness of cells targeted by these mediators. IL-4 and IL-13 are cytokines important in the initial generation of antibody and inflammatory cell responses to anaphylaxis. No comparable studies have been conducted in humans, but anaphylactic effects in mice depend on IL-4Rα-dependent IL-4/IL-13 activation of the transcription factor, STAT-6 (signal transducer and activator of transcription 6).⁵ Eosinophils may be inflammatory (release cytotoxic granule-associated proteins, for example) or anti-inflammatory (metabolize vasoactive mediators, for example).

Under rigid experimental conditions, histamine infusion alone is sufficient to produce most of the symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H1) and histamine 2 (H2) receptors. Vasodilation, hypotension, and flushing are mediated by both H1 receptors and H2 receptors. H1 receptors alone mediate coronary artery vasoconstriction, tachycardia, vascular permeability, pruritus, bronchospasm, and rhinorrhea. H2 receptors increase atrial and ventricular contractility, atrial chronotropy, and coronary artery vasodilation. H3 receptors in experimental models of canine anaphylaxis appear to influence cardiovascular responses to norepinephrine. The importance of H3 receptors in humans is unknown.

Effects on the Cardiovascular System

Anaphylaxis has been associated clinically with myocardial ischemia, atrial and ventricular arrhythmias, conduction defects, and T-wave abnormalities. Whether such changes are related to direct mediator effects on the myocardium, to exacerbation of preexisting myocardial insufficiency by the adverse hemodynamic effects of anaphylaxis, to epinephrine released endogenously by the adrenals in response to stress, or to therapeutically injected epinephrine is unclear.

Since mast cells accumulate at sites of coronary atherosclerotic plaques, and immunoglobulins bound to mast cells can trigger mast cell degranulation, some investigators have suggested that anaphylaxis may promote plaque rupture, thus risking myocardial ischemia. Stimulation of the H1 histamine receptor may also produce coronary artery vasospasm. PAF also delays atrioventricular conduction, decreases coronary artery blood flow, and has negative inotropic effects.

Calcitonin gene-related peptide (CGRP), a sensory neurotransmitter that is widely distributed in cardiovascular tissues, may help to counteract coronary artery vasoconstriction during anaphylaxis. CGRP relaxes vascular smooth muscle and has cardioprotective effects in animal models of anaphylaxis.

While tachycardia is the rule, bradycardia can occur during anaphylaxis. Thus, bradycardia may not be as useful to separate anaphylaxis from a vasodepressor reaction as previously thought. Relative bradycardia (initial tachycardia followed by decreased heart rate despite worsening hypotension) has been reported in the setting of experimentally induced insect sting anaphylaxis.

Two distinct physiologic responses occur in mammals experiencing hypovolemia.⁶ The initial response to hypovolemia is a baroreceptor-mediated increase in overall cardiac sympathetic drive and a concomitant withdrawal of resting vagal drive, which together produce peripheral vasoconstriction and tachycardia. When effective blood volume decreases by 20-30 percent, a second phase follows, which is characterized by withdrawal of vasoconstrictor drive, relative or absolute bradycardia, increased vasopressin, further catecholamine release as the adrenals become more active, and hypotension. Hypotension in this hypovolemic setting is independent of the bradycardia, since it persists when the bradycardia reverses with atropine administration.

The implications of relative or absolute bradycardia in human anaphylaxis and hypovolemic shock have not been studied. However, one retrospective review of approximately 11,000 trauma patients found that mortality was lower with the 29 percent of hypotensive patients who were bradycardic when they were compared to the group of hypotensive individuals who were tachycardic, after adjustment for other mortality factors.⁷ Thus, bradycardia may have a specific compensatory role in these settings.

Conduction defects and sympatholytic medications may also produce bradycardia. Excessive venous pooling with decreased venous return (also seen in vasodepressor reactions) may activate tension-sensitive sensory receptors in the inferoposterior portions of the left ventricle, thus resulting in a cardio-inhibitory (Bezold-Jarisch) reflex that stimulates the vagus nerve and causes bradycardia.

Frequency

United States

The true incidence is unknown. Moneret-Vautrin et al reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population.⁸ Neugut et al estimated that 1-15% of the US population is at risk of experiencing an anaphylactic or anaphylactoid reaction.⁹ They estimated that the rate of actual anaphylaxis to food was 0.0004%, 0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.

A population-based study from Olmsted County, Minnesota, found an average annual incidence of anaphylaxis of 21 cases per 100,000 person-years.¹⁰ Ingestion of a suspect food was the cause in 36% of cases; a medication, subcutaneous immunotherapy (SCIT), or a diagnostic agent was the cause in 17% of cases; and an insect sting was the cause in 15% of cases. Thirty-two percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently from July through September, which is attributable to insect stings.

In a study of patients referred to a university-affiliated allergy-immunology practice in Memphis, Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise in 7% (anaphylaxis due to insect stings or SCIT were excluded from the study).¹¹ The cause of anaphylaxis could not be determined in 59% of patients (ie, they were diagnosed with idiopathic anaphylaxis). A separate study estimated the number of cases of idiopathic anaphylaxis in the United States to be 20,000-47,000 cases per year (approximately 8-19 episodes per 100,000 person-years).

International

The incidence of anaphylaxis does not appear to vary significantly between countries. Two European studies detected a lower average annual incidence than found in the Olmsted County study (3.2 cases of anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis per 100,000 person-years in Munich, Germany¹² ). Rates in Europe range from 1-3 cases per 10,000.^13,12 Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an indicator of perceived risk that future anaphylaxis may occur.¹⁴

Mortality/Morbidity

• Fatalities from anaphylaxis are infrequent but not rare. Estimates range from 0.65-2% of patients with anaphylaxis.^15,16 The case-fatality rate from the Olmsted County study was 0.65%.¹⁰ Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 150 deaths per year in the United States. Severe reactions to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case per 50,000-100,000 courses. Insect sting anaphylaxis causes approximately 25-50 deaths per year. Anaphylaxis to radiocontrast media (RCM) was estimated to have caused 500 deaths in 1982, although this number has likely decreased because of increased awareness and the use of pretreatment regimens and/or lower osmolar agents for patients with a history of RCM reaction.
• In the United Kingdom, half of fatal anaphylaxis episodes have an iatrogenic cause (eg, anesthesia, antibiotics, RCM), while foods and insect stings each account for a quarter of the fatal episodes.
• The most common causes of death are cardiovascular collapse and respiratory compromise. One report examined 214 anaphylactic fatalities for which the mode of death could be surmised in 196, 98 of which were due to asphyxia (49 lower airways [bronchospasm], 26 both upper and lower airways, and 23 upper airways [angioedema]). The fatalities from acute bronchospasm occurred almost exclusively in those with preexisting asthma. Another analysis of 23 unselected cases of fatal anaphylaxis determined that 16 of 20 “immediate” deaths (death occurring within one hour of symptom onset) and 16 of the 23 cases that underwent autopsy were due to upper airway edema.
• Death can occur rapidly. An analysis of anaphylaxis fatalities occurring in the United Kingdom from 1992 to 2001 revealed the interval between initial onset of food anaphylaxis symptoms and fatal cardiopulmonary arrest averaged 25-35 minutes, which was longer than for drugs (mean, 10-20 minutes pre-hospital; 5 minutes in-hospital) or for insect stings (10-15 minutes).

Race

• Race has no known effect on the risk of anaphylaxis.

Sex

• In the Olmsted County study, men and women were equally affected.¹⁰
• The Memphis study showed a slight female predominance.¹¹
• Earlier studies have suggested that episodes of anaphylaxis to intravenous muscle relaxants, aspirin, and latex are more common in women, while insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.

Age

• Anaphylaxis can occur at any age. In the Olmsted County study, the age range was 6 months to 89 years.¹⁰ The mean age was 29 ±19 years. The Memphis study had an age range of 1-79 years, with a mean of 37 years.¹¹
• Simons and colleagues noted the highest frequency of epinephrine prescriptions for boys aged 12-17 months (5.3%).¹⁴ The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and 0.3% for those aged 65 years or older.
• Severe food allergy is more common in children than in adults. However, the frequency in adults may be increasing, since severe food allergy often persists into adulthood.
• Anaphylaxis to radiocontrast media (RCM), insect stings, and anesthetics has been reported to be more common in adults than in children. Whether this is a function of exposure frequency or increased sensitivity is unclear.

Other risk factors

• Atopy is a risk factor. In the Olmsted County study, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis).¹⁰ The Memphis study detected atopy in 37% of the patients.¹¹ Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy does not appear to be a risk factor for reactions to penicillin or insect stings.
• Route and timing of administration affect anaphylactic potential. The oral route of administration is less likely to cause a reaction, and such reactions are usually less severe, although fatal reactions occur following ingestions of foods by someone who is allergic. The longer the interval between exposures, the less likely an anaphylactic (IgE-mediated) reaction will recur. This is thought to be due to catabolism and decreased synthesis of allergen-specific IgE over time. This does not appear to be the case for IgE-independent reactions.
• Geographic location previously was thought to be irrelevant, but a British report has challenged that assumption. Analysis of hospital discharge summaries after anaphylaxis suggests that individuals living in rural areas and in the southern and western parts of England have an increased incidence of anaphylaxis.
• Asthma is a risk factor for fatal anaphylaxis.
• Delayed administration of epinephrine is also a risk factor for fatal outcomes.¹⁷
• Posture also influences anaphylaxis outcomes. In a retrospective review of pre-hospital anaphylactic fatalities in the UK, the postural history was known for ten individuals.¹⁸ Four of the ten fatalities were associated with the assumption of an upright or sitting posture during anaphylaxis. Postmortem findings were consistent with pulseless electrical activity and an "empty heart" attributed to reduced venous return from vasodilation and redistribution of intravascular volume from the central to the peripheral compartment.

Clinical

History

In most studies, the frequency of signs and symptoms of anaphylaxis is grouped by organ system. For example, 100% of patients with anaphylaxis in the Olmsted County study had cutaneous manifestations, consistent with the study's definition of anaphylaxis, which required one symptom of generalized mediator release (mostly skin manifestations).¹⁰ Nevertheless, other studies have reported that 90% of patients have cutaneous involvement. The Olmsted study observed that 69% had respiratory manifestations, 41% had cardiovascular involvement, and 24% had oral or gastrointestinal manifestations.¹⁰ Other studies have reported similar findings.

Children, however, may be different. An Australian study evaluated 57 children under age 16 years who presented to a pediatric emergency department over a three-year period. Cutaneous features were noted in 82.5%, whereas 95% had respiratory symptoms.

• Patients often initially describe a sense of impending doom, accompanied by pruritus and flushing. This can evolve rapidly into the following symptoms, broken down by organ system:
  • Cutaneous/ocular - Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus, warmth, and swelling
  • Respiratory - Nasal congestion, rhinorrhea, throat tightness, wheezing, shortness of breath, cough, hoarseness
  • Cardiovascular - Dizziness, weakness, syncope, chest pain, palpitations
  • Gastrointestinal – Dysphagia, nausea, vomiting, diarrhea, bloating, cramps
  • Neurologic - Headache, dizziness, blurred vision, and seizure (very rare and often associated with hypotension)
  • Other – Metallic taste, feeling of impending doom
• Symptoms usually begin within 5-30 minutes from the time the culprit antigen is injected but can occur within seconds. If the antigen is ingested, symptoms usually occur within minutes to 2 hours. In rare cases, symptoms can be delayed in onset for several hours. Anaphylaxis, however, occurs as part of a clinical continuum. It can begin with relatively minor cutaneous symptoms and rapidly progress to life-threatening respiratory or cardiovascular manifestations. In general, the more rapidly anaphylaxis develops after exposure to an offending stimulus, the more likely the reaction is to be severe.

Physical

The first priority should be to assess the patient's airway, breathing, circulation, and adequacy of mentation (eg, alertness, orientation, coherence of thought).

• Respiratory
  • Severe angioedema of the tongue and lips may obstruct airflow.
  • Laryngeal edema may manifest as stridor or severe air hunger.
  • Loss of voice, hoarseness, and/or dysphonia may occur.
  • Bronchospasm, airway edema, and mucus hypersecretion may manifest as wheezing. In the surgical setting, increased pressure of ventilation can be the only manifestation of bronchospasm.
  • Hypoxia can cause altered mentation.
• Cardiovascular
  • Tachycardia is present in one fourth of patients, usually as a compensatory response to reduced intravascular volume or to stress from compensatory catecholamine release.
  • Bradycardia is more suggestive of a vasodepressor (vasovagal) reaction, although it has been observed in anaphylaxis (see Pathophysiology).
  • Hypotension (and resultant loss of consciousness) may be observed secondary to capillary leak, vasodilation, and hypoxic myocardial depression.
  • Cardiovascular collapse and shock can occur immediately, without any other findings. This is an especially important consideration in the surgical setting.
• Cutaneous
  • Cutaneous findings may be delayed or absent in rapidly progressive anaphylaxis. Urticaria (hives) can occur anywhere on the body, often localizing to the superficial dermal layers of the palms, soles, and inner thighs. The lesions vary in size and are erythematous, raised, and highly pruritic.
  • Angioedema (soft tissue swelling) is also commonly observed. These lesions involve the deeper dermal layers of skin. It is usually nonpruritic and nonpitting. Common areas of involvement are the larynx, lips, eyelids, hands, feet, and genitalia.
  • Generalized (whole-body) erythema (or flushing) without urticaria or angioedema is also occasionally observed.
• Gastrointestinal: Vomiting, diarrhea, and abdominal distention are frequently observed.

Causes

Immunologic

• IgE-mediated anaphylaxis: This is the classic form of anaphylaxis, whereby a sensitizing antigen elicits an IgE antibody response in a susceptible individual. The antigen-specific IgE antibodies then bind to mast cells and basophils. Subsequent exposure to the sensitizing antigen causes cross-linking of cell-bound IgE, resulting in mast cell (and/or basophil) degranulation. Typical examples of IgE-mediated anaphylaxis include the reactions to many drugs, insect stings, and foods.
  • Certain drugs cause IgE-mediated anaphylaxis. Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillin and other beta-lactam antibiotics.
    • Penicillin is metabolized to a major determinant, benzylpenicilloyl, and multiple minor determinants. Penicillin and its metabolites are haptens, small molecules that only elicit an immune response when conjugated with carrier proteins.
    • Other beta-lactam antibiotics may cross-react with penicillins or may have unique structures that also act as haptens. The incidence rate of anaphylaxis to cephalosporins in penicillin-anaphylactic patients appears to be much less than the 10% frequently quoted. Pichichero reviewed this complicated literature and offers specific guidance for the use of cephalosporins in patients who have a history of IgE-mediated reactions to penicillin.¹⁹
    • Patients with less well-defined reactions to penicillin have a very low risk (1-2%) of developing anaphylaxis to cephalosporins. The rate of skin-test reactivity to imipenem in patients with a known penicillin allergy is almost 50%. In contrast, no known in vitro or clinical crossreactivity exists between penicillins and aztreonam.
    • Many other drugs have been implicated less frequently in IgE-mediated anaphylaxis.
  • In the surgical setting, anaphylactic reactions are most often due to muscle relaxants and latex but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. Volatile anesthetic agents can cause immune-mediated hepatic toxicity but have not been implicated in anaphylactic reactions.
  • Insect stings, that is, venoms from Hymenoptera insects (eg, bees, yellow jackets, hornets, wasps, fire ants), can elicit an allergen-specific IgE antibody response. From 0.5%-3% of the US population experiences a systemic reaction after being stung.²⁰
  • Hypersensitivity to foods is a problem encountered throughout the industrialized world.¹⁷ In the United States, an estimated 4 million Americans have well-substantiated food allergies. In Montreal, 1.5% of early elementary school students were found to be sensitized to peanuts. Reactions to foods are thought to be the most common prehospital (outpatient) cause of anaphylaxis and are estimated to cause 125 deaths per year in the United States.
    • Certain foods are more likely than others to elicit an IgE antibody response and lead to anaphylaxis. Foods likely to elicit an IgE antibody response in all age groups include peanuts, tree nuts, fish, and shellfish. Foods likely to elicit an IgE antibody response in children also include eggs, soy, and milk.
    • An analysis of 32 fatalities thought to be due to food-induced anaphylaxis revealed that peanuts likely were the responsible food in 62% of the cases. In placebo-controlled food challenges, peanut-sensitive patients can react to as little as 100 µg of peanut protein.²¹ The Olmsted County study, in agreement with earlier studies, found that food ingestion was the leading cause of anaphylaxis, accounting for as many as one third of all cases.¹⁰ Scombroid fish poisoning can occasionally mimic food-induced anaphylaxis. Bacteria in spoiled fish produce enzymes capable of decarboxylating histidine to produce biogenic amines, including histamine and cis-urocanic acid, which is also capable of mast cell degranulation.
  • Latex hypersensitivity is a phenomenon that has been recognized in the last 20 years, corresponding with the increased use of latex gloves because of the HIV and hepatitis B and C epidemics and the institution of universal precautions. In 1995, an estimated 8-17% of healthcare professionals were at risk for latex reactions. The incidence rate is decreasing, at least in part, because of increased awareness, improved manufacturing practices, and a change to unpowdered latex and nonlatex gloves.
  • Allergen-specific subcutaneous immunotherapy (SCIT) can cause IgE-mediated anaphylaxis. Allergy injections are a common trigger for anaphylaxis. This is not unexpected because the treatment is based on injecting an allergen to which the patient is sensitive. However, life-threatening reactions are rare. Three studies suggest that fatalities from SCIT occur at a rate of approximately 1 per 2,500,000 injections.^22,23,24 A total of 104 fatalities due to SCIT and skin testing were reported from 1945-2001.
    
    Risk factors for severe anaphylaxis due to immunotherapy include poorly controlled asthma, concurrent use of beta-blockers, high allergen dose, errors in administration, and lack of a sufficient observation period following the injection. Near-fatal reactions (NFR) to subcutaneous immunotherapy also have been examined retrospectively. Of 646 allergist-immunologists who responded to a survey on reactions, 273 reported NFR. The investigators defined an NFR as respiratory compromise, hypotension, or both, requiring emergency epinephrine. Hypotension was reported in 80% and respiratory failure occurred in 10% of NFRs, exclusively in subjects with asthma. Epinephrine was delayed or not administered in 6% of these cases.

Aspirin and nonsteroidal anti-inflammatory drugs

• Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in the past have been classified as IgE-independent because reactions were thought to occur from aberrant metabolism of arachidonic acid. Isolated cutaneous reactions to aspirin/NSAIDs and bronchospasm in aspirin-sensitive asthmatics (often in association with nasal polyposis) are indeed mediated through IgE-independent mechanisms. Blockade of cyclooxygenase by these drugs causes the prostanoid pathway to shut down, resulting in an overproduction of leukotrienes via the 5-lipoxygenase pathway. These patients have marked cross-reactivity between aspirin and most NSAIDs.
• Anaphylaxis after taking these drugs apparently occurs via a different mechanism that is more consistent with IgE-mediated anaphylaxis. With true anaphylaxis, the different cyclooxygenase inhibitors do not appear to cross-react. Anaphylaxis only occurs after 2 or more exposures to the implicated drug, suggesting a need for prior sensitization. Finally, patients with true anaphylaxis do not usually have underlying asthma, nasal polyposis, or urticaria. In one study of nearly 52,000 people taking NSAIDs, 35 developed anaphylactic shock.

Immunologic, IgE-independent reactions

• Complement-mediated reactions
  • Anaphylaxis resulting from administration of blood products, including intravenous immunoglobulin, or animal antiserum is due, at least in part, to activation of complement. Immune complexes formed either in vivo or in vitro can activate the complement cascade.
  • Certain byproducts of the cascade, namely plasma-activated complement 3 (C3a), plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a), are called anaphylatoxins and are capable of causing mast cell/basophil degranulation.
• Exercise-induced anaphylaxis
  • This is a rare syndrome that can take one of two forms. The first form is ingestant dependent, requiring both exercise and the recent ingestion of particular foods (eg, wheat, celery) or medications (eg, NSAIDs) to cause an episode of anaphylaxis. In these patients, exercise alone does not produce an episode, and ingesting the culprit food or medication alone does not cause an episode.
  • The second form is characterized by intermittent episodes of anaphylaxis during exercise, independent of any food ingestion. Anaphylaxis does not necessarily occur during every episode of physical exertion.
• Anaphylaxis associated with systemic mastocytosis
  • Anaphylaxis can be a manifestation of systemic mastocytosis, a disease characterized by excessive mast cell numbers in multiple organs.
  • Such patients appear to be at increased risk for food and venom reactions. Alcohol, vancomycin, opioids, radiocontrast media (RCM), and other biologic agents that can degranulate mast cells directly are discouraged.
• Idiopathic anaphylaxis²⁵
  • This is a syndrome of recurrent anaphylaxis for which no consistent triggers can be determined despite an exhaustive search. This recurrent syndrome should be distinguished from a single episode of anaphylaxis for which the etiology may be unclear.
  • Most patients treated with antihistamines and steroids have complete remission following tapering of steroids. Others require long-term prophylaxis with high doses of H1 antihistamines.
  • Idiopathic anaphylaxis can be categorized as infrequent (<6 episodes per year) or frequent (³6 episodes per year or 2 or more episodes within the last 2 months).²⁵ One approach is expectant treatment with epinephrine, antihistamines, and prednisone for individuals who have infrequent episodes and a prolonged taper of prednisone for those with frequent episodes.
  • Most of these patients are female, and atopy appears to be an underlying risk factor.
  • Two thirds of patients have 5 or fewer episodes per year, while one third have more than 5 episodes per year.
  • A subpopulation of women develops anaphylaxis in relationship to their menstrual cycle; this phenomenon is known as catamenial anaphylaxis.^26,27 In severe cases, these patients require manipulation of their hormonal levels by medical pituitary suppression and even oophorectomy. Most of these patients react to shifts in progesterone levels, and the diagnosis can be confirmed by provoking an anaphylactic event through administration of low doses of progesterone.

• Certain agents (ie, direct mast cell activators) are thought to cause direct, nonimmunologic release of mediators from mast cells. These include opioids, RCM, dextrans, protamine, and vancomycin. Mechanisms underlying these reactions are poorly understood but may involve specific receptors (eg, opioids) or non–receptor-mediated mast cell activation (eg, hyperosmolarity). Evidence also exists that RCM, dextrans, and protamine can activate several inflammatory pathways, including complement, coagulation, and vasoactive (kallikrein-kinin) systems.

Differential Diagnoses

Angioedema
Malignant Carcinoid Syndrome
Mastocytosis, Systemic
Pheochromocytoma
Thyroid, Medullary Carcinoma

Other Problems to Be Considered

• Vasodepressor (vasovagal) reaction (probably the most common masquerader)
• Other forms of shock (ie, hypovolemic, cardiogenic, septic)
• Flushing syndrome
  • Red man syndrome (vancomycin)
  • Pancreatic polypeptide tumors
  • Postmenopausal patient
  • Ethanol-induced
  • Autonomic epilepsy
• Monosodium glutamate poisoning
• Scombroid fish poisoning
• Capillary leak syndrome
• Pulmonary embolism
• Myocardial dysfunction
• Foreign body aspiration (young children, especially)
• Poisoning, acute
• Neurologic (stroke, seizure)
• Nonorganic disease
  • Panic attack
  • Hyperventilation
  • Vocal cord dysfunction syndrome
  • Somatoform anaphylaxis

Workup

Laboratory Studies

• Anaphylaxis is a clinical diagnosis based on typical systemic manifestations, often with a history of acute exposure to a causative agent. Laboratory studies are not usually required and are rarely helpful.
• If the diagnosis is unclear, especially with a recurrent syndrome, or if other diseases need to be excluded, some limited laboratory studies are indicated.
  • For example, if carcinoid syndrome is considered, urinary 5-hydroxyindoleacetic acid levels should be measured.
  • If a patient is seen shortly after an episode, plasma histamine, urinary histamine metabolites, or serum tryptase measurements may be helpful in confirming the diagnosis.²
    • Plasma histamine levels rise within 10 minutes of onset but fall again within 30 minutes.
    • Urinary histamine levels are generally not dependable, as this test can be affected by diet and by bacteria in the urine. Urinary histamine metabolites measurement is a better test but is not generally available.
    • Serum mature tryptase (previously called beta-tryptase) levels peak 60-90 minutes after the start of an episode and may persist for as long as 5 hours. The estimated positive predictive value of tryptase elevations in 259 subjects with anesthesia-associated anaphylaxis is 92.6%, and the estimated negative predictive value of normal tryptase levels is 54.3%. Serial tryptase measurements might improve diagnostic sensitivity, but further investigation is needed.
    • Detecting the rise of histamine or tryptase levels can be difficult, and some patients might have a rise in one but not the other. In one emergency department study evaluating patients with acute allergic reactions, 42 of 97 had elevated histamine while 20 had elevated tryptase levels.²⁸ No correlation was demonstrated between the levels of tryptase and histamine.
    • Basal levels of total and mature tryptase between episodes of anaphylaxis can be helpful to rule out systemic mastocytosis. Patients with mastocytosis constitutively produce large quantities of alpha-tryptase, while individuals with anaphylaxis from other causes have normal levels of alpha-tryptase at baseline between episodes of anaphylaxis. During anaphylaxis, a ratio of total tryptase (alpha + mature) to mature tryptase of 20 or greater is consistent with mastocytosis, whereas a ratio of 10 or less suggests anaphylaxis of another etiology.

Imaging Studies

• No role exists for imaging studies in the diagnosis or management of anaphylaxis.

Other Tests

• Once an acute episode of anaphylaxis has occurred, additional testing may be helpful to identify an etiologic agent.
  • Patient diary: A thorough history remains the best test to determine a causative agent. For recurrent idiopathic episodes, a patient diary may be helpful to implicate specific foods or drugs.
  • Food reactions: If the patient's history suggests a possible association with eating, percutaneous food-skin tests and/or in vitro IgE tests (eg, radioallergosorbent assay test [RAST] or ImmunoCAP tests [Phadia AB, Uppsala, Sweden]) can be performed, with an understanding that false-positive results may occur. The rate of false positives is about 50% for both skin tests and RAST, whereas ImmunoCAP has about 95% positive predictive value. Conversely, the negative predictive value of skin testing is about 95% (may not be reliable for fresh fruits/vegetables or crustaceans because of the lack of labile allergenic proteins in commercial extracts).
    
    Many pan-allergens (eg, profilins, chitinases, lipid transfer proteins, tropomyosin) can add to the confusion, as foods may share pathogen-related proteins with nonfood allergens. Intradermal skin testing and IgG RAST tests have no role in food-skin testing. A double-blind, placebo-controlled food challenge may need to be performed to confirm clinical reactivity. However, when a particular food is clearly related temporally to the reaction, a food-skin test should not be performed with standard concentrations of food extracts because deaths have occurred secondary to food-skin testing, particularly with peanuts.
  • Insect stings: If the patient's history suggests an insect sting, skin testing and in vitro IgE tests to Hymenoptera venoms should be performed. The in vitro IgE tests should be considered because cases have occurred in patients with negative skin test results and with severe clinical reactivity and positive in vitro IgE results.
    • A patient's ability to identify the type of flying insect is unreliable, generally mandating testing of all flying Hymenoptera. For example, many patients confuse yellow jackets and bees. However, exceptions for this testing for multiple insect venoms can be made for patients whose stings were accompanied by sterile pustule formation within 24 hours (pathognomonic for fire ant sting) or for whom an impaled stinger and abdominal remnant were found at the sting site (the honeybee eviscerates itself as it stings). In these cases, testing may be limited to fire ant and honeybee allergen-specific IgE, respectively.
    • Skin testing and in vitro IgE testing should be performed 4-6 weeks following the episode of anaphylaxis to improve the sensitivity of the diagnostic test.
  • Suspected medication etiology
    • If the patient's history suggests a penicillin etiology and the reagents are available, skin testing for penicillin should be performed with the appropriate positive and negative controls. Penicillin G and major determinant (Pre-Pen) are usually commercially available for skin testing, although at the time this was last updated, Pre-Pen was unavailable in the United States. Minor determinant mix (MDM) is available primarily at research centers. The minor determinants comprise only 5% of penicillin metabolites but are implicated in anaphylaxis risk. Therefore, if MDM is not available for skin testing for patients with a good history, a desensitization protocol may be the safest path regardless of skin test results.
    • If MDM is not available for skin testing for patients with a history that is not suggestive of an immediate hypersensitivity reaction who have negative results to penicillin G and Pre-Pen, penicillin should only be administered as an incremental challenge under close medical observation. If possible, give oral penicillin before administering it intravenously or intramuscularly.
    • Skin testing for reactivity to other beta-lactam antibiotics, or any other medicine for that matter, should be considered experimental because the haptenic determinants are unknown. Skin testing with the parent drug may be beneficial if the results are positive, but a negative result does not exclude the potential for severe clinical reactivity.
  • Testing for IgE-independent etiologies: Because these reactions are not mediated through IgE, skin testing has no role in diagnosis. No other diagnostic tests help assess the risk of recurrent IgE-independent reactions.

Treatment

Medical Care

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Basic equipment and medication should be readily available in the physician's office. Lieberman et al have described this in great detail.^29,30

• For the initial assessment, check the airway closely. If needed, establish and maintain an airway and/or provide ventilatory assistance. Assess the level of consciousness and obtain blood pressure, pulse, and oximetry values.
• Place the patient in the supine position with legs elevated, and begin supplemental oxygen.
• Administer intramuscular epinephrine immediately (the thigh muscle is preferable; see Medication).^30,14 Epinephrine maintains the blood pressure, antagonizes the effects of the released mediators, and inhibits further release of mediators from mast cells and basophils. Health care professionals are sometimes reluctant to administer epinephrine for fear of adverse effects. However, the use of epinephrine for anaphylaxis has no absolute contraindications. It is the drug of choice and it is usually well tolerated and potentially lifesaving. Anaphylactic deaths correlate with a delay in the administration of epinephrine. The initial dose can be repeated as necessary, depending on the response.
• Intramuscular administration of epinephrine in the thigh (vastus lateralis) results in higher and more rapid maximum plasma concentrations of epinephrine compared with the intramuscular or subcutaneous administration in the arm (deltoid) of asymptomatic children and adults.³¹ However, similar studies comparing intramuscular injections to subcutaneous injections in the thigh have not yet been done. Obesity or other conditions that enlarge the subcutaneous fat pad may prevent intramuscular access.
• Remove the source of the antigen if possible (eg, remove stinger after honeybee sting or stop drug infusion). If anaphylaxis occurs after injection of allergen-specific SCIT, a large local reaction often occurs. Place a tourniquet above the injection site and, after intramuscular epinephrine is administered, inject up to 0.1 mL of epinephrine into the large local reaction site to slow absorbance.
• The standard treatment of anaphylaxis should also include antihistamines and corticosteroids. However, antihistamines have a much slower onset of action than epinephrine, they exert minimal effect on blood pressure, and they should not be administered alone as treatment.
• Antihistamine therapy thus is considered adjunctive to epinephrine. Administer both an H1 blocker and an H2 blocker because studies have shown the combination to be superior to an H1 blocker alone in relieving the histamine-mediated symptoms. Diphenhydramine and ranitidine are an appropriate combination. Intravenous administration ensures that effective dosing is not impaired by hemodynamic compromise, which adversely affects gastrointestinal or intramuscular absorption. However, oral or intramuscular administration of antihistamines may suffice for milder anaphylaxis.
• Establish intravenous access for (1) the administration of adjunctive medications and (2) the administration of intravenous fluids to maintain blood pressure, if needed.
• Racemic epinephrine via a nebulizer can be used to reduce laryngeal swelling, but it does not replace intramuscular administration of epinephrine.
• Treat bronchospasm that has not responded to intramuscular epinephrine with inhaled beta2-adrenergic agonists such as albuterol.
• Corticosteroids have no immediate effect on anaphylaxis. However, administer them early to try to prevent a potential late-phase reaction (biphasic anaphylaxis). Patients with asthma or other conditions recently treated with a corticosteroid may be at increased risk for severe or fatal anaphylaxis and may receive additional benefit if corticosteroids are administered to them during anaphylaxis. The authors recommend corticosteroid treatment for all patients with anaphylaxis. If absorption is a concern, intravenous preparations should be used.
• Maintaining proper blood pressure is important in the treatment of anaphylactic reactions.
  • Hypotension is often the most difficult manifestation of anaphylaxis to treat.
  • Persons with protracted hypotension must be monitored in an intensive care setting.
  • Because hypotension in anaphylaxis is due to a dramatic shift of intravascular volume, the fundamental treatment intervention after epinephrine is aggressive intravenous fluid administration. Large volumes of crystalloid may be required, potentially exceeding 5 L. The exact amount should be individualized and based on blood pressure and urine output. In severe cases, invasive monitoring of central venous pressure and cardiac output may be required.
  • Vasopressors may also be needed to support blood pressure. Intravenous epinephrine (1:10,000 preparation) can be administered as a continuous infusion, especially when the response to intramuscular epinephrine (1:1000) is poor. Dopamine infusion can also be used.
  • Patients with anaphylaxis who are taking a beta-adrenergic blocking agent (eg, for hypertension, migraine prophylaxis) can have refractory anaphylaxis that is poorly responsive to standard measures. Glucagon might be effective in this situation.³² It has both inotropic effects and chronotropic effects on the heart by increasing intracellular levels of cyclic adenosine 3,'5'-monophosphate, independent of the beta-adrenergic receptors. Glucagon can also reverse bronchospasm.
• Since adequate oxygenation also depends on ventilation, establishing and maintaining an airway or providing ventilatory assistance may be necessary. One of the quickest, easiest, and most effective ways to support ventilation involves a one-way valve facemask with oxygen inlet port (eg, Pocket-Mask [Laerdal Medical Corporation, Gatesville, Tex] or similar device). Artificial ventilation via the mouth-to-mask technique with oxygen attached to the inlet port has provided oxygen saturations comparable to endotracheal intubation. Patients with adequate spontaneous respirations may breathe through the mask.
• Clinicians proficient in advanced airway management may consider additional intervention, where appropriate. For example, severe laryngeal edema may occur so rapidly during anaphylaxis that endotracheal intubation becomes impossible. Therefore, an endotracheal tube should be inserted promptly if laryngeal edema does not reverse promptly with epinephrine. If intubation fails, cricothyrotomy probably should be attempted next since it is easier to perform than an emergency tracheostomy.
• Depending on its severity, refractory hypotension may require placement of an invasive cardiovascular monitor (central venous catheter) and arterial line.
• Treatment of cardiopulmonary arrest is discussed elsewhere.
• Anti-IgE (eg, omalizumab) complexes circulating (but not receptor-bound) IgE and keeps it from binding to its receptors. It does not remove IgE bound to receptors and takes several months to have a substantial effect. It should not be used in an acute setting and would not be expected to influence IgE-independent or non-immunologic events.

Surgical Care

This is limited to the possible need for surgical intervention to establish airway access.

Consultations

• Most patients with anaphylaxis should be referred to an allergist-immunologist for further evaluation and treatment. However, the Olmsted County study demonstrated that only 52% of patients were referred for such a consultation,¹⁰ and emergency departments fared worse in both civilian and military settings, 12-20% and 29%, respectively.
• In the case of severe anaphylaxis requiring admission to the intensive care unit, a critical care specialist should be consulted.
• Prophylaxis for intravenous radiocontrast media (RCM) involves prednisone (or hydrocortisone), diphenhydramine, ranitidine (or another H2 antihistamine), and/or the use of a different low osmolar contrast agent.
  • Use a radiocontrast agent with lower osmolarity.
  • Administer prednisone (50 mg PO) or hydrocortisone (200 mg IV) at 13, 7, and 1 hour before the radiocontrast procedure.
  • Administer diphenhydramine (50 mg PO/IV) and ranitidine (150 mg PO or 50 mg IV) with or without ephedrine (25 mg PO) 1 hour before the procedure. Ephedrine should not be used in patients with hypertension, coronary artery disease (CAD), a strong family history of CAD (for older patients), arrhythmia, thyrotoxicosis, monoamine oxidase inhibitor use, or porphyria.
• Short-term desensitization procedures can be used for medication allergy in some circumstances in which no therapeutic alternative exists.
  • Published protocols exist for short-term desensitization and are available for various medications. Consult an allergist-immunologist skilled in desensitization procedures to perform these protocols. Most protocols require the patient to be in an intensive care unit setting throughout the procedure and to have established intravenous access and epinephrine at the bedside before the procedure starts. Obtain informed consent prior to the procedure. Anaphylaxis is a potential complication of this procedure.
  • A typical desensitization protocol for beta-lactam antibiotics provides the patient a starting dose that is 6-7 logs below the usual therapeutic dose and increases the dose by 1 log every 20-30 minutes.³³
• Pretreatment protocols do not work for IgE-independent anaphylaxis or cytotoxic dermatitis (erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis).
• Patients should be given epinephrine autoinjectors and should be instructed in the use of the device. Good evidence suggests that physicians underprescribe epinephrine and that patients (or their parents) fail to use epinephrine as quickly as possible.^31,34

Diet

The only dietary consideration is the future avoidance of a suspect or culprit food. Clinical trials are presently evaluating short-term oral desensitization for some foods, such as peanuts.

Activity

Once the acute episode of anaphylaxis has resolved, no activity limitations are necessary, except in the case of exercise-induced anaphylaxis.

Medication

The primary medication for acute anaphylaxis is epinephrine. All other therapies are adjunctive, including antihistamines, corticosteroids, and albuterol. Dopamine may be required to maintain blood pressure, and glucagon can be used in patients taking beta-blockers who have refractory anaphylaxis.

Adrenergic agonists

These agents help maintain blood pressure, antagonize effects of released mediators, and prevent further release of mediators.

Epinephrine (Adrenaline, EpiPen, EpiPen Jr, Twinject)

Drug of choice for treating anaphylaxis. Has alpha-agonist effects that include increased peripheral vascular resistance and reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Dosing

Adult

0.2-0.5 mL (0.2-0.5 mg) of 1:1000 solution IM; repeat prn, depending on response
1-2 mL (0.1-0.2 mg) of 1:10,000 preparation (0.1 mg/mL) IV q5-20min prn or continuous IV infusion of 1-4 mcg/min for more critical situations

EpiPen (Dey Laboratories, Napa, CA) autoinjector for adults available with single 0.3-mg (1:1,000 v/v) dose

The Twinject (Verus Pharmaceuticals, San Diego, CA) is pen-sized device containing two 0.3-mg doses of epinephrine; first of two doses in both cases is delivered by autoinjector while second is injected manually

Pediatric

0.01 mg/kg (max. dose 0.3 mg) IM prn
"Rule of 6" calculation for infusion: 0.6 X body weight (kg) = number of milligrams diluted to total 100 mL of saline; then 1 mL/h delivers 0.1 mcg/kg/min IV infusion

EpiPen Jr., with 0.15 mg (1:2,000 v/v) dose, is available for children <30 kg; EpiPen may be used for larger children

Twinject is pen-sized device containing two doses of epinephrine available either as 0.15 or 0.3 mg formulation; first of two doses in both cases is delivered by autoinjector while second is injected manually

Interactions

Beta-blockers antagonize physiologic effects; increases toxicity of alpha-blocking agents and halogenated inhalational anesthetics; TCAs and MAOIs potentiate effects; digoxin potentiates arrhythmogenic effects

Contraindications

No absolute contraindications in life-threatening anaphylaxis; documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; during labor (may delay second stage of labor)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly persons and those with prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, or cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; adverse effects include anxiety, headache, palpitations, and hypertension

Antihistamines

These agents block effects of released histamine at H1 receptor, thereby treating flushing, urticarial lesions, vasodilation, and smooth muscle contraction in bronchial tree and GI tract.

Diphenhydramine (Benadryl)

Widely available with a long history of efficacy and relative safety. FDA indication for anaphylaxis. IV administration provides faster onset of action.

Dosing

Adult

10-50 mg IV/IM q4h prn; IV rate not to exceed 25 mg/min; not to exceed 400 mg/d
25-50 mg PO q6-8h prn; not to exceed 400 mg/d

Pediatric

12.5-25 mg PO tid/qid or 5 mg/kg/d or 150 mg/m²/d divided tid/qid; not to exceed 300 mg/d
5 mg/kg/d IV/IM or 150 mg/m²/d divided qid; IV rate not to exceed 25 mg/min; daily dose not to exceed 300 mg/d

Interactions

Potentiates effect of alcohol and other CNS depressants (eg, hypnotics, sedatives, tranquilizers); MAOIs prolong and intensify anticholinergic effects of antihistamines

Contraindications

Documented hypersensitivity; concurrent use of MAOIs

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in breastfeeding and newborns secondary to risk of convulsions and death in the baby; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; adverse effects include drowsiness, reduced mental alertness, and xerostomia

Histamine2-receptor antagonists

These agents block effects of released histamine at H2 receptors, thereby treating vasodilation, possibly some cardiac effects, and glandular hypersecretion. H2 blockers with H1 blockers have additive benefit over H1 blockers alone in treating anaphylaxis. Ranitidine (Zantac) probably preferred over cimetidine (Tagamet) in anaphylaxis in light of the risk for hypotension with rapidly infused cimetidine and the multiple, complex drug interactions with cimetidine. Famotidine (Pepcid) IV is another good alternative.

Ranitidine (Zantac)

H2 antagonist, which, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.

Dosing

Adult

50 mg/dose IV/IM q6-8h
IV bolus administration: Dilute 50 mg in 20 mL NS (concentration of 2.5 mg/mL), inject at rate not >4 mL/min (5 min)
Alternatively, 150 mg PO bid; not to exceed 600 mg/d

Pediatric

<12 years: Not established
>12 years:
1.25-2.5 mg/kg/dose PO q12h; not to exceed 300 mg/d
0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d

Interactions

May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; if CrCl is <50 mL/min, maintain 50-mg dose and increase administration interval to 18-24 h; IV administration for >5 d may cause ALT elevations; case reports suggest ranitidine may precipitate acute porphyria

Bronchodilators

These agents stimulate beta2-adrenergic receptors in bronchial smooth muscle, causing bronchodilation.

Albuterol (Proventil, Ventolin)

Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.

Dosing

Adult

Nebulizer: 2.5-5 mg q4-6h in 2-5 mL sterile NS or water; to make solution, dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS (more frequent administration can be used for severe bronchospasm)
MDI: 1-2 puffs q4-6h; more frequent administration can be used for severe bronchospasm

Pediatric

Nebulizer
<5 years: 1.25-2.5 mg in 1-2.5 mL q4-6h; to make solution, dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS
>5 years: Administer as in adults
MDI
<12 years: 1-2 puffs qid with tube spacer
>12 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents; may exacerbate diuretic-induced hypokalemia; may decrease digoxin levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disorders (eg, coronary artery disease, cardiac arrhythmias, severe hypertension), hyperthyroidism, diabetes mellitus, and seizure disorder; adverse effects include tremor and mild tachycardia

Corticosteroids

Bind to the intracellular glucocorticoid receptors in inflammatory cells with multiple downstream immunomodulating effects. Glucocorticoids might prevent persistent or biphasic anaphylaxis. Patients with asthma or other conditions recently treated with a corticosteroid may be at increased risk for severe or fatal anaphylaxis and may receive additional benefit if corticosteroids are administered to them during anaphylaxis.

Methylprednisolone (Solu-Medrol)

May help prevent late-phase allergic reactions (biphasic anaphylaxis). No immediate effects.

Dosing

Adult

Loading: 125-250 mg IV over several min
Maintenance: 0.25-1 mg/kg/dose IV q6h for up to 5 d

Pediatric

Loading: 2 mg/kg IV
Maintenance: Administer as in adults

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; concomitant use with NSAIDs increases risk of peptic ulcer

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use (most are unlikely with short-term use for acute anaphylaxis)

Positive inotropic agents

These agents help maintain blood pressure independent of adrenergic receptors by increasing intracellular levels of cyclic AMP. In addition, stimulate release of endogenous catecholamines.

Glucagon (GlucaGen)

Probably the drug of choice for severe anaphylaxis in patients taking beta-blockers (should be used in addition to epinephrine, NOT as a substitute).

Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Also increases force of contraction in heart and has a relaxant effect on GI tract.

Dose used for anaphylaxis is higher than usual dose of 1 mg (1 U) IV/IM/SC used to treat hypoglycemia.

Dosing

Adult

1-5 mg IV bolus, followed by infusion of 5-15 mcg/min titrated against blood pressure

Pediatric

Hypoglycemia
<20 kg: 0.5 mg (0.5 U) IV/IM/SC or a dose equivalent to 20-30 mcg/kg
>20 kg: 1 mg (1 U) IV/IM/SC
Anaphylaxis: May need higher doses

Interactions

Effects of anticoagulants may be enhanced (although onset may be delayed); monitor prothrombin activity for signs of bleeding in patients receiving anticoagulants and adjust dose accordingly

Contraindications

Documented hypersensitivity; pheochromocytoma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include nausea, vomiting, sudden and marked increase in blood pressure in patients with pheochromocytoma, and severe rebound hypoglycemia in patients with insulinoma

Vasopressors

These agents are useful as adjunctive therapy to IV fluids to treat refractory hypotension from anaphylaxis.

Dopamine (Intropin)

Considered drug of choice for anaphylaxis-induced refractory hypotension. Stimulates both adrenergic and dopaminergic receptors.

Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and peripheral vasoconstriction produced by higher doses.

More than 50% of patients are satisfactorily maintained on doses <20 mcg/kg/min.

Dosing

Adult

2-5 mcg/kg/min IV; after initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response obtained; not to exceed 50 mcg/kg/min

Pediatric

Administer as in adults; 6 X body weight (in kg) = No of mg diluted to total 100 mL of saline; then 1 mL delivered 1 mcg/kg/min

Interactions

Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects

Contraindications

Documented hypersensitivity; pheochromocytoma; ventricular fibrillation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure closely during infusion; prior to infusion, correct hypovolemia; monitoring central venous pressure or left ventricular filling pressure may be helpful for detecting and treating hypovolemia; extravasation can cause necrosis of surrounding tissue, which is treated with phentolamine injected at the site

Follow-up

Further Inpatient Care

• Because of the potential for biphasic reactions, the patient should be observed for as long as 24 hours after a severe episode of anaphylaxis.³⁵
• In milder episodes, a 2-hour observation period after the symptoms have subsided is usually adequate.
• Indications for hospital admission include initial phases of anaphylaxis characterized by hypotension, poorly controlled asthma, respiratory failure or hypoxemia, a biphasic reaction or prior history of biphasic anaphylaxis, and secondary complications such as arrhythmias or myocardial ischemia.
• Hypotension should be treated aggressively with intravenous fluids and vasopressors (epinephrine and dopamine) in an intensive care unit setting with invasive monitoring as required.
• Persistent bronchospasm should be treated by continuing albuterol and intravenous steroid administration.
• Biphasic reactions should be treated by continuing steroids and directing therapy at the specific manifestations of the late-phase response.

Further Outpatient Care

• At discharge, all patients should be provided an epinephrine autoinjector and receive proper instruction on how to self-administer it in case of a subsequent episode.³⁴ They should also carry diphenhydramine and take this in conjunction with use of the epinephrine autoinjector. Furthermore, they should be instructed to keep an epinephrine autoinjector with them at all times, to keep the device from extremes of heat, and to replace any such device prior to its expiration date.
• Patients should be instructed to have ready and prompt access to emergency medical services for transportation to the closest emergency department for treatment.
• Patients should also be instructed that if an epinephrine autoinjector is used, they should immediately seek emergency care because epinephrine is very short acting and biphasic reactions can occur.
• Therapy with antihistamines and oral glucocorticoids should probably continue at home for another 2-3 days to prevent recurrence.
• The most important aspect of outpatient follow-up is evaluation by an allergist-immunologist.
  • Skin testing and/or in vitro IgE tests for foods, stinging insects, medications, or latex should be performed as directed by the patient's history. Documented hypersensitivity to latex is an indication for evaluation of possible allergy cross-reacting foods (eg, banana, kiwi, avocado).
  • If the patient's history and skin test or in vitro IgE tests results confirm Hymenoptera sensitivity as the probable cause of anaphylaxis, venom-specific immunotherapy should be initiated to prevent future episodes.
  • Future avoidance of culprit foods, medications, latex, or radiocontrast media (RCM) must be emphasized.
  • If a culprit medication is required in the future and no other alternatives are available, a desensitization procedure should be performed by the allergist/immunologist, usually in an intensive care unit setting.
  • If RCM is required in the future, a pretreatment protocol may be used (see Prophylaxis for intravenous RCM).
  • The patient must be provided a prescription for an epinephrine autoinjector (EpiPen, EpiPen Jr, or Twinject) and instructed in its proper use.

Inpatient & Outpatient Medications

• Inpatient medications are those listed in Medication.
• Outpatient medications are the oral forms of antihistamines and corticosteroids that should be continued for a short time (a few days) following an episode. The benefit of these drugs is more theoretical because no studies exist that prove their benefit in this setting.
  • See Medication for the oral doses of diphenhydramine and ranitidine.
  • A convenient oral corticosteroid is prednisone. No proven best dose exists. In adults, a dose of 1 mg/kg/d in divided doses is probably adequate; in children, a dose of 0.5-1 mg/kg twice daily is appropriate. Tapering is not necessary unless the patient has been taking steroids chronically.
• Patients with frequent idiopathic anaphylaxis may benefit from daily antihistamine therapy (both H1 antagonists and H2 antagonists) or, in rare circumstances, daily corticosteroid therapy. For daily therapy, diphenhydramine or hydroxyzine is often used first. Second-generation less-sedating antihistamines may be preferable because of decreased adverse effects. In their adult doses, these include fexofenadine (Allegra) at 180 mg/d, loratadine (Claritin) at 10 mg/d, cetirizine (Zyrtec) at 10 mg/d, desloratadine (Clarinex) at 5 mg/d, and levocetirizine (Xyzal) at 5mg/d. However, none has been specifically evaluated in anaphylaxis prevention. Some specialists prescribe extra doses of antihistamines as needed and as tolerated to control symptoms.
• The most important medication following an episode of anaphylaxis is an epinephrine automatic injector, which the patient should always have immediately available in case of recurrence. Epinephrine is sensitive to both light and temperature; it should not be stored in a refrigerator or in the glove compartment of a motor vehicle, for example.
  • An EpiPen (Dey Laboratories, Napa, CA) autoinjector for adults is available with a single 0.3-mg (1:1,000 v/v) dose. Similarly, an EpiPen Jr., with a 0.15-mg (1:2,000 v/v) dose, is available for children who weigh less than 30 kg. The Twinject (Verus Pharmaceuticals, San Diego, CA) is a pen-sized device containing two doses of epinephrine available either as a 0.15 or a 0.3 mg formulation. The first of the two doses in both cases is delivered by autoinjector, while the second is injected manually. For more information, see EpiPen.com or Twinject.com.
  • Placebo syringes are recommended as educational tools. Live demonstrations of injections might be considered on a case by case basis when the patient or parent expresses a fear of injection.³⁴
  • The patient should be instructed to obtain emergent medical care immediately after injecting the epinephrine because the effect is short lived (<15 min) and additional doses of epinephrine and other therapy may be required.

Transfer

• The physician's office should be prepared to initiate therapy for anaphylaxis, and patients who receive treatment should be monitored continuously to facilitate prompt detection of new clinical findings or treatment complications.
• A patient should be transferred to an emergency facility depending on the clinical severity of the reaction, response to treatment, and the likelihood that other complications will occur.

Deterrence/Prevention

• Some anaphylactic reactions are so severe that treatment is unsuccessful and death occurs. This underscores the critical importance of education, avoidance, and prevention. An allergist-immunologist can provide comprehensive professional advice on these matters.³⁶
• Prophylactic treatment with antihistamines may give sufficient protection in some patients, but this is variable.
• Avoidance is the only form of prevention for most inciting agents.³⁶ Insect sting anaphylaxis can be prevented with allergen immunotherapy, which is highly effective. IgE-independent anaphylactic reactions to radiocontrast media (RCM) can be prevented with pretreatment and use of low osmolar agents. Anti-IgE may be a good prophylactic agent for severe food allergy, but the one study published to date was with TNX-901, which is not being marketed. A phase II multicenter study with omalizumab (Xolair) in peanut allergy was discontinued prematurely because of safety concerns in some study subjects. Obtained data were insufficient to draw any conclusions, but a slight trend existed toward greater tolerability of peanuts in subjects treated with omalizumab compared to placebo.
• Patients at risk for recurrent anaphylaxis should wear a MedicAlert bracelet (see MedicAlert Foundation).³⁶ They should also avoid the use of beta-blockers, tricyclic antidepressants, and monoamine oxidase inhibitors because of potential drug interactions with necessary therapies. Angiotensin-converting enzyme inhibitors may also be a potential problem.
• Patients at risk for recurrent anaphylaxis might benefit from a written Action Plan (see Patient Education).³⁶ The use and benefit of such plans has yet to be formally evaluated.^37,38

Complications

• Death from anaphylaxis occurs, but it is uncommon (see Mortality/Morbidity).
• Complications are also unusual, with most patients recovering completely.
• Respiratory failure from severe bronchospasm or laryngeal edema can cause hypoxia, which could lead to brain injury if prolonged.
• Hypotension and hypoxia may lead to cardiac ischemia or arrhythmias.

Prognosis

• The Olmsted County study detected a total of 154 episodes involving 133 people in a 5-year period.¹⁰ Most patients (116) had only 1 episode in those 5 years. Thirteen people had 2 episodes, and 4 people had 3 episodes.
• In contrast, in the Memphis study, 48% of patients had 3 or more anaphylactic episodes.¹¹ Of the 112 patients who responded to survey, however, 38 patients (34%) reported a recurrence of symptoms and the remaining 74 patients (66%) reported remission of symptoms. Overall, 85% of patients were either in remission or reported diminished symptom severity in a subsequent episode or episodes. The Memphis study evaluated a referral population and also deliberately excluded patients with anaphylaxis due to insect stings or SCIT.¹¹

Patient Education

• Avoidance education is crucial, especially in younger patients with food anaphylaxis. Important issues include cross-contamination and inadequate labeling of foods. The Food Allergy & Anaphylaxis Network is an excellent resource for families.
• Patients must be educated regarding the indications for and proper technique of epinephrine autoinjector administration and the need to seek further medical assistance following administration.
• Patients with sensitivity to multiple antibiotics should be provided a list of alternative antibiotics. They can present this list to their primary care physicians when antibiotic therapy is required.
• For excellent patient education resources, visit eMedicine's Allergy Center and Allergic Reaction and Anaphylactic Shock Center. Also, see eMedicine's patient education articles Severe Allergic Reaction (Anaphylactic Shock), Food Allergy, and Drug Allergy.
• Other recommended Web sites
  • World Allergy Organization (WAO)
  • Resuscitation Council
  • American Academy of Allergy, Asthma, and Immunology (AAAAI)
  • American College of Allergy, Asthma, and Immunology
  • Joint Council of Allergy, Asthma, and Immunology
  • Food Allergy and Anaphylaxis Network (FAAN)
  • British Allergy Foundation
  • Anaphylaxis Canada (The websites of other national and regional allergy/immunology organizations also provide useful perspectives.)
• Action plans for healthcare professionals
  • AAAAI (Spanish language versions of the following AAAAI anaphylaxis materials are now available: the AAAAI Anaphylaxis Emergency Action Plan, Killer Allergy information page, AAAAI Anaphylaxis Tips to Remember brochure, and AAAAI Anaphylaxis Easy Reader page.)
  • FAAN English language version
  • FAAN Spanish language version
• School, child care, or camp settings
  • New South Wales Department of Health: Eat safely at school to prevent allergic reactions
  • FAAN School Guidelines 
• Information for patients and their families
  • Anaphylaxis Campaign
  • FAAN

Miscellaneous

Medicolegal Pitfalls

• Failure to consider anaphylaxis in a patient presenting with syncope or hypotension
• Failure to prescribe an epinephrine automatic injector and to document patient education regarding storage and use
• Failure to diagnose the cause of anaphylaxis where a means of prevention can be identified
• Failure to avoid prescribing a drug to which the patient is known to be sensitive or a similar, cross-reacting drug
• Failure to administer epinephrine expediently instead of less-effective medications
• Desensitizing a patient to a specific drug without documenting the need for the drug, failure to obtain informed consent, and a lack of adequate training

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Keywords

anaphylaxis, systemic allergic reaction, anaphylactic reaction, anaphylactoid reaction, allergic reaction, allergies, peanut allergy, latex allergy, shellfish allergy, hypersensitivity reaction, food allergy, insect sting, Hymenoptera venom, wasp sting, bee sting, yellow jacket sting, hornet sting, penicillin allergy, radiocontrast hypersensitivity, cardiovascular collapse, laryngeal edema, atopy, atopic disease, fire ant sting, immunotherapy, platelet activating factor, PAF, anaphylactic shock, EpiPen, epipen, food allergies, bee allergy, bee sting allergy

Contributor Information and Disclosures

Author

Stephen F Kemp, MD, FACP, Professor of Medicine, Associate Professor of Pediatrics, Director of Allergy and Immunology Fellowship Program, Departments of Medicine and Pediatrics, Associate Director of Division of Clinical Immunology and Allergy, Department of Medicine, University of Mississippi Medical Center; Consultant in Allergy and Immunology, Medical Service, G V (Sonny) Montgomery Veterans Affairs Medical Center
Stephen F Kemp, MD, FACP is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, American Medical Association, Association of Subspecialty Professors, Joint Council of Allergy, Asthma and Immunology, Mississippi State Medical Association, and Southern Society for Clinical Investigation
Disclosure: Dey LP Honoraria Speaking and teaching; Verus Pharmaceuticals Consulting fee Consulting; Pfizer Consulting fee Endpoint Committee; Intelliject None Consulting

Coauthor(s)

G William Palmer, MD, Consulting Staff, Shoreline Allergy and Asthma Associates
G William Palmer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Medical Editor

Stephen C Dreskin, MD, PhD, Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, University of Colorado Health Sciences Center
Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Samuel R Marney, Jr, MD, Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine
Samuel R Marney, Jr, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, and Tennessee Medical Association
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Stephen C Dreskin, MD, PhD, to the development and writing of this article.

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