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Anaphylaxis

  • Author: S Shahzad Mustafa, MD; Chief Editor: Michael A Kaliner, MD  more...
 
Updated: May 31, 2016
 

Practice Essentials

Anaphylaxis is an acute, potentially fatal, multiorgan system reaction caused by the release of chemical mediators from mast cells and basophils.[1, 2] The classic form involves prior sensitization to an allergen with later reexposure, producing symptoms via an immunologic mechanism.

Signs and symptoms

Anaphylaxis most commonly affects the cutaneous, respiratory, cardiovascular, and gastrointestinal systems. The skin or mucous membranes are involved in 80-90% of cases. A majority of adult patients have some combination of urticaria, erythema, pruritus, or angioedema. However, for poorly understood reasons, children may present more commonly with respiratory symptoms followed by cutaneous symptoms.[3]  It is also important to note that some of the most severe cases of anaphylaxis present in the absence of skin findings.

Initially, patients often experience pruritus and flushing. Other symptoms can evolve rapidly, such as the following:

  • Dermatologic/ocular: Flushing, urticaria, angioedema, cutaneous and/or conjunctival injection or pruritus, warmth, and swelling
  • Respiratory: Nasal congestion, coryza, rhinorrhea, sneezing, throat tightness, wheezing, shortness of breath, cough, hoarseness, dyspnea
  • 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

See Clinical Presentation for more detail.

Diagnosis

Anaphylaxis is primarily a clinical diagnosis. The first priority in the physical examination should be to assess the patient’s airway, breathing, circulation, and adequacy of mentation (eg, alertness, orientation, coherence of thought).

Examination may reveal the following findings:

  • General appearance and vital signs: Vary according to the severity of the anaphylactic episode and the organ system(s) affected; patients are commonly restless and anxious
  • Respiratory findings: Severe angioedema of the tongue and lips; tachypnea; stridor or severe air hunger; loss of voice, hoarseness, and/or dysphonia; wheezing
  • Cardiovascular: Tachycardia, hypotension; cardiovascular collapse and shock can occur immediately, without any other findings
  • Neurologic: Altered mentation; depressed level of consciousness or may be agitated and/or combative
  • Dermatologic: Classic skin manifestation is urticaria (ie, hives) anywhere on the body; angioedema (soft-tissue swelling); generalized (whole-body) erythema (or flushing) without urticaria or angioedema
  • Gastrointestinal: Vomiting, diarrhea, and abdominal distention

Testing

Laboratory studies are not usually required and are rarely helpful. However, if the diagnosis is unclear, especially with a recurrent syndrome, or if other diseases need to be excluded, the following laboratory studies may be ordered in specific situations:

  • Serum tryptase may help confirm the diagnosis of anaphylaxis [2] .
  • Urinary 24-hour histamine may help in the diagnosis of recurrent anaphylaxis
  • Urinary 24-hour 5-hydroxyindoleacetic acid levels: If carcinoid syndrome is a consideration

Skin testing, in vitro immunoglobulin E (IgE) tests, or both may be used to determine the stimulus causing the anaphylactic reaction. Such studies may include the following:

  • Testing for food allergy(ies)
  • Testing for medication allergy(ies)
  • Testing for causes of IgE-independent reactions

See Workup for more detail.

Management

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Patient management and disposition are dependent on the severity of the initial reaction and the treatment response. Measures beyond basic life support are not necessary for patients with purely local reactions. Patients with refractory or very severe anaphylaxis (with cardiovascular and/or severe respiratory symptoms) should be admitted or treated and observed for a longer period in the emergency department or an observation area.

Nonpharmacotherapy

Supportive care for patients with suspected anaphylaxis includes the following:

  • Airway management (eg, ventilator support with bag/valve/mask, endotracheal intubation)
  • High-flow oxygen
  • Cardiac monitoring and/or pulse oximetry
  • Intravenous access (large bore)
  • Fluid resuscitation with isotonic crystalloid solution
  • Supine position (or position of comfort if dyspneic or vomiting) with legs elevated

Pharmacotherapy

The primary drug treatments for acute anaphylactic reactions are epinephrine and H1 antihistamines. Medications used in patients with anaphylaxis include the following:

  • Adrenergic agonists (eg, epinephrine)
  • Antihistamines (eg, diphenhydramine, hydroxyzine)
  • H2 receptor antagonists (eg, cimetidine, ranitidine, famotidine)
  • Bronchodilators (eg, albuterol)
  • Corticosteroids (eg, methylprednisolone, prednisone)
  • Positive inotropic agents (eg, glucagon)
  • Vasopressors (eg, dopamine)

Surgical option

In extreme circumstances, cricothyrotomy or catheter jet ventilation may be lifesaving when orotracheal intubation or bag/valve/mask ventilation is not effective. Cricothyrotomy is easier to perform than emergency tracheostomy.

See Treatment and Medication for more detail.

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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. The term is derived from the Greek words ana - (“up, back, again”) and phylaxis (“guarding, protection, immunity”).

Anaphylaxis is an acute, potentially fatal, multiorgan system reaction caused by the release of chemical mediators from mast cells and basophils.[1, 2] The classic form involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. (See Pathophysiology and Etiology.)

The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. (See Clinical Presentation.)

Anaphylaxis has no universally accepted clinical definition. It is a clinical diagnosis based on typical systemic manifestations, often with a history of acute exposure to a causative agent. (See Diagnosis.)

Because anaphylaxis is primarily a clinical diagnosis, laboratory studies are not usually required and are rarely helpful. However, if the diagnosis is unclear, especially with a recurrent syndrome, or if other diseases need to be excluded, some limited laboratory studies are indicated. Skin testing and in vitro IgE tests may be helpful. (See Workup.)

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Disposition of patients with anaphylaxis depends on the severity of the initial reaction and the response to treatment.

Go to Pediatric Anaphylaxis and Pediatric Exercise-Induced Anaphylaxis for complete information on these topics.

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Pathophysiology

The traditional nomenclature for anaphylaxis reserves the term anaphylactic for reactions mediated by immunoglobulin E (IgE) and the term anaphylactoid for non-IgE-mediated reactions, which can be clinically indistinguishable. The World Allergy Organization has recommended replacing this terminology with immunologic (IgE-mediated and non–IgE-mediated [eg, IgG and immune complex complement–mediated]) and nonimmunologic anaphylaxis (events resulting in sudden mast cell and basophil degranulation in the absence of immunoglobulins).[4]

The physiologic responses to the release of anaphylaxis mediators include smooth muscle spasm in the respiratory and gastrointestinal (GI) tracts, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis.

Cardiovascular effects result from decreased vascular tone and capillary leakage. 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.

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.

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.

Interleukin (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).

Additional mediators include newly generated lipid-derived mediators such as prostaglandin D2, leukotriene B4, and platelet-activating factor (PAF), as well as the cysteinyl leukotrienes, such as LTC4, LTD4, and LTE4. These mediators further contribute to the proinflammatory cascade seen in anaphylaxis.

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 H1 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.

Processes inducing cardiovascular changes

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.

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%, 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.

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.

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.

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Etiology

IgE-mediated anaphylaxis 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.

Other types of immunologic anaphylaxis do not involve IgE. For example, anaphylaxis resulting from administration of blood products, including intravenous immunoglobulin, or animal antiserum is due, at least in part, to complement activation. Immune complexes formed in vivo or in vitro can activate the complement cascade. Certain byproducts of the cascade—plasma-activated complement 3 (C3a), plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a)—are called anaphylatoxins and can cause mast cell/basophil degranulation.

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. In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific IgE attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds.

Certain agents are thought to cause direct nonimmunologic release of mediators from mast cells, a process not mediated by IgE. These include opioids, 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).

Inciting agents

The most common inciting agents in anaphylaxis are foods, Hymenoptera stings, and intravenous (IV) contrast materials. Anaphylaxis may also be idiopathic.

Immunologic IgE-mediated reactions

Typical examples of IgE-mediated anaphylaxis include the reactions to many foods, drugs, and insect stings.

Hypersensitivity to foods is a problem encountered throughout the industrialized world.[8] In the United States, an estimated 4 million Americans have well-substantiated food allergies. A study from Australia showed that more than 10% of 12-month-old children had challenge-proven IgE-mediated food allergies.[9] 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.

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. Those likely to elicit an IgE antibody response in children also include cow’s milk, eggs, wheat, and soy.

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.[10] The Rochester Epidemiology Project, 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.[11]

In the past, a history of IgE-mediated egg allergy has been a contraindication to receiving the annual influenza vaccination. A few years ago, egg-allergic individuals received influenza vaccination, but typically with a graded multi-dose protocol or based on skin prick testing to the vaccine itself. Given a dearth of recent evidence that egg-allergic individuals can safely receive the influenza vaccine with no increased risk of systemic reaction as compared to the general population, the most recent guidelines now recommend that all egg-allergic individuals should be vaccinated with a single dose of influenza vaccine. Furthermore, skin testing has no role because no evidence suggests this reliably identifies individuals at risk of a systemic reaction.[12, 13]

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.

Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillin and other beta-lactam antibiotics. Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis.

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.

Reactions to cephalosporins may occur in penicillin-allergic patients. In these patients, older agents such as cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic reaction than newer agents such as cefprozil, cefuroxime, ceftazidime, or ceftriaxone. This increased reactivity with the older agents is due to greater antigenic similarity of the side chain not present with the newer second- and third-generation agents.

One report suggested that the actual incidence of anaphylaxis to cephalosporins in penicillin-anaphylactic patients is much lower than the 10% frequently quoted—perhaps 1%, with most reactions considered mild.[14] A retrospective study evaluated 606 hospitalized patients with a history of penicillin allergy who were given a cephalosporin. Only one patient (0.17%) had a reaction, and it was minor.[15]

Another paper indicated that patients with a history of allergy to penicillin seem to have a higher risk (by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in those with no history of penicillin allergy (ie, at least part of the observed “cross-reactivity” may represent a general state of immune hyperresponsiveness, rather than true cross-reactivity).[16]

Pichichero reviewed the complicated literature and offered specific guidance for the use of cephalosporins in patients who have a history of IgE-mediated reactions to penicillin.[17]

Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions to penicillins. However, approximately 95% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions. 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 cross-reactivity exists between penicillins and aztreonam.

When either a penicillin or a cephalosporin is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history is indefinite, the drug may be administered under close observation; however, when possible, obtain the patient’s informed consent. Immediate treatment measures for anaphylaxis should be available. Alternatively, when the history is more convincing, an alternative agent should be chosen if it provides similar efficacy or one must pursue a desensitization protocol.

Many other drugs have been implicated in IgE-mediated anaphylaxis, albeit less frequently. In the surgical setting, anaphylactic reactions are most often due to muscle relaxants but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. The prevalence of latex allergy was higher during the 1980s (due to the HIV and hepatitis B and C epidemics and the institution of universal precautions), but the incidence has decreased significantly since the widespread use of latex-free materials. If latex is responsible for anaphylaxis in the perioperative setting, reactions tend to occur during maintenance anesthesia, whereas other agents tend to cause reactions during the induction of anesthesia. Volatile anesthetic agents can cause immune-mediated hepatic toxicity but have not been implicated in anaphylactic reactions.[18]

Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. From 0.5%-3% of the US population experiences a systemic reaction after being stung.[19] In the United States, Hymenoptera envenomations result in fewer than 100 reported deaths per year. Local reaction and urticaria without other manifestations of anaphylaxis are much more common than full-blown anaphylaxis after Hymenoptera stings. Adults with generalized urticaria are at increased risk for anaphylaxis with future stings, but a local reaction, regardless of severity, is not a risk factor for anaphylaxis.

Caution patients treated and released from the emergency department (ED) after an episode of anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when possible. Consider referral to an allergist for desensitization, particularly when further exposure is likely. Additionally, consider prescribing a treatment kit with an epinephrine autoinjector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

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 death per 2,500,000 injections.[20, 21, 22] 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 (NFRs) to subcutaneous immunotherapy also have been examined retrospectively. Of 646 allergist-immunologists who responded to a survey on reactions, 273 reported NFRs. 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.

Immunologic reactions to aspirin, NSAIDs, and ACE inhibitors

Reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in the past have been classified as IgE-independent because they 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, however, 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 occurs only 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.

Angiotensin-converting enzyme (ACE) inhibitors, widely used in the treatment of hypertension, are associated with angioedema in 0.5-1.0% of patients who take them. Systemic anaphylaxis is rarely associated with these agents.

Immunologic IgE-independent reactions

Anaphylaxis may result from administration of blood products, including IV immunoglobulin, or animal antiserum, at least partly as a consequence of activation of the complement cascade. Certain byproducts of the cascade are capable of causing mast cell/basophil degranulation. (See Pathophysiology.)

Exercise-induced anaphylaxis is a rare syndrome that can take 1 of 2 forms. The first form is food dependent, requiring 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, similarly, 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 can be a manifestation of systemic mastocytosis, a disease characterized by excessive mast cell burden in multiple organs. Such patients appear to be at increased risk for food and venom reactions. Alcohol, vancomycin, opioids, radiocontrast media, and other biologic agents that can directly degranulate mast cells are generally discouraged in these patients.

Nonimmunologic reactions

Certain agents, including opioids, dextrans, protamine, and vancomycin, are thought to cause direct, nonimmunologic release of mediators from mast cells. Evidence also exists that dextrans and protamine can activate several inflammatory pathways, including complement, coagulation, and vasoactive (kallikrein-kinin) systems.

Intravenously administered radiocontrast media cause an anaphylactoid reaction that is clinically similar to true anaphylaxis and is treated in the same way. The reaction is not related to prior exposure. Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Reactions to radiocontrast media usually are mild (most commonly urticarial), with only rare fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures.

Pretreatment with antihistamines or corticosteroids and use of low-molecular-weight (LMW) contrast agents lead to lower rates of anaphylactoid reactions to IV radiocontrast media (approximately 0.5%). Consider these measures for patients who have prior history of reaction, since rate of recurrence is estimated at 17-60%. Some institutions use only LMW agents. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.

Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic reaction is more difficult to treat in those taking beta-blockers.

Shellfish or iodine allergy is not a contraindication to use of IV contrast and does not mandate a pretreatment regimen. As with any allergic patient, give consideration to use of LMW contrast agents. In fact, the term iodine allergy is a misnomer. Iodine is an essential trace element present throughout the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior contrast reaction, a shellfish allergy, or a contact reaction to povidone-iodine (Betadine).

Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these agents.

Idiopathic anaphylaxis

Idiopathic anaphylaxis is a syndrome of recurrent anaphylaxis for which no consistent triggers can be determined despite an exhaustive search.[23] This recurrent syndrome should be distinguished from a single episode of anaphylaxis for which the etiology may be unclear.

Idiopathic anaphylaxis can be categorized as infrequent (< 6 episodes per year) or frequent (≥6 episodes per year or 2 or more episodes within the last 2 months).[23] 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.[24, 25] 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.

Biphasic and persistent anaphylaxis

The reported incidence of biphasic (recurrent) anaphylaxis varies from less than 1% to a maximum of 23%. Additionally, the reported time of onset of the late phase may vary from 1 to 72 hours (most occur within 8-10 h). Potential risk factors include severity of the initial phase, delayed or suboptimal doses of epinephrine during initial treatment, laryngeal edema or hypotension during the initial phase, delayed onset of symptoms after exposure to the culprit antigen (often a food or insect sting), or prior history of biphasic anaphylaxis.[26]

Persistent anaphylaxis, anaphylaxis that may last from 5-32 hours, occurred in 7 of 25 subjects (28%) in the Stark and Sullivan report, with 2 fatalities.[27] Of 13 subjects analyzed in a report on fatal or near-fatal anaphylaxis to foods, 3 (23%) similarly experienced persistent anaphylaxis.[28] Retrospective data from other investigators, however, suggest that persistent anaphylaxis is uncommon.

Neither biphasic nor persistent anaphylaxis can be predicted from the severity of the initial phase of an anaphylactic reaction. Since life-threatening manifestations of anaphylaxis may recur, it may be necessary to monitor patients 24 hours or more after apparent recovery from the initial phase.[26] When prescribing epinephrine, all patients should be instructed to have 2 injectors on hand at all times.

Risk factors

As mentioned above, atopy is a risk factor for anaphylaxis. In the Rochester Epidemiology Project, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis).[11] The Memphis study detected atopy in 37% of the patients.[29] 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 that an 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.

A retrospective emergency department study of 302 patients presenting with anaphylaxis, 87 (29%) of whom were taking at least 1 antihypertensive medication, found that antihypertensive pharmacotherapy increased the risk of organ system involvement and hospitalization.[30, 31] There was a more than 2-fold increased risk of involvement in 3 or more organ systems when ACE inhibitors, beta blockers, diuretics, or any antihypertensive medications were used. Most of these agents were also associated with an increased risk for inpatient admission.[30, 31]

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Epidemiology

The true incidence of anaphylaxis is unknown. Some clinicians reserve the term for the full-blown syndrome, whereas others use it to describe milder cases. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed.

A review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.[32]

United States statistics

Neugut et al estimated that 1-15% of the US population is at risk of experiencing an anaphylactic or anaphylactoid reaction.[33] 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 Rochester, Minnesota, found an average annual incidence of anaphylaxis of 58.9 cases per 100,000 person-years, which had increased from 46.9 cases per 100,000 in 1990.[11] Of identified causes, ingestion of a specific food was responsible for 33%, insect stings for 18.5%, and medications for 13.7%. Twenty-five percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently from July through September, a difference that 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 was excluded from the study).[29] The cause could not be determined in 59% (ie, they were diagnosed with idiopathic anaphylaxis). A separate study estimated that there are 20,000-47,000 cases of idiopathic anaphylaxis in the United States per year (approximately 8-19 episodes per 100,000 person-years).

Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas. Exposure and therefore reactions to medications are more common in industrialized areas.

International statistics

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 Rochester 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, Germany[34] ). Rates in Europe range from 1-3 cases per 10,000.[35, 34] However, the incidence of anaphylaxis may be increasing.[36]

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.[37] Moneret-Vautrin et al reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population.[38]

Age distribution for anaphylaxis

Anaphylaxis can occur at any age. In the Rochester study, the mean age was 29.3 years (range, 0.8 to 78.2 years). Age-specific rates were highest for ages 0-19 years (70 cases per 100,000 person-years).[11] The Memphis study had an age range of 1-79 years, with a mean of 37 years.[29] Simons and colleagues noted the highest frequency of epinephrine prescriptions for boys aged 12-17 months (5.3%).[37] 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, 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.

Go to Pediatric Anaphylaxis and Pediatric Exercise-Induced Anaphylaxis for more complete information on these topics.

Sex distribution for anaphylaxis

The Rochester and Memphis studies both showed a slight female predominance.[11, 29] Earlier studies have suggested that episodes of anaphylaxis to IV muscle relaxants, aspirin, and latex are more common in women, whereas insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.

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Prognosis

Fatal anaphylaxis is infrequent but not rare; milder forms occur much more frequently. Up to 500-1000 fatal cases of anaphylaxis per year are estimated to occur in the United States. Estimated mortality rates range from 0.65-2% of patients with anaphylaxis.[39, 40]

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 125 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. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States, but this is considered to be an underestimate.

Anaphylaxis to conventional radiocontrast media (RCM) was estimated to have caused up to 900 fatalities in 1975, or 0.009% of patients receiving RCM.[41] In one series, the reported risk of adverse reactions (mild or severe) in patients receiving lower osmolar RCM agents is 3.13% compared with 12.66% for patients receiving conventional RCM.[42] The study also reported premedication did not lower the risk of nonionic reactions further. The rate of fatal anaphylaxis is also reduced significantly by lower-osmolar RCM, approximately 1 in 168,000 administrations.[43]

In the United Kingdom, half of fatal anaphylaxis episodes are of iatrogenic origin (eg, anesthesia, antibiotics, radiocontrast media), 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).

Asthma is a risk factor for fatal anaphylaxis. Delayed administration of epinephrine is also a risk factor for fatal outcomes.[8]

Posture also influences anaphylaxis outcomes. In a retrospective review of prehospital anaphylactic fatalities in the United Kingdom, the postural history was known for 10 individuals.[44] Four of the 10 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.

Patients may experience multiple anaphylactic episodes. The Rochester study detected a total of 154 anaphylactic episodes involving 133 people in a 5-year period.[11] 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.[29] 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 either were 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.[29]

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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, as well as physicians. A study of children with food allergy visiting a subspecialty allergy clinic found 59% had an epinephrine autoinjector with them, although 71% of parents reported keeping the autoinjector available at all times. The only variable positively associated with having an autoinjector available was epinephrine autoinjector instruction.[45]

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.

Avoidance education is also important for persons who are hypersensitive to insect stings. Caution patients to avoid use of perfumes or hygiene products that include perfumes, particularly floral scents, as these attract flying Hymenoptera. Brightly colored clothing attracts bees and other pollinating insects. Avoid locations of known hives or nests, and avoid using equipment that disturbs the hive.

Persons who are sensitive to Hymenoptera and who must be outdoors should carry an epinephrine autoinjector (see below). Inform patients who react to Hymenoptera venom of the availability of desensitization therapy. On discharge, warn patients of the possibility of recurrent symptoms, and instruct them to seek further care if this occurs.

In 2011, the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma & Immunology, and the Joint Council of Allergy, Asthma and Immunology, issued an updated practice parameter on insect sting hypersensitivity. The practice parameter states that patients with a possible systemic reaction should be referred to an allergist or immunologist, where they should be educated about their risk of another reaction, their options for preventative treatment, and the benefits of wearing a medical identification necklace or bracelet. Avoiding insect stings and dealing with an emergency should be discussed.[46] The 2010 Joint Task Force updated anaphylaxis parameter and the 2011 World Allergy Organization guidelines are generally in accordance with these recommendations.[47, 48]

For patient education information, see eMedicineHealth’s Allergies Center. Also, see eMedicineHealth's patient education articles Severe Allergic Reaction (Anaphylactic Shock), Food Allergy, and Drug Allergy.

Epinephrine autoinjector instruction

Good evidence suggests that physicians underprescribe epinephrine and that patients (or their parents) fail to use epinephrine as quickly as possible.[49, 50, 51] Accordingly, at discharge, all patients should be provided an epinephrine autoinjector and should receive proper instruction on how to self-administer it in case of a subsequent episode.[50]

Patients should be instructed to keep an epinephrine autoinjector with them at all times; they should also carry diphenhydramine and take this in conjunction with use of the epinephrine autoinjector. They should be instructed to keep the device from extremes of temperature. Epinephrine is sensitive to both light and temperature and therefore should not be stored, for example, in a refrigerator or in a motor vehicle glove compartment. They also should be instructed to replace any epinephrine autoinjector before its expiration date.

Patients should be instructed to have ready and prompt access to emergency medical services for transportation to the closest ED for treatment. They should also be instructed to obtain emergency medical care immediately after injecting the epinephrine because the effect is short lived (< 15 min) and biphasic reactions can occur.

An EpiPen (Dey Pharma, Napa, Calif) 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. Auvi-Q (Sanofi) comes in similar dosing, and has the advantage of being a more compact device that provides visual and audio cues to help with proper administration.

The Adrenaclick (Schionogi USA, Inc., Florham Park, NJ) is also available as a single-dose autoinjector of either 0.15 mg or 0.3 mg. The Twinject (Schionogi USA, Inc., Florham Park, NJ) is a pen-sized device containing 2 doses of epinephrine available either as a 0.15- or 0.3-mg formulation. In both cases, the first of the 2 doses is delivered by autoinjector, and the second is injected manually.

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.[50]

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Contributor Information and Disclosures
Author

S Shahzad Mustafa, MD Physician in Allergy, Immunology, and Rheumatology, Rochester General Medical Group; Clinical Assistant Professor of Medicine, University of Rochester School of Medicine and Dentistry

S Shahzad Mustafa, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, Finger Lakes Allergy Society

Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; 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, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Roy Alson, MD, PhD, FACEP, FAAEM Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare

Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: Air Medical Physician Association, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and World Association for Disaster and Emergency Medicine

Disclosure: Nothing to disclose.

Stephen C Dreskin, MD, PhD Professor of Medicine, Departments of Internal Medicine, Director of Allergy, Asthma, and Immunology Practice, 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 College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology

Disclosure: Genentech Consulting fee Consulting; American Health Insurance Plans Consulting fee Consulting; Johns Hopkins School of Public Health Consulting fee Consulting; Array BioPharma Consulting fee Consulting

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; Staff Physician and 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, Association of Subspecialty Professors, Joint Council of Allergy, Asthma and Immunology, Mississippi State Medical Association, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Richard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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.

Matthew M Rice, MD, JD, FACEP Senior Vice President, Chief Medical Officer, Northwest Emergency Physicians of TeamHealth; Assistant Clinical Professor of Medicine, University of Washington School of Medicine

Matthew M Rice, MD, JD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, Society for Academic Emergency Medicine, and Washington State Medical Association

Disclosure: Team Health Salary Employment

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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