Anaphylaxis

Introduction

Background

Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are usually prominent dermal and systemic signs and symptoms. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. A recent consensus report reviewed the definition and management of anaphylaxis.

Pathophysiology

Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase.

In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. 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. Histamine release in skin causes urticarial skin lesions.

The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency

United States

The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1000 fatal cases of anaphylaxis per year are estimated to occur in the United States. A recent review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.

The incidence of anaphylaxis appears to be increasing, especially cases in children attributed to food allergy.

International

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.

Mortality/Morbidity

Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.

Race

Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.

Sex

Differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Overall, women have a higher incidence of anaphylaxis than men, but, in some series of children, males predominate.

Age

Anaphylaxis occurs in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

Clinical

History

• Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema.
• The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction.
• Eyes may itch and tearing may be noted. Conjunctival injection may occur.
• Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia).
• GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy.
• In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or health care provider. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed.
• For reasons that are not well understood, a lack of dermal findings is more common in children than in adults.

Physical

• General
  • Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension.
  • Place emphasis on determining the patient's respiratory and cardiovascular status.
  • Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause.
  • General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions.
• Skin
  • The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin.
  • In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on reexposure.
  • Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia.
• Pulmonary
  • Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis.
  • Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema.
  • In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway.
• Cardiovascular
  • Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone.
  • Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension.
  • Relative bradycardia has been reported.

Causes

• A wide variety of substances can cause anaphylaxis. Drugs and foods are the most common causes. Peanuts, tree nuts, and shellfish are the most commonly implicated foods, while antibiotics (especially penicillins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs. Anaphylaxis also may be idiopathic.
• The most common cause (86% in one study) of anaphylaxis in children is food.
• In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On reexposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent.
• Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

• Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and frequent use of these agents. Although concern for cross-sensitivity has been present because of their molecular and immunologic similarity, there is growing evidence that this association is not significant and is based on historic data with early cephalosporins.
  • Prior reports, based on skin testing, indicated that about 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins.
    • One report suggested that the actual incidence of clinical cross-reactivity is lower (perhaps 1%), with most reactions considered mild.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").
    • One 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.
    • A review of the topic of penicillin and cephalosporin "cross-reactivity" concluded that the widely quoted 10% "cross-reactivity" is a myth.
    • In penicillin-allergic patients, cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic reaction than 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.
  • Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions. However, approximately 85% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions.
    • When a drug in either class 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, a desensitization or prophylactic pretreatment protocol may be instituted or another agent selected.
• Reactions to medications tend to be more severe and rapid in onset when the antibiotic is administered parenterally.
• A drug reaction may occur in a patient with no prior history of drug exposure.
• Aspirin and NSAIDs commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity often occurs between aspirin and the various NSAIDs.
• ACE inhibitors (ACEI), 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. The reaction is thought to be mediated by bradykinin and is considerably more common in African Americans.

Intravenous radiocontrast media

• IV administered radiocontrast media causes 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. 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 low molecular weight (LMW) contrast.
  • 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). Manage these patients as indicated earlier.
• Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.
• Reactions to radiocontrast 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.
• 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.
• Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. 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. 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.

Hymenoptera stings

• Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are therefore difficult to estimate. 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. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis.
• Caution patients treated and released from the 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 auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

Food and environmental allergies

• Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include peanuts, tree nuts, legumes, fish and shellfish, milk, and eggs. Reports of severe allergic reactions to peanuts are increasing.
• Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery).

Anaphylaxis

Introduction

Background

Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are usually prominent dermal and systemic signs and symptoms. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. A recent consensus report reviewed the definition and management of anaphylaxis.

Pathophysiology

Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase.

In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. 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. Histamine release in skin causes urticarial skin lesions.

The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency

United States

The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1000 fatal cases of anaphylaxis per year are estimated to occur in the United States. A recent review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.

The incidence of anaphylaxis appears to be increasing, especially cases in children attributed to food allergy.

International

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.

Mortality/Morbidity

Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.

Race

Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.

Sex

Differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Overall, women have a higher incidence of anaphylaxis than men, but, in some series of children, males predominate.

Age

Anaphylaxis occurs in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

Clinical

History

• Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema.
• The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction.
• Eyes may itch and tearing may be noted. Conjunctival injection may occur.
• Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia).
• GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy.
• In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or health care provider. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed.
• For reasons that are not well understood, a lack of dermal findings is more common in children than in adults.

Physical

• General
  • Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension.
  • Place emphasis on determining the patient's respiratory and cardiovascular status.
  • Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause.
  • General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions.
• Skin
  • The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin.
  • In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on reexposure.
  • Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia.
• Pulmonary
  • Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis.
  • Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema.
  • In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway.
• Cardiovascular
  • Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone.
  • Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension.
  • Relative bradycardia has been reported.

Causes

• A wide variety of substances can cause anaphylaxis. Drugs and foods are the most common causes. Peanuts, tree nuts, and shellfish are the most commonly implicated foods, while antibiotics (especially penicillins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs. Anaphylaxis also may be idiopathic.
• The most common cause (86% in one study) of anaphylaxis in children is food.
• In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On reexposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent.
• Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

• Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and frequent use of these agents. Although concern for cross-sensitivity has been present because of their molecular and immunologic similarity, there is growing evidence that this association is not significant and is based on historic data with early cephalosporins.
  • Prior reports, based on skin testing, indicated that about 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins.
    • One report suggested that the actual incidence of clinical cross-reactivity is lower (perhaps 1%), with most reactions considered mild.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").
    • One 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.
    • A review of the topic of penicillin and cephalosporin "cross-reactivity" concluded that the widely quoted 10% "cross-reactivity" is a myth.
    • In penicillin-allergic patients, cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic reaction than 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.
  • Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions. However, approximately 85% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions.
    • When a drug in either class 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, a desensitization or prophylactic pretreatment protocol may be instituted or another agent selected.
• Reactions to medications tend to be more severe and rapid in onset when the antibiotic is administered parenterally.
• A drug reaction may occur in a patient with no prior history of drug exposure.
• Aspirin and NSAIDs commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity often occurs between aspirin and the various NSAIDs.
• ACE inhibitors (ACEI), 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. The reaction is thought to be mediated by bradykinin and is considerably more common in African Americans.

Intravenous radiocontrast media

• IV administered radiocontrast media causes 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. 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 low molecular weight (LMW) contrast.
  • 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). Manage these patients as indicated earlier.
• Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.
• Reactions to radiocontrast 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.
• 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.
• Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. 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. 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.

Hymenoptera stings

• Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are therefore difficult to estimate. 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. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis.
• Caution patients treated and released from the 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 auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

Food and environmental allergies

• Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include peanuts, tree nuts, legumes, fish and shellfish, milk, and eggs. Reports of severe allergic reactions to peanuts are increasing.
• Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery).

Women's Health Patient information: Anaphylaxis

Patient information:
Liza C O'Dowd, MDBurton Zweiman, MD

UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.2 is current through April 2007; this topic was last changed on September 07, 2006. The next version of UpToDate (15.3) will be released in October 2007.
INTRODUCTION — Anaphylaxis is a sudden, potentially life-threatening allergic reaction. Allergic reactions can be triggered by foods, medications, exercise, latex, or insect stings, or unknown triggers.
Every year, about 500 to 1000 people die from severe anaphylaxis. However, many more people likely experience mild or moderate anaphylaxis and do not seek medical care. As a result, the true frequency of anaphylaxis is unknown.
The severity of anaphylactic reactions can be minimized by recognizing the symptoms early, having the proper medications available for self-treatment, and seeking emergency medical care promptly. It is also important to try to identify the specific trigger for each person, although this is not always possible.
PHYSIOLOGY — Anaphylaxis occurs when a trigger activates immune cells, which then release large amounts of multiple substances, including histamine, into the blood stream. This sets off a number of reactions, including itching, dilated blood vessels (leading to low blood pressure and rapid heart rate), mucus secretion, stimulation of the nervous system, and activation of other cells of the immune system. These reactions cause the symptoms that are commonly associated with anaphylaxis.
In some people with anaphylaxis, abnormal antibodies called IgE (proteins that normally fight infections and protect the body) are made in response to non-harmful things, like food or medicines. These IgE antibodies can trigger a violent immune response when the person is later exposed to that food or medicine. The immune response is so strong and uncontrolled that the reaction itself can be harmful. In other people with anaphylaxis, these abnormal IgE proteins are not found, and the reaction is thought to have been caused by other processes.
SYMPTOMS — Symptoms of anaphylaxis generally begin within 5 to 60 minutes of exposure to a trigger. Some patients may not develop symptoms for several hours.
Anaphylaxis can produce symptoms throughout the body: Skin: Itching, flushing, urticaria (hives), and angioedema (swelling). Eyes: Itching, tearing, and swelling of the tissues around the eyes. Nose and mouth: Sneezing, runny nose, nasal congestion, itching of the mouth, and a metallic taste. Lungs and throat: Difficulty breathing, wheezing, increased airway secretions, swelling of the upper throat and/or tongue, hoarseness, sounds of labored breathing, and a sensation of choking. Heart: Very rapid heartbeat, arrhythmia (an irregular heart beat), low blood pressure, and cardiac arrest (a cessation of the heart's pumping action). Digestive system: Nausea, vomiting, abdominal cramps, bloating, and diarrhea. Nervous system: Dizziness, weakness, fainting, and a sense of impending doom.
The most common symptoms of anaphylaxis are urticaria (hives) and angioedema (swelling of the tissues under the skin), which occur in nearly 90 percent of people who have anaphylaxis. These symptoms usually begin after a period of generalized itching, flushing, and sometimes a growing sense of impending doom.
Respiratory symptoms occur in about 50 percent of people who have anaphylaxis and are especially common in people who also have asthma. Gastrointestinal symptoms occur in 30 percent of people. Anaphylactic shock (extremely low blood pressure) occurs in 30 percent of people who have a reaction. Low blood pressure can cause lightheadedness, dizziness, tunnel vision, and loss of consciousness (passing out). These are serious symptoms.
Less commonly, a person may have biphasic or protracted anaphylaxis. A patient with biphasic anaphylaxis has a reaction that resolves but recurs one to eight hours later; second reactions have occurred as much as 72 hours later. A patient with protracted anaphylaxis has signs and symptoms that persist for up to 48 hours despite treatment.
CAUSES — Anaphylaxis triggers can include: Foods, especially seafood, milk, peanuts and tree nuts Drugs, especially certain antibiotics (such as penicillin), nonsteroidal anti-inflammatory drugs (such as aspirin or ibuprofen), drugs used for chemotherapy, and angiotensin-converting enzyme (ACE) inhibitors (See "Patient information: Allergy to penicillin and other antibiotics") Venom from insects, including bees, wasps, kissing bugs, and fire ants Some substances used during x-ray procedures (radiocontrast media) Transfused blood and blood products Exercise or exertion Latex from natural rubber, used to make gloves, balloons, and some medical products
In some cases, a thorough evaluation by an allergy specialist will not identify any specific trigger. This condition is called idiopathic anaphylaxis and is more common in adults than in children.
Food allergies in children — Anaphylaxis in children often results from food allergies. Food allergies are most likely to develop in the first three years of life, when many foods are introduced into a child's diet. Allergies to hen's egg, peanuts, cow's milk, soy, fish, and wheat are among the most common food allergies that children develop. In children over the age of three years, peanuts are the most common allergen. Children often outgrow allergies to milk, eggs, and soybeans. However, allergies to peanuts, other tree nuts, fish and seafood tend to persist.
RISK FACTORS — Several factors help to predict which individuals are most likely to experience anaphylaxis and which factors are most likely to trigger anaphylaxis in specific groups of people.
Age — Children are more likely than adults to have anaphylactic reactions to foods. Adults are more likely to have anaphylactic reactions to antibiotics, radiocontrast media, insect stings, anesthetic drugs, and certain intravenous medicines. They are also more likely to have idiopathic anaphylaxis.
Gender — Overall, women are somewhat more likely to experience anaphylaxis.
Asthma — People with asthma are more likely to experience anaphylaxis and to have more severe respiratory problems during anaphylaxis. The combination of food allergy (especially to peanuts and tree nuts) and asthma seems to put people at risk for particularly dangerous attacks of anaphylaxis.
History of anaphylaxis — People who have had an anaphylactic reaction in the past are at increased risk of future anaphylactic reactions. For example, people who have had an anaphylactic reaction to certain antibiotics are four to six times more likely to have another reaction to these antibiotics when compared to the general population. Similarly, 60 percent of people who have had an allergic reaction to a bee or wasp sting have a severe reaction if stung again, and up to 40 percent of people who have had a reaction to radiocontrast media have a repeat reaction if they are given it again (unless they are given medications to prevent a reaction).
Multiple exposures — People who are exposed to several different allergic stimuli at the same time have an increased risk of anaphylaxis. For example, people who receive immunotherapy (regular injections, also called allergy shots) to decrease a their sensitivity to allergens are more likely to have a severe reaction to their injections during the season(s) when natural exposure is greatest (eg, allergy season, usually spring and fall in most regions of the United States).
DIAGNOSIS — The diagnosis of anaphylaxis is usually based upon the presence of characteristics symptoms, particularly if there is an accompanying story of exposure to a potential trigger, such as a new medicine or insect sting.
However, other problems, such as food poisoning, a severe asthma attack, or cardiac events, can sometimes look like anaphylaxis. In such cases, further evaluation by allergists or other specialists may be needed to clarify the diagnosis. In some cases, the diagnosis of anaphylaxis is difficult to establish.
TREATMENT — A patient who has had an anaphylactic reaction should talk with their healthcare provider to design a plan for responding to future reactions. A plan can minimize the severity of an anaphylactic reaction and ensure that the best treatments are given. Many people find that developing a plan is reassuring, even if it is never needed.
Because anaphylaxis can be life-threatening, it should be treated as an emergency. Most people with moderate to severe anaphylaxis are hospitalized for observation, even when emergency treatment brings the symptoms under control. This hospitalization enables prompt treatment if the symptoms reappear several hours later.
Self-treatment — Patients with allergies or who have a history of anaphylaxis should always carry two epinephrine autoinjectors. A full description of epinephrine autoinjectors is available separately. (See "Patient information: Use of an epinephrine autoinjector").
Remove the cause — The trigger for the anaphylactic reaction should be promptly removed, whenever possible. This removal may entail stopping a drug, or in the case of an insect sting, dislodging the stinger with the edge of a credit card or coin. Patients should not attempt to pull the stinger out of the skin.
Respiratory and cardiovascular support — The initial treatment of anaphylaxis addresses any life-threatening respiratory and cardiovascular symptoms. This treatment may require inserting a breathing (endotracheal) tube to keep a person's airways open. Treatment may also include medications to treat low blood pressure and cardiac arrhythmias (irregular heart beat).
Drug therapy — Many different drugs are used to treat anaphylaxis, including epinephrine, asthma medications, antihistamines, and corticosteroids. Intravenous fluids are also frequently used to increase and maintain blood pressure.
Epinephrine is the most effective drug for the treatment of anaphylaxis. It treats all the symptoms of anaphylaxis, and is the most important treatment for the severe symptoms that can occur: low blood pressure, chest tightness or wheezing, and throat closure. (See "Patient information: Use of an epinephrine autoinjector").
Antihistamines can be given by injection or pill, and are almost always given to patients during anaphylaxis. Inhaled medications, such as albuterol, are given during anaphylaxis if a person has difficulty breathing, chest tightness, or coughing. Corticosteroids, such as prednisone, do not work rapidly enough to stop the immediate signs and symptoms of anaphylaxis. However, they may prevent a recurrence in the hours following an anaphylactic reaction and prevent late reactions, such as asthma attacks.
PREVENTION — Anaphylaxis is a frightening experience for the person who suffers the reaction, as well as for the people around him or her. It is normal to worry about future reactions. A few simple measures can reduce this risk.
Allergist evaluation — Anyone who has experienced an anaphylactic reaction should be evaluated by an allergist - a doctor who specializes in the diagnosis and treatment of allergies and related conditions. An allergist may recommend skin tests or blood testing to help identify the stimuli that triggered anaphylaxis. As stated above, a specific trigger cannot be identified in all cases, although an allergist can provide advice about how best to manage this situation as well.
Avoiding triggers — When a trigger can be identified, it can often be avoided. For example, a person with a known food allergy may be able to prevent anaphylactic reactions by carefully eliminating that food from their diet. A healthcare provider can provide strategies for identifying the food in processed products and when dining out.
Eliminating a food requires that a person carefully read food labels on everything they plan to eat, not just the foods that are most likely to contain the allergy trigger. The United States Food Allergen Labeling and Consumer Protection Act (which affects foods labeled on or after January 2006) requires that the nutrition labels on food packages clearly identify eight potential allergy triggers: milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans. Other potential allergy triggers may be identified with names that are less clear (eg, spices, flavorings, or colorings that may cause an allergic reaction). In addition, "substitute" foods that are used to lower the fat content or replace other components of a food may not remove the allergenic proteins. As an example, some egg substitutes (which are lower in cholesterol) still contain egg white proteins.
People with allergies to bees, wasps, or hornets can wear protective clothing, learn to stay calm around insects, avoid wearing scented sprays or lotions, and take care when outdoors to reduce the likelihood of being stung.
Wear a device identifying the allergy — People who have allergies or have experienced an anaphylactic reaction should wear a bracelet, necklace, or similar alert tag at all times. If another reaction occurs and the person is too ill to explain their condition, this will help responders get the proper care for the person as quickly as possible. This measure is especially important in children.
The alert tag should include a list of known allergies, as well as the name and phone number of an emergency contact. One device, Medic Alert®, provides a toll-free number that emergency medical workers can call to find out a person's medical history, list of medications, family emergency contact numbers, and healthcare provider names and numbers.
Other preventive measures — Other measures to prevent future episodes of anaphylaxis include immunotherapy (injections to reduce sensitivity) for bee and wasp stings, antibiotic desensitization, and premedication with antihistamines and corticosteroids before radiocontrast administration.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. The National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html) American Academy of Allergy, Asthma, and Immunology
(www.aaaai.org) Anaphylaxis Foundation and Anaphylaxis Network of Canada
(www.anaphylaxis.org) The Anaphylaxis Campaign
(www.anaphylaxis.org.uk)