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).