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Anaphylaxis is an immediate, life-threatening hypersensitivity or allergic reaction (Gell and Coombs Type I—Immediate hypersensitivity reaction). It can be triggered by exposure to various antigens from foods, drugs, or insect stings, and also by latex, exercise, or other diagnostic agents. Unfortunately, in up to two thirds of patients presenting for evaluation of anaphylaxis, no specific trigger can be identified. If triggers of anaphylaxis can be identified by history and confirmed by diagnostic testing, then patients identified as at risk for anaphylactic reactions should be prescribed life-saving rescue medications that can be administered in the field and be given specific instructions to seek immediate emergency medical evaluation if symptoms develop. This chapter will focus on the definition, pathophysiology, clinical presentation, diagnosis, and treatment of anaphylaxis to provide internists and general practitioners with the knowledge required to care for patients with anaphylaxis in their clinical practice. The most recent set of practice parameters for the diagnosis and management of anaphylaxis were issued by the Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology in 2005. |
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Incidence
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Anaphylaxis is a systemic, immediate hypersensitivity reaction caused by immunoglobulin (Ig) E-dependent activation of effector cells of the immune system, predominantly mast cells and basophils. Mediators elaborated by these effector cells are responsible for the symptoms of anaphylaxis, which may involve the cutaneous, respiratory, gastrointestinal, or cardiovascular systems. Anaphylactoid reactions are clinically similar to anaphylactic reactions but are not mediated by IgE-dependent activation. Thus, regardless of triggering cause, anaphylactic or anaphylactoid reactions occur as a consequence of inappropriate and overwhelming mast cell or basophil activation and will be discussed as a single clinical entity in this chapter. |
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The true incidence of anaphylaxis is difficult to determine because it is underdiagnosed and underreported. It is estimated that 500 to 1,000 fatalities caused by anaphylaxis occur per year in the United States.1 In-hospital anaphylaxis complicates roughly one of every 5,000 admissions and occurs at a rate in ambulatory individuals of 21 per 100,000 person-years.2,3 Various studies have implicated either drugs or foods as the most common causative agents. Risk factors affecting the incidence of anaphylaxis have been identified (Table 1). These include:
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The clinical symptoms of anaphylaxis derive from the proinflammatory and vasoactive mediators (Table 2) released by the sudden and overwhelming degranulation of mast cells and basophils. Anaphylactic reactions are triggered by the cross-linking of the high-affinity IgE receptor by receptor-bound IgE that recognizes antigens such as food, drug, or insect venom. Complement protein anaphylatoxins such as C3a and C5a may also trigger mast cell or basophil degranulation, whereas nonsteroidal anti-inflammatory agents may trigger cell activation by altering arachidonic acid metabolism. After degranulation, preformed mediators such as histamine and tryptase and newly synthesized mediators such as inflammatory prostaglandins, cysteinyl leukotrienes, platelet-activating factor, and nitric oxide have diverse effects on target organs, which include vasodilation, airway smooth-muscle contraction, mucus hypersecretion, activation of the autonomic nervous system, platelet aggregation, and subsequent recruitment of more inflammatory cells. These mediators directly contribute to increased airway resistance and to the fall in PO2 seen during anaphylaxis. From a hemodynamic standpoint, these mediators trigger vasodilation with subsequent dramatic and sudden intravascular fluid volume depletion followed by a compensatory catecholamine response that may or may not be effective in maintaining systemic vascular resistance. Cardiac output, which initially increases, may fall as a result of myocardial depression, resulting in hypotension. Etiology Exercise-induced anaphylaxis occurs during or immediately after vigorous physical exercise, and often after eating a meal. Specific foods have been linked to exercise-induced anaphylaxis. Often, target foods can be tolerated without anaphylaxis in the absence of exercise and exercise can be tolerated without ingestion of these foods. But if specific foods are ingested followed by exercise, then anaphylaxis can occur.15 However, food ingestion does not need to precede the development of exercise-induced anaphylaxis—it can follow. Exercise-induced anaphylaxis has also been diagnosed in patients who exercised first and then ingested a target food within 3 hours of exercise. In addition, a subset of patients with exercise-induced anaphylaxis can develop anaphylaxis when exercising before or after ingestion of any food at all, not only a specific food. Cholinergic urticaria, or hives that are triggered by an increase in core body temperature, can occur with exercise and can be mistaken for exercise-induced anaphylaxis. If foods, drug, venoms, or other triggers such as physical exercise have not been identified as a cause and no external antigen can be identified as the trigger, then the patient may be classified as having idiopathic anaphylaxis. |
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After exposure to an antigenic trigger, symptoms generally develop within 5 to 30 minutes, although, less commonly, symptoms can occur up to several hours after the exposure (Table 4). Five percent to 20% of patients who suffer an initial anaphylactic event can experience biphasic anaphylaxis, in which symptoms recur up to 8 hours after the initial event, presumably due to a late-phase reaction triggered by the recruitment of inflammatory cells after the initial hypersensitivity response.16,17 Up to 6% of patients with anaphylaxis may experience biphasic symptoms.18 Protracted anaphylaxis occurs at a rate of less than 1% in patients who experience persistent symptoms for up to 48 hours after initial exposure. Biphasic or protracted anaphylaxis occurs more commonly in patients who develop delayed symptoms upon antigen exposure or who received the antigen by the oral route (PO).19
Cutaneous manifestations in anaphylaxis are most common, manifesting as urticaria and/or angioedema, flushing, or generalized pruritis. Respiratory symptoms are next most frequent, with patients developing dyspnea, wheezing, or laryngeal edema. Chest radiographs may demonstrate hyperinflation, and pulmonary mechanics reveal increased peak airway pressures, reduced peak flow, and fall in the FEV1, suggesting airway obstruction. Acute respiratory distress syndrome can complicate anaphylaxis despite aggressive resuscitation.20 Cardiovascular symptoms include cardiovascular collapse, tachycardia or relative bradycardia, and arrhythmias. Death from anaphylaxis results from cardiovascular collapse, intractable bronchospasm, or upper airway edema that causes airway obstruction. Gastrointestinal manifestations, including nausea, vomiting, diarrhea, or abdominal pain and cramping may also occur. Neurologic manifestations include seizures, impaired consciousness, muscle spasms, headache, and "a sense of impending doom." |
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Anaphylaxis is a clinical diagnosis suggested by:
Measurement of serum tryptase or plasma or urine histamine levels may be useful in confirming the diagnosis of anaphylaxis. Plasma histamine levels rise within 5 minutes after the onset of anaphylaxis but fall within 30 to 60 minutes; thus, because of its short half-life in the blood, this test is often difficult to obtain.21 A 24-hour urine specimen for N-methyl-histamine may be more useful in the context of an acute reaction when compared with a baseline urine collection obtained later when the patient is symptom-free.22 Tryptase is a relatively mast-cell-specific protease that is released upon mast-cell degranulation; its serum level peaks at 1 hour postevent and may be detectable for up to 6 hours.23 If serum specimens can be obtained between 1 and 6 hours after the event, finding an elevated serum tryptase level to compare with a baseline level obtained when the patient is asymptomatic may confirm that symptoms were due to an anaphylactic/anaphylactoid reaction. Diagnostic testing, if possible, is critical in identifying the triggering antigen. This may be done with cutaneous or serum radioallergosorbent testing, usually overseen by a specialist in allergy and immunology. Often a methodical and detailed history that carefully reviews over-the-counter medications, ingested foods and drugs, insect stings, physical activities prior to the event, and so forth is the best test. Masqueraders of anaphylaxis must be considered and excluded (Table 5). Unfortunately, no clear trigger can be documented in most cases. Of note, diagnostic skin testing should be delayed for at least 6 weeks after the event in order to obtain an accurate skin test.24 |
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Rapid recognition of an acute anaphylactic event is essential to prevent an adverse outcome. Initial steps to stabilize the patient per Advanced Cardiac Life Support protocols should begin with an assessment of the patient's airway and cardiopulmonary status (Table 6). The airway may have to be secured by intubation or emergent cricothyroidotomy if angioedema from anaphylaxis leads to airway compromise. Intravenous (IV) access should be obtained, and any obvious triggering antigen (for example, an insect stinger or an ongoing IV infusion of medication) should be removed from the patient if identified. Vital signs should be monitored, with Trendelenberg positioning and oxygen used if necessary. At the very least, patients should be kept in the supine position, as deaths have occurred within seconds of moving a patient in the midst of an anaphylactic event from the supine to the upright position.25 If any of these essential tasks cannot be performed, the patient should be immediately transported to a facility experienced in the management of acute anaphylaxis.
Epinephrine is the drug of choice in the treatment of anaphylaxis and should be administered immediately upon diagnosis. Fatality rates are the highest in cases where epinephrine administration is delayed.5 Adult patients should receive 0.3 to 0.5 mL of intramuscular (IM) epinephrine 1:1000 (0.3 to 0.5 mg) every 10 to 15 minutes. IM administration in the lateral thigh is the recommended site of delivery, as suggested by studies examining optimal absorption rates per injection location.26,27 If there is no response and the patient is developing signs and symptoms of shock or cardiovascular collapse, then 0.5 to 1.0 mL of epinephrine 1:10,000 (0.1 mg) IV every 10 to 20 minutes can be given. If IV access cannot be obtained, then epinephrine can be administered by the endotracheal tube. Continuous IV epinephrine infusions have also been used, but its titration for hemodynamic benefit should be done in an ICU setting. Other vasopressor medications such as dopamine, norepinephrine, or phenylephrine have also been used in conjunction with colloids or crystalloids for persistent hypotension. H1 antagonists (eg, diphenhydramine 25 to 50 mg PO/IM/IV) and H2 antagonists (eg, ranitidine 50 mg IM/IV) can be useful as adjuncts, and corticosteroids (eg, hydrocortisone 100 mg to 1 gram IV or prednisone 30 to 60 mg PO) used as adjuncts may have a role in preventing the late-phase response. If a patient on beta blockers experiences anaphylaxis, then an IV bolus of glucagon 1 mg may be useful to prevent refractory hypotension and relative bradycardia. Inhaled beta-adrenergic aerosols may be useful in the treatment of anaphylaxis-associated bronchospasm. A patient who has had an anaphylactic event should be given specific recommendations based on available diagnostic testing to prevent and treat future episodes (Table 7). Patients should obtain and wear at all times a medical alert bracelet or tag identifying their risk for anaphylaxis. This can expedite medical treatment should they have an event leaving them unable to communicate with potential rescuers. Patients should be prescribed self-injectible epinephrine and instructed in its use. If an etiologic trigger has been identified through history and diagnostic testing, then specific instructions should be given to avoid future episodes. In selected cases, further risk reduction can be achieved under the care of an allergy and immunology specialist. In the case of stinging-insect hypersensitivity, specific allergen immunotherapy to selected insect venoms is greater than 95% effective in preventing future systemic reactions to stings28 (this is discussed in depth in the chapter on venom allergy). For hypersensitivity to beta-lactam antibiotics, drug desensitization can reduce the risk of anaphylaxis and allow the patient to receive optimal antimicrobial therapy.29 In the case of anaphylactoid reactions to radiocontrast media, premedication regimens using antihistamines and steroids in combination with a low osmolar contrast agent can significantly reduce, although not eliminate, the risk of anaphylactoid reactions.30 Beta-blocker and angiotensin-converting enzyme inhibitors should be discontinued, if possible. If a patient has been diagnosed with exercise-induced anaphylaxis and diagnostic testing has identified a specific food trigger, then the patient must refrain from eating that food for 4 to 6 hours before or after exercise. If no specific food is identified, then the patient should limit physical exercise or stop immediately upon development of prodromal symptoms. Pretreatment with H1 blockers is not considered effective. The patient should always exercise with a partner and carry self-injectible epinephrine at all times. In the case of idiopathic anaphylaxis, if there are more than six episodes of anaphylaxis per year, the patient may benefit from long-term prednisone therapy to induce "remission."31 Patients may be prescribed prednisone 40 to 60 mg PO daily in conjunction with hydroxyzine, albuterol, and self-injectible epinephrine followed by conversion after 1 to 6 weeks of prednisone to alternate-day dosing and reduction of the prednisone dose by 5 to 10 mg/dose/month until tapered completely off. The diagnosis and management of idiopathic anaphylaxis should be performed in conjunction with a specialist experienced in anaphylaxis. |
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The most feared outcome of an anaphylaxis is death. Although deaths resulting from anaphylaxis are rare, many are potentially preventable. Many of the deaths from anaphylaxis are iatrogenic, and the presence of asthma is a risk factor.32,33 As previously mentioned, the delayed use of epinephrine is a risk factor for a poor outcome, with physicians often waiting until after cardiac arrest has occurred before administering epinephrine.34 Nevertheless, some patients may still die despite receiving epinephrine. Poor outcomes can occur regardless of the antigenic trigger, and death can occur even in idiopathic anaphylaxis. |
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