Anaphylaxis
Frederic F. Little
Helen M. Hollingsworth
Anaphylaxis is the most severe and potentially fatal form of the immediate hypersensitivity reactions. The term anaphylaxis (antiphylaxis) is derived from the Greek and means “against protection” [1]. It describes the shock-like state that is caused by contact with a substance and contrasts with the term prophylaxis, which denotes a beneficial or protective state resulting from contact with a substance.
The clinical features of anaphylactic reactions are the physiologic sequelae of release of chemical mediators from tissue-based mast cells and circulating basophils and include a potential for life-threatening vascular collapse and respiratory obstruction [2,3]. A clinically and physiologically indistinguishable hypersensitivity reaction, which is called an anaphylactoid reaction, differs from anaphylactic reactions only because the chemical mediators are released by nonimmunologic mechanisms. Since the clinical features are indistinguishable, both will be referred to collectively as anaphylactic reactions [4].
Estimation of the annual incidence of anaphylactic reactions is hampered by complex coding and incomplete reporting. A recent European study estimated annual incidences of severe and fatal anaphylaxis at 1 to 3 per 10,000 and 1 to 3 per million, respectively [5]. Extrapolations from a comprehensive study of emergency department visits in a geographically defined U.S. population predict about 245,000 outpatient episodes of severe anaphylaxis annually. The additional cases consequent to medicines and radiocontrast media in hospitalized patients would at least equal the emergency room number. An estimated 1,500 people die of anaphylaxis per year, stressing the importance of prevention, as well as prompt diagnosis and treatment [6,7].
Pathophysiology of Anaphylactic Reactions
Mechanisms of Release of Chemical Mediators
In humans, anaphylaxis involves a series of steps that result in the release of chemical mediators from tissue-based mast cells and circulating basophils. First, contact with an antigen stimulates the generation of antibodies of the immunoglobulin E (IgE) class. Next, the IgE molecules bind by way of their Fc receptor to a glycoprotein receptor on the cell-surface membrane of tissue mast cells and blood-borne basophils, the so-called target cells. As many as 4,000 to 100,000 IgE molecules normally bind to a single target cell, and up to 100,000 to 500,000 in atopic individuals [8,9]. This binding may remain for weeks to months. When two IgE molecules with the same Fab binding (antigen recognition) specificity are in close proximity on the surface of mast cells and basophils, the cells are termed sensitized.
For subsequent antigenic exposure to stimulate the release of mediators from mast cells and basophils, the specific antigen must bind to the Fab portion of two IgE molecules fixed to the surface of the target cell. This bridging of two IgE molecules initiates a series of biochemical modifications called the activation–secretion response (Fig. 194.1). This sequence causes secretion of preformed primary mediators of anaphylaxis from cytoplasmic granules in target cells, including histamine, serotonin, eosinophil chemotactic factor of anaphylaxis (ECF-A), heparin, neutrophil chemotactic factor, and proteolytic enzymes that include tryptase [10].
The activation–secretion response also stimulates synthesis of kallikrein [11,12] and newly generated, secondary lipid mediators, which include platelet-activating factor (PAF) [1]; prostaglandin D2 (PGD2), a product of the cyclooxygenase pathway of arachidonic acid metabolism [12]; and leukotrienes C4, D4, and E4 (LTC4, LTD4, and LTE4), products of the lipoxygenase pathway of arachidonic acid metabolism. Several cytokines are also released after activation, including interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, and IL-6), tumor necrosis factor, endothelin-1, and granulocyte-macrophage colony stimulating factor [13].
A variety of substances may induce IgE antibody formation and, on subsequent challenge, provoke anaphylactic reactions [14]. The most common substances are drugs, insect venoms, foods, and allergen extracts used in specific immunotherapy (SIT) [15,16]. These and other less common causes of IgE-mediated anaphylaxis are outlined in Table 194.1.
Non–IgE-mediated anaphylaxis occurs when certain ingested or infused substances cause direct mast cell and basophil activation. Clinically significant examples of non–IgE-mediated anaphylaxis are noted in Table 194.2. The administration of blood, serum, or immunoglobulins to patients who are IgA deficient can result in immune complex formation between donor IgA and recipient IgG anti-IgA antibodies [4,17]. These immune complexes fix complement causing activation of the complement cascade with release of the C3a and C5a complement fragments. C3a and C5a are anaphylatoxins and can directly activate mast cells and basophils.
Physiologic Properties of the Chemical Mediators of Anaphylaxis
The most important chemical mediators of anaphylaxis are histamine, cysteinyl leukotrienes (LTC4, LTD4, and LTE4), PAF, and bradykinin. Physiologically, these substances increase arteriolar vasodilatation, enhance capillary permeability, recruit other inflammatory cells, and precipitate bronchoconstriction (reviewed in [18]). The contribution of multiple mediators other than histamine explains the limited benefit of antihistamines alone in treating anaphylaxis.
Histamine (reviewed in [19]) acts to (a) increase capillary permeability by stimulating terminal arteriolar dilatation and contraction of endothelial cells in postcapillary venules, which opens intercellular gaps, and, as a result, causes the development of urticaria and angioedema; (b) increase secretion from nasal and bronchial mucous glands; (c) stimulate
contraction of smooth muscle; (d) enhance prostaglandin synthesis; (e) chemotactically modulate eosinophil migration; and (f) regulate parasympathetic afferent nerve stimulation (a process blocked by atropine), which increases airway resistance and decreases lung compliance. Studies of histamine infusion in normal human volunteers suggest that vasodilatation is mediated by both H1 and H2 receptors, whereas bronchoconstriction and tachycardia are mediated by H1 receptors alone [20].
contraction of smooth muscle; (d) enhance prostaglandin synthesis; (e) chemotactically modulate eosinophil migration; and (f) regulate parasympathetic afferent nerve stimulation (a process blocked by atropine), which increases airway resistance and decreases lung compliance. Studies of histamine infusion in normal human volunteers suggest that vasodilatation is mediated by both H1 and H2 receptors, whereas bronchoconstriction and tachycardia are mediated by H1 receptors alone [20].
 Figure 194.1. Chemical mediator release. When two IgE molecules are bridged by an antigen that is specifically recognized by those IgE molecules, a cascade of transmembrane and intracellular events is triggered. The end result is the extrusion of granule contents (mediators) into the extracellular space and elaboration of other, newly formed mediators. Tyrosine kinase appears to be an important intramembrane messenger that initiates the intracellular cascades. At least one cascade involves PLC, which mediates calcium influx into the cell and catalyzes hydrolysis of phosphatidylinositol into the secondary messengers 1,4,5-IP3 and 1,2-DAG. IP3 plays a role in calcium mobilization; DAG mediates production of arachidonic acid metabolites and activates PKC. PKC, in turn, participates in the fusion of granules within the cell membrane. PLA2 mediates the conversion of membrane phospholipid into arachidonic acid, resulting in elaboration of prostaglandins and leukotrienes. Ag, antigen; DAG, diacylglycerol; IgE, immunoglobulin E; IP3, inositol triphosphate; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C. |
Table 194.1 Causes of Immunoglobulin E–Mediated Anaphylaxisa | ||||||||||||||||||||||||||||||||||||
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Table 194.2 Causes of Non–Immunoglobulin E-Mediated Anaphylaxisa | ||
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In anaphylaxis, LTC4, LTD4, and LTE4 (a) induce a prolonged constrictive effect, on bronchial smooth muscle, which affects the peripheral more than the central airways, (b) increase vascular permeability, and (c) act as chemotactic agents for other inflammatory cells [21,22]. In fact, leukotrienes are far more potent bronchoconstrictors than histamine.
Two additional modulators of anaphylaxis are bradykinin, which appears to be activated by mast cell kallikrein and PAF. Bradykinin stimulates a slow, sustained contraction of bronchial and vascular smooth muscles while increasing vascular permeability and secretion from mucous glands [15]. PAF contributes to the pulmonary and cardiovascular manifestations of anaphylaxis by inducing platelet aggregation with release of serotonin, adenosine triphosphate, and lysosomal enzymes from preformed granules [23,24]. In addition, PAF is a potent chemotactic factor for eosinophils and can directly increase vascular permeability [25].
Thus, the physiologic consequences of chemical–mediator release in anaphylaxis are (a) an increased vascular permeability; (b) an increased secretion from nasal and bronchiolar mucous glands; (c) smooth muscle contraction in the blood vessels, the bronchioles, the gastrointestinal tract, and the uterus; (d) migration–attraction of eosinophils and neutrophils; (e) bradykinin generation stimulated by kallikrein substances; and (f) induction of platelet aggregation and degranulation. These events coordinate to increase the vascular permeability that in turn permits the access of a variety of plasma proteins (antibodies, complement, kinins, and coagulation proteins) to tissue sites, which further contributes to the observed inflammation. Substances such as PAF and Hageman factor potentially contribute to local coagulation abnormalities, which may also be seen in anaphylactic reactions [20].
Clinical and Laboratory Features
Mast cells are concentrated in the skin, in the mucous membranes of the respiratory and gastrointestinal tracts, and in the perivenular tissue, while basophils are located in the bloodstream, all of which are potential sites of exposure to offending antigens (e.g., food, drugs, insect venom, and diagnostic agents) [26]. These sites are also most commonly involved in the manifestations of anaphylaxis. Urticaria, angioedema, respiratory obstruction, and vascular collapse are the most important clinical features of anaphylaxis, and these signs and symptoms are due to the direct effects of mast cell and basophil-derived mediators on affected organ systems. Other clinical manifestations may include (a) a sense of fright or impending doom, (b) weakness or dizziness, (c) sweating, (d) sneezing, (e) rhinorrhea, (f) conjunctivitis, (g) generalized pruritus and swelling, (h) cough, (i) wheezing, stridor, or breathlessness, (j) choking, (k) dysphagia, (l) vomiting or diarrhea, (m) abdominal pain, (n) incontinence, (o) uterine cramps, and (p) loss of consciousness.
Profound hypotension and shock may develop as a result of significant arteriolar vasodilatation, increased vascular permeability, cardiac arrhythmias [27,28], or irreversible cardiac failure [29], even in the absence of respiratory or other symptoms [3,30]. Furthermore, transient or sustained hypotension may result in local tissue ischemia, stroke, myocardial infarction, or death [30,31]. Intravascular coagulation, evidenced by a fall in the levels of factors V, VIII, fibrinogen, kininogen, and complement components, has also been described [32].
Anaphylaxis-induced fatalities most often result from involvement of the respiratory tract [31,33,34]. Structures throughout the respiratory tract may be affected, but respiratory failure is generally the result of upper respiratory tract obstruction due to laryngeal edema or obstruction of small airways due to bronchoconstriction, mucosal edema, and hypersecretion of mucus [35,36]. Intra-alveolar hemorrhage and acute respiratory distress syndrome have been reported [36,37].
The physical examination of a patient with anaphylactic shock often reveals a rapid, weak, irregular, or unobtainable pulse; tachypnea, respiratory distress, cyanosis, hoarseness, stridor, or dysphagia secondary to laryngeal edema; diminished breath sounds, crackles, cough, wheezes, and hyperinflated lungs due to severe bronchoconstriction; urticaria; angioedema or conjunctival edema (Table 194.3) [38]. Any patient may manifest only a subset of these findings, sometimes only cardiovascular collapse or only stridor and breathlessness.
Laboratory findings in anaphylaxis are varied. Biochemical abnormalities in anaphylaxis include elevation of serum histamine and tryptase levels, depression of serum complement components, and decreased levels of high-molecular-weight kininogen. Although these biochemical abnormalities codify our understanding of the pathophysiology of anaphylaxis, they are rarely evaluated in the management of clinically established anaphylaxis. As discussed in the next section, serum tryptase may be helpful retrospectively when the diagnosis is uncertain [39].
Although there have been no systematic reviews of electrocardiographic findings, reports describe disturbances in rate,
rhythm, repolarization, and ectopy [40,41,42], as well as myocardial infarction [28,43]. Chest radiography may reveal hyperinflation caused by severe bronchoconstriction.
rhythm, repolarization, and ectopy [40,41,42], as well as myocardial infarction [28,43]. Chest radiography may reveal hyperinflation caused by severe bronchoconstriction.
Table 194.3 Clinical Manifestations of Anaphylactic Reactions | ||||||||||||||||||||||||||||||||||||||||||||
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Diagnosis and Differential Diagnosis of Anaphylaxis
Development of the characteristic clinical features of anaphylaxis shortly after exposure to an antigen or other inciting agent usually establishes the diagnosis of an anaphylactic reaction [2]. The setting is often suggestive as well: a patient who has just received an antibiotic injection or radiographic contrast media infusion or one who presents to the emergency room after a yellow jacket sting.
The clinical disorders that may be confused with anaphylaxis are sudden, acute bronchoconstriction in an asthmatic, vasovagal syncope, tension pneumothorax, mechanical airway obstruction, pulmonary edema, cardiac arrhythmias, myocardial infarction with cardiogenic shock, aspiration of a food bolus, pulmonary embolism, seizures, acute drug toxicity, hereditary angioedema, cold or idiopathic urticaria, septic shock, and toxic shock syndrome [15].
Initial laboratory testing often is not helpful. However, serum obtained during the acute episode can be assayed subsequently for tryptase and histamine. Total serum tryptase levels include both α- and β-tryptase. The former is increased in systemic mastocytosis and the latter can be elevated for up to 6 hours after suspected anaphylaxis onset [44]. However, the sensitivity of serum β-tryptase is suboptimal as levels can be normal after documented anaphylaxis, especially if caused by foods [45]. There may be a role for serial measurements in documenting the course of systemic mast cell and basophil degranulation [38]. Serum histamine is rarely assessed clinically because it must be obtained within the first hour after a reaction and requires special handling.
Retrospectively, measurement of antigen (allergen)-specific IgE antibodies by an ImmunoCAP (or similar assay, which have replaced radioallergosorbent tests [RAST]) may be helpful. Specific skin tests may also define allergic sensitivity. Skin testing must be done in a carefully controlled setting due to the risk of provoking another severe reaction. Cutaneous assessment for the presence of antigen-specific IgE may be negative for several days after a reaction, because mast cell and basophil degranulation at the time of the initial reaction may lead to a refractory period. This can be avoided by delaying testing for 4 to 6 weeks [46].
Clinical Course of Anaphylactic Reactions
Clinical criteria that make the diagnosis of anaphylaxis “highly likely” have been codified [2]. The characteristic features of anaphylactic reactions are (a) the rapid onset of clinical manifestations that follow contact with or the administration of antigen and (b) the rapid progression of symptoms to a severe and potentially fatal outcome. Recognition of the early signs and symptoms of anaphylaxis and prompt treatment are imperative in preventing progression to irreversible shock and death [38].
The constellation of clinical symptoms as well as their severity and duration is variable but will depend to some extent on the mode of antigen exposure. Anaphylaxis may occur within seconds following parenteral introduction of antigen [32] and usually occurs within 30 minutes. In contrast, anaphylaxis that follows oral administration of an antigen may develop within minutes to several hours [47]. Generally, the more rapid the onset of symptoms, the more severe will be the reaction [1]. Mild systemic reactions often last for several hours, rarely more than 24 hours. Severe manifestations, such as laryngeal edema, bronchoconstriction, and hypotension, if not fatal, may persist or recur for several days. However, even severe manifestations may resolve within minutes of treatment. About 5% to 20% of patients will experience biphasic or protracted anaphylaxis, with signs and symptoms recurring up to 24 hours or persisting beyond 24 hours after initial presentation [38]. This highlights the need for close observation after initial response to treatment.
Treatment of Anaphylaxis
The key to successful treatment of anaphylaxis is prompt intervention to support cardiopulmonary function and prevent further exposure to the inciting stimulus when possible. The prompt administration of epinephrine is critical, and should be supplemented with aggressive use of vasopressors, fluid replacement, and medications as indicated to counteract the effects of released chemical mediators [38]. Injectable epinephrine, tourniquets, intravenous infusion materials and fluids, antihistamines, intubation equipment, a tracheostomy set, and individuals trained to use these materials should be available. Since symptoms of a systemic anaphylactic reaction may be followed by potentially fatal manifestations, patients must be serially examined and continuously monitored [38]. Many therapeutic and diagnostic agents frequently employed in intensive care settings (e.g., antibiotics, radiographic contrast) may induce anaphylactic reactions. Thus, the anticipation and the preparedness to deal with these potential reactions are very important.
Emergency Measures
The evaluation of individuals who are suspected of having anaphylaxis must be performed rapidly. The cause and mechanism of antigen exposure should be ascertained to assess how long the inciting antigen has been present and, when possible, to limit further absorption. A history of previous allergic reactions and former treatment may help to guide immediate therapy, obviating the need to try previously failed regimens in a life-threatening situation [48].
Supportive Cardiopulmonary Measures
Particular attention to the respiratory and cardiovascular systems is paramount and must include assessment for laryngeal edema and bronchoconstriction, as well as monitoring oxygenation, blood pressure, and cardiac rhythm [48].
Ensuring adequate ventilation and oxygenation is essential. Supplemental oxygen should be administered and pulse oximetry monitored. Intubation and assisted ventilation may be necessary in cases of severe bronchoconstriction, and ventilator management strategies such as those used for treatment of status asthmaticus may be necessary. These techniques are discussed in Chapters 48 and 58.
Although intubation is usually feasible, edema of the tongue, larynx, or vocal cords may obstruct the upper airway and preclude oropharyngeal or nasopharyngeal intubation. To ensure a patent airway in such instances, cricothyroidotomy or tracheotomy may be necessary (see Chapter 12) [49]. Cricothyroidotomy is preferred to tracheotomy when performed in an emergent situation, as the former is easier to perform and is usually safer [49]. Contraindications to cricothyroidotomy include a suspected neck fracture or a serious injury to the larynx or cricoid cartilage.
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