Reviews and Feature ArticlesAnaphylaxis: A review of causes and mechanisms☆,☆☆
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Epidemiology and definition
Anaphylaxis is not a reportable disease, and both its morbidity and mortality are probably underestimated (Table 1).3, 4, 5, 6, 7, 8, 9, 10, 11, 12
Overall Approximately 154 annual fatal episodes per 1,000,000 hospitalzed subjects occur internationally.4 The estimated risk of anaphylaxis per person in the United States is 1% to 3%.5, 6 US projection on the basis of data from Olmsted County, Minn: For population of 280 million
Proposed immunopathologic mechanisms
Some authors reserve the term anaphylaxis only for IgE-dependent events and the term anaphylactoid to describe IgE-independent reactions that otherwise are clinically indistinguishable. Coombs and Gell28 first classified 4 types of hypersensitivity (immunopathologic) reactions: I, immediate (IgE-dependent); II, cytotoxic (IgG, IgM dependent); III, immune complexes (IgG, IgM complex dependent); and IV, delayed (T-lymphocyte dependent). Not only can IgE-dependent reactions cause anaphylaxis but
Pathophysiology and chemical mediators of anaphylaxis
Biochemical mediators and chemotactic substances are released systemically during the degranulation of mast cells and basophils. These include preformed granule-associated substances, such as histamine, tryptase, chymase, and heparin; histamine-releasing factor and other cytokines; and newly generated lipid-derived mediators, such as PGD2, leukotriene (LT) B4, platelet-activating factor, and the cysteinyl leukotrienes LTC4, LTD4, and LTE4. Eosinophils might play either a proinflammatory role
Shock organs in anaphylaxis
Organ system involvement, which varies from species to species, determines the clinical course of anaphylaxis of whatever cause. Factors that determine a specific shock organ include variations in the immune response, the location of smooth muscle, and the distribution and rate of degradation and responsiveness to chemical mediators.26 In the guinea pig there is bronchial smooth muscle constriction, which leads to bronchospasm, hypoxemia, and death.49, 50 Anaphylaxis in rabbits produces fatal
The heart as shock organ in anaphylaxis
Chemical mediators of anaphylaxis appear to affect the myocardium directly.34, 52 H1 receptors mediate coronary artery vasoconstriction and increase vascular permeability, whereas H2 receptors increase atrial and ventricular contractile forces, atrial rate, and coronary artery vasodilation. The interaction of H1 and H2 receptor stimulation appears to mediate decreased diastolic pressure and increased pulse pressure.53 Animal studies suggest a possible modulatory role for H3 receptors.35
Agents that cause anaphylaxis
Virtually any agent capable of activating mast cells or basophils might potentially cause anaphylaxis. Table 2 classifies common causes by their proposed pathophysiologic mechanism. However, as previously stated, more than one mechanism might be active in some cases of anaphylaxis. The most common identifiable causes of anaphylaxis are foods, medications, insect stings, and allergen immunotherapy injections.5, 24, 48, 65 Anaphylaxis to peanuts or tree nuts is of special concern because of its
β-Adrenergic blockade
Subjects taking any β-adrenergic antagonists, orally or topically, might be more likely to experience severe anaphylactic reactions characterized by paradoxical bradycardia, profound hypotension, and severe bronchospasm. These agents might impede treatment effectiveness with epinephrine. Dosage increases of isoproterenol (a nonselective β-adrenergic agonist) up to 80-fold are necessary experimentally to overcome β-receptor blockade.68 Both β1 and β2 antagonists might inhibit the β-adrenergic
Recurrent and persistent anaphylaxis
Recurrent or biphasic anaphylaxis occurs 8 to 12 hours after the initial attack in up to 20% of subjects who experience anaphylaxis.15, 70, 71, 72, 73 Stark and Sullivan73 reported biphasic anaphylaxis in 5 (20%) of 25 subjects. Douglas et al,71 however, observed incidences of 5% and 7% in 44 outpatients and 59 inpatients, respectively, over a 4-year period. Brazil and MacNamara70 retrospectively reviewed 34 subjects admitted for observation after anaphylaxis. Six (18%) had biphasic episodes.
Intramuscular injections of epinephrine in anaphylaxis
Absorption is complete and more rapid (mean maximum plasma epinephrine concentration of 2136 ± 351 pg/mL at a mean time of 8 ± 2 minutes) in children who receive epinephrine intramuscularly in the thigh with an autoinjector.74 Intramuscular injection into the thigh (vastus lateralis) in adults is also superior to intramuscular or subcutaneous injection into the arm (deltoid), neither of which achieves elevated plasma epinephrine levels compared with endogenous epinephrine levels associated with
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Department of Internal Medicine, University of South Florida College of Medicine and the James A. Haley Veterans Administration Hospital, Tampa.
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Reprint requests: Richard F. Lockey, MD, University of South Florida College of Medicine, Division of Allergy and Immunology, c/o V.A. Medical Center, 13000 Bruce B. Downs Blvd (111D), Tampa, FL 33612.