INTRODUCTION

Anaphylaxis is a severe, potentially fatal hypersensitivity reaction and may involve multiple organ systems, including the skin and eyes, respiratory tract, cardiovascular system, nervous system, and gastrointestinal (GI) tract (Box 168-1). Anaphylaxis can be triggered by a variety of antigens, but most commonly by insect and reptile venoms, antimicrobial agents, nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, opiates, vaccines, foods, and physical factors such as cold and exercise. Traditionally, hypersensitivity reactions were classified into four types: type I: immediate (immunoglobulin, [IgE]-dependent), type II: cytotoxic (IgG, IgM dependent), type III: immune complexes (IgG, IgM complex dependent), and type IV: delayed (T lymphocyte dependent).

Anaphylaxis was attributed to type I reactions, and anaphylactoid reactions were attributed to non–IgE-mediated reactions. However, it is now known that cytotoxic (e.g., blood transfusion reactions) and immune complex (e.g., complexes of IgG administered intravenously or intramuscularly) reactions can cause anaphylaxis.

An alternative classification system based on seven immunopathologic mechanisms with both protective and destructive functions has been proposed: (1) immune-mediated inactivation and activation reactions of biologically active molecules, (2) antibody-mediated cytotoxic or cytolytic reactions, (3) immune complex reactions, (4) allergic reactions, (5) T lymphocyte–mediated cytotoxicity, (6) delayed hypersensitivity, and (7) granulomatous reactions.¹ Several of these immunopathologic mechanisms might be actively causing anaphylaxis in a given patient.

PATHOPHYSIOLOGY

In murine models, two immunologic pathways of anaphylaxis have been identified. One pathway involves IgE receptors, mast cells, basophils, histamine, prostaglandins, leukotrienes, serotonin, and platelet-activating factor. A second pathway involves IgG, Fcγ, macrophages, and platelet-activating factor.² With immune-mediated anaphylaxis, previous exposure to an antigen results in sensitization, and IgE is produced and bound to the cell surface of mast cells and basophils by high-affinity receptors (FcγRI) for the Fc portion of the immunoglobulin. With repeated exposure, the antigen causes cross-linkage of two IgE molecules, and the cell is activated to release the anaphylaxis mediators: histamine, heparin, tryptase, kallikreins, proteases, proteoglycans, eosinophilic chemotactic factor of anaphylaxis, and neutrophil chemotactic factor of anaphylaxis.

Histamine and leukotrienes are potent vasoactive mediators, and their release from eosinophils and basophils increases vascular permeability and vasodilation. Hypovolemia then results from plasma leakage into the interstitial space. Histamine acts through H₁, H₂, and H₃ receptors to promote shock during allergen challenge. H₁ receptors mediate coronary vasoconstriction and cardiac depression, whereas H₂ receptors mediate gastric acid production and, when stimulated, produce coronary and systemic vasodilation and increases in heart rate and ventricular contractility. The H₁ receptor activation results in rhinitis, pruritus, and bronchoconstriction and stimulates endothelial cells to convert L-arginine into nitric oxide (NO), a potent vasodilator. Increased NO production decreases venous return. The resulting hypotension and hypoxemia/hypercapnia worsens the cardiovascular collapse.³

H₃ receptors have been identified on presynaptic terminals of sympathetic effector nerves that innervate the heart and systemic vasculature. These receptors inhibit endogenous norepinephrine release from sympathetic nerves, so activation accentuates the degree of shock observed during antigen challenge because compensatory neural adrenergic stimulation is blocked.⁴

Cross-linking of the FcγRI receptors also activates phospholipase A₂, setting off production of prostaglandins, thromboxanes, platelet activating factor, and leukotrienes. The protein kinases stimulate the synthesis of cytokines responsible for the late-phase inflammatory response. Cytotoxic events involving IgM or IgG, immune aggregates, activation of complement, kallikrein-kinin, or coagulation systems may also be involved in anaphylaxis. The systemic anaphylactic response is rapid; release of mediators from activated immune cells occurs within seconds to minutes, the arachidonic acid cascade is activated within minutes, and cytokine synthesis begins within hours.⁵