Allergy, Anaphylaxis, and Angioedema

Background and Terminology

The prevalence of allergic disease has significantly increased over the past several decades, particularly in developed societies. It is currently estimated that 30% of the worldwide population suffer from some component of allergy, including 5% to 8% with food allergies. This has contributed to increased financial burdens on our health care systems and morbidity in affected individuals. This is largely attributed to changes in lifestyle, diet, antibiotic use, smaller families, and the “hygiene hypothesis,” which centers around decreased microbial exposure in developed countries. ^,

The human immune system comprises cellular and humoral components working together in a highly complex and coordinated fashion to achieve the primary goal of protecting the human host from potentially harmful offenders. The immune system, however, can overreact to otherwise harmless agents, producing an inappropriate response that may be harmful to the host, thereby giving rise to allergy or allergic diseases. These hypersensitivity reactions are manifested in clinical symptoms ranging from nuisance-level to fatal. For practical purposes, the term allergy is used in this chapter to refer to mast cell–mediated hypersensitivity reactions. For most allergic diseases to occur, predisposed individuals require exposure to allergens through sensitization. Substances that elicit an allergic reaction are referred to as allergens, and those that elicit an antibody response are termed antigens.

On the allergic continuum, there are several important allergic syndromes ( Fig. 106.1 ). Urticaria (wheels, hives) is a common allergic reaction to foods, drugs, temperature changes, or physical stimuli. It is clinically characterized by a raised central swelling of variable size with surrounding reflex erythema, combined with an itching or burning sensation, with the skin typically returning to its baseline appearance within 30 minutes to 24 hours.

Angioedema is characterized by sudden swelling of the subcutaneous or mucous membranes and tends to be more painful than pruritic. In general, it is slower to resolve compared to urticaria, and if the tongue or larynx is involved, it can result in airway compromise. Angioedema can occur through one of two different mechanisms. Allergic (histaminergic) angioedema occurs in response to exposure to foods, drugs, or physical stimuli. Nonallergic (non-histaminergic) angioedema may be hereditary (termed hereditary angioedema [HAE]) or medication-induced (e.g., angiotensin-converting enzyme [ACE] inhibitor angioedema).

At the other extreme of this allergic continuum is anaphylaxis, a life-threatening systemic reaction, characterized by acute onset and multiorgan involvement. It is a type I hypersensitivity reaction (allergic), mediated by immunoglobulin E (IgE). In its most common form, anaphylaxis is precipitated by exposure to allergens in previously sensitized individuals (immunologic). Previously, the term anaphylactoid reaction referred to a syndrome clinically similar to anaphylaxis that is not mediated by IgE (non-immunologic). Its clinical presentation and treatment are identical to that of anaphylaxis. Non-IgE (non-immunologic) reactions appear to result from direct degranulation of mast cells (and basophils) and may follow a single, first-time exposure to certain inciting agents (e.g., NSAIDs, monoclonal antibodies, local anesthetics, chemotherapeutic drugs). The World Allergy Organization (WAO) guidelines use the term anaphylaxis to refer to both IgE- and non-IgE-mediated reactions, obviating the need for the term anaphylactoid reaction, although this term is still often used . ^,

Pathophysiology

Immunologic responses to antigens are coordinated by two systems: the innate immune system, and the more recently evolved adaptive immune system ( Fig. 106.2 ). The innate immune system is considered the first line of defense and is characterized by its nonspecific but rapid responses to offending agents or microbes. Its effector components include resident cells (epithelial cells, mast cells, macrophages, dendritic cells, antimicrobial proteins), infiltrative cells (natural killer cells, neutrophils, monocytes, dendritic cells), and various proteins (antimicrobial peptides, complements, cytokines, and the pathogenic pattern recognition receptor [PRR] system). The innate system responds to danger signals rapidly and nonspecifically, whereas the adaptive immune system takes time for antigen-specific cells (B and T cells) to amplify through a process known as clonal expansion to mount a specific immune response. The T and B lymphocytes are capable of recognizing a myriad of antigens through a vast library of antibodies and receptors (up to 10 ¹⁵ ). ^{, ,}

The adaptive and innate immune systems originate from the common pluripotential hematopoietic stem cells. When the host encounters a foreign antigen, the cellular components of the adaptive immune system interact with the cellular and protein components of the innate immune system to mount a coordinated defense aimed at neutralization of the antigen.

Mast cells, basophils, and their mediators are the central effectors in allergy and anaphylaxis. Exposure of a genetically predisposed individual to an allergen leads to the synthesis and release of allergen-specific IgE by plasma cells into the circulation. Fixation of this allergen-specific IgE to surface receptors on mast cells completes the process known as sensitization. These IgE-bearing mast cells usually reside in the mucosal surfaces, submucosal tissue (around venules), and cutaneous surfaces, where they are capable of becoming activated on re-exposure to a specific allergen. Cross-linking of the mast cell receptors by a specific multivalent allergen sets off a cascade of conformational and biochemical events, causing the degranulation of preformed mediators, subsequent generation and release of arachidonic acid metabolites, elaboration of cytokines and chemokines, and activation of the cellular components by the innate and adaptive systems. This series of events ultimately leads to the clinical syndromes of allergy and anaphylaxis ( Fig 106.3 ). ^{, ,}

Classification of Reactions

The term allergy is commonly used to describe clinical illnesses produced by excessive immune responses by a normal immune system to otherwise innocuous allergens. The classic Coombs and Gell classification can be adapted to categorize these hypersensitivity reactions ( Box 106.1 ).

Type I reactions (immediate hypersensitivity) are IgE mediated and account for most allergic and anaphylactic reactions. Exposure to sensitizing allergens causes mediators from mast cells and basophils to be released through both IgE-dependent and IgE-independent (direct mast cell degranulation) mechanisms. Rhinitis caused by ragweed pollen and anaphylaxis caused by foods are examples of the IgE-dependent mechanism.