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.

Severity Spectrum of Allergic Disease.

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 . ^,

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 ). ^{, ,}

Developmental Pathways of the Immune and Hematopoietic Systems.

CFU-GEMM, Colony-forming unit for granulocyte, erythroid, myeloid, and megakaryocyte.

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 ). ^{, ,}

Activation of mast cells with degranulation of mast cell mediators by antigen cross-linking of adjacent immunoglobulin E (IgE) on the cell surface. PAF, Platelet-activating factor.

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.

The prevalence of anaphylaxis and related hospital admissions has increased over the past two decades. The incidence is difficult to determine, but anaphylaxis is estimated to occur in roughly 2% of the worldwide population and as high as 5% in the United States. ^, While fatal anaphylaxis is rare, representing less than 1% of cases, there is evidence that medication-induced fatalities are increasing in North America and that food-induced fatalities are increasing in Australia.

The severity of anaphylaxis varies between different age groups depending on the specific trigger and cofactors, but in general, pregnant women, infants, teenagers, and elders have been shown to have an increased incidence of anaphylaxis. Additional risk factors include atopy (genetic predisposition to develop allergic disease), peanut and tree nut allergy, emotional stress, seasonal occurrence in summer to fall months, higher socioeconomic status, premenstrual age, and the presence of acute infection. Severe anaphylaxis has been associated with poorly controlled asthma, history of mastocytosis, heavy physical exertion, exposure to a trigger during the concomitant use of certain medications (ACE inhibitors, beta-blockers, and nonsteroidal antiinflammatory drugs [NSAIDs]), history of a previous anaphylactic reaction, delayed epinephrine administration, and upright position at the onset of symptoms ( Box 106.2 ). ^{, , , ,}

In general, the more rapid an anaphylaxis reaction occurs after an exposure, the more likely it is to be severe and potentially fatal. The dose, frequency, duration, and route of administration of a drug can also affect the tendency to develop an anaphylactic reaction (e.g., the parenteral route is more likely to lead to an anaphylactic reaction than the oral route). ^{, ,} One interesting aspect of drug-related anaphylaxis is the constancy of administration. An anaphylactic reaction may not occur in an otherwise susceptible patient as long as a drug is administered at regular intervals. The same patient, however, may experience an anaphylactic reaction if the drug is resumed after an interruption of therapy.

ACE-inhibitor use can cause an accumulation of kinins and bradykinin and thus can exacerbate the angioedema component of anaphylaxis. Beta-adrenergic blockers may oppose the actions of adrenergic agents used in anaphylaxis treatment. Recent evidence suggests that taking an ACE inhibitor or a beta-blocker increases the risk of severe anaphylaxis (and even more so when taken concurrently) but does not necessarily increase the incidence of initial anaphylactic reactions. ^,

Virtually any agent that is capable of activating mast cells or basophils can potentially precipitate an anaphylactic reaction. However, in up to 60% of adults and 10% of children, an inciting agent cannot be identified, which is classified as idiopathic anaphylaxis . When a trigger can be determined, foods, insect stings, and medications are the most common causes. Box 106.3 lists many of the common agents by their proposed immunologic mechanism. ^{, , ,}

Idiopathic Anaphylaxis

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