Parameter	Type of Reaction
Reaction	Anaphylactic	Cytotoxic	Immune complex	T cell–dependent
Antibody	IgE^∗	IgG, possibly other immunoglobulins	Antigen-antibody complexes (IgG, IgM)^∗	None
Complement involved	No	Yes^∗	Yes^∗	No
Cells involved	Mast cells, basophils, granules (histamine)^∗	Effector cells (macrophages, polymorphonuclear leukocytes)^∗	Macrophages, mast cells	Antigen-specific T cells
Cytokines involved	Yes^∗	No	Yes^∗	Yes (T cell cytokines)^∗
Comparative description	Antibody mediated, immediate	Antibody dependent; complement or cell mediated	Immune complex mediated (immune complex disease)	T cell-mediated, delayed type
Mechanism of tissue injury	Allergic and anaphylactic reactions	Target cell lysis; cell-mediated cytotoxicity	Immune complex deposition, inflammation	Inflammation, cellular infiltration
Examples	Anaphylaxis Hay fever Asthma Food allergy	Transfusion reactions Hemolytic disease of newborn Thrombocytopenia	Arthus reaction Serum sickness Systemic lupus erythematosus	Allergy or infection Contact dermatitis

Types of Hypersensitivity Reactions

The four types of hypersensitivity reaction (I to IV) are defined by the principal mechanism responsible for a specific cell or tissue injury that occurs during an immune response (Table 26-2). Types I, II, and III reactions are antibody dependent and type IV is cell mediated. Some overlapping occurs among the various types of hypersensitivity reactions, but there are major differences in how each type is diagnosed and treated.

Table 26-2

Mediators of Anaphylaxis

Mediator	Primary Action
Histamine	Increases vascular permeability; promotes contraction of smooth muscle
Leukotrienes	Alter bronchial smooth muscle and enhance effects of histamine on target organs
Basophil kallikrein	Generates kinins
Serotonin	Contracts smooth muscle
Platelet-activating factor	Enhances the release of histamine and serotonin from platelets that affect smooth muscle tone and vascular permeability
Eosinophil chemotactic factor of anaphylaxis	Attracts eosinophils to area of activity; these cells release secondary mediators that may limit the effects of primary mediators
Prostaglandins	Affect smooth muscle tone and vascular permeability

Type I Reactions

Type I hypersensitivity reactions can range from life-threatening anaphylactic reactions to milder manifestations associated with food allergies.

Etiology

Atopic allergies are mostly naturally occurring, and the source of antigenic exposure is not always known. Atopic illnesses were among the first antibody-associated diseases demonstrating a strong familial or genetic tendency.

Several groups of agents cause anaphylactic reactions. The two most common agents are drugs (e.g., systemic penicillin) and insect stings. Insects of the order Hymenoptera (e.g., common hornet, yellow jacket, yellow hornet, paper wasp) are examples of insects causing the most serious reactions. Immune-mediated IgE adverse food reactions (Box 26-1) can be fatal.

Box 26-1 Diagnosis of IgE-Mediated Food Allergy

The National Institute of Allergy and Infectious Diseases (NIAID) Expert Panel recommends:

• Considering food allergy in individuals presenting with anaphylaxis or any combination of symptoms that occur within minutes to hours of ingesting food, especially in young children and/or if symptoms have followed the ingestion of a specific food on more than one occasion. In addition, infants, young children, and selected older children diagnosed with certain disorders, such as moderate to severe atopic dermatitis (AD), eosinophilic esophagitis (EoE), enterocolitis, enteropathy, and allergic proctocolitis (AP) should be considered for FA.

• Using medical history and physical examination to aid in the diagnosis of FA.

• Confirming parent and patient reports of FA because multiple studies demonstrate that 50% to 90%of presumed FAs are not allergies.

• Performing an SPT (skin puncture test) to assist in the identification of foods that may be provoking IgE-mediated food-induced allergic reactions, but the SPT alone cannot be considered diagnostic of FA.

• Not using intradermal testing or measuring total serum IgE to make a diagnosis of FA.

• Using allergen-specific serum IgE (sIgE) tests for identifying foods that potentially provoke IgE-mediated food-induced allergic reactions, but not using these tests as diagnostic of FA.

• Not using an atopy patch test (APT) in the routine evaluation of noncontact FA.

• Not using the combination of SPTs, sIgE tests, and APTs for the routine diagnosis of FA.

• Eliminating one or a few specific foods from the diet may be useful in the diagnosis of FA, especially in identifying foods responsible for some non–IgE-mediated food-induced allergic disorders, such as food protein–induced enterocolitis syndrome (FPIES), AP, and Heiner syndrome, and some mixed IgE- and non-IgE–mediated food-induced allergic disorders, such as EoE.

• Using oral food challenges for diagnosing FA. The double-blind, placebo-controlled food challenge is the gold standard. However, a single-blind or open-food challenge may be considered diagnostic under certain circumstances. If either of these challenges elicits no symptoms (i.e., the challenge is negative), then FA can be ruled out, but when either challenge elicits objective symptoms (i.e., the challenge is positive) and those objective symptoms correlate with medical history and are supported by laboratory tests, then a diagnosis of FA is supported.

• Not using any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA: basophil histamine release or activation, lymphocyte stimulation, facial thermography, gastric juice analysis, endoscopic allergen provocation, hair analysis, applied kinesiology, provocation neutralization allergen-specific IgG4, cytotoxicity assays, electrodermal test (Vega), mediator release assay (LEAP diet).

Adapted from National Institute of Allergy and Infectious Diseases: Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report, 2011(http://www.niaid.nih.gov/topics/foodAllergy/clinical/Documents/FAguidelinesPatient.pdf).

Immunologic Activity

Mast cells (tissue basophils) are the cellular receptors for IgE, which attaches to their outer surface. These cells are common in connective tissues, lungs, and uterus and around blood vessels. They are also abundant in the liver, kidney, spleen, heart, and other organs. The granules contain a complex of heparin, histamine, and zinc ions, with heparin in a ratio of approximately 6:1 with histamine.

Immediate hypersensitivity is the basis of acute allergic reactions caused by molecules released by mast cells when an allergen interacts with membrane-bound IgE (Fig. 26-1). Acute allergic reactions result from the release of preformed granule-associated mediators, membrane-derived lipids, cytokines, and chemokines when an allergen interacts with IgE that is bound to mast cells or basophils by the alpha chain of the high-affinity IgE receptor (FcεRI-α). This antigen receptor also occurs on antigen-presenting cells, where it can facilitate the IgE-dependent trapping and presentation of allergen to T cells.

Figure 26-1 Pathways leading to acute and chronic allergic reactions.
Acute allergic reactions are caused by the antigen-induced release of histamine and lipid mediators from mast cells. In the skin and upper airways, basophils (not shown) may also participate in allergic tissue reactions. Chronic allergic reactions, including the late-phase reaction, may depend on a combination of pathways, including recruitment of eosinophils, liberation of mast cell products by histamine-releasing factors, and neurogenic inflammation involving neurotrophins and neuropeptides. *Th2,* T-helper cell type 2; *MHC,* major histocompatibility complex. (Adapted from Kay AB: Allergy and allergic disease, N Engl J Med 344:30–38, 2001.)

Histamine, leukotriene C4, interleukin-4 (IL-4), and interleukin-13 (IL-13) are major mediators of allergy and asthma. All are formed by basophils and released in large quantities after stimulation with interleukin-3; IL-3’s effect is restricted to basophil granulocytes. Basophil granulocytes should be considered as key effector cells in type 2 helper T (Th2) cell immune responses and allergic inflammation. IL-3 strongly induces messenger ribonucleic acid (mRNA) for granzyme B, a major effector of granule-mediated cytotoxicity.

Anaphylactic Reaction

Anaphylaxis is the clinical response to immunologic formation and fixation between a specific antigen and a tissue-fixing antibody. This reaction is usually mediated by IgE antibody and occurs in the following three stages:

1. The offending antigen attaches to the IgE antibody fixed to the surface membrane of mast cells and basophils. Cross-linking of two IgE molecules is necessary to initiate mediator release from mast cells.

2. Activated mast cells and basophils release various mediators.

3. The effects of mediator release produce vascular changes and activation of platelets, eosinophils, neutrophils, and the coagulation cascade.

It is believed that physical allergies (e.g., to heat, cold, ultraviolet light) cause a physiochemical derangement of proteins or polysaccharides of the skin and transform them into autoantigens responsible for the allergic reaction. Most, if not all, of these reactions are caused by the action of a self-directed IgE.

Anaphylactoid Reaction

Anaphylactoid reactions (anaphylaxis-like) are clinically similar to anaphylaxis and can result from immunologically inert materials that activate serum and tissue proteases and the alternate pathway of the complement system. Anaphylactoid reactions are not mediated by antigen-antibody interaction; instead, offending substances act directly on the mast cells, causing release of mediators, or on the tissues, such as anaphylotoxins of the complement cascade (e.g., C3a, C5a). Direct chemical degranulation of mast cells may be the cause of anaphylactoid reactions resulting from the infusion of macromolecules, such as proteins.

Atopic Reaction

In a person with atopy, exposure of the skin, nose, or airway to an allergen produces allergen-specific IgG antibodies. In response to the allergen, the T cells (when tested in vitro) exhibit moderate proliferation and production of interferon-γ (IFN-γ) by type 1 helper T (Th1) cells. In comparison, individuals with atopy have an exaggerated response characterized by the production of allergen-specific IgE antibodies and positive reactions to extracts of common airborne allergens when tested with a skin prick test. T cells from the blood of atopic patients respond to allergens in vitro by inducing cytokines produced by Th2 cells (e.g., IL-4, IL-5, IL-13), rather than cytokines produced by Th1 cells (e.g., IFN-γ, IL-2).

There are always exceptions to the rule, but the immunologic hallmark of allergic disease is the infiltration of affected tissue by Th2 cells.

Signs and Symptoms

Although everyone inhales airborne allergens derived from pollen, house dust mites, and animal dander, children and adults without atopy produce an asymptomatic, low-grade immunologic response. In a person with atopy, exposure of the skin, nose, or airway to a single dose of allergen produces symptoms (skin redness, sneezing, wheezing) within minutes. Depending on the amount of allergen, immediate hypersensitivity reactions are followed by a late-phase reaction that reaches a peak 6 to 9 hours after exposure to the allergen and then slowly subsides.

Localized Reaction

A localized reaction occurs as an immediate response to mediators released from mast cell degranulation. Local reactions can consist of urticaria and angioedema at the site of antigen exposure or angioedema of the bowel after ingestion of certain foods. Localized reactions are severe but rarely fatal. Skin reactions are characterized be the appearance of redness and itching at the site of the introduction of the allergen. This phenomenon is the basic principle of the skin test to diagnose an allergy or confirm sensitivity to a specific antigen.

Generalized Reaction

A generalized (anaphylactic) reaction is produced by mediators such as cytokines and vasoactive amines (e.g., histamine) from mast cells. Anaphylactic reactions are dramatic and rapid in onset. The physiologic effects of the primary and secondary mediators on the target organs, such as the cardiovascular or respiratory system, gastrointestinal (GI) tract, or the skin, define the signs and symptoms of anaphylaxis. Several important pharmacologically active compounds are discharged from mast cells and basophils during anaphylaxis (see Table 26-2).

Histamine release leads to constriction of bronchial smooth muscle, edema of the trachea and larynx, and stimulation of smooth muscle in the GI tract, which causes vomiting and diarrhea. The resulting breakdown of cutaneous vascular integrity results in urticaria and angioedema; vasodilation causes a reduction of circulating blood volume and a progressive fall in blood pressure, leading to shock. Kinins also alter vascular permeability and blood pressure.

The body’s so-called natural moderators of anaphylaxis are the enzymes that decompose the mediators of anaphylaxis. Antihistamines have no effect on histamine release from mast cells or basophils. In human beings, antihistamines are effective antagonists of edema and pruritus, probably related to their blockage of a histamine-induced increase in capillary permeability but are relatively less effective in preventing bronchoconstriction.

Allergic Disease in Children

Atopic children characteristically experience a progression of allergic disease called allergy march (see later, ImmunoCAP discussion). The formation of IgE antibodies begins early in life, and sensitization can be detected before clinical symptoms. Sensitization to food allergens such as cow’s milk is manifested as colic or chronic otitis. The highest incidence of sensitization is at age 2 years. After 3 years of age, food sensitivities tend to decrease; sensitization to inhalant allergens typically increases during the preschool years. In most children with asthma, symptoms begin before age 5 years. Risk factors for allergic asthma include a family history of allergy, sensitization to food allergens, total serum IgE higher than 100 kU/L before age 6 years, living in an allergen-rich environment, and smoking.

Testing for Type I Hypersensitivity Reactions

In addition to a patient history and physical examination, an in vivo testing protocol can be used to assist in the identification of foods that may provoke allergic reactions. Skin testing can be performed by a skin puncture test (SPT) to assist in the identification of foods that may provoke IgE-mediated, food-induced allergic reactions or a patch test.

The SPT alone cannot be considered diagnostic of FA. Placing a drop of a solution containing a possible allergen on the skin is the basis of skin testing. A series of scratches or needle pricks allows the solution to enter the skin. If the skin develops a red, raised, itchy area, this is a positive reaction, which usually means that the person is allergic to that particular allergen. Skin testing is a simple outpatient technique to screen for many potential allergens, but may not be suitable for pediatric patients, pregnant women, or other groups. The procedure carries the risk of triggering a systemic reaction (e.g., anaphylactic reaction) or initiating a new sensitivity.

A patch test may be used for the evaluation of contact food allergies. Skin patch testing involves taping a patch that has been soaked in the allergen solution to the skin for 24 to 72 hours. This type of testing is used to detect contact dermatitis.

Laboratory Evaluation of Allergic Reactions

Advantages of in vitro testing include the lack of risk of a systemic hypersensitivity reaction and the lack of dependence on skin reactivity, which can be influenced by drugs, disease, or the patient’s age. Detection of an increased amount of total IgE or allergen-specific IgE in serum indicates an increased probability of an allergic disorder, parasitic infection, or aspergillosis. In vitro laboratory testing can be performed by a variety of methods.

The clinical significance of serum allergen-specific IgE (sIgE) in allergic disorders has long been recognized. The quantitative determination of serum sIgE antibodies is an essential component for differential diagnosis and for identifying the causative allergens for proper medical treatment. The quality and availability of allergens, reagent stability, and degree of automation all influence the method of testing. Based on thousands of test results, a generic curve indicates what an allergen-specific IgE antibody value can mean in relation to symptoms. Although a final diagnosis should always be based on the physicians’ overall impression of the patient, a general rule of thumb is that the higher the IgE antibody value, the greater the likelihood of symptoms appearing.

ImmunoCAP

The U.S. Food and Drug Administration (FDA) has approved ImmunoCAP to provide an in vitro quantitative measurement of IgE in human serum (Fig. 26-2). It is considered to be the gold standard for the analysis of allergen-specific IgE. It is intended for in vitro use as an aid in the clinical diagnosis of IgE-mediated allergic disorders in conjunction with other clinical findings (Table 26-3) .

Table 26-3

Comparison of Tests for Specific IgE

Parameter	Skin Prick Testing	Intradermal Testing	Blood Testing (ImmunoCAP)
Sensitivity (%)	93.6	60.0	87.2
Specificity (%)	80.1	32.3	90.5

Adapted from Choo-Kang LR: Specific IgE testing: objective laboratory evidence supports allergy diagnosis and treatment, Med Lab Observer MLO 38:10–14, 2006.