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 can be fatal.

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. 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.

Histamine, leukotriene C4, interleukin-4 (IL-4), and inter leukin-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.

Fig1. Pathways leading to acute and chronic allergic reactions.

Anaphylactic Reaction. Anaphylaxis is the clinical response to immunologic formation and fixation between a specific anti gen 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 poly saccharides 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 macro molecules, 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 red ness 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 com pounds are discharged from mast cells and basophils during anaphylaxis (see Table 1).

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. The formation of IgE anti bodies 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 avail ability 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. 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 2) .

ImmunoCAP assays can be performed for hundreds of allergens, such as weeds, trees, pollens, mold, food, and animal dander. It offers testing for over 650 different allergens and 70 allergen components for sensitive and specific quantitative detection of allergen-specific IgE antibodies.

Fig2.  ImmunoCAP test—principle, steps, and evaluation. ECP, Eosinophilic cationic protein. (Courtesy Phadia AB, Uppsala, Sweden.)

Table 2. Comparison of Tests for Specific IgE

The substances to which a patient is exposed will generally dictate the allergens to test. Some allergens are more common as causes of allergy than others. Factors to consider are the following:

• Patient’s age

• Symptoms

• Home environment (e.g., pets, hobbies)

 • Geographic location of patient’s residence

An example of a pediatric allergy, the march (progression) profile, includes testing for allergens to Alternaria alternata (Alternaria tenuis; mold), cat dander, cockroach (German), Der matophagoides pteronyssinus (Dermatophagoides farinae; mites), dog dander, egg white, codfish, whitefish, cow’s milk, peanut, soybean, wheat, and total serum IgE. Food profile allergens might include corn, egg white, cow’s milk, orange, peanut, shrimp, soybean, and wheat.

Respiratory allergen inhalants can include A. alternata (A. tenuis), cat epithelium and dander, dog dander, elm tree, Hormodendrum hordei (Cladosporium herbarum; fungi), house dust, June grass, Kentucky bluegrass, mountain cedar (juniper) tree, and Russian thistle. Respiratory subtropical Florida allergens include A. alternata (A. tenuis), Aspergillus fumigatus, pine, Australian pine, Bahia grass, Bermuda grass, cat dander, cockroach (German), common short ragweed, D. farinae (D. pteronyssinus; mites), dog dander, Hormodendrum hordei (Cladosporium herbarum; fungi), oak tree, pecan (white hickory) tree, Penicillium notatum, pigweed, and total serum IgE.

The clinical use of inhaled steroids is becoming increasingly popular because of their antiinflammatory effects, although overtreatment may have serious side effects. To ensure the lowest effective dosage throughout treatment, the laboratory can periodically monitor the occurrence in serum of ECP-2 released from inflammatory cells. Eosinophil cationic protein (ECP) released by eosinophils can be detected in body fluids.

 Chemiluminescent Enzyme Immunoassay. A third-generation sIgE method (Immulite 2000; Siemens Healthcare Diagnostics, Tarrytown, NY) is a solid-phase (bead), two-step chemiluminescent enzyme immunoassay (EIA). Allergens are covalently lined to a soluble polymer-ligand matrix, allowing immunochemical reactions to occur in liquid phases for random access automation.

Treatment

Treatment of patients with allergies involves identifying and eliminating or avoiding possible allergens. Drug therapy and desensitization are two treatment strategies. Drug Therapy. Drug treatments include the following:

 • Epinephrine (adrenaline) can be lifesaving in anaphylaxis. Epinephrine stimulates both α-adrenergic and β-adrenergic receptors, decreases vascular permeability, increases blood pressure, and reverses airway obstruction.

• Antihistamines block specific histamine receptors and play an important role in allergies affecting the skin, nose, and mucous membranes. Antihistamines act much slower than epinephrine in treating anaphylaxis and are not very useful in asthma because histamine is not an important allergic mediator released by mast cells in the lung.

• Specific receptor antagonists block the effects of leukotrienes. One drug, montelukast, reduces the amount of airway inflammation in asthma.

• Corticosteroids, often given topically, are widely used in the prevention of symptoms in patients with allergy.

 • Other drugs in development aim to block the Th2 cytokine pathway or prevent IgE binding to FcεRI-α.

Desensitization. Desensitization, or immunotherapy, is a well-established technique to improve allergy symptoms caused by specific allergens (e.g., hay fever; Fig. 26-3). If a patient has a history of life-threatening conditions, and if other treatment alternatives are unsatisfactory, desensitization is used to prevent anaphylaxis resulting from insect stings (e.g., yellow jackets). It is best if only one allergen is incriminated.

Fig3. Proposed mechanisms of specific immunotherapy (hyposensitization or desensitization).

Specific immunotherapy is associated with downregulation of the cytokines produced by Th2 cells, upregulation of cytokines produced by Th1 cells, and induction of regulatory T (Treg) cells. These changes in produce inhibition of allergic inflammation, increases in cytokines that control the production of IgE (IFN-γ and IL-12), production of blocking antibodies (IgG), and release of cytokines involved in allergen-specific hyporesponsiveness (IL-10 and transforming growth factor-β).

Different routes of desensitization induce different T-cell populations—Th1 and Treg cells in the case of subcutaneous administration and Th2 cells in the case of a sting on the skin.

For desensitization to insect venom, venom is injected subcutaneously in increasing doses at fixed intervals. Treatment starts with very small doses of venom because there is a risk of inducing anaphylactic shock. Over time, the patient is injected with increasing quantities of venom, eventually corresponding to the amount of venom in the insect sting. Once desensitization has been carried out, high levels of allergen-specific IgG will bind venom and prevent it from cross-linking IgE on mast cells. After following the prescribed treatment protocol, more than 90% of patients will not develop anaphylaxis if they are stung again.