Immediate Hypersensitivity Reactions

Contributor Information and Disclosures Author Miriam K Anand, MD, FAAAAI, FACAAI Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd Miriam K Anand, MD, FAAAAI, FACAAI is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, and American Medical Association Disclosure: Nothing to disclose. Coauthor(s) John M Routes, MD Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics, Chief, Section of Allergy and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin John M Routes, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Microbiology, American Society for Virology, Clinical Immunology Society, and Federation of American Societies for Experimental Biology Disclosure: Nothing to disclose. Specialty Editor Board Stephen Rosenfeld, MD Professor Emeritus, Department of Medicine, Allergy, Immunology and Rheumatology Unit, University of Rochester School of Medicine and Dentistry Stephen Rosenfeld, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American Federation for Clinical Research, Clinical Immunology Society, and Medical Society of the State of New York Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital

Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, Michigan Allergy and Asthma Society, Michigan State Medical Society, Royal College of Physicians and Surgeons of Canada, and Society for Experimental Biology and Medicine Disclosure: Secretory IgA, Inc. Ownership interest Management position Timothy D Rice, MD Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians Disclosure: Nothing to disclose. Chief Editor Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians Disclosure: Alcon Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering/Merck Consulting fee Consulting; Teva Consulting fee Consulting; Meda Honoraria Speaking and teaching; Ista Consulting

Pathophysiology
Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. T helper (TH) cells, which are CD4+, have been divided into 2 broad classes based on the cytokines they produce: TH1 and TH2.[5, 6] Regulatory T cells (Tregs) are CD4+CD25+ and may also play a role.[7] TH1 cells produce interferon gamma, interleukin (IL)2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells.[8, 5, 6] Current evidence suggests that Tregs may also actively inhibit TH2 responses to allergens.[7] The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then

processed by the dendritic cell, an antigen-presenting cell.[9] The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen. TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamine-primed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigen-specific IgE antibodies. For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present peptides from it, bound to the major histocompatibility class II molecules found on B-cell surfaces, to the antigen receptors on TH2 cells. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production (see image below).

Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin Emediated allergic reaction.

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:[5, 6]
Preformed mediators

Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.

Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a as well as C5.[10] Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of alphatryptase. Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.

Newly formed mediators

Arachidonic acid metabolites o Leukotrienes - Produced via the lipoxygenase pathway Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar constriction Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis o Cyclooxygenase products Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils Prostaglandin F2-alpha - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils. Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release. Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell released heparin, has been described.[11, 12] Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.[3]

Cytokines

IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis. IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release. IL-6: IL-6 promotes mucus production. IL-13: This cytokine has many of the same effects as IL-4. Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells.[13]

The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather than pruritic. Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes. Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing. Anaphylaxis: Systemic release of the above mediators affects more than one system and is known as anaphylaxis. In addition to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and asphyxiation.[3, 6]

Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators. These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acutephase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-48 hours. Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils

can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgEmediated responses.[6]

Epidemiology
Frequency United States

The prevalence of atopic diseases had increased significantly in the 1980s and 1990s in industrialized societies.[14] Allergic rhinitis is the most prevalent allergic disease;[4] it affects approximately 17-22% or more of the population.[15] Asthma is estimated to affect approximately 22.2 million people in the United States.[16] Ninety percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults.[15] Atopic dermatitis had also increased in prevalence in the 1980s and 1990s; prevalence in the United States is likely similar to that in Europe (see international information below).[5] The prevalence of anaphylaxis is approximately 1-3% in industrialized countries.

International

Approximately 300 million people worldwide are estimated to have asthma. Prevalence rates vary around the world and are estimated to be from 3-38% in children[17] and 2-12% in adults.[18] The International Study of Asthma and Allergies in Childhood (ISAAC) is an epidemiological research program that was established in 1991 to evaluate asthma, eczema, and allergic rhinitis in children worldwide. The study is composed of 3 phases. Phase 1 used questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations in centers around the world. Most of these data were collected in the mid 1990s. Phase 2 was designed to assess possible etiological factors based on information gathered from Phase 1. Phase 3 is a repetition of Phase 1 to assess trends in prevalence.[19] Data from ISAAC show variations in the prevalence of allergic diseases between countries. ISAAC researchers found significant variability in the prevalence of allergic rhinoconjunctivitis in children from 56 countries. Rates varied from 1.439.7% and, although sites varied, a general trend of increasing prevalence of allergic rhinoconjunctivitis was found over the 7 years between phases 1 and 3.[20] Similar to other allergic diseases, the prevalence in atopic dermatitis varies widely between countries. Prevalence varies from 1.4% in China to 21.8% in Morocco, and prevalence is generally increasing.[20] Asthma, as with other atopic diseases, was previously increasing in prevalence.[21, 22] Data from a study from England suggest that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.[23] Hospital admissions for anaphylaxis, however, have increased by 600% over the past decade in England and by 400% for food

allergy. Admission rates for urticaria increased 100%, and admission rates for angioedema increased 20%, which suggests that these allergic diseases may be increasing in prevalence. Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations than in rural populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.[14] o The prevalence of asthma in East Germany prior to 1990 was lower than in West Germany, despite the fact that East Germany had more air pollution. o Over the 10 years after unification, the prevalence of asthma in the former East Germany has increased and is now comparable with that of former West Germany.[14] o In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease.[24] o These findings have led to the hygiene hypothesis, which proposes that early exposure to infectious agents or endotoxins helps direct the immune system toward a TH1 cellpredominant response that, in turn, inhibits the production of TH2 cells. A TH1 response does not lead to allergies, while a cleaner, more hygienic environment may lead to TH2 predominance and more allergies.[25]

Mortality/Morbidity

Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare.[6] In 1995, 5579 people died from asthma in the United States. Since 1999, the rate of death from asthma for individuals between 5 and 34 years of age seems to have declined.[26] Approximately 500 people die annually from anaphylaxis in the United States. Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.

Race

Differences in the prevalence of allergic diseases with respect to race were previously thought to be more related to environmental factors than to true racial differences. For example, the prevalence of asthma is 2.5 times higher in African Americans than in whites in the United States.[4] Asthma is more prevalent in inner-city populations, and this was thought to explain the difference. One study found a higher risk of asthma mortality in blacks than in other ethnic groups, however, and this was independent of socioeconomic status. This suggests that a difference based on ethnicity alone could exist.[27]

Sex

Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys during the first

decade of life;[4] after puberty, prevalence is higher in females.[5] The maleto-female ratio of children who have atopic disease is approximately 1.8:1. Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.[5]

Age

In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.[15] Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in adults. Some food allergies, such as allergy to peanuts, may last a lifetime. Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life (beginning in adolescence) and can also have asthma that is more severe.
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