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Immediate Hypersensitivity Reactions

  • Author: Becky Buelow, MD, MS; Chief Editor: Michael A Kaliner, MD  more...
 
Updated: Feb 09, 2015
 

Background

The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms can sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system.[1] It divides the hypersensitivity reactions into the following 4 types:

  • Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils. [2] Examples include anaphylaxis and allergic rhinoconjunctivitis.
  • Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation. An example is drug-induced hemolytic anemia.
  • Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation. An example is serum sickness.
  • Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies. An example is contact dermatitis from poison ivy or nickel allergy.

Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et al.[3] This system divides immunopathologic responses into the following 7 categories:

  • Inactivation/activation antibody reactions
  • Cytotoxic or cytolytic antibody reactions
  • Immune-complex reactions
  • Allergic reactions
  • T-cell cytotoxic reactions
  • Delayed hypersensitivity reactions
  • Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions (see Pathophysiology). In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from non-IgE-mediated (formerly called anaphylactoid) reactions that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye, opiates, or vancomycin and appear similar clinically to urticaria or even anaphylaxis.[4, 5]

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.[6]

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly mentioned, refer to the articles on these topics for more detail. For example, see Allergic and Environmental Asthma; Anaphylaxis; Food Allergies; Rhinitis, Allergic; and Urticaria.

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Pathophysiology

Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. CD4+ T-cells are divided into 3 broad classes: effector T-cells, memory T-cells, and T-regulatory (Treg) cells. Effector T-cells are further divided based on the cytokines they produce: TH1, TH2, and TH17 cells. TH1 cells produce interferon-gamma and interleukin (IL)-2, and promote a cell-mediated immune response. TH2 cells produce IL-4 and IL-13, which then act on B-cells to promote the production of antigen-specific IgE. TH17 cells produce IL-17, IL-21, and IL-22 to help fight extracellular pathogens, to produce antimicrobial peptides, and to promote neutrophil inflammation essential for immunity at the skin and mucosal surfaces.[57] Memory T-cells rapidly differentiate into effector T-cells in secondary immune responses. CD4+CD25+FOXP3+ Treg cells are essential in peripheral tolerance and serve to suppress dysregulated immuneresponses.CD4+CD25+FOXP3+Tregs inhibit TH2 cytokine production through the secretion and action of IL-10 and TGF-beta. Proper function of CD4+CD25+FOXP3+ Treg cells has been shown to be important in the tolerance of allergens.[8] Abnormalities in the CD4+CD25+FOXP3+ Treg population may play a role in the development of allergic disease.

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 an antigen-presenting cell (APC), such as a dendritic cell, macrophage, or B-cell.[7, 8] The antigen-presenting cells then migrate to lymph nodes, where they prime naïve TH cells that bear receptors for the specific antigen.

After antigen priming, naïve TH cells differentiate into TH1, TH2, or TH17 cells based upon antigen and cytokine signaling. In the case of allergen sensitization, the differentiation of naïve TH cells is skewed toward a TH2 phenotype. These allergen-primed TH2 cells then release IL-4, IL-5, IL-9, and IL-13. IL-5 plays a role in eosinophil development, recruitment, and activation. IL-9 plays a regulatory role in mast cells activation. IL-4 and IL-13 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. Sensitizatio Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated 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:[9, 10]

Preformed mediators

See the list below:

  • 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 role is not completely understood, but it can cleave C3, C3a, and C5 in addition to playing a role in airway remodeling. [11, 8] 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 alpha-tryptase.
  • 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

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

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.[12, 13] 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.[4]

Cytokines

See the list below:

  • IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
  • IL-5: IL-5 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: IL-13 has many of the same effects as IL-4.
  • Tumor necrosis factor-alpha: Tumor necrosis factor-alpha is a pro-inflammatory cytokine which activates neutrophils and eosinophils and increases monocyte chemotaxis. [14, 8]

The collective biological activities of the aforementioned 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, resulting in symptoms in 2 or more organ systems, is considered 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. [4, 10]

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 acute-phase 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 24-72 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-allergic patient who owns a cat) 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. Collectively, this results 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/IgE–mediated responses.[10]

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Epidemiology

Frequency

United States

  • The prevalence of atopic diseases (i.e., asthma, allergic rhinitis, food allergy, and atopic dermatitis) has increased since the year 2000. [8]
  • Allergic rhinitis is the most prevalent allergic disease; [6] it affects approximately 17-22% or more of the population. [15]
  • Asthma was estimated to affect approximately 25.7 million people in the United States in 2010. Asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010. [16] Ninety percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults. [15]
  • Atopic dermatitis has increased in prevalence worldwide over the last decade. [8]
  • The prevalence of anaphylaxis may be as high as 2%, with an increase in younger patients. [17]

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[18] and 2-12% in adults.[19]

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 this data was 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.[20] 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 1.4-39.7% and, although sites varied, a general trend of increasing prevalence of allergic rhinoconjunctivitis was found over the 7 years between phases 1 and 3.[21]

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.[21, 8]

Asthma, as with other atopic diseases, was previously increasing in prevalence.[22, 23] Data from a study from England suggest that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.[24] 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 difference 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.[25]

  • 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.
  • 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. [25]
  • In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease. [26]
  • 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 cell–predominant 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. [27]

Mortality/Morbidity

Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare.[10] Between 2007-2009 in the United States, the asthma death rate per 1,000 persons was 0.15.[28] The death rate was 75% higher for blacks compared to whites, 30% higher for females compared to males, and nearly 7 times higher for adults than children. Approximately 500 people die annually from anaphylaxis in the United States.

Allergic diseases are a significant cause of morbidity. In 2007, $56 billion was spent on medical costs, lost school, and work days and early deaths due to asthma in the United States alone.[29] Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.

Race

The reason for the differences in the prevalence of allergic diseases with respect to race are complex and not completely understood. In the US between 2008-2010, multiracial individuals had the highest asthma prevalence at 14.1%.[28] Next, blacks had a prevalence of 11.2%, followed by American Indian/Alaska Native at 9.4%, and whites at 7.7%.[28] Among the Hispanic population, the highest asthma prevalence rates were seen in persons of Puerto Rican (16.1%) and Mexican (5.4%) descents.[28] Asthma prevalence was also higher in persons with a family income below the poverty level.[28] Thus, it is likely that differences in allergic diseases among different racial or ethnic groups is multifactorial and includes genetic, environmental, and socioeconomic factors.

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;[6] after puberty, prevalence is higher in females.[9] The male-to-female ratio of children who have atopic disease is nearly 2:1.

Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.[9]

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 shellfish, 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.[9, 8]

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Contributor Information and Disclosures
Author

Becky Buelow, MD, MS Instructor, Section of Allergy and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin

Becky Buelow, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, Wisconsin Allergy Society

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 College of Allergy, Asthma and Immunology, Clinical Immunology Society, Federation of American Societies for Experimental Biology, American Society for Virology, American Association of Immunologists, American Society for Microbiology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont 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, Michigan State Medical Society, Michigan Allergy and Asthma Society, American College of Physicians, American Federation for Medical Research, Royal College of Physicians and Surgeons of Canada, Society for Experimental Biology and Medicine

Disclosure: Received ownership interest from Secretory IgA, Inc. for management position; Received ownership interest from siRNAx, Inc. for management position.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; 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, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Miriam K Anand, MD, FAAAAI, FACAAI Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd; Clinical Assistant Professor, Midwestern School of Osteopathic Medicine

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: TEVA pharmaceuticals Honoraria Speaking and teaching

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Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.
Table.
Age Step 1 Step 2 Step 3 Step 4 Step 5 Step 6
0-4 years SABA PRN Low-dose ICS Medium-dose ICS Medium-dose ICS plus LABA or montelukast High-dose ICS plus LABA or montelukast High-dose ICS plus LABA or montelukast and oral corticosteroids
5-11 years SABA PRN Low-dose ICS Low-dose ICS plus LABA or LTRA or theophylline Medium-dose ICS plus LABA High-dose ICS plus LABA High-dose ICS plus LABA plus oral corticosteroids
12 years or older SABA PRN Low-dose ICS Low-dose ICS plus LABA or medium-dose ICS Medium-dose ICS plus LABA High-dose ICS plus LABA High-dose ICS plus LABA plus oral corticosteroids
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