INTRODUCTION — Allergen-specific immunoglobulin E (IgE) is integral to the pathogenesis of allergic disorders. However, the utility of measuring total serum IgE or allergen-specific IgE for purposes of diagnosis and management is variable. It is important to recognize that levels of total IgE rarely provide information about IgE to specific allergens, and the presence of IgE to a specific allergen does not necessarily equate to a clinically meaningful allergic response to that substance. It is also necessary to demonstrate that the individual develops appropriate signs and symptoms upon exposure to the allergen in question.
This topic will review basic concepts concerning the generation of the allergic response and provide an overview of the roles of total and allergen-specific IgE in various allergic diseases. The biology of IgE and the diagnosis of specific allergic diseases are discussed separately. (See "The biology of IgE" and "Asthma in adolescents and adults: Evaluation and diagnosis" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)
TERMINOLOGY — The terms "atopy," "sensitization," and "allergy" are often used loosely in the medical literature, although each has a distinct definition.
Atopy — Atopy is the genetic predilection to produce specific IgE following exposure to allergens. At a cellular level, atopy appears to result, in part, from a predisposition toward a certain response on the part of CD4+ T helper cells called a T helper type 2 (Th2) response . The CD4 molecule is a coreceptor in the T cell receptor complex and also binds proteins of the major histocompatibility complex (MHC). Th2 cells secrete large quantities of interleukin-4 (IL-4) and interleukin-13 (IL-13), which promote the production of allergen-specific IgE by plasma cells. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th2' and "The biology of IgE", section on 'Regulation of synthesis'.)
Sensitization — Sensitization refers to the production of allergen-specific IgE. Sensitization to an allergen is not synonymous with being allergic to that allergen, because individuals may produce IgE to allergens in a given substance, but not develop symptoms upon exposure to that substance. It is unclear why some individuals demonstrate only sensitization while others have active allergic disease.
Sensitization is usually demonstrated by skin testing or in vitro immunoassays for IgE to specific allergens (sometimes referred to as radioallergosorbent or RAST testing, although this term describes an antiquated form of the test). Thus, sensitization is necessary but not sufficient for the development of allergic disease. Because a person can be sensitized to an allergen but not react to it upon exposure, it is prudent to limit allergy testing to those allergens which are implicated by the clinical history.
The production of allergen-specific IgE is summarized briefly here in simplified form and reviewed in greater detail elsewhere. (See "The biology of IgE", section on 'Synthesis' and "Immunoglobulin genetics" and "Normal B and T lymphocyte development".)
Once a substance enters the body (through ingestion, inhalation, or injection), it is degraded, and allergens (usually proteins but occasionally carbohydrates) are taken up by antigen-presenting cells (APCs), including macrophages, CD1+ dendritic cells, B cells, and possibly, epithelial cells. APCs further degrade the allergen and present peptide fragments of it on the cell surface in the setting of class II MHC molecules. The peptide/MHC II complexes are recognized by Th2 cells. (See "Antigen-presenting cells".)
Th2 cells then interact with B cells and in the presence of various costimulatory signals, stimulate the B cell to mature into a plasma cell that produces IgE specific to the component of the allergen in question. B cell maturation primarily occurs within mucosal lymphoid tissue.
After IgE antibodies specific for a certain allergen are synthesized and secreted, they diffuse throughout the body, binding to high-affinity receptors (Fc-epsilon-RI) on mast cells in the tissues and basophils in the circulating blood (figure 1).
Allergy — Individuals are considered to have clinically significant allergy or allergic disease when they have both allergen-specific IgE and develop symptoms upon exposure to substances containing that allergen. Therefore, greater numbers of people are sensitized to an allergen than are clinically allergic to it. This was illustrated in the National Health and Nutrition Examination Survey (NHANES) 2005-2006, in which over 8000 people from the general population of the United States were interviewed and tested (using in vitro blood tests) for sensitization to 19 common inhalant allergens . Specific IgE antibodies to at least one allergen were present in 44 percent, whereas only 34 percent had symptoms suggestive of allergic disease. Similar findings have been documented for food allergy. In a population-based birth cohort study in the United Kingdom, 12 percent of children were sensitized to peanut at eight years of age, but only 2 percent were allergic .
A sensitized person may develop symptoms when re-exposed to the relevant allergen if the allergen is able to bind to IgE antibodies on the surface of mast cells and basophils in sufficient numbers to cause clustering (called cross-linking) of the IgE molecules. Cross-linking of enough IgE receptors results in the generation of activating signals. Upon activation, mast cells and basophils release preformed and newly-formed chemical and protein mediators, which directly and indirectly lead to the signs and symptoms of allergic reactions. These mediators include histamine, prostaglandins, leukotrienes, platelet-activating factor, cytokines, and others. (See "Mast cell-derived mediators".)
Common allergic diseases include allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, stinging insect venom allergy, and drug allergy.
The atopic march — Atopic dermatitis, allergic rhinitis, and asthma often affect the same patients and develop in temporal succession. This progression from atopic dermatitis in infancy to allergic rhinitis and asthma in childhood and young adulthood is referred to as the "allergic march" or "atopic march" [4-7]. Nearly 80 percent of children with atopic dermatitis will subsequently develop allergic rhinitis or asthma .
RELATIONSHIPS BETWEEN TOTAL IgE LEVELS AND ALLERGIC DISEASE — A total serum IgE level of 100 international units (IU)/mL is typically cited as the upper limit of normal in older adolescents and adults. Elevations in total serum IgE are seen in several types of disorders, including allergic diseases, some primary immunodeficiencies, parasitic and viral infections, certain inflammatory diseases, some malignancies, and several other diseases (table 1). Thus, elevated total serum IgE is not specific to allergic disease. Studies concerning allergic diseases are reviewed here, while studies of IgE in other diseases are reviewed separately. (See "The biology of IgE", section on 'Increased total IgE'.)
Elevated total serum IgE — Many patients with allergic disorders have elevated levels of total IgE; however, there is no specific cutoff value that discriminates patients with allergic disease from those without, and there is considerable overlap [9,10]. Thus, total IgE by itself is rarely adequate to diagnose allergic disease. The following studies are illustrative:
●Adults with IgE >66 IU/mL have a 37-fold greater risk of having allergen-specific IgE antibodies to aeroallergens compared with those patients with the lowest levels of total IgE .
●In one study, school-aged children had a mean IgE level of 51 IU/mL. Children with both atopic dermatitis and asthma had mean IgE levels of 985 IU/mL; those with asthma alone, 305 IU/mL; those with eczema alone, 273 IU/mL, and those with allergic rhinitis, 171 IU/mL .
●Among atopic patients of all ages, those with atopic dermatitis tend to have the highest IgE levels followed by atopic asthma, perennial allergic rhinitis, and seasonal allergic rhinitis .
●Using a total serum IgE level of 100 IU/mL to discriminate allergic from nonallergic patients, the sensitivity was 78 percent for patients with asthma and 60 percent for rhinitis, but 20 percent of patients were misclassified .
Low or normal levels of total serum IgE — Low levels of total serum IgE cannot be used to exclude the presence of atopic disease, because of the wide overlap in total serum IgE among atopic and nonatopic populations. Patients with low or normal serum IgE levels could still have local production of allergen-specific IgE in the tissues or a high ratio of allergen-specific to total IgE. (See "The biology of IgE", section on 'Localized IgE production'.)
Utility in predicting the development of allergic disease — Because elevations in total serum IgE are associated with established allergic disease, researchers have questioned whether IgE levels predict its development. Studies suggest that elevated total IgE is associated with an increased risk of allergic disease, although there is significant overlap between affected and unaffected individuals, such that the measurement is most useful in the context of population studies rather than in the diagnosis or management of an individual.
Cord blood — Cord blood IgE levels have been studied in an attempt to identify newborns who are at increased risk for the development of allergic disease. Maternal IgE does not normally cross the placenta, although fetal cord blood can be contaminated by maternal blood during late pregnancy and delivery and must be carefully collected . The majority of studies suggest that elevated total IgE in cord blood is an indicator of higher risk. As examples, studies have shown that newborns with elevated cord IgE levels had an increased risk of developing urticarial food reactions at 1 year of age , atopic dermatitis by 2 years of age , allergen sensitization and wheezing at 7 years of age , or allergic rhinitis by 11 and 20 years of age . However, no relationship was found between cord blood IgE levels and the development of asthma, allergic rhinitis, or atopic dermatitis by the time the child was 18 to 21 years of age despite a modest association with total IgE levels at those ages in another study . (See "The biology of IgE", section on 'Childhood levels'.)
Childhood IgE levels — Elevated IgE in young children appears to be an early predictor of the subsequent development of allergen-specific IgE and allergic disease . However, the clinical utility of this is limited by the extensive overlap between atopic and nonatopic individuals and the fact that patients with asthma have higher total IgE compared with nonasthmatics, regardless of atopic status. (See 'Relationships between total IgE levels and allergic disease' above and 'Asthma' below.)
Timeline of sensitization — In most cases, the presence of allergen-specific IgE precedes the onset of symptoms by several years. In a study of nearly 1000 college students, subjects were evaluated initially and again 7 and 16 years later using questionnaires and skin testing . At the seven-year follow-up, subjects with prior positive skin tests demonstrated an increased risk of developing allergic rhinitis and asthma. When these same patients were reassessed 16 years later, a 2.3-fold greater risk of developing allergic rhinitis was found in those subjects with positive allergen skin tests . Positive allergy skin tests and allergic rhinitis increased the likelihood of developing asthma by threefold.
In a small minority of patients, sensitization occurs only in the affected tissues, presumably due to low levels of allergen-specific IgE being produced by local mucosal plasma cells. This phenomenon of local IgE production is termed "entopy." In such patients, allergen-specific IgE is not demonstrable by either allergy skin testing or blood work, which presents diagnostic challenges. This is best described for some patients with rhinitis who have negative skin tests and in vitro tests for allergen-specific IgE, yet react to challenge with inhaled allergen. (See "Chronic nonallergic rhinitis", section on 'Diagnosis'.)
THE ROLE OF IgE IN SPECIFIC DISORDERS — The role of total and allergen-specific IgE levels in pathogenesis and diagnosis differs among the leading allergic disorders.
Asthma — Children and adults with asthma tend to have higher IgE levels than individuals without asthma, although there is no absolute cutoff that distinguishes between the two groups . Conversely, nonatopic patients with high levels of IgE are more likely to have asthma than those with normal IgE levels . In one study, nonallergic patients with a total serum IgE level greater than 150 international units (IU)/mL were at a fivefold higher risk of having asthma . Still, the increase in elevated total IgE in asthmatics compared with nonasthmatics is generally driven by atopic individuals .
Increased expression of the high-affinity IgE receptor (Fc-epsilon-RI) has been demonstrated on cells in the airways of both atopic and nonatopic asthma patients compared with nonatopic control patients [27-29]. IgE positively regulates Fc-epsilon-RI levels, so both IgE and Fc-epsilon-RI tend to increase or decrease in parallel. Patients with atopic dermatitis and asthma are more likely than controls to have mutations in the alpha subunit of Fc-epsilon-R1 (the subunit that directly binds to IgE) associated with increased serum IgE levels .
In allergic patients with asthma, anti-IgE therapy (omalizumab) improves symptoms, reduces exacerbations and medication requirements, and decreases multiple inflammatory markers, demonstrating the role of IgE in allergic asthma. Total IgE levels are required for appropriate dosing of omalizumab in persistent asthma patients. (See "Anti-IgE therapy", section on 'Efficacy'.)
Lung function correlates with IgE — IgE levels correlate with asthma severity. Serum IgE levels are proportionately higher in asthmatic patients with lower lung function (forced expiratory volume in one second [FEV1]) . This may also be true for allergen-specific IgE. In patients with lower respiratory symptoms to specific aeroallergens (eg, cat), levels of allergen-specific IgE correlated well with asthma symptoms and lung function .
One of the key features of asthma is airway hyper-responsiveness, typically measured by bronchoprovocation challenges. In patients with asthma, elevated total IgE levels are associated with positive responses to methacholine challenges . Airway hyper-responsiveness in children correlates closely with total IgE levels, even after exclusion of children with asthma . However, airway hyper-responsiveness was more closely correlated to positive allergen skin test reactions than total IgE levels in children .
Smoking is associated with increased IgE levels in a dose-dependent fashion, possibly due to the lack of expected decreases in IgE levels with aging . The inverse relationship between IgE levels and lung function was stronger in asthmatic patients in both current and never smokers, compared with nonasthmatic subjects .
Allergic bronchopulmonary aspergillosis — Allergic bronchopulmonary aspergillosis (ABPA) is one of the few disorders in which total IgE values are used directly in diagnosis and treatment. ABPA typically occurs in patients with asthma or cystic fibrosis. The ubiquitous mold Aspergillus fumigatus causes localized immunologic-mediated damage in the lung. Diagnostic features include increased total IgE (>417 kU/L for patients with asthma and >1000 kU/L for those with cystic fibrosis) and evidence of increased specific IgE and IgG to A. fumigatus . Levels of total IgE increase during exacerbations of ABPA and fall with successful therapy. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Diagnosis'.)
Allergic rhinitis — Allergic rhinitis is associated with positive skin test reactions (or allergen-specific IgE antibodies), but is independent of total IgE levels . Measurement of total IgE has low sensitivity (44 percent) for identification of patients with current allergic rhinitis . In patients with perennial allergic rhinitis, total IgE levels did not correlate with either skin test reactivity or in vitro-specific IgE testing . In addition, a normal IgE level does not rule out allergic rhinitis . The diagnosis of allergic rhinitis, seasonal or perennial, requires a suggestive history and physical exam and the demonstration of specific IgE to clinically relevant aeroallergens . (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis".)
Atopic dermatitis — Even though it is called atopic dermatitis, about 30 percent of patients are nonatopic, as determined by the absence of other allergic diseases, negative skin tests for common inhalant and food allergens, and normal total serum IgE levels . The importance of allergic triggers remains controversial. (See "Role of allergy in atopic dermatitis (eczema)".)
Elevated total IgE levels can be demonstrated in 80 to 85 percent of patients with atopic dermatitis, although the precise relationship between the elevated IgE levels and disease pathogenesis is unclear . Some individuals have extremely high total IgE levels. Children with very high IgE (ie, >10,000 kU/L) are at greater risk for severe atopic dermatitis, sensitization to food and inhaled allergens, and anaphylaxis, compared with children with lesser elevations (ie, 1000 to 4000 kU/L) .
In patients with atopic dermatitis, the rate of sensitization to foods ranges from 30 to 80 percent, depending on the population studied, although the actual rate of confirmed food allergy is much lower. The diagnosis of food allergy in patients with atopic dermatitis is reviewed in detail separately. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Allergen sensitization'.)
Food allergy — Assessment of food-specific IgE is predominantly useful for the evaluation of immediate allergic reactions, such as those that cause hives, wheezing, or anaphylaxis. Foods are also associated with other types of adverse reactions including celiac sprue (gluten sensitivity) and lactose intolerance, neither of which are IgE mediated. (See "Clinical manifestations of food allergy: An overview", section on 'Non-IgE-mediated reactions'.)
Total IgE levels should not be used to make a diagnosis of food allergy . The gold standard testing for food allergy is the double-blind, placebo-controlled oral challenge to the food in question. However, because this can be a labor intensive procedure and can potentially induce severe allergic reactions, alternatives such as skin prick testing and in vitro food-specific IgE testing are often performed instead. The information from these tests must be interpreted in the context of the patient's clinical history, because patients can have food-specific IgE and not react to ingestion of that food. Interpretation of test results in the context of the patient's pretest probability often requires expertise. (See "Oral food challenges for diagnosis and management of food allergies" and "Diagnostic evaluation of IgE-mediated food allergy".)
Venom allergy — Patients who have experienced a systemic allergic reaction to a stinging insect (ie, bee, wasp, fire ant) should be evaluated for venom allergy . Skin testing is the preferred method of diagnosing venom allergy. If initial testing is negative, in vitro testing for venom-specific IgE can be performed or skin testing can be repeated .
Measurement of total IgE has no role in the diagnosis of venom allergy. Patients with confirmed venom allergy should be offered venom immunotherapy, which is highly effective at reducing the risk of reactions to subsequent stings. (See "Diagnosis of Hymenoptera venom allergy".)
Drug allergy — In patients with a history suggestive of an immediate hypersensitivity allergic reaction, skin testing to solutions of the drug in question can be helpful to confirm the diagnosis . Penicillin is the only drug with validated testing available, although skin testing is performed with other medications as well. (See "An approach to the patient with drug allergy", section on 'Testing for immediate reactions'.)
In vitro testing for drug-specific IgE is not generally useful, because its sensitivity is inferior to skin testing . Total serum IgE is of no value in the evaluation of drug allergy.
Chronic urticaria — Chronic idiopathic urticaria is defined as spontaneous wheals and/or angioedema daily or near daily for more than six weeks without any identifiable cause. About 40 percent of these patients produce immunoglobulin G (IgG) autoantibodies to either IgE or its high-affinity receptor, Fc-epsilon-RI. Despite IgE levels not being associated with this disease, the use of anti-IgE (omalizumab) therapy has been effective in reducing signs (number of hives) and symptoms (itch severity) in patients who remain symptomatic despite standard treatments [52,53]. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
RATIO OF ALLERGEN-SPECIFIC IgE TO TOTAL IgE — The ratio of allergen-specific IgE to total IgE has been termed the "specific activity" . Its utility has been examined in the diagnosis of several allergic disorders and in predicting individuals' responses to omalizumab therapy. One study found that in the diagnosis of food allergy, the specific activity was no more useful than allergen-specific IgE alone . However, in the treatment of asthma with omalizumab, a specific activity greater than 3 to 4 percent was predictive of a reduced response to omalizumab therapy . The ratio of allergen-specific IgE to total IgE remains largely a research tool, and overall clinical usefulness has not been established.
●Allergen-specific immunoglobulin E (IgE) production is a fundamental component of the pathogenesis of allergic disease. However, the measurement of total IgE and allergen-specific IgE has variable utility in the diagnosis and management of allergic disorders. (See 'Introduction' above.)
●Atopy refers to the genetic predilection to produce allergen-specific IgE. Sensitization refers to the presence of allergen-specific IgE in the absence of clinical disease. Individuals are considered to have clinically significant allergy or allergic disease when they have both allergen-specific IgE and develop symptoms upon exposure to that allergen. (See 'Terminology' above.)
●Elevated total IgE is seen with some allergic disorders, as well as several nonallergic diseases (table 1). Many patients (although not all) with allergic disorders have elevated levels of total IgE. However, there is no specific cutoff value that discriminates patients with allergic disease from those without, and there is considerable overlap. (See 'Relationships between total IgE levels and allergic disease' above.)
●Elevated total IgE is associated with an increased risk of allergic disease, although there is significant overlap between affected and unaffected individuals, such that the measurement is most useful in the context of population studies, rather than in the diagnosis or management of an individual. Allergen-specific IgE is usually detectable several years before a person becomes reactive to that allergen, although only a subset of sensitized people will ever develop symptoms. (See 'Utility in predicting the development of allergic disease' above.)
●The role of total and allergen-specific IgE levels in pathogenesis and diagnosis differs among the leading allergic disorders. Asthma correlates with increased total IgE levels, regardless of atopic status. Allergic rhinitis is associated with allergen-specific IgE antibodies, although not with total IgE levels. Patients with atopic dermatitis may have very elevated levels of total IgE, although only a minority of patients (mostly children with severe atopic dermatitis) has clinically apparent allergic reactions to food. Thus the usefulness of measuring total IgE in allergic rhinitis and atopic dermatitis is very limited. (See 'The role of IgE in specific disorders' above.)
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