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. 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.
Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.
Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation.
Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies.
Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et al. This system divides immunopathologic responses into the following 7 categories:
Inactivation/activation antibody reactions
Cytotoxic or cytolytic antibody reactions
T-cell cytotoxic reactions
Delayed hypersensitivity 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 pseudoallergic (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 by resulting in urticaria or anaphylaxis.
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.
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.
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.
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.
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. 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 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:[5, 6]
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. 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
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
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.
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.
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 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 24-48 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/IgE–mediated responses.
The prevalence of atopic diseases had increased significantly in the 1980s and 1990s in industrialized societies.
Allergic rhinitis is the most prevalent allergic disease; it affects approximately 17-22% or more of the population.
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. Ninety percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults.
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).
The prevalence of anaphylaxis is approximately 1-3% in industrialized countries.
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 and 2-12% in adults.
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. 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.
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.
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. 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.
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.
In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease.
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.
Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare. 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. 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.
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. 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.
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; after puberty, prevalence is higher in females. The male-to-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.
In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.
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.
History findings vary depending on which organ systems are affected.
Patients may report skin itching, localized or diffuse pruritus, dizziness, faintness, and diaphoresis. Difficulty breathing can result from angioedema of the pharyngeal tissue, from bronchoconstriction, or from both. Patients may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. Patients may experience uterine cramping or urinary urgency. Patients can have a sudden onset of respiratory and/or circulatory collapse and go into anaphylactic shock.
Symptoms usually begin within minutes of allergen exposure (eg, drug administration, insect sting, food ingestion, allergen immunotherapy) but can recur hours after the initial exposure (late-phase reaction).
Patients may not be able to identify the allergen either because they are unaware of the allergy (eg, first reaction to insect sting) or because they were unaware of exposure to the allergen (eg, a patient who is allergic to peanuts who eats a processed food containing hidden peanut protein).
Particular attention should be given to new or recently changed medications. A history specific for insect stings or new environmental exposures should be obtained. If applicable, a food history should also be obtained. Exercise-induced anaphylaxis may be associated with prior ingestion of a food (eg, wheat, peanut, tree nuts, celery) or drug (eg, NSAID) that does not produce symptoms when ingested without subsequent exercise.
Symptoms consist of congestion; sneezing; itchy, runny nose and eyes; and itching of the palate and inner ear. Patients may also report postnasal drip, which can cause sore throat, coughing, or throat clearing.
Rhinoconjunctivitis usually results from exposure to aeroallergens and can be seasonal or perennial. Airborne allergens typically also cause ocular symptoms consisting of itchy eyes, tearing, swelling or redness of the eyes.
Repeated exposure to the allergen can result in chronic allergic inflammation, which causes chronic nasal congestion that can be further complicated by sinusitis.
Allergen exposure results in bronchoconstriction, and patients may report shortness of breath (eg, difficulty getting air out), wheezing, cough, and/or chest tightness.
Long-term allergen exposure can cause chronic changes of increased difficulty breathing and chest tightness, and the patient may give a history of repeated rescue inhaler use or reduced peak flows.
Diffuse hives or wheals may occur and cause significant pruritus; individual wheals resolve after minutes to hours, but new wheals can continue to form.
Acute urticaria (lasting < 6 wk) can be caused by viral infections, foods, drugs, or contact allergens.
Chronic urticaria lasts longer than 6 weeks. Although many causes are possible, often, a cause is not found. In many cases, this is not due to antigen-IgE – mediated immediate hypersensitivity but to an autoantibody to the high affinity IgE receptor or to IgE itself.
Angioedema is localized tissue swelling that can occur in soft tissues throughout the body. Patients may report pain at the site of swelling instead of pruritus, which occurs with urticaria.
Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or hoarseness may be present. Angioedema of the laryngopharynx can be life threatening.
This condition is an eczematous cutaneous eruption more common in children than in adults; it can be exacerbated by allergen exposure, especially food allergies, in some patients.
Patients report significant pruritus that causes scratching, which produces the lesions. Superinfection with staphylococcal organisms can occur, particularly in severely excoriated or cracked lesions.
Patients may report nausea, vomiting, abdominal cramping, and diarrhea after ingestion of the offending food.
Note that other mechanisms (eg, lactose intolerance) commonly cause these symptoms.
Eosinophilic esophagitis and gastritis are newly recognized syndromes that are likely allergic in nature.
Physical examination findings vary with the organ system involved.
Vital signs should be monitored closely because patients can quickly progress to circulatory and/or respiratory failure. Tachycardia may precede hypotension. Patients who are hypotensive may have reflex tachycardia, but bradycardia can also occur in 5%.
Patients may have urticaria, angioedema, or both. Angioedema of the airway and throat can result in respiratory failure or asphyxiation; therefore, this dangerous occurrence must be closely monitored.
Patients may be wheezing during the respiratory examination, which is secondary to bronchoconstriction.
Confusion and alteration of mental status can occur.
Patients may sneeze, be congested, have a runny nose, or have frequent throat clearing and/or cough from postnasal drip.
Sclera may be injected, and patients may have dark rings under the eyes (ie, allergic shiners).
Nasal mucosa can be boggy and pale, usually with clear drainage.
The pharynx may have a cobblestone appearance reflecting lymphoid hyperplasia from postnasal mucus drainage.
The patient may have frontal or maxillary sinus tenderness from chronic sinus congestion or infection.
Findings can vary depending on the patient and the severity of symptoms. Patients may be coughing or appear short of breath. Wheezing may be present, but it might not be heard in patients with milder symptoms or, if the asthma is very severe, patients may not move enough air to produce wheezing.
Breaths may be shallow or the patient may have a prolonged expiratory phase.
Cyanosis of the lips, fingers, or toes (caused by hypoxemia) may occur with severe asthma.
Urticaria is usually represented by wheals with surrounding erythema. Wheals from allergic causes usually last a few minutes to a few hours. Wheals due to cutaneous vasculitis may last more than 24 hours and may leave postinflammatory hyperpigmentation upon healing.
Angioedema is localized swelling of the soft tissues that can occur anywhere but is particularly concerning if pharyngeal or laryngeal tissues are involved.
The physical examination findings can vary with the severity of the disease. In less severe cases, skin can appear normal, dry, or with erythematous papules. In more severe cases, patients can have extremely dry, lichenified, cracked, and, sometimes, crusted lesions.
In infants, the head and extensor surfaces are more involved, whereas in older children and adults, the flexural surfaces tend to be affected.
Atopy is defined as the genetic predisposition to form IgE antibodies in response to exposure to allergens. Therefore, a genetic predisposition exists for the development of atopic diseases. Mutations of specific alleles on the long arm of chromosome 5 have been associated with higher levels of IL-4 and IgE and are known as IL-4 promoter polymorphisms. Impaired function of Treg cells may also contribute to the development of atopic diseases.
Environmental issues also play an important role, although the role that exposure at an early age to certain antigens might play in either the progression to or the protection from the development of an allergic response remains unclear. Some studies have shown that children in day care and those with older siblings may be less likely to develop allergic disease. The environment certainly can help determine the allergens to which the patient will be exposed. For example, children in inner cities are more likely to be sensitized to cockroaches than are children in suburban or rural areas. Similarly, dust mites, a potent allergen, are primarily found in humid climates, and those who have never been exposed to such a climate are less likely to be allergic to mites.
Reactions can be elicited by various aeroallergens (eg, pollen, animal dander), drugs, or insect stings.
Other possible causes are latex, drug, and food allergy.
Allergens can be complete protein antigens or low–molecular-weight proteins capable of eliciting an IgE response.
Pollen and animal dander represent complete protein antigens.
Haptens are low–molecular-weight (inorganic) antigens that are not capable of eliciting an allergic response by themselves. They must bind to serum or tissue proteins in order to elicit a response. This is a typical cause of drug hypersensitivity reactions. Note that all drug hypersensitivity reactions are not mediated by IgE. In addition to anaphylactoid reactions, drug reactions can be caused by cytotoxicity and immune-complex formation and by other immunopathologic mechanisms.
The most common food allergens are peanuts, tree nuts, finned fish, shellfish, eggs, milk, soy, and wheat.
Certain foods can cross-react with latex allergens. These foods include banana, kiwi, chestnut, avocado, pineapple, passion fruit, apricot, and grape.
Bee, wasp, yellow jacket, hornet, and fire ant stings can cause IgE-mediated reactions.
While anaphylaxis is the most serious reaction, localized swelling and inflammation can also occur and do not by themselves indicate increased risk of a subsequent life-threatening reaction.
At least 50 Americans die each year from anaphylaxis caused by a stinging insect.
Non–IgE-mediated mast cell and basophil degranulation can occur from a variety of substances. Although the mechanisms are different, the clinical manifestations can appear the same.
Causes can include radiocontrast dye, opiates, and vancomycin (eg, red man syndrome).
Patients can be pretreated with glucocorticosteroids and both H1 and H2 antihistamines prior to exposure to iodinated radiocontrast dye. This, together with the use of low-osmolal nonionic dye, reduces the risk of a repeat reaction to approximately 1%.
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause reactions by causing release of leukotrienes via the 5-lipoxygenase pathway of arachidonic acid metabolism. Patients susceptible to this syndrome can develop acute asthma exacerbation, nasal congestion, urticaria, or angioedema after ingestion. However, note that in rare cases, patients can have what are thought to be true IgE-mediated anaphylactic reactions to a specific NSAID. In these cases, no cross-reactivity occurs with other NSAIDs.
Some laboratory tests may be helpful in determining whether a reaction is truly allergic in nature.
Obtaining a serum tryptase level soon after the onset of symptoms can be helpful in differentiating anaphylaxis from other forms of shock and from other symptom complexes that may be confused with anaphylaxis. The tryptase level can be elevated, which is indicative of mast cell degranulation. False-negative results can occur. Ideally, the tryptase level should be drawn within 4 hours after the event, but it can be drawn up to 15 hours later. Measurement of urinary histamine may also be useful.
An elevated eosinophil count may be observed in patients with atopic disease.
IgE levels may be elevated in patients who are atopic, but the level does not necessarily correlate with clinical symptoms.
The radioallergosorbent test (RAST) and other in vitro IgE assays measure antigen-specific IgE and can be useful in identifying which allergens are causing symptoms for the patient. More sensitive tests have been available in recent years and have a greater positive predictive value for foods. These tests can sometimes detect clinically irrelevant allergens, however, creating false-positive results to some foods. Molecular diagnostic tests are now available that can detect allergenicity to specific food protein molecules known to trigger IgE-mediated reactions.
Skin tests can be performed in the outpatient setting in the allergist's office and are very useful in the evaluation and management of allergic rhinitis and allergic asthma.
Skin prick tests involve pricking the skin where diagnostic allergen has been placed. A positive reaction consists of a wheal and flare that occurs within 15-20 minutes. Use of proper controls is a key component to interpretation of the tests but is often not included with kits marketed to nonspecialists.
Intradermal (ID) tests involve injecting allergen into the superficial dermis. ID tests have many more false positive reactions, and the clinical significance of a positive ID test is questionable.
Food skin tests have a higher false-positive rate than skin tests for aeroallergens, but negative food skin test results can be helpful in excluding IgE-mediated allergies, including food-related exercise-induced anaphylaxis, especially if a fresh food is used as the antigen.
For the most part, standardized diagnostic allergens are not available for drugs. Penicillin is the only drug for which a standardized diagnostic allergen exists, but even this test is only available for the major determinant, one of many possible allergens in the penicillins. Nonstandardized skin tests can be performed for the minor determinants in penicillin or for other drugs (ie, by pricking the skin where drug solution has been placed). Protocols are available for testing to certain medicines, such as penicillin and local anesthetics. Nonstandardized tests to other medicines are only useful if findings are positive.
Spirometry/pulmonary function tests
Spirometry or pulmonary function tests offer an objective means of assessing asthma.
Peak-flow meters can also be used for this and can be used by patients at home to monitor their status. Personal spirometers that measure FEV 1 are now also available for home use.
Inhalation challenge with histamine, methacholine, mannitol, and specific allergen can be used to confirm airway hypersensitivity or allergen sensitivity.
Measurement of exhaled nitric oxide can be used to evaluate inflammation in the airways seen with asthma and to follow efficacy of or adherence to anti-inflammatory medications (eg, inhaled corticosteroids).
Nasal smear tests
A nasal smear can be performed to look for eosinophils. However, regular use of a nasal corticosteroid can lower the eosinophil count.
Elevated eosinophil levels can be consistent with allergic rhinitis.
Induced sputum: Sputum induced from the airways can be evaluated for eosinophils, which is a measure of inflammation seen in asthma.
Treatment may vary depending on the type of allergic reaction. Some general observations are made below, but refer to articles on the specific topics for more details about treatment (eg, Anaphylaxis; Rhinitis, Allergic; Allergic and Environmental Asthma; Urticaria).
Assessment of the reaction is described as follows:
Withdraw the offending agent if applicable (eg, stop drug infusion).
Check the airway and secure if needed. Patients with respiratory compromise may need to be intubated. If laryngeal edema causes oral intubation to be difficult, a tracheostomy must be performed.
Assess the level of consciousness and vital signs.
Treatment is as follows:
Administer epinephrine immediately (see Medication).
Start intravenous fluids; these should be administered rapidly and as blood pressure and overall fluid status warrant.
Consider other vasopressors (eg, dopamine) if hypotension does not respond to the above measures. Norepinephrine may be used if dopamine is not effective. Importantly, isoproterenol should not be used because it is a peripheral vasodilator. Patients with beta-adrenergic blockade may be particularly difficult to treat. They have both chronotropic and inotropic cardiac suppression and may not respond to the above treatments. Glucagon has positive inotropic and chronotropic effects and is the drug of choice in these cases. Atropine can also be used but will only be effective in treating bradycardia.
H1- and H2-receptor blockers can be helpful in alleviating hypotension, pruritus, urticaria, rhinorrhea, and other symptoms. Cimetidine, when combined with any of several H1 antihistamines, has been demonstrated to block histamine-induced hypotension. Other H2 blockers have not been studied in this context.
Use albuterol nebulizers if needed.
Administer a corticosteroid, which is believed to help prevent or control the late-phase reaction.
Transfer the patient to the hospital for further observation and care.
Late phase reactions can occur 4-6 hours after the initial reaction and can be as severe as or worse than the original reaction. In some cases, late phase reactions can occur up to 36 hours later. Education of the patient and observation is, therefore, important.
Prevention is as follows:
Avoid the triggering allergen as much as possible.
Patients should be given a prescription for at least 2 autoinjectable epinephrine doses (eg, 2 EpiPens or 1 Twinject) and instructed in their proper use. Importantly, patients must carry them at all times.
Patients can also be instructed to carry both an H1 and an H2 antihistamine with them.
Patients must wear a Medic Alert type of bracelet to alert emergency responders to the possibility of anaphylaxis.
Patients should be taught what measures to take in case of a future anaphylactic reaction, ie, immediately administer epinephrine and take the antihistamine, call emergency services (eg, 911), or go to the nearest emergency department (even if feeling better after the epinephrine).
Specific allergen immunotherapy is highly effective in preventing anaphylaxis from hymenoptera stings and should always be considered for patients who have experienced a systemic reaction after an insect sting.
Avoid the offending allergen, if possible.
Oral H1-receptor blockers are helpful for controlling itchiness, rhinorrhea, and lacrimation but most have little effect on nasal congestion.
Administer an intranasal glucocorticosteroid to control nasal symptoms, including nasal congestion. These medications need to be used regularly to be effective, and patients may need to use them for a week or more before maximum effect is seen.
Other topical nasal agents include azelastine and olopatadine (H1-receptor blockers) and cromolyn (a mast cell stabilizer).
Nasal azelastine and olopatadine have the advantage of treating rhinorrhea, nasal itchiness, sneezing, and also congestion. Azelastine has been shown to be helpful in treating both allergic and nonallergic vasomotor rhinitis. Nasal antihistamines have a rapid onset of action and can be used on an as-needed basis. Topical nasal decongestants can provide immediate relief of nasal congestion and can be used temporarily and as needed. Patients should be cautioned not to use them for more than a few days, however, as they can cause rebound congestion (rhinitis medicamentosa).
Topical decongestants, mast cell stabilizers, or antihistamines can be used for ocular symptoms; artificial tears might be helpful in mild cases, and this product can be refrigerated for an extra cooling effect. Cold compresses can also be used.
Again, use of topical decongestants should be limited to a few days, as longer use can result in rebound vasodilation.
Antigen-injection immunotherapy is very effective in treating inhalant allergies and can be considered in patients whose symptoms do not respond well to medications or in patients who cannot avoid the allergen in question (eg, cat owner allergic to cats). The mechanism of action of immunotherapy is not yet fully elucidated. Immunotherapy causes antigen-specific immunoglobulin G 4 to be formed and lowers antigen-specific IgE over time. Some authorities theorize that immunotherapy results in an increase in the TH1-to-TH2 cell ratio.[32, 33] Regulatory T cells may also play an important role.
An alternative to antigen-injection immunotherapy, aka, subcutaneous immunotherapy (SCIT), is sublingual/swallow immunotherapy (SLIT), which is currently being used with increasing frequency in Europe. It involves having the patient hold extract under the tongue for 1-3 minutes before swallowing. It offers the advantage of a lower likelihood of systemic adverse effects and has been shown to reduce allergic rhinitis and asthma symptoms. Studies thus far, however, indicate that SCIT may have a more significant impact on these symptoms than SLIT. SLIT is still being evaluated for FDA approval in the United States. Sublingual drop kits being sold to nonspecialists in the United States are not based on doses or extract content shown to be effective in European trials.
Avoid the offending allergen, if possible.
A key factor in controlling allergic asthma is controlling allergic rhinitis symptoms.
Therapy depends on the severity of disease.
Patients should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed.
Inhaled glucocorticosteroids should be added if appropriate. In general, these medications are used if symptoms occur more than twice weekly or if abnormal spirometry findings reverse with the inhalation of a short-acting bronchodilator. For more refractory symptoms, a long-acting beta agonist may be added to the inhaled glucocorticoid.
Leukotriene inhibitors can also be added.
Systemic corticosteroid bursts may need to be used for exacerbations of severe cases.
Patients with allergic asthma may respond well to specific allergen immunotherapy.
In patients refractory to the usual medications and who have antigen-specific IgE to perennial environmental aeroallergens (positive skin test or RAST result), therapy with omalizumab (Xolair), a humanized monoclonal antibody that prevents binding of IgE to high-affinity IgE receptors on mast cells and basophils, may result in improvement.[35, 36, 37]
Avoid the offending allergen if known.
An H1-receptor blocker should be added. If symptoms are not controlled with this alone, an H2-receptor blocker, leukotriene inhibitor, or oral glucocorticosteroid can be added. Most patients require higher than the usual doses; employing twice daily H1 and H2 antihistamines for successful control is not uncommon.
Avoid the offending allergen if possible, and properly hydrate and care for the skin.
Topical glucocorticosteroids and topical immunomodulators (eg, tacrolimus) can be used.[38, 39]
Consultation with an allergist, pulmonologist, and/or critical care medicine specialist may be necessary for protracted anaphylactic shock or severe asthma exacerbations.
Consult an allergist or immunologist for the following conditions:
Allergic rhinitis not easily controlled with medications
Nonallergic, vasomotor rhinopathy
Asthma: Of patients with asthma, at least 50% of adults have allergies as factors causing or contributing to their asthmatic inflammation. More than 90% of children with asthma are allergic. Consider an allergy evaluation for seasonal bronchitis.
Allergy evaluation prior to the initiation of Xolair
Chronic urticaria or angioedema (>6 wk), or severe intermittent urticaria or angioedema, even if individual attacks last < 6 wk
History of anaphylaxis from insect bite or sting
History of anaphylaxis with unknown cause
Possible drug desensitization (if known allergy to drug for which no good alternatives are available)
Sinusitis before proceeding to surgery; nasal polyposis
Food allergy or idiosyncrasy
Persistent or bothersome conjunctivitis
Eosinophilic esophagitis or gastritis
Suspicion of congenital or acquired immune abnormalities
Diagnosis and treatment of acquired immunoglobulin deficiencies
Patients should avoid foods to which they are allergic.
Certain food proteins can cross-react with other proteins (eg, latex with avocado, banana, kiwi, chestnut, pineapple, passion fruit, apricot, and grape; ragweed with watermelon, cantaloupe, and honeydew melon; tree fruits with birch pollen).
Patients must be counseled about these possible cross-reactivities and should avoid the food if it causes symptoms.
Medical therapy varies somewhat depending on which type of allergic reaction is being treated. Some of the drugs and their categories are listed here, but refer to the articles on the specific allergic reaction for more detail.
Should be administered immediately for anaphylaxis/anaphylactic shock. Multiple preparations allow for delivery SC, IM, IV, or ET. Doses can be repeated q5min prn to maintain blood pressure (and as heart rate allows).
First-line choice to reverse effects of systemic vasodilation and increased vasopermeability observed with anaphylaxis. Although not the first choice for bronchoconstriction, epinephrine can also relieve some symptoms of bronchospasm and rhinitis. In the past, protocols called for subcutaneous or intravenous administration of epinephrine. However, studies have shown that intramuscular epinephrine leads to higher plasma levels than subcutaneous delivery. Intramuscular administration is now preferred over subcutaneous administration.[40, 41]
Predosed autoinjectable epinephrine is available in at least 2 forms, which include EpiPen and Twinject. Two doses of each are available (0.3 mg for EpiPen or Twinject 0.3 and 0.15 mg for EpiPen Jr. or Twinject 0.15). One Twinject pen actually has 2 doses of epinephrine available, which can be administered separately, and also has directions printed on a wraparound label on the pen that can be referred to at the time of use. The EpiPen has also been redesigned for easier use and has instructions on the pen. EpiPen Two-packs contain 2 pens and, therefore, 2 doses. Twinject Two-packs contain 2 pens for a total of 4 doses.
Sympathomimetic that stimulates beta-2 receptors, leading to bronchodilation. Used for bronchospasm refractory to epinephrine with anaphylaxis. First-line choice for acute bronchospasm associated with asthma.
Fluticasone, budesonide, and mometasone are steroids. They inhibit bronchoconstriction mechanisms, may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. Also may have vasoconstrictive activity.
Salmeterol and formoterol relax the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasm. Effect may also facilitate expectoration. Advair is available both as an HFA-propelled MDI and as a dry powder inhaler. Symbicort and Dulera are only available as an MDI.
Adverse effects are more likely to occur when administered at high or more frequent doses than recommended.
Inhaled bronchodilators are beta-agonists that come in short- and long-acting forms. Short-acting bronchodilators are used to treat acute bronchospasm. Can also be used prophylactically. For example, a patient with a history of asthma exacerbation in the presence of cats can use a short-acting bronchodilator before exposure to cats. Long-acting bronchodilators (eg, salmeterol) can be used twice daily and to help maintain bronchodilation over 12 h. In asthma patients, they should only be used in conjunction with inhaled glucocorticoids.
Pirbuterol and formoterol have both short- and long-acting activity. Onset of action is approximately 15 min, but effects last up to 12 h. Of note, when long-acting beta agonists are used alone, concern exists of increased mortality in asthma patients. These medications should be combined with an inhaled corticosteroid and should be reserved for patients with more frequent or moderate to severe symptoms or lung function. Finally, levalbuterol is the R-enantiomer of albuterol and is available in nebulizer and metered dose inhaler (MDI) forms. Advantage of levalbuterol is that it is less likely to cause paradoxical bronchospasm than racemic albuterol.
Previously, MDIs were made using chlorofluorocarbons (CFCs) as the propellant. However, the use of CFCs has been phased out because of environmental concerns. For this reason, companies are now making MDIs with hydrofluoroalkane-134a (HFA), which is not damaging to the ozone layer. CFC inhalers are no longer available in the United States.
Immunosuppressing agents and, thus, can decrease inflammation. Have particular efficacy in skin eruptions and bronchospasm. Role in anaphylactic shock is limited, although believed to help prevent delayed type of anaphylaxis.
Several different formulations are available; only one is listed. Others include methylprednisolone, dexamethasone, prednisolone (often used in children), and hydrocortisone. Depending on type of corticosteroid, oral, intravenous, and topical forms may be available. In more severe cases of anaphylaxis and asthma, intravenous forms of corticosteroids can be used initially. These can later be switched to oral forms as doses are tapered.
Inhaled corticosteroids are another form of corticosteroids and are key in controlling inflammation of bronchial airways and nasal mucosa. Similarly, topical corticosteroids are useful in treating atopic dermatitis.
Most widely available antihistamine (available OTC). Sedating antihistamines may be necessary to control more severe allergic reactions because they are very potent. Dosing interval of diphenhydramine is 4-6 h. Nonsedating antihistamines are all now available in a 24-h formulation but can only be administered PO.
An effective antihistamine delivered via the intranasal route. Mechanism is similar to oral antihistamines. Systemic absorption occurs and may cause sedation, headache, and nasal burning.
Forms complex with histamine for H1-receptor sites in blood vessels, GI tract, and respiratory tract.
Use prn or qd. Use alone or in combination with other medications. Unlike oral antihistamines, has some effect on nasal congestion. Helpful for vasomotor rhinitis. Some patients experience a bitter taste. Systemic absorption may occur, resulting in sedation (reported in approximately 11% of patients).
Selectively inhibits histamine H1 receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.
Type 1 histamine-receptor blockers act to block action of histamine on H1 receptor after its release from mast cells and basophils. Most effective when used prophylactically. Sedating first-generation and nonsedating second-generation H1 antihistamines are available. Typically, sedating antihistamines have more adverse anticholinergic effects. Sedating antihistamines include diphenhydramine, hydroxyzine, cyproheptadine, chlorpheniramine, and brompheniramine. Nonsedating antihistamines include cetirizine (cause drowsiness in 15% people), fexofenadine, loratadine, and desloratadine. Desloratadine and fexofenadine may also help decrease nasal congestion. Liquid forms are more rapidly absorbed orally and should be used for immediate treatment of an allergic reaction if intravenous access is not available.
Multiple formulations are available. Cimetidine was first to be widely used but tends to have more drug interactions than other H2-receptor blockers. If no response to H1-receptor antagonist alone, coadministration with an H2-receptor antagonist can help relieve symptoms of itching and flushing in anaphylaxis, pruritus, and urticaria. Cimetidine plus an H1 blocker blocks cardiovascular effects of histamine.
Can be administered in addition to H1-receptor blockers for additional control of urticaria and angioedema. Examples include ranitidine, famotidine, and cimetidine. Cimetidine has been studied more extensively for this indication than other members of this class.
Leukotrienes are synthesized by degranulated mast cells and basophils and likely contribute significantly to symptoms of allergic reactions. Three leukotriene inhibitors are now available in the United States. Montelukast and zafirlukast act as leukotriene D4-receptor blockers, whereas zileuton acts to inhibit production of leukotrienes B4, C4, D4, and E4. Disadvantages of the latter medication are its qid dosing and the need to monitor liver enzymes. However, a sustained release formulation is now available, permitting q12 h dosing; zileuton’s ability to inhibit synthesis of leukotrienes C4 and B4 as well as D4 may lead to increased use of this leukotriene modulator for certain indications.
Tacrolimus is a calcineurin inhibitor initially used in oral form as an immunosuppressant for transplantation patients. It has since been developed in topical form (Protopic) and can be used to treat atopic dermatitis that does not respond well to topical corticosteroids. A similar topical agent, pimecrolimus (Elidel), became available in the past few years and is indicated for mild atopic dermatitis. Systemic calcineurin inhibitors have been shown to cause immunosuppression and certain malignancies such as lymphoma. In January 2006, the FDA issued a black box warning for topical tacrolimus and pimecrolimus for these reasons. To date, studies have not shown significant systemic absorption, systemic immunosuppression, or increased risk of malignancy with the topical formulations. Trials are currently underway to assess possible benefit of inhaled tacrolimus for asthma.
Omalizumab (Xolair) is a monoclonal anti-IgE antibody indicated for refractory asthma. Has been shown to greatly improve severity of asthma in patients and can be used to help patients dependent on oral steroids to be weaned from steroids. Omalizumab has also been shown to decrease allergic response to peanuts in patients with severe peanut allergy. This could be helpful in preventing anaphylaxis from accidental peanut exposure in patients who normally would not tolerate even the slightest exposure to peanut allergen, but it only has FDA approval for asthma at this time. Patients should undergo a full allergy evaluation prior to starting omalizumab, if needed, because it interferes with prick skin test and RAST results.
Avoidance of the allergen is the best method of prevention, but this is not always possible (eg, avoiding insect stings). For this reason, patients should always have their rescue medications with them (eg, EpiPen, albuterol MDI). Allergen-specific immunotherapy is known to be disease modifying for aeroallergens and stinging insect venom.
Miriam K Anand, MD, FAAAAI, FACAAI, Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd
Disclosure: TEVA pharmaceuticals Honoraria Speaking and teaching
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
Disclosure: Nothing to disclose.
Stephen Rosenfeld, MD, Professor Emeritus, Department of Medicine, Allergy, Immunology and Rheumatology Unit, University of Rochester School of Medicine and Dentistry
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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
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
Disclosure: Nothing to disclose.
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