Author and Editor Disclosure

Synonyms and related keywords: type I hypersensitivity reactions, allergic reactions, IgE-mediated reactions, immunoglobulin E-mediated reactions, atopy, immunopathology, immediate hypersensitivity reactions, cytotoxic hypersensitivity reactions, delayed hypersensitivity reactions, anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, drug reaction, atopic dermatitis, inactivation antibody reactions, activation antibody reactions, cytotoxic antibody reactions, cytolytic antibody reactions, immune-complex reactions, T-cell cytotoxic reactions, granulomatous reactions

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. 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
• 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 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.

Pathophysiology

Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. T helper (TH) cells, which are CD4+, have been divided into 2 broad classes based on the cytokines they produce: TH1 and TH2. Regulatory T cells (Tregs) are CD4+CD25+ and may also play a role.¹

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. Current evidence suggests that Tregs may also actively inhibit TH2 responses to allergens.¹

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 it to the TH2 cells on the major histocompatibility class II molecules found on B-cell surfaces. 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 1).

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:

Preformed mediators

• Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
• Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. 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 kinins to produce bradykinin. 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.

Cytokines

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

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 then 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.

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.

Frequency

United States

• 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 is estimated to affect more than 20 million people. 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 below, International).
• The prevalence of anaphylaxis is approximately 1-3% in industrialized countries.

International

• The estimated prevalence of atopic dermatitis among school children in various European countries is 15-20%.
• Asthma, as with other atopic diseases, was previously increasing in prevalence.^{2, 3} Data from a recent study from England suggest that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.⁴ Hospital admissions for anaphylaxis, however, have increased by 600% over the past decade in that country 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 compared with 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.⁵
  
  
  • 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 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/Morbidity

• 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. Approximately 500 people die annually from anaphylaxis in the United States.
• Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.

Race

• Any differences in the prevalence of allergic diseases with respect to race seem to be more related to environmental factors than to true racial differences. For example, in the United States, the prevalence of asthma is 2.5 times higher in African Americans than in whites. Asthma is more prevalent in inner-city populations, and this may explain the difference.

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; 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.

Age

• 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

History findings vary depending on which organ systems are affected.

• Anaphylaxis
• • Patients may report dizziness, faintness, diaphoresis, and pruritus. Difficulty breathing can result from angioedema of the pharyngeal tissue and from bronchoconstriction. 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 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.
• Allergic rhinoconjunctivitis
• • Symptoms consist of 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, 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.
• Allergic asthma
• • 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.
• Urticaria/angioedema
• • 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 foods, drugs, or contact allergens.
  • Chronic urticaria lasts longer than 6 weeks. Although many causes are possible, often, a cause is not found.
  • 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.
• Atopic dermatitis
• • 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 can occur, particularly in severely excoriated or cracked lesions.
• GI involvement
• • 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 may be allergic in nature.

Physical

Physical examination findings vary with the organ system involved.

• Anaphylaxis
• • 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 have a reflex tachycardia, but bradycardia can also occur in 5%. Flushing and tachycardia are usually the first and are invariant symptoms of anaphylaxis.
  • Patients may have urticaria, angioedema, or both. Angioedema of the airway and throat can result in respiratory failure or asphyxiation; therefore, this 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.
• Allergic rhinoconjunctivitis
• • Patients may sneeze 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 from postnasal mucus drainage.
  • The patient may have frontal or maxillary sinus tenderness from chronic nasal congestion or infection.
• Allergic asthma
• • 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 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 may occur with severe asthma caused by hypoxemia.
• Urticaria/angioedema
• • 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 up to 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.
• Atopic dermatitis
• • 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, 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.

Causes

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 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 children in 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.

• Allergic reactions
• • Reactions can be elicited by various aeroallergens (eg, pollen, animal dander), drugs, or insect stings.
  • Other possible causes are latex allergy and food allergy.
• Allergens
• • 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.
• Foods
• • 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.
• Hymenoptera
• • 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.
• Anaphylactoid reactions
• • 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.

Allergic and Environmental Asthma
Anaphylaxis
Angioedema
Asthma
Bronchitis
Carcinoid Lung Tumors
Cardiogenic Shock
Chronic Bronchitis
Chronic Obstructive Pulmonary Disease
Emphysema
Farmer's Lung
Food Allergies
Food Poisoning
Heart Failure
Hereditary Angioedema
Hypersensitivity Pneumonitis
Irritable Bowel Syndrome
Pulmonary Embolism
Shock, Distributive
Sinusitis, Acute
Sinusitis, Chronic
Syncope
Upper Respiratory Tract Infection
Urticaria

Other Problems to be Considered

Aspergillosis
Nonallergic Rhinitis

Lab Studies

• Some laboratory tests may be helpful in determining whether a reaction is truly allergic in nature.
  
  
  • Obtaining a 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. A more sensitive type of RAST is known as the CAP-RAST (Pharmacia; Uppsala, Sweden) and has a greater positive predictive value for foods.

Other Tests

• Skin tests
• • 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 dropped. A positive reaction consists of a wheal and flare that occurs within 15-20 minutes.
  • 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.
  • 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 is only available for the major determinant, one of many possible allergens in the penicillins. While 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), these tests 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.
  • Inhalation challenge with histamine, methacholine, and specific allergen can be used to confirm airway hypersensitivity or allergen sensitivity.
• Nasal smear tests
• • A nasal smear can be performed to look for eosinophils.
  • Elevated eosinophil levels can be consistent with allergic rhinitis.

Medical Care

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).

• Anaphylaxis
• • 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).
• Allergic rhinitis
• • Avoid the offending allergen, if possible.
  • 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 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 (an H1-receptor blocker) and cromolyn (a mast cell stabilizer).
  • Nasal azelastine has the advantage of treating both allergic and nonallergic vasomotor rhinitis and also treating congestion. Topical nasal decongestants can provide immediate relief of nasal congestion and can be used temporarily. Patients should be cautioned not to use them for more than a few days, however, as they can cause rebound congestion (aka, 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 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. Regulatory T cells may also play an important role.
• Asthma
• • 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.
    • Long-acting beta-agonists and inhaled glucocorticosteroids should be added if appropriate. In general, these medications are used if symptoms occur more than twice weekly or if spirometry findings are abnormal in the absence of symptoms.
    • 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 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.^{6, 7}
• Urticaria/angioedema
• • 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.
• Atopic dermatitis
• • Avoid the offending allergen if possible, and properly hydrate and care for the skin.
  • Topical glucocorticosteroids and topical immunomodulators (eg, tacrolimus) can be used.

Consultations

• Consultation with a 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 rhinitis
  • 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.
  • Chronic urticaria or angioedema (>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)
  • Atopic dermatitis
  • Sinusitis before proceeding to surgery
  • Persistent or bothersome conjunctivitis
  • Eosinophilic esophagitis or gastritis
  • Suspicion of congenital or acquired immune abnormalities
  • Diagnosis and treatment of acquired immunoglobulin deficiencies

Diet

• 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).
  • 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.

Drug Category: Vasopressors

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.

Predosed autoinjectable epinephrine is now available in 2 forms: 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. EpiPen Duopacks contain 2 pens and, therefore, 2 doses. Twinject Two-packs contain 2 pens for a total of 4 doses.

Drug Name	Epinephrine (Adrenalin, Bronitin, EpiPen, Twinject)
Description	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).
Adult Dose	IM: 0.25-0.50 mL of a 1:1000 solution for moderate symptoms; repeat prn; anterior lateral thigh is preferred site for severe anaphylaxis; Self-injection (IM): Preloaded autoinjector (EpiPen or Twinject) IV: 0.5-1 mL of 1:10000 solution for severe symptoms; repeat prn; continuous infusion at 0.1-1 mcg/kg/min may be required for anaphylactic shock ET: 1 mL of 1:10,000 solution in 10 mL NS; repeat prn
Pediatric Dose	IM: 0.01 mg/kg of 1:1000 solution; repeat q5min prn; not to exceed 0.3-0.5 mg; anterior lateral thigh is preferred site for severe anaphylaxis Self-injection (IM): Preloaded autoinjector (EpiPen Jr or Twinject 0.15) IV: 0.01 mg/kg of 1:10000 solution; repeat prn ET: 0.01 mg/kg of a 1:1000 solution in 5 mL NS; repeat prn
Contraindications	Documented hypersensitivity; relative (not absolute) contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias
Interactions	Beta-blockers decrease effectiveness; may decrease effectiveness of diabetic medications; MAOIs, methyldopa, methylphenidate, TCAs, thyroxine, and sodium bicarbonate can potentiate effects of all sympathomimetics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Consult PDR for all possible adverse effects; caution should be used in patients with known severe CAD, advanced age, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias

Drug Category: Bronchodilators

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.

Pirbuterol is now available and is both a short- and long-acting form. 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. 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 is being 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. Once all previously manufactured CFC MDIs have been distributed, only HFA forms will be available. Importantly, note that, while a spacer should be used with traditional MDIs, spacers may not be necessary for certain HFA inhalers.

Drug Name	Albuterol (ProAir HFA, Ventolin HFA, Proventil HFA)
Description	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.
Adult Dose	1.25-5 mg in 2-5 mL of sterile 0.9% NS solution via nebulization 2-4 puffs via MDI q4-6h prn; not to exceed 12 puffs/d
Pediatric Dose	PO <2 years: Not established 2-5 years: 0.1-0.2 mg/kg/dose divided tid; not to exceed 12 mg/d 5-12 years: 2 mg/dose divided tid or qid; not to exceed 24 mg/d >12 years: Administer as in adults MDI <12 years: 1-2 puffs qid with tube spacer >12 years: Administer as in adults Nebulizer <5 years: 1.25-2.5 mg in 1-2.5 mL q4-6h; to make solution, dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS >5 years: Administer as in adults
Contraindications	Documented hypersensitivity; relative contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Anecdotally, has been used during pregnancy for approximately 40 y and detrimental effects have not been reported; consult PDR for all possible adverse effects; caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Drug Name	Fluticasone and Salmeterol (Advair)
Description	Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. Also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasms. Effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended.
Adult Dose	1 inhalation bid; not to exceed 500 mcg fluticasone/50 mcg salmeterol
Pediatric Dose	<4 years: Not established 4 to 12 years: 1 inhalation bid; not to exceed 100 mcg fluticasone/50 mcg salmeterol >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma, angina, tachycardia, and cardiac arrhythmias associated with tachycardia
Interactions	Coadministration of fluticasone with CYP450 3A4 isoenzyme inhibitors (eg, amprenavir, atazanavir, darunavir, delavirdine, fosamprenavir, indinavir, ketoconazole, nelfinavir, ritonavir, tipranavir) decreases fluticasone elimination and increases plasma fluticasone levels, case reports of iatrogenic Cushingoid symptoms have been reported Concomitant use of salmeterol with beta-blockers may decrease bronchodilating and vasodilating effects of beta agonists; concurrent administration of salmeterol with methyldopa may increase pressor response; coadministration of salmeterol with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia resulting from diuretics may worsen when coadministered with salmeterol
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Coughing, upper respiratory tract infection, and bronchitis may occur with fluticasone; not indicated to treat acute asthmatic symptoms; black box FDA warning describes that chronic use of salmeterol may result in increased asthma morbidity and mortality, use only as additional therapy for patients not adequately controlled on other asthma-controller medications (eg, low- to medium-dose inhaled corticosteroids) or patients whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including salmeterol

Drug Category: Corticosteroids

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.

Drug Name	Prednisone (Deltasone, Orasone, Meticorten)
Description	Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis. Doses below are general guidelines for usage; dosing is highly individualized.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; length and dose of therapy varies with severity of the condition being treated; doses must be tapered for patients on steroids for more than 14 days
Pediatric Dose	1-2 mg/kg PO qd or divided bid/qid; length and dose of therapy varies with severity of the condition being treated; doses must be tapered for patients on steroids for more than 14 days
Contraindications	Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Abrupt discontinuation after long-term use (4-6 wk) can result in adrenal insufficiency/crisis; although relatively safe for short-term usage, long-term use can result in undesirable adverse effects, including osteoporosis, cataracts, and weight gain; patients who are on long-term steroids should be placed on a bisphosphonate and calcium/vitamin D supplementation for osteoporosis prevention; consult PDR for all possible adverse effects; may worsen diabetes mellitus, congestive heart failure, infections, peptic ulcer disease, volume status, myasthenia gravis, and psychoses; hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications

Drug Category: Histamine1-receptor antagonists (antihistamines)

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 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.

Drug Name	Diphenhydramine (Benadryl, Dihydrex injection, Belix)
Description	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.
Adult Dose	12.5-50 mg PO/IV/IM q4-6h; not to exceed 400 mg qd
Pediatric Dose	<6 years: 5 mg/kg/d PO/IV; not to exceed 300 mg qd 6-12 years: 12.5-25 mg PO q6-8h; not to exceed 300 mg qd >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patients taking medications that can cause disulfiramlike reactions
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Warn patients to not drive or operate heavy machinery; administer with caution to elderly patients, patients with a seizure history, and children; can have additive adverse anticholinergic effects and can cause somnolence; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur; consult PDR for all possible adverse effects

Drug Name	Azelastine (Astelin)
Description	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).
Adult Dose	2 puffs/nostril (137 mcg/puff) bid
Pediatric Dose	<5 years: Not established 5-12 years: 1 puff/nostril (137 mcg/puff) bid >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Increases CNS toxicity of CNS depressant medications
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hepatic or renal dysfunction; doses higher than 10 mg/d may cause drowsiness

Drug Name	Cetirizine (Zyrtec)
Description	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.
Adult Dose	5-10 mg PO qd
Pediatric Dose	Oral syrup: <6 months: Not established 6-12 months: 2.5 mg PO qd 12-24 months: 2.5 mg PO qd-bid 2-5 years: 2.5-5 mg PO qd >5 years: 5-10 mg PO qd Chewable tablet: <2 years: Not established 2-5 years: For children taking cetirizine syrup 5 mg PO qd, may take chewable tablet at same dose (do not substitute 5 mg chewable tablets for children taking oral syrup 2.5 mg/d) >5 years and adults: 5-10 mg PO qd
Contraindications	Documented hypersensitivity
Interactions	Increases CNS toxicity of depressants
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in hepatic or renal dysfunction; doses higher than 10 mg/d may cause drowsiness

Drug Category: Histamine2- antagonists

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.

Drug Name	Ranitidine (Zantac)
Description	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.
Adult Dose	150 mg PO bid; not to exceed 600 mg/d; alternatively, 50 mg/dose IV/IM q6-8h
Pediatric Dose	<12 years: Not established >12 years: 1.25-1.5 mg/kg/dose PO q12h; not to exceed 300 mg/d; alternatively, 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; consult PDR for all possible adverse effects

Drug Category: Leukotriene inhibitors

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-receptor blockers, whereas zileuton acts to inhibit production of leukotrienes. Disadvantages of the latter medication are its qid dosing and the need to monitor liver enzymes.

Drug Name	Montelukast (Singulair)
Description	Leukotriene inhibitors can be a helpful addition to asthma and allergic rhinitis not well controlled with H1-receptor blockers and inhaled corticosteroids.
Adult Dose	10 mg PO qd
Pediatric Dose	<2 years: Not established 2-5 years: 4 mg PO qpm 6-14 years: 5 mg PO qpm >14 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Phenobarbital and rifampin reduce effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated to reverse acute asthma attacks; not for use as monotherapy in management of exercise-induced bronchospasm; consult PDR for all possible adverse effects

Drug Category: Immunomodulators

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.⁸ 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.

Drug Name	Tacrolimus (Protopic)
Description	Reduces itching and inflammation by suppressing release of cytokines from T cells. Can be used in patients as young as 2 y. More expensive than topical corticosteroids.
Adult Dose	Apply 0.03% ointment or 0.1% ointment to affected areas bid
Pediatric Dose	<2 years: Not established >2 years: Administer as in adults
Contraindications	Documented hypersensitivity to tacrolimus or components of ointment
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause burning sensation during first few days of application; skin can become photosensitive, and patients should be cautioned about exposure to direct or artificial sunlight and to use sunscreen; safety and efficacy in infected atopic dermatitis is not known; application under occlusion, which may promote systemic exposure, has not been evaluated (do not use with occlusive dressings); absorption following topical applications is minimal (relative to systemic administration), but tacrolimus is excreted in human milk, and thus, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother (potential for serious adverse reactions in nursing infants should also be a concern); consult PDR for listing of all adverse effects

Drug Category: Monoclonal antibodies

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.

Drug Name	Omalizumab (Xolair)
Description	Binds to IgE and thereby prevents IgE from binding to mast cells and basophils.
Adult Dose	Dependent on serum IgE level and body weight Serum IgE 30-100 30-90 kg: 150 mg SC monthly 90-150 kg: 300 mg SC monthly Serum IgE levels 101-200 30-90 kg: 300 mg SC monthly 90-150 kg: 225 mg twice monthly Serum IgE 201-300 30-60 kg: 300 mg monthly 61-90 kg: 225 mg twice monthly 91-150 kg: 300 mg q2wk Serum IgE levels 301-400 30-70 kg: 225 mg twice monthly 71-90 kg: 300 mg q2wk Serum IgE 401-500 30-70 kg: 300 mg q2wk 70-90 kg: 375 mg twice monthly Serum IgE 501-600 30-60 kg: 300 mg q2wk 61-70 kg: 375 mg q2wk Serum IgE 601-700 30-60 kg: 375 mg q2wk Manufacturer did not seek approval for dosing with IgE >700 or for IgE 601-700 for people weighing >60 kg because high resultant doses would be cost prohibitive
Pediatric Dose	>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	No formal drug interaction studies have been performed
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Not indicated to reverse acute asthma attacks; systemic or inhaled corticosteroids should not be abruptly discontinued with initiation of omalizumab; serum IgE levels increase after initiation of therapy because of omalizumab-IgE complex formation and may remain high up to 1 y after discontinuation; therefore, serum IgE levels should not be routinely checked; patients may have false-negative skin prick test and RAST results

Deterrence/Prevention

• 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).

Patient Education

• Patients with a known inciting agent should be advised in avoidance techniques, including immunologic cross-reactivity as is encountered in latex allergies.
• Patients must be educated in the proper use of their maintenance and rescue medications.
• For excellent patient education resources, visit eMedicine's Allergic Reaction and Anaphylactic Shock Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Severe Allergic Reaction (Anaphylactic Shock) and Hives and Angioedema.

Medical/Legal Pitfalls

• If an inciting agent is established, discussing the importance of antigen avoidance and possible outcomes in the event of reexposure is important.
• Patients with latex allergies must avoid all products containing latex (eg, gloves, balloons, condoms, elastic). Nonlatex gloves should be available at their place of employment (if applicable). If such a patient requires surgery, a latex-free operating room must be provided.
• If the patient reports a history of hives, angioedema, or anaphylaxis with any previous medication, medications from an alternative class should be used, if needed. If this is not possible, the patient should be referred to an allergist for desensitization to the medication. Administering a test dose of the medication without further evaluation is not safe.
• Patients with a history of anaphylaxis should be given a prescription for at least 2 doses of autoinjectable epinephrine (eg, 2 EpiPens or 1 Twinject) and instructed in their use. Importantly, they should carry these devices at all times. Prescribing multiple pens can be helpful so that patients can keep them readily available (eg, at work, at home, in purse/pocket). They also should be aware of the expiration dates of the pens so that new ones can be issued if needed. Liquid diphenhydramine should also be kept on hand and used in the event of a reaction. Patients should be cautioned against driving or operating heavy machinery, as diphenhydramine can cause drowsiness.
• Patients with a history of anaphylactic reactions to certain medications should get a Medi-Alert bracelet that indicates which drugs cause the reactions. This may also be helpful for patients with anaphylactic reactions to foods.

Special Concerns

• Pregnancy
• • Patients may experience improvement, worsening, or no change in the frequency and severity of allergic reactions during pregnancy.
  • No human studies have been performed with antihistamines. Currently, the first-generation sedating antihistamines (eg, chlorpheniramine, diphenhydramine [category B], cyproheptadine) are used in pregnancy if needed. Chlorpheniramine is available in a time-release formula (ie, bid dosing) and may cause less drowsiness than some of the others. Most of the nonsedating antihistamines are category C and should be avoided. However, cetirizine and loratadine are category B drugs, as is the leukotriene antagonist montelukast.
  • Systemic corticosteroids can be administered after the first trimester if necessary. Inhaled budesonide for the treatment of asthma is a category B drug. In addition, nasal and inhaled cromolyn and inhaled nedocromil are minimally absorbed and are considered safe. Both are category B. Terbutaline, but not albuterol, is also a category B drug.
• Elderly patients
• • Antihistamines can have adverse anticholinergic effects and therefore must be used with caution in elderly patients.
  • Adverse corticosteroid effects can be especially problematic for elderly patients because these patients are at greater risk for having or developing osteoporosis, cataracts, or GI ulcers.