Immediate Hypersensitivity Reactions

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Background

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

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

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

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

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

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

Pathophysiology

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

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by an antigen-presenting cell (APC), such as a dendritic cell, macrophage, or B-cell.[7, 8] The antigen-presenting cells then migrate to lymph nodes, where they prime naïve TH cells that bear receptors for the specific antigen.

After antigen priming, naïve TH cells differentiate into TH1, TH2, or TH17 cells based upon antigen and cytokine signaling. In the case of allergen sensitization, the differentiation of naïve TH cells is skewed toward a TH2 phenotype. These allergen-primed TH2 cells then release IL-4, IL-5, IL-9, and IL-13. IL-5 plays a role in eosinophil development, recruitment, and activation. IL-9 plays a regulatory role in mast cells activation. IL-4 and IL-13 act on B cells to promote production of antigen-specific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present peptides from it, bound to the major histocompatibility class II molecules found on B-cell surfaces, to the antigen receptors on TH2 cells. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production (see image below).


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Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:[9, 10]

Preformed mediators

Newly formed mediators

Arachidonic acid metabolites

Leukotrienes - Produced via the lipoxygenase pathway:

Cyclooxygenase products:

Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.

Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.

Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell–released heparin, has been described.[12, 13] Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.[4]

Cytokines

The collective biological activities of the aforementioned mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-72 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-allergic patient who owns a cat) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. Collectively, this results in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–mediated responses.[10]

Epidemiology

Frequency

United States

International

Approximately 300 million people worldwide are estimated to have asthma. Prevalence rates vary around the world and are estimated to be from 3-38% in children[18] and 2-12% in adults.[19]

The International Study of Asthma and Allergies in Childhood (ISAAC) is an epidemiological research program that was established in 1991 to evaluate asthma, eczema, and allergic rhinitis in children worldwide. The study is composed of 3 phases. Phase 1 used questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations in centers around the world. Most of this data was collected in the mid 1990s. Phase 2 was designed to assess possible etiological factors based on information gathered from Phase 1. Phase 3 is a repetition of Phase 1 to assess trends in prevalence.[20] Data from ISAAC show variations in the prevalence of allergic diseases between countries.

ISAAC researchers found significant variability in the prevalence of allergic rhinoconjunctivitis in children from 56 countries. Rates varied from 1.4-39.7% and, although sites varied, a general trend of increasing prevalence of allergic rhinoconjunctivitis was found over the 7 years between phases 1 and 3.[21]

Similar to other allergic diseases, the prevalence in atopic dermatitis varies widely between countries. Prevalence varies from 1.4% in China to 21.8% in Morocco, and prevalence is generally increasing.[21, 8]

Asthma, as with other atopic diseases, was previously increasing in prevalence.[22, 23] Data from a study from England suggest that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.[24] Hospital admissions for anaphylaxis, however, have increased by 600% over the past decade in England and by 400% for food allergy. Admission rates for urticaria increased 100%, and admission rates for angioedema increased 20%, which suggests that these allergic diseases may be increasing in prevalence.

Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations than in rural populations. This difference was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.[25]

Mortality/Morbidity

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

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

Race

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

Sex

Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys during the first decade of life;[6] after puberty, prevalence is higher in females.[9] The male-to-female ratio of children who have atopic disease is nearly 2:1.

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

Age

In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.[15]

Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in adults. Some food allergies, such as allergy to shellfish, may last a lifetime.

Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life (beginning in adolescence) and can also have asthma that is more severe.[9, 8]

History

History findings vary depending on which organ systems are affected.

Anaphylaxis

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.[30]

Allergic rhinoconjunctivitis

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.

Allergic asthma

In 2007, the National Asthma Education and Prevention Program (NAEPP) Expert Panel from the National Heart, Lung, and Blood Institute (NHLBI) released guidelines on the diagnosis and management of asthma. The classification of an asthmatic depends on the age of the patient (ages 0-4 years of age, 5-11 years of age, and 12 years and older).[31]

Asthmatics are classified into 4 groups: intermittent, mild persistent, moderate persistent, and severe persistent.[31] Each classification is based on severity. Severity is classified by risk (exacerbations requiring oral systemic corticosteroids) and impairment (symptoms, nighttime awakenings, interference with normal activity, short-acting beta2-agonist use [not for premedication before exercise], and lung function if able to perform spirometry).[31] These symptoms are assessed each visit to make medical decisions.

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.

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 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, the etiology is termed idiopathic.

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 exacerbates the lesions. Superinfection with staphylococcal organisms can occur, particularly in severely excoriated or cracked lesions.

GI allergies

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 possibly 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 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 have abdominal cramping, nausea, vomiting and/or diarrhea.

Allergic rhinoconjunctivitis

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.

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 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/angioedema

Urticaria occurs in the dermis of the skin from increased vascular permeability from the action of vasoactive substances released from mast cells and basophils.[8] It 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, may be painful, and may leave postinflammatory hyperpigmentation upon healing.

Angioedema is localized swelling of the deep dermis, subcutaneous or submucosal tissue secondary to vascular leak. Sites of angiodema are typically the lips, tongue, pharynx, cheeks, eyes, hands and feet, penis and scrotum, and/or bowel wall. If laryngeal edema is present, a diagnosis of idiopathic anaphylaxis should be entertained.

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, 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.

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.[32] Impaired function of Treg cells can also contribute to the development of atopic diseases.[33]

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.

Allergic reactions

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

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 non-IgE-mediated 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 40 Americans die each year from anaphylaxis caused by a stinging insect.

Non-IgE-mediated 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, profuse rhinorrhea, ocular itching/injection, skin erythema, angioedema, and even life-threatening anaphylaxis with hypotension and shock after ingestion.[8] 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.

Laboratory Studies

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, especially when food is the cause of anaphylaxis. Ideally, the tryptase level should be drawn within 4 hours after the event.

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.

In vitro assays that measure serum antigen-specific IgE (i.e., radioallergosorbent test [RAST], ImmunoCAP, Immunolite) 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.[34]

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, allergic asthma, food allergy, venom allergy and Penicillin drug allergy.

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 environmental allergen into the superficial dermis. ID tests have many more false positive reactions, and the clinical significance of a positive ID test is questionable. ID tests are used for drug allergy (Penicillin and local anesthetic skin testing) and venom allergy testing. ID tests are never used for food allergy testing.

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. No standardized food testing extracts are available.

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.

Skin tests are useful in identifying hypersensitivity to venom. Testing should only be performed in patients who have diffuse cutaneous symptoms and are ≥16 years old or in patients who have systemic symptoms. Unfortunately false-negatives do occur, but if testing is positive then venom immunotherapy can be life-saving.

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. It is important to remember readings from peak-flow meters are effort dependent. Personal spirometers that measure FEV1 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 as well as nonallergic rhinitis with eosinophilia syndrome (NARES).

Induced sputum: Sputum induced from the airways can be evaluated for eosinophils, which is a measure of inflammation seen in asthma.

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:

Treatment is as follows:

Prevention is as follows:

Allergic rhinitis

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).

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 or sterile saline 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 G4 to be formed and lowers antigen-specific IgE over time. It is thought to dampen the TH2 response. Some feel it also tips the balance of TH2 and TH1 towards a TH1 phenotype. Importantly, regulatory T cells play an important role through the production suppressive cytokines IL-10 and TGF-β.[35, 8]

An alternative to antigen-injection immunotherapy, aka, subcutaneous immunotherapy (SCIT), is sublingual/swallow immunotherapy (SLIT), which is used in Europe and has been approved by the FDA in the United States. The SLIT formulations approved for use in the US are Ragwitek, Grastek, and Oralair. The first dose of each tablet needs to be supervised by an allergist. Each patient should be prescribed and taught how and when to use auto-injectable epinephrine.

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 as well as age of patient. In 2007, the National Asthma Education and Prevention Program (NAEPP) Expert Panel from the National Heart, Lung, and Blood Institute (NHLBI) released guidelines on the diagnosis and management of asthma. These guidelines use a stepwise treatment approach based on age and severity of the asthmatic treated.[31]


View Table

See Table

Symptoms and SABA use should be reassessed after starting treatment. If patients are well-controlled for 3 months, step down therapy may be employed. Conversely, if a patient’s symptoms are not well-controlled, step up therapy is warranted.

All patients with asthma should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed for acute symptoms.

Patients with exercise-induced bronchospasm (EIB) should receive short-acting beta2-agonist treatment 15-20 minutes prior to exercise.

Systemic corticosteroid bursts may need to be used for exacerbations of severe cases.

Patients with allergic asthma may respond well to specific allergen immunotherapy. This is recommended from Steps 2-4 in patients 5 years or older.[31]

In patients 12 years or older refractory to the usual medications (Steps 5 and 6) who have antigen-specific IgE to perennial environmental aeroallergens, may benefit from therapy with omalizumab (Xolair), a humanized monoclonal antibody that prevents binding of IgE to high-affinity IgE receptors on mast cells and basophils.[39, 40, 41, 31]

Urticaria/angioedema

Avoid the offending allergen if known.

A second-generation H1-receptor blocker should be added for monotherapy (i.e., cetirizine 10 mg daily).[42]

If symptoms are not controlled with this alone, the dose of the second generation H1 antagonist can be increased up to four times the recommended dose (i.e., cetirizine 20 mg BID). Alternatively, another second generation H1 antagonist (i.e., fexofenadine) or a first generation H1 antagonist (i.e., hydroxyzine at bedtime) can be added. Other possible treatments with H2 antagonists or leukotriene modifiers can also be added.[42]

If symptoms continue to occur, increasing the first generation H1 antagonist may be helpful.[42]

Omalizumab has been found to be useful in patients with chronic urticaria refractory to high dose treatment with H1 antihistamines (ref60) and is now FDA approved for refractory chronic urticaria. In addition, other biologics such as cyclosporine.[42]

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.[43, 44]

Consultations

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:

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; tree fruits with birch pollen).

Patients must be counseled about these possible cross-reactivities and should avoid the food if it causes symptoms.

Medication Summary

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.

Epinephrine (Adrenalin, EpiPen, Auvi-Q, Adrenaclick)

Clinical Context:  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).

Class Summary

Epinephrine is the first medication that should be used 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.[45, 46]

Predosed autoinjectable epinephrine is available in at least 3 forms, which include EpiPen, Auvi-Q, and Epinephrine auto-injector. Two doses of each are available (0.3 mg for EpiPen, Auvi-Q, and Epinephrine auto-injector, and 0.15 mg for EpiPen Jr., Auvi-Q, or Epinephrine auto-injector). EpiPen, Auvi-Q, and Epinephrine auto-injectors all come in two-packs (i.e., 2 auto-injectors). Auvi-Q comes with a trainer and is only available in the English language.

Albuterol (ProAir HFA, Ventolin HFA, Proventil HFA)

Clinical Context:  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.

Salmeterol and fluticasone (Advair)

Clinical Context:  Salmeterol: Selective LABA; stimulates intracellular adenyl cyclase resulting in increased cAMP levels causing bronchial smooth muscle relaxation; also inhibits release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Fluticasone: Trifluorinated corticosteroid with potent anti-inflammatory activity; inhibits multiple cell types (eg, mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (eg, histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response.

Formoterol and budesonide (Symbicort)

Clinical Context:  Formoterol: Long-acting selective beta2-adrenergic agonist with rapid onset of action; acts locally as bronchodilator; stimulates intracellular adenyl cyclase, which results in increased cyclic adenosine monophosphate levels, causing relaxation of bronchial smooth muscle and inhibition of release of mast cell mediators.

Budesonide: Anti-inflammatory corticosteroid; has potent glucocorticoid activity and weak mineralocorticoid activity.

Formoterol and mometasone (Dulera)

Clinical Context:  Mometasone: Glucocorticoid; elicits local anti-inflammatory effects on respiratory tract with minimal systemic absorption.

Formoterol: Long-acting selective beta2-adrenergic agonist with rapid onset of action; acts locally as bronchodilator; stimulates intracellular adenyl cyclase, which results in increased cyclic adenosine monophosphate levels, causing relaxation of bronchial smooth muscle and inhibition of release of mast cell mediators.

Levalbuterol (Xopenex)

Clinical Context:  Used for treatment or prevention of bronchospasm. A selective beta2-agonist agent. Albuterol is a racemic mixture, while levalbuterol contains only the active R- enantiomer of albuterol. The S-enantiomer does not bind to beta2-receptors, but may be responsible for some adverse effects of racemic albuterol, including bronchial hyperreactivity and reduced pulmonary function during prolonged use.

Class Summary

Inhaled bronchodilators are beta-agonists that come in short- and long-acting forms. Short-acting bronchodilators (i.e., albuterol) 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 in conjunction with inhaled glucocorticoids and to help maintain bronchodilation over 12 hours. Long acting beta-agonists are not recommended as monotherapy and their use has been associated with asthma-related death.[47] The FDA has issued a “black box warning” on medications containing long-acting beta-agonists due to this concern. This “black box warning” remains controversial as treatment with an inhaled corticosteroid plus a long acting beta-agonist has been found to be safe and efficacious in the treatment of asthma.[48]

Pirbuterol and formoterol have both short- and long-acting activity. Onset of action is approximately 15 min, but effects last up to 12 hours. Again, 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.

Prednisone (Rayos)

Clinical Context:  Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis. Doses below are general guidelines for usage; dosing is highly individualized.

Methylprednisolone (A-Methapred, Medrol, Solu-Medrol, Depo-Medrol)

Clinical Context:  Potent glucocorticoid with minimal to no mineralocorticoid activity.

Modulates carbohydrate, protein, and lipid metabolism and maintenance of fluid and electrolyte homeostasis.

Controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level.

Dexamethasone (Baycadron)

Clinical Context:  Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis.

Prednisolone (Orapred, Millipred, FLo-Pred, Prelone)

Clinical Context:  Glucocorticosteroid; elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level.

Hydrocortisone (A-Hydrocort, Cortef, Solu-Cortef)

Clinical Context:  Glucocorticoid; elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, and reversing capillary permeability.

Class Summary

Immunosuppressing agents, such as corticosteroids, can decrease inflammation. They are particularly efficacious in the treatment of skin eruptions and bronchospasm. Additionally, the role of corticosteroids in anaphylactic shock is limited, although believed to help prevent delayed type of anaphylaxis.

Several different formulations are available. 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.

Fexofenadine (Allegra)

Clinical Context:  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.

Cetirizine (Zyrtec)

Clinical Context:  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 as sedation occurs in 10-15% of persons using cetirizine.

Levocetirizine (Xyzal)

Clinical Context:  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.

Desloratadine (Clarinex)

Clinical Context:  Long-acting antihistamine (H1 receptor antagonist). Selectively inhibits receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites.

Loratadine (Claritin, Alavert)

Clinical Context:  Long-acting antihistamine (H1 receptor antagonist). Selectively inhibits receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites.

Azelastine (Astepro)

Clinical Context:  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).

Olopatadine (Patanase)

Clinical Context:  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).

Class Summary

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. The use of sedating antihistamines are discouraged because the nonsedating antihistamines, such as cetirizine and fexofenadine, are highly efficacious with reduced central nervous system side effects. Other nonsedating antihistamines include loratadine (not as efficacious as cetirizine or fexofenadine), levocetirizine, and desloratadine. Intranasal antihistamines azelastine and oloptadine can directly help with nasal congestion. Liquid forms are more rapidly absorbed orally and should be used for immediate treatment of an allergic reactionif intravenous access is not available.

Ranitidine (Zantac)

Clinical Context:  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.

Famotidine (Pepcid, Heartburn Relief Max)

Clinical Context:  Blocks H2 receptors of gastric parietal cells, leading to inhibition of gastric secretions. 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.

Class Summary

Can be administered in addition to H1-receptor blockers for additional control of urticaria and angioedema. Examples include ranitidine, famotidine, and cimetidine. Even though cimetidine has been studied more extensively for this indication than other members of this class, ranitidine and famotidine should be used given the significant drug interactions of cimetidine with other medications.

Montelukast (Singulair)

Clinical Context:  Leukotriene inhibitors can be a helpful addition to asthma and allergic rhinitis not well controlled with H1-receptor blockers and inhaled corticosteroids.

Zafirlukast (Accolate)

Clinical Context:  Leukotriene pathway inhibitor. Not for use in acute episodes of asthma.

Class Summary

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 inhibits 5-lipoxygenase thereby inhibiting the production of all the leukotrienes (leukotrienes B4, C4, D4, and E4). A disadvantage of zileuton is potential liver toxicity; liver enzymes should be drawn before the institution of therapy and periodically thereafter. A sustained release formulation of zileuton is available, permitting q12 h dosing.

Tacrolimus ointment (Protopic)

Clinical Context:  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.

Pimecrolimus (Elidel)

Clinical Context:  Calcineurin inhibitor; inhibits T-cell activation; also shown to inhibit release of inflammatory mediators from mast cells.

Class Summary

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.[43] 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)

Clinical Context:  Binds to IgE and thereby prevents IgE from binding to mast cells and basophils.

Class Summary

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 improve urticaria in patients with chronic idiopathic or spontaneous urticaria recalcitrant to standard licensed doses of H1 antihistamines.[49] Additionally, omalizumab has also been shown to decrease allergic response to peanuts in patients with severe peanut allergy[50] , which could be helpful in preventing anaphylaxis from accidental peanut exposure. To date, omalizumab does not have FDA approval for peanut allergy but is approved for asthma and chronic idiopathic urticaria. Patients should undergo a full allergy evaluation prior to starting omalizumab, if needed, because it interferes with prick skin test and in vitro serum specific IgE assay results.

Zileuton (Zyflo, Zyflo CR)

Clinical Context:  Inhibitor of 5-lipoxygenase, which inhibits formation of LTB4, LTC4, LTD4, & LTE4

Inhibition of leukotriene formation reduces eosinophil and neutrophil migration, neutrophil and monocyte aggregation, capillary permeability, and smooth muscle contraction.

Class Summary

These agents inhibit leukotriene formation.

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). Allergen-specific immunotherapy is known to be disease modifying for aeroallergens and stinging insect venom.

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

John M Routes, MD, Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics, Chief, Section of Allergy and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Specialty Editors

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; siRNAx, 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.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy

Disclosure: Teva Honoraria Speaking and teaching; Meda Honoraria Speaking and teaching; genentech Honoraria Speaking and teaching; sunovian Consulting fee Consulting

Additional Contributors

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

Miriam K Anand, MD, FAAAAI, FACAAI is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, and American Medical Association

Disclosure: TEVA pharmaceuticals Honoraria Speaking and teaching

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Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

AgeStep 1Step 2Step 3Step 4Step 5Step 6
0-4 yearsSABA PRNLow-dose ICSMedium-dose ICSMedium-dose ICS plus LABA or montelukastHigh-dose ICS plus LABA or montelukastHigh-dose ICS plus LABA or montelukast and oral corticosteroids
5-11 yearsSABA PRNLow-dose ICSLow-dose ICS plus LABA or LTRA or theophyllineMedium-dose ICS plus LABAHigh-dose ICS plus LABAHigh-dose ICS plus LABA plus oral corticosteroids
12 years or olderSABA PRNLow-dose ICSLow-dose ICS plus LABA or medium-dose ICSMedium-dose ICS plus LABAHigh-dose ICS plus LABAHigh-dose ICS plus LABA plus oral corticosteroids