Allergic and Environmental Asthma

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Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased bronchial reactivity, and airway inflammation. Asthma results from complex interactions among inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous system. In genetically susceptible individuals, these interactions can lead the patient with asthma to symptoms of breathlessness, wheezing, cough, and chest tightness.

Causes or triggers of asthma can be divided into allergic and nonallergic etiologies. Aeroallergens can include seasonal pollen, mold spores, dust mites, animal allergens, and food (especially in children). Monosodium glutamate does not appear to be an allergen. ^{[1, 2, 3]}

Nonallergic causes of asthma can include smoke, odors, cold air and weather, chemicals, medications (eg, aspirin and other nonsteroidal anti-inflammatory drugs [NSAIDs)], beta-blockers), exercise, hormonal changes (eg, pregnancy, menstrual cycle), and bisulfite food additives.

Genetic differences may alter susceptibility to asthma, as well as responsiveness to asthma medications. ^[4] Significant genetic variation exists between and within racial and ethnic groups, but the issue is confounded by important coexisting economic, cultural, and environmental differences, including geography (place of birth). ^[5]

Go to Pediatric Asthma, Status Asthmaticus, Exercise-Induced Asthma, and Asthma in Pregnancy for complete information on these topics.

In the United States, asthma is annually responsible for 1.5 million emergency department visits, 500,000 hospital admissions (third leading preventable cause), and 100 million days of restricted activity. Medical expenses, as well as lost work and productivity, cost an estimated $12.7 billion in 1998. In Western countries, the financial burden on patients ranges from $300 to $1,300 per patient year, increasing with more severe disease.

Worldwide, economic costs for asthma are more than those for tuberculosis and acquired immunodeficiency syndrome (AIDS) combined. Cost is associated with disease severity ^[6] ; more than half of all expenditures are attributed to the 10-20% of patients with the most severe disease.

Risk factors for asthma include a family history of allergic disease, the presence of allergen-specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, cigarette smoke, obesity, and lower socioeconomic status.

A recent study by Zhang et al suggests that those children who are genetically predisposed to asthma may be at an even higher risk if they are overweight beyond infancy. ^[7]

Data from the Prevention of Allergy: Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) Study and the Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community Advanced (GABRIELA) Study reinforce the concept of the hygiene hypothesis. ^[8] Using a cross-sectional design, the authors compared children living on farms to those in a reference group with respect to the prevalence of asthma and to the diversity of microbial exposure. The studies found that children who lived on farms had a lower prevalence of asthma and atopy and were exposed to a greater variety of environmental microorganisms than children in the reference group. The diversity of microbial exposure was inversely related to the risk of asthma (odds ratio for PARSIFAL, 0.62; 95% confidence interval [CI], 0.44-0.89; odds ratio for GABRIELA, 0.86; 95% CI, 0.75-0.99).

Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through different pathways, the resulting effects all lead to increased bronchial reactivity.

The importance of allergy in asthma has been well established. For example, exposure to dust mites in the first year of life is associated with later development of asthma and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization have been shown to increase asthma morbidity.

Allergies trigger asthma attacks in 60-90% of children and in 50% of adults. Approximately 75-85% of patients with asthma have positive (immediate) skin test results. In children, this sensitization is associated with disease activity.

Although most people with asthma have aeroallergen-induced symptoms, some individuals manifest symptoms with nonallergic triggers. About 3-10% of people with asthma are sensitive to NSAIDs. Approximately 5-10% of people with asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms after viral respiratory tract infections.

Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms, pulmonary function test findings, and airway hyperreactivity (AHR) improve with avoidance of environmental allergens. Removing even 1 of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures.

The etiology of asthma is likely multifactorial. Genetic factors may control individual predispositions to asthma. Genetics may also be associated with responses to medications. Variation in the beta-adrenergic receptor gene of the Arg-Arg type has been associated with adverse responses to inhaled, short-acting beta-agonist inhalers.

Genetics alone, however, cannot account for significant increases in asthma prevalence (see Epidemiology, below), as genetic factors take several generations to develop, and asthma and atopy are not always co-inherited.

One theory to explain the increased prevalence of allergic disease is that, with fewer infectious stimuli in the environment, the in utero T_H 2 allergic cytokine state never switches to the T_H 1 state.

The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes, following inhalation of the allergen.

Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to 10 hours later, a late allergic response may occur, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.

Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced by cytokines to develop into T_H 1 (ie, by interferon-gamma, interleukin [IL]–2) or T_H 2 (ie, by IL-4, IL-5, IL-9, IL-13) cells. Regulatory T cells (Treg) appear to play an important role in T_H 2-cell response to allergens. Allergens drive the cytokine pattern toward T_H 2, which promotes B-cell IgE production and eosinophil recruitment.

Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and basophils; with subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell and basophil. Preformed mast-cell mediators, such as histamine and proteases, are released, leading to the EAR.

Newly formed mediators, such as leukotriene C₄ and prostaglandin D_2, also contribute to the EAR.

Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha [TNF-α]) are released from mast cells and are generated de novo after mast-cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings.

The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway.

The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients.

Prevalence in the United States

The general prevalence of asthma is difficult to determine, because definitions and survey methods vary, but the incidence of the condition appears to be on the rise. The disease’s prevalence has been estimated as 10.9%, with asthma affecting more than 22 million people, including more than 6 million children. ^{[9, 4]}

International prevalence

Global Initiative for Asthma (GINA) researchers noted that, with regard to asthma in general, there have been increases in prevalence, morbidity, mortality, and economic burden over the past 40 years, especially in children. ^[9] Asthma affects more than 300 million people worldwide, and some reports suggest that asthma prevalence is increasing by 50% every decade. ^[9]

The highest recorded prevalences of asthma outside North America are in the United Kingdom (>15%), New Zealand (15.1%), and Australia (14.7%). ^[10]

In the United States, mortality from asthma in general has increased, especially in children who live in inner-city areas, despite advances in disease understanding and therapy. The number of asthma-related deaths annually in the United States decreased from 5067 (1960-1962) to a low of 1870 (1975-1978), and then increased to 5429 (1993-1995).

Hospitalization and death rates are 50% higher for African American adults than white adults and 150% higher in children.

Worldwide, approximately 180,000 deaths annually are attributed to asthma; most deaths occur in persons older than age 45 years.

Increased morbidity is multifactorial; morbidity may be increased by increased exposure to indoor allergens, less exposure to viral infections early in life, more environmental pollution, overuse of short-acting beta-2 agonists, underuse of anti-inflammatory medications, and limited access to or education about health care.

Boys have been shown to be at greater risk for asthma than girls. In children younger than 14 years, the prevalence of asthma is twice as high in boys as it is in girls.

This difference narrows with age, however; women aged 40 years have a greater prevalence of asthma than do men of the same age.

Disease onset can occur in people of any age, but children often present when younger than 6 years. Asthma is one of the most common chronic diseases of childhood. ^{[11, 12]}

All patients should be asked about or should undergo assessment regarding exacerbation of asthma symptoms.

Assessments should be made regarding the following, when examining symptom exacerbation patients with perennial asthma symptoms:

Pet in the home (especially in the bedroom and/or bed)

School, day care, or work environment

Moisture, dampness, and humidifier use

Mold and musty odors in any part of the home

Cockroaches in the home

It should be determined whether the patient’s symptoms worsen after the patient vacuums rugs (a typical sign of dust mite allergen).

Assessments should be made with regard to the following, when looking at symptom exacerbation in patients with seasonal asthma symptoms (which may extend beyond 1 season in temperate or tropical climates):

Early spring – Trees

Late spring and summer – Grasses

Summer and fall – Dry molds

Fall – Weeds

Assessments should be made regarding the following, when looking at symptom exacerbation in patients who may have environmentally related asthma:

Personal or secondary tobacco smoke exposure in or out of the home

Gas-burning stoves, fireplaces, or heaters used in the home

Sprays or chemical agents at work, home, or with hobbies

Symptoms only at 1 place (ie, at work during week with no symptoms on weekends)

School or business associates with similar problems

Symptoms after eating (dried, canned, or processed food)

Medications, such as beta blockers (including eye drops), aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs)

Physical examination findings are often normal.

Nasal mucosal swelling, discharge, polyps, or sinus percussion tenderness may suggest associated allergic rhinitis or sinusitis. Wheezing heard only or mostly over the neck may suggest vocal cord dysfunction (VCD) or other laryngeal abnormality, although VCD can be present without a localizing wheeze. Increased jugular venous distension may point to an alternative explanation, such as heart failure, for the patient’s dyspnea and wheezing. Similarly, palpation of cervical or supraclavicular adenopathy would suggest malignancy, sarcoidosis, or infection.

Findings are normal. Patients with status asthmaticus may have a pulsus paradoxus greater than 10 mm Hg. A murmur, S3 gallop, or rub suggests a cardiac problem and not asthma.

During an acute asthma exacerbation, lung examination findings may include wheezing, rhonchi, hyperinflation, or a prolonged expiratory phase. With severe disease, lung auscultation may reveal absent breath sounds (indicating poor air movement) or signs of respiratory distress and failure (eg, nasal flaring, grunting, accessory muscle use, cyanosis). Focal wheezing may indicate foreign body or other airway obstruction, such as a tumor.

Check the patient for atopic dermatitis.

Digital clubbing should not be present. Edema should also not be present. If edema is found, this suggests right- or left-sided heart failure.

Alpha1-Antitrypsin Deficiency

Aspergillosis

Bronchiolitis

Bronchitis

Chronic Bronchitis

Congestive Heart Failure and Pulmonary Edema

Emphysema

Foreign Body Aspiration

Immunoglobulin G Deficiency

Mixed Connective-Tissue Disease

Polymyositis

Pulmonary Embolism

Sarcoidosis

Sinusitis, Chronic

Undifferentiated Connective-Tissue Disease

Vascular Rings

Vocal Cord Dysfunction

Conditions that can mimic the symptoms of asthma include the following ^[13] :

Alpha1-antitrypsin deficiency

Aspergillosis

Bronchiolitis

Bronchitis

Chronic bronchitis

Congestive heart failure and pulmonary edema

Emphysema

Foreign body aspiration

Immunoglobulin G deficiency

Mixed connective-tissue disease

Polymyositis

Pulmonary embolism

Sarcoidosis

Chronic sinusitis

Undifferentiated connective-tissue disease

Vascular rings

Vocal cord dysfunction

In children and young adults, the following conditions can also have symptoms similar to those of asthma:

Vocal cord dysfunction

Cystic fibrosis

Congenital cardiac anomalies

Pulmonary anomalies

Pertussis

Primary ciliary dyskinesia

Tracheomalacia/bronchomalacia

Habit-cough syndrome

Hyperventilation

Exercise-induced supraventricular tachycardia

Exercise-induced laryngomalacia

Viral infections

In adults, the following conditions can also mimic asthma:

Vocal cord dysfunction

Gastroesophageal reflux

Post-infectious reactive airways disease (usually lasts less than 6 months)

COPD/emphysema

Congestive heart failure

Pulmonary embolism

Bronchiectasis

Hypersensitivity pneumonitis

Aspiration

Cystic fibrosis

Chronic eosinophilic pneumonia

Endobronchial tumor or other obstructing lesion

Churg-Strauss syndrome (allergic angiitis and granulomatosis)

Allergic bronchopulmonary aspergillosis

Reactive airways dysfunction syndrome

With regard to the last item above, reactive airways dysfunction syndrome is a distinct entity caused by exposure to a single, large, inhaled agent leading to asthma symptoms within 24 hours and lasting 3 months or longer.

Elderly patients frequently have medical conditions that can mimic asthma.

Symptom improvement with asthma therapy is suggestive, but not diagnostic, of asthma. Symptoms alone do not necessarily reflect asthma severity. Infants may be treated empirically. In patients older than 5 years, however, objectively demonstrating reversible airflow obstruction with pulmonary function tests, if possible, is essential.

In infants and children younger than age 4 years, pulmonary function tests are difficult to perform, because cooperation can be limited and reference ranges are not standardized.

Go to Peak Flow Rate Measurement for complete information on this topic.

Obstruction is defined as a ratio of less than 70% of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC). FEV₁ is normally greater than 80% of values predicted by age. However, some have suggested alternative methods of definigdefining obstruction in pulmonary tests. ^{[14, 15]}

Young patients with a supranormal FVC can sometimes have a reduced FEV₁/FVC ratio without having obstructive lung disease. Reversibility can be shown by administering a short-acting beta-2 agonist inhaler with a resultant 12% and more than 200-mL improvement in FEV₁ or FVC. ^[16] If no response occurs, 2-3 weeks of oral or inhaled corticosteroids (20 mg twice daily for the average patient) may be required to demonstrate an improvement in airflow. Note that airflow obstruction in some patients with chronic obstructive pulmonary disease may be partially reversible.

Relative annual risk of exacerbations may be related to FEV₁. A 15% drop in FEV1 after 6 minutes of running or other exercise can be diagnostic of exercise-induced bronchospasm. A 20% variation in the peak expiratory flow rate (PEFR) between high and low values is highly suggestive of asthma, but formal pulmonary function testing (as above) is recommended, because the PEFR is extremely effort-dependent.

Skin testing is one of the most useful ways of determining specific allergen sensitivity. Such tests for allergen-specific IgE are necessary if the clinician is to provide informed advice to patients about allergen avoidance techniques; they are also necessary for planning allergen immunotherapy regimens.

Skin tests have the advantage of being immediately available and visible to patients, which may reinforce to patients the need for environmental control and, possibly, immunotherapy.

Skin testing is recommended for antigens to which the patient is exposed rather than testing with a standard panel. Skin test findings have a fairly high false-positive rate but a very good negative predictive value. Thus, a positive test result does not mean that a patient is currently being exposed to an allergen or that he or she will react to it in a natural exposure. A negative test result generally rules out the possibility that an allergen is having an impact on the patient’s asthma. ^[17]

Antihistamine medications and tricyclic antidepressants (TCAs) interfere with allergy skin testing; short courses of oral glucocorticoids at moderate doses do not.

Testing should not be performed during an asthma exacerbation, and the testing site should be equipped for the treatment of rare, life-threatening reactions.

Skin testing is performed with controls (eg, histamine and saline) to avoid false-positive (dermatographism) or false-negative results. Identification of allergen triggers can assist in formulating an environmental control strategy, titration of therapy (ie, seasonal exacerbation), or an immunotherapy regimen.

Blood tests (in vitro) for allergen-specific IgE, such as the radioallergosorbent test (RAST), may be used in place of skin testing if dermatologic disease is generalized, if antihistamine or TCA use cannot be suspended (which affects skin testing but not in vitro testing), or if skin testing is relatively contraindicated. However, skin testing is more specific, more sensitive, and usually less expensive than in vitro testing.

The serum IgE level is elevated only approximately half the time in patients with allergic disease. Obtaining an IgE level is not indicated in most patients with asthma, although levels greater than 1000 ng/mL (1 IU= 2.4 ng) may suggest an alternate diagnosis, such as allergic bronchopulmonary aspergillosis. Confounding illness, such as atopic dermatitis, may also result in high IgE levels.

A study that explored immunological determinants associated with severe refractory asthma found that the mean level of enterotoxin-specific IgE was 3-fold higher in patients with severe asthma compared with patients with nonsevere asthma (P = 0.01). ^[18] It was also significantly associated with low respiratory function parameters (FEV₁, FEV1/FVC, and MEF 25/75) and increased airway reversibility in response to albuterol. This suggests a role for staphylococcal enterotoxins in the asthma pathogenesis.

Sputum and serum eosinophilia tests are not routinely performed or required for diagnosis, although some authors have found that they are useful for guiding therapy. Decrease in sputum eosinophilia may suggest asthma control or responsiveness to inhaled steroids. However, a study of 50 patients with allergic asthma found no significant correlation between sputum eosinophils measured 7 and 24 hours after bronchoprovocation and early or late bronchoconstrictor responses. ^[19]

Note that a finding of greater than 1000 eosinophils per microliter of peripheral blood can indicate parasitic infestation, drug allergies, or eosinophilic pulmonary disorders, such as allergic bronchopulmonary aspergillosis or Churg-Strauss syndrome.

Staining nasal secretions with Hansel stain is sometimes used to assess for nasal eosinophilia, but the sensitivity and specificity of this stain are low.

Exhaled nitric oxide (eNO) levels correlate with eosinophilic airway inflammation and are reduced by corticosteroid therapy. However, in a large, randomized trial of inner-city adolescent asthma patients, using eNO to guide medication decisions resulted in higher doses of inhaled corticosteroids being given without clinically important improvements in symptomatic asthma control. ^[20]

Exhaled breath condensate and exhaled breath temperature are also novel biomarkers that have been studied.

In older patients, an elevated serum brain natriuretic peptide (BNP) level may help to indicate heart failure as a primary or contributing cause of dyspnea and wheezing.

An asthma specialist can perform bronchoprovocation testing with exercise, histamine, methacholine, or eucapnic voluntary hyperventilation. The results from these tests have a very high negative predictive value and are useful for excluding the diagnosis of asthma.

The most common challenge is with increasing doses of inhaled methacholine. A 20% decline in FEV₁ with a methacholine concentration of 8 mg/mL or less is considered a positive (abnormal) test result. This testing should be avoided during pregnancy, because of the risk of precipitating an asthma attack and because methacholine is a class C drug (ie, fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus).

These are taken only if pneumonia, large airway lesions, or heart failure is suggested; if symptoms are atypical or refractory to therapy; if the patient has unilateral or focal wheezing; or if the patient has new adult-onset asthma symptoms.

Go to Imaging in Asthma for complete information on this topic.

Consider computed tomography (CT) scans of the sinuses if chronic sinusitis is suggested. About 65% of people with severe asthma have concomitant sinusitis.

These are indicated in select patients to help exclude interstitial lung disease, bronchiectasis, bronchiolitis, or infection.

These are performed if congestive heart failure is suggested based on history and physical examination findings.

Allergen-inhalation challenges can be performed in selected patients but are generally not needed or recommended. This test requires an available allergen solution and specialized centers able to handle potentially significant reactions. A negative test finding may allow continued exposure to an allergen (eg, family pet); a positive test finding can dramatically indicate that the patient should avoid a particular allergen. This test is often needed to help diagnose occupational asthma.

A trial of allergen avoidance may be diagnostic and therapeutic, but because it is difficult or impossible to avoid most allergens completely, failure to improve with an attempt at allergen avoidance cannot rule out the presence of an allergy to those allergens.

If restrictive or other lung disease is suggested by history, physical examination, or pulmonary function testing findings, additional data must be obtained, including complete lung volumes, respiratory muscle strength, diffusion capacity, and a high-resolution CT scan.

The goals of treatment are to minimize symptoms, improve quality of life, decrease the need for urgent care or hospitalizations, normalize pulmonary function test results, and decrease the inflammatory process that leads to airway remodeling.

Guidelines from the National Heart, Lung, and Blood Institute ^[4] have simplified classifications so that FEV₁ or peak flow < 40% predicted indicates severe asthma exacerbation/potential benefit of adjunctive therapies, and that >70% is a goal for discharge from the emergency care setting. ^[21]

Severe exacerbations require standard care that includes supplemental oxygen (goal PaO₂ >60 mm Hg, arterial oxygen saturation >90%); systemic intravenous/oral corticosteroids (doubling the dose of inhaled corticosteroids is not effective ^{[22, 23]} ); nebulized medications, including levalbuterol and nebulized anticholinergics; intravenous fluids; and even noninvasive or invasive ventilatory support if needed.

Magnesium sulfate, heliox (helium-oxygen gas mixture), or both can be used, but such treatment has not been systematically shown to be helpful. Antibiotics offer no added benefit during an asthma exacerbation but are often given if pneumonia is suspected.

The most important facet of medical care is the use of anti-inflammatory medications (usually, inhaled corticosteroids) in patients at all stages beyond mild intermittent asthma. Even the use of such medications in children improves many outcomes, including quality of life, although it does not, as had initially been hypothesized, appear to affect the natural history of the disease. ^{[24, 25, 26, 27]}

These medications do not appear to cause significant adverse effects at moderate doses (eg, on growth, bone density, eyes, adrenal sufficiency). Unfortunately, in some series, fewer than half of the patients admitted to the hospital for asthma were receiving or taking their recommended anti-inflammatory medications (this was likely an issue of adherence as well as prescription).

The safety of long-acting beta agonists has been questioned because of SMART (the Salmeterol Multicenter Asthma Research Trial). In this study, which involved approximately 25,000 patients, respiratory- and asthma-related deaths were greater in the group that received salmeterol than in the placebo group (although this signal was statistically significant only in African Americans). ^[28]

Most experts continue to recommend the addition of long-acting beta agonists when disease is not adequately controlled by low-dose, inhaled corticosteroids, but they stress that long-acting beta agonists should not be used without inhaled corticosteroids. Medications that combine both drugs in a single delivery device in an effort to increase patient convenience, compliance, and possibly safety, include Advair (fluticasone and salmeterol) and Symbicort (formoterol and budesonide).

Patients should be counseled about the SMART findings whenever an inhaler containing these medications is prescribed.

A combination of an inhaled corticosteroid and long-acting beta agonist (STAY trial, using budesonide/formoterol ^[29] ) for maintenance and reliever medication in patients with moderate to severe asthma may lower the risk of severe exacerbations, reduce the need for systemic steroids, and improve symptoms, compared with a fixed maintenance dose of a similar medication or a 4-fold increase in the inhaled corticosteroid dose. ^[30] In patients with inadequately controlled severe allergic asthma who are receiving high-dose ICS and long-acting beta agonists, omalizumab provided additional clinical benefit. ^[31]

Elderly patients are more likely to experience adverse effects from asthma medications.

Note:  In December 2008, an advisory panel to the FDA voted to ban 2 long-acting beta agonists (LABAs)—Serevent (salmeterol) and Foradil (formoterol)—as monotherapy (meaning by itself, without inhaled corticosteroids also) for treating asthma in adults and children. ^[32] This guidance will likely apply to other medications in the same class, such as arformoterol (Brovana).

Serevent and Foradil will remain on the market to treat chronic obstructive pulmonary disorders. The panel also voted to continue allowing the use of Symbicort (formoterol plus budesonide) and Advair (salmeterol plus fluticasone), as these drugs contain LABAs and steroids (as discussed above).

In February 2010, the FDA announced additional safety controls regarding the use of LABAs. As previously announced, these medications should never be used as monotherapy to treat asthma in children or adults. The additional safety controls also institute labeling requirements for manufacturers, including recommendations that LABAs, even as combination therapy, should be used for the shortest possible duration. For more information, see the FDA news release. ^[33]

In 2017, the FDA removed box warnings about the possibility of asthma-related death from asthma and COPD inhalers delivering fixed-dose combinations of ICS and LABA drugs. The removal comes after an FDA review of four large clinical safety trials which showed no increase in serious asthma-related side effects with the ICS/LABA fixed-dose products than with ICS agents alone. ^[34]

Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on this topic.

Allergen avoidance takes different forms, depending on the specific allergen size and characteristics. Improvement in symptoms after avoidance of the allergen should result rather rapidly, although the allergen itself (eg, cat dander) may linger in the environment for months after primary removal of the source. A multifaceted approach is necessary, as individual interventions are rarely successful by themselves.

Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their home regularly. If a patient cannot avoid vacuuming, he or she should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. If possible, consideration should be given to moving to a higher floor in the house (less dust and mold) or a different neighborhood (fewer cockroaches).

Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven to be effective for people with chronic asthma, and the generation of ozone by these machines may be harmful to some. Specific factors related to the home are described below.

Guidelines on work-related asthma from the European Respiratory Society advocate exposure elimination as the preferred primary prevention approach, with reduction to exposure as the next best option. A screening and surveillance program should be established for workers at risk of asthma. ^[35]

The primary allergen associated with dust mites is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not very effective.

Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters, the most important intervention), washing other bedding in hot water (the most effective temperature being 130°F [54.4°C]), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Other measures include minimizing the number of soft toys and either washing them weekly or periodically putting them in the freezer. Decreasing room humidity (< 50%) is another means of reducing exposure to avoid dust mites.

Conclusions from a Cochrane Review study indicated that acaricides and extensive, bedroom-based environmental control programs may help to reduce rhinitis symptoms. If such measures are considered appropriate, they should be the interventions of choice. However, analysis also indicated that the isolated use of bedding that is impermeable to house dust mites is not likely to be effective in reducing rhinitis symptoms caused by dust mites. ^[36]

Because of its small size, this allergen is predominantly an airborne, indoor type. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly. Antigen may remain in a home for 6 months or more after cats are removed from the home, and cat antigen may be found in homes and offices where cats were never present, highlighting the importance of frequent cleaning.

Twenty percent of homes without visible infestation still produce sensitizing levels of allergen. Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.

Avoidance includes keeping areas dry (eg, removing carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.

Avoidance is difficult or impossible, but efforts to reduce exposure include closing windows and doors; using air conditioning and high-efficiency particulate air filters in the car and home; staying inside during the midday and afternoon, when pollen counts are highest; wearing glasses or sunglasses; wearing a face mask over the nose and mouth when mowing the lawn; and, if possible, vacationing in a different ecosystem during pollen season.

Pollen may increase sensitivity to other airborne allergens, possibly because its protease enzymes make epithelial membranes more permeable by disrupting their transmembrane adhesion proteins, according to a European study. ^[37]

Consider increasing medications preseason.

The use of repeated injections of small doses of allergen is effective in treating allergic rhinitis, and positive effects may persist even years after treatment has been stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting (hymenoptera venom) reactions. ^[38]

The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.

Supporters of this treatment for asthma argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis). The acquisition of new sensitivities can be reduced or eliminated with the use of immunotherapy in monosensitized or oligosensitized children.

In a 2003 meta-analysis of 75 randomized, controlled trials, Abramson et al reported that immunotherapy decreased asthma symptoms and the need for medication. ^[39] Another study showed improved PEFR and decreased use of medications in a highly selected group of children, but only for the first year of therapy.

Despite the fact that the cost may be $800 for the first year and $170 per year thereafter (1996 estimate), a study designed to evaluate the cost-effectiveness of subcutaneous immunotherapy (SCIT) in addition to symptomatic therapy (ST) compared with ST alone found that all patients receiving SCIT demonstrated improved medical outcomes and cost savings. ^[40]

Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms; the individual is sensitized (ie, positive skin test or RAST findings); the allergen cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy, and a vaccine to the allergen is available. This treatment is especially useful if the asthma is associated with allergic rhinitis.

Referral to an allergist is required. The patient must commit to a course of 3-5 years of therapy (although a trial of several months can be considered).

Risks in allergen immunotherapy include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate from this treatment is 0.7 deaths per million population. Uncontrolled asthma is a major risk factor for immunotherapy-related death; therefore, appropriate caution should be exercised.

Monitoring and resuscitation personnel and equipment are required in allergen immunotherapy.

Allergen immunotherapy should be avoided if the patient is taking beta blockers or is having an asthma exacerbation (ie, PEFR < 70% of patient’s personal best) or has moderate or worse fixed obstruction.

Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but “major allergen content” may be a more standardized and reliable method of dosing and for characterizing allergen extracts; however, not all allergens have been standardized.

Extracts with modifications that decrease allergenicity (adverse reactions) without reducing immunogenicity (effectiveness) are under investigation.

Sublingual immunotherapy has been shown to improve allergic rhinitis symptoms (including in pediatric patients) and allergic asthma. While adverse reactions do occur, sublingual immunotherapy is safe enough for home administration. Based on limited data, sublingual therapy, at least in the short term, may be about half as effective as traditional subcutaneous injection. ^[41]

SL immunotherapy may not be appropriate for everyone. Those affected by multiple allergens may not obtain relief of all of their symptoms by taking immunotherapy for only a single or several allergens. SL immunotherapy is more convenient than weekly injections for individuals with limited, specific allergies that match the SL product.

In April 2014, the FDA approved an SL tablet consisting of 5 calibrated grass pollen extracts (Oralair). It contains Perennial Ryegrass (Lolium perenne), Kentucky bluegrass (Poa pratensis), Timothy grass (Phleum pratense), Orchard grass (Dactylis glomerata), and Sweet Vernal grass (Anthoxanthum odoratum). The Oralair SL tablet needs to be initiated 4 months prior to the season for the specific allergen.

A second SL immunotherapy for Timothy grass (Grastek) was also approved in April 2014 for adults and children aged 5 years or older. It should be initiated at least 12 weeks before the start of the grass pollen season. Efficacy and safety in North America was established in a large study (n=1500) of adults and children aged 5-65 years. Results showed a 23% improvement of symptoms in the entire grass pollen season. ^[42]

A third SL immunotherapy for ragweed (Ragwitek) was also approved in April 2014 for adults aged 18 years or older. Effectiveness studies included about 760 patients. Phase 3 clinical trials showed reduced rhinoconjunctivitis symptoms over the entire season by 27-43% compared with placebo. ^{[43, 44]}

A sublingual (SL) house dust mite immunotherapy (Odactra) was approved by the FDA in 2017. It is a standardized allergen extract indicated as daily SL immunotherapy for allergic rhinitis, with or without conjunctivitis, confirmed by in vitro testing for IgE antibodies to Dermatophagoides farinae or Dermatophagoides pteronyssinus house dust mites, or skin testing to licensed house dust mite allergen extracts.

The first dose must be given in a healthcare setting under the supervision of a physician with experience in diagnosis and treatment of allergic diseases. Patient monitoring for signs or symptoms of a severe systemic or local allergic reaction is required following administration. Life-threatening allergic reactions are described in a boxed warning within the prescribing information. The boxed warning also includes the need to prescribe autoinjectable epinephrine for the patient to have while using HDM immunotherapy.

Approval was based on a double-blind, multicenter trial (n = 1482) in adolescents and adults with HDM allergic rhinitis with or without conjunctivitis (AR/C). Over a 52-week period, HDM immunotherapy improved rhinoconjunctivitis score and visual analog scale-assessed AR/C symptoms (P <0.001).<ref>45</ref>

Omalizumab (Xolair) was approved by the FDA in 2003 for use in adults and adolescents (≥12 y) with persistent, moderate to severe asthma who have a positive skin-test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Patients who use this medication should have IgE levels between 30 and 700 IU and should not weigh more than 150 kg.

Omalizumab is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell receptor, thereby preventing cell degranulation without causing degranulation itself.

Therapy has been shown to decrease free IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase bronchospasm (70%), and a decrease in the number, migration, and activity of eosinophils. levels drop quickly and remain low for at least a month. This therapy is also effective, but not FDA-approved, for allergic rhinitis.

Multiple phase 3 trials show that, compared with placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), a higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and the use of rescue inhalers and emergency departments may also be improved. Omalizumab has been shown to reduce the number of asthma exacerbations. Studies have shown that omalizumab decreases steroid burden while increasing lung function and quality of life when combined with inhaled corticosteroid treatment in patients younger than 12 years with moderate-to-severe asthma. ^{[46, 47]}

Prescribers must be prepared and equipped to recognize and treat anaphylaxis should it occur (0.1% in studies and 0.2% in postmarketing surveillance). Guidelines are evolving, but recommendations advise observation of patients for 2 hours after the first 2 injections and then for 30 minutes for injections thereafter. Reactions have been reported 4 days later. Patients must carry self-injectable epinephrine kits.

Other adverse effects are rare and include upper respiratory infection symptoms, headache, and urticaria (2%) without anaphylaxis. Transient thrombocytopenia has also been noted but not in humans.

Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune-complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit a patient’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.

Cardiovascular risks are also under investigation. The EXCELS trial (Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma) is currently underway. ^[48]

Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $6,110 to $36,600 annually, so omalizumab is a second-line therapy for patients with persistent, moderate to severe allergic asthma that is not fully controlled by standard therapy. ^[6]

All patients should receive assistance with smoking cessation. While smoking cessation is essential for numerous reasons, it particularly appears to increase corticosteroid responsiveness in patients with asthma.

All patients should receive an annual flu shot. A pneumococcal pneumonia vaccination is not required unless indicated based on age (ie, >65 y). Asthma symptoms do not increase after these shots, because the antigens in the vaccinations are not alive.

Evaluating and treating patients for associated conditions (eg, rhinitis, sinusitis, gastroesophageal reflux disease [GERD]) can be important components of therapy. In one study, treating the GERD symptoms of patients with asthma with a proton pump inhibitor for 6 months reduced asthma exacerbations and improved quality of life but did not improve asthma symptoms or pulmonary function or reduce albuterol usage. ^[49]

Signs of well-controlled asthma include the following:

Symptoms ≤2 days per week

Nighttime awakenings ≤2 times per month

Short-acting beta-agonist use (rescue) < 2 days per week

No limitation in normal activity

FEV₁ or peak flow >80% predicted/personal best

Validated questionnaire scores, such as ATAQ 0, ACQ ≤0.75, and ACT ≥20 (discussed below)

Recommended actions in patients with well-controlled asthma include maintenance of current step, continuation of regular follow-up (every 1-6 mo), and consideration of step down if the asthma remains well controlled for at least 3 months.

Signs that asthma has not been well controlled include the following:

Symptoms >2 days per week

Nighttime awakenings 1-3 times per week

Short-acting beta-agonist use (rescue) >2 days per week

Some limitation in normal activity

FEV₁ or peak flow >60-80% predicted/personal best

Validated questionnaire scores ATAQ 1-2, ACQ ≥1.50, ACT 16-19

Two or more exacerbations requiring oral systemic corticosteroids per year

Recommended actions when asthma has not been well controlled include stepping up 1 step, reevaluating the patient in 2-6 weeks, and considering alternative treatment options if adverse effects occur with therapy.

Indications of very poorly controlled asthma include the following:

Symptoms throughout the day

Nighttime awakenings ≥4 times per week

Short-acting beta-agonist use (rescue) several times per day

Extreme limitation in normal activity

FEV₁ or peak flow < 60% predicted/personal best

Two or more exacerbations requiring oral systemic corticosteroids per year

Recommended actions when asthma is under very poor control include considering a short course of oral systemic corticosteroids, stepping up 1-2 steps, reevaluating the patient in 2 weeks, and considering alternative treatment options if adverse effects occur with therapy.

In 2-6 weeks, in poorly controlled cases, evaluate the level of asthma control that has been achieved and adjust therapy accordingly. Review adherence to medications, inhaler technique, environmental control, and comorbid conditions. A progressive loss of lung function and the adverse effects of medication should also be included in the overall assessment of risk.

Several published, but proprietary, questionnaire instruments may be useful in assessing asthma control. Such validated questionnaires include the Asthma Control Questionnaire (ACQ), the Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT). Low scores (3-4 in ATAQ or ≤15 in ACT) indicate poor control.

Consult a pulmonologist, allergist/immunologist, or both for any of the following:

Difficulty controlling disease after 3-6 months, including frequent attacks, need for rescue inhaler (>1 rescue inhaler use per mo), use of oral steroids more than 2 times per year, or step-4 therapy or higher required (or step 2 or higher if aged < 3 y)

Poor quality of life

Immunotherapy under consideration

Intensive education needed

Refractory cough

Abnormal chest radiograph findings

Life-threatening asthma exacerbation

Patient or parent request

Appropriate referral is needed if significant psychologic, social, or family problems are present.

Aside from avoiding known food allergens or additives, diet is not restricted beyond recommendations for patients with concomitant GERD.

Maintaining physical activity and exercise is essential to avoid deconditioning. Susceptible individuals should decrease outdoor activity during midday and afternoon when pollen counts are highest. A short-acting beta-2 agonist and/or cromolyn metered-dose inhaler (MDI) can be used 15-30 minutes before exercise if needed. ^[50]

Several studies have demonstrated that regular aerobic conditioning and weight loss may improve airway physiology and patients’ sense of dyspnea. ^{[51, 52]}

Consider admission to a hospital if the patient develops refractory symptoms with a marked decrease in spirometry or borderline oxygenation. Intravenous or oral corticosteroids (3- to 10-d course) may be required.

A reduced forced expiratory volume in 1 second (FEV₁) or peak expiratory flow rate (PEFR) to less than 50% of the patient’s personal best, normocapnia or hypercapnia, severe symptoms, or mental status changes warrants admission to an intensive care unit (ICU).

If the patient responds to therapy, examination findings are normal 1 hour after the last medication dose, and the FEV₁ or PEFR is >70% of patient’s personal best, consider discharging the patient home on therapy to include oral steroids and scheduling a follow-up visit within 1 week.

Consider arranging a home visit to screen for environmental exposures and assess compliance with avoidance measures. According to a randomized, controlled evaluation of community health worker intervention with African American children hospitalized for asthma, the presence of an asthma coach can reduce hospitalization. ^[53]

These individuals should be referred to a specialist. The goal is the lowest possible oral glucocorticoid dose for the shortest possible duration. Patients must be screened and then referred or treated for complications, such as cataracts (optometry/ophthalmology screening annually) and osteoporosis (bone densitometry, supplemental calcium, and vitamin D at a minimum, if not contraindicated).

Excluding problems that can mimic asthma, such as VCD in “refractory” glucocorticoid-dependent cases, is important. A truncated inspiratory flow-volume loop on pulmonary function tests suggests possible VCD with corroboratory adduction of the vocal cords during inspiration.

The safety of long-acting beta agonists has been questioned because of the SMART trial. ^[28] (See Pharmacotherapy, above.)

Pulmonary function testing is difficult to perform in children below age 4 years, because cooperation can be limited and reference ranges are not standardized. Fewer medications have been studied and approved for patients in this age group.

These patients frequently have other medical diseases that can mimic asthma, and they are more likely to experience adverse effects from asthma medications.

Asthma affects up to 8% of pregnant women, and these patients should be treated similarly to, and possibly even more aggressively than, other patients, given the detrimental effects of hypoxia on maternal and fetal outcomes. During pregnancy, airway hyperreactivity (AHR) generally is stable to improved 69% of the time and worse 31% of the time.

Theophylline may be associated with drug toxicity in the newborn because of poor clearance.

Beclomethasone is an older and, therefore, better-studied inhaled steroid for use during pregnancy. However, budesonide is the only inhaled corticosteroid with an FDA pregnancy rating of B (ie, fetal risk not confirmed in studies in humans but has been shown in some studies in animals). Thus, budesonide should be the drug of choice for pregnant women with asthma.

Systemic glucocorticoids may increase the risk of preeclampsia and decreased birth weight but should be used if asthma exacerbation is severe, because untreated asthma bears its own risks on the pregnancy.

Long-acting beta agonists have a pregnancy rating of C (ie, fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus).

Leukotriene pathway medications generally should not be used because of a lack of safety information, although montelukast is a category B drug.

Immunotherapy should not be started nor dosage escalated during pregnancy, given the rare, but significant, risk of anaphylaxis. If already begun, immunotherapy may be maintained without further dose escalation.

Signs that may indicate a poor prognosis in asthma (ie, risk factors for death) are as follows:

Severe exacerbations – Intubation, ICU stay, 2 or more hospitalizations per year, 3 or more urgent clinic or emergency department visits per year

More than 2 short-acting beta-2 agonist MDIs per month

Glucocorticoid dependence

Poor patient perception of airflow obstruction

Significant medical comorbidities

Psychiatric disease

Illicit drug use

Sensitivity to Alternaria species (an outdoor mold)

Females, ethnic minorities, people with a low annual family income (defined as less than $20,000/y in the United States), and persons with poor access to or education about health care have worse outcomes than do other individuals.

Many young children “outgrow” asthma, especially boys who have no personal or family history of atopy. However, clinical experience shows that many teenagers who become asthma-free may experience asthma again in their 20s and 30s. Perinatal exposure to allergens or passive smoke has been postulated to make outgrowing asthma less likely.

Patients should be informed that upper airway allergic symptoms can be an early warning system for allergic asthma.

Parents with a history of allergies should be advised that some evidence suggests that environmental control measures may potentially prevent sensitization in their children. Simple, but unproven, measures include removing bedroom carpet, avoiding passive smoke exposure, venting gas appliances, increasing fish and vegetable intake, and breastfeeding.

For patient education information, see eMedicineHealth’s Asthma Center, as well as Asthma, Asthma FAQ, Occupational Asthma, and Asthma Medications.

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William F Kelly, III, MD Associate Professor of Medicine, Uniformed Services University of the Health Sciences; Staff Physician, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Walter Reed National Military Medical Center

William F Kelly, III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Chest Physicians

Disclosure: Nothing to disclose.

Brian M Cohee, MD Fellow in Pulmonary and Critical Care Medicine, Walter Reed National Military Medical Center

Brian M Cohee, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Thoracic Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

John J Oppenheimer, MD Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

John J Oppenheimer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, New Jersey Allergy, Asthma and Immunology society

Disclosure: Received research grant from: quintiles, PRA, ICON, Novartis: Adjudication<br/>Received consulting fee from AZ for consulting; Received consulting fee from Glaxo, Myelin, Meda for consulting; Received grant/research funds from Glaxo for independent contractor; Received consulting fee from Merck for consulting; Received honoraria from Annals of Allergy Asthma Immunology for none; Partner received honoraria from ABAI for none. for: Atlantic Health System.

Gregory J Argyros, Col, MD Chief, Graduate Medical and Dental Education, J7/Joint Task Force, National Capital Region Medical; Professor of Medicine, Uniformed Services University of the Health Sciences

Gregory J Argyros, Col, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society

Disclosure: Nothing to disclose.

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

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

Stephen C Dreskin, MD, PhD Professor of Medicine, Departments of Internal Medicine, Director of Allergy, Asthma, and Immunology Practice, University of Colorado Health Sciences Center

Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, Joint Council of Allergy, Asthma and Immunology, American Association of Immunologists

Disclosure: Received consulting fee from Genentech for consulting; Received grant support from NIH for research; Received consulting fee from Clinical Immunization and Safety Assessment (CISA) Network (administered by Vanderbilt University) for consulting; Received consulting fee from o Member, Medical Expert Panel, Division of Vaccine Injury Compensation (DVIC), Department of Health and Human Services. for med legal reviews; Received consulting fee from o Member, Medical Expert Panel, Vaccine Review, Pfize.

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

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Allergic and Environmental Asthma

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