eMedicine Specialties > Allergy and Immunology > Asthma

Allergic and Environmental Asthma

William F Kelly III, MD, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Staff Physician, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Walter Reed Army Medical Center
John J Oppenheimer, MD, Clinical Associate Professor, University of Medicine and Dentistry of New Jersey; Director Clinical Research, Pulmonary and Allergy Associates, PA; 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

Updated: Jun 17, 2009

Introduction

Background

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.

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.

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. Exposure to dust mites within 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 has 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 nonsteroidal antiinflammatory drugs (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 one of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures.

Pathophysiology

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 ten 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). 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 D₂ 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.

Frequency

United States

Prevalence is difficult to determine because definitions and survey methods vary, but the prevalence of asthma appears to be on the rise. Asthma has a prevalence of 10.9%, affecting more than 22 million people, including more than 6 million children.^1,2

International

Global Initiative for Asthma (GINA) researchers note an increase in prevalence, morbidity, mortality, and economic burden over the past 40 years, especially in children.¹ Asthma affects more than 300 million people worldwide, and some reports suggest asthma prevalence is increasing by 50% every decade.¹ The highest recorded prevalences outside North America are in the United Kingdom (>15%), New Zealand (15.1%), and Australia (14.7%).³

Mortality/Morbidity

• In the United States, mortality has increased, especially in children who live in inner-city areas, despite advances in disease understanding and therapy. The number of deaths annually decreased from 5067 (1960-1962) to a low of 1870 (1975-1978) and then increased to 5429 (1993-1995). Worldwide, approximately 180,000 deaths annually are attributed to asthma; most deaths occur in those older than 45 years.
• In the United States, asthma is annually responsible for 1.5 million emergency department (ED) 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.
• 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.
• Worldwide, economic costs for asthma are more than costs for tuberculosis and AIDS combined. Cost is associated with disease severity;⁴ more than half of all expenditures are attributed to the 10-20% of patients with the most severe disease.

Race

• Genetic differences may alter susceptibility to asthma as well as responsiveness to asthma medications.² 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 Associations have been suggested between polymorphisms in the B2-adrenergic receptor (ADRB2) and reduced responsiveness and increased adverse effects with long-acting beta-agonist bronchodilators. More recent studies suggest this is not the case.⁶
• Females, ethnic minorities, people with a low annual family income (<$20,000/y in the United States), and persons with poor access to or education about health care have worse outcomes than other individuals.
• Hospitalization and death rates are 50% higher for African American adults than white adults and 150% higher in children.
• Asthma is rare in Eskimos.

Sex

• Boys have been shown to be at greater risk for asthma than girls. In children younger than 14 years, the prevalence is twice as high in boys than in girls.
• The difference narrows with age, and women aged 40 years have a greater prevalence than men of the same age.

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.
• 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.

Clinical

History

The classic history consists of wheeze, cough, and dyspnea. The predictive value of any single parameter is approximately 30% but is much higher when parameters are combined. Chest discomfort (eg, pain, tightness, congestion, inability to take a full breath) is also common. Some patients may have cough without other symptoms. Refractory chest colds may also suggest the diagnosis.

• Record the following:
  • Age of onset
  • Frequency and severity of daytime and nocturnal symptoms
  • Symptom triggers, such as exercise, animals, irritants (smoke), and occupation (worse on workdays)
  • Seasonal and geographic variation, including presence of symptoms indoors and outdoors
  • Limits on activity, lost work or school days, and quality of life
  • Number of emergency department and urgent clinic visits, hospital admissions, intensive care unit (ICU) stays, and need for mechanical ventilation
  • Past treatments, including oral and inhaled steroids, frequency of rescue inhaler use, immunotherapy, and environmental avoidance
  • Family history of asthma
  • Personal or family history of atopy, allergy, rhinitis (including nonallergic rhinitis), or sinusitis
  • Gastroesophageal reflux symptoms
  • Food allergy
  • Growth (children)
  • Atopic dermatitis
• All patients should be asked about or should undergo assessment regarding exacerbation of symptoms, as follows:
  • Allergic
    • Perennial symptoms - Pet in the home (especially in the bedroom, bed, or both), 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; worsening of symptoms after vacuuming rugs (typical of dust mite allergen)
    • Seasonal symptoms (may extend beyond one season in temperate or tropical climates) - Early spring (trees), late spring and summer (grasses), summer and fall (dry molds), and fall (weeds)
  • Environmental
    • Personal or secondary tobacco smoke exposure in or out of the home
    • Gas-burning stoves, fireplaces, or heaters used in home
    • Sprays or chemical agents at work, home, or with hobbies
    • Symptoms only at one 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 NSAIDs

Physical

Physical examination findings are often normal.

• Head and neck: 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, though 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.
• Cardiac: 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.
• Respiratory: During an acute asthma exacerbation, lung examination findings may include wheezing, rhonchi, hyperinflation, or 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.
• Skin: Check the patient for atopic dermatitis.
• Extremities: Digital clubbing should not be present. Edema should also not be present. If edema is found, this suggests right- or left-sided heart failure.

Causes

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 cannot account for the significant increases in prevalence, as genetic factors take several generations to develop, and asthma and atopy are not always co-inherited. Several environmental or lifestyle factors have been implicated.

• The hygiene hypothesis proposes that cleaner environments have led to less immunological stress, reducing the development of an asthma-protective T_H 1 cytokine phenotype.
• Measles infection, BCG vaccine administration, hepatitis A seropositivity, and other stimuli that increase production of interferon-gamma and IL-12 may inhibit the T_H 2 allergic response.
• In selected series, vaccinations, fewer childhood infections, liberal use of antibiotics, more processed food in diets, smaller families, and less exposure to day care environments have been associated with increased atopy and asthma. This is exemplified in western versus eastern Germany; asthma, atopy, and AHR are more prevalent in western Germany, while bronchitis is more common in eastern Germany.
• 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.
• Causes or triggers of asthma can be divided as follows:
  • Allergic: 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.⁷
  • Nonallergic: These may include smoke, odors, cold air and weather, chemicals, medications (eg, aspirin, other NSAIDs, beta-blockers), exercise, hormonal changes (eg, pregnancy, menstrual cycle), and bisulfite food additives.

Differential Diagnoses

Other Problems to Be Considered

Children and young adults
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

Adults
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: This 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.

Workup

Laboratory Studies

• The most important tests are pulmonary function tests (see Other Tests).
• Skin testing is one of the most useful ways to determine specific allergen sensitivity. Skin tests or in-vitro tests for allergen-specific IgE such as radioallergosorbent tests (RAST), fluorescent allergosorbent tests (FAST), or CAP tests are necessary for informed advice to patients about allergen avoidance techniques, and 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 (see Other Tests).
• 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).
• 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. 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.
• Exhaled nitric oxide levels correlate with eosinophilic airway inflammation and are reduced by corticosteroid therapy. These levels may also help predict the onset of exacerbations. Exhaled breath condensate and exhaled breath temperature are also novel biomarkers that have been studied. Cost and availability of monitors need to improve before this modality can become routine in general practice in medical offices or home use.
• In older patients, an elevated serum brain natriuretic peptide (BNP) level may help suggest heart failure as a primary or contributing cause of dyspnea and wheezing.

Imaging Studies

• Chest radiographs: 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.
• Modified or limited sinus CT scans: Consider CT scans of the sinuses if chronic sinusitis is suggested. About 65% of people with severe asthma have concomitant sinusitis.
• Chest CT scans: These are indicated in select patients to help exclude interstitial lung disease, bronchiectasis, bronchiolitis, or infection.
• Echocardiograms: These are performed if congestive heart failure is suggested based on history and physical examination findings.

Other Tests

• 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, objectively demonstrating reversible airflow obstruction with pulmonary function tests, if possible, is essential.
  • Obstruction is defined as a ratio 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. Young patients with a supranormal FVC can sometimes have a reduced FEV₁ -to-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.⁸  If no response, 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.
  • 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.
• Skin testing should be performed to help detect the presence of allergen-specific IgE against environmental triggers that are suggested based on the patient's history.
  • 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.⁹ 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.
• RAST testing may be used in place of skin testing if dermatologic disease is generalized, antihistamine or TCA use cannot be suspended (these do not interfere with RAST results), or skin testing is relatively contraindicated. However, skin testing is more specific, more sensitive, and usually less expensive than RAST testing.
• 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 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.
• Perform a barium swallow, endoscopy, or 24-hour pH probe (the Bravo study is now possible in selected centers) to help diagnose gastroesophageal reflux disease (GERD) if a patient’s condition is refractory to asthma therapy. Empiric medical therapy is often tried without performing these tests, especially if a patient has symptoms of GERD. In cases of GERD, a prolonged trial may be necessary. The median time to improvement of GERD-induced cough has been reported as 3 months.¹⁰
• Measure oxygenation (ie, with pulse oximetry or arterial blood gas testing) in selected patients.
• Perform sweat chloride testing for cystic fibrosis or immunoglobulin level testing for immunodeficiency if these conditions are suggested.
• Staining nasal secretions with Hansel stain is sometimes used to assess for nasal eosinophilia, which is suggestive of allergy; however, the sensitivity and specificity of this stain are low.

Procedures

• Direct and indirect laryngoscopies are indicated if vocal cord dysfunction (VCD) or another laryngeal abnormality is suggested. A flow-volume curve on pulmonary function test may demonstrate extrathoracic obstruction, supporting the diagnosis of VCD.
• Cardiac stress testing, cardiopulmonary exercise testing, or both may be indicated if the etiology of dyspnea cannot be determined.

Histologic Findings

The diagnosis of asthma is not made histologically. However, autopsy and bronchoscopic biopsy findings include mucus plugging, inflammatory cell infiltrates and debris, vascular permeability, mucosal edema, and epithelial exfoliation. Remodeling, consisting of hypertrophy of smooth muscle, squamous and goblet cell metaplasia, mucous gland hypertrophy, and basement membrane thickening due to collagen and other matrix protein deposition, may be present.

Sputum analysis results show creola bodies (ie, bronchial regenerative cells with nuclear atypia), Charcot-Leyden crystals (ie, residual product of eosinophils), and Curschmann spirals (ie, concentric layers of mucous and debris).

Staging

In asthma staging for adults (including youths ≥12 y), note that severity should be assigned to the most severe category in which any feature occurs.

• Intermittent
  • Daytime symptoms 2 or fewer times per week
  • Nighttime awakenings 2 or fewer times per month
  • Use of short-acting beta-agonist for symptom control (not including taking preventively prior to exercise) 2 or fewer times per week
  • No interference in normal activity
  • Lung function normal between exacerbations, FEV₁ >80% predicted, FEV₁/FVC ratio normal (85% for ages 8-19 y, 80% for 20-39 y, 75% for 40-59 y, 70% for 60-80 y)
  • Exacerbations requiring oral systemic corticosteroids once per year at most
  • Recommended therapy is Step 1 - Short-acting beta-agonists as needed
• Mild persistent
  • Daytime symptoms more than twice per week, but not daily
  • Nighttime awakenings 3-4 times per month
  • Use of short-acting beta-agonist for symptom control (not including taking preventively prior to exercise) more than 2 times per week but not daily and not more than once on any one day
  • Minor limitation in normal activity
  • FEV₁ >80% predicted, FEV₁/FVC ratio normal (85% for ages 8-19 y, 80% for 20-39 y, 75% for 40-59 y, 70% for 60-80 y)
  • Two or more exacerbations requiring oral systemic corticosteroids per year
  • Recommended therapy is Step 2 - Low-dose inhaled corticosteroids (preferred) or (alternative) cromolyn, leukotriene receptor antagonist, nedocromil, or theophylline
• Moderate persistent
  • Daily symptoms
  • Nighttime awakenings more than once per week but not nightly
  • Daily use of short-acting beta-agonist for symptom control (not including taking preventively prior to exercise)
  • Some limitation in normal activity
  • FEV₁ >60% but <80% predicted, FEV₁/FVC ratio reduced 5% (normal FEV₁/FVC is 85% for ages 8-19 y, 80% for 20-39 y, 75% for 40-59 y, 70% for 60-80 y)
  • Two or more exacerbations requiring oral systemic corticosteroids per year
  • Recommended therapy is Step 3, plus consider short course of oral systemic corticosteroids. Step 3 consists of (preferred) a low-dose inhaled corticosteroid plus a long acting beta-agonist or (alternative) a medium-dosed inhaled corticosteroid. Other alternative options include low-dose inhaled corticosteroid plus a leukotriene receptor antagonist, theophylline, or zileuton.
• Severe persistent
  • Symptoms throughout the day
  • Nighttime awakenings often 7 times per week
  • Use of short-acting beta-agonist for symptoms control several times per day (not including taking preventively prior to exercise)
  • Extremely limited in normal activity
  • FEV₁ <60% predicted, FEV₁/FVC ratio reduced more than 5% (normal FEV₁/FVC is 85% for ages 8-19 y, 80% for 20-39 y, 75% for 40-59 y, 70% for 60-80 y)
  • Two or more exacerbations requiring oral systemic corticosteroids per year
  • Recommended therapy is Step 4 or 5, plus consider a short course of oral systemic corticosteroids. Step 4 consists of (preferred) medium-dose inhaled corticosteroids plus a long-acting beta-agonist or (alternative) a medium-dose inhaled corticosteroid plus a leukotriene receptor antagonist, theophylline, or zileuton. Step 5 consists of high-dose inhaled corticosteroids plus a long-acting beta-agonist and consider anti-IgE therapy omalizumab in patients with allergies.

Of note, Step 6 is high-dose inhaled corticosteroids plus a long-acting beta-agonist plus oral systemic corticosteroids and consider omalizumab.

Consider allergen immunotherapy (see Treatment) for Steps 2-4 for patients who have allergic asthma.

All patients should have a short-acting beta-agonist as needed for symptoms.

Control

• Well controlled
  • 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 
  • Recommended action: Maintain current step, continue regular follow-up (every 1-6 mo), consider step down if well controlled for at least 3 months.
• Not well controlled
  • 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 action: Step up 1 step, reevaluate in 2-6 weeks, and consider alternative treatment options if adverse effects occur with therapy.
• Very poorly controlled
  • 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 system corticosteroids per year
  • Recommended action: Consider a short course of oral systemic corticosteroids, step up 1-2 steps, reevaluate in 2 weeks, and consider alternative treatment options if adverse effects occur with therapy.
  • In 2-6 weeks, evaluate the level of asthma control that is achieved and adjust therapy accordingly. Review adherence to medications, inhaler technique, environmental control, and comorbid conditions. Progressive loss of lung function and adverse effects of medication should also be included in the overall assessment of risk.

Treatment

Medical Care

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. For this discussion, treatment is divided into pharmacotherapy, environmental control, allergen immunotherapy, antibodies against IgE, and education.

• Pharmacotherapy
  • The most important facet of medical care is the use of anti-inflammatory medication (usually inhaled corticosteroids) in patients at all stages beyond mild intermittent asthma. Even use in children improves many outcomes, including quality of life, though it does not appear to affect the natural history of the disease as initially hypothesized.^11,12,13,14 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 the patients admitted to the hospital for asthma were receiving or taking their recommended antiinflammatory medications (this was likely an issue of adherence as well as prescription).
  • The safety of long-acting beta-agonists has been questioned because of the SMART trial of approximately 25,000 patients, in which the respiratory- and asthma-related deaths were increased in the group that received salmeterol compared to placebo (this signal was only statistically significant in African Americans).¹⁵ Most experts continue to recommend the addition of long-acting beta-agonists when disease is not adequately controlled by low-dose inhaled corticosteroids but stress that long-acting beta-agonists should not be used without inhaled corticosteroids.
  • Combination of an inhaled corticosteroids and long-acting beta-agonist (STAY trial using budesonide/formoterol¹⁶ ) for both maintenance and reliever medication in patients with moderate to severe asthma may reduce 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.¹¹⁶
  • Exacerbations: NHLBI EP-3 2007 guidelines² 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. 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^17,18 ), nebulized medications including levalbuterol, 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 this treatment has not been systematically shown to be helpful. Antibiotics offer no added benefit during an asthma exacerbation.
  • 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, GERD, sinusitis) 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.
  • See Staging and Medication for more information.
• Environmental control
  • Allergen avoidance takes different forms, depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen should result rather rapidly, though 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 homes 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 can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches). Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven 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 include the following (see Indoor Aeroallergens for more details):
    • Dust mites (Dermatophagoides pteronyssinus and farina, size 30 µm): The primary allergen 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 (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity (<50%).
      • A recent Cochrane Review noted that most trials to date have been small and of poor methodological quality. Therefore, clinicians cannot easily offer definitive recommendations on the role of house dust mite avoidance measures in the management of perennial allergic rhinitis that is sensitive to house dust mites.
      • Conclusions from this analysis suggest that acaricides and extensive bedroom-based environmental control programs may help reduce rhinitis symptoms. If such measures are considered appropriate, they should be the interventions of choice. However, analysis also indicated that 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.¹⁹
    • Cats and other animals (dander or saliva, urine, or serum proteins, size 1-20 µm): Because of its small size, this allergen is predominantly an airborne indoor allergen. 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.
    • Cockroaches (size 30 µm): 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.
    • Indoor molds (size 1-150 µm): Avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.
    • Pollen (size 1-150 µm): 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, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing in a different ecosystem during pollen season.
• Allergen immunotherapy
  • Repeated injections of small doses of allergen have been used for more than almost 100 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting (hymenoptera venom) reactions. 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 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). Acquisition of new sensitivities can be reduced or eliminated with immunotherapy of mono- or oligo-sensitized children.
  • In a 2003 meta-analysis of 75 randomized controlled trials, Abramson et al reported that immunotherapy decreased asthma symptoms and need for medication.²⁰ 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/y thereafter (1996 estimate), a recent 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.²¹
  • 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. As discussed above, this treatment is especially useful if 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).
  • Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, 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. A major risk factor for immunotherapy-related fatalities includes uncontrolled asthma; therefore, appropriate caution should be exercised.
  • 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 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.
• Antibodies to IgE antibody - Omalizumab
  • Omalizumab (Xolair) was approved by the FDA in 2003 for adults and adolescents (>12 y) with moderate-to-severe persistent 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 should have IgE levels between 30 and 700 IU and should not weigh more than 150 kg.
  • This 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 for allergic rhinitis.
  • Multiple phase 3 trials show that, compared to placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency department may also be improved. Omalizumab has been shown to reduce the number of asthma exacerbations.
  • Prescribers must be prepared and equipped to recognize and treat anaphylaxis should it occur. Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1% in studies and 0.2% in postmarketing surveillance). 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 one’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.
  • 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 moderate-to-severe persistent allergic asthma that is not fully controlled on standard therapy.⁴
• Novel approaches - Bronchial thermoplasty
  • This technique involves delivering controlled thermal energy to the airway during bronchoscopy (tube inserted down throat into airways) to reduce smooth-muscle mass and, therefore, reduce bronchoconstriction. In a study of 112 patients with moderate to severe asthma, the rate of mild exacerbations, morning peak flow, symptom scores, and rescue albuterol usage improved over a 1-year period.²² However, FEV₁ did not change, and asthma symptoms commonly increased early during treatment. Further study is required.
• Education: See Patient Education.

Consultations

• 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 psychological, social, or family problems are present.

Diet

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

Activity

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. Several recent studies have demonstrated that regular aerobic conditioning and weight loss may improve airway physiology and patients' sense of dyspnea.^23,24

Medication

Antiinflammatory medications (especially inhaled glucocorticosteroids) are now the mainstay of therapy and the single most effective therapy for adults with asthma. Antiinflammatory medications are proven to improve lung function (ie, FEV₁, AHR) and to decrease symptoms, exacerbation frequency, and the need for rescue inhalers.

Short-acting inhaled beta-2 agonists, as needed, are most effective for rapid relief of asthma symptoms. No benefit and some risk of developing tolerance occur with regular long-term use. Those with the genetic predisposition (Arg-Arg on the 16 codon of the beta-2 receptor) may experience loss of lung function with regular use of a short-acting inhaled beta-2 agonist.²⁵ These agents should still be available to the patient, even if he or she is using a long-acting beta-2 agonist (LABA). As an aside, in 2005, the US Food and Drug Administration (FDA) ruled that the sale of inhalers using chlorofluorocarbon (CFC) propellants would be prohibited after 2008 because of concerns about atmospheric ozone depletion.^26,27 Based on clinical trials, the change to hydrofluoroalkane (HFA)-based inhalers should not change efficacy and safety; however, patients may find the taste or texture different.

The safety of long-acting beta-agonists has been questioned because of the SMART trial of approximately 25,000 patients, in which the respiratory- and asthma-related deaths were increased in the group that received salmeterol compared to placebo.¹⁵ Most experts continue to recommend addition of long-acting beta-agonists when disease is not adequately controlled by low-or moderate-dose inhaled corticosteroids, but 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).

Glucocorticoids may increase cell beta-2 agonist receptors, which, in turn, may enhance the action of the combination products.

According to the 1998 Leukotriene Working Group, leukotriene pathway modifiers may be useful as first-line therapy for mild persistent asthma or as an add-on or glucocorticoid-sparing medication in other cases.¹⁸ These agents are less effective than glucocorticoid inhalers but tend to improve compliance because dosing is oral and once daily, and usage appears more reasonable for those unable or unwilling to take glucocorticoids. Leukotriene receptor blockers montelukast and zafirlukast are available, as is the controlled release form of the leukotriene synthesis inhibitor zileuton. A recent study determined that LTM were most effective in younger patients as well as those with near-normal lung function.²⁸

When adding to a medication regimen for asthma (referred to as stepping up therapy), consider adding LABA to inhaled corticosteroids for persistent symptoms with impaired FEV₁. Patients with symptoms but normal lung function (especially those with symptomatic allergic rhinitis) might benefit first from a leukotriene pathway modifier. Of course, some patients may ultimately be treated with both types of medications for optimum management.

Mast cell stabilizers can also be used. Cromolyn sodium (Intal) indirectly blocks calcium influx into mast cells, preventing inflammatory mediator release. Adults can use it in a metered-dose inhaler (MDI; 2-4 puffs 3-4 times daily) or in a nebulized form (1 ampule 3-4 times daily). Because of its safety profile, this agent is often begun in children; however, it may take a month to work. The pediatric dose is 1-2 puffs via an MDI 3-4 times daily or 1 ampule via a nebulizer 3-4 times daily. Cromolyn sodium tends to work best in young and highly allergic patients.

Nedocromil (Tilade) has similar effects, although it is structurally distinct. The adult dose is 2-4 puffs via an MDI 2-3 times daily. The pediatric regimen is 1-2 puffs via an MDI 2-4 times daily. MDIs may be used with a spacer as necessary (mask if <2 y). Patients should activate the MDI while breathing in slowly, and then they should hold their breath for 10 seconds if possible.

Using a spacer or holding the inhaler 2 inches from the mouth may improve delivery. The recent change from chlorofluorocarbon to hydrofluoroalkane propellants with smaller particle size may help deliver more medication to the smaller airways. In inhalers without a dose counter, the only reliable way to determine if the inhaler is empty is to count the number of doses. The importance of an empty inhaler was highlighted in a recent study that found that 25% of beta-2 agonist users reported that their rescue inhaler was empty during an exacerbation.²⁹ This reinforces the importance of adding dose counters to metered-dose inhalers. Patients should rinse their mouths with water and spit after using a glucocorticoid inhaler to prevent oral thrush and dysphonia. An alcohol-containing mouthwash may be more effective than water.

Breath-actuated inhalers are easier to use for less coordinated individuals. A dry-powder inhaler (DPI) allows rapid inhalation. These devices also often have built-in dose counters. Particle sizes of the medications delivered from these devices are generally larger than those from MDIs.

Consider recommending a nebulizer if the patient is younger than 2 years or is unable to use an MDI or DPI because of cough, severe dyspnea, or poor coordination.

Additionally, recombinant DNA-derived humanized IgG monoclonal antibodies to IgE, omalizumab, are now available to treat moderate-to-severe persistent asthma in patients who react to perennial allergens and whose symptoms are not controlled by inhaled corticosteroids.

Bronchodilators

Provide immediate relief of bronchospasm. Preferentially (but not exclusively) bind beta2-adrenergic receptors, resulting in conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP), relaxation of bronchial smooth muscle, and decreased release of inflammatory mediators. Anticholinergic agent ipratropium is included here because it has an additive beneficial effect when given with bronchodilators in acute severe asthma.

Note: In December 2008, an advisory panel to the FDA voted to ban 2 long-acting beta agonists (LABA), Serevent (salmeterol) and Foradil (formoterol), for treating asthma in adults and children.³⁰ 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 both long-acting beta agonists and steroids. The panel may also recommend that LABAs (without or without inhaled steroids) not be used in children. For more information, visit www.fda.gov.

Albuterol (Proventil, Ventolin, Airet, Pro Aire)

Beta-agonist. Relaxes bronchial smooth muscle by action on beta-2 receptors with little effect on cardiac muscle contractility.

Dosing

Adult

4 mg PO q12h; not to exceed 32 mg/d
MDI: 1-2 puffs q4-6h prn; not to exceed 12 puffs/d
Nebulizer: 2.5 mg tid/qid

Pediatric

PO
<12 years: 0.3-0.6 mg/kg/d, not to exceed 8 mg/d
>12 years: Administer as in adults
MDI
<4 years: Not established
>4 years: Administer as in adults
Nebulizer
<2 years: Not established
2-12 years: 0.1-0.15 mg/kg/dose, not to exceed 2.5 mg tid/qid prn
>12 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increasing need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Bitolterol (Tornalate)

Stimulates beta-2 receptors directly to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.

Dosing

Adult

2 puffs q8h prn

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity; tachycardia resulting from cardiac arrhythmia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Metaproterenol (Alupent, Metaprel)

Relaxes bronchial smooth muscle by action on beta2-adrenergic receptors with little effect on cardiac muscle contractility. Generally not recommended because of excessive cardiac stimulation, especially in high doses.

Dosing

Adult

MDI: 2-3 puffs q3-4h prn
Nebulizer: 0.01 mg/kg; not to exceed 0.3 mL of 5% solution q4h prn
PO: 20 mg tid/qid

Pediatric

<6 years: 2 mg/kg/d PO
6-9 years: 10 mg PO tid/qid
>9 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Pirbuterol (Maxair)

Acts directly on beta2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.

Dosing

Adult

1-2 puffs q4-6h prn

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increase in need for this rescue medication may indicate clinical destabilization requiring medical reevaluation

Terbutaline (Brethaire, Brethine, Bricanyl)

Acts directly on beta-2 receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.

Dosing

Adult

MDI: 2 puffs q4-6h prn
SC: 0.25 mg
PO: 5 mg tid

Pediatric

<12 years: Not established
12-15 years: 2.5 mg PO tid
>15 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity; tachycardia resulting from cardiac arrhythmias

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Through intracellular shunting, may decrease serum potassium levels, which can produce adverse cardiovascular effects; decrease is usually transient and may not require supplementation

Salmeterol (Serevent)

Long-acting bronchodilator - works by relaxing smooth muscles of bronchioles and relieving bronchospasms. Effect may also facilitate expectoration.

Inhaler does not replace anti-inflammatory medications but can be added to decrease rescue inhaler use. Evening dose may be useful for nocturnal symptoms. SR PO albuterol has greater systemic sympathomimetic adverse effects and is considered an alternate therapy only. WARNING: Data from a large placebo-controlled US study (SMART trial) that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179).

Note: In December 2008, an advisory panel to the FDA voted to ban 2 long-acting beta agonists (LABA), Serevent (salmeterol) and Foradil (formoterol), for treating asthma in adults and children. 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 both long-acting beta agonists and steroids. The panel may also recommend that LABAs (without or without inhaled steroids) not be used in children. For more information, visit www.fda.gov.

Dosing

Adult

PO: 4 mg q12h
MDI: 2 puffs (or 1 blister pack) q12h

Pediatric

PO: 0.3-0.6 mg/kg/d; not to exceed 8 mg
MDI: 1-2 puffs (or 1 blister pack) q12h

Interactions

Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia due to diuretics may worsen

Contraindications

Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmia associated with tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not indicated to treat acute asthmatic symptoms; sympathomimetic responses (tremor, tachycardia) can occur and may be significant in some patients with cardiovascular disease; onset of action can be delayed (does not preclude need for short-acting bronchodilators)

Formoterol (Foradil Aerolizer, Perforomist inhalant solution)

Long-acting beta-2-adrenergic agonist. Relaxes smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, thereby relieving bronchospasms. Effect may also facilitate expectoration. Shown to improve symptoms and morning peak flows. It also may enhance sensitivity of glucocorticoid receptors.

Incidence of adverse effects higher when administered at more frequent doses than recommended. Bronchodilating effect lasts >12 h. Use in addition to regular use of anticholinergic agents. Useful where bronchodilators used frequently. Available as oral inhalant powder capsule and administered via Aerolizer inhaler.

Note: In December 2008, an advisory panel to the FDA voted to ban 2 long-acting beta agonists (LABA), Serevent (salmeterol) and Foradil (formoterol), for treating asthma in adults and children. 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 both long-acting beta agonists and steroids. The panel may also recommend that LABAs (without or without inhaled steroids) not be used in children. For more information, visit www.fda.gov.

Dosing

Adult

12 mcg inhaled (1 inhalation) bid at least 12 h apart

Pediatric

<5 years: Not established
>5 years: Administer as in adults

Interactions

Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia resulting from diuretics, corticosteroids, or theophylline derivatives may worsen; drugs that widen QTc interval (eg, quinidine, procainamide, pimozide, moxifloxacin, sparfloxacin, gatifloxacin, sotalol, thioridazine, amiodarone) may potentiate cardiovascular adverse effects; concomitant use with other beta-adrenergic agonists may result in additive effects

Contraindications

Documented hypersensitivity, angina, acutely deteriorating asthma, and cardiac arrhythmias associated with tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not indicated to treat acute asthmatic symptoms or acute deterioration of COPD; not a substitute for inhaled corticosteroids; adverse effects include paroxysmal bronchospasm, tremors, nervousness, and tachycardia; caution in coronary insufficiency, arrhythmias, hypertension, diabetes mellitus, hyperthyroidism; higher incidence of cardiovascular risks with doses >12 mcg bid; black box FDA warning describes that chronic use of long-acting beta2-adrenergic inhalers may result in increased asthma morbidity and mortality, use only as additional therapy for patients not adequately controlled on other asthma-controller medications (eg, low- to medium-dose inhaled corticosteroids) or patients whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including formoterol

Ipratropium (Atrovent)

DOC for beta-2 agonist-induced bronchospasm. Chemically related to atropine and has antisecretory properties. Inhibits vagally mediated reflexes by increasing cyclic GMP, causing local bronchial smooth muscle dilation. Not effective for exercise-induced symptoms. Additive to, but slower than, effects of beta-2 agonists.

Dosing

Adult

Nebulizer: 1 U dose vial (500 mcg) q30min for 3 doses, then q2-4h prn
MDI: 4-8 puffs prn initially; not to exceed 12 puffs/d

Pediatric

Nebulizer: 250 mcg q20min for 3 doses, then q2-4h prn
MDI: 4-8 puffs prn initially; not to exceed 6 puffs/d

Interactions

Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid)

Structurally classified as a methylxanthine, it acts as a bronchodilator. Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation.

For bronchodilation, near toxic (>20 mg/dL) levels are usually required. Less effective than glucocorticoids but may be glucocorticoid-sparing agent. Routine drug level monitoring required (goal: 5-15 mcg/mL).

Dosing

Adult

10 mg/kg/d (not to exceed 300 mg) PO initially; not to exceed 800 mg/d maintenance

Pediatric

<1 year: 0.2 (times age in wk) plus 5 (estimated in mg/kg/d) maximum PO
>1 year: 16 mg/kg/d PO; not to exceed 400 mg/d; alternatively, 10 mg/kg/d IV

Interactions

Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects
Effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon

Contraindications

Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in peptic ulcer, hypertension, tachyarrhythmia, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Levalbuterol (Xopenex)

Beta-agonist for bronchospasm. Relaxes bronchial smooth muscle by action on beta 2-receptors with little effect on cardiac muscle contractility.

Available as inhaler or as tablets. Inhaler used for acute episodes of bronchospasm or for prevention of bronchospasm.

Dosing

Adult

0.63 mg via nebulizer tid, separate each dose by 6-8 h

Pediatric

<6 years: Not established
6-12 years: 0.31 mg via nebulizer tid, separate each dose by 6-8 h; not to exceed 0.63 mg tid
>12 years: Administer as in adults

Interactions

Decreased efficacy with beta-blockers; digoxin levels may be decreased; may potentiate the kaliuretic effects of drugs, such as, loop or thiazide diuretics; decreases serum digoxin levels by 16-22%; MAOIs may potentiate vascular constriction, extreme caution advised with coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Doses higher than 0.63 mg tid may cause tachycardia; immediate hypersensitivity reactions reported; caution in patients with hypokalemia; may cause paradoxical bronchospasm and increased pulse rate or blood pressure

Tiotropium (Spiriva)

A quaternary ammonium compound. Elicits anticholinergic/antimuscarinic effects with inhibitory effects on M₃ receptors on airway smooth muscles, leading to bronchodilation. Available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. Helps COPD patients by dilating narrowed airways and keeping them open for 24 h.

Dosing

Adult

Inhale contents of 1 cap (18 mcg) via HandiHaler device qd

Pediatric

Not established

Interactions

Coadministration with other anticholinergic containing drugs (eg, ipratropium) may increase toxicity risk

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

For maintenance treatment only; not effective for acute (rescue) therapy of bronchospasm; discontinue use and consider other treatments if immediate hypersensitivity reactions (including angioedema) or paradoxical bronchospasm occur; caution with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction; commonly causes dry mouth; may cause constipation, increased heart rate, blurred vision, glaucoma, and urinary difficulty or retention; monitor patients with moderate-to-severe renal impairment

Arformoterol (Brovana)

(R, R)-enantiomer of formoterol, a selective, long-acting beta-2 adrenergic receptor agonist (beta-2 agonist) that has 2-fold greater potency than racemic formoterol (which contains both [S, S] and [R, R]-enantiomers).
Pharmacologic effects of beta-2 adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Note: In December 2008, an advisory panel to the FDA voted to ban 2 long-acting beta agonists (LABA), Serevent (salmeterol) and Foradil (formoterol), for treating asthma in adults and children. 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 both long-acting beta agonists and steroids. The panel may also recommend that LABAs (without or without inhaled steroids) not be used in children. For more information, visit www.fda.gov.

Dosing

Adult

15 mcg bid (morning and evening) by nebulization; total daily dose > 30 mcg (15 mcg bid) not recommended

Pediatric

Not established

Interactions

Concomitant treatment with methylxanthines (aminophylline, theophylline), steroids, or diuretics may potentiate hypokalemic effect of adrenergic agonists; beta-blockers block therapeutic effects of beta agonists and may produce bronchospasm in patients with COPD; drugs known to prolong the QTc interval may potentiate cardiovascular effects of arformoterol; MAOIs may potentiate the cardiovascular effects of arformoterol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not indicated for the treatment of acute episodes of bronchospasm; caution in cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; can produce a clinically significant cardiovascular effect in some patients, including increases in pulse rate, blood pressure, and/or symptoms (may need to discontinue drug); not for use more often, or at higher doses than recommended

Monoclonal antibodies

Recombinant, DNA-derived agents inhibit IgE binding to the high-affinity IgE receptor on mast cells and basophils, causing a decrease in release of mediators of the allergic response.

Omalizumab (Xolair)

Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE receptor on surface of mast cells and basophils. By inhibiting IgE binding, surface IgE receptors are down-regulated, and release of mediators of allergic response is inhibited. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

Dosing

Adult

150-375 mg SC q2-4wk; inject slowly over 5-10 seconds because of viscosity; not to exceed 150 mg/injection site
Precise dose and frequency established by serum total IgE level (IU/mL)

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not effective to treat acute asthma; do not abruptly discontinue inhaled corticosteroids when initiating omalizumab; malignancy rate among treated patients (0.5%) was numerically higher than among control patients (0.2%); malignancies varied, and further long-term observation needed to fully assess risk; may cause injection-site reaction and anaphylaxis, sometimes delayed

Glucocorticoids

Maintenance medications that decrease inflammatory mediators to limit airway remodeling. Must be taken regularly to be beneficial. Do not relieve acute bronchospasm; short-acting bronchodilators must be available. The multiple formulations are not equivalent on a per-dose or per-mcg basis. Inhaled corticosteroids are one of the most important developments in asthma management because they decrease inflammation. Proven to improve lung function (ie, FEV₁, airway hyperactivity) and decrease symptoms, exacerbation frequency, and need for rescue inhalers.

Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Individual patients experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

Dose ranges as recommended by NHLBI.

Fluticasone (Flovent)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically.

Dosing

Adult

MDI
Low dose: 88-264 mcg
Medium dose: 264-660 mcg
High dose: >660 mcg
DPI
Low dose: 100-300 mcg
Medium dose: 300-600 mcg
High dose: >600 mcg

Pediatric

MDI
Low dose: 88-176 mcg
Medium dose: 176-440 mcg
High dose: >440 mcg
DPI
Low dose: 100-200 mcg
Medium dose: 200-400 mcg
High dose: >400 mcg

Interactions

None reported

Contraindications

Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Flunisolide (AeroBid)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.

Dosing

Adult

Low dose: 2-4 puffs
Medium dose: 4-8 puffs
High dose: >8 puffs

Pediatric

Low dose: 2-3 puffs
Medium dose: 4-5 puffs
High dose: >5 puffs

Interactions

None reported

Contraindications

Documented hypersensitivity: bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Triamcinolone (Azmacort)

Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.

Dosing

Adult

Low dose: 4-10 puffs
Medium dose: 10-20 puffs
High dose: >20 puffs

Pediatric

Low dose: 4-8 puffs
Medium dose: 8-12 puffs
High dose: >12 puffs

Interactions

Coadministration with barbiturates, phenytoin, and rifampin decreases effects

Contraindications

Documented hypersensitivity, bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Beclomethasone (QVAR inhalant 40 and 80 mcg)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. Readily absorbed through nasopharyngeal mucosa and GI tract. Has a weak hypothalamic-pituitary-adrenocortical (HPA) axis inhibitory potency when applied topically.

Most reliable during pregnancy because has been in use for many years with no significant problems observed. May decrease number and activity of inflammatory cells, resulting in decreased airway inflammation. This corticosteroid is soluble in the new HFA propellant, resulting in the smallest particle sizes of any of the inhaled corticosteroids, with resultant deep penetration into the airways. This may be of benefit in treating small airway disease, although greater systemic absorption can result from alveolar deposition, so the recommended doses are smaller than for the previously available non-HFA preparations of beclomethasone, Vanceril, and Beclovent.

Various dose preparations are available and must be titrated in conjunction with other medications patient is taking. Most inhaled PO medications have effect in 24 h.

Dosing

Adult

Patients previously using bronchodilators only: 40-80 mcg bid; not to exceed 320 mcg bid
Patients previously using inhaled corticosteroids: 40-160 mcg bid; not to exceed 320 mcg bid
Low dose: 80-240 mcg/d
Medium dose: 240-480 mcg/d
High dose: >480 mcg/d

Pediatric

5-11 years:
Low dose: 80-160 mcg/d
Medium dose: >160-320 mcg/d
High dose: >320 mcg/d

≥12 years: Refer to adult dosing

Interactions

Coadministration with ketoconazole may increase plasma levels but does not appear to be clinically significant

Contraindications

Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not for acute attack; weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Budesonide (Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort Aqua Intranasal)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.

Dosing

Adult

DPI
Low dose: 200-600 mcg
Medium dose: 600-1200 mcg
High dose: 1200 mcg

Pediatric

Inhalation suspension for children
Low dose: 0.5 mg
Medium dose: 1 mg
High dose: 2 mg

Interactions

None reported

Contraindications

Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Mometasone (Asmanex Twisthaler)

Corticosteroid for oral inhalation. May depress formation, release, and activity of endogenous mediators of inflammation.

Dosing

Adult

Patients who received bronchodilators alone: 220 mcg inhaled PO qhs; if needed, may increase to 220 mcg bid
Patients who received inhaled corticosteroids: 220 mcg inhaled PO qhs; if needed, may increase to 220 mcg bid
Patients who received oral corticosteroids: 440 mcg inhaled PO bid
Once-daily administration should be taken only in the evening
Low dose: 220 mcg/d
Medium dose: 440 mcg/d
High dose: >440 mcg/d

Pediatric

<4 years: Not established
4-11 years: 110 mcg inhaled PO qhs
>11 years: Administer as in adults

Interactions

Strong CYP3A4 inhibitors (eg, ketoconazole) may increase plasma levels

Contraindications

Documented hypersensitivity; status asthmaticus or other acute asthmatic episodes

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not effective for relief of acute bronchospasm; orally inhaled corticosteroids may cause Candida albicans infection in the mouth and pharynx; may worsen existing tuberculosis or fungal, bacterial, viral, and parasitic infections; may suppress HPA axis; long-term use may reduce bone mineral density and suppress growth in children; increases risk for glaucoma and cataracts; common adverse effects include headache, allergic rhinitis, pharyngitis, upper respiratory tract infection, sinusitis, oral candidiasis, dysmenorrhea, musculoskeletal pain, back pain, and dyspepsia

Ciclesonide (Alvesco)

Aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 years and older. Not indicated for relief of acute bronchospasm.

After asthma stability achieved, best to titrate to lowest effective dosage to reduce possibility of adverse effects. For patients who do not respond adequately to starting dose after 4 wk of therapy, higher doses may provide additional asthma control.

Dosing

Adult

Oral inhalation:
Patients previously on bronchodilator therapy alone: 80 mcg bid; not to exceed 160 mcg bid
Patients on previous inhaled corticosteroids: 80 mcg bid; not to exceed 320 mcg bid
Patients on previous oral corticosteroids: 320 mcg bid; not to exceed 320 mcg bid

Pediatric

<12 years: Not indicated
≥12 years: Administer as in adults

Interactions

Coadministration with oral ketoconazole may increase AUC but does not appear to be clinically significant

Contraindications

Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not for acute attack; caution when replacing systemic corticosteroids because of risk of adrenal insufficiency; may decrease growth velocity in pediatric patients; caution with active or quiescent tuberculosis infection or with untreated fungal, viral, or bacterial infections; rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure reported

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Goal is lowest dose and shortest duration effective for disease control. Conversion: Methylprednisolone (Medrol) dose equal to four fifths of desired prednisone dose.
Prednisolone (Prelone, Pediapred) dose equal to prednisone dose.

Dosing

Adult

40-60 mg/d PO for 3-10 d as burst; 5-60 mg/d PO qd or qod for long-term use prn for disease control; divided doses (20 mg tid) are more effective than 60 mg qd but are also associated with more adverse effects

Pediatric

1-2 mg/kg/d PO for 3-10 d as burst; not to exceed 60 mg/d; 0.25-2 mg/kg qd or qod for long-term use prn for disease control

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction; viral infection, connective tissue infections, fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, weight gain, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur; qod therapy lessens adverse effects

Leukotriene-modifying agents

Consist of leukotriene receptor antagonists (eg, zafirlukast and montelukast) and synthesis inhibitors (eg, zileuton).

Zafirlukast (Accolate)

Leukotriene pathway inhibitors. Antagonizes leukotriene E4 and D4 receptors. Not for use in acute episodes of asthma.

Dosing

Adult

20 mg PO bid

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Warfarin and theophylline levels must be monitored closely if coadministered with zafirlukast or zileuton; do not take with food

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Not indicated to reverse acute asthma attacks; not for use as monotherapy in the management of exercise-induced bronchospasm
Neuropsychiatric events have been reported, and following further FDA evaluation, the prescribing information has been updated to include case reports during postmarketing surveillance that include agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor

Montelukast (Singulair)

Inhibits effects by leukotriene receptors E4 and D4, which has been associated with asthma including airway edema, smooth muscle contraction, and cellular activity associated with the symptoms.

Dosing

Adult

10 mg PO qhs

Pediatric

<12 months: Not established
12-23 months: 1 packet of 4 mg oral granules PO hs
2-5 years: 4 mg PO (as chewable tab) qhs
6-14 years: 5 mg PO (as chewable tab) qhs
>14 years: Administer as in adults

Interactions

Phenobarbital and rifampin may reduce AUC of montelukast

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Not indicated for immediate relief of acute asthma symptoms, use appropriate short-acting inhaled beta2-agonist inhaler for exacerbations; not for use as monotherapy in management of exercise-induced bronchospasm (EIB); if already taking montelukast daily (eg, chronic asthma, allergic rhinitis), do not take an additional dose to prevent EIB; administration for chronic asthma has not been established to prevent acute EIB; chewable tab contains phenylalanine, caution with phenylketonuria
Neuropsychiatric events have been reported, and following further FDA evaluation, the prescribing information has been updated to include case reports during postmarketing surveillance that include agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor

Zileuton (Zyflo)

Inhibits leukotriene formation, which in turn decreases neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, capillary permeability, and smooth muscle contractions.

Dosing

Adult

Immediate release: 600 mg PO qid pc and hs (No longer available in US)
Extended release: 1200 mg (2 tab) PO bid; administer within 1 h after morning and evening meals

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Increases the toxicity of propranolol, warfarin, and theophylline

Contraindications

Documented hypersensitivity; active liver disease or transaminase elevation greater than or equal to 3 times the upper limit the normal value

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in liver disease; elevation of liver function tests may occur, ALT should be monitored; not indicated in the reversal of acute asthma attacks
Neuropsychiatric events have been reported, and following further FDA evaluation, the prescribing information has been updated to include case reports during postmarketing surveillance that include agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor

Follow-up

Further Inpatient Care

• 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 ICU. 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^17,18 ), nebulized medications including albuterol, 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 this 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.
  • 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.

Further Outpatient Care

• Medical office visits should occur every 6-12 months (every 1-6 mo if severe) and should include the following assessments:
  • Reassess severity, compliance, and response to therapy. Consider giving patients a written questionnaire such as the Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), or Asthma Therapy Assessment Questionnaire (ATAQ).
    • The American Lung Association has endorsed the ACT, a 5-question self-assessment tool for patients. The ACT asks about symptoms experienced during the previous 4 weeks. Scores ≤19 (out of a possible 25) suggest inadequate asthma control worthy of discussion with a clinician.
    • Other scorecards include the ACQ³¹ and the ATAQ.³²
  • Objectively measure pulmonary function; initially check office spirometry, follow up with objective measures of lung function at each visit. If spirometry is not available, PEFR can be used.³³
  • Reinforce inhaler technique and asthma management plan.
  • Ensure compliance with environmental avoidance techniques, and consider additional efforts (add one at a time).
  • 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.³⁴
  • Consider modifying (stepping up or stepping down) doses of maintenance medications, if appropriate.

Prognosis

• Signs that may indicate a poor prognosis (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 (ED) visits per year
  • More than 2 short-acting beta-2 agonist metered-dose inhalers (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)

Patient Education

• Patient compliance rates for medications can be as low as 50%. Compliance with environmental measures, including mattress covers for dust mites, may be even worse. Health care professionals are also at fault, with only 63% of internists and only 81% of asthma specialists prescribing inhaled glucocorticoids according to recommended guidelines. In one study, more than 40% of patients did not feel that their asthma was well-controlled. Education reduces ED visits, but objective evidence for other outcome measures is limited. Adequate education programs for parents and/or patients include the following:
  • Asthma disease description
  • Identification and control of environmental triggers
  • Proper medication use: Take off the cap and shake the inhaler (not needed for dry-powder inhaler [DPI]). Breathe out deeply and hold the inhaler with lips pursed around the orifice or as far as 2 inches from the face or use a spacer. Depress the inhaler concurrent with slow inspiration. Hold breath for 10 seconds. Repeat until the desired dose is achieved (wait 1 min for short-acting beta-agonists).
  • Upper airway allergic symptoms: These can be an early warning system for allergic asthma.
  • Written self-management plan according to PEFR, exposure, and symptoms: For example, a drop below 80% is considered the yellow zone, and additional intervention is needed; a drop below 50% is considered the red zone (severe exacerbation), and the patient should seek medical assistance. While PEFR information has not been consistently shown to be of value over symptoms monitoring alone, the conservative approach would be to include this objective monitoring.
  • Parents with a history of allergies: These parents 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.
• Additional resources for health care professionals are available on the Internet and include the following:
  • Allergy & Asthma Network Mothers of Asthmatics 1-800-878-4403
  • American Academy of Allergy, Asthma, and Immunology 1-414-272-6071
  • American College of Allergy, Asthma and Immunology 1-800-842-7777
  • Lung information from the NHLBI 1-301-592-8573
  • American Lung Association 1-800-586-487
  • National Jewish Medical and Research Center 1-800-222-Lung
  • Association of Asthma Educators1-800-988-7747
  • Asthma and Allergy Foundation of America1-800-727-8462
  • Food Allergy & Anaphylaxis Network1-800-929-040
• For additional patient education resources, visit eMedicine's Asthma Center. Also, see eMedicine's patient education articles Asthma, Asthma FAQs, Occupational Asthma, and Understanding Asthma Medications.
• For asthma resources from Medscape and eMedicine, visit Asthma News and Articles, Asthma Clinical Reference, and Asthma CME.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize conditions in the differential diagnosis (eg, foreign body aspiration in a child)
• Failure to provide sufficient treatment for pregnant women
• Prescribing long-term inhaled beta-agonists without also prescribing inhaled corticosteroids.
  • The safety of long-acting beta-agonists has been questioned because of the SMART trial of approximately 25,000 patients, in which the respiratory- and asthma-related deaths were increased in the group that received salmeterol compared to placebo.¹⁵ (This signal was only statistically significant in African Americans.)
  • Most experts continue to recommend the addition of long-acting beta-agonists when disease is not adequately controlled by low- or medium-dose inhaled corticosteroids but stress that long-acting beta-agonists should not be used without inhaled corticosteroids.
  • Patients should be counseled regarding these findings when medications that contain a long-acting beta-agonist are to be prescribed. This discussion should be documented.³⁵
• Failure to provide short-term rescue agents (eg, inhaled beta-2 agonists) and long-term maintenance medications
• Failure to refer patients whose conditions are refractory to treatment to specialists and subjecting them to inappropriate long-term treatment (eg, long-term prednisone when the patient actually has vocal cord dysfunction [VCD])

Special Concerns

• Patients dependent on oral glucocorticoids: 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.
• Patients on long-acting beta-agonists: The safety of long-acting beta-agonists has been questioned because of the SMART trial of approximately 25,000 patients, in which the respiratory- and asthma-related deaths were increased in the group that received salmeterol compared to placebo (this signal was only statistically significant in African Americans).¹⁵ Most experts continue to recommend addition of long-acting beta-agonists when disease is not adequately controlled by low- or moderate-dose inhaled corticosteroids but stress that long-acting beta-agonists should not be used without inhaled corticosteroids. Patients should also be counseled about these findings whenever an inhaler containing these medications is prescribed.³⁵
• Infants and children younger than 4 years: Pulmonary function testing is difficult to perform because cooperation can be limited and reference ranges are not standardized. Fewer medications have been studied and approved for patients in this age group.
• Elderly patients: These patients frequently have other medical diseases that can mimic asthma and are more likely to experience adverse effects from asthma medications.
• Pregnant patients: Asthma affects up to 8% of pregnant women, and these patients should be treated similarly and possibly even more aggressively than other patients, given the detrimental effects of hypoxia on maternal and fetal outcomes. Generally during pregnancy, airway hyperreactivity (AHR) is stable to improved 69% of the time and worse 31% of the time. The following are specific interventions:
  • 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. 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 are category C.
  • Leukotriene pathway medications generally should not be used because of a lack of safety information, though 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.

References

1. Braman SS. The global burden of asthma. Chest. Jul 2006;130(1 Suppl):4S-12S. [Medline].

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Keywords

reactive airways disease, RAD, occupational asthma, reversible airway obstruction, increased bronchial reactivity, airway inflammation, passive smoke inhalation, allergic disease, aeroallergen exposure, viral respiratory illness, allergen-specific immunoglobulin E, allergen-specific IgE, allergen immunotherapy, airway hyperreactivity, AHR, airway remodeling, status asthmaticus, atopy, asthma triggers, nonallergic rhinitis, early allergic response, EAR, late allergic response, LAR, mite antigens, cockroach antigens, occupation-induced airway disease, occupation-induced asthma, industry-induced airway disease, industry-induced asthma, industrial asthma, occupational asthma, seasonal pollen allergens, mold spore allergens, dust mite allergens, animal allergens, food allergens, breath-actuated inhaler, BDI, dry-powder inhaler, DPI, metered-dose inhaler, MDI, breath actuated inhaler, dry powder inhaler, metered dose inhaler

Contributor Information and Disclosures

Author

William F Kelly III, MD, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Staff Physician, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Walter Reed Army Medical Center
William F Kelly III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, and American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

John J Oppenheimer, MD, Clinical Associate Professor, University of Medicine and Dentistry of New Jersey; Director 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 and American College of Allergy, Asthma and Immunology
Disclosure: AZ, Glaxo, Schering, Sepracor, Novartis/Genetic, Apieron Grant/research funds Other; AZ, Glaxo, Schering, Sepracor, Novartis/Genetic Honoraria Speaking and teaching

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, and American Thoracic Society
Disclosure: Nothing to disclose.

Medical Editor

Stephen Rosenfeld, MD, Professor Emeritus, Department of Medicine, Allergy, Immunology and Rheumatology Unit, University of Rochester School of Medicine and Dentistry
Stephen Rosenfeld, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American Federation for Clinical Research, Clinical Immunology Society, and Medical Society of the State of New York
Disclosure: Elan Ownership interest None; Invitrogen Ownership interest None; Merck Ownership interest None; Pfizer Ownership interest None; Medco Health Ownership interest None; Millipore Ownership interest None

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Stephen C Dreskin, MD, PhD, Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, 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 Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
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
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, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

The authors and editors of eMedicine gratefully acknowledge the contributions of author Rohit K Katial, MD, to the development of the previous edition of this article.

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