Jeffrey Stokes, MD

Asthma is a chronic respiratory disease affecting 20 million people in the United States, including 6.1 million children. Allergies are among the most common risk factors for the development of asthma, and they often trigger acute episodes. Because the economic and health care burden of asthma has increased over the past 20 years, physicians should be familiar with current management guidelines, as well as with the many medications available. Early diagnosis and appropriate treatment can prevent asthma exacerbations and improve the quality of life of patients.

Objective testing with spirometry or bronchoprovocation are necessary for the diagnosis of asthma.  

Allergens are a common trigger of asthma exacerbations in adults and children.  

-agonists are the most effective medications for relieving acute bronchospasm or acute exacerbations of asthma. 

Asthma is a chronic inflammatory disorder of the airways that affects 20 million people in the United States,

The burden of asthma has increased during the past 2 decades. In 2002, asthma accounted for 13.9 million outpatient visits, 1.9 million emergency department visits, 484,000 hospitalizations, and 4261 deaths.

The inflammation in asthma is associated with reversible airway obstruction and hyperresponsiveness of the airways to a variety of stimuli.

Asthma is extremely heterogenous, with a wide variety of genetic, environmental, psychosocial, and biologic factors contributing to many disease presentations. 

Asthma is classified according to the frequency of symptoms and objective pulmonary function measurements. Individuals with any severity of disease, including mild intermittent, can have a severe, life-threatening exacerbation, and the disease can change in severity over time. 

Environmental or "allergic" extrinsic asthma is a subclassification of asthma that is based on a precipitating exogenous, allergic cause. In intrinsic asthma, no allergic cause is identifiable. Some 90% of asthmatics younger than 16 years, 70% of those younger than 30 years, and 50% of those older than 30 years have allergic asthma.

The common symptoms of asthma are also seen in a variety of other conditions, resulting in an extensive differential diagnosis (Table 1). As with any disease, the key to diagnosis is a detailed history and physical examination. 

Typically, asthma is characterized by sudden or recurrent episodes of coughing and wheezing and/or shortness of breath, which are often worse at night. From 50% to 80% of asthmatic children develop symptoms in the first 5 years of life.

Depending on the susceptibilities of the individual patient, symptoms may develop or worsen in response to triggers, such as exercise, viral infection, changes in the weather, emotional stress, menses, airborne chemicals, dust, or a variety of allergens, including animal dander, house-dust mites, and mold. 

Other risk factors include a family history of allergy or asthma, bronchial hyperresponsiveness, atopy, viral respiratory illness, cigarette smoking or passive exposure to tobacco smoke, low socioeconomic status, and black or Hispanic ethnicity.

The physical examination focuses on assessment of the upper respiratory tract, chest, and skin. Inspiratory and expiratory rhonchi and wheezes, a prolonged exhalation phase, and hyperexpansion of the thorax are typical findings. Anormal chest examination does not rule out asthma, because significant respiratory compromise can be present without wheezing. Patients with severe airway obstruction can have other symptoms, such as tachycardia, tachypnea, the use of accessory muscles for breathing, or pulsus paradoxus (an exaggerated fall of systolic blood pressure on inspiration). Patients with concomitant rhinitis may exhibit increased nasal secretions, nasal mucosal swelling, and occasionally nasal polyps. Rhinitis is present in up to 75% of patients with asthma.

Atopic dermatitis or eczema is common, especially in younger patients. 

Without objective tests, physicians can correctly predict pulmonary function only about 50% of the time and correctly diagnose asthma only about 63% to 74% of the time.

can confirm the diagnosis of asthma based on objective measures of reversible airway obstruction or airway hyperresponsiveness. The parameters measured before and after using a shortacting bronchodilator to identify reversible airway obstruction are forced expiratory volume in 1 second (FEV

), forced vital capacity (FVC), and ratio of FEV

 to FVC. Clinically significant reversibility is defined as an increase in FEV

of 12% or more and 200 mL after administration of a short-acting bronchodilator or after treatment with corticosteroids.

Normally, the volume exhaled in 1 second is approximately 80% of total volume, and the volume after 3 seconds is equal to FVC. In obstructive lung disease, lung volume exhaled after 1 second is less than 80% of total; after 3 seconds, the volume exhaled is still less than the FVC. 

Another useful measure is the flow-volume loop, formed by plotting both inspiratory and expiratory flow versus volume. A flow-volume maneuver is accomplished by initial tidal breathing followed by a maximal inspiration with a maximal forced exhalation. Airway obstruction is noted by a concave expiratory flow loop. The peak expiratory flow, also known as the forced expiratory flow maximum (FEF

), is at the apex of the expiratory curve. The FEF

is effort-dependent; it will decrease in obstructive lung disease but is not as sensitive a measure of airway obstruction as FEV

Perform spirometry at the initial assessment and after the patient's symptoms have been stabilized.

 Repeat at least every 1 to 2 years thereafter to assess airway function. Frequency of spirometry testing depends on the severity of asthma; patients with more severe disease require more frequent spirograms. 

. When spirometry results are normal in a patient with high clinical suspicion of asthma, bronchoprovocation with methacholine chloride (Provocholine) or an exercise challenge can be helpful in diagnosing airway hyperresponsiveness. Methacholine inhalation challenges are Food and Drug Administration (FDA)-approved tests with standardized reagents and procedures. A positive challenge is expressed as either the provocative concentration (PC

) administered that resulted in a 20% decline in FEV

, the greater the airway responsiveness. Airway reactivity would also be increased in allergic rhinitis, cystic fibrosis, chronic obstructive pulmonary disease, and viral infections or recent oxidant exposure in healthy patients.

A positive methacholine challenge does not definitively diagnose asthma, especially in an atopic patient, but a negative challenge renders the diagnosis unlikely. 

For patients with exercise-induced bronchospasm (EIB), an exercise challenge or hyperventilation of cold, dry air simulates the conditions that usually induce bronchospasm.

Typically in EIB, the maximal fall in FEV

occurs within 10 to 15 minutes after exercising. A decrease in FEV

of 10% from baseline is suspicious for EIB, while a decline of 15% or more is diagnostic.

Up to 40% of nonasthmatic atopic individuals may demonstrate EIB, whereas only 6% to 13% of the general population has bronchospasm.

Asthma is frequently associated with concurrent atopy, which is often referred to as extrinsic asthma. Skin or in vitro testing (eg, radioallergosorbent tests) can reliably determine the presence of antigen-specific immunoglobulin (Ig)E

and define specific aeroallergen sensitivity. 

Allergens are a common trigger of asthma exacerbations in adults and children. Sensitization to indoor allergens, such as house-dust mites, animal dander, or cockroaches, and the outdoor fungus 

are significant risk factors for developing asthma. Outdoor pollens, such as grass or ragweed, are commonly associated with seasonal asthma exacerbations.

Allergy testing and consultation with an allergist/immunologist are helpful in patients with a suspected allergic component. Patients with asthma, especially those with persistent disease, should be questioned about exposure to inhalant allergens at home, at school, and in the workplace. 

Pharmacologic therapy for asthma is typically determined by the severity and characteristics of the disease (eg, acute or persistent asthma). The goals of asthma therapy include preventing symptoms and exacerbations and obtaining normal or near-normal lung function. 

A stepped-care approach is recommended to keep symptoms and rescue bronchodilator use to a minimum. Initiate therapy at a higher step than the patient's actual level of severity to quickly establish control, and then step down to the minimum medication necessary to maintain that control. In 2002, the National Institutes of Health updated its detailed treatment algorithm.

Some medications are used in the acute setting only, whereas others are designed for the long-term control of asthma. 

-agonists?including albuterol (AccuNeb, Proventil, Ventolin), pirbuterol (Maxair Autohaler), bitolterol (Tornalate), metaproterenol (Alupent), levalbuterol (Xopenex; the pure isomer of albuterol), and terbutaline (Brethine)?are the most effective medications for relieving acute bronchospasm or acute exacerbations of asthma. Their onset of action is within 15 minutes, with peak improvement seen in less than 60 to 90 minutes; their bronchodilatory effect may persist for 3 to more than 6 hours.

Regularly scheduled daily use is not recommended. Patient use of more than 1 canister per month of a short-acting beta

-agonist indicates inadequate asthma control.

 Common side effects include tremor, tachycardia, and nervousness. 

-agonists, such as salmeterol xinafoate (Serevent Diskus) or formoterol fumarate (Foradil Aerolizer), are used for maintenance therapy and are not appropriate for acute exacerbations (Table 2). These agents should not be used as monotherapy; they should be added to inhaled corticosteroid therapy for patients with moderate-to-severe persistent asthma. 

Better asthma control has been demonstrated when long-acting beta

-agonists are added to baseline inhaled corticosteroids than when doubling the dose of the inhaled steroids.

Combination therapy with inhaled corticosteroids and long-acting beta

-agonists is the preferred treatment for patients older than 5 years who have moderate-to-severe persistent asthma.

Theophylline (eg, Bronkodyl, Elixophyllin, Theolair) produces airway smooth muscle relaxation and bronchodilation and has some mild anti-inflammatory effects. Even though it is a bronchodilator, it is generally not recommended for acute exacerbations. Theophylline is indicated for the long-term control and prevention of asthma symptoms, either as monotherapy or as add-on therapy to inhaled corticosteroids. Because of its narrow therapeutic index, it is essential to maintain drug levels between 5 and 15 ?g/mL to avoid dose-related side effects, such as nausea, vomiting, epigastric pain, palpitations, tachycardia, seizures, or hypotension. 

Cromolyn sodium (Intal, Nasalcrom) and nedocromil sodium (Tilade) are anti-inflammatory maintenance medications that act on chloride channels. Beneficial effects typically occur in the first 2 weeks but may take up to 4 to 6 weeks. These agents can be used as an alternative, albeit a less effective one, to low-dose inhaled corticosteroids in patients with mild persistent asthma.

The 4-times daily dosing regimens make these agents less desirable than drugs that can be dosed once or twice daily. 

Leukotriene modifiers can be used for both longterm control and for the prevention of asthma symptoms. The 2 classes of leukotriene modifiers are leukotriene receptor antagonists, such as zafirlukast (Accolate) and montelukast sodium (Singulair), and leukotriene synthesis inhibitors, such as zileuton (Zyflo). Leukotriene receptor antagonists are selective competitive inhibitors of cysteinyl leukotriene 1 receptors. These medications have shown efficacy in mild persistent asthma and EIB as monotherapy and as add-on therapy to inhaled corticosteroids in moderate-to-severe persistent asthma.

Zileuton inhibits 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid, but its 4-times daily dosing and side effects involving elevated liver enzymes have limited its usefulness. The 2002 National Asthma Education and Prevention Program guidelines recommend leukotriene modifiers as an alternative therapy to low-dose inhaled corticosteroids in patients with mild persistent asthma.

Because of their potent anti-inflammatory activity, inhaled corticosteroids are the most effective long-term agents for persistent asthma.

They are available as metered- dose inhalers, dry-powder inhalers (DPI), and nebulizer solutions (Table 3). Their maximum therapeutic benefit may not be achieved for 1 to 2 weeks or longer after initiation of treatment, although some improvement has been observed within the first 24 hours.

The newest addition to this class of drugs is the once-daily DPI mometasone furoate (Asmanex), which received FDA approval in March 2005. It is indicated for use as maintenance therapy in adults and children 12 years and older and as add-on therapy. In clinical trials, mometasone dosed daily in the evening has been shown to be as effective as either budesonide twice daily or fluticasone twice daily in controlling asthma symptoms and lung function.

Systemic side effects with inhaled corticosteroids are rare and depend on the dose and potency of the agent, the amount deposited in the lungs, and the oral bioavailability of the portion swallowed. The delivery device and the propellant affect lung deposition and potential local side effects, such as oral candidiasis, dysphonia, or reflex cough. Recent long-term growth studies in children have demonstrated an initial mild decrease in linear height, but cumulative decreases were not shown, and there was no effect on final adult height.

The exact risk of osteoporosis and fracture after long-term use of inhaled corticosteroids in adult asthmatics is still unclear.

To help reduce the dosage and the resulting systemic side effects, a long-acting beta

-agonist should be added for patients with moderate- to-severe persistent asthma.

Jeffrey Stokes, MD

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