The Approach to the Patient with Allergic Asthma

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.

Jeffrey Stokes, MDAssistant Professor of Medicine

Professor and Associate Chair,

Chief, Division of Allergy/Immunology

Division of Allergy/Immunology,

Omaha, Neb

PRACTICE POINTS

• 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.
• Short-acting beta²-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,¹ 6.1 million of whom are children.² 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.³ The inflammation in asthma is associated with reversible airway obstruction and hyperresponsiveness of the airways to a variety of stimuli.⁴ 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.⁵

Making the Diagnosis

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.

The history

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.⁶ 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.⁷

The physical examination

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.⁸ Atopic dermatitis or eczema is common, especially in younger patients.

Objective testing

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.⁹

Spirometry testing

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 (FEV₁), forced vital capacity (FVC), and ratio of FEV₁ to FVC. Clinically significant reversibility is defined as an increase in FEV¹ of 12% or more and 200 mL after administration of a short-acting bronchodilator or after treatment with corticosteroids.¹⁰ 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^max), is at the apex of the expiratory curve. The FEF^max is effort-dependent; it will decrease in obstructive lung disease but is not as sensitive a measure of airway obstruction as FEV₁.

Perform spirometry at the initial assessment and after the patient's symptoms have been stabilized.⁴ 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.

Bronchoprovocation testing

. 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 (PC²⁰) or dose (PD²⁰) administered that resulted in a 20% decline in FEV₁. The lower the PC²⁰ or PD²⁰, 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.⁵ 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.⁵ Typically in EIB, the maximal fall in FEV¹ occurs within 10 to 15 minutes after exercising. A decrease in FEV¹ of 10% from baseline is suspicious for EIB, while a decline of 15% or more is diagnostic.⁵ Up to 40% of nonasthmatic atopic individuals may demonstrate EIB, whereas only 6% to 13% of the general population has bronchospasm.¹¹

Allergy testing

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)E⁵ and define specific aeroallergen sensitivity.

Alternaria

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.⁴

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.

Drug Therapy

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.⁴

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

Beta²-adrenergic agonists

Short-acting beta²-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.¹² Regularly scheduled daily use is not recommended. Patient use of more than 1 canister per month of a short-acting beta²-agonist indicates inadequate asthma control.⁴ Common side effects include tremor, tachycardia, and nervousness.

Long-acting beta²-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 beta²-agonists are added to baseline inhaled corticosteroids than when doubling the dose of the inhaled steroids.¹³ Combination therapy with inhaled corticosteroids and long-acting beta²-agonists is the preferred treatment for patients older than 5 years who have moderate-to-severe persistent asthma.¹⁴

Theophylline

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 and nedocromil

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.¹⁴ The 4-times daily dosing regimens make these agents less desirable than drugs that can be dosed once or twice daily.

Leukotriene modifiers

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.¹⁵ 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.¹⁴

Inhaled corticosteroids

Because of their potent anti-inflammatory activity, inhaled corticosteroids are the most effective long-term agents for persistent asthma.¹⁴ 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.¹⁶

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.^17,18

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.^19,20 The exact risk of osteoporosis and fracture after long-term use of inhaled corticosteroids in adult asthmatics is still unclear.⁷ To help reduce the dosage and the resulting systemic side effects, a long-acting beta²-agonist should be added for patients with moderate- to-severe persistent asthma.¹⁴

Oral or parenteral corticosteroids

Corticosteroids administered orally have potent anti-inflammatory activity, generally within 24 hours. Oral corticosteroids are used as short-term (ie, 3-10 days) therapy at approximately 1 to 2 mg/kg daily during asthma exacerbations or rarely for long-term treatment in select patients with severe, persistent asthma patients (in alternate-day or low daily doses). Reversible side effects associated with short-term use include increased appetite, fluid retention, and mood alteration. There is generally no need to taper corticosteroids when they are given as short bursts. Long-term use can lead to serious side effects, such as hypothalamic-pituitary-adrenal function suppression, hypertension, Cushing's syndrome, or muscle weakness. These drugs should be carefully tapered when used long-term.

Allergen Therapy in the Asthmatic Patient

Allergies are among the most common risk factors for the development of asthma, and they often trigger acute episodes. The presence of comorbid conditions, such as gastroesophageal reflux, sinusitis, or seasonal allergic rhinitis needs to be assessed and, if found, treated. Once allergens are identified in asthmatic patients, specific therapies should be instituted, such as allergen avoidance or allergen immunotherapy, in addition to the traditional asthma treatments.

If atopy is present, avoidance of precipitating triggers, such as by using encasement of pillows and mattresses for patients with dust-mite allergy, or pet avoidance in patients with pet allergies, can improve control. Oral antihistamines, though effective for allergic rhinitis and urticaria, are not as effective for treating allergic asthma.

Allergen immunotherapy, or "allergy shots," is effective in treating allergic rhinitis as well as allergic asthma. Allergen immunotherapy desensitizes patients to the specific allergens contained in the extracts, thus making them less allergic over time. Generally, allergen immunotherapy is given for several years.^21,22

Immunotherapy is the only therapy to date that has been shown to reduce the incidence of new sensitizations to other allergens as well as to prevent the development of asthma in patients with allergic rhinitis.²² Allergen immunotherapy should only be administered after appropriate testing and consultation with an allergy/immunology specialist.

In 2003, the FDA approved the first anti-IgE monoclonal antibody (omalizumab [Xolair]) for the treatment of moderate-to-severe allergic asthma in patients 12 years and older.

Omalizumab has been shown to reduce the number and incidence of asthma exacerbations in allergic asthma, lessen the need for corticosteroids and rescue medications, increase the time to first exacerbation, and reduce the likelihood of hospitalization and rehospitalization.^23-25 However, this drug appears to be most effective in patients with more severe disease.²⁶ Like immunotherapy, it should only be prescribed in consultation with a specialist. It is given subcutaneously every 2 to 4 weeks, depending on the total serum IgE level and the patient's weight.

Conclusion

Asthma is a chronic inflammatory pulmonary disorder that requires avoidance of allergic and other triggers. Early and appropriate treatment is necessary to reduce morbidity and mortality and improve the patient's quality of life. Once the disease is under control, a stepped approach is recommended for maintenance therapy. The minimum effective dose of inhaled corticosteroids and other agents should be chosen to decrease the risk of side effects. Appropriate treatment of allergic asthma will allow patients to engage in normal daily activities and minimize limitations.

Disclosure statement

Dr Casale is on the speaker's bureau of Aventis, Genentech, Novartis, and Merck. He has also received grant/research support from Capnia, Corixa, Dynavax, Genentech, IDEC, MediciNova, Merck, NIAID/ITN, Novartis, Ono, and Pfizer. He has been on Hoffman-Laroche's Data Safety Monitoring Board, and has been a consultant for Allux, Aperon, Aventis, Corixa, Genentech, Merck, Novartis, and Sugitomo. Dr Stokes has nothing to disclose.

SELF-ASSESSMENT TEST

1. Which of the following criteria is the best diagnostic criterion for allergic asthma?

• Normal chest x-ray
• Positive allergy skin tests

2. Which of the following disorders most frequently coexists with allergic asthma?

• Allergic rhinitis
• Vocal cord dysfunction

3. Risk factors for the development of allergic asthma include:

• Allergen immunotherapy for allergic rhinitis

Alternaria

• Family history of food allergy

4. Which of the following drugs would be the best "rescue" treatment for acute exacerbations?

• Montelukast
• Albuterol

5. Which of these drug classes is considered to be the most effective long-term controller for patients with persistent asthma?

• Leukotriene modifiers
• Long-acting beta²-agonists

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Answers:

1. D; 2. B; 3. C; 4. D; 5. A