Good asthma management depends on prevention and optimal delivery of inhaled medications during attacks.

Asthma is a chronic inflammatory disease of the airways characterized by episodic symptoms (eg, wheezing, chest tightness, cough, dyspnea), variable airflow obstruction, and increased bronchial hyperresponsiveness. Exercise-induced asthma is a narrowing of the airways that occurs after 6 to 8 minutes of vigorous exercise. It affects 70% to 90% of all patients with asthma as well as 40% of children with allergies but no clinical signs of asthma.¹ Exercise-induced asthma usually peaks 3 to 12 minutes after stopping the exercise and resolves within 30 to 60 minutes.

It is estimated that approximately 15 million people in the United States have asthma.^2-4 An estimated 5 million children have asthma, making it the most common chronic disease of childhood.^2-4 Based on data collected from the 2000 Behavioral Risk Factor Surveillance System (BRFSS) survey,⁵ approximately 7.2% of adults residing in the United States report having asthma, and 10.5% of US adults report having had asthma at some time in their lives. This represents an increase of nearly 80% in the prevalence rate of asthma among adults since 1980.

The increase in asthma prevalence in children is even more striking. During the years 1990 to 1992, when the overall prevalence of asthma was 4.6%, the prevalence for persons under 18 years of age was 6.1%.⁶ Although the prevalence of asthma has increased across all age groups, it has been most pronounced among children between infancy and 4 years of age.⁴

An analysis of trends in the cost of illness for asthma revealed that, of the 12 million visits to hospital emergency departments annually due to respiratory system diseases, 1.6 million were by patients with a primary diagnosis of asthma.⁷ Asthma-related emergency department use could be reduced significantly with improvements in trigger identification and avoidance and implementation of efforts to improve adherence with the therapeutic regimen.

General Asthma Management Principles
The role of patient education in achieving adequate asthma control is well documented.^8,9 Pharmacoeconomic and quality-of-life benefits also have been demonstrated when a patient education program is included in the asthma management plan.^10,11 Asthma education entails repeated instruction on avoiding allergens or other irritants known to exacerbate symptoms, as well as the correct use of rescue medications, inhalers, and peak-flow monitors.

Periodic assessment and monitoring of symptoms and signs, lung function, quality of life, frequency of exacerbations, drug therapy (compliance, side effects), and patient satisfaction with care are necessary to ensure that the goals of management are being met. Patients can be instructed when to contact their physicians for advice, when to step up reliever therapy, when to initiate or step up anti-inflammatory therapy, and when to seek emergency department care on the basis of symptoms and response to treatment.

Drug Treatment
b2-Agonists. b2-agonists are the most effective form of bronchodilator therapy.³ Most of these agents are short-acting, with rapid onset of action, making them the drug of choice for managing acute exacerbations. Short-acting agents also are used to prevent exercise-induced asthma exacerbations by administration 15 minutes prior to exercise. Short-acting agents include albuterol, levalbuterol (R-albuterol), bitolterol, pirbuterol, and terbutaline.

Long-acting b2-agonists, which include inhaled salmeterol and oral sustained-release albuterol, typically have a duration of bronchodilation of 12 hours following a single dose, and are used as an adjunct to anti-inflammatory therapy for the long-term control of symptoms. The magnitude of bronchodilation produced by long-acting b2-agonists is generally equivalent to that of short-acting formulations. The bronchodilator effect produced by long-acting b2-agonists may mask increased airway inflammation. One study of salmeterol therapy used bronchoalveolar lavage inflammatory indices to examine conflicting claims that long-acting b2-agonists may have an anti-inflammatory effect or that they may worsen asthma control; the study was unable to demonstrate a significant change in either direction.¹² It is, however, important to note that the bronchoprotective effect of these agents may decrease over time. For this reason, patients should be instructed not to depend on prompt relief from long-acting b2-agonists during acute asthma attacks.^13,14

Long-acting b2-agonists are used primarily in combination with inhaled corticosteroids when symptoms are insufficiently controlled on corticosteroids alone, and they may be useful in controlling nighttime symptoms. The addition of inhaled salmeterol to low- or medium-dose inhaled corticosteroids has been shown to be more effective in improving lung function and symptom control than doubling the dose of corticosteroids.^15,16

Corticosteroids. Inhaled corticosteroids have been established as the most effective agents for long-term control of asthma because of their potent anti-inflammatory effect.³ Although their mechanism of action is not completely understood, they inhibit the production of cytokines and nonspecifically interrupt the inflammatory process.¹⁷ They are clinically effective in reducing airway hyperresponsiveness and inhibiting the late allergic reaction. Symptom control, particularly at night, can be enhanced by adding a long-acting b2-agonist. Inhaled corticosteroids used in the treatment of asthma include beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide.

The propensity for adverse effects with inhaled corticosteroids is modest if they are used properly and are well balanced by the significant clinical benefits achieved with these agents. Despite this generally favorable safety profile, the potential for adverse systemic effects—particularly when used in high doses—remains a concern.¹⁸ In general, however, use of low-to-moderate doses of systemic corticosteroids is not a major concern.

Oral corticosteroids such as methylprednisolone, prednisolone, and prednisone may be useful for the treatment of severe asthma flare-ups. Early recognition of failure of bronchodilators to reverse an episode is key to successful treatment of severe asthma flare-ups. Because oral corticosteroids usually take 12 to 24 hours to become effective, it is important to initiate use early in a flare-up.

Some patients with severe asthma need oral corticosteroids on a long-term basis. Alternate-day dosing is preferred, and ongoing attempts should be made to find the minimum dose required for control. Potential long-term side effects include cataracts, osteoporosis, weight gain, skin fragility, fluid retention, growth suppression, exacerbation of diabetes, and suppression of the hypothalamic-pituitary-adrenal axis.

Leukotriene Modifiers. Leukotrienes, a family of lipid mediators derived from arachidonic acid, are produced by leukocytes and many other cells, including those found in the lung. Leukotrienes are potent mediators of airway smooth muscle contraction that work late in the inflammatory cascade by increasing vascular permeability as well as mucous secretions, and recruiting and activating inflammatory cells in asthmatic airways.^19,20 Currently available leukotriene modifiers work by blocking the enzyme 5-lipoxygenase, thereby inhibiting the lipoxygenase pathway of arachidonic acid metabolism (zileuton), or by preventing leukotrienes from binding to their receptors (montelukast and zafirlukast).

Leukotriene modifiers are administered orally once or twice daily, and may be used as monotherapy for patients with mild to moderate asthma, or as an adjunct to inhaled corticosteroids to enhance control in moderate to severe asthma. They also may be useful for patients with exercise-induced asthma and are well tolerated. However, the ability of leukotriene modifiers to provide long-term control of asthma symptoms has recently been called into question. One retrospective analysis of five randomized, double-blind, double-dummy 4- to 12-week studies of 1,742 asthma patients found that treatment with leukotriene modifiers resulted in small improvements in asthma symptoms, minimal improvements in lung function, and increases in asthma exacerbations; whereas treatment with inhaled corticosteroids significantly improved pulmonary function and overall asthma control.²¹

Anticholinergic Agents. Cholinergic innervation is an important factor in the regulation of airway smooth muscle tone. Anticholinergic agents produce bronchodilation by inhibiting muscarinic cholinergic receptors. They also reduce intrinsic vagal tone in the airways, and may decrease mucus gland secretion. Anticholinergic agents used in the treatment of asthma include ipratropium bromide and tiotropium bromide.

Cromones. According to the National Asthma Education and Prevention Program (NAEPP) Expert Panel of the National Institutes of Health (NIH), cromolyn sodium and nedocromil have been shown to provide symptom control greater than that achieved with placebo in some clinical trials, and reduce the number of asthma exacerbations leading to hospitalization, particularly in children.² These results, along with a favorable safety profile, justify consideration of these medications as treatment options. The overall efficacy of cromones has been called into question, however; therefore, the NAEPP recommends that inhaled corticosteroids should be the preferred treatment option for mild persistent asthma in adults and, by extrapolation until published comparison data become available, for children.²

Methylxanthines. Theophylline is a methylxanthine bronchodilator that is sometimes used for long-term control of symptoms, particularly for nighttime symptoms. It can, however, produce gastrointestinal (gastric upset) and central nervous system (insomnia) symptoms, even at the usual therapeutic doses. It may also reduce lower esophageal sphincter tone, thereby predisposing patients to gastroesophageal reflux. Toxicities are dose related and can include tachycardia, nausea, central nervous system stimulation, hyperglycemia, hypokalemia, and seizures.²² Because of its narrow therapeutic window, serum monitoring of serum theophylline concentration is mandatory.

Humanized Monoclonal Antibody to IgE. In the past few years, our understanding of the pathogenesis of asthma has advanced considerably. Asthma is now recognized as an allergic disease mediated by a number of molecules, including immunoglobulin E (IgE), a glycoprotein central to immune mediators in allergic responses. Specific high-affinity receptors on mast cells, basophils, and Langerhans cells bind through the constant (Fc) region of IgE antibodies. In the sensitized individual, when allergen infiltrates the airways and binds to IgE on mast cells, it triggers the release of multiple mediators that produce allergic symptoms. IgE also binds to low-affinity receptors on the surface of B cells, macrophages, and other cells, suggesting that IgE antibodies may modulate inflammatory and immune activities by other mechanisms.^23-25

Humanized monoclonal antibodies (MAbs) against IgE represent a significant advance in asthma pharmacotherapy. Anti-IgE MAbs have the ability to inhibit binding of free IgE to cell membrane receptors.^26-28 Omalizumab, the first humanized anti-IgE MAb, was developed to interfere early in the allergic process by targeting the source of allergy symptoms. By binding to circulating IgE in the blood, this antibody blocks the release of inflammatory mediators by keeping the IgE from binding to mast cells.²⁷ These inflammatory mediators, which include histamine, prostaglandins, and leukotrienes, play a role in the pathogenesis of allergic diseases such as allergic asthma, allergic rhinitis, and atopic dermatitis. This approach is an important step forward, because severe asthma is poorly controlled by existing therapies other than oral corticosteroids. Omalizumab is administered subcutaneously once every 2 or 4 weeks depending on baseline serum total IgE level and body weight. It has been evaluated in adolescents and adults with moderate to severe allergic asthma in two multicenter, randomized, double-blind, placebo-controlled trials designed to measure clinical outcomes, such as effect on symptoms and effect on number of exacerbations.^26,29 The study population in both of the trials (which were of similar design) was made up of 1,071 patients whose asthma was inadequately controlled despite daily inhaled corticosteroid treatment. In both studies, the addition of omalizumab to a constant dose of inhaled corticosteroids resulted in a significant reduction in the frequency of exacerbations compared with inhaled-corticosteroid treatment alone. In addition, omalizumab treatment resulted in a significantly greater reduction in cortico-steroid requirement than placebo.

Magnesium. Recent research has focused on the role of magnesium in the pathogenesis of asthma. Reduced intracellular magnesium stores may be related to bronchospasm in the general population, although there does not appear to be a therapeutic role for dietary magnesium in patients with chronic stable asthma.³⁰ Some studies, though, have suggested that intravenous (IV) administration of magnesium sulfate may improve bronchodilation in patients with an acute exacerbation of asthma.^31,32 In a relatively recent meta-analysis of IV magnesium sulfate for acute asthma attacks in the emergency department, the therapeutic benefits clearly outweighed the risks.33 Further research is needed to more definitively establish the role of IV magnesium in patients with acute asthma attacks.

Value of Spirometry
Spirometry measures the rate at which the lung changes volume during forced breathing maneuvers. Spirometry begins with a full inhalation, followed by a forced expiration that rapidly empties the lungs. Expiration is continued for as long as possible or until a plateau in exhaled volume is reached. These efforts are then measured, recorded, graphed, and analyzed.

Spirometry is a powerful tool that can be used to detect, follow, and manage patients with asthma and other lung disorders. Technologic advancements have made spirometry much more reliable than it used to be and relatively simple to incorporate into a routine office visit. The National Lung Health Education Program (NLHEP) recommends the widespread use of office spirometry for diagnosis, for assessment of symptom severity, and to monitor the effectiveness of treatment in patients with known or suspected chronic lung disease.³⁴

Spirometry is also used to categorize the severity of asthma. The NAEPP defines⁴ general categories of asthma severity according to spirometric measurements^1-3: mild intermittent asthma is characterized by an FEV1 or PEF of 80% or more of the predicted value and a PEF variability of less than 20%. Mild persistent asthma is characterized by an FEV1 or PEF of 80% or more of the predicted value, with a PEF variability of 20% to 30%. Moderate persistent asthma is characterized by an FEV1 or PEF of more than 60% but less than 80% of the predicted value and a PEF variability of more than 30%. Severe persistent asthma is categorized by an FEV1 or PEF of 60% or less of predicted value and a PEF variability of more than 30%.

Spirometry, in conjunction with an exercise challenge, can be useful in establishing the diagnosis of exercise-induced asthma. At home, PEF monitoring is an important component of managing exercise-induced asthma; patients should avoid exercising if PEF is low (ie, falls 20% below the predicted or personal best value).^2,3

Special Considerations in Exercise-Induced Asthma
All asthma patients should be encouraged to exercise. The challenge in patients with exercise-induced asthma, however, is to engage in exercise without precipitating an attack of exercised-induced asthma. There are several tips respiratory care practitioners can give their patients to avoid exercise-induced asthma attacks. These include: 1) taking an inhaled b2-agonist or cromolyn <30 minutes before exercising (if prescribed); 2) warming up and cooling down when exercising; 3) exercising in warm humid air or covering the face when the air is cold; 4) avoiding exercising outside in the afternoon and evening when pollen, mold, or ozone counts are high; and 5) avoiding exercising altogether when asthma is unstable or PEFs are low.¹

Optimizing Drug Delivery
Respiratory care personnel can optimize therapy by ensuring maximal drug delivery of inhaled medications. This includes an appropriate choice of drug-delivery device and correct technique. Poor metered-dose inhaler (MDI) technique is a common problem. Several studies have shown that less than 50% of patients demonstrate correct technique.³⁵ Lack of adequate instruction may contribute to this problem. Fewer than 50% of patients use correct MDI technique after receiving only written instructions.³⁶ Demonstrating MDI technique to the patient has been shown to improve the effectiveness of instruction.³⁷ Some patients may require several attempts to achieve adequate technique. In addition, a significant proportion of patients may require repeated review and instruction in order to maintain correct technique.

Some patients may require either spacing devices or an alternative route of drug administration. Young children may also need a spacer (with or without face masks) or nebulizers. Different sizes of face masks and spacers are available. All patients receiving inhaled corticosteroids should use a spacing device if the drug delivery system prescribed does not have one built-in. Selection of a drug delivery system that facilitates correct MDI technique and has a built-in spacer may reduce or eliminate problems with suboptimal drug delivery. Patients should also be counseled to rinse their mouth and spit after use of inhaled corticosteroids to avoid local side effects.

Summary
Asthma and exercise-induced asthma are global problems that appear to be on the rise. Both can cause significant morbidity and mortality, and may result in enormous health care utilization and societal costs. Good management of the patient with asthma depends on appropriate pharmacotherapy and methods to optimize drug delivery of inhaled medications. For patients with exercise-induced asthma, preventive measures before exercise may mitigate the chances of having an exacerbation.

John D. Zoidis, MD, is a contributing writer for RT.

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