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Concise Review for Clinicians

Management of Persistent Symptoms in Patients With Asthma


KAISER G. LIM, MD
The main goals of asthma therapy are to control symptoms, prevent acute attacks, and maintain lung function as close to normal as possible. Customizing the regimen to relieve the patients symptoms and control airway inflammation is important. If asthma is not well controlled, an initial inhaled corticosteroid boost will treat the underlying heightened airway inflammation, and the addition of a long-acting 2-adrenergic agonist or leukotriene receptor antagonist will rapidly control symptoms. Most patients do not require prolonged treatment with expensive combination or additive agents. Exercise-induced bronchoconstriction is a common source of symptoms. Treatments for scheduled and unscheduled exercises differ. Inhaled corticosteroids prevent frequent and severe asthma exacerbations. When patients have persistent symptoms despite a pharmacological regimen, environmental factors and nonpharmacological interventions must be considered before medication is increased. When an inhaled corticosteroid is being considered, issues of compliance, drug delivery device, and proper inhaler techniques are as important as issues of potency, clinical efficacy, and adverse effects. The new hydrofluoroalkane preparations offer more lung deposition and may be important in treating inflammation of the small airways in patients with asthma. Mayo Clin Proc. 2002;77:1333-1339
EIB = exercise-induced bronchoconstriction; FEV1 = forced expiratory volume in 1 second; HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; pMDI = pressurized metereddose inhaler

ontrol of asthma symptoms is important since patients experience respiratory difficulty. Symptoms do not always correlate strongly with objective measures of airway dysfunction, airway inflammation, or corticosteroid requirement.1-3 As a therapeutic end point, resolution of asthma symptoms is not always synonymous with resolution of the underlying airway obstruction and hyperresponsiveness.4,5 Symptoms rather than underlying disease severity reflect the level of asthma control.6 This fact is important because symptom-based severity categorization is often used to guide therapeutic decisions. Titrating anti-inflammatory medication based on symptoms is an imperfect science. High proportions of patients with asthma do not reliably detect changes in their lung function.7-9 The perception of dyspnea associated with bronchoconstriction varies among patients.10 There is wide variability in bronchodilator use, even for similar degrees of bronchoconstriction. The initial choice of anti-inflammatory therapy is an inhaled corticosteroid (ICS).11 The prescribed initial dose often reflects the physicians clinical assessment of asthma severity.6 In the United States, specialists tend to pick higher doses, whereas internists and pediatricians prescribe
From the Division of Pulmonary and Critical Care Medicine and Internal Medicine, Mayo Clinic, Rochester, Minn. A question-and-answer section appears at the end of this article. Address reprint requests and correspondence to Kaiser G. Lim, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2002;77:1333-1339 1333

lower doses of an ICS. Once the initial dose of ICS has been determined, clinicians must choose an appropriate strategy if the patient continues to be symptomatic. This is the so-called step 3 option. However, several aspects of anti-inflammatory therapy are unclear. For example, the treatment regimen necessary to control asthma symptoms may be insufficient for resolving inflammation, maximizing airway function, and preventing the accelerated longitudinal decline in lung function.12 Additionally, it is unclear whether complete resolution of airway inflammation results in normalization of other features of asthma, ie, bronchial hyperresponsiveness and stabilization of airway function.13 A noninvasive, clinically convenient test to detect and measure airway inflammation does not exist. There is no equivalency of glycosylated hemoglobin to gauge adequacy of anti-inflammatory therapy. With no objective measure of inflammation, titration of therapy has been used to achieve symptomatic control. A highly symptomatic patient may require only a small dose of an ICS for symptomatic control, whereas a patient with severe, persistent asthma needs high doses of an ICS.14 Itemizing the patients specific complaints, ie, symptoms, is important. By targeting symptoms with specific pharmacological intervention, the clinician can monitor treatment efficacy and determine the necessary therapeutic duration. This approach is more logical than a generic strategy of advocating additive or combination therapy for the persistently symptomatic patient already using an ICS. The following key questions should be addressed. Does the patient have concurrent problems, such as sinusitis, rhini 2002 Mayo Foundation for Medical Education and Research

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Table 1. Five-Minute Assessment of Asthma Control


Nocturnal awakenings in the past 2 mo Frequency of bronchodilator use/frequency of bronchodilator refill Exercise or functional capacity Exacerbation frequency and duration Current peak flow and personal best peak flow

tis, or gastroesophageal reflux disease, that may affect asthma control? When is the patient symptomatic? (Is it exercise related, during exposure to cold air, nocturnal?) Is the patient exposed to environmental triggers that need to be eliminated? Is the patients dose of ICS adequate? Asthma control can be assessed quickly (Table 1). Issues of asthma control that influence the patients quality of life include nocturnal symptoms, ability to exercise, and frequency of breathlessness. Inquiring about the patients current peak flow rate correlates current lung function and symptoms. It will also be an opportunity to educate the patient regarding home monitoring and other self-management skills. This article reviews pharmacological intervention, but nonpharmacological treatment options must not be neglected. The clinician should quickly review triggers, compliance with allergen avoidance, and other possible environmental and/or nonpharmacological options in patients with asthma. DOSAGE OF ICS When an asthmatic patient receiving an ICS has persistent or increased symptoms, adequacy of the anti-inflammatory therapy is often an issue. The recommendation to increase the ICS dose in a persistently symptomatic patient assumes that the dose-response relationship is linear. However, dose dependency has been shown only with prednisone discontinuation in corticosteroid-dependent asthmatic patients and in providing protection against exercise-induced asthma.15,16 A dose-response improvement in forced expiratory volume in 1 second (FEV1) and in asthma symptoms has been difficult to demonstrate in patients with mild to moderate asthma.17 At low doses, inhaled glucocorticoids profoundly improve the FEV1 until it is close to the plateau portion of the curve. The dose-response relationship to asthma symptoms, like daytime and evening symptoms and daily bronchodilator use, is similarly flat. Objective assessment of airway function in patients with persistent asthma symptoms is important before the dose of inhaled glucocorticoids is increased. A decrease in FEV1 or peak flow rate from baseline may indicate heightened airway inflammation or bronchial hyperresponsiveness, a relative inadequacy of anti-inflammatory therapy, and a requirement for a higher dose of the ICS. A stable or unchanged FEV1 or peak flow rate from baseline may

indicate that the symptoms are due to other concurrent illnesses like sinusitis, rhinitis, gastroesophageal reflux, or heart failure. A decline in FEV1 from baseline in a patient with increasing asthma symptoms is a helpful adjunct in determining the need for increasing ICS therapy. If the patients symptoms are related to exercise or cold exposure, even if the lung function or FEV1 is stable, an empirical trial of ICS boost may be necessary.18 A high sputum eosinophil count (>5%) indicates the need for a higher dose of ICS. In a symptomatic patient with mild to moderate asthma, an initial boost of an ICS with higher doses of an ICS for 4 to 6 weeks will be effective for most cases of heightened airway inflammation that may be causing more symptoms. This would be equivalent to 4 to 6 weeks of 880 g of fluticasone propionate or 800 to 1600 g of budesonide. Of note, airway inflammation takes time to resolve. The time to peak FEV1 improvement with inhaled glucocorticoids is generally 2 to 4 weeks. In the meantime, a second agent can be added for rapid control of symptoms while airway inflammation and heightened bronchial hyperresponsiveness respond to the higher dose of ICS. The addition of a longacting -adrenergic bronchodilator or a leukotriene receptor antagonist can lead to faster control of nocturnal symptoms and exercise- and cold-induced bronchoconstriction, reducing the need for rescue albuterol usage.19 Long-acting -adrenergic bronchodilators like salmeterol xinafoate and formoterol fumarate are more potent that leukotriene receptor antagonists and theophylline.20 The longer duration of bronchodilation is advantageous in blunting exerciseand cold-induced bronchoconstriction and in providing nocturnal symptomatic relief. Leukotriene receptor antagonists like zafirlukast and montelukast sodium may have additional anti-inflammatory action, whereas long-acting -adrenergic bronchodilators do not have anti-inflammatory effects on the airways. There should be a set time limit to the use of additive or combination therapy in light of the expense. In patients with mild and moderate asthma, it is unclear which patients should receive combination therapy beyond 6 weeks.21,22 Once symptoms improve, a low to medium dose of ICS alone is often sufficient. This is termed stepping down.23 Additive therapy should be considered an escalation of treatment intensity. No data are available regarding the efficacy of combination treatment in young children. In patients with moderate to severe asthma who have frequent exacerbations and severe symptoms, a longer duration of combination therapy may be required. Once the patients condition is stable and a reduction in the dose of ICS is being considered, use of a long-acting -adrenergic bronchodilator should be discontinued. This approach simplifies the treatment regimen, avoids masking of symptoms, and allows optimal titration of the ICS.24 Conceptu-

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ally, the use of a long-acting bronchodilator is similar to scheduled, regular use of a short-acting bronchodilator. The need for rescue medication is a valuable indicator of asthma control. It measures how often the patient is dyspneic enough to require a bronchodilator. In patients with moderate to severe asthma, additive therapy has been used as a corticosteroid-sparing strategy. A long-acting -adrenergic bronchodilator and a leukotriene receptor antagonist each can reduce the maintenance ICS dose by less than 20%.25,26 In choosing an ICS, issues of compliance, drug delivery device, and proper inhaler techniques are as important as issues of potency, clinical efficacy, and adverse effects. Ultimately, lung delivery of the ICS benefits the patient. The ideal ICS should have high anti-inflammatory activity, low systemic bioavailability, faster breakdown, and a superior delivery system. The potencies of currently available ICSs are as follows: fluticasone > budesonide = beclomethasone > flunisonide = triamcinolone, with a ratio relative to fluticasone of 1 to 0.5 to 0.25.27-30 Current evidence does not support an efficacy difference among the ICSs, but evidence suggests substantial differences in potency. This is an important fact because differences in potency can be overcome by administering equipotent doses (more puffs with the less potent medications), whereas compounds differing in efficacy cannot produce the same maximal effect regardless of the dose of the less efficacious drug. In comparing drugs with differing potency, differences in systemic activity are important. A highly potent medication at a lower dose may have less absolute systemic availability compared with a lower potency medication used at an equipotent dose that is 4 times higher to achieve equal clinical efficacy and may result in higher absolute systemic availability. Patient education about medication use should be concise and pertinent.31,32 In choosing ICS dosages, cost differences are important. The monthly cost of fluticasone at 110 g is more expensive at 2 puffs twice daily than fluticasone at 220 g at 1 puff twice daily. While in the physicians office, the patient must demonstrate the ability to use the prescribed inhaler properly. In elderly patients, a normal score on the Mini-Mental State Examination does not rule out ideomotor apraxia, which can interfere with proper inhaler technique.33 A person with arthritis may be unable to use a pressurized metered-dose inhaler (pMDI). The 4 skills associated with a good pMDI technique are slow inspiratory airflow rate, coordination of actuation with inspiration, breath-holding at end inspiration, and deep inspiration.34 Dry powder inhalers have the advantage of a natural coordination between inspiration and generation of the aerosol cloud. They are simpler to use and need no spacers. Mouth rinsing is necessary to prevent dyspho-

nia and thrush. Although bulky and less portable, a largevolume spacer (750 mL) can substantially enhance lung delivery from a pMDI. The 1-way valved spacers decrease oropharyngeal deposition. Common mistakes in the use of a 1-way valved spacer include an inadequately primed spacer with high static electricity, multiple actuations for a single breath, and delay between actuation and inhalation. A 1-way valved spacer improves coordination between actuation of a pMDI and inspiration, and it provides a 20second window after actuation into the spacer for inhalation. If inspiration occurs beyond this time, the suspended particles will adhere to the spacer wall. Multiple actuations of medication for a single breath into the spacer cause drug particles to coalesce and increase in size. This decreases drug delivery to the lung. The spacer should be rinsed regularly and allowed to air-dry without wiping. Rinsing reduces the electrostatic charge that causes particles to adhere to the inner spacer walls. The potency of the corticosteroid, the dose used, and its systemic availability determine systemic activity.29,30 The appropriate selection of a drug delivery device for the patient, the use of a spacer with a pMDI, and the proper inhaler technique also influence systemic availability. If high doses are required, maximizing the actual amount of drug delivered to the lung (inspired portion) and reducing the swallowed or intestinal tract absorption achieve a more favorable benefit-to-risk ratio. The degree of systemic bioavailability represents an interplay of factors, including first-pass liver metabolism, elimination and accumulation in blood, tissue uptake, and receptor occupancy. All ICSs have dose-related systemic adverse effects, but these are fewer compared with those associated with an equivalent dose of oral corticosteroids.35 Skin bruising due to high doses of ICS correlates with degree of adrenal suppression. The dose-related adrenal suppression ratio of oral prednisolone to inhaled fluticasone is estimated to be equivalent on a 10- to 1-mg basis. Although there is considerable degree of interindividual susceptibility, adrenal suppression can be observed with doses of ICSs greater than 1.5 mg/d (0.8 mg/d for fluticasone). This dose has been associated with a significant reduction in bone density. No evidence supports important long-term growth effects in children. In fact, studies show that such children achieve predicted adult height.35 Long-term high-dose ICS use increases the risk of posterior subcapsular cataract, skin bruising, and to a smaller degree glaucoma. Local adverse effects include dysphonia and oral thrush. Sustained-release theophylline improves sleep, exercise tolerance, and airway function.36 Theophylline is less effective than inhaled -agonists and has more adverse effects. The advent of long-acting inhaled 2-agonists has further diminished the clinical use of theophylline in combination

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therapy for moderate to severe persistent asthma. The variable clearance, narrow therapeutic index, drug interactions, severity of toxic reactions, frequent monitoring, and attention to dosing have contributed to the diminished importance of theophylline in the treatment of asthma. Leukotriene receptor antagonists are not as potent as long-acting -adrenergic bronchodilators,20 but they are convenient and potentially anti-inflammatory. Leukotriene receptor antagonists block an important mediator pathway that is not affected by corticosteroids.37 An advantage of leukotriene receptor antagonists over long-acting -adrenergic bronchodilators is the lack of tachyphylaxis in preventing exercise-induced bronchoconstriction (EIB).38 Also, they can be useful in reducing daytime symptoms and nocturnal awakenings as well as mild cold-induced bronchoconstriction and EIB. EXERCISE-INDUCED BRONCHOCONSTRICTION Exercise-induced bronchoconstriction refers to the transient narrowing of the airways after exercise, defined by a decrease in FEV1 of at least 10% to 15%.39 A drying effect and heat loss occur when a large volume of air moves through the airways during vigorous exercise.40,41 Exercise provokes bronchoconstriction in 40% to 80% of the population with clinically recognized asthma. In healthy nonasthmatic subjects, exercise increases FEV1. Exerciseinduced bronchoconstriction is associated with mediator release. Although EIB correlates with methacholine (r=0.54) and histamine (r=0.44), 30% to 45% of subjects with EIB have no bronchoconstriction response to inhaled histamine.40 Exercise-induced asthma is an important feature of childhood and adult asthma. The overall control of airway inflammation, intensity of exercise, degree of airway hyperreactivity, ambient temperature and humidity, and presence of allergens and air pollutants determine the severity of exercise-induced asthma. Exercise-induced bronchoconstriction is one of the first symptoms of asthma to emerge and the last to resolve after treatment with an ICS. The presence of EIB in patients with asthma may be an indication that airway inflammation is currently active. Treatment with an ICS is necessary to reduce EIB in such patients. The severity of EIB correlates with the number of asthma attacks per year. Patients should be informed that an ICS before exercise or short-term use of an ICS does not relieve EIB. Ascertaining that the concurrent dose of ICS is sufficient is important. To control EIB, higher doses of an ICS are required compared with doses sufficient to control other symptoms of asthma, including cough or nocturnal awakening. By controlling the underlying airway inflammation in patients with asthma, ICS should attenuate EIB by at least 50%.

Specific therapy for EIB depends on whether symptoms arise during scheduled activities (gym or football practice) or during spontaneous increases in activity that is part of daily living (running after a child or free play during recess). Premedication with albuterol plus a warm-up exercise may prevent EIB during scheduled exercises. The use of submaximal exercise up to 80% of the maximum aerobic output, warm-up exercises in hot humid air (steam room), and warm-up sprints of 30 seconds duration at least 2 minutes apart 30 minutes before exercise should prevent EIB in 50% of patients within 60 minutes and last 2 to 4 hours. Regular use of albuterol does not decrease effectiveness of premedication to prevent EIB.42 Besides albuterol, mast cell stabilizers like cromolyn sodium and nedocromil are second-line choices because they are less effective than 2-agonists. An additive effect on bronchoprotection is observed when cromolyn and a 2-agonist are used together. For spontaneous increases in activity during work or recess when premedication can be difficult, a leukotriene receptor antagonist or a long-acting 2-bronchodilator can be added. These have the advantage of twice-daily or daily dosing and are convenient, especially for children. With intermittent use, the long-acting bronchodilators salmeterol and formoterol are potent in almost completely blunting EIB for 4 to 12 hours. Some patients develop tolerance to the bronchoprotective function of long-acting bronchodilators with regular treatment. This loss of bronchoprotection against EIB occurs with a once-daily dose of salmeterol and with the recommended twice-daily dose. Tachyphylaxis can occur as early as the fifth dose. Both airway cooling and drying during exercise stimulate the release of mediators, including leukotrienes. Leukotriene synthesis inhibitors and receptor antagonists have been shown to protect against EIB to a lesser degree compared with premedication with albuterol or with a long-acting bronchodilator. There is no loss of bronchoprotection to EIB with leukotriene antagonists. Combination therapy is an important advance in the treatment of asthma. The clinician can tailor the therapeutic regimen according to the patients needs. Although this is not a new concept, combination therapy allows clinicians to articulate and refine the ways in which patient symptoms can be matched with treatment. REDUCTION IN ASTHMA EXACERBATION The key to preventing asthma exacerbation in patients with persistent symptoms is regular use of an inhaled glucocorticoid. In patients with mild to moderate asthma, a single maintenance dose of budesonide at bedtime can reduce the frequency of asthma exacerbation. A high dose of inhaled budesonide is more effective than a low dose of budesonide

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or low-dose budesonide plus formoterol in preventing exacerbation.43 A recent study showing decreased exacerbation rates in patients using ICS therapy and a long-acting bronchodilator compared with maintenance with a corticosteroid alone may have reflected patient selection bias and an inadequate dose of the ICS alone.22 Regular ICS use in these patients resulted in fewer and briefer episodes with less severe exacerbation. In children with intermittent symptoms arising usually after a viral upper respiratory tract infection, continued regular use of an ICS after exacerbation resolution did not prevent future exacerbation.44 If a patient has had an acute exacerbation, a 2-week course of a systemic glucocorticoid plus an ICS boost may be necessary to control symptoms and airway inflammation. Studies suggest that tapering prednisone in all patients after a brief burst of prednisone may be unnecessary.45,46 Tapering the corticosteroid may be appropriate in patients who require daily prednisone or have received frequent prednisone bursts. Prolonged adrenal suppression is uncommon during a 2- to 3-week course of prednisone at 0.4 to 0.6 mg/kg per day. Because of concurrent use of an ICS boost, concern about inadequate anti-inflammatory therapy if prednisone is not tapered over time is no longer an issue. In recent studies, ICSs have been useful in acute asthma. Dosages of 2 mg (10 puffs) of inhaled fluticasone daily, 800 g (4 puffs) of budesonide, and 6 mg/h (24 puffs) of flunisolide were used for acute asthma with good results.18,47,48 In adults, this strategy was as effective as 40 mg of prednisone in resolving an acute exacerbation of asthma. In children, prednisone may be a better choice because of their inability to tolerate the ICS dose.49 SMALL AIRWAY INVOLVEMENT IN ASTHMA Autopsy studies, bronchoscopic biopsies, and radiographic imaging studies reveal that the small airways (<2 mm in diameter) are involved in asthma.50 The advent of hydrofluoroalkanes (HFAs) as propellants in pMDIs has potentially important implications in treatment with topical medications. The HFA formulation allows for a finer mist, smaller particle, and quantitatively increased deposition (4to 5-fold) in the lungs as well as penetration into the distal airways and lungs. The HFA-based pMDIs are clinically equivalent to chlorofluorocarbon-based metered-dose inhalers.51 It is important to recognize the difficulty in dealing with HFA-based therapies. Traditional physiological outcome measures of FEV1 and peak flow rate improvements do not apply to small airways; these are for large- and medium-sized airways. No accepted direct method exists for measuring function of the small airways. High-resolution computed tomography of the lungs can quantify the degree of air trapping as an indirect measure of disease of the small airways.52 Thus far, no published study supports

the concept that treatment extending to the small airways is superior. This is important because many of the ICSs and bronchodilators are being converted to dry powder inhalers, whereas others are moving toward an HFA-based formulation to comply with environmental concerns about ozone depletion by chlorofluorocarbons. It is conceptually attractive to speculate on the role of the small airways in patients with asthma who have severe, persistently fixed airway obstruction. SUMMARY Therapy should be targeted to the specific asthma symptom, and airway function should be determined in symptomatic patients. Short-term addition of a leukotriene receptor antagonist or a long-acting bronchodilator helps to control symptoms rapidly. Patients should discontinue use of long-acting bronchodilators when their dose of ICS is being tapered. In treating EIB, scheduled exercise should be distinguished from unscheduled exercise. When a brief (<3 weeks) prednisone burst is given for an acute asthma exacerbation, it may not always be necessary to taper the prednisone dose as long as the ICS dose is increased correspondingly. This strategy should not be used in patients with asthma who require daily prednisone or frequent bursts of prednisone for asthma control.

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Mayo Clin Proc, December 2002, Vol 77

Managing Persistent Asthma

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Questions About Asthma Therapy


1. Which one of the following is the best option when a patient with cat allergies who is taking an ICS presents with increasing symptoms? a. Increase the ICS dose b. Add a long-acting bronchodilator c. Add a leukotriene receptor antagonist d. Tell the patient to get rid of the cat e. Add theophylline 2. Which one of the following statements about use of an ICS in patients with mild to moderate asthma is false? a. It is the most reliable anti-inflammatory agent available b. It is useful as maintenance therapy for patients with episodic flares associated with viral upper respiratory tract infection c. It reduces asthma exacerbations d. It reduces exercise-induced asthma e. It reduces hospitalization 3. Which one of the following statements about exercise-induced asthma is false? a. It is caused by drying and rewarming of the airways b. It is the first symptom to appear and the last to resolve during an exacerbation c. It can be controlled with higher doses of an ICS d. It can be prevented by premedication with albuterol e. It is ruled out by a negative methacholine challenge 4. Which one of the following statements about involvement of the small airways in asthma is true? a. The peak flow rate measures obstruction of the small airways b. The FEV1 measures obstruction of the small airways c. Inflammation is present in the small airways of patients with asthma d. Dry powder inhalers produce smaller aerosolized particles than do HFA-based inhalers e. HFA-based inhalers have less lung deposition compared with dry powder inhalers 5. Which one of the following is true regarding leukotriene receptor antagonists and long-acting 2-adrenergic agonists? a. Both are equipotent as bronchodilators b. Long-acting 2-adrenergic agonists are more effective as corticosteroid-sparing agents than are leukotriene receptor antagonists c. Both are anti-inflammatory d. Both are effective in blunting EIB e. Either is a better alternative to an ICS as monotherapy for asthma

Correct answers: 1. d, 2. b, 3. e, 4. c, 5. d