Does Mild Persistent Asthma Require Regular Treatment?
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《新英格兰医药杂志》
Current national1 and international2 guidelines recommend regularly scheduled treatment with inhaled corticosteroids for patients with mild persistent asthma. This recommendation is supported by solid evidence that such treatment achieves and maintains asthma control.3,4 Although there is not universal agreement,3,5 there are data, reviewed by Vignola, that suggest that continuous suppression of airway inflammation by means of inhaled corticosteroids (referred to as controller therapy) may not only control asthma but also prevent its progression.6
In this issue of the Journal, Boushey et al. challenge this recommendation.7 They compared three treatment protocols in patients with mild persistent asthma. In one protocol, patients were treated with inhaled budesonide twice daily; in a second, patients received oral zafirlukast twice daily; and in a third, patients received no controller therapy. All patients were advised to use a course of inhaled or oral corticosteroids if their asthma symptoms worsened. Surprisingly, the group treated with no controller therapy had neither significantly poorer lung function nor a greater frequency of asthma exacerbations than those who received regular treatment. Boushey et al. estimated that the only treatment these patients needed was one course of inhaled budesonide on average every two years or oral corticosteroids on average every eight years. The only clinically relevant difference in outcome between the group receiving regular treatment with inhaled corticosteroids and the group receiving intermittent treatment with inhaled corticosteroids was that patients in the latter group had 26 more days over the course of a year with asthma symptoms.
What is important about the study by Boushey et al. is its assessment of the efficacy of a self-management plan of intermittent treatment of mild persistent asthma. The plan consisted of symptom-driven treatment of mild-to-moderate exacerbations with a short course of moderate doses of inhaled corticosteroids. Although current guidelines recommend starting or increasing the dose of inhaled corticosteroids when asthma symptoms worsen, these recommendations have not been tested in properly designed and powered randomized clinical trials, particularly in patients with mild asthma not regularly treated with corticosteroids. In patients with moderate asthma who are already receiving daily inhaled corticosteroids, only one study has shown that an intermittent fourfold increase in the dose is effective,8 whereas two other studies have shown that a twofold increase in the dose is ineffective.9,10 There are no data about the intermittent use of inhaled corticosteroids in the long-term treatment of patients with mild asthma not regularly treated with corticosteroids.
The pioneering study by Boushey et al. has partially filled this information gap and provides a potential treatment option for patients with mild persistent asthma not regularly treated with corticosteroids. Their results suggest that a short course of inhaled corticosteroids, when indicated by exacerbations of symptoms, may be the only treatment these patients require. However, questions remain. A placebo control was used only for continuous treatment with inhaled budesonide or zafirlukast; the intermittent-treatment plan with inhaled corticosteroids was used in all three groups of patients. No group received intermittent treatment with placebo or bronchodilators alone; thus, we cannot definitively conclude that the intermittent-treatment plan is superior to the simple use of rescue medication with bronchodilators. Therefore, a placebo-controlled study designed with adequate statistical power to test the clinically relevant outcomes (symptoms, the quality of life, and exacerbations of asthma) is still needed to confirm the efficacy of this management plan.
Moreover, since the population and the design of the study by Boushey et al. differ from those of the two previous studies supporting the need for regular treatment,3,4 the results are not directly comparable. Although the lung function of the subjects in the study by Boushey et al. was similar to that in the two previous studies,3,4 only adults who were nonsmokers and who had a much longer history of asthma and a lower incidence of exacerbations were included (the other studies included smokers and children). Moreover, the low percentage of eosinophils in the sputum and the low concentration of nitric oxide in the exhaled air, both markers of the severity of asthma, suggest that the patients enrolled by Boushey et al. had a very mild form of persistent asthma.11,12 To complicate matters, before randomization, all patients received about two weeks of treatment with clinical doses of oral and inhaled corticosteroids and zafirlukast. Thus, the initial intensive treatment and the symptom-based plan to treat exacerbations may have had a carryover effect, contributing to a reduction in asthma symptoms and in the number and severity of exacerbations in the patients studied.
Intermittent treatment of mild persistent asthma with inhaled corticosteroids is certainly a more appealing approach than regular treatment, especially because it involves a trivial cumulative exposure to corticosteroids. This is particularly meaningful for young patients with asthma, who may require lifelong treatment with inhaled corticosteroids and thus face an increased risk of adverse effects.13 On the other hand, even if intermittent treatment with inhaled corticosteroids is effective clinically, such treatment does not suppress the chronic, albeit very mild, airway inflammation or the airway hyperresponsiveness associated with the disease.7 This leaves us with the possibility that in patients with mild persistent asthma who are not regularly treated with inhaled corticosteroids, more severe asthma may develop, accompanied by a progressive loss of lung function with irreversible airflow limitation.
Is this a serious concern? Although there is evidence of an accelerated rate of decline of lung function in patients with asthma,14 there are conflicting data on the efficacy of regular treatment with inhaled corticosteroids in preventing that decline.3,5 The year-long study by Boushey et al., although showing no evidence of an excessive decline in lung function, was too short and had insufficient statistical power to address this question. No randomized clinical trial has yet properly addressed the question of whether airway inflammation must be suppressed to prevent the progression of asthma, even if the Childhood Asthma Management Program study has clearly shown that in children with mild-to-moderate asthma, the lack of regular treatment with inhaled corticosteroids for four to six years is not associated with progression of the disease.5 Thus, longer and more comprehensive studies, including evaluations of markers of airway inflammation, are required.
In the meantime, will the results of this study change our clinical practice? They may indeed, since the option of intermittent treatment with inhaled corticosteroids complies with the philosophy of achieving and maintaining control of asthma with the least amount of medication.1,2 This approach may be feasible in patients with mild persistent asthma who have never received corticosteroids, but such patients should have the same characteristics as the patients in the study by Boushey et al., and the initial period of intensive treatment should not be omitted. Patients should be informed about the pros and cons of this strategy, including the absence of a risk of major adverse events (severe exacerbations and hospitalization) as well as the slightly increased risk of a greater number of days with symptoms.
Intermittent treatment might also be offered to patients with mild persistent asthma as an intermediate step to the withdrawal of controller medication, if their disease is well controlled by regular treatment with inhaled corticosteroids. The chief concern in recommending this intermittent-treatment plan is that it requires a very careful assessment of the severity of asthma, the risk being that an underestimation of severity may be associated with undertreatment of patients with more severe asthma.4
The paradigm that inhaled corticosteroids control asthma because they suppress airway inflammation is appealing, but it is not really supported by solid data, since other treatments that inhibit airway inflammation are clinically ineffective.15 At the present time, the treatment of asthma should still be based on patient-centered outcomes, with the use of the least amount of medication required to achieve control. With this approach, the severity of asthma will be reflected by the amount of medication required to maintain control, and the border between different levels of severity, and particularly between mild intermittent and mild persistent asthma, may become blurred.
Dr. Fabbri reports having received lecture fees from Altana, AstraZeneca, Boehringer Ingeheim, Schering-Plough, Merck, Roche, Novartis, and Pfizer; having served on the advisory boards of Altana, Schering-Plough, Chiesi, Novartis, Boehringer Ingelheim, and Pfizer; and having received grant support from Boehringer Ingelheim, Miat, Schering-Plough, Pfizer, UCB Pharma, Altana, Menarini, Chiesi, GlaxoSmithKline, Merck, AstraZeneca, and the Italian Ministry for University and Research.
I am indebted to Ms. Mary McKenney for her careful editorial review and to Dr. Elisa Veratelli for her scientific secretarial assistance.
Source Information
From the Clinica di Malattie dell'Apparato Respiratorio, Università degli Studi di Modena e Reggio Emilia–Policlinico di Modena, Modena, Italy.
References
NAEPP Expert Panel report: guidelines for the diagnosis and management of asthma — update on selected topics 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, June 2002. (NIH publication no. 02-5075.)
Global Initiative for Asthma. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Updated 2004. Bethesda, Md.: National Heart, Lung, and Blood Institute, 2004.
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-1063.
Vignola AM. Effects of inhaled corticosteroids, leukotriene receptor antagonists, or both, plus long-acting beta2-agonists on asthma pathophysiology: a review of the evidence. Drugs 2003;63:Suppl 2:35-51.
Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.
Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma. Chest 2000;117:440-446.
FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-556.
Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271-275.
Louis R, Sele J, Henket M, et al. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy 2002;57:907-912.
Kharitonov SA, Gonio F, Kelly C, Meah S, Barnes PJ. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003;21:433-438.
Wong CA, Walsh LJ, Smith CJ, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000;355:1399-1403.
James AL, Palmer LJ, Kicic E, et al. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171:109-114.
Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199-204.(Leonardo M. Fabbri, M.D.)
In this issue of the Journal, Boushey et al. challenge this recommendation.7 They compared three treatment protocols in patients with mild persistent asthma. In one protocol, patients were treated with inhaled budesonide twice daily; in a second, patients received oral zafirlukast twice daily; and in a third, patients received no controller therapy. All patients were advised to use a course of inhaled or oral corticosteroids if their asthma symptoms worsened. Surprisingly, the group treated with no controller therapy had neither significantly poorer lung function nor a greater frequency of asthma exacerbations than those who received regular treatment. Boushey et al. estimated that the only treatment these patients needed was one course of inhaled budesonide on average every two years or oral corticosteroids on average every eight years. The only clinically relevant difference in outcome between the group receiving regular treatment with inhaled corticosteroids and the group receiving intermittent treatment with inhaled corticosteroids was that patients in the latter group had 26 more days over the course of a year with asthma symptoms.
What is important about the study by Boushey et al. is its assessment of the efficacy of a self-management plan of intermittent treatment of mild persistent asthma. The plan consisted of symptom-driven treatment of mild-to-moderate exacerbations with a short course of moderate doses of inhaled corticosteroids. Although current guidelines recommend starting or increasing the dose of inhaled corticosteroids when asthma symptoms worsen, these recommendations have not been tested in properly designed and powered randomized clinical trials, particularly in patients with mild asthma not regularly treated with corticosteroids. In patients with moderate asthma who are already receiving daily inhaled corticosteroids, only one study has shown that an intermittent fourfold increase in the dose is effective,8 whereas two other studies have shown that a twofold increase in the dose is ineffective.9,10 There are no data about the intermittent use of inhaled corticosteroids in the long-term treatment of patients with mild asthma not regularly treated with corticosteroids.
The pioneering study by Boushey et al. has partially filled this information gap and provides a potential treatment option for patients with mild persistent asthma not regularly treated with corticosteroids. Their results suggest that a short course of inhaled corticosteroids, when indicated by exacerbations of symptoms, may be the only treatment these patients require. However, questions remain. A placebo control was used only for continuous treatment with inhaled budesonide or zafirlukast; the intermittent-treatment plan with inhaled corticosteroids was used in all three groups of patients. No group received intermittent treatment with placebo or bronchodilators alone; thus, we cannot definitively conclude that the intermittent-treatment plan is superior to the simple use of rescue medication with bronchodilators. Therefore, a placebo-controlled study designed with adequate statistical power to test the clinically relevant outcomes (symptoms, the quality of life, and exacerbations of asthma) is still needed to confirm the efficacy of this management plan.
Moreover, since the population and the design of the study by Boushey et al. differ from those of the two previous studies supporting the need for regular treatment,3,4 the results are not directly comparable. Although the lung function of the subjects in the study by Boushey et al. was similar to that in the two previous studies,3,4 only adults who were nonsmokers and who had a much longer history of asthma and a lower incidence of exacerbations were included (the other studies included smokers and children). Moreover, the low percentage of eosinophils in the sputum and the low concentration of nitric oxide in the exhaled air, both markers of the severity of asthma, suggest that the patients enrolled by Boushey et al. had a very mild form of persistent asthma.11,12 To complicate matters, before randomization, all patients received about two weeks of treatment with clinical doses of oral and inhaled corticosteroids and zafirlukast. Thus, the initial intensive treatment and the symptom-based plan to treat exacerbations may have had a carryover effect, contributing to a reduction in asthma symptoms and in the number and severity of exacerbations in the patients studied.
Intermittent treatment of mild persistent asthma with inhaled corticosteroids is certainly a more appealing approach than regular treatment, especially because it involves a trivial cumulative exposure to corticosteroids. This is particularly meaningful for young patients with asthma, who may require lifelong treatment with inhaled corticosteroids and thus face an increased risk of adverse effects.13 On the other hand, even if intermittent treatment with inhaled corticosteroids is effective clinically, such treatment does not suppress the chronic, albeit very mild, airway inflammation or the airway hyperresponsiveness associated with the disease.7 This leaves us with the possibility that in patients with mild persistent asthma who are not regularly treated with inhaled corticosteroids, more severe asthma may develop, accompanied by a progressive loss of lung function with irreversible airflow limitation.
Is this a serious concern? Although there is evidence of an accelerated rate of decline of lung function in patients with asthma,14 there are conflicting data on the efficacy of regular treatment with inhaled corticosteroids in preventing that decline.3,5 The year-long study by Boushey et al., although showing no evidence of an excessive decline in lung function, was too short and had insufficient statistical power to address this question. No randomized clinical trial has yet properly addressed the question of whether airway inflammation must be suppressed to prevent the progression of asthma, even if the Childhood Asthma Management Program study has clearly shown that in children with mild-to-moderate asthma, the lack of regular treatment with inhaled corticosteroids for four to six years is not associated with progression of the disease.5 Thus, longer and more comprehensive studies, including evaluations of markers of airway inflammation, are required.
In the meantime, will the results of this study change our clinical practice? They may indeed, since the option of intermittent treatment with inhaled corticosteroids complies with the philosophy of achieving and maintaining control of asthma with the least amount of medication.1,2 This approach may be feasible in patients with mild persistent asthma who have never received corticosteroids, but such patients should have the same characteristics as the patients in the study by Boushey et al., and the initial period of intensive treatment should not be omitted. Patients should be informed about the pros and cons of this strategy, including the absence of a risk of major adverse events (severe exacerbations and hospitalization) as well as the slightly increased risk of a greater number of days with symptoms.
Intermittent treatment might also be offered to patients with mild persistent asthma as an intermediate step to the withdrawal of controller medication, if their disease is well controlled by regular treatment with inhaled corticosteroids. The chief concern in recommending this intermittent-treatment plan is that it requires a very careful assessment of the severity of asthma, the risk being that an underestimation of severity may be associated with undertreatment of patients with more severe asthma.4
The paradigm that inhaled corticosteroids control asthma because they suppress airway inflammation is appealing, but it is not really supported by solid data, since other treatments that inhibit airway inflammation are clinically ineffective.15 At the present time, the treatment of asthma should still be based on patient-centered outcomes, with the use of the least amount of medication required to achieve control. With this approach, the severity of asthma will be reflected by the amount of medication required to maintain control, and the border between different levels of severity, and particularly between mild intermittent and mild persistent asthma, may become blurred.
Dr. Fabbri reports having received lecture fees from Altana, AstraZeneca, Boehringer Ingeheim, Schering-Plough, Merck, Roche, Novartis, and Pfizer; having served on the advisory boards of Altana, Schering-Plough, Chiesi, Novartis, Boehringer Ingelheim, and Pfizer; and having received grant support from Boehringer Ingelheim, Miat, Schering-Plough, Pfizer, UCB Pharma, Altana, Menarini, Chiesi, GlaxoSmithKline, Merck, AstraZeneca, and the Italian Ministry for University and Research.
I am indebted to Ms. Mary McKenney for her careful editorial review and to Dr. Elisa Veratelli for her scientific secretarial assistance.
Source Information
From the Clinica di Malattie dell'Apparato Respiratorio, Università degli Studi di Modena e Reggio Emilia–Policlinico di Modena, Modena, Italy.
References
NAEPP Expert Panel report: guidelines for the diagnosis and management of asthma — update on selected topics 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, June 2002. (NIH publication no. 02-5075.)
Global Initiative for Asthma. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Updated 2004. Bethesda, Md.: National Heart, Lung, and Blood Institute, 2004.
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-1063.
Vignola AM. Effects of inhaled corticosteroids, leukotriene receptor antagonists, or both, plus long-acting beta2-agonists on asthma pathophysiology: a review of the evidence. Drugs 2003;63:Suppl 2:35-51.
Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.
Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma. Chest 2000;117:440-446.
FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-556.
Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271-275.
Louis R, Sele J, Henket M, et al. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy 2002;57:907-912.
Kharitonov SA, Gonio F, Kelly C, Meah S, Barnes PJ. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003;21:433-438.
Wong CA, Walsh LJ, Smith CJ, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000;355:1399-1403.
James AL, Palmer LJ, Kicic E, et al. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171:109-114.
Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199-204.(Leonardo M. Fabbri, M.D.)