Original Article
Daily versus As-Needed Corticosteroids for Mild Persistent Asthma
N Engl J Med 2005; 352:1519-1528April 14, 2005
- Abstract
Background
Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period.
Methods
In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life.
Results
The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P<0.001), the percentage of eosinophils in sputum (P=0.007), exhaled nitric oxide levels (P=0.006), scores for asthma control (P<0.001), and the number of symptom-free days (P=0.03), but not in post-bronchodilator FEV1 (P=0.29) or in the quality of life (P=0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.
Conclusions
It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended.
Media in This Article
Figure 1
Enrollment and Outcome.Figure 2
Number of 10-Day Courses of Open-Label Budesonide Initiated by Patients in Each Group, as Guided by the Symptom-Based Action Plan.Article Activity
- Article
Treatment guidelines recommend daily antiinflammatory therapy to control mild persistent asthma.1,2 This recommendation for so-called controller therapy was prompted by studies reporting that such treatment improves physiological measures of airway obstruction (peak expiratory flow [PEF] and forced expiratory volume in one second [FEV1]), the severity of symptoms, the frequency of exacerbations, and the quality of life3-5 and was reinforced by reports that inhaled corticosteroid treatment may prevent progressive loss of pulmonary function.6-8 However, analysis of pharmacy records suggests that most patients infrequently renew their prescriptions for controller medications (inhaled corticosteroids and leukotriene-receptor antagonists).9
We reasoned that patients with mild asthma may be using their treatment intermittently because they do not perceive the need for daily therapy. To analyze whether this strategy could be an acceptable approach to treatment in patients with mild persistent asthma, we modified a symptom-based action plan to guide the use of inhaled or oral corticosteroids when signs or symptoms of asthma worsened.10 In a three-way study — the Improving Asthma Control (IMPACT) Trial — we compared the level of asthma control obtained with the use of this intermittent-treatment approach with that obtained with use of the intermittent-treatment plan plus daily treatment with a controller medication, either an inhaled corticosteroid (budesonide) or a leukotriene-receptor antagonist (zafirlukast). Morning PEF, a widely used and robust indicator of airflow obstruction, was the primary outcome indicator. Secondary outcomes included the frequency of asthma exacerbations, the number of days lost from work or school, the number of symptom-free days, asthma-related quality of life, and a panel of physiological and biologic measures of asthma activity.
Methods
Patients
Patients were recruited between February 2000 and May 2002 at six centers with the use of methods and equipment described previously.11,12 The protocol was approved by the institutional review board of each center, and written informed consent was obtained from each participant. Inclusion criteria were physician-diagnosed asthma, an age of 18 to 65 years, and an FEV1, measured more than four hours after the most recent use of a bronchodilator, that was at least 70 percent of the predicted value. All patients had an increase in the FEV1 of at least 12 percent and at least 200 ml after the inhalation of albuterol or a fall in FEV1 of at least 20 percent after inhaling a concentration of methacholine of less than 16 mg per milliliter (PC20; lower concentrations indicate greater reactivity).
Exclusion criteria included cigarette smoking, respiratory tract infection or corticosteroid use in the previous six weeks, and hospitalization or two or more visits to the emergency department for asthma in the previous year. Patients qualifying at a screening visit were instructed in the use of an electronic peak flowmeter (AirWatch, ENACT Health Management Systems) and were given a diary to record morning and evening PEF, asthma symptoms, nocturnal awakenings related to asthma, and as-needed albuterol use. They were instructed to take one puff from a placebo-dispensing dry-powder inhaler (Turbuhaler, AstraZeneca), which was identical in appearance to the device used to dispense inhaled budesonide, and one placebo tablet (identical in appearance to zafirlukast) twice a day.
We enrolled patients only if their diary records and findings during visits in the next four weeks met the criteria for mild persistent asthma (self-treatment with a beta-agonist more than two days per week, nighttime awakenings related to asthma more than two days per month, or variability in the PEF of 20 to 30 percent). Apart from accepting a baseline FEV1 as low as 70 percent of the predicted value, we excluded patients if they met any criteria for persistent moderate asthma (i.e., daily self-treatment with a beta-agonist, nighttime awakenings once a week, or more than 30 percent variability in PEF).1 Enrollment also required at least 70 percent adherence to diary keeping, Turbuhaler use (by counting the number of doses remaining in the inhaler), and tablet use (established by pill counts and by electronic drug-exposure monitoring [eDEM, Aardex] of the time and date of each opening of the pill bottle).13 PEF measurements were made and diaries were kept for four weeks during the run-in period, at the midpoint of the study, and at the end of the study.
Protocol
On entry, all patients received 10 minutes of instruction in a symptom-based asthma treatment plan (details of the plan are provided in the Supplementary Appendix, available with the full text of this article at www.nejm.org). The plan called for patients to take open-label budesonide (800 μg twice daily) for 10 days or prednisone (0.5 mg per kilogram of body weight per day) for 5 days if their asthma symptoms worsened.10 The patients' understanding of this plan was not formally evaluated, but they did receive a written summary of the plan, and the plan was reviewed briefly at each study visit.
After completing the run-in period, the patients were assigned to one of three parallel treatment groups: twice-daily oral placebo and inhalation of 200 μg of budesonide, twice-daily oral zafirlukast (20 mg) and inhalation of placebo, or twice-daily oral and inhaled placebo (intermittent treatment) (Figure 1Figure 1
Enrollment and Outcome.) (see the Supplementary Appendix for details of the procedures at visits). Treatment assignment was stratified according to center, and the use of an adaptive randomization scheme ensured balance with respect to PC20, age, and racial or ethnic group.Budesonide, zafirlukast, and matched placebos in identical delivery systems (pills or Turbuhaler) were donated by AstraZeneca. Representatives of the company reviewed and commented on the protocol but made no other contribution to its design, conduct, interpretation, or presentation.
The run-in and treatment phases both ended with a 10-to-14-day period of intense combined therapy, consisting of 0.5 mg of prednisone per kilogram per day, 800 μg of budesonide twice daily, and 20 mg of zafirlukast twice daily, plus treatment as needed with albuterol (540 to 720 μg), to eliminate any easily reversed causes of airflow obstruction affecting PEF or FEV1.
At study visits, FEV1 was measured, adherence to treatment was assessed, the degree of asthma control was assessed by means of a seven-item questionnaire (in which a score of 0 indicated no symptoms and a score of 6 severe symptoms),14 medication-related side effects were assessed, and symptom-related impairment or discomfort was evaluated by means of the Asthma Symptom Utility Index.15 The Asthma Symptom Utility Index is derived from a 10-item questionnaire completed by the patient. Scores range from 0 to 1, with higher scores indicating fewer symptoms. At visits during the periods in which diaries were maintained (four weeks during the run-in period and at the midpoint and end of the treatment periods, and during the two weeks of the two periods of intense combined treatment), peak flow was obtained from the diary records. Questionnaires about the number of symptom-free days, adverse events, and health care use were administered at all study visits and by means of telephone calls between visits. When these questionnaires identified patients who had had worsening of asthma symptoms, they were asked whether they had used the symptom-based action plan and this information was recorded.
The asthma-related quality of life was assessed by means of a questionnaire at enrollment and at the end of treatment16; patients rate the degree of impairment caused by asthma during the preceding 14 days and respond to each of the 32 items using a 7-point scale on which a score of 1 indicates maximal impairment and a score of 7 no impairment. Changes in the score of 0.5, 1.0, and 1.5 correspond to small, moderate, and large differences, respectively. The questionnaire can be used to provide an overall score and scores in four areas: limitation of activities, asthma symptoms, emotional functioning, and symptoms arising from environmental exposures. Exhaled nitric oxide, the PC20, and the percentage of eosinophils in sputum were measured at enrollment and at the end of treatment (Figure 1).
Outcome Variables
The primary outcome variable was the change from baseline in two-week average morning PEF. Other objective outcome variables were the changes from baseline in the FEV1 before bronchodilator use, the FEV1 after treatment with 540 to 720 μg of albuterol, and the morning PEF during the period of intense combined therapy and FEV1 after the period of intense combined therapy. We also measured the frequency of asthma exacerbations warranting the initiation of prednisone therapy according to the symptom-based action plan (whether initiated or not). Patients were instructed to notify their study center about these events, but we also identified such events by asking specific questions at study visits and during telephone contacts. Other patient-reported outcomes were responses to standard questionnaires on asthma control, asthma-related quality of life, symptom-free days, symptom-related impairment or discomfort, days missed from work or school, and adverse events (see above).
Statistical Analysis
The trial was designed to show the superiority of any one treatment over either of the other two. The primary outcomes were evaluated as the average percent change from the end of the run-in period to the end of treatment and were initially compared by means of analysis of variance. Pairwise comparisons between groups were evaluated if the P value for the overall test was less than 0.048 (by a two-sided test, adjusted for an interim analysis at the 0.005 level). These comparisons were then adjusted for baseline characteristics by including in an analysis-of-covariance model effects such as center, interaction between center and treatment, age, baseline PC20, baseline FEV1, duration of asthma, and other important baseline covariates listed in Table 1Table 1
Baseline Characteristics of the Patients. (the list of covariates analyzed for each outcome is provided in the Supplementary Appendix). Repeated-measures analysis of covariance was also used on outcomes measured repeatedly throughout the study to evaluate correlated data.The times to the first exacerbation of asthma were compared by means of Kaplan–Meier curves and the log-rank test. A repeated-measures proportional-hazards approach was used to compare groups, allowing for multiple exacerbations per patient.17,18 The patient-reported outcomes regarding asthma control and symptoms throughout the trial were evaluated with repeated-measures analysis of covariance.
The primary end point compared among the groups was the change in morning PEF from randomization to the end of the trial. Using the standard deviation for morning PEF of 36.6 liters per minute noted in a previous study,11 we calculated that a sample of 216 patients would provide a statistical power of 90 percent to detect the difference widely considered to be of clinical significance, 25 liters per minute, at a significance level of 4.8 percent, allowing a dropout rate of 15 percent. For the secondary end point — change in morning PEF from the first to the second period of intense combined therapy — we used the variability observed in the corticosteroid run-in period of a previous trial.12 We calculated that if 199 patients completed the study, the study would have a statistical power of 80 percent to detect a difference of 21 liters per minute in this morning PEF during the period of intense combined therapy between any two treatment groups. We further calculated that this sample would provide 80 percent power to detect a change of 13 liters per minute in morning PEF within groups.
Results
Of 411 patients who were enrolled after screening, 225 underwent randomization and 199 completed the study (Figure 1). The treatment groups were well matched (Table 1). Twenty-six patients withdrew after randomization, 6 each from the budesonide and intermittent-treatment groups and 14 from the zafirlukast group (P=0.10). Reasons for withdrawal included loss to follow-up (in six patients), pregnancy (four patients), personal constraints (four patients), side effects possibly related to study medications (two patients), dissatisfaction with asthma control (one patient), and miscellaneous reasons (nine patients).
Adherence to study medication regimens, estimated from counting unused doses in the Turbuhaler and from pill counts and eDEM records, exceeded 90 percent and was similar among the groups. The use of open-label budesonide was no greater in the intermittent-treatment group than in the groups taking daily budesonide or zafirlukast (Figure 2Figure 2
Number of 10-Day Courses of Open-Label Budesonide Initiated by Patients in Each Group, as Guided by the Symptom-Based Action Plan.). Inhaled budesonide was taken for only 55 percent of the episodes of mild-to-moderate worsening of symptoms as defined by the asthma action plan (Supplementary Appendix). The average per-patient use of a daily controller medication over the year of the study was 47.8 weeks for the budesonide and zafirlukast groups (92 percent adherence × 52 weeks) and 0.48 week for the intermittent-treatment group.The primary outcome, the change in morning PEF from the final two weeks of the run-in period to the final two weeks of the year of treatment, did not differ significantly among the groups, increasing about 7.8 percent (32 liters per minute) in all groups (P=0.90) (Table 2Table 2
Average Changes in Primary and Secondary Outcome Measures over a One-Year Period.). The increases in average morning PEF from the first to the second period of intense combined therapy were also similar among the groups (3.5 to 5.7 percent, P=0.61) (Table 2), even after adjustment for center, age, minority status, and PC20.The pre-bronchodilator FEV1 increased more in the budesonide group than in the other two groups (P=0.005) (Table 2), but the changes in post-bronchodilator FEV1 did not differ significantly among the groups (P=0.29) (Table 2). The average changes in post-bronchodilator FEV1 in the budesonide and intermittent-treatment groups were –1.7 percent and –1.0 percent, respectively, resulting in an average difference between groups of –0.7 percentage point. The 95 percent confidence interval for this difference was –2.1 percent (i.e., greater decrease in the budesonide group) to 0.7 percent (greater decrease in the intermittent-treatment group).
The change in post-bronchodilator FEV1 in the 46 patients with an FEV1 at entry that was 70 to 79 percent of the predicted value was not significantly different from that in the 144 patients with an FEV1 at entry that was at least 80 percent of the predicted value (P=0.59) (data not shown). The FEV1 measured after the period of intense combined therapy declined similarly in all groups. Patients treated with budesonide had greater improvements in the percentage of eosinophils in sputum, exhaled nitric oxide values, and PC20 values than did the patients in either of the other two groups (Table 2). As compared with intermittent treatment, treatment with zafirlukast produced no significantly greater improvement in any outcome.
Thirty exacerbations of symptoms warranting treatment with prednisone occurred in 25 (11.1 percent) patients, an overall rate of 0.13 per patient-year. The proportion of patients who had one or more exacerbations did not differ significantly among the groups (one exacerbation in eight patients in the budesonide group and three in two patients in this group; one exacerbation in six patients in the zafirlukast group; and one exacerbation in seven patients in the intermittent-treatment group and three in one patient in this group).
Kaplan–Meier curves showed no significant differences among the groups, whether they were plotted as the time to a first event (P=0.39 by the log-rank test) (Figure 3Figure 3
Kaplan–Meier Estimates of the Time to a First Exacerbation of Asthma.) or allowed multiple events per patient (P=0.24). The 12-month Kaplan–Meier exacerbation rates for the budesonide and intermittent-treatment groups were 16.1 percent and 11.3 percent, respectively, resulting in an average difference (i.e., positive sign indicates more exacerbations in the budesonide group) of +4.8 percentage points. The 95 percent confidence interval for this difference was –7 percent (lower in the budesonide group) to 16 percent (higher in the budesonide group). Patients initiated prednisone treatment for only 36.7 percent of the episodes (5 of 14 episodes in the budesonide group, 2 of 6 in the zafirlukast group, and 4 of 10 in the intermittent-treatment group). Five exacerbations required a visit to the emergency department (three in the budesonide group and one each in the other two groups). None warranted hospitalization. Altogether, patients missed 13 days from work or school because of asthma (7 days in the budesonide group, 2 days in the zafirlukast group, and 4 days in the intermittent-treatment group; P=0.18).Of the patient-reported outcomes, the improvements in the asthma control score and in the number of symptom-free days were significantly greater with budesonide treatment than with either zafirlukast or intermittent treatment, which did not differ significantly from each other (Table 2). The greater number of symptom-free days over a 2-week period with budesonide (9.9 days) than with zafirlukast (8.7 days) or intermittent treatment (8.8 days) translates to 26 additional symptom-free days per year (95 percent confidence interval, 1.8 to 48.5). This was not associated, however, with any difference in the changes in the scores for the asthma-related quality of life, which improved in all groups (Table 2).
Neither the overall frequency of adverse events nor the frequency of severe events (36 or 37 in each group) differed significantly among the groups; seven of the patients with severe events required hospitalization. In this blinded study, no hospitalization was deemed by the investigators as being related to the study, study medication, or asthma.
Discussion
Our study of 225 patients with mild persistent asthma showed no clinically significant difference among the three treatment groups with respect to morning PEF. Although other objective measures of lung function and airway biology were improved and patients reported 26 more days free from symptoms of asthma per year when treated with budesonide on a daily basis than with the other treatments, the frequency of asthma exacerbations did not differ significantly among the groups. Although our study was not designed as a noninferiority trial and, thus, the findings must be considered preliminary, these data suggest that a novel approach to the treatment of persistent asthma — symptom-driven intermittent treatment with inhaled or oral corticosteroids — may be possible. Since the intermittent use of inhaled corticosteroids could decrease the adverse effects of these agents,19 our data provide the impetus for a large-scale trial to test this novel approach to asthma treatment.
Epidemiologic studies have reported that the use of inhaled corticosteroids reduces asthma-related hospitalizations and deaths,20,21 and some previous clinical studies of mild asthma have reported that inhaled corticosteroid therapy reduces the frequency of exacerbations and the rate of decline in the results of tests of airway caliber (PEF, FEV1, or post-bronchodilator FEV1),3-5 so the suggestion that a large subgroup of patients with asthma may not require daily controller treatment will arouse concern.
However, the protective effect in the epidemiologic studies was most apparent by far in patients using frequent doses of an inhaled beta-agonist,20 a pattern inconsistent with the criteria for mild persistent asthma. In our study of 411 patients who appeared on original screening to meet the criteria for mild persistent asthma, 64 were found to have asthma that was too severe and 30 asthma that was too mild to qualify. We believe that the lack of a difference among our treatment groups may reflect the low rate of exacerbations in patients who consistently meet the criteria for mild persistent asthma. This possibility is supported by our finding of a rate of exacerbations warranting prednisone treatment in our intermittent-treatment group (0.11 per patient-year) well below the rates reported in previous studies of mild asthma (0.21 to 0.77 per patient-year).3-5
This difference in asthma severity could also account for the difference from previous studies reporting that continuous corticosteroid therapy prevented a decline in airway function in patients with mild asthma.3-5 We found no treatment-attributable difference in the change in post-bronchodilator FEV1. Our study was shorter than the previous studies, but the preponderance of the differences between treatment groups in these studies occurred during the first year, and we noted no such effect. Our findings are consistent with those of the Childhood Asthma Management Program trial, a study of children with asthma, which showed no effect of five years of treatment with an inhaled corticosteroid on the change in post-bronchodilator FEV1.22 Furthermore, the robustness of our findings, as reflected by the confidence intervals for the differences in the decline in post-bronchodilator FEV1 and in exacerbation rates, suggests that the treatment benefits that our study might have missed may be so small as not to justify the expense, potential adverse effects, and inconvenience of daily treatment with a controller therapy of all patients with mild persistent asthma.
We did find that budesonide (but not zafirlukast) improved markers of airway inflammation, such as bronchial reactivity, the percentage of eosinophils in sputum, and exhaled nitric oxide. It is noteworthy, however, that low-grade inflammation similar to that seen in our patients has been reported in patients with spontaneous, complete, sustained clinical remission of asthma,23,24 who are not now considered candidates for daily controller treatment.
We found that daily treatment with budesonide (but not zafirlukast) was associated with a significant increase in the number of symptom-free days and a trend toward improvement in the scores for a weighted symptom utility index, but not in asthma-related quality of life. This lack of improvement in the quality of life may reflect the light burden of symptoms of mild asthma. In asthma of this severity, symptoms are occasional and are usually promptly relieved by treatment with an inhaled bronchodilator. Whether the increase in symptom-free days is worth the costs of treatment, both fiscal and with respect to long-term side effects, may thus be an individual, subjective judgment best left to the patient and his or her health care provider.19
It is fair to ask whether the approach to treatment in our intermittent-treatment group could be practically applied outside of the artificial conditions of a clinical trial. We tried to mimic true clinical conditions by basing the action plan on symptoms, rather than on peak flow. All our patients were given an open-label budesonide inhaler, prednisone tablets, and 10 minutes of instruction in the symptom-based action plan. This instruction was reinforced by a written summary and by reminders of the plan at each visit and a telephone call (every six weeks). This attention to teaching an action plan might limit the generalizability of our findings. However, even under these conditions, patients took budesonide for only 55 percent of the episodes of mild-to-moderate worsening of symptoms and prednisone for only 37 percent of the episodes severe enough to warrant its use. We also found no significant difference in the rate of exacerbations warranting prednisone treatment in patients who should have but did not take budesonide (7 of 22) than in those who should have and did (15 of 21). Taken together, these observations suggest that close, formal adherence to the action plan may not have accounted for our findings.
In adults with long-standing, mild persistent asthma who were given medication and instructed to initiate corticosteroid therapy according to a symptom-based action plan, regularly scheduled controller treatment with either inhaled budesonide or oral zafirlukast had no significant effect on the rate of severe exacerbations, impairment in the quality of life, or the rate of loss of pulmonary function over a period of one year. These findings suggest that the novel approach of treating patients with mild persistent asthma with inhaled and oral corticosteroids as needed may be viable. Longer and larger studies will be needed before this approach to asthma treatment can be recommended.
Supported by grants (5 U10 HL051810, 5 U10 HL051823, 5 U10 HL051831, 5 U10 HL051834, 5 U10 HL051843, 5 U10 HL051845, and 5 U10 HL056443) from the National Institutes of Health.
Dr. Boushey reports having received consulting fees from GlaxoSmithKline and Aventis and lecture fees from GlaxoSmithKline and Genentech/Novartis; Dr. Sorkness, consulting fees from GlaxoSmithKline and lecture fees from GlaxoSmithKline, AstraZeneca, and Genentech/Novartis; Dr. Sullivan, consulting fees from AstraZeneca, Merck, Schering-Plough, and GlaxoSmithKline and lecture fees from AstraZeneca, Schering-Plough, and Pfizer; Dr. Fahy, consulting fees from Xoma Tularik, AstraZeneca, and Aventis; Dr. Lazarus, consulting fees from Merck, Schering, GlaxoSmithKline, and Critical Therapeutics and lecture fees from Boehringer-Ingelheim and Merck; Dr. Chinchilli, consulting fees from Wyeth and Procter & Gamble and lecture fees from Bristol-Myers Squibb and Aventis; Dr. Craig, consulting fees from Merck; Dr. Dimango, grant support from Genentech/Novartis; and Dr. Deykin, consulting fees from AstraZeneca, Genentech/Novartis, Intermune, and Roche; lecture fees from GlaxoSmithKline; and grant support from Merck. Dr. Fish is an employee of Genentech. Dr. Kraft reports having received consulting fees from Genentech/Novartis and AstraZeneca and lecture fees from Merck and Genentech/Novartis; Dr. Lemanske, consulting fees from Aventis and AstraZeneca and lecture fees from Aventis, AstraZeneca, Novartis, Merck, and GlaxoSmithKline; Dr. Martin, consulting fees and lecture fees from GlaxoSmithKline, Aventis, Merck, Ivax, and Genentech/Novartis and grant support from GlaxoSmithKline; Dr. Peters, consulting fees from AstraZeneca, Genentech/Novartis, Discovery, IDEC, Roche, RAND Corporation, and the Respiratory Disease Foundation; lecture fees from AstraZeneca, Genentech/Novartis, and Merck; and grant support from GlaxoSmithKline, Boehringer Ingelheim, Novartis, AstraZeneca, Pfizer, Altana, Centocor, and Abaris; Dr. Szefler, consulting fees from AstraZeneca, GlaxoSmithKline, Aventis, and Merck; lecture fees from GlaxoSmithKline and Genentech/Novartis; and grant support from Ross Pharmaceuticals and AstraZeneca; Dr. Wechsler, consulting fees from Merck and Genentech/Novartis; lecture fees from Merck, GlaxoSmithKline, and Genentech/Novartis, and grant support from Merck; and Dr. Israel, consulting fees from Merck, Schering-Plough, and Genentech/Novartis; lecture fees from Genentech and Merck; and grant support from GlaxoSmithKline, AstraZeneca, Genentech, and Merck.
We are indebted to Reuben Cherniack, M.D. (National Jewish Medical and Research Center, Denver), James P. Kiley, Ph.D. (National Heart, Lung, and Blood Institute, Bethesda, Md.), and Hector G. Ortega, M.D., Sc.D. (National Heart, Lung, and Blood Institute, Bethesda, Md.), for their valuable contributions to the design, conduct, and interpretation of this study.
Source Information
From the University of California at San Francisco, San Francisco (H.A.B., J.V.F., S.C.L.); University of Wisconsin, Madison (C.A.S., R.F.L.); Pennsylvania State University College of Medicine, Hershey (T.S.K., V.M.C., T.J.C., E.A.M., N.J.R.); University of Washington, Seattle (S.D.S.); Harlem Lung Center and Columbia University, New York (E.A.D., J.K.F., J.G.F., G.R.P.); Brigham and Women's Hospital and Harvard Medical School, Boston (A.D., M.E.W., E.I.); Thomas Jefferson University, Philadelphia (J.E.F., F.T.L., S.P.P.); and the National Jewish Medical and Research Center, Denver (M.K., R.J.M., S.J.S.).
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The Childhood Asthma Management Program Research Group
Full Text | Web of Science | Medline23
van den Toorn LM ,Prins JB ,Overbeek SE ,Hoogsteden HC ,de Jongste JC . Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162:953-957
Web of Science | Medline24
van den Toorn LM ,Overbeek SE ,de Jongste JC ,Leman K ,Hoogsteden HC ,Prins JB . Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164:2107-2113[Erratum, Am J Respir Crit Care Med 2002;166:1143.]
Web of Science | Medline
- Citing Articles (98)
Citing Articles
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Bhupendrasinh F Chauhan, Caroline Chartrand, Francine M Ducharme, Francine M Ducharme. 2012. Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. .
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F. N. Schleich, R. Asandei, M. Manise, J. Sele, L. Seidel, R. Louis. (2012) Is FENO50 useful diagnostic tool in suspected asthma?. International Journal of Clinical Practice 66:2, 158-165
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Pakit Vichyanond, Rattana Pensrichon, Suruthai Kurasirikul. (2012) Progress in the management of childhood asthma. Asia Pacific Allergy 2:1, 15
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Paolo Montuschi, Peter J. Barnes. (2011) New perspectives in pharmacological treatment of mild persistent asthma. Drug Discovery Today 16:23-24, 1084-1091
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Hengameh H. Raissy, Kathryn Blake. (2011) As Needed Use of Inhaled Corticosteroids for Management of Mild Persistent Asthma in Children. Pediatric Allergy, Immunology, and Pulmonology111109073411001
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Alex Thomas, Robert F. Lemanske, Daniel J. Jackson. (2011) Approaches to stepping up and stepping down care in asthmatic patients. Journal of Allergy and Clinical Immunology 128:5, 915-924
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Christian Bime, Jessica Nguyen, Robert A. Wise. (2011) Measures of asthma control. Current Opinion in Pulmonary Medicine1
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Matthew A. Rank, Juliette T. Liesinger, Jeanette Y. Ziegenfuss, Megan E. Branda, Kaiser G. Lim, Barbara P. Yawn, Nilay D. Shah. (2011) The impact of asthma medication guidelines on asthma controller use and on asthma exacerbation rates comparing 1997–1998 and 2004–2005. Annals of Allergy, Asthma & Immunology
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Jerry A. Krishnan, Bruce G. Bender, Frederick S. Wamboldt, Stanley J. Szefler, N. Franklin Adkinson, Robert S. Zeiger, Robert A. Wise, Andrew L. Bilderback, Cynthia S. Rand. (2011) Adherence to inhaled corticosteroids: An ancillary study of the Childhood Asthma Management Program clinical trial. Journal of Allergy and Clinical Immunology
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L. Keoki Williams, Edward L. Peterson, Karen Wells, Brian K. Ahmedani, Rajesh Kumar, Esteban G. Burchard, Vimal K. Chowdhry, David Favro, David E. Lanfear, Manel Pladevall. (2011) Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. Journal of Allergy and Clinical Immunology
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Stanley J. Szefler. (2011) Advancing asthma care: The glass is only half full!. Journal of Allergy and Clinical Immunology 128:3, 485-494
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Timothy Craig, Laura Quinn. (2011) Asthma Clinical Research Network: Lessons Learned. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78:5, 671-682
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L. Li, C. Shen, A. C. Wu, X. Li. (2011) Propensity Score-based Sensitivity Analysis Method for Uncontrolled Confounding. American Journal of Epidemiology 174:3, 345-353
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Stuart W. Stoloff, H.W. Kelly. (2011) Updates on the use of inhaled corticosteroids in asthma. Current Opinion in Allergy and Clinical Immunology1
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Shamsah Kazani, Jonathan Sadeh, Sreedhar Bunga, Michael E. Wechsler, Elliot Israel. (2011) Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma. Respiratory Medicine 105:5, 667-673
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K Deepa Bhat, William J Calhoun. (2011) Symptom-adjusted therapy in asthma: it is time to listen to our patients. Expert Review of Clinical Immunology 7:3, 259-261
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J. Richard Landis. (2011) Measures of Agreement and Concordance With Clinical Research Applications. Statistics in Biopharmaceutical Research 3:2, 185-209
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Sabina Antonela Antoniu, Italo Sampablo, Mauro Carone. (2011) Tiotropium in the treatment of asthma. Expert Opinion on Pharmacotherapy 12:3, 489-491
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Fernando D Martinez, Vernon M Chinchilli, Wayne J Morgan, Susan J Boehmer, Robert F Lemanske, David T Mauger, Robert C Strunk, Stanley J Szefler, Robert S Zeiger, Leonard B Bacharier, Elizabeth Bade, Ronina A Covar, Noah J Friedman, Theresa W Guilbert, Hengameh Heidarian-Raissy, H William Kelly, Jonathan Malka-Rais, Michael H Mellon, Christine A Sorkness, Lynn Taussig. (2011) Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. The Lancet 377:9766, 650-657
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Parameswaran Nair. (2011) Early interventions with inhaled corticosteroids in asthma: benefits and risks. Current Opinion in Pulmonary Medicine 17:1, 12-15
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Bradley S Quon, J. Mark FitzGerald, Catherine Lemière, Neal Shahidi, Francine M Ducharme, Francine M Ducharme. 2010. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. .
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Prakash Navaratnam, Eduardo Urdaneta, John McLaughlin, Howard S. Friedman. (2010) Incidence of Exacerbations and Hospitalizations Is Reduced and Time to Exacerbations Is Prolonged with Mometasone Furoate Dry Powder Inhaler Versus Beclomethasone Dipropionate Hydrofluoroalkane Aerosol in Patients with Mild Asthma. Health Outcomes Research in Medicine 1:2, e93-e102
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Andrew Bush. (2010) The problem of preschool wheeze: new developments, new questions. Acta medica Lituanica 17:1, 40-50
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Paolo M. Renzi, Lisa A. Howard, Hector G. Ortega, Faiz F. Ahmad, Kenneth R. Chapman. (2010) Low-dose fluticasone propionate with and without salmeterol in steroid-naïve patients with mild, uncontrolled asthma. Respiratory Medicine 104:4, 510-517
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G Walter Canonica, Christopher Brightling. (2010) Section 3. A Discussion of Flexible Dosing and Patient-Centered Therapy. World Allergy Organization Journal 3:2, 31-37
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Stephen T Holgate. (2010) Has the time come to rethink the pathogenesis of asthma?. Current Opinion in Allergy and Clinical Immunology 10:1, 48-53
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Gustavo J. Rodrigo, Vicente Plaza Moral, Santiago Bardagí Forns, José A. Castro-Rodríguez, Alfredo de Diego Damiá, Santos Liñán Cortés, Carlos Melero Moreno, Luis J. Nannini, Hugo Neffen, Jorge Salas. (2010) Guía ALERTA 2. América Latina y España: Recomendaciones para la prevención y el Tratamiento de la exacerbación Asmática. Archivos de Bronconeumología 46, 2-20
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Gregory S. Sawicki, Robert C. Strunk, Brooke Schuemann, Robert Annett, Scott Weiss, Anne L. Fuhlbrigge. (2010) Patterns of inhaled corticosteroid use and asthma control in the Childhood Asthma Management Program Continuation Study. Annals of Allergy, Asthma & Immunology 104:1, 30-35
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Stephen T. Holgate, Hasan S. Arshad, Graham C. Roberts, Peter H. Howarth, Philipp Thurner, Donna E. Davies. (2009) A new look at the pathogenesis of asthma. Clinical Science 118:7, 439-450
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Louis-Philippe Boulet, Hélène Turcotte, Philippe Prince, Catherine Lemière, Ronald Olivenstein, Catherine Laprise, Pierre Larivée, Paul Bégin, Michel Laviolette. (2009) Benefits of low-dose inhaled fluticasone on airway response and inflammation in mild asthma. Respiratory Medicine 103:10, 1554-1563
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Kian Fan Chung, Gaetano Caramori, Ian M. Adcock. (2009) Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future. European Journal of Clinical Pharmacology 65:9, 853-871
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E. Rand Sutherland, Erik B. Lehman, Mihaela Teodorescu, Michael E. Wechsler. (2009) Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. Journal of Allergy and Clinical Immunology 123:6, 1328-1334.e1
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Fanta, Christopher H., . (2009) Asthma. New England Journal of Medicine 360:10, 1002-1014
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Kristen B. Van Dole, Arlene S. Swern, Kathleen Newcomb, Linda Nelsen. (2009) Seasonal patterns in health care use and pharmaceutical claims for asthma prescriptions for preschool- and school-aged children. Annals of Allergy, Asthma & Immunology 102:3, 198-204
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J. Paul SEALE, Christine JENKINS, Richard WOOD-BAKER, A. Munro NEVILLE. (2009) Benefits of fixed-dose combination therapy with inhaled corticosteroids and long-acting bronchodilators as initial maintenance therapy in the management of asthma. Respirology 14:2, 224-229
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William W. Busse. (2009) Reply. Journal of Allergy and Clinical Immunology 123:3, 710-711
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Jose E. Gereda, Carlos Baena-Cagnani. (2009) The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) follow-up study does not support early and daily treatment. Journal of Allergy and Clinical Immunology 123:3, 710
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Andrea J. Apter. (2009) Advances in adult asthma diagnosis and treatment and health outcomes, education, delivery, and quality in 2008. Journal of Allergy and Clinical Immunology 123:1, 35-40
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David G. Greenhalgh. (2009) Steroids in the Treatment of Smoke Inhalation Injury. Journal of Burn Care & Research 30:1, 165-169
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Alberto Papi. (2009) Treatment strategies in mild asthma. Current Opinion in Pulmonary Medicine 15:1, 29-34
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(2009) GEMA (Guía española del manejo del asma). Archivos de Bronconeumología 45, 2-35
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Andrew Bush. (2009) Role of corticosteroids in preschool wheeze: going, going, but not gone. Therapy 6:1, 31-39
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Andrew Bush. 2009. Pediatric AsthmaHow Early Life Events Cause Lifelong Respiratory Disease. , 791-821.
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Rodolfo M. Pascual, Stephen P. Peters. 2009. Management of Chronic AsthmaIn Adults. , 761-774.
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Zorica Zivkovic, Sofija Cerovic, Zoran Vukasinovic, Jasmina Jocic-Stojanovic. (2009) News in childhood asthma therapy. Srpski arhiv za celokupno lekarstvo 137:9-10, 558-561
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M. A. Rank, G. W. Volcheck, J. T. C. Li, A. M. Patel, K. G. Lim. (2008) Formulating an Effective and Efficient Written Asthma Action Plan. Mayo Clinic Proceedings 83:11, 1263-1270
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Bruce G. Bender, Allison Rankin, Zung Vu Tran, Frederick S. Wamboldt. (2008) Brief-interval telephone surveys of medication adherence and asthma symptoms in the Childhood Asthma Management Program Continuation Study. Annals of Allergy, Asthma & Immunology 101:4, 382-386
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Chiara Folli, Desideria Descalzi, Francesca Scordamaglia, Anna Maria Riccio, Cinzia Gamalero, Giorgio Walter Canonica. (2008) New insights into airway remodelling in asthma and its possible modulation. Current Opinion in Allergy and Clinical Immunology 8:5, 367-375
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Dirkje S. Postma, Huib A. M. Kerstjens, Nick H. T. Hacken. (2008) RETRACTED ARTICLE: Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all?. Naunyn-Schmiedeberg's Archives of Pharmacology 378:2, 203-215
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Olof Selroos. (2008) Effect of disease duration on dose–response of inhaled budesonide in asthma. Respiratory Medicine 102:7, 1065-1072
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Fabrizio Spinozzi, Diletta de Benedictis, FM de Benedictis. (2008) Apoptosis, airway inflammation and anti-asthma therapy: From immunobiology to clinical application. Pediatric Allergy and Immunology 19:4, 287-295
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Rob Stirling. (2008) Airway inflammation: An important marker of control for asthma guidelines?. Journal of Allergy and Clinical Immunology 121:5, 1293
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Ramón San Miguel, Ana María López-González, Eduardo Sanchez-Iriso, Javier Mar, Juan M. Cabasés. (2008) Measuring health-related quality of life in drug clinical trials: is it given due importance?. Pharmacy World & Science 30:2, 154-160
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Timothy J. Craig, Tonya S. King, Robert F. Lemanske, Michael E. Wechsler, Nikolina Icitovic, Ronald R. Zimmerman, Stephen Wasserman. (2008) Aeroallergen sensitization correlates with PC20 and exhaled nitric oxide in subjects with mild-to-moderate asthma. Journal of Allergy and Clinical Immunology 121:3, 671-677
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Clare S Murray. (2008) Can inhaled corticosteroids influence the natural history of asthma?. Current Opinion in Allergy and Clinical Immunology 8:1, 77-81
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C. Taube, R. Buhl. (2008) Therapie des Asthma bronchiale. Der Pneumologe 5:1, 24-31
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Louis I. Landau, Fernando D. Martinez. 2008. Treatment. , 829-844.
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William W. Busse, Robert F. Lemanske. (2007) Expert Panel Report 3: Moving forward to improve asthma care. Journal of Allergy and Clinical Immunology 120:5, 1012-1014
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P. Y. Hahn, T. I. Morgenthaler, K. G. Lim. (2007) Use of Exhaled Nitric Oxide in Predicting Response to Inhaled Corticosteroids for Chronic Cough. Mayo Clinic Proceedings 82:11, 1350-1355
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Fabio L.M. Ricciardolo. (2007) The treatment of asthma in children: Inhaled corticosteroids. Pulmonary Pharmacology & Therapeutics 20:5, 473-482
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Martin M. Zdanowicz. (2007) Pharmacotherapy of Asthma. American Journal of Pharmaceutical Education 71:5, 98
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(2007) Beclomethasone and Albuterol in Mild Asthma. New England Journal of Medicine 357:5, 506-507
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(2007) Reducing Asthma Treatment. New England Journal of Medicine 357:5, 504-506
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M. S. Koh, L. B. Irving. (2007) Evidence-based pharmacologic treatment for mild asthma. International Journal of Clinical Practice 61:8, 1375-1379
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Tonya S. King, Vernon M. Chinchilli, Kai-Ling Wang, Josep L. Carrasco. (2007) A Class of Repeated Measures Concordance Correlation Coefficients. Journal of Biopharmaceutical Statistics 17:4, 653-672
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Antonius Schneider, Michel Wensing, Renate Quinzler, Christiane Bieber, Joachim Szecsenyi. (2007) Higher preference for participation in treatment decisions is associated with lower medication adherence in asthma patients. Patient Education and Counseling 67:1-2, 57-62
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Andreas von Leupoldt, Frank Kanniess, Bernhard Dahme. (2007) The influence of corticosteroids on the perception of dyspnea in asthma. Respiratory Medicine 101:6, 1079-1087
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D. Dusser, D. Montani, P. Chanez, J. de Blic, C. Delacourt, A. Deschildre, P. Devillier, A. Didier, C. Leroyer, C. Marguet, Y. Martinat, J. Piquet, C. Raherison, P. Serrier, I. Tillie-Leblond, A.-B. Tonnel, M. T. de Lara, M. Humbert. (2007) Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 62:6, 591-604
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The American Lung Association Asthma Clinical Research Centers. (2007) Randomized Comparison of Strategies for Reducing Treatment in Mild Persistent Asthma. New England Journal of Medicine 356:20, 2027-2039
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Papi, Alberto, Canonica, Giorgio W., Maestrelli, Piero, Paggiaro, Pierluigi, Olivieri, Dario, Pozzi, Ernesto, Crimi, Nunzio, Vignola, Antonio M., Morelli, Paolo, Nicolini, Gabriele, Fabbri, Leonardo M., . (2007) Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma. New England Journal of Medicine 356:20, 2040-2052
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(2007) Treatment of Mild Persistent Asthma. New England Journal of Medicine 356:20, 2096-2100
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Cynthia Rand, Andrew Bilderback, Kathleen Schiller, Jonathan M. Edelman, Carolyn M. Hustad, Robert S. Zeiger. (2007) Adherence with montelukast or fluticasone in a long-term clinical trial: Results from the Mild Asthma Montelukast Versus Inhaled Corticosteroid Trial. Journal of Allergy and Clinical Immunology 119:4, 916-923
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Olof Selroos. (2007) A smarter way to manage asthma with a combination of a long-acting ? 2 -agonist and inhaled corticosteroid. Therapeutics and Clinical Risk Management 3:2, 349-359
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John Oppenheimer. (2007) The new mantra of asthma care—control. Annals of Allergy, Asthma & Immunology 98:3, 205-206
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Wan C Tan. (2007) Insights into Early Treatment of Mild Asthma. Pediatric Drugs 9:4, 219-226
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Richard J. Martin, Stanley J. Szefler, Tonya S. King, Monica Kraft, Homer A. Boushey, Vernon M. Chinchilli, Timothy J. Craig, Emily A. DiMango, Aaron Deykin, John V. Fahy, Elliot Israel, Stephen C. Lazarus, Robert F. Lemanske, Frank T. Leone, Gene R. Pesola, Stephen P. Peters, Christine A. Sorkness, Lisa A. Szwejbka, Michael E. Wechsler. (2007) The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial. Journal of Allergy and Clinical Immunology 119:1, 73-80
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Ferran Morell, Teresa Genover, Leonardo Reyes, Esther Benaque, Àlex Roger, Jaume Ferrer. (2007) La población de asmáticos ambulatorios y su control tras adaptar el tratamiento a las recomendaciones internacionales (ASMACAP I). Archivos de Bronconeumología 43:1, 29-35
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Loren C. Denlinger, Christine A. Sorkness, Vernon M. Chinchilli, Robert F. Lemanske. (2007) Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network. Journal of Allergy and Clinical Immunology 119:1, 3-11
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Harold J Farber, Michael Schatz. (2007) Health Plan Employer Data and Information Set (HEDIS®) Criteria to Determine the Quality of Asthma Care in Children. Disease Management & Health Outcomes 15:5, 279-287
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Christopher L. Carroll, Anita Bhandari, Craig M. Schramm, Aaron R. Zucker. (2006) Chronic inhaled corticosteroids do not affect the course of acute severe asthma exacerbations in children. Pediatric Pulmonology 41:12, 1213-1217
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James Kemp. (2006) Is there a best outcome measurement for patients with asthma?. Annals of Allergy, Asthma & Immunology 97:4, 432-439
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Paul M O'Byrne, Krishnan Parameswaran. (2006) Pharmacological management of mild or moderate persistent asthma. The Lancet 368:9537, 794-803
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Jay M. Portnoy, Donna Jennings. (2006) Utilization patterns in an asthma intervention. Annals of Allergy, Asthma & Immunology 97:1, S25-S30
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Sabina A Antoniu. (2006) Daily versus intermittent corticosteroids for the treatment of mild persistent asthma. Expert Opinion on Pharmacotherapy 7:9, 1235-1238
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Bisgaard, Hans, Hermansen, Mette Northman, Loland, Lotte, Halkjaer, Liselotte Brydensholt, Buchvald, Frederik, . (2006) Intermittent Inhaled Corticosteroids in Infants with Episodic Wheezing. New England Journal of Medicine 354:19, 1998-2005
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M. Tonelli, E. Bacci, F.L. Dente, M.L. Bartoli, S. Cianchetti, A. Di Franco, B. Vagaggini, M. Zingoni, P.L. Paggiaro. (2006) Predictors of symptom recurrence after low-dose inhaled corticosteroid cessation in mild persistent asthma. Respiratory Medicine 100:4, 622-629
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Chitra Dinakar. (2006) Monitoring of asthma control in children. Current Opinion in Allergy and Clinical Immunology 6:2, 113-118
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Stephen Stick. (2006) Inflammatory markers should be the basis of monitoring asthma. Paediatric Respiratory Reviews 7, S93-S95
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Helen K Reddel. (2006) Peak flow monitoring in clinical practice and clinical asthma trials. Current Opinion in Pulmonary Medicine 12:1, 75-81
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Takashi Kusunoki, Tomoko Miyajima, Toshiyuki Kitoh, Tatsuya Fujii, Masatoshi Ito. (2006) Nihon Shoni Arerugi Gakkaishi. The Japanese Journal of Pediatric Allergy and Clinical Immunollogy 20:5, 497-504
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Manabu Akazawa, David A Stempel. (2006) Single-Inhaler Combination Therapy for Asthma. PharmacoEconomics 24:10, 971-988
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S WILLSIE. (2006) Daily Versus As-Needed Corticosteroids for Mild Persistent AsthmaBoushey HA, for the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network (Univ of California at San Francisco; et al) N Engl J Med 352:1519-1528, 2005§. Yearbook of Pulmonary Disease 2006, 28-29
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Joseph Spahn, Anne-Marie Irani. (2005) Regular Use of Inhaled Corticosteroids in Children with Persistent Asthma. Pediatric Asthma, Allergy & Immunology 18:4, 247-258
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Paul M. O'Byrne. (2005) Initiation, Dose Reduction, and Duration of Inhaled Corticosteroid Therapy. Immunology and Allergy Clinics of North America 25:3, 511-521
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Guy F. Joos, Guy G. Brusselle, Helen Van Hoecke, Paul Van Cauwenberge, Jean Bousquet, Romain A. Pauwels. (2005) Positioning of Glucocorticosteroids in Asthma and Allergic Rhinitis Guidelines (Versus Other Therapies). Immunology and Allergy Clinics of North America 25:3, 597-612
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(2005) Treatment of Mild Asthma. New England Journal of Medicine 353:4, 424-427
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Deykin, Aaron, . (2005) Targeting Biologic Markers in Asthma — Is Exhaled Nitric Oxide the Bull's-Eye?. New England Journal of Medicine 352:21, 2233-2235
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Fabbri, Leonardo M., . (2005) Does Mild Persistent Asthma Require Regular Treatment?. New England Journal of Medicine 352:15, 1589-1591
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