© 2005 American Thoracic Society doi: 10.1164/rccm.2505003
Daily Inhaled Corticosteroid Treatment Should Not Be Prescribed for Mild Persistent AsthmaUniversity of California at San Francisco, San Francisco, California The repeatedly demonstrated value of inhaled corticosteroid (ICS) therapy for patients with active, symptomatic asthma (1), coupled with evidence of its antiinflammatory action (2, 3), gave inhaled corticosteroids pride of place in the first edition of the National Asthma Expert Prevention Program's "Guidelines for the Diagnosis and Management of Asthma" (4). Daily use of an ICS was recommended as the first choice for maintenance or "controller" therapy for moderate or severe asthma. Only mild asthma was exempted. The recommendation was extended to "mild persistent" asthma when the Guidelines were revised in 1997 (5). This extension was driven by reports that some patients with long-standing asthma have severe, irreversible airflow obstruction (6–8) and by longitudinal studies showing asthma to be associated with an accelerated rate of loss of pulmonary function (9, 10). Additional impetus came from the findings of one prospective and two retrospective studies of patients with mild–moderate asthma suggesting that regular treatment with an ICS prevented this accelerated loss in pulmonary function, but that if it was delayed as little as 2 years, the benefit was severely reduced (11–14). More or less coincidently, reports appeared describing "remodeling" of the airways in chronic asthma, with hyperplasia of all tissue elements, deposition of collagen, and increases in extracellular matrix causing thickening of the bronchial wall, heightening bronchial reactivity and presumably causing "irreversible," or at best slowly or poorly reversible, obstruction to airflow (15). This remodeling was considered most likely a consequence of bronchial inflammation (16), establishing an additional rationale for early introduction of antiinflammatory therapy, preferably with an inhaled corticosteroid: the prevention of irreversible loss of pulmonary function. Because persistent inflammation was thought likely responsible for progressive loss of function, the 1997 revision of the Guidelines recommended daily antiinflammatory treatment of even mild asthma if it is persistent (5). Hence, the category of "mild asthma" was subdivided into "mild intermittent" and "mild persistent" categories. A precise definition of "mild persistent" asthma could not be drawn from a basis of evidence, so the committee of experts responsible for the Guidelines simply did its best, drawing on published information and its own collective experience. The criteria developed describe asthma that is mild indeed. Any of the following qualify: symptoms requiring bronchodilator treatment more than twice a week, but not as often as once a day; nighttime awakenings due to asthma more than twice a month, but not as often as once a week; or peak flow variability of 20 to 30%. Even without any of these symptoms, an FEV1 of less than 80% predicted classifies asthma severity as moderate, not mild. The Guidelines have been widely published, and although the greater use of ICS they advocate has been credited with improvements in the rates of hospitalization for asthma (17), their uptake and adoption has been disappointing. Pharmacy records show, for example, that individuals with asthma prescribed an inhaled corticosteroid refill their prescription infrequently (18). Most asthma is mild or moderate in severity, so this presumably means that patients with these forms of asthma do not feel the need, or are not persuaded of the importance, of taking treatment regularly. This does not mean, of course, that the Guidelines are wrong, but it does invite consideration of why patients decline to take treatment regularly, or why their health care providers do not urge them to do so. The first and perhaps most compelling reason for taking a treatment is that it causes a perceptible and important benefit, like relieving discomfort, increasing functional capacity, or improving quality of life. The second reason is that it reduces the risk of harm in the future, like severe exacerbations of asthma, irreversible and limiting loss of function, or progression to a more severe form of the disease requiring riskier or more toxic treatment. For asthma qualifying as "mild persistent asthma" the symptoms are by definition mild, and in any case are usually relieved promptly by inhalation of an inexpensive bronchodilator. And, at least as perceived by individual patients, the frequency and severity of exacerbations may be too low to justify the inconvenience and expense of taking an ICS every day. As for the risk of progressive loss of pulmonary function, leading to a dotage limited by dyspnea, the patient must trust the physician's advice that such progression is likely and that it is prevented by adhering to daily ICS treatment. Before a reluctant population is further urged to adhere to the recommendations of experts, the Asthma Clinical Research Network (ACRN) thought it worth examining the actual importance—in patients meeting the defined criteria for "mild persistent asthma"—of strict adherence to twice daily therapy with an "anti-inflammatory, controller" therapy, in comparison to simply taking short courses of an inhaled corticosteroid when asthmatic symptoms flared, which most patients seem inclined to do. Accordingly, we designed the Improving Asthma Control Trial ("IMPACT") to compare in adult patients who met the criteria for "mild persistent asthma" over 4 weeks of monitoring by symptom diary and daily peak flow (PEF) the effects of daily budesonide, daily zafirlukast, and daily placebo (19). All patients were instructed to initiate brief courses of inhaled or oral corticosteroid therapy as guided by a symptom-based action plan, and, importantly, all were given the medications to have immediately on hand. Thus the "placebo" group is best described as receiving "intermittent only" treatment. Two hundred twenty-five subjects were randomized and followed for 12 months. The effects of the three treatments were compared in four domains: pulmonary function (morning PEF, and FEV1 measured before and after albuterol inhalation, bronchial reactivity to methacholine); frequency of exacerbations (worsening of symptoms warranting treatment with prednisone, emergency visits, or hospitalizations); symptoms and function (symptom-free days, asthma symptom utility index, days lost from work or school, asthma-related quality of life); and markers of inflammation (induced sputum eosinophil percentage, exhaled nitric oxide). Knowing that inhaled corticosteroids have a rapid-onset, rapid-offset effect on airway caliber (20–23), we thought it important to compare not just baseline and postalbuterol FEV1, but also FEV1 measured after a short (10–14 day) but intense course of prednisone, high-dose inhaled budesonide, and oral zafirlukast, plus acute treatment with albuterol. We reasoned that if ICS treatment prevented "remodeling" any greater loss in function in the "intermittent only" group should not reverse with a short course of antiinflammatory therapy. Our findings showed that the three groups had almost identical changes in morning PEF, and that whereas budesonide produced greater improvement in prebronchodilator FEV1, the changes in FEV1 measured after albuterol were again highly similar, declining 0.5 to 2.0% in all three groups (19). At least in these subjects with mild asthma, the period of intense therapy proved unnecessary: mean FEV1 after this treatment did not differ from that measured after four to eight puffs of albuterol alone. Budesonide had other demonstrable effects: it reduced sputum eosinophils, FeNO, and bronchial reactivity, and increased the number of symptom-free days more than the other treatments. But neither budesonide nor zafirlukast differed from "intermittent only" in effects on frequency of exacerbations, asthma control, or asthma-related quality of life. These findings were robust. The confidence intervals for the difference in the rate of exacerbations and in the decline in postalbuterol FEV1 in the "intermittent only" and the daily budesonide group were wide, and slightly favored intermittent treatment, suggesting that it is unlikely that a larger study would demonstrate a difference. If a larger, longer study corroborates our findings, it will indicate that adult patients who meet NIH-guidelines criteria for "mild persistent asthma" do not require daily treatment with an antiinflammatory medication, provided they are instructed in a symptom-guided action plan for initiating inhaled or oral corticosteroid treatment, and are given the medications to have at hand. More precisely, it will indicate that they do not require daily treatment with an antiinflammatory agent if the goals of therapy are to prevent exacerbations and to prevent or slow an accelerated rate of loss of pulmonary function. But what is to be made of the improvements in symptom-free days? Is that not a goal of therapy? It is, of course, but its importance is a function of the severity of the symptoms prevented and of the availability of other treatments. The lack of change in the "symptom-utility index" and in quality of life suggests that the study's participants did not accord much importance to the increase in days without symptoms. Recall that to qualify as "mild persistent asthma" symptoms must be slight and infrequent. Then what about buseonide's observed antiinflammatory activity? It reduced sputum eosinophils, FeNO, and bronchial reactivity. Is that not sufficient as a rationale for therapy? Our response is "maybe not." Recall again that that low-grade inflammation similar to that seen in our subjects has been reported in patients with spontaneous, complete, sustained clinical remission of asthma (24), and no one is now seriously proposing that they are candidates for daily controller treatment. In the current era of awareness of the limitations to resources for health care, the question as to whether adults with long-standing mild persistent asthma, like those enrolled in IMPACT, require daily controller therapy should be considered as well in terms of cost. If even 25% of the approximately 15 million Americans with asthma have "mild, persistent asthma," and 1 canister of an inhaled corticosteroid is needed per patient-year when taken only "as needed" versus 12 when taken regularly, then at $50/cannister, universal compliance with the recommendation for daily treatment would increase expenditures by over $2 billion/year. The findings of the IMPACT study question whether the benefits of this treatment justify the expense. If the sole benefit of direct importance to the patient is an increase in symptom-free days, a less expensive, sensible approach is for the patient and health-care provider to discuss the advantages, disadvantages, and costs, both in dollars and in risks of toxicity, and decide together whether regular, daily treatment, or "as-needed" symptom-driven treatment, is the better plan. FOOTNOTES Conflict of Interest Statement: H.A.B. received $11,900 in 2003 and $14,400 in 2004 from GlaxoSmithKline for service on a Steering Committee for a multicenter study and for chairing and speaking at conferences. He received $2,500 in honoraria in 2004 and $3,000 for consulting in 2005 for Altana, $1,000 for consulting in 2003 from Sanofi-Aventis, $1,500 in honoraria in 2004 from Boehringer-Ingelheim, and $2,500 for consulting in 2005 from Sumitomo. REFERENCES
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