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Therapeutic Responses in Asthma and COPD*: Corticosteroids FREE TO VIEW

Michael J. Larj, MD, FCCP; Eugene R. Bleecker, MD, FCCP
Author and Funding Information

*From the Center for Human Genomics, Division of Pulmonary and Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to: Eugene Bleecker, MD, FCCP, Co-Director, Center for Human Genomics, Professor of Medicine, Wake Forest University School of Medicine, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157-1008; e-mail: ebleeck@wfubmc.edu



Chest. 2004;126(2_suppl_1):138S-149S. doi:10.1378/chest.126.2_suppl_1.138S
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The effects of inhaled corticosteroids (ICSs) in asthma include reduced severity of symptoms, improved pulmonary function, diminished bronchial hyperresponsiveness (BHR), prevention of exacerbations, and possible prevention of airway wall remodeling. Compared with an inhaled β2-agonist, ICSs improve airway function and BHR, reduce bronchial-epithelium abnormalities, decrease bronchial inflammation, and reduce inflammatory-cell infiltration into the bronchial lamina propria; thus, they may prevent airway remodeling. In children, early use of ICSs may result in improved airway function over time. ICSs reduce use of prednisone, asthma medications, hospitalizations, and urgent-care visits. The primary side effects of ICSs in children are limited to transient reduction in growth. Compared with a leukotriene receptor antagonist (LTRA), ICSs produced a greater change from baseline in FEV1 and greater reductions in symptoms. A long-acting β2-agonist (LABA) combined with an ICS produced greater improvements than does therapy with ICSs even at higher doses. In COPD, the therapeutic value of ICSs is not as clear. While clinical trials in patients with mild COPD have not shown a reduction in decline in FEV1 over time, other studies have shown that ICS therapy reduces exacerbations in patients with more severe COPD. Combination therapy with both ICS and LABA has recently been shown to be effective in COPD, where studies have documented additive improvement in FEV1. Overall, the same therapeutic approaches show clinical effectiveness in both asthma and COPD. This supports the hypothesis that there are some similarities in these obstructive airway diseases. Future approaches should further define phenotypes, perhaps based in part on pharmacogenetic factors that will guide anti-inflammatory therapy in asthma and COPD.

Figures in this Article

Inflammation is an important component of the development and progression of both asthma and COPD. Thus, anti-inflammatory interventions are therapeutically effective and may prevent disease progression in certain stages of development of these obstructive airway diseases. Treatment of inflammation should reduce bronchial hyperresponsiveness (BHR) and improve airway function. Clinically, anti-inflammatory therapy reduces symptoms and disease exacerbations, which should be common goals of therapy for both disorders. Understanding which clinical phenotypes as well as whether pharmacogenetic factors are important in anti-inflammatory inventions may improve our understanding about the pathogenesis of asthma and COPD.

Current national asthma education guidelines1 recommend the use of inhaled corticosteroids (ICSs) as first-line therapy for all stages of persistent asthma. Corticosteroids are the most potent and consistently effective long-term control medications for asthma. Their broad action on the inflammatory process accounts for their efficacy as preventive therapy. Their clinical effects include reduction in severity of symptoms, improvement in pulmonary function, diminished BHR, prevention of asthma exacerbations, and possibly the prevention of airway wall remodeling.1

Thus, in patients with asthma, the use of ICSs represents standard therapy for persistent disease because of their effects on the pathophysiologic abnormalities characteristic of asthma, and their excellent clinical response in this disease. Laitinen and coworkers23 evaluated the effects of ICSs on airway inflammation, comparing the ICS budesonide and an inhaled β2-agonist, terbutaline. Their effects on clinical symptoms, lung function, and airway inflammation were studied in 14 adult patients with newly diagnosed asthma identified in a large, long-term interventional trial.,23 The study was conducted using a randomized, double-blind, parallel-group design. Seven patients were treated with inhaled budesonide (ICS), 600 μg bid, while another seven patients received inhaled terbutaline (β2-agonist), 375 μg bid, by metered-dose inhaler with a spacer. Bronchial biopsy samples obtained before randomization and after 3 months of treatment were analyzed using electron microscopy.

Both groups improved clinically. However, treatment with the ICS was more effective than the β2-agonist in improving morning and evening peak expiratory flow (PEF) rates, as well as BHR to inhaled histamine. Treatment with ICSs was accompanied by increased numbers of ciliated airway cells and intraepithelial nerves and fewer inflammatory cells, including eosinophils, in the epithelium (Fig 1 ).4 These changes were not observed in specimens from β2-agonist–treated patients. The authors concluded that, in contrast to inhaled β2-agonists, ICSs improved lung function and BHR in adult subjects with asthma treated for 3 months, and were more effective in ameliorating abnormalities of the bronchial epithelium and decreasing inflammation in the airways.,4

Basement membrane thickness was measured in endobronchial samples before and after 6 weeks of therapy with the ICS fluticasone propionate (FP). A double-blind, parallel-group study5 examined the effect of short-term treatment with inhaled FP in 20 nonsmoking asthmatic patients who required only β2-agonists to control their symptoms. Therapy with this ICS (FP, 250 μg bid) or placebo was administered for 6 weeks. Methacholine challenge was performed before treatment, after 3 weeks, and at the end of treatment. Each patient underwent bronchoscopy with BAL and bronchial biopsy before and after treatment. Eight patients in the placebo group and nine patients in the ICS group completed the study.

BHR to methacholine decreased significantly after 6 weeks of treatment with the ICS (p < 0.05). Additionally, the number of eosinophils and mast cells in the lamina propria in bronchial biopsy specimens was significantly smaller in the ICS group than in the placebo group (p < 0.02 and p < 0.01, respectively). Furthermore, in the ICS group, basement membrane thickness was significantly decreased when compared with that of the placebo group (p < 0.05). These studies show that treatment with a low-dose ICS reduces inflammatory cell infiltration into the airway mucosa and reduces airway remodeling in mild asthma.5

More recently, Sont and coworkers6 studied the long-term efficacy of lower- and higher-dose strategies using ICSs in asthma. They found that the higher dosing strategy of ICSs based on reducing BHR produced improved symptom control and resulted in improvements in airway structure identified by examination of serial bronchial biopsies. Seventy-five adults with mild-to-moderate asthma were assessed every 3 months for 2 years, at each visit having an FEV1 evaluation and methacholine challenge. ICSs were adjusted according to a stepwise approach based on four severity classes of BHR. Bronchoscopic biopsies were performed at entry and after 2 years.

Patients whose treatment was guided by following BHR had a 1.8-fold lower rate of mild exacerbations than did patients in the reference strategy group based only on symptom control. FEV1 also improved significantly more in the BHR strategy group. This was accompanied by a greater reduction in thickness of the subepithelial reticular layer in the BHR strategy group than in the reference strategy subjects, as evaluated by bronchial biopsies. Therefore, the investigators proposed that reducing BHR in conjunction with optimizing control of symptoms and lung function may lead to more effective management of asthma with a reduction in markers of chronic airways inflammation. These results may imply a role for the monitoring of BHR or other surrogate markers of inflammation in the long-term management of persistent asthma.6

Agertoft and Pederson7 illustrated the importance of early treatment with ICSs in asthma. They compared the annual change in FEV1 percentage of predicted value with the number of years that asthma symptoms started before ICS treatment was initiated. They measured growth and pulmonary function in children with asthma during long-term treatment with ICSs and compared these findings with those obtained from children not treated with ICSs. Two hundred sixteen children were followed up at 6-month intervals for 1 to 2 years while not receiving an ICS and then for 3 to 6 years while receiving an ICS. Sixty-two children treated with theophylline, β2-agonists, and sodium cromoglycate, but not with ICSs, were also followed up for 3 to 7 years (control subjects).

During the period of ICS therapy, the mean daily dose of ICS significantly decreased, and no signs of tachyphylaxis to the treatment were observed. Also, ICS treatment was associated with a significant reduction in the number of annual hospital admissions due to acute severe asthma. In patients not treated with ICSs, an annual decrease in percentage of predicted FEV1 of 1 to 3% was found. In contrast, FEV1 improved significantly with time during ICS treatment, compared with both the run-in period in the treated group and in the control group. Furthermore, there was a significant relationship between the duration of asthma at the start of ICSs and the annual increase in FEV1 during ICS therapy. After 3 years of treatment with ICSs, children who started this therapy later than 5 years after the onset of asthma had significantly lower FEV1 (96%) than the children who received ICSs within the first 2 years after the onset of their asthma (101%).7

Panhuysen and coworkers8 showed that initiating therapy with ICSs earlier in correlation to the onset of asthma symptoms was related to a better long-term outcome. They investigated asthma-related outcomes in a population of 181 adult patients 13 to 44 years of age who were extensively tested between 1962 and 1970 and in whom asthma was diagnosed. When retested 25 years later, 38 subjects (21%) did not show BHR, 45 subjects (25%) showed a FEV1 > 90% predicted, and 72 subjects (40%) did not report pulmonary symptoms. Absence of asthma after 25 years was associated with a younger age and less severe airway obstruction at first testing, while absence of BHR was associated with a younger age, a higher FEV1, and a shorter untreated period.,8 These findings are consistent with a 3-year follow-up study in which Haahtela3 showed that asthmatic patients initially treated with β2-agonists alone did not show the same improvement when placed on ICSs after 2 years as did asthmatics who were initially treated with ICSs at the start of the clinical trial. These studies lend support to the hypothesis that milder disease and earlier intervention with ICSs are important for an improved outcome in asthma.

ICSs in children have been shown to result in fewer courses of prednisone and decreased use of additional asthma medications when administered over long periods of time. Prior to the Childhood Asthma Management Program sponsored by the National Heart, Lung, and Blood Institute, anti-inflammatory therapies such as ICSs or nedocromil were recommended for the treatment of children with asthma, although information was limited on their long-term use. The purpose of the Childhood Asthma Management Program was to prospectively evaluate long-term anti-inflammatory therapy in childhood asthma. One thousand forty-one children from 5 through 12 years of age with mild-to-moderate asthma were randomized to receive 200 μg bid of budesonide (311 children), 8 mg bid of nedocromil (312 children), or matching placebo (418 children). The participants were treated for 4 to 6 years.

There was no significant difference between either treatment and placebo in the primary outcome—the degree of change in the FEV1 expressed as a percentage of the predicted value, after the administration of a bronchodilator. Compared with the children assigned to placebo, the children assigned to receive ICSs experienced a significantly smaller decline in the ratio of FEV1 to FVC, expressed as a percentage, before the administration of a bronchodilator (decline in FEV1/FVC, 0.2% vs 1.8%). The children administered ICSs also had decreased bronchial responsiveness to methacholine, fewer hospitalizations (2.5 per 100 person-years vs 4.4 per 100 person-years), fewer urgent visits (12 per 100 person-years vs 22 per 100 person-years), greater reduction in the need for albuterol for symptoms, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medications were required (Fig 2 ).9 Compared with placebo, nedocromil significantly reduced urgent-care visits (16 per person-years vs 22 per 100 person-years) and courses of prednisone. The mean increase in height in the ICS group was 1.1 cm less than in the placebo group (22.7 cm vs 23.8 cm, p = 0.005); this difference was evident mostly within the first year. The height increase was similar in the nedocromil and placebo groups. In children with mild-to-moderate asthma, neither ICSs nor nedocromil were better than placebo in improving lung function, but ICSs improved airway responsiveness and provided significantly better control of asthma than placebo or nedocromil. The side effects of ICSs were limited to a small, transient reduction in growth velocity.9

The following study helps illustrate the overall individual patient response to either an ICS or a leukotriene receptor antagonist (LTRA). Figure 3 shows the distribution of FEV1 response to either an ICS or LTRA.10 Eight hundred ninety-five patients 15 to 85 years of age with chronic asthma and an FEV1 50 to 85% of predicted were randomized to either inhaled beclomethasone (ICS), 200 μg bid, administered with a spacer device; montelukast (LTRA), 10 mg qd at bedtime; or placebo. Primary end points were daytime asthma symptom score and FEV1. Secondary end points were PEF rates in the morning and evening, as-needed β2-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes.

During the 12 weeks of treatment, the average percentage change from baseline FEV1 was 13.1% with ICS, 7.4% with LTRA, and 0.7% with placebo (p < 0.001 for each active treatment compared with placebo; p < 0.01 for ICS compared with the LTRA). The average change from baseline in daytime symptom score was − 0.62 for ICS, − 0.41 for LTRA, and − 0.17 for placebo. Each agent improved PEF rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number days with effective asthma control, and decreased the number of days with asthma exacerbations.10 It is important to note that when describing patients’ responses to ICS and LTRA in terms of FEV1, in this study, approximately 21% of patients showed no improvement in FEV1 while receiving an ICS, and 38% showed no improvement in FEV1 while receiving an LTRA.

There are two important issues that must be considered in the interpretation of this study. The first is that when evaluating therapeutic responses using pulmonary function, subjects in each treatment group must be matched for baseline spirometry (FEV1). It is not clear whether this was done in this study. The second is that the dose of ICS was low (400 μg/d of beclomethasone), and probably well below the peak dose response for this ICS. These issues may effect interpretation of responder patterns to each of these asthma therapies. However, this study demonstrates the less-than-uniform response in FEV1 and variability in patient response to asthma therapy. The findings imply that individual responses to these two drugs may be caused by other factors, including pharmacogenetic factors (Fig 3).10

The addition of a long-acting β2-agonist (LABA) to ICS rather than increasing the dose of ICS has become standard therapy in poorly controlled asthma. This is because the combination of these two therapies appears to provide improved asthma control. The two strategies have been compared in a number of randomized, double-blind, parallel-group trials. The first study that used this approach, by Greening and coworkers,11 evaluated 429 adult asthmatic patients who had asthma symptoms despite maintenance treatment with 200 μg bid of inhaled beclomethasone dipropionate (ICS). Two hundred twenty participants were assigned to salmeterol (LABA), 50 μg bid plus ICSs, and 206 patients were treated with a higher-dose ICSs (500 μg bid) for 6 months.

The mean morning PEF increased from baseline in both groups, but the increase was greater in the LABA/ICS group than in the higher-dose ICS group at all time points (differences, 16 to 21 L/min, p < 0.05). Mean evening PEF also increased with LABA/ICS, but not with higher-dose ICS. There were significant differences in favor of LABA/ICS in diurnal variation of PEF, in use of rescue bronchodilator (albuterol), and in daytime and nighttime symptoms. There was no significant difference between the groups in adverse events or asthma exacerbations, indicating that in this group of patients, treatment with LABA was not associated with any risk of deteriorating asthma control over 6 months.11 Compared with high-dose ICSs, low-dose ICSs plus LABA improved lung function, decreased symptoms, decreased as-needed albuterol use, decreased exacerbations, and reduced the need to increase ICS dose.

The findings of Greening and colleagues11have been replicated numerous times by other investigators. To further examine the benefits of adding LABA compared with increasing the dose of ICS in poorly controlled asthma, Shrewsbury and colleagues12 performed a systematic review of randomized, double-blind clinical trials with independent data extraction and validation, with summary data from study reports and manuscripts. Efficacy and exacerbations were the major end points. Among the therapeutic trials using LABAs, there were nine parallel-group trials of ≥ 12 weeks with 3,685 symptomatic patients with asthma aged ≥ 12 years who were evaluated.

Compared with patients receiving increased doses of ICSs, patients receiving LABAs in addition to ICSs had greater morning PEF measurements at 3 months and 6 months. FEV1 also increased at 3 months and 6 months, as did the mean percentage of days and nights without symptoms and the mean percentage of days and nights without the need for rescue treatment. Fewer patients experienced an exacerbation with a LABA, and the proportion of patients with moderate or severe exacerbations was also lower. This meta-analysis supported the scientific evidence that the addition of an LABA in symptomatic patients with asthma on low-to-moderate doses of ICSs improved lung function and increased the number of days and nights without symptoms or the need for rescue treatment, without increase in asthma exacerbations.12

The effect of ICS and LABA combined in asthma, measured as improvement in FEV1, was evaluated in a study13 of 349 patients with asthma previously treated with medium doses of ICS. Subjects were randomized to treatment with salmeterol (LABA) 50 μg combined with FP (ICS) 250 μg, salmeterol 50 μg, ICS 250 μg, or placebo, each administered bid through a dry-powder inhaler device for 12 weeks.

Mean change in FEV1 at end point was significantly greater with combined LABA/ICS (0.48 L) than with placebo (0.11 L), LABA (0.05 L), or ICS (0.25 L). The combination of an LABA and an ICS significantly increased the area under the 12-h serial FEV1 curve relative to baseline over that seen with placebo, LABA, or ICS at day 1, week 1, and week 12. Patients receiving combination therapy had a significantly greater probability of remaining in the study without being withdrawn because of worsening asthma or an asthma exacerbation than did patients in the placebo, LABA, or ICS groups. The combination of an ICS and LABA significantly increased morning PEF at end point (53.5 L/min) compared with placebo (14 L/min), LABA (11.6 L/min), or ICS (15.2 L/min). This combination significantly reduced asthma symptom scores and supplemental albuterol use, and significantly increased the percentage of nights with no awakenings compared with placebo or individual therapy. Thus, combined therapy with LABA/ICS in this larger trial provided better asthma control and a significant improvement in pulmonary function than did the individual agents.13

A further important clinical issue is whether combination therapy reduces asthma exacerbations. This question was examined in the Formoterol and Corticosteroids Establishing Therapy trial,14 a double-blind study comparing the effects of adding inhaled formoterol to both lower and higher doses of the ICS budesonide. After a 4-week run-in period of treatment with budesonide (800 μg bid), 852 symptomatic asthma patients were randomly assigned to one of four treatments administered twice daily by means of a dry-powder inhaler: 100 μg of budesonide plus placebo, 100 μg of budesonide plus 12 μg of formoterol (LABA), 400 μg of budesonide plus placebo, or 400 μg of budesonide plus 12 μg of formoterol. Treatment continued for 1 year, and compared the frequency of exacerbations of asthma, symptoms, and changes in lung function in the four groups.

The rates of severe and mild exacerbations were reduced by 26% and 40%, respectively, when the LABA was added to the lower dose of ICS. The higher dose of ICS alone reduced the rates of severe and mild exacerbations by 49% and 37%, respectively. Patients treated with LABA and the higher dose of ICS had the greatest reductions, 63% and 62%, respectively. Asthma symptoms and pulmonary function improved with both LABA and the higher dose of ICS, but the improvements with the addition of LABA were greater.14

Many of the findings that suggest that ICSs are useful in asthma may be applied to patients with COPD who have a reversible component to their airflow obstruction. This was shown in a comparison of bronchodilator therapy with or without ICS therapy for COPD. In this clinical trial,15 the clinical phenotypes included subjects who had asthma and COPD. This multicenter trial employed three therapeutic regimens in which a β2-agonist (terbutaline, 250 μg/puff, two puffs qid) was combined with an ICS (beclomethasone, 800 μg/d), an anticholinergic and β2-agonist (ipratropium bromide, 160 μg/d, and salbutamol), or placebo (salbutamol alone). Two hundred seventy-four patients with BHR and obstruction, aged 18 to 60 years, were followed up for 2.5 years. The mean FEV1 was 64% of predicted, and the mean provocative concentration of histamine causing a 20% fall in FEV1 was 0.26 mg/mL.

Withdrawal from the study, due mainly to exacerbations of respiratory symptoms, was less frequent in the ICS group (12 of 91 patients) than in either the anticholinergic group (45 of 92 patients) or the placebo (β2-agonist) group (44 of 91 patients). The mean FEV1 increased by approximately 10.3% of predicted in the ICS group within 3 months and remained stable thereafter, while it did not change in the other two groups. The provocative concentration of histamine causing a 20% fall in FEV1 increased by 2.0 doubling concentrations in the ICS group but did not change in the other groups. Improvement with ICS was greatest in nonsmokers, younger patients (age < 40 years), patients with an allergic history, and patients with higher levels of BHR. However, all phenotypes (subgroups), even those with predominately a COPD phenotype, showed improvement with ICS therapy compared with the two bronchodilator groups. In patients having features of COPD, the addition of ICSs reduced BHR and improved airways obstruction.15 Traditionally, ICSs have been reserved for patients with asthma and have not been recommended in COPD. The results of this study supported the need for additional studies evaluating the value of ICSs in patients with COPD.

The Copenhagen lung study16 evaluated the long-term efficacy of ICS in COPD. The decline in FEV1 and respiratory symptoms were the primary end points in this 3-year, placebo-controlled study of patients with COPD. Inclusion criteria were an FEV1/FVC < 70%, FEV1 that showed no response (< 15% change) to 1 mg of inhaled terbutaline or prednisolone 37.5 mg po qd for 10 days, and no history of asthma. At baseline, the patients’ mean FEV1 was 85%, and the mean age was 59 years. Two hundred ninety patients were randomly assigned budesonide (ICS), 800 μg in the morning plus 400 μg in the evening daily for 6 months followed by 400 μg bid for 30 months, or placebo for 36 months.

The rates of FEV1 decline were 42 mL/yr in the placebo group and 45 mL/yr in the ICS group. The declines in FEV1 over time were not significantly different. No effect of ICSs was observed on respiratory symptoms. Three hundred sixteen exacerbations occurred during the study period, 155 in the ICS group and 161 in the placebo group. Although this study showed no clinical benefit of ICSs in patients with COPD recruited from the general population, these patients had no reversibility to β2-agonists or oral corticosteroids and had minimal airflow obstruction, indicating very mild COPD.16

The second part of the Lung Health Study sought to determine whether a program of therapy with ICS after an unsuccessful smoking cessation program reduced the rate of decline in FEV1 in smokers who have mild-to-moderate COPD. Patients were randomized to triamcinolone acetate (ICS), 1,200 μg qd, compared with placebo for 3 years in a randomized, double-blind trial.17 Eleven hundred subjects were enrolled, of which 90% were current smokers. The mean FEV1 was 64% of predicted with a mean FEV1/FVC ratio of 57%. FEV1 deteriorated equally in both groups, but in the ICS group, BHR decreased and dyspnea was reduced. In addition, there were fewer new respiratory symptoms, hospitalizations, and clinic visits with the use of ICS.,17

The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease18 was a 3-year trial comparing the use of ICS with placebo in current smokers with COPD. After a six-month run-in period, 1,277 subjects (mean age, 52 years; mean FEV1, 77% predicted; 73% men) were randomly assigned to twice-daily treatment with 400 μg of budesonide (ICS) or placebo, inhaled from a dry-powder inhaler, for 3 years. Subjects 30 to 65 years of age were eligible if they were currently smoking at least five cigarettes per day and had smoked cigarettes for at least 10 years, or if their smoking history totaled at least 5 pack-years. Postbronchodilator FEV1 had to be between 50% and 100% of the predicted normal value, and the ratio of prebronchodilator FEV1 to slow vital capacity had to be < 70%. The increase in FEV1 after the inhalation of 1 mg of terbutaline from a dry-powder inhaler had to be < 10% of the predicted normal value. The change in FEV1 between the end of the first 3-month period of the run-in phase and the end of the second phase had to be < 15%. Subjects with a history of asthma, allergic rhinitis, or allergic eczema were excluded. The use of inhaled glucocorticoids other than the study medication, beta-blockers, cromones, or long-acting inhaled β2-adrenergic agonists was not allowed.

Of the 1,277 subjects, 912 subjects (71%) completed the study. During the first 6 months of the study, the FEV1 improved at the rate of 17 mL/yr in the ICS group compared with a decline of 81 mL/yr in the placebo group (p < 0.001). The median decline in postbronchodilator FEV1 over the remaining 3-year period was 140 mL in the ICS group and 180 mL in the placebo group (p = 0.05), or 4.3% and 5.3% of the predicted value, respectively. From 9 months to the end of treatment, the FEV1 declined at similar rates in the two groups (p = 0.39). This suggested that in persons with mild COPD and reduced bronchodilator reversibility who continue smoking, the use of ICS was associated with a small initial improvement in lung function but had no effect on the long-term progressive decline in pulmonary function.18

As in the prior studies, the subjects in this trial had mild airflow obstruction and minimal bronchodilator reversibility, and may have represented smokers with a relatively slower rate of decline than is found in some individuals who acquire significant COPD. This is consistent with frequently quoted long-term data from Fletcher and Peto,19 who showed that in patients who acquire COPD, FEV1 declines more rapidly over a lifetime, but in most smokers clinically significant airflow obstruction may never develop.

The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study20 sought to determine the effect of long-term ICSs on lung function, respiratory exacerbations, and health status in patients with moderate-to-severe COPD. The ISOLDE study20 was a double-blind, placebo-controlled study enrolling 751 men and women between 40 and 75 years of age with mean FEV1 of < 50% predicted. FP (ICS), 500 μg bid, or placebo was administered from a metered-dose inhaler. The primary outcome measures were rate of decline in FEV1, health status, frequency of exacerbations, and withdrawals due to respiratory symptoms.

Once again, there was no significant difference in the annual rate of decline in FEV1. However, the mean FEV1 after bronchodilator remained significantly higher throughout the study in subjects receiving ICSs than in subjects receiving placebo (p < 0.001) [Fig 4 ].20 Median exacerbation rate was reduced by 25%, from 1.32/yr with placebo to 0.99/yr with ICS (p = 0.026). Health status as measured by the St. George’s Respiratory Questionnaire deteriorated by 3.2 U/yr with placebo and 2.0 U/yr with ICSs (p = 0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25%) than in the ICS group (19%) [p = 0.034]. The most important finding in this study was that patients receiving ICSs had fewer exacerbations and a slower decline in health status.20These results have led to a recommendation for the use of ICSs in moderate-to-severe COPD to reduce exacerbations.21

In the COPE study, van der Valk et al22 studied the effect of discontinuation of ICSs in patients with COPD. The time to first exacerbation adjusted for smoking was the primary study end point. After four months of treatment with inhaled FP (ICS) 1,000 μg/d, 244 patients were randomized to either continue ICS treatment or to receive placebo for 6 months; 123 patients continued with ICS, and 121 received placebo. In the ICS group, 58 patients (47%) had at least one exacerbation compared with 69 patients (57%) in the placebo group (Fig 5 ).,22 In the placebo group, 26 patients (21.5%) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed ICSs, compared with 6 patients (4.9%) in the ICS group. Over a 6-month period, a significant difference in favor of the ICS group was observed in the total score, activity score, and symptom score on the St. George’s Respiratory Questionnaire. This study indicates that discontinuation of ICSs in patients with COPD is associated with a more rapid onset and higher risk of exacerbations and a significant deterioration in several aspects of health status.22

Current Recommendations (Global Initiative for Chronic Obstructive Lung Disease Guidelines)

The current Global Initiative for Chronic Obstructive Lung Disease guidelines21 for the treatment of COPD address the use of ICSs in this disease. Oral corticosteroids have proven beneficial during COPD exacerbations, but are not recommended during stable disease because of their risks. ICSs do not appear to prevent decline in lung function, but current Global Initiative for Chronic Obstructive Lung Disease guidelines21 state that they are useful when there is a prominent reversible component or labile course, or frequent hospitalizations and exacerbations. More studies in COPD report a positive effect on clinical outcomes with ICS therapy.

Combination Therapy With ICS and LABA in COPD

The Trial of Inhaled Steroids and Long Acting β2 Agonists (TRISTAN)23 proposed that the combination of a LABA and ICS would improve lung function and decrease the frequency of acute exacerbations in COPD. In many ways, this study adapted current approaches used in asthma therapy to the treatment of COPD. One thousand four hundred sixty-five patients with COPD were recruited and randomized to either 50 μg salmeterol (LABA) bid (n = 372), 500 μg fluticasone propionate (ICS) bid (n = 374), 50 μg salmeterol (LABA) and 500 μg fluticasone propionate (ICS) bid (n = 358), or placebo (n = 361) for 12 months. The primary outcome was the pretreatment FEV1 after 12 months therapy. Secondary outcomes were other lung function measurements, symptoms, rescue bronchodilator use, number of exacerbations, patient withdrawals, and disease-specific health status.

All active treatments improved lung function, symptoms, and health status and reduced the use of rescue medication and frequency of exacerbations. Compared with placebo, all active treatments significantly reduced the number of exacerbations each year and the number of exacerbations that required treatment with oral corticosteroids. The rate of exacerbations fell by 25% in the combination group as opposed to 20% and 19% in the LABA and ICS groups respectively, compared with placebo. The treatment effect was more pronounced in patients with severe disease (baseline FEV1 <50% of predicted). Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL), LABA (73 mL), or ICS alone (95 mL, p < 0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms as well.23

The findings from TRISTAN23were similar to the results of a recent report by Hanania et al,24 who compared the combination of a lower-dose ICS (fluticasone, 250 μg) and LABA (salmeterol) in patients with COPD. Seven hundred twenty-three patients were enrolled, and the average FEV1 was 42% predicted. After 24 weeks, treatment with the combination of the lower-dose ICS and LABA significantly (p < 0.012) increased the morning predose FEV1 (165 mL) compared with LABA alone (91 mL) and placebo (1 mL). Morning predose FEV1 increased 109 mL with ICS alone. The combination significantly (p < 0.001) increased the 2-h postdose FEV1 (281 mL) compared with ICS (147 mL) and placebo (58 mL). LABA alone increased the 2-h postdose FEV1 by 200 mL. These significant treatment effects were sustained over a period of 24 weeks (Fig 6 ).,24

In summary, use of ICSs in COPD decreased the frequency and severity of exacerbations and improved quality of life. However, the use of ICSs did not modify the long-term decline in FEV1. In TRISTAN23, the use of both ICS and LABA improved FEV1 over 12 months. This was corroborated by Hanania et al,24 who showed a similar improvement in FEV1 over a 24-week period with lower-dose ICSs. Future research directions should attempt to define the factors that determine which patients with asthma or COPD will better respond to therapeutic interventions by investigating disease phenotypes and evaluating biomarkers that predict therapeutic responses. This will be even more important as new therapeutic interventions are developed in the future.

The variable therapeutic responses to ICSs in obstructive airway diseases, including asthma and COPD, raise questions about variation in genes that cause this differing response. The concept of a drug response profile for each patient based on genetic characteristics is a potential approach that may provide optimal care for each individual. Pharmacogenetics is defined as the study of the hereditary basis characterizing variation in individual response to drugs. To further these concepts and the use of pharmacogenetic techniques, we must first identify the variation in pharmacologic response intrinsic to each individual and elucidate its molecular genetic mechanisms. The clinical significance of the difference in response must be defined and the use of rapid screening tests that will allow clinicians to individualize drug therapy based on genetic factors must be made available.

Some of the pharmacogenetic drug interactions in asthma that have proved or may prove to be of further utility in evaluating individual responses include β2-adrenergic receptor polymorphisms, 5-lipoxygenase promoter polymorphisms, and polymorphisms in the glucocorticoid receptor (Fig 7 ).25

Glucocorticoid-receptor variations have been associated with variance in individual responses in a number of incidents. The so-called “steroid-resistant asthmatic” may have decreased steroid responsiveness in relation to glucocorticoid receptor function, genotype, or phenotype. This is an important area of active investigation and should include the relationship between the glucocorticoid receptor as well as other genes that may affect corticosteroid function and therapeutic drug responses.

Pharmacogenetics should improve therapy by improving clinical markers and improving the ability to predict therapeutic efficacy with greater clarity. Additionally, this field of investigation may allow individualized and simplified dosing, improved safety and, it is hoped, enhanced patient adherence to prescribed therapies.

ICSs have proven to be clinically beneficial in asthma, decreasing rates of exacerbations, improving lung function long-term, diminishing decline in lung function, decreasing airway remodeling, and reducing the need for use of supplemental medications. In COPD, ICS use has been useful in disease phenotypes where patients with COPD have greater degrees of bronchodilator response, evidence of allergic or inflammatory response, frequent exacerbations, or a labile course. Interestingly, the use of combination therapy with LABAs and ICSs recently has been shown to be effective in both asthma and COPD, perhaps suggesting that there are some similar pathophysiologic characteristics in these two diseases.

Factors affecting variable patient response to these agents require continued investigation. There is variability in response in patients with severe asthma or steroid-resistant asthmatics. Clearly, ICSs, while not as effective in COPD, do produce measurable clinical responses in some patients with this disease. Thus, future approaches should more clearly define the phenotype in patients with obstructive airways disease who are evaluated and respond to specific therapies. This approach should include pharmacogenetic approaches, since genetic factors may interact with disease characteristics in the regulation of therapeutic responses in both asthma and COPD.

Abbreviations: BHR = bronchial hyperresponsiveness; FP = fluticasone propionate; ICS = inhaled corticosteroid; ISOLDE = Inhaled Steroids in Obstructive Lung Disease in Europe; LABA = long-acting β2-agonist; LTRA = leukotriene receptor antagonist; PEF = peak expiratory flow; TRISTAN = Trial of Inhaled Steroids and Long-Acting β2 Agonists

Dr. Bleecker has received research grants from Astra Zeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pharmacia, and Schering. He also has been a consultant for Astra Zeneca, Genentech, GlaxoSmithKline, Novartis, and Wyeth.

Figure Jump LinkFigure 1. Effects of ICSs on inflammation. Shown is an electron micrograph of endobronchial biopsy samples before and after 3 months of therapy with ICSs. Reproduced with permission from Laitinen et al.4Grahic Jump Location
Figure Jump LinkFigure 2. ICSs in children results in fewer courses of prednisone and decreased use of additional asthma medications when compared with nedocromil and placebo. Reproduced with permission from the Childhood Asthma Management Program Research Group.9 Bud = budesonide; Ned = nedocromil; Plbo = placebo.Grahic Jump Location
Figure Jump LinkFigure 3. Distribution of FEV1 response in 895 asthmatic patients aged 15 to 85 years treated with either beclomethasone or montelukast for 12 weeks. Adapted from Malmstrom et al.10Grahic Jump Location
Figure Jump LinkFigure 4. ISOLDE study: Mean postbronchodilator FEV1 over 3 years of therapy with ICSs or placebo. Reproduced with permission from Burge et al.20Grahic Jump Location
Figure Jump LinkFigure 5. Time to first exacerbation adjusted for smoking for patients assigned to ICS or placebo after 4 months of ICS therapy previously. Reproduced with permission from van der Valk et al.22Grahic Jump Location
Figure Jump LinkFigure 6. Mean change in pre- and post-dose FEV1 in COPD patients receiving combination therapy with ICS and LABA. Adapted from Hanania et al.24 mcg = microgram; SM = salmeterol; FSC = fluticasone/salmeterol combination.Grahic Jump Location
Figure Jump LinkFigure 7. Glucocorticoid receptor transcription map. Adapted from Breslin et al.25 bp = base-pair.Grahic Jump Location
. National Heart, Lung, and Blood Institute (2002)National Asthma Education and Prevention Program expert panel report: guidelines for diagnosis and management of asthma; update on selected topics 2002. National Institutes of Health. Bethesda, MD: workshop report publication No. 02–5075
 
Haahtela, T, Jarvinen, M, Kava, T, et al Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma.N Engl J Med1991;325,388-392
 
Haahtela, T, Jarvinen, M, Kava, T, et al Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma.N Engl J Med1994;331,700-705
 
Laitinen, LA, Laitinen, A, Haahtela, T A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial.J Allergy Clin Immunol1992;90,32-42
 
Olivieri, D, Chetta, A, Del Donno, M, et al Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study.Am J Respir Crit Care Med1997;155,1864-1871
 
Sont, JK, Willems, LN, Bel, EH, et al Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment: the AMPUL study group.Am J Respir Crit Care Med1999;159,1043-1051
 
Agertoft, L, Pedersen, S Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children.Respir Med1994;88,373-381
 
Panhuysen, CI, Vonk, JM, Koeter, GH, et al Adult patients may outgrow their asthma: a 25-year follow-up study.Am J Respir Crit Care Med1997;155,1267-1272
 
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.N Engl J Med2000;343,1054-1063
 
Malmstrom, K, Rodriguez-Gomez, G, Guerra, J, et al Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Montelukast/Beclomethasone Study Group.Ann Intern Med1999;130,487-495
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group.Lancet1994;344,219-224
 
Shrewsbury, S, Pyke, S, Britton, M Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA).BMJ2000;320,1368-1373
 
Shapiro, G, Lumry, W, Wolfe, J, et al Combined salmeterol 50 microg and fluticasone propionate 250 microg in the Diskus device for the treatment of asthma.Am J Respir Crit Care Med2000;161,527-534
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.N Engl J Med1997;337,1405-1411
 
Kerstjens, HA, Brand, PL, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group.N Engl J Med1992;327,1413-1419
 
Vestbo, J, Sorensen, T, Lange, P, et al Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial.Lancet1999;353,1819-1823
 
Anthonisen, NR, Connett, JE, Kiley, JP, et al Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study.JAMA1994;272,1497-1505
 
Pauwels, RA, Lofdahl, CG, Laitinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.N Engl J Med1999;340,1948-1953
 
Fletcher, C, Peto, R The natural history of chronic airflow obstruction.BMJ1977;1,1645-1648
 
Burge, PS, Calverley, PM, Jones, PW, et al Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.BMJ2000;320,1297-1303
 
Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary.Am J Respir Crit Care Med2001;163,1256-1276
 
van der Valk, P, V, Monninkhof, E, van der Palen, J, et al Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study.Am J Respir Crit Care Med2002;166,1358-1363
 
Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2003;361,449-456
 
Hanania, NA, Darken, P, Horstman, D, et al The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD.Chest2003;124,834-843
 
Breslin, MB, Geng, CD, Vedeckis, WV Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids.Mol Endocrinol2001;15,1381-1395
 

Figures

Figure Jump LinkFigure 1. Effects of ICSs on inflammation. Shown is an electron micrograph of endobronchial biopsy samples before and after 3 months of therapy with ICSs. Reproduced with permission from Laitinen et al.4Grahic Jump Location
Figure Jump LinkFigure 2. ICSs in children results in fewer courses of prednisone and decreased use of additional asthma medications when compared with nedocromil and placebo. Reproduced with permission from the Childhood Asthma Management Program Research Group.9 Bud = budesonide; Ned = nedocromil; Plbo = placebo.Grahic Jump Location
Figure Jump LinkFigure 3. Distribution of FEV1 response in 895 asthmatic patients aged 15 to 85 years treated with either beclomethasone or montelukast for 12 weeks. Adapted from Malmstrom et al.10Grahic Jump Location
Figure Jump LinkFigure 4. ISOLDE study: Mean postbronchodilator FEV1 over 3 years of therapy with ICSs or placebo. Reproduced with permission from Burge et al.20Grahic Jump Location
Figure Jump LinkFigure 5. Time to first exacerbation adjusted for smoking for patients assigned to ICS or placebo after 4 months of ICS therapy previously. Reproduced with permission from van der Valk et al.22Grahic Jump Location
Figure Jump LinkFigure 6. Mean change in pre- and post-dose FEV1 in COPD patients receiving combination therapy with ICS and LABA. Adapted from Hanania et al.24 mcg = microgram; SM = salmeterol; FSC = fluticasone/salmeterol combination.Grahic Jump Location
Figure Jump LinkFigure 7. Glucocorticoid receptor transcription map. Adapted from Breslin et al.25 bp = base-pair.Grahic Jump Location

Tables

References

. National Heart, Lung, and Blood Institute (2002)National Asthma Education and Prevention Program expert panel report: guidelines for diagnosis and management of asthma; update on selected topics 2002. National Institutes of Health. Bethesda, MD: workshop report publication No. 02–5075
 
Haahtela, T, Jarvinen, M, Kava, T, et al Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma.N Engl J Med1991;325,388-392
 
Haahtela, T, Jarvinen, M, Kava, T, et al Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma.N Engl J Med1994;331,700-705
 
Laitinen, LA, Laitinen, A, Haahtela, T A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial.J Allergy Clin Immunol1992;90,32-42
 
Olivieri, D, Chetta, A, Del Donno, M, et al Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study.Am J Respir Crit Care Med1997;155,1864-1871
 
Sont, JK, Willems, LN, Bel, EH, et al Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment: the AMPUL study group.Am J Respir Crit Care Med1999;159,1043-1051
 
Agertoft, L, Pedersen, S Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children.Respir Med1994;88,373-381
 
Panhuysen, CI, Vonk, JM, Koeter, GH, et al Adult patients may outgrow their asthma: a 25-year follow-up study.Am J Respir Crit Care Med1997;155,1267-1272
 
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.N Engl J Med2000;343,1054-1063
 
Malmstrom, K, Rodriguez-Gomez, G, Guerra, J, et al Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Montelukast/Beclomethasone Study Group.Ann Intern Med1999;130,487-495
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group.Lancet1994;344,219-224
 
Shrewsbury, S, Pyke, S, Britton, M Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA).BMJ2000;320,1368-1373
 
Shapiro, G, Lumry, W, Wolfe, J, et al Combined salmeterol 50 microg and fluticasone propionate 250 microg in the Diskus device for the treatment of asthma.Am J Respir Crit Care Med2000;161,527-534
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.N Engl J Med1997;337,1405-1411
 
Kerstjens, HA, Brand, PL, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group.N Engl J Med1992;327,1413-1419
 
Vestbo, J, Sorensen, T, Lange, P, et al Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial.Lancet1999;353,1819-1823
 
Anthonisen, NR, Connett, JE, Kiley, JP, et al Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study.JAMA1994;272,1497-1505
 
Pauwels, RA, Lofdahl, CG, Laitinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.N Engl J Med1999;340,1948-1953
 
Fletcher, C, Peto, R The natural history of chronic airflow obstruction.BMJ1977;1,1645-1648
 
Burge, PS, Calverley, PM, Jones, PW, et al Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.BMJ2000;320,1297-1303
 
Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary.Am J Respir Crit Care Med2001;163,1256-1276
 
van der Valk, P, V, Monninkhof, E, van der Palen, J, et al Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study.Am J Respir Crit Care Med2002;166,1358-1363
 
Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2003;361,449-456
 
Hanania, NA, Darken, P, Horstman, D, et al The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD.Chest2003;124,834-843
 
Breslin, MB, Geng, CD, Vedeckis, WV Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids.Mol Endocrinol2001;15,1381-1395
 
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