Proceedings of the American Thoracic Society Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Donohue, J. F.
Right arrow Articles by Ohar, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Donohue, J. F.
Right arrow Articles by Ohar, J. A.
The Proceedings of the American Thoracic Society 1:152-160 (2004)
© 2004 The American Thoracic Society

Effects of Corticosteroids on Lung Function in Asthma and Chronic Obstructive Pulmonary Disease

James F. Donohue and Jill A. Ohar

Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill; and Division of Pulmonary and Critical Care Medicine, Wake Forest University, Winston-Salem, North Carolina

Correspondence and requests for reprints should be addressed to James F. Donohue, M.D., Department of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, 4125 Bioinformatics Bldg., CB 7020, Chapel Hill, NC 27599-7020. E-mail: jdonohue{at}med.unc.edu


   ABSTRACT
TOP
 ABSTRACT
EVALUATING RESPONSE TO...
 CORTICOSTEROIDS FOR ASTHMA
 CORTICOSTEROIDS FOR COPD
 NOVEL CORTICOSTEROIDS
 REFERENCES
 
Both oral and inhaled corticosteroids have clinically significant effects on symptoms, exacerbations, health status, and lung function in asthma, and to a lesser extent in chronic obstructive pulmonary disease (COPD). Change in FEV1 does not correlate well with functional tests in COPD and may not be the best measure of response to treatment. Inhaled corticosteroids may be beneficial when added to a ß-agonist for treatment of acute asthma, and the efficacy of oral corticosteroids in this setting is well established. Oral corticosteroids inconsistently improve lung function in stable outpatients with COPD. Individual inhaled corticosteroids do not have a marked effect, but the combination of fluticasone propionate and salmeterol and the combination of budesonide plus formoterol seem to improve FEV1 over treatment with the individual components. In addition, there is convincing evidence for the use of systemic corticosteroids during acute exacerbations of COPD. Some evidence suggests that patients with COPD who respond to corticosteroids have eosinophilic inflammation and other attributes of an asthma phenotype.

Key Words: acute exacerbations • dose–response relationship • FEV1 • inhaled corticosteroids • oral corticosteroids

This article reviews the important clinical papers on the effects of corticosteroids on lung function, primarily pre- and postdose FEV1, in asthma and chronic obstructive pulmonary disease (COPD). According to published guidelines, inhaled corticosteroids (ICS) are the most effective controller medication in stable persistent asthma. Better results are obtained when treatment is initiated as soon as the diagnosis is made; longer duration of treatment provides more sustained benefits than treatment that is intermittent or used for short periods (1). Thus, ICS are recommended as first-line therapy in stable persistent asthma.

The role of ICS in COPD remains controversial, although their use has increased while the use of theophylline has declined. Van Andel and colleagues, in a review of 3,720 patients with moderate to severe COPD who were enrolled in 10 studies, noted that the percentage of patients using ICS increased from 13.2% in 1987 to 41.4% in 1995, whereas the use of oral theophylline declined from 63.4 to 29% (2). Oral corticosteroid (OCS) use in this study declined from 30.1 to 16.4%.

OCS are recommended for treatment of acute exacerbations of both asthma and COPD (3, 4). The use of ICS to treat acute exacerbations of asthma is under investigation; however, there is little evidence for their use in acute exacerbations of COPD. OCS are not recommended for chronic use in either condition; nevertheless, they are often given for long periods to some patients with severe or refractory disease.

Finally, although the use of ICS clearly affects mortality in asthma, the long-term effects of ICS on mortality in COPD are debated (5, 6).


   EVALUATING RESPONSE TO CORTICOSTEROIDS
TOP
 ABSTRACT
 EVALUATING RESPONSE TO...
CORTICOSTEROIDS FOR ASTHMA
 CORTICOSTEROIDS FOR COPD
 NOVEL CORTICOSTEROIDS
 REFERENCES
 
Lung Function
Traditionally, the effects of a therapeutic agent on lung function have been assessed using spirometry, which is readily available, fairly reproducible, and easy to perform in a variety of clinical settings. In a cross-sectional survey of 2,633 adults in Nottingham, England, aged 18 to 70 years, questionnaire data were obtained on cough, wheeze, shortness of breath, and general self-reported breathing problems along with measurement of spirometry. The FEV1% predicted was the measure of airflow impairment most closely associated with chronic respiratory symptoms in this population. The odds of having symptoms increased with declining levels of FEV1 (7). Similarly, improvement in FEV1 has generally been assumed to correlate with improvement in other outcomes in persistent asthma, and some research supports that view. For example, Fuhlbrigge and colleagues correlated the proportion of pediatric patients having either a self- or parent-reported asthma attack in the subsequent year and FEV1 decile (8). A strong association existed between increasing risk of an asthma attack and a lower FEV1.

However, variability and lack of predictive ability present potential problems when FEV1 is used as an endpoint in trials of asthma therapies. Zhang and colleagues (9) evaluated data from two 12-week clinical trials of beclomethasone and montelukast that involved a total of 1,576 patients. Large within-patient variability over serial visits was noted in FEV1, morning peak expiratory flow rate (PEFR), daily symptom score, and ß-agonist use. There was at best only moderate correlation between changes in FEV1 and PEFR, or between changes in FEV1 and daily symptom score. The overall predictive value of FEV1 was 70%. Thus, in patients with asthma the use of FEV1 to estimate long-term response to treatment may be unreliable.

In patients with COPD, changes in FEV1 are even less well correlated with survival, functional tests such as the 6-minute walk, or changes in health status/quality of life. Therefore, in COPD FEV1 may not be the most representative measure of disease severity (10). Although improvement in FEV1 is important, the best correlates with dyspnea in patients with COPD may be changes in inspiratory airflow or reduction of dynamic hyperinflation (11, 12). Changes in elastic recoil and destruction of lung parenchyma due to emphysema lead to loss of the capacity to hold airways open, causing dynamic collapse and flow limitation on exhalation.

FEV1 is useful in assessing the response to bronchodilators in patients with COPD; however, additional responders can be identified by assessing lung volume at rest and during exercise. For example, Newton and associates (13) reported that albuterol improved FEV1 in 33% of patients with severe COPD-induced hyperinflation. However, when lung volumes measured before and after bronchodilators were considered in the analysis, the overall response rate increased to 76%. Similarly, Di Marco and coworkers (14) reported a much greater increase in inspiratory capacity after bronchodilator administration than after placebo, which correlated with the improvement of dyspnea at rest. In a study of patients with nonsevere asthma or COPD, the reduction in dyspnea was associated with improvement in both FEV1 and forced inspiratory volume in 1 second (FIV1) after bronchodilator administration. In severe COPD the improvement was only in FIV1 (15).

Few studies of OCS or ICS have evaluated variables other than FEV1, FVC, FEV1/FVC, or PEFR. Although measurements of expiratory airflow are probably sufficient in asthma, improvement associated with OCS and ICS therapy may be underestimated in COPD. Clearly, more physiologic studies are needed.

Minimum Clinically Important Differences
Santanello and coworkers (16) addressed the question regarding minimum clinically important differences for asthma measurements in a clinical trial. Patients were able to perceive a change in PEFR of 19 L/minute and a change of 0.23 L (10%) in FEV1. Most studies of ICS in moderate to severe asthma achieve this level of improvement, because the baseline FEV1 is below 80%. However, in mild asthma the increase in FEV1 is much less.

The minimum clinically important differences for COPD are unknown at this time. One study found that the minimal increase in FEV1 that could be detected by COPD patients was 112 ml or 4% predicted (17). However, the increases in FEV1 with OCS and ICS are in the 100 ml range and below the threshold described in asthma. An increase of 100 ml with systemic corticosteroids in acute exacerbations of COPD was associated with a decreased risk of treatment failure in the SCCOPE trial (18). Minimum clinically important differences have been established for the Chronic Respiratory Disease Questionnaire with regard to patients with COPD (19) and for the Quality of Life for Respiratory Illness Questionnaire with regard to both patients with asthma and with COPD (20).

Compliance
Patient compliance is another problem in evaluating the FEV1 response to ICS in asthma. Segala and associates, in a study of 347 patients with asthma followed for 3 years, reaffirmed that after adjustment for disease severity, poor asthma control was associated with poor compliance, among other factors (21). Apter and coworkers recently identified barriers to adherence, including knowledge of the function of ICS, perception of the risks and benefits of ICS, self-efficacy, and other factors. Adherence was 60 ± 30% with ICS. "Favorable patient attitude" was associated with greater adherence (22). In a recent comparison of medication fills during a 12-month observation period, adherence was significantly better with montelukast than with fluticasone propionate (23). The refill persistence for ICS can be increased by combining the ICS with a long-acting ß-agonist (LABA) (24).

"Steroid phobia" is regarded as a common phenomenon in asthma that often contributes to poor compliance. However, it appears that physicians are more concerned, because they were much more likely to rate ICS as the medication patients wanted to be rid of than were parents or patients themselves (25). Compliance in the CAMP study (Childhood Asthma Management Program) was 73.7% with budesonide, 76% with placebo, and 70% with nedocromil (26).

Compliance is also an issue in evaluating lung function in COPD, which is more prevalent among socioeconomically disadvantaged individuals (27). Even so, compliance with bronchodilators appears to be good. In a survey of at-home nebulizer use for COPD, adherence was described as excellent (28). A single inhaler containing ipratropium and albuterol increased compliance (odds ratio 1.77) over two separate inhalers (29). In one study, compliance was measured by counting the number of used dry power inhalation devices returned. Compliance was 72% in the early COPD and 71% in asthma. Conviction of the importance of treatment influenced compliance more positively than perceived side effects (30).


   CORTICOSTEROIDS FOR ASTHMA
TOP
 ABSTRACT
 EVALUATING RESPONSE TO...
 CORTICOSTEROIDS FOR ASTHMA
CORTICOSTEROIDS FOR COPD
 NOVEL CORTICOSTEROIDS
 REFERENCES
 
Dose–Response Relationships with ICS
ICS are recommended for most patients with asthma. The dose is increased as required to maintain control. The British National Formulary recommends a therapeutic dosage range of 200 to 2,000 µg/day of fluticasone propionate, whereas the British Thoracic Society recommends 400 to 1,000 µg/day of fluticasone propionate and 800 to 2,000 µg/day of budesonide or beclomethasone, delivered through a large-volume spacer. In earlier guidelines, the National Asthma Education Expert Panel recommended titrating the dosage to the stage of asthma. However, it appears that much lower doses may be adequate. Holt and associates recently examined the dose–response relationship of fluticasone propionate in adolescents and adults with asthma (31). The main outcome measures were FEV1, morning and evening PEFR, nocturnal awakenings, ß-agonist use, and major exacerbations. Eight studies involving 2,324 patients were included in this meta-analysis. The dose–response curve began to plateau at 100 to 200 µg/day and peaked at 500 µg/day. These doses produced 90% of the benefit of 1,000 µg/day. A dose of about 600 µg induced a change in FEV1 of 0.71 L, in morning PEFR of 50 L/minute, and in evening PEFR of 51 L/minute, as well as a reduction in ß-agonist use of 2.36 puffs/day.

Low and medium doses of ICS were also adequate in a recent study by the Asthma Clinical Research Network (32). Near-maximal FEV1 increase occurred with low-dose fluticasone propionate (88 µg/day) and medium-dose beclomethasone (672 µg/day). Similarly, near-maximal improvement in bronchial hyperresponsiveness, measured by methacholine challenge, occurred with low-dose fluticasone propionate and medium-dose beclomethasone, both delivered via metered-dose inhaler. High-dose ICS therapy (704 µg/day fluticasone propionate or 1,344 µg/day beclomethasone) did not increase FEV1 or the provocative concentration that produces a 20% fall in FEV1 (PC20), but it did increase systemic effects. In a related study, improvement in lung function occurred rapidly in patients with mild to moderate persistent asthma receiving an ICS, with no clear-cut dose–response relationship (33).

Conversely, in a meta-analysis of 25 studies, Currie and coworkers found that high doses of ICS (>= 1,000 µg) conferred greater improvements in bronchial hyperresponsiveness than lower doses (34). In two studies of OCS-dependent individuals with asthma, higher doses of fluticasone propionate have allowed greater reduction in prednisone dose (35, 36). Martin and colleagues, in a comparison of the systemic effects of six ICS preparations, established a method to study dose response based on equisystemic cortisol suppression (37). Four increasingly large doses were given at 1-week intervals. Only placebo and fluticasone propionate given via dry powder inhaler failed to demonstrate a significant dose–response effect.

In summary, although there is no relationship between ICS dose and FEV1, there may be a dose-related response with respect to other pertinent outcomes, such as reduction in prednisone dose, bronchial hyperresponsiveness, and cortisol suppression.

Table 1 (38–45) presents results of clinical trials of ICS in patients with mild to severe persistent asthma.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Randomized clinical trials of inhaled corticosteroids for asthma

 
ICS for Acute Asthma
ICS may be beneficial when added to a ß-agonist in the emergency department. Several randomized controlled trials have demonstrated improved outcomes in pulmonary function and a 50% reduction in admission rate when an ICS is added to customary therapy (46). In a double-blind study, Rodrigo and Rodrigo randomly assigned 94 patients presenting to an emergency department with exacerbations of asthma to receive 400 µg salbutamol and placebo every 10 minutes for 3 hours, or the same dose of salbutamol plus 1 mg flunisolide on the same schedule. Compared with the control group, FEV1 and PEFR were significantly better in the group receiving combination therapy at 90, 120, 150, and 180 minutes. The investigators concluded that the onset of action of an ICS is much faster than that of systemic steroids and may be due to localized airway responses, such as vasoconstriction. (47). Separately, a high-dose ICS was compared with systemic corticosteroids in 40 patients hospitalized with acute asthma. After 8 doses of IV corticosteroids, participants received either inhaled flunisolide (250 µg per puff, 8 puffs twice daily), or continued systemic corticosteroids. The increase in FEV1 was 1.6 to 2.3 L in the flunisolide group and 1.4 to 2.1 L in the systemic corticosteroid group by Day 7 (48).

OCS for Acute Asthma
OCS are effective in acute asthma. Pulmonary function slowly improves, beginning within 6 to 12 hours, and OCS therapy reduces relapse rates and hospital admission rates. However, no equivalent increase in lung function has been noted with the use of increasingly higher doses, and no benefit in onset of action, magnitude of effect, or duration of effect is seen with OCS versus IV corticosteroids.

There are advantages of systemic corticosteroids over ICS in the emergency department. In a double-blind study, 100 children with acute severe asthma (FEV1 < 60%) were randomized to either prednisone 2 mg/kg or inhaled fluticasone propionate 2,000 µg via metered-dose inhaler through a spacing device. The increase in FEV1 was 9.4% with fluticasone propionate compared with 18.9% with prednisone at 4 hours after treatment. Twenty-five percent of subjects on fluticasone propionate, but none on the OCS, exhibited a decline in FEV1. Sixteen (31%) versus 5 (10%) of the children were hospitalized in the fluticasone- and prednisone-treated groups, respectively (49). Coyle and associates (50) evaluated the effectiveness of acute asthma care in a cohort of 365 inner-city adults, divided approximately into thirds according to disease severity. In all groups, systemic corticosteroids given at the time of hospital discharge significantly increased PEFR measured at the 2- to 3-week follow-up visit (ß = 26.1; 95% confidence interval [CI], 1.8-50.5; p = 0.04).

The optimal duration of OCS therapy is unknown. In a prospective trial, 44 adults hospitalized with acute asthma received 40 mg of oral prednisolone daily for 5 days, followed by 5 days of prednisolone or placebo. At Day 21, the PEFR was only 6 L/minute lower in patients who had received 5 days of prednisolone than in those who had been treated for 10 days (51).

Newer Formulations of ICS
Hydrofluoroalkane (HFA) propellants are used in newer formulations of ICS metered-dose inhalers as alternatives to chlorofluorocarbon (CFC) propellants. The HFA devices administer a particle of 1.2 µm mass median aerodynamic diameter as opposed to 3.8 µm with CFC-based devices (52). Lung deposition with an HFA propellant is 68% as opposed to 19.7% with CFC. Theoretically, particles administered by HFA devices should be deposited deeper into the lung, penetrating the small airways (those < 2 mm in diameter). Because the peripheral airways contribute only a small fraction of total airway resistance, spirometry does not detect changes well. Other measures, such as closing volume, can reflect obstruction in small airways, and closing volume is increased in patients with mild asthma and frequent exacerbations (53).

Studies are needed to assess the physiologic effects on the smaller airways of these newer formulations of ICS, as well as their longer-term effects on pulmonary function. Theoretically, delivery of ICS with HFA devices may have an effect on airway remodeling.


   CORTICOSTEROIDS FOR COPD
TOP
 ABSTRACT
 EVALUATING RESPONSE TO...
 CORTICOSTEROIDS FOR ASTHMA
 CORTICOSTEROIDS FOR COPD
NOVEL CORTICOSTEROIDS
 REFERENCES
 
Identifying Responders
The question of steroid-responsive COPD has been raised repeatedly for years. Does the response to systemic corticosteroids predict the "steroid responder group" that will benefit from ICS? Does reversibility to ß-agonists predict steroid responders? The American Thoracic Society and the British Thoracic Society recommend a trial of OCS for 2 weeks or more to identify potential ICS responders. In the ISOLDE (Inhaled Steroid in Obstructive Lung Disease in Europe) study, 524 patients with COPD were given oral prednisolone (0.6 mg/kg for 14 days) before 3 years of treatment with fluticasone propionate. The postbronchodilator FEV1 increased by a mean of 60 ml after oral prednisolone, with a wide unimodal distribution. The OCS challenge was a poor predictor of the response to ICS, however. Response to prednisolone was unrelated to the change in FEV1 during the 3-year follow-up period, in both the placebo group and the fluticasone propionate group. Current smoking was the best predictor of change in FEV1 after prednisolone; in ex-smokers the increase was 74 ml, whereas in current smokers it was only 35 ml. There was no relationship between the change in FEV1 and the response to inhaled bronchodilators, baseline FEV1, atopic status, age, and sex (54).

Some have postulated that corticosteroid responders in the COPD population have asthmatic qualities. Chanez and colleagues (55) published data on 25 patients with COPD who received 1.5 mg/kg of prednisolone for 15 days. Twelve of 25 patients exhibited an increase in FEV1 of at least 12% and 200 ml. Responders had a greater amount of eosinophils and eosinophilic cationic protein in their bronchoalveolar lavage fluid compared with nonresponders, and biopsies of responders revealed a thickened basement membrane. Fujimoto and coworkers studied the effects of corticosteroids on airway inflammation and their association with the reversibility of airflow obstruction in response to an OCS. In 24 patients with emphysema who received 20 mg of prednisolone for 2 weeks, eosinophilic inflammation was related to OCS reversibility (56). Similar findings were reported by Papi and coworkers, who found that even partial bronchodilator reversibility was associated with increased exhaled nitric oxide and sputum eosinophilia (57). Pizzichini and associates reported that sputum eosinophilia predicted improvement in FEV1 after prednisone (58).

Overall, it appears that neither responsiveness to a single dose of ß-agonist nor responsiveness to a 14-day trial with an OCS is a reliable predictor of response to ICS. A 2- to 3-month empiric trial of ICS is needed to determine whether there is any clinical benefit.

ICS for COPD
LUNG FUNCTION.
Early reviews suggested a possible role for ICS in slowing the decline of FEV1 in COPD. Now, multiple large, controlled trials conducted over 3-year periods, as well as meta-analyses of those trials, have conclusively demonstrated that ICS have no important effect on the yearly decline in FEV1.

Riancho and colleagues performed a meta-analysis of 12 placebo-controlled trials of ICS in COPD. Short-term studies showed that ICS induced a small increase in FEV1 (mean 96 ml after 1 to 6 months). Longer-term studies indicated that after 1 to 3 years of continued therapy, FEV1 was higher in steroid-treated subjects than in control subjects, but only by 51 ml (59). In a meta-analysis of six large trials, Sin and colleagues noted an increase in baseline trough FEV1 of only 45 ml (95% CI, 22–69 ml) (60). Alsaeedi and associates, in a systematic review of nine randomized, placebo-controlled trials, concluded that ICS had a beneficial effect on COPD exacerbations but had a variable effect on pulmonary function, regardless of whether patients were pretreated with a systemic steroid (61). Concurrent cigarette smoking has lessened the improvement in FEV1 in some studies, but not all.

Questions about the different ICS preparations, dose responsiveness, duration of therapy, and clinical benefits and risks are being addressed (62). Many controlled short-term studies have been performed with beclomethasone, budesonide, or fluticasone propionate, with equivocal effect on benefit in lung function. Beclomethasone has significantly improved FEV1, FVC, and PEFR when compared with placebo (63–66). Budesonide did not improve FEV1 in patients with COPD studied for 6 weeks to 6 months (67–73), but it has been shown to improve dyspnea (74), and it improved FEV1 in ß-agonist responders (75). In the International COPD Study, fluticasone propionate 1,000 µg/day for 6 months significantly slowed the decline in lung function from 110 to 40 ml/year and improved mean baseline FEV1 by 150 ml versus placebo (76). These improvements were much larger than in most studies.

However, four larger and longer studies showed no effect of ICS on the rate of decline in FEV1 (Table 2 [77–80]). Furthermore, in the most recent meta-analysis of the long-term effects of ICS, the FEV1 decline in 3,571 patients followed for 24 to 54 months was not influenced by ICS. The summary estimate for the difference between the placebo and treatment groups was 5.0 ± 3.2 ml/year (81).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Longer-term studies of effect of inhaled corticosteroids on fev1 in chronic obstructive pulmonary disease

 
More recently, the efficacy of the combination of fluticasone propionate with salmeterol has been compared with that of the individual components. Overall, combination therapy was effective in improving trough FEV1 compared with placebo (101 ml/year; 95% CI, 76–126 ml/year), LABA (34 ml/year; 95% CI, 11–57 ml/year), and ICS (50 ml/year; 95% CI, 26–74 ml/year) (60). In one study, the predose FEV1 in 691 patients with COPD increased by 156 ml (14%) with 500 µg fluticasone propionate plus 50 µg salmeterol bid, by 105 ml with fluticasone propionate alone, and by 107 ml with salmeterol alone; it decreased by 4 ml with placebo. The 2-hour postdose increases in FEV1 were 261, 138, 133, and 0 ml for the combination, fluticasone propionate alone, salmeterol alone, and placebo, respectively (82). The results of the TRISTAN study (TRial of Inhaled STeroids ANd long-acting ß2-agonists) were similar (83). Combination therapy increased pretreatment FEV1 by 133 ml more than did placebo. A similar improvement in lung function has been obtained with budesonide plus formoterol in COPD (84, 85).

The combination of 250 µg fluticasone propionate plus 50 µg salmeterol twice daily compares favorably with 36 µg ipratropium bromide plus 206 µg albuterol four times daily for the treatment of COPD (86). A large prospective study of the role of ICS in COPD is ongoing, and results should be available in 2,006 (87). To date, the benefits noted on lung function have been modest. Other outcomes, such as health-related quality of life, exacerbations, hospitalization rates, and mortality, will no doubt be more informative for decision-making on this class of agents.

ACUTE EXACERBATIONS.
There are few studies of ICS use for treatment of acute exacerbations in COPD, in contrast to treatment of acute asthma. Nebulized budesonide was compared with oral prednisone or placebo in a double-blind study of 199 patients with exacerbations of COPD requiring hospitalization. The increase in FEV1 at 72 hours was 0.10 L greater with budesonide than with placebo, 0.16 L greater with prednisone than with placebo, and 0.06 L greater with prednisone than with budesonide. The latter difference was not statistically significant. Thus, nebulized budesonide 2 mg every 6 hours may be an alternative to 30 mg of prednisone in the treatment of nonacidotic acute exacerbations of COPD, but further studies are needed (88).

Nava and Compagnoni (89) studied 12 hypercapnic patients with COPD on ventilators, with a baseline FEV1 of 13% predicted, and found that a brief trial of fluticasone propionate induced a bronchodilator response, which seemed to be principally related to a reduction in airway resistance. The response was evidenced by significant changes in static intrinsic positive end-expiratory pressure, maximal respiratory resistance, and minimal respiratory resistance, whereas changes in FEV1 significantly underestimated the effect. The use of nebulized ICS in hospitalized and intubated patients with acute respiratory failure has not been adequately studied.

EFFECTS OF DISCONTINUING ICS USE.
A double-blind, single-center study investigated the effects of discontinuing fluticasone propionate 1,000 µg/day for 4 months. Withdrawal of fluticasone propionate was associated with a higher risk of exacerbations, more rapid onset of exacerbations, and deterioration in health-related quality of life, with a mere 38 ml difference in FEV1 (90). In a crossover study, elderly patients with severe irreversible COPD received 6 weeks of placebo and 6 weeks of beclomethasone. Mean FEV1 was significantly reduced during placebo administration (1.6 L vs. 1.7 L at baseline), and the mean change in FEV1 was significantly poorer during the placebo phase (–6.28%) than during beclomethasone treatment (+5.03%) (91).

OCS for COPD
Although not recommended by the GOLD guidelines (Global Initiative for Chronic Obstructive Lung Disease) or the American Thoracic Society, OCS are given to a substantial number of patients with COPD.

LUNG FUNCTION.
The effects of OCS on lung function in stable outpatients with COPD have been evaluated in a limited fashion. Callahan and coworkers (92) performed a meta-analysis of 15 studies, collectively involving 445 subjects, that were completed before 1989. Prednisone 30 to 60 mg, administered for 7 to 21 days, was associated with an increase in FEV1 of >= 20% in 16% of individuals. Rice and colleagues discontinued OCS use in a population of patients with COPD with little change in clinical status (93). In an observational study, Postma and colleagues found that prednisone 10 mg daily for 20 years had a stabilizing effect on FEV1. The improvement came after 6 to 24 months (94). A randomized prospective trial by Renkema and associates (95) compared the effects of prednisone 5 mg/day plus budesonide 600 µg/day with budesonide alone or placebo during a 2-year period. The decline of FEV1 in patients actively treated with corticosteroids was smaller than that in patients who received placebo. Fabbri and coworkers evaluated differences in airway inflammation in patients with similar degrees of fixed airflow obstruction due to asthma or COPD (baseline FEV1 = 56% predicted). Both groups received an inhaled bronchodilator and a 15-day course of prednisone 50 mg daily. Those with a history of asthma improved by 251 ml with the bronchodilator and by 320 ml with an OCS, whereas the improvements in subjects with COPD were 122 and 100 ml, respectively (96). In 21 patients with chronic severe COPD (baseline FEV1 = 0.86 L), Nishimura and colleagues (97) noted no additional improvement in FEV1 or FVC when they added 30 mg/day of prednisolone to beclomethasone. In summary, the improvement in FEV1 with OCS in stable COPD is inconsistent and at best modest, and the benefits are not outweighed by the increase in side effects.

ACUTE EXACERBATIONS.
The evidence supporting the use of systemic corticosteroids during acute COPD exacerbations is quite convincing. Albert and colleagues (98) found that FEV1, although not FVC, increased at a faster rate when acute exacerbations were treated with intravenous methylprednisolone for 3 days, compared with placebo. In another study, tapering doses of prednisone or placebo were given over 9 days to 27 outpatients with COPD with acute exacerbations. The FEV1 was greater at 3 and 10 days in the prednisone-treated group (99). In a trial of 30 mg prednisone once daily, FEV1 increased by 90 ml at 5 days versus 30 ml with placebo. However, there was no difference in FEV1 at 6 weeks (100). Emerman and coworkers (101) determined that a single dose of 100 mg intravenous methylprednisolone did not improve spirometric parameters in 96 patients in the emergency department with acute exacerbations of COPD.

In the SCCOPE trial, conducted at U.S. Veterans' Hospitals, intravenous methylprednisolone followed by oral prednisone for either 2 or 6 weeks promoted a maximal increase in FEV1 of 0.120 L. This occurred on the first day and in a unimodal distribution, with no identifiable responder or nonresponder group (102). The increase in FEV1 persisted for 3 days, but there was no difference between the prednisone- and placebo-treated groups at 2 weeks. The steroid arm had a shorter hospital stay. No additional benefit was derived from the use of prednisone for 6 weeks, and the incidence of steroid-related adverse events was increased with 6 weeks versus 2 weeks of therapy.

Singh and colleagues recently performed a meta-analysis of eight studies evaluating the effects of systemic corticosteroids on acute exacerbations of COPD. Five studies found significant improvement in FEV1 (> 20%), while one published article and two abstracts reported no increase (103). Riancho and coworkers reviewed six studies of systemic corticosteroids in acute exacerbations of COPD. The FEV1 improved at 3 days by a weighted mean difference of 89 ml and at 7 to 14 days by 200 ml (104).

Regarding the optimal length of treatment, Sayiner and associates (105) showed that 10 days of systemic corticosteroids effected greater improvement in FEV1 and FVC than 3 days in 34 patients with COPD hospitalized with acute exacerbations. In a randomized, double-blind, placebo-controlled trial of 147 patients with COPD being discharged from the emergency department, outpatient treatment with 10 days of oral prednisone 40 mg conferred significantly greater improvement in FEV1 than placebo (34 vs. 15%, respectively). Prednisone therapy also improved the relapse rate, time to relapse, and dyspnea (106). McCrory and coworkers evaluated randomized, placebo-controlled trials of OCS in acute exacerbations of COPD. They concluded that the increase in FEV1 was 100 ml in the first 3 days of therapy (107).

In summary, most studies show benefit of OCS on lung function in the treatment of acute exacerbations of COPD, at least in the first few days, and a benefit in reducing relapse rates.

Ventilatory Control and Muscle Force
Corticosteroids may decrease inspiratory muscle strength in certain patients with COPD, although the data are inconsistent (108). In one study of long-term use of an OCS (21 mg/day for 5 years) in 19 subjects with asthma, maximum inspiratory pressure was equivalent to that in patients not on OCS (109). However, in another study, 8 of 21 patients admitted to the hospital with an exacerbation of COPD or asthma had myopathy with generalized muscle weakness after long-term use of an OCS (110).

The perception of bronchoconstriction may be impaired or blunted in some patients with asthma, particularly those recently hospitalized and those with severe steroid-dependent asthma (111). Patients with a poor perception of their symptoms seem to have an increased risk of an asthma attack. Perhaps those with severe asthma "adapt" to airway obstruction, or poor perception may lead to severe asthma. In a study of 134 patients with asthma undergoing histamine challenge, both initial FEV1 and bronchial hyperresponsiveness were significantly correlated with the perception of breathlessness. A low baseline FEV1 and increased bronchial hyperresponsiveness correlated with a low perception of bronchoconstriction (112).

ICS may reverse some of this impaired perception. In a recent study, patients with severe asthma were randomized to treatment with budesonide 1,600 or 3,200 µg for 8 weeks, titrated down over 72 weeks. Borg scores were recorded during histamine challenge, and perception of bronchoconstriction was estimated as the slope of Borg score divided by the percentage decline in FEV1. The slope increased significantly at 8 weeks but was not related to the dose or to inflammatory markers (113). Higgs and Laszlo found that 1 week of budesonide therapy altered perception of breathlessness, although no significant improvement in FEV1 or PEFR was noted (114). Bijl-Hofland and colleagues reported that the combination of a LABA and an ICS improved perception of histamine-induced bronchoconstriction in asthma, but the combination of a short-acting ß-agonist and ICS did not (115). The clinical relevance of changes in perception of induced airway narrowing to actual asthma symptoms is unknown.


   NOVEL CORTICOSTEROIDS
TOP
 ABSTRACT
 EVALUATING RESPONSE TO...
 CORTICOSTEROIDS FOR ASTHMA
 CORTICOSTEROIDS FOR COPD
 NOVEL CORTICOSTEROIDS
REFERENCES
 
Corticosteroids produce their effects by activating the glucocorticoid receptor in cells to directly or indirectly regulate transcription of target genes. The principal molecular mechanisms by which corticosteroids modify gene expression are transactivation (positive regulation of gene transcription) and transrepression (negative regulation of gene transcription). The antiinflammatory effects of corticosteroids are mediated to a major extent via transrepression, while many side effects are due to transactivation. A new generation of corticosteroids are being developed that preferentially induce transrepression with little or no transactivation (116). These drugs are becoming known as "dissociated" steroids because of the dissociation between transrepression and transactivation.

Another new approach is to develop a "soft" steroid, one that has limited or no systemic side effects because it is delivered only close to its site of action or is degraded into inactive metabolites (117). The most promising agent for asthma is ciclesonide, a prodrug that is cleaved by esterase into an active form in the lung. The active compound is without clinically relevant effects on the hypothalamic-pituitary-adrenal axis, because it is activated only in bronchial mucosa and the absorbed fraction is highly plasma protein–bound (118). In patients with mild allergic asthma, Larsen and colleagues determined that ciclesonide significantly reduces the decline in FEV1 after antigen challenge, from 0.426 to 0.233 L soon after the challenge and from 0.44 to 0.213 L in the late phase (119). Postma and colleagues have documented that ciclesonide is equally effective whether inhaled in the morning or evening, although evening administration seems to lead to more pronounced improvement in morning PEFR (120).

SUMMARY
In general, lung function as measured by FEV1 improves in individuals with asthma using corticosteroids, and FEV1 is a reasonable measure of efficacy when evaluating treatments. However, the conclusion is different for COPD, where FEV1 response is not well correlated with functional tests. OCS inconsistently improve lung function in stable outpatients with COPD. Individual ICS do not have a marked effect, but the combination of fluticasone propionate and salmeterol and the combination of budesonide plus formoterol seem to improve FEV1 over treatment with the individual components. In addition, there is convincing evidence for the use of OCS during acute exacerbations of COPD. Some evidence suggests that patients with COPD who respond to corticosteroids have eosinophilic inflammation and other attributes of an asthma phenotype.


   ACKNOWLEDGMENTS
 
J.F.D. has consultancies with Altana (2003–2004) and received $2,000 and GlaxoSmithKline (GSK) (2003) and received $2,000 and is on the Advisory Board of Altana (2003–2004) receiving $4,000, AstraZeneca (2003–2004) receiving $4,000 and GSK (2002–2004) receiving $12,000 and has received lecture fees from AstraZeneca in (2003) for $2,000 and GSK in (2002–2004) for $8,000. J.A.O. received lecture fees from medical education companies and holds $3,500 in Sepracor stock and her daughter is a Boehringer Ingelheim representative. The University of North Carolina has research contracts with GlaxoSmithKline, Altana, and AstraZeneca in which J.F.D. is principle investigator.

(Received in original form February 17, 2004; accepted in final form September 7, 2004)


   REFERENCES
TOP
 ABSTRACT
 EVALUATING RESPONSE TO...
 CORTICOSTEROIDS FOR ASTHMA
 CORTICOSTEROIDS FOR COPD
 NOVEL CORTICOSTEROIDS
 REFERENCES
 

  1. Parameswaran K, O'Byrne PM, Sears MR. Inhaled corticosteroids for asthma: common clinical quandaries. J Asthma 2003;40:107–118.[CrossRef][Medline]
  2. Van Andel AE, Reisner C, Menjoge SS, Witek TJ. Analysis of inhaled corticosteroid and oral theophylline use among patients with stable COPD from 1987 to 1995. Chest 1999;115:703–707.[Abstract/Free Full Text]
  3. National Asthma Education and Prevention Program. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. J Allergy Clin Immunol 2002;110:S141–S219.[Medline]
  4. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1256–1276.[Free Full Text]
  5. Suissa S. Effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immortal time bias in observational studies. Am J Respir Crit Care Med 2003;168:49–53.[Abstract/Free Full Text]
  6. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:580–584.[Abstract/Free Full Text]
  7. Jakeways N, McKeever T, Lewis SA, Weiss ST, Britton J. Relationship between FEV1 reduction and respiratory symptoms in the general population. Eur Respir J 2003;21:658–663.[Abstract/Free Full Text]
  8. Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, Weiss ST. FEV1 is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 2001;107:61–67.[CrossRef][Medline]
  9. Zhang J, Yu C, Holgate ST, Reiss TF. Variability and lack of predictive ability of asthma end-points in clinical trials. Eur Respir J 2002;20:1102–1109.[Abstract/Free Full Text]
  10. Niewoehner DE. Impact of drug classes used in COPD on outcome measures other than exacerbations. Eur Respir Rev 2002;12:11–12.
  11. Mahler DA. Assessing severity and treatment effects in COPD: what outcome measures are available? Eur Respir Rev 2002;12:7–8.
  12. Rubin BK, Ramirez O, Ohar JA. Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis. Chest 1996;109:348–352.[Abstract/Free Full Text]
  13. Newton MF, O'Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002;121:1042–1050.[Abstract/Free Full Text]
  14. Di Marco F, Milic-Emili J, Boveri B, Carlucci P, Santus P, Casanova F, Cazzola M, Centanni S. Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD. Eur Respir J 2003;21:86–94.[Abstract/Free Full Text]
  15. Taube C, Kanniess F, Grönke L, Richter K, Mücke M, Paasch K, Eichler G, Jörres RA, Magnussen H. Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma. Respir Med 2002;97:568–577.
  16. Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999;14:23–27.[Abstract]
  17. Redelmeier DA, Goldstein RS, Min ST, Hyland RH. Spirometry and dyspnea in patients with COPD: when small differences mean little. Chest 1996;109:1163–1168.[Abstract/Free Full Text]
  18. Niewoehner DE, Collins D, Erbland ML. Relation of FEV1 to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. Am J Respir Crit Care Med 2000;161:1201–1205.[Medline]
  19. Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol 1999;52:861–873.[CrossRef][Medline]
  20. van Stel HF, Maille AR, Colland VT, Everaerd W. Interpretation of change and longitudinal validity of the quality of life for respiratory illness questionnaire (QoLRIQ) in inpatient pulmonary rehabilitation. Qual Life Res 2003;12:133–145.[CrossRef][Medline]
  21. Segala C, Soussan D, Priol G, Lepage T, Martinat Y, Rogeaux Y, Touron D, Neukrich F. Factors predicting the severity and the degree of symptom control of asthma in a recently diagnosed cohort of adult patients (A.S.M.A study). Rev Mal Respir 2003;20:191–199. (translation).[Medline]
  22. Apter AJ, Boston RC, George M, Norfleet AL, Tenhave T, Coyne JC, Birck K, Reisine ST, Cucchiara AJ, Feldman HI. Modifiable barriers to adherence to inhaled steroids among adults with asthma: it's not just black and white. J Allergy Clin Immunol 2003;111:1219–1226.[CrossRef][Medline]
  23. Bukstein DA, Luskin AT, Bernstein A. "Real-world" effectiveness of daily controller medicine in children with mild persistent asthma. Ann Allergy Asthma Immunol 2003;90:543–549.[Medline]
  24. Stoloff SW, Stempel DA, Meyer J, Stanford RH, Carranza-Rosenzweis JR. Improved refill persistance with fluticasone propionate and salmeterol in a single inhaler compared with other controlled therapies. J Allergy Clin Immunol 2004; (In press)
  25. Gillissen A, Lecheler J. Corticophobia in asthma. Med Klin 2003;98:417–422. (translation).[CrossRef][Medline]
  26. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054–1063.[Abstract/Free Full Text]
  27. Yohannes AM, Hardy CC. Treatment of chronic obstructive pulmonary disease in older patients: a practical guide. Drugs Aging 2003;20:209–228.[CrossRef][Medline]
  28. Barta SK, Crawford A, Roberts CM. Survey of patients' views of domiciliary nebuliser treatment for chronic lung disease. Respir Med 2002;96:375–381.[CrossRef][Medline]
  29. Chrischilles E, Gilden D, Kubisiak J, Rubenstein L, Shah H. Delivery of ipratropium and albuterol combination therapy for chronic obstructive pulmonary disease: effectiveness of a two-in-one inhaler versus separate inhalers. Am J Manag Care 2002;8:902–911.[Medline]
  30. van Grunsven PM, van Schayck CP, van Deuveren M, van Herwaarden CLA, Akkermans RP, van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study. J Asthma 2000;37:225–234.[Medline]
  31. Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:1–8.[Abstract/Free Full Text]
  32. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, et al. for the Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410–418.[CrossRef][Medline]
  33. Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, Furlong A, Shah T, Knobil K. Time to onset of effect of fluticasone propionate in patients with asthma. J Allergy Clin Immunol 1999;103:780–788.[CrossRef][Medline]
  34. Currie GP, Fowler SJ, Lipworth BJ. Dose response of inhaled corticosteroids on bronchial hyperresponsiveness: a meta-analysis. Ann Allergy Asthma Immunol 2003;90:194–198.[Medline]
  35. Noonan M, Chervinsky P, Busse WW, Weisberg SC, Pinnas J, de Boisblanc BP, Boltansky H, Pearlman D, Repsher L, Kellerman D. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am J Respir Crit Care Med 1995; 152:1467–1473.[Abstract]
  36. Nelson HS, Busse WW, deBoisblanc BP, Berger WE, Noonan MJ, Webb DR, Wolford JP, Mahajan PS, Hamedani AG, Shah T, Harding SM. Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma. J Allergy Clin Immunol 1999;103:267–275.[CrossRef][Medline]
  37. Martin RJ, Szefler SJ, Chinchilli VM, Kraft M, Dolovich M, Boushey HA, Cherniak RM, Craig TJ, Drazen JM, Fagan JK. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165:1377–1383.[Abstract/Free Full Text]
  38. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen Y-Z, Ohlsson SV, Ullman A, Lamm CJ, O'Byrne PM, on behalf of START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071–1076.[CrossRef][Medline]
  39. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054–1063.
  40. Shapiro G, Lumry W, Wolfe J, Given J, White MV, Woodring A, Baitinger L, House K, Prillaman B, Shah T. Combined salmeterol 50 µg and fluticasone propionate 250 µg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000;161:527–534.[Abstract/Free Full Text]
  41. Kavuru M, Melamed J, Gross G, LaForce C, House K, Prillaman B, Baitinger L, Woodring A, Shah T. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2000;105:1108–1116.[CrossRef][Medline]
  42. Aubier M, Pieters WR, Schlösser NJJ, Steinmetz K-O. Salmeterol/fluticasone propionate (50/500 µg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999;93:876–884.[CrossRef][Medline]
  43. Ind PW, Dal Negro R, Colman NC, Fletcher CP, Browning D, James MH. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Respir Med 2003;97:555–562.[CrossRef][Medline]
  44. Kerstjens HAM, Brand PLP, Hughes MD, Robinson NJ, Postma DS, Sluiter HJ, Bleecker ER, Dekhuijzen PNR, de Jong PM, Mengelers HJJ, et al., and the Dutch Chronic Non-Specific Lung Disease Study Group. 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 Med 1992; 327:1413–1419.
  45. Verona E, Petrov D, Cserhati E, Hofman J, Geppe N, Medley H, Hughes S. Fluticasone propionate in asthma: a long term dose comparison study. Arch Dis Child 2003;88:503–509.[Abstract/Free Full Text]
  46. Gibbs MA, Camargo CA Jr, Rowe BH, Silverman RA. State of the art: therapeutic controversies in severe acute asthma. Acad Emerg Med 2000;7:800–815.[Medline]
  47. Rodrigo G, Rodrigo C. Inhaled flunisolide for acute severe asthma. Am J Respir Crit Care Med 1998;157:698–703.[Abstract/Free Full Text]
  48. Lee-Wong M, Dayrit FM, Kohli AR, Acquah S, Mayo PH. Comparison of high-dose inhaled flunisolide to systemic corticosteroids in severe adult asthma. Chest 2002;122:1208–1213.[Abstract/Free Full Text]
  49. Schuh S, Reisman J, Alshehri M, Dupuis A, Corey M, Arseneault R, Alothman G, Tennis O, Canny G. A comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma. N Engl J Med 2000;343:689–694.[Abstract/Free Full Text]
  50. Coyle YM, Aragaki CC, Hynan LS, Gruchalla RS, Khan DA. Effectiveness of acute asthma care among inner-city adults. Arch Intern Med 2003;163:1591–1596.[Abstract/Free Full Text]
  51. Jones AM, Munavvar M, Vail A, Aldridge RE, Hopkinson L, Rayner C, O'Driscoll BR. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med 2002; 96:950–954.[CrossRef][Medline]
  52. Corren J, Tashkin DP. Evaluation of efficacy and safety of flunisolide hydrofluoroalkane for the treatment of asthma. Clin Ther 2003;25:776–798.[CrossRef][Medline]
  53. in 't Veen JCCM, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:1902–1906.[Abstract/Free Full Text]
  54. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, on behalf of the ISOLDE Study Group. Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study. Thorax 2003;58:654–658.[Abstract/Free Full Text]
  55. Chanez P, Vignola AM, O'Shaugnessy T, Enander I, Li D, Jeffery PK, Bousquet J. Corticosteroid reversibility in COPD is related to features of asthma. Am J Respir Crit Care Med 1997;155:1529–1534.[Abstract]
  56. Fujimoto K, Kubo K, Yamamoto H, Yamaguchi S, Matsuzawa Y. Eosinophilic inflammation in the airway is related to glucocorticoid reversibility in patients with pulmonary emphysema. Chest 1999;115:697–702.[Abstract/Free Full Text]
  57. Papi A, Romagnoli M, Baraldo S, Braccioni F, Guzzinati I, Saetta M, Ciaccia A, Fabbri LM. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1773–1777.[Abstract/Free Full Text]
  58. Pizzichini E, Pizzichini MMM, Gibson P, Parameswaran K, Gleich GJ, Berman L, Dolovich J. hargreave FE. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 1998;158:1511–1517.[Abstract/Free Full Text]
  59. Riancho JA, Cubian I, Portero I. Effectiveness of inhaled corticosteroids in chronic obstructive lung disease: systematic review. Med Clin (Barc) 2002;118:446–451. (translation)[Medline]
  60. Sin DD, McAlister FA, Man SFP, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003;290:2301–2312.[Abstract/Free Full Text]
  61. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:59–65.[CrossRef][Medline]
  62. McEvoy CE, Niewoehner DE. Corticosteroids in chronic obstructive pulmonary disease: clinical benefits and risks. Clin Chest Med 2000;21:739–752.[CrossRef][Medline]
  63. Kerstjens HA, Brand PL, Hughes MD, Robinson NJ, Postma DS, Sluiter HJ, Bleecker ER, Dekhuijzen PN, de Jong PM, Mengeles HJ, et al. for the Dutch Chronic Non-Specific Lung Disease Study Group. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. N Engl J Med 1992; 327:1413–1419.[Abstract]
  64. Thompson AB, Daughton D, Robbins RA, Ghafouri MA, Oehlerking M, Rennard SI. Intraluminal airway inflammation in chronic bronchitis: characterization and correlation with clinical parameters. Am Rev Respir Dis 1989;140:1527–1537.[Medline]
  65. Dompeling E, van Schayck CP, Molema J, Folgering H, van Grunsven PM, van Weel C. Inhaled beclomethasone improves the course of asthma and COPD. Eur Respir J 1992;5:945–952.[Abstract]
  66. Robertson AS, Gove RI, Wieland GA, Burge PS. A double-blind comparison of oral prednisolone 40 mg/day with inhaled beclomethasone dipropionate 1500 µg/day in patients with adult onset chronic obstructive airways disease. Eur J Respir Dis 1986;69:565–569.
  67. Engel T, Heinig JH, Madsen O, Hansen M, Weeke ER. A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. Eur Respir J 1989;2:935–939.[Abstract]
  68. Watson A, Lim TK, Joyce H, Pride NB. Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction. Chest 1992; 101:350–355.[Abstract/Free Full Text]
  69. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997;155:542–548.[Abstract]
  70. Bourbeau J, Rouleau MY, Boucher S. Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease. Thorax 1998;53:477–482.[Abstract/Free Full Text]
  71. Wempe JB, Postma DS, Breederveld N, Kort E, van der Mark TW, Koëter GH. Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease. Thorax 1992;47:616–621.[Abstract/Free Full Text]
  72. Wesseling GJ, Quaedvlieg M, Wouters EFM. Inhaled budesonide in chronic bronchitis: effects on respiratory impedance. Eur Respir J 1991; 4:1101–1105.[Abstract]
  73. Rutgers SR, Koëter GH, van der Mark TW, Postma DS. Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5'-monophosphate in COPD. Am J Respir Crit Care Med 1998;157:880–886.[Abstract/Free Full Text]
  74. Auffarth B, Postma DS, de Monchy JGR, van der Mark TW, Boorsma M, Koëter GH. Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease. Thorax 1991;46:372–377.[Abstract/Free Full Text]
  75. Weiner P, Weiner M, Azgad Y, Zamir D. Inhaled budesonide therapy for patients with stable COPD. Chest 1995;108:1568–1571.[Abstract/Free Full Text]
  76. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J, on behalf of the International COPD Study Group. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773–780. [Erratum in: Lancet 1998;351:1968][CrossRef][Medline]
  77. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen TK, on behalf of the ISOLDE study investigators. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–1303.[Abstract/Free Full Text]
  78. Pauwels RA, Löfdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV, for the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340:1948–1953.[Abstract/Free Full Text]
  79. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;363:1819–1823.
  80. Mapp CE. Inhaled glucocorticoids in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1960–1961.[Free Full Text]
  81. Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease: a meta-analysis. Ann Intern Med 2003;138:969–973.[Abstract/Free Full Text]
  82. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1084–1091.[Abstract/Free Full Text]
  83. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C, for the TRISTAN. (Trial of Inhaled Steroids and Long-Acting ß2 Agonists) Study Group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–456. [Erratum in: Lancet 2003;361:1660.][CrossRef][Medline]
  84. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912–919.[Abstract/Free Full Text]
  85. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74–81.[Abstract/Free Full Text]
  86. Donohue JF, Kalberg C, Emmett A, Merchant K, Knobil K. A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD. Treat Respir Med 2004;3:173–181.[CrossRef][Medline]
  87. The Torch Study Group. The TORCH (TOwards a Revolution in COPD Health) survival study protocol. Eur Respir J 2004;24:206–210.[Abstract/Free Full Text]
  88. Maltais F, Ostinelli J, Bourbeau J, Tonnel AB, Jacquemet N, Haddon J, Rouleau M, Boukhana M, Martinot JB, Duroux P. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2002; 165:698–703.[Abstract/Free Full Text]
  89. Nava S, Compagnoni ML. Controlled short-term trial of fluticasone propionate in ventilator-dependent patients with COPD. Chest 2000; 118:990–999.[Abstract/Free Full Text]
  90. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002;166:1358–1363.[Abstract/Free Full Text]
  91. O'Brien A, Russo-Magno P, Karki A, Hiranniramol S, Hardin M, Kaszuba M, Sherman C, Rounds S. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Am J Respir Crit Care Med 2001;164:365–371.[Abstract/Free Full Text]
  92. Callahan CM, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: a meta-analysis. Ann Intern Med 1991;114:216–223.
  93. Rice KL, Leatherman JW, Duane PG, Snyder LS, Harmon KR, Abel J, Niewoehner DE. Aminophylline for acute exacerbations of chronic obstructive pulmonary disease: a controlled trial. Ann Intern Med 1987;107:305–309.
  94. Postma DS, Peters I, Steenhuis EJ, Sluiter HJ. Moderately severe chronic airflow obstruction: can corticosteroids slow down obstruction? Eur Respir J 1988;1:22–26.[Abstract]
  95. Renkema TEJ, Schouten JP, Koëter GH, Postma DS. Effects of long-term treatment with corticosteroids in COPD. Chest 1996;109:1156–1162.[Abstract/Free Full Text]
  96. Fabbri LM, Romagnoli M, Corbetta L, Casoni G, Busljetic K, Turato G, Ligabue G, Ciaccia A, Saetta M, Papi A. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:418–424.[Abstract/Free Full Text]
  97. Nishimura K, Ikeda A, Koyama H, Zhang M, Tsukino M, Hajiro T, Izumi T. Additive effects of prednisolone and beclomethasone dipropionate in patients with stable chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2000;13:225–230.[CrossRef][Medline]
  98. Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980;92:753–758.
  99. Thompson WH, Nielson CP, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996;154:407–412.[Medline]
  100. Davies L, Angus RM, Calverley PMA. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354:456–460.[CrossRef][Medline]
  101. Emerman CL, Connors AF, Lukens TW, May ME, Effron D. A randomized controlled trial of methylprednisolone in the emergency treatment of acute exacerbations of COPD. Chest 1989;95:563–567.[Medline]
  102. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA, for the Department of Veterans Affairs Cooperative Study Group. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999;340:1941–1947.
  103. Singh JM, Palda VA, Stanbrook MB, Chapman KR. Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease: a systematic review. Arch Intern Med 2002;162:2527–2536.[Abstract/Free Full Text]
  104. Riancho JA, Portero I, Cubian I. [The efficacy of corticosteroids in exacerbations of chronic obstructive pulmonary disease: meta-analysis of published studies] Med Clin (Barc) 2000;114:681–684.
  105. Sayiner A, Aytemur ZA, Cirit M, Unsal I. Systemic glucocorticoids in severe exacerbations of COPD. Chest 2001;119:726–730.[Abstract/Free Full Text]
  106. Aaron SD, Vandemheen KL, Hebert P, Dales R, Stiell IG, Ahuja J, Dickinson G, Brison R, Rowe BH, Dreyer J. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618–2625.[Abstract/Free Full Text]
  107. McCrory DC, Brown C, Gelfand SE, Bach PB. Management of acute exacerbations of COPD: a summary and appraisal of published evidence. Chest 2001;119:1190–1209.[Abstract/Free Full Text]
  108. Laghi F, Tobin MJ. Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10–48.[Abstract/Free Full Text]
  109. Perez T, Becquart LA, Stach B, Wallaert B, Tonnel AB. Inspiratory muscle strength and endurance in steroid-dependent asthma. Am J Respir Crit Care Med 1996;153:610–615.[Abstract]
  110. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16.[Abstract]
  111. in't Veen JCCM, Smits HH, Ravensberg AJJ, Hiemstra PS, Sterk PJ, Bel EH. Impaired perception of dyspnea in patients with severe asthma: relation to sputum eosinophils. Am J Respir Crit Care Med 1998;158:1134–1141.[Abstract/Free Full Text]
  112. Bijl-Hofland ID, Cloosterman SGM, Folgering HTM, Akkermans RP, van Schayck CP. Relation of the perception of airway obstruction to the severity of asthma. Thorax 1999;54:15–19.[Abstract/Free Full Text]
  113. Salome CM, Reddel HK, Ware SI, Roberts AM, Jenkins CR, Marks GB, Woolcock AJ. Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am J Respir Crit Care Med 2002;165:15–21.[Abstract/Free Full Text]
  114. Higgs CMB, Laszlo G. Influence of treatment with beclomethasone, cromoglycate and theophylline on perception of bronchoconstriction in patients with bronchial asthma. Clin Sci (Lond) 1996;90:227–234.[Medline]
  115. Bijl-Hofland ID, Cloosterman SGM, Folgering HTM, van den Elshout FJJ, van Weel C, van Schayck CP. Inhaled corticosteroids, combined with long-acting ß2-agonists, improve the perception of bronchoconstriction in asthma. Am J Respir Crit Care Med 2001;164:764–769.[Abstract/Free Full Text]
  116. Caramori G, Adcock I. Pharmacology of airway inflammation in asthma and COPD. Pulm Pharmacol Ther 2003;16:247–277.[CrossRef][Medline]
  117. Belvisi MG, Hele DJ. Soft steroids: a new approach to the treatment of inflammatory airways disease. Pulm Pharmacol Ther 2003;16:321–325.[CrossRef][Medline]
  118. Weinbrenner A, Hüneke D, Zschiesche M, Engel G, Timmer W, Steinijans VW, Bethke T, Wurst W, Drollman A, Kaatz HJ, et al. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002;87:2160–2163.[Abstract/Free Full Text]
  119. Larsen BB, Nielsen LP, Engelstatter R, Steinijans V, Dahl R. Effect of ciclesonide on allergen challenge in subjects with bronchial asthma. Allergy 2003;58:207–212.[CrossRef][Medline]
  120. Postma DS, Sevette C, Martinat Y, Schlosser N, Aumann J, Kafe H. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J 2001;17:1083–1088.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
A. Livraghi, B. R. Grubb, E. J. Hudson, K. J. Wilkinson, J. K. Sheehan, M. A. Mall, W. K. O'Neal, R. C. Boucher, and S. H. Randell
Airway and Lung Pathology Due to Mucosal Surface Dehydration in {beta}-Epithelial Na+ Channel-Overexpressing Mice: Role of TNF-{alpha} and IL-4R{alpha} Signaling, Influence of Neonatal Development, and Limited Efficacy of Glucocorticoid Treatment
J. Immunol., April 1, 2009; 182(7): 4357 - 4367.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Donohue, J. F.
Right arrow Articles by Ohar, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Donohue, J. F.
Right arrow Articles by Ohar, J. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS