Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysis
© Qi Gan et al; licensee BioMed Central Ltd. 2005
Received: 13 September 2004
Accepted: 11 February 2005
Published: 11 February 2005
Whether inhaled corticosteroids suppress airway inflammation in chronic obstructive pulmonary disease (COPD) remains controversial. We sought to determine the effects of inhaled corticosteroids on sputum indices of inflammation in stable COPD.
We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Databases for randomized, controlled clinical trials that used induced sputum to evaluate the effect of inhaled corticosteroids in stable COPD. For each chosen study, we calculated the mean differences in the concentrations of sputum cells before and after treatment in both intervention and control groups. These values were then converted into standardized mean differences to accommodate the differences in patient selection, clinical treatment, and biochemical procedures that were employed across original studies. If significant heterogeneity was present (p < 0.10), then a random effects model was used to pool the original data. In the absence of significant heterogeneity, a fixed effects model was used.
We identified six original studies that met the inclusion criteria (N = 162 participants). In studies with higher cumulative dose (≥ 60 mg) or longer duration of therapy (≥ 6 weeks), inhaled corticosteroids were uniformly effective in reducing the total cell, neutrophil, and lymphocyte counts. In contrast, studies with lower cumulative dose (< 60 mg) or shorter duration of therapy (< 6 weeks) did not demonstrate a favorable effect of inhaled corticosteroids on these sputum indices.
Our study suggests that prolonged therapy with inhaled corticosteroids is effective in reducing airway inflammation in stable COPD.
Chronic obstructive pulmonary disease (COPD) is characterized by prominent airway inflammation [1, 2]. The intensity of the inflammation strongly correlates with disease severity [3, 4] and increases even further during exacerbations . Moreover, increased expression of inflammatory markers in the sputum is associated with increased risk of exacerbations . The attenuation of the inflammatory process, on the other hand, is associated with improvements in lung function and airway hyperresponsiveness in COPD . It is possible therefore that the inflammatory process is an integral component in COPD pathogenesis and may represent an important therapeutic target in improving the health status and outcomes of COPD patients [1, 2].
One potential therapy for down-regulating the inflammatory process in the airways is through the use of corticosteroids, which are potent but non-specific anti-inflammatory agents. Some in vitro studies have demonstrated that inhaled corticosteroids can modulate certain aspects of the inflammatory cascade in COPD [8, 9]; however, other studies have shown less favorable results [10, 11]. Despite this uncertainty, large clinical trials have shown that these medications reduce clinically relevant exacerbations by ~30% and improve health status of patients with moderate to severe disease ; their withdrawal, on the other hand, leads to increased risk of exacerbations and worsening of health status . Since airway inflammation is associated with exacerbations  and since inhaled corticosteroids reduce exacerbations , they may also have salutary effect on airway inflammation in COPD. However, to date, the clinical studies, which have addressed this issue, have been small in size and scope and may not have had sufficient statistical power (on their own) to detect subtle but important effect of these medications on inflammatory indices in the airways. Additionally, there may be important methodologic differences between the positive and negative studies that could potentially explain the discrepancy. We, therefore, conducted a systematic review and a meta-analysis to determine whether inhaled corticosteroids do or do not suppress airway inflammation in patients with stable COPD and to explore the potential causes for the heterogeneity in reports.
Search for relevant studies
MEDLINE (1966–2004), EMBASE (1980–2004), CINAHL (1982–2004), and the Cochrane Databases were searched for randomized, controlled clinical trials that used induced sputum to evaluate the effect of inhaled steroids on airway inflammation in stable COPD. The search was restricted on articles published in the English language, using human participants. Subject headings included disease-specific search terms (COPD, lung diseases, pulmonary diseases, airway obstruction, obstructive pulmonary disease, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary emphysema, or mediastinal emphysema), drug-specific search terms (glucocorticosteroids, corticosteroids, beclomethasone, budesonide, fluticasone, or triamcinolone), and laboratory method-specific search terms (biopsy, bronchoalveolar lavage, or sputum). We also scanned the bibliographies and reference lists of retrieved articles to supplement the electronic searches. We contacted the primary authors for additional data and/or clarification of data.
Study selection and data abstraction
The primary objective of this meta-analysis was to compare the changes in sputum inflammatory indices among stable COPD patients before and after treatment with inhaled corticosteroids, using the control group in each individual studies as the referent. We chose sputum as the primary source of the analysis because there was a marked scarcity of quality studies which had evaluated the effect of inhaled corticosteroids from bronchoalveolar lavage fluid or tissue biopsy specimens. The inflammatory indices included total cell, neutrophil, macrophage, eosinophil, lymphocyte, and epithelial cell counts and interleukin (IL)-8 levels. Since the actions of oral corticosteroids may differ from those of inhaled corticosteroids, we excluded studies that evaluated the effects of oral corticosteroids on sputum inflammatory indices. From each selected article, two investigators (WQG, DDS) abstracted the following baseline information: the source of data, study design, inclusion and exclusion criteria, concomitant drugs, demographics of study participants including sample size, age, sex, current smoking status, pack-years of smoking history, predicted forced expiratory volume in one second (FEV1), the ratio of FEV1 to forced vital capacity (FVC), percent predicted reversibility with inhaled bronchodilator, the specific brand of inhaled corticosteroids and the dose as well as the duration of therapy. Cumulative dose of inhaled corticosteroids was calculated by multiplying the average daily dose by the total days of treatment. All formulations were converted to beclomethasone equivalent based on the recommendations from the Canadian Asthma Consensus Report . Any questions or discrepancies were resolved through iteration and consensus.
To accommodate any differences in patient selection, clinical treatment, and biochemical procedures that were employed across the original studies, we converted the absolute mean differences in the concentrations of the inflammatory cells between the intervention and control groups into standardized mean differences. For each study, standardized mean difference was derived by dividing the mean change in the inflammatory cell concentration at follow-up visit from the baseline visit between intervention and control groups by a pooled standard deviation of the mean change [15, 16]. A negative standardized mean difference indicated that the participants assigned to inhaled corticosteroids had lower cell counts compared with placebo at the end of the study phase; whereas a positive number denoted increased cell count relative to the control group. For each inflammatory cell, we tested the heterogeneity of results across the studies, using a Cochran Q test. If significant heterogeneity was present (p < 0.10), then a random effects model was used. In the absence of significant heterogeneity, a fixed effects model was used . We also evaluated the potential modifying effect of cumulative dose and the duration of therapy of the trials. We reasoned that trials that had higher cumulative dose (or longer duration of therapy) defined as greater or equal to the median cumulative dose (or duration of therapy) of all the trials included in this meta-analysis would be more "positive" than those that used lower doses (or were shorter in duration). All analyses were conducted using Review Manager version 4.2 (Revman; The Cochrane Collaboration, Oxford, England) and were two-tailed in nature.
Baseline information on original studies included in the meta-analysis.
Sugiura et al 2003 
Randomized, placebo-controlled parallel design.
FEV1/FVC < 0.7; all patients wereex-smokers who had stopped smoking for at least 1 year beforethe study.
A history of perennial allergic rhinitis; positiveallergen skin prick tests and RAST assay; a history of periodicwheezing; an improvement in FEV1 of more than 12 % predicted oran absolute increase of 200 ml after inhalation of 200 μg salbutamol; had bronchial or respiratory tract infectionsin the month preceding the study; had taken systemic steroids in the 2 monthsbefore the study or inhaled steroids in the month beforethe study.
Keatings et al 1997 
Outpatient clinics in different hospitals
Randomized, single-blind, crossover design with 3–7 day run in period. The clinical part of the study was single-blind, but all differential cell counting and assayswere carried out in a double blind fashion.
FEV1/FVC < 0.7; FEV1 < 70% predicted; reversibility with inhaled albuterol of <10% of predicted FEV1; smoking history of at least 10 pack-years; negative results on skin prick testing to four common aeroallergens.
Patients who had taken inhaled or oral steroids or who had suffered an exacerbation of their airway disease in the previous 6 weeks, or patients with any history of asthma or variability in symptoms were excluded.
Albuterol was allowed.
Culpitt et al 1999 
Randomized, double-blind, placebo-controlled crossover design with a run-in period of 2 weeks.
FEV1/FVC < 0.7; postbronchodilat or FEV1 <85% predicted; reversibility with inhaled β2-agonist of <15% of predicted FEV1; smoking history of at least 20 pack-years.
Patients who had taken inhaled or oral steroids or who had suffered an exacerbation of their airway disease in the previous 6 weeks, or patients with any history of asthma or atopy or variability in symptoms were excluded.
Three subjects had concomitant treatment with albuterol (200 μg twice a day) and ipratropium bromide (40 μg twice a day), one subject with albuterol (200 μg as needed) alone.
Samples were considered adequate for analysis if there was < 50% squamous cell contamination.
Confalonieri 1998 
Randomised, controlled, open study. The clinical parts of the study was open, but all differential cell counting was carried out in a double blind fashion.
FEV1/FVC <88% of predicted in men and <89% in women; all patients were current smokers.
Patients who had taken inhaled or oral steroids or had suffered a respiratory tract infection in the previous three months were excluded.
None of the patients was taking theophyllines or long acting β2 agonists.
Samples were discarded if viability levels were 50% or less, or squamous contamination was 20% or more. An overall differential cell count on 500 nucleated non-squamous cells was performed by two examiners and results reported as mean of the two counts.
Mirici et al 2001 
Randomized, double-blind, placebo-controlled parallel design.
FEV1 < 70% predicted; no self-reported asthma; reversibility with inhaled terbutaline of <15% of predicted FEV1; current smokers.
Long-term treatment with oral or inhaled steroids within 6 months of study entry; A respiratory tract infection in previous 3 months; pregnancy or lactation, or presence of other serious systemic diseases.
β2 – agonists of all kinds, theophylline, and mucolytics were allowed.
Samples were discarded if viabilitylevels were 50% or less, or squamous contamination was 20% or more
Yildiz et al 2000 
Randomized, placebo-controlled parallel design with a run-in period of 2 weeks.
FEV1/FVC < 0.7; FEV1 < 70% predicted; reversibility with inhaled albuterol of <10% of predicted; smoking history of at least 10 pack-years.
Patients with any history of asthma or variability in symptoms, and patients who had taken inhaled or oral steroids or had suffered a respiratory tract infection or exacerbation in the previous 6 weeks were excluded.
All of the patients continued to inhale both salbutamol and ipatropium bromide. In 9 patients, sustained release theophylline was also administered.
The characteristics of COPD patients at baseline.
Number of Patients
Current Smokers (%)
FEV1 (% predicted)
Reversibility (% predicted)
Cumulative dose (mg) #
Total and differential cell counts at baseline and the standard mean difference (SMD) in cell counts between intervention group and placebo group after treatment.
Number (× 104/mL)
SMD (95% CI)
Number (× 104/mL)
SMD (95% CI)
Number (× 104/mL)
SMD (95% CI)
Number (× 104/mL)
SMD (95% CI)
Number (× 104/mL)
SMD (95% CI)
-0.6 (-1.6 to 0.4)
-2.2 (-3.4 to -1.0)
-0.5 (-1.4 to 0.5)
-1.1 (-2.1 to -0.1)
0.2 (-0.5 to 0.9)
-0.4 (-1.1 to 0.3)
-3.4 (-4.5 to -2.3)
-0.5 (-1.2 to 0.2)
-0.6 (-1.3 to 0.1)
-0.3 (-0.9 to 0.3)
-1.0 (-1.7 to -0.3)
-7.5 (-9.3 to -5.6)
-0.7 (-1.4 to -0.1)
0.2 (-0.4 to 0.8)
0.5 (-0.5 to 1.5)
0.2 (-0.8 to 1.2)
0.1 (-0.9 to 1.1)
0.04 (-0.9 to 1.0)
-0.2 (-1.2 to 0.8)
-0.3 (-1.1 to 0.5)
-0.3 (-1.1 to 0.5)
-0.4 (-1.2 to 0.4)
-0.2 (-0.9 to 0.6)
-0.1 (-0.9 to 0.7)
-0.4 (-1.1 to 0.4)
0.0 (-0.7 to 0.8)
-0.2 (-1.0 to 0.6)
0.2 (-0.7 to 1.2)
-0.4 (-0.8 to -0.1)
-2.2 (-3.8 to -0.5)
-0.4 (-0.7 to -0.1)
-0.3 (-0.6 to 0.1)
-0.02 (-0.3 to 0.3)
By combining data across the clinical studies, we increased statistical power to demonstrate a salutary effect of moderate to high doses of inhaled corticosteroids on some inflammatory indices in the sputum of patients with stable COPD. Over a short term, these medications reduced neutrophil, lymphocyte and epithelial cell counts in the sputum of stable COPD patients. They had smaller (and insignificant) effect on sputum eosinophils and IL-8. They had little effect on sputum macrophages. Although the magnitudes of these reductions were relatively small, they may explain why inhaled corticosteroids decrease cough and sputum production , reduce exacerbations , and hospitalizations .
We also found that duration of therapy and total cumulative dose, which are related constructs, made a material difference to the overall results. Short trials (less than 6 weeks in duration) were uniformly "negative"; while longer term trials (at least 6 weeks of therapy) were mostly positive. Similarly, trials that exposed the patients to higher cumulative dose were more "positive" than those that exposed patients to lower dose. This suggests that duration of therapy and total cumulative doses may be important determinants of the effect of inhaled corticosteroids on airway inflammation.
Although corticosteroids delay neutrophil apoptosis and may increase neutrophil survival [11, 26], they also have significant inhibitory action on neutrophil performance. Likely through the annexin-I (lipocortin-1) pathways, for instance, corticosteroids interfere with neutrophil chemotaxis, adhesion, transmigration, oxidative bursts, and phagocytosis, thereby down-regulating the overall inflammatory cascade [9, 27]. Indeed, Llewellyn-Jones and co-workers  showed that 4 weeks of inhaled fluticasone therapy can significantly reduce sputum chemotactic activity for neutrophils and increase its elastase inhibitory capacity in patients with well-characterized COPD. These data suggest that inhaled corticosteroids can reduce recruitment and/or adhesion of neutrophils to the airways of COPD patients, thereby lowering the overall concentration of these cells in COPD airways.
Superficially, the present data on sputum eosinophils appear to be inconsistent with the known effect of corticosteroids in general on eosinophils. Many experiments have shown that eosinophils are exquisitely sensitive to corticosteroids [29, 30]. The current data, however, suggest otherwise. Several studies have demonstrated that among COPD patients with irreversible airflow obstruction (as was the case for a majority of patients enrolled in the original studies contained in this meta-analysis), eosinophils are present in relatively small quantities in the sputum of such patients [10, 31]. In most COPD patients, eosinophils account for less than 2% of the total cells in the sputum. This could have introduced a "floor" bias wherein the overall signal to the noise ratio for eosinophils may have been too small to detect subtle but important effect of inhaled corticosteroids on these cells. Although by combining data from these published studies we increased the power of the present analysis to detect salient changes in the inflammatory indices of the sputum, we may still have had insufficient power for analyses of cells with a relatively small signal. Our analysis may also have had insufficient power to assess the effects of inhaled corticosteroids on FEV1. Although there was a trend towards improvement, we did not find a statistically significant effect of inhaled corticosteroids on FEV1. Larger randomized trials have demonstrated, however, that inhaled corticosteroids significantly improve FEV1 over the first three to six months of therapy [25, 32–34], suggesting that for certain endpoints our present analysis still lacked sufficient power. Therefore, the "negative" associations must be interpreted cautiously. It is also important to note that none of the studies included in the present review evaluated the effects of inhaled corticosteroids on the function or performance of inflammatory cells in the airway. Thus, we can not discount the possibility that these medications could have salutary effects on the functional performance of these cells.
In the present review, we did not include randomized studies that used bronchoalveolar lavage (BAL) or bronchial biopsies to measure inflammatory cells in the airways. However, in one study, Balbi and colleagues  observed significant reductions in the total number of cells, neutrophil counts, IL-8, and myeloperoxidase levels in the BAL fluid of COPD patients after 6 weeks of inhaled beclomethasone therapy. A similar finding was observed and reported by Thompson and coworkers . In another experiment, Hattotuwa at al  randomly treated a group of COPD patients with 3 months of inhaled fluticasone propionate (1 mg/d) or placebo. The group that received fluticasone had significantly fewer mast cells in the subepithelial layer as well as a reduced ratio of CD8 to CD4 positive cells in the epithelial layer than those treated with placebo. Most importantly, the fluticasone group had significant improvements in cough and sputum scores and decreased use of reliever medications and experienced fewer exacerbations than did the placebo group . Verhoeven et al  evaluated 23 patients with COPD and randomly treated 10 patients to fluticasone (1 mg/d) and the remainder to placebo. After 6 months, fluticasone treatment resulted in a significant reduction in the number of MBP and CD68 positive cells in the lamina propria and reduced tryptase levels in the epithelium. In addition, there was a trend towards fewer CD3, CD4 CD68 positive cells in epithelium of the group treated with fluticasone compared with the group treated with placebo . The results from the BAL and bronchial biopsy studies largely support data from the sputum studies and are consistent with the notion that inhaled corticosteroids reduce airway inflammation in COPD.
We also did not include studies that used systemic corticosteroids. Barcyk and colleagues  have reported that oral prednisone therapy (0.5 mg/kg/d) for 2 weeks significantly reduced myeloperoxidase levels in the sputum of COPD patients. Brightling and colleagues  showed that 2 weeks of oral prednisone therapy resulted in fewer eosinophils in the sputum of COPD patients. Similar findings were reported by Fujimoto and colleagues . These data suggest that oral prednisone can reduce certain components of airway inflammation (e.g. eosinophils) in COPD; however, most of the studies were very short in duration, which makes it difficult to compare these data against those studies that used inhaled corticosteroids.
Although in the present review, we could not adequately determine the effects of tobacco smoke exposure on the relationship between inhaled corticosteroids and airway inflammation, there is a growing body of evidence to suggest that active smoking may attenuate the effectiveness of corticosteroids in suppressing airway inflammation. Active smoking increases oxidative stress and up-regulates the production of various pro-inflammatory cytokines including Il-6, IL-8, IL-1β and monocyte chemoattractant protein-1 in airways, which may through a series of complex pathways lead to a state of steroid resistance . Additionally, cigarette smoke may reduce histone deacetylase activity and its expression in alveolar macrophages, making these cells relatively resistant to corticosteroids since one of the principal targets of corticosteroid action is by switching off gene expression of inflammatory genes through the recruitment of histone deacetylases . Therefore smoking cessation remains the single most important intervention in COPD management. Inhaled corticosteroids should be considered as a possible adjunctive therapy in patients who remain symptomatic despite smoking cessation.
There are certain limitations with the present analysis. First, although we used stringent entry criteria in order to minimize the heterogeneity in the research methods employed by each of the selected study, there were still some variations in the study design, the exposure medications, and the target population across the original studies. However, the differences in the characteristics of the studies were relatively small and unlikely to have materially affected the overall findings of the current review. We also contacted the primary authors to clarify any ambiguities or to obtain additional data, where necessary, to further minimize the "noise" inherent to meta-analyses. Moreover, to accommodate various differences in the methodology of data collection and laboratory techniques employed across the original studies, we converted the individual data into standardized mean estimates, which enhanced the comparability of data across the original studies. Second, it is possible that corticosteroid therapy could have affected the volume of sputum recovery, decreasing the total sputum cell counts in those patients exposed to this therapy. To mitigate this possibility, the cell counts were expressed as cells per volume of sputum recovered.
In summary, the present meta-analysis suggests that inhaled corticosteroids when used for longer than 6 weeks can significantly reduce neutrophil counts and other inflammatory indices in the sputum of patients with stable COPD. Large randomized controlled trials are needed in the future to confirm these early findings and to determine whether these salutary effects persist longer than 3 to 4 months of therapy.
chronic obstructive pulmonary disease
- FEV1 :
forced expiratory volume in 1 second
forced vital capacity
standard deviationIL-8 interleukin-8
The authors thank Dr. Füsu Yildiz, Dr. Hisatoshi Sugiura, and Dr. Arzu Mirici for providing additional data for this study.
DDS is supported by a Canada Research Chair (Respiration) and a Michael Smith/St. Paul's Hospital Foundation Professorship in COPD.
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