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Clinical Investigations: INHALED STEROIDS |

A Randomized Controlled Trial on the Effect of Inhaled Corticosteroids on Airways Inflammation in Adult Cigarette Smokers* FREE TO VIEW

Gerard Cox, MB; Lori Whitehead, MD, FCCP; Myrna Dolovich, PEng; Manel Jordana, MD; Jack Gauldie, PhD; Michael T. Newhouse, MD, FCCP
Author and Funding Information

*From the Firestone Regional Chest and Allergy Unit (Drs. Cox, Whitehead, and Newhouse, and Ms. Dolovich), St. Joseph’s Hospital, Hamilton, Ontario, Canada; and the Department of Pathology (Drs. Jordana and Gauldie), McMaster University, Hamilton, Ontario, Canada.

Correspondence to: Gerard Cox, MB, Firestone Regional Chest and Allergy Unit, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, Ontario L8N 4A6, Canada; e-mail: coxp@fhs.csu.mcmaster.ca



Chest. 1999;115(5):1271-1277. doi:10.1378/chest.115.5.1271
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Study objective: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers.

Design: This was a randomized, placebo-controlled, double-blinded clinical trial.

Setting: The subjects were recruited from the community by advertising.

Participants: Seventy-one adults with a≥ 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily.

Intervention: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 μg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days.

Measurements and results: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment.

Conclusions: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 μg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.

Abbreviations: BDP = beclomethasone dipropionate; DTPA = diethylenetriamine pentaacetic acid; FEF25–75% = forced expiratory flow after 25 to 75% of vital capacity has been expelled; MDI = metered-dose inhaler; PC20 = concentration required to induce a 20% fall in FEV1; T1/2 = time needed to clear 50% of the inhaled DTPA initially deposited in the airways

Cigarette smoking is associated with neutrophilic inflammation of the airways and with lung parenchyma.1In 15 to 20% of smokers, this inflammation leads to the development of chronic bronchitis and emphysema.2Once established, these diseases tend to progress and treatment is largely supportive.3Despite the strong association between smoking and lung diseases, many adults continue their smoking habit.4The patients with established disease may respond to systemic corticosteroid therapy with a reduction in sputum production, and a minority of patients, about 5 to 15%, respond with an improvement in pulmonary function.56 Although many patients with mild-to-moderate chronic airflow limitation due to smoking-related diseases are treated with inhaled corticosteroids, there is conflicting evidence about the effectiveness of this form of therapy.78

Chronic airflow limitation is the functional result of airway and parenchymal lung damage that can be caused by the oxidant and proteolytic products of neutrophils.910 Persistent neutrophilic inflammation has been documented in the lungs and airways of smokers,1112 and this has prompted studies of treatment using immunomodulatory agents.13A dose-dependent relationship between smoking and airways inflammation has been documented,14as well as a reduction in the indexes of inflammation following the cessation of smoking.15The examination of spontaneous16 or induced1718 sputum has been described, and this method provides a noninvasive and repeatable means to survey airways inflammation. The sputum of subjects with chronic bronchitis contains increased neutrophils, in contrast to the characteristic eosinophilic inflammation seen in subjects with a similar airflow obstruction due to asthma.16 Because the production of neutrophil chemoattractants and survival stimuli by the structural cells of the respiratory tract are inhibited by corticosteroids,1920 and because inhaled corticosteroids can control eosinophilic inflammation and can prevent the development of chronic airflow limitation,7,2122 we postulated that the neutrophilic inflammation due to cigarette smoking might also respond to this intervention. We investigated the effect of 4 weeks of treatment with inhaled beclomethasone diproprionate (BDP), 500 μg bid, on noninvasive measures of airways inflammation in adults with a moderate smoking history and no airflow obstruction. Because airflow limitation due to smoking is largely irreversible once it has become established, we chose to study subjects in the early phase of this condition (with inflammation of the airways but without extensive structural injury). The study was randomized, double blinded, and placebo controlled with 30 subjects in each group. The hypothesis behind this intervention was reduction of the extent of airways inflammation as assessed by the examination of sputum, the responsiveness to a methacholine challenge, and the epithelial clearance of radiolabeled diethylenetriamine pentaacetic acid (DTPA) in the airways.

Subjects

Subjects who were current smokers and had a daily cough productive of sputum were recruited from the community through newspaper and poster advertisements. The subjects were not receiving any other form of anti-inflammatory or inhaled therapy. The inclusion criteria included the following: (1) a smoking habit of ≥ 5 but< 20 pack-years (1 pack-year is an average of 25 cigarettes daily for 1 year), thus excluding those subjects having large smoke exposure but few respiratory consequences, as they would have a very low risk of ever developing a chronic airflow limitation; (2) an agreement by the subject not to change his/her smoking pattern until the study was completed; (3) a vital capacity of 75 to 125% of predicted, and an FEV1 of > 70% of predicted; (4) no history of asthma, no previous use of inhaled or ingested corticosteroids, and no history of an illness that would require inhaled or ingested corticosteroids; (5) daily production of sputum; and (6) an age between 18 and 50 years old. The subjects were excluded if they had the following: (1) a history of variable symptoms, breathlessness, wheeze, or cough that suggested asthma; (2) an increase of ≥ 15% in the FEV1 after bronchodilator therapy; (3) were unable to comply with the study schedule or the medication use; and (4) a change in symptoms suggesting an upper respiratory tract infection during the last 4 weeks prior to recruitment.

The study was approved by the St. Joseph’s Hospital Research Committee, and informed consent was given by all of the subjects.

Study Design

Following their identification by telephone contact, the subjects were assessed at a screening visit using a symptom questionnaire, a physical examination, and spirometry before and after the administration of 100 μg of inhaled salbutamol. After they signed informed consent documents, the subjects were instructed in the correct use of a metered-dose inhaler (MDI) equipped with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) to minimize the likelihood of local steroid side effects and to ensure the delivery of the drug. A placebo inhaler was provided to all subjects. The subjects were instructed to rinse their mouths after using the MDI, and they were advised to make up for any single missed doses within 24 h by taking an additional dose at midday. Two weeks later, on study day −2, the subjects were reviewed. Compliance was evaluated by reviewing the subject’s diary and by weighing the placebo MDI. A compliance of > 80% was required before the subject could proceed to randomization. The randomization schedule was generated in blocks of four, and the code was held by the hospital pharmacist. After randomization, treatment with inhaled BDP, 250 μg/puff at 2 puffs bid, or a matching placebo was started on study day 0 and continued for 28 days. This dose was selected to deliver a quantity of drug sufficient to exert anti-inflammatory effects and not to produce systemic side effects.23 The effective aerosol technique was confirmed by the study personnel. The subjects were reviewed at 2 weeks to monitor the use and inhalation of the study drug and to look for evidence of side effects. The subjects were advised to contact the study team in the event of sore throat, hoarseness, flu-like illness, or other change in the respiratory state. The subjects were asked not to change their brand of cigarette or their smoking habit during the study; compliance was assessed using a questionnaire at the review visit and upon exit from the study.

Airways Measurements, Sputum Examination, and Bronchial Provocation Tests

Sputum was obtained on the 3 consecutive days prior to the start of the study (study days −2, −1, and 0) and on the last 3 days of treatment (study days 26, 27, and 28). The samples were processed as previously described.16 In brief, sputum plugs were selected to avoid salivary contamination, and smears were prepared. After air-drying, the slides were fixed in methanol and stained with May-Grünwald-Giemsa stains. After coding, the samples were evaluated by the same observer, who remained masked as to their source. On study day −1, a sample of sputum was also induced by consecutive inhalations of saline solution at 3%, 4%, or 5% delivered using an ultrasonic nebulizer (Medix; Clement Clarke International; Essex, UK).24 Each solution was inhaled for 5 min and was repeated once before using the next higher concentration, to a maximum of six inhalations. A sputum sample was requested and spirometry (Spirolite 201; Medical Systems; Greenvale, NY) was performed after each inhalation. The procedure was stopped if the FEV1 fell by 20%. Because it was anticipated that the steroid treatment might reduce sputum production, it was proposed to obtain induced samples on study day 27 if spontaneous samples could not be obtained.

During the six visits, spirometry was used to measure the FEV1, as well as forced expiratory flow after 25 to 75% of vital capacity was expelled (FEF25–75%), expressed as a percentage of predicted. At the first visit, spirometry was also repeated 15 min after the administration of 100 μg inhaled salbutamol. On study days 0 and 28, the bronchial responsiveness to inhaled methacholine was assessed using doubling concentrations, each inhaled during tidal breathing for 2 min (to a maximum of 256 mg/mL), as previously described.25 The results are expressed as the concentration required to induce a 20% fall in the FEV1 (PC20).

The pulmonary clearance of radiolabeled DTPA (99mTc-DTPA) was measured on study days −1, 0, 27, and 28, as previously described.26Aerosolized DPTA droplets (mass median aerodynamic diameter, 0.65 μm; geometric SD, 1.6) were generated (Ultravent Aerosol System; Mallinckrodt Medical; St. Louis, MO) and inhaled over 15 min by tidal breathing. The lung transepithelial clearance was measured and expressed as the time needed to clear 50% of the inhaled DTPA initially deposited in the airways (T1/2). This is a nonspecific but sensitive measure of the permeability of the mucosal surfaces of the lower respiratory tract.27Active smokers with a normal airflow typically have markedly accelerated rates of clearance, and these rates have been shown to return toward normal from 1 to 6 weeks after the smoker has stopped smoking.2829

Statistical Analysis

The sample size was calculated with an anticipated 50% fractional reduction of sputum neutrophils as having clinical significance. The alpha error was specified at 0.05 and the beta error at 0.2, so that a minimum of 28 patients were required in each group.

The results were expressed as the mean (± SD) or mean (± SEM) where indicated. The changes over the period of treatment were calculated by subtracting the pretreatment from the posttreatment values. The primary outcome measure was the change in sputum neutrophilia observed in the BDP-treated group compared to the change seen in the placebo-treated group. Secondary outcomes included (1) the change in lung mucosal permeability, (2) the change in bronchial responsiveness to inhaled methacholine, and (3) the change in midexpiratory flow rates. The differences between the treatment group and the control group were analyzed using an unpaired Student’s t test except where noted, and statistical significance was accepted at a p value of< 0.05.

A total of 71 subjects completed the screening visit. Subsequently, 11 of the 71 subjects were not entered into the study because of poor compliance; 8 subjects did not take the inhaled medication as directed, and 3 were not able to attend the required assessment visits as scheduled. Sixty subjects, therefore, were randomized in the study. The demographic variables of the subjects in both groups are shown in Table 1 and are presented as mean (± SD). The groups were comparable with respect to age, gender, smoking history, severity of symptoms, and pulmonary function. There were trends toward differences between the groups that did not reach statistical significance, including a slightly longer smoking history and more symptoms of chronic bronchitis in the actively treated group, and a slightly lower FEV1 in the placebo group. Sputum production was an entry criterion for the study, but not all of the subjects had sputum production consistently for 90 consecutive days in each of the prior 2 years; therefore, these subjects were deemed not to have chronic bronchitis.

Pulmonary Function

The treatment had no effect on the measures of airflow. The FEF25–75%, expressed as a percentage of predicted, was similar in the two groups at baseline. This measure did not change significantly over time in either group, as shown in Table 2 . This measurement was highly reliable, as there was little difference in the results obtained on consecutive days.

One subject had a recorded PC20 of 9 mg/mL that was below the normal range; in our laboratory, this measure falls within the borderline abnormal range. This finding indicates that our clinical description and criteria successfully excluded the subjects with bronchial hyperreactivity and symptoms due to asthma. There were no differences in the mean PC20 of the groups before or after treatment. The PC20 could not be precisely determined in > 40% of the subjects in both groups because it exceeded 256 mg/mL. Using the criterion of doubling or halving the PC20 did not reveal any differences between the groups either; in the placebo group, three PC20 measures increased and two decreased, whereas in the treatment group, three PC20 measures increased and three decreased.

Sputum Cellularity

At baseline, the mean percentage (± SEM) of neutrophils in the spontaneously produced sputum was comparable in the placebo and treatment groups, respectively: 26.3 ± 3.6% vs 20.6 ± 3.5% (n = 28; p = 0.26; Table 3 ). When comparing sputum samples obtained on the same day (study day− 1), the induced sputum consistently yielded higher mean proportions (± SD) of neutrophils than the spontaneously produced sputum, respectively: 46.2 ± 21.2% vs 27.1 ± 24% (n = 34; p < 0.01). However, because all of the subjects could produce sputum spontaneously at the end of the treatment period, it was not necessary to obtain induced samples. Four weeks of BDP therapy did not affect the proportion of neutrophils found in the sputum (Table 3). Four weeks of placebo therapy did not affect the proportion of neutrophils found in the sputum either, indicating the stability of this measurement over time, as has been found previously.18

In the treatment group, the mean initial levels (± SEM) of eosinophil were higher than the levels seen after treatment, respectively: 1.16 ± 0.46% vs 0.42 ± 0.06% (p > 0.05). Again, these data suggest that we successfully excluded subjects with asthma from our study, and the trend of change is consistent with the expected effect of treatment with inhaled corticosteroids.

Lung Permeability

Similar to previous studies in smokers, our subjects (n = 60) showed a rapid clearance of inhaled DTPA with a mean T1/2 value (± SD) of 36.1 ± 13.7 min. In our laboratory, the normal value for T1/2 is 115 ± 40 min. We found excellent repeatability for this measurement made on two separate occasions (before treatment and after treatment); the mean T1/2 values (± SD) obtained on study day −1 and study day 0 were similar, respectively: 36.8 ± 13.2 vs 35.5 ± 14.3 min. There was no difference between the two groups at baseline (Table 4 ). Active treatment with BDP did not alter the rates of clearance significantly, and there was no difference between the two groups as a result of BDP treatment.

Compliance and Side Effects

No treatment side effects were encountered. None of the subjects complained of increased cough due to inhaler use or of sore throat suggesting oropharyngeal candidiasis. Compliance during the 28-day study period, as assessed using subject diaries and the weighing of aerosol canisters at study days 14 and 28, was > 80% for all of the subjects.

In this study, the regular use of inhaled corticosteroids at a moderate dosage (the equivalent of 15 to 20 mg of prednisone po) did not alter the host response to cigarette smoking as compared to the placebo therapy. The administration of 1,000 μg of inhaled BDP is an effective therapy for airways inflammation due to asthma. This dose is associated with local drug concentrations in the airways of up to 10−7 mol/L.30 Under the conditions of adequate compliance that were apparent with the prescribed study medication, we conclude that this formulation of inhaled corticosteroid therapy is not effective in reducing pulmonary inflammation caused by smoking.

The two groups were similar following their assignment by randomization. There were no major differences between the groups for any of the relevant variables. Minor differences included a higher proportion of subjects in the treatment group who had chronic bronchitis by definition. This difference is not likely to have contributed to the negative outcome seen with the active treatment, particularly as such symptoms have been shown to be ameliorated by corticosteroid treatment. Both groups had an approximately equal history of prior and current cigarette consumption. Similarly, there were no changes in the reported cigarette consumption over the course of the study; but, because we did not include an objective measurement of active cigarette smoking, possible changes in cigarette consumption could not be confirmed. We would expect, however, that such changes would be equally frequent in both groups.

Despite the reported compliance and the dose prescribed, it is possible that the lack of treatment effect is dose related. Under various clinical situations with inhaled medications, compliance rates of from 30 to 70% have been reported, but these percentages appear to increase when the subjects are aware that their compliance is being monitored.31 Without using an electromechanical counter in the MDI, it is impossible to be certain of when compliance has been achieved, as incidents of “dumping” of aerosol prior to follow-up visits have been noted.

We chose a BDP dosage of 1,000 μg/d based on reports in the literature and on our experience with steroid treatment of lung cells in vitro.1921 For the management of patients with an eosinophilic inflammation of the airways due to asthma, BDP, 1,000 μg/d, is effective in reducing the symptoms and the pathologic severity of the disease.21 Also, the control of asthma with such a regimen is associated with an improvement in bronchial responsiveness, as assessed by a methacholine challenge.32 In subjects with mild airflow obstruction and chronic bronchitis due to cigarette smoking, BDP, 1,000 μg/d, was reported to improve spirometry measures and to reduce the visual appearance of airways inflammation at bronchoscopy.33 Drug concentrations in the airways in the range of 10−8 to 10−7 mol/L are well within the effective range for corticosteroid effects on lung cells in vitro.,30 Processes such as alveolar macrophage production of the neutrophil chemoattractant interleukin-1 (interleukin-8), epithelial cell production of interleukin-8, and neutrophil survival factors (granulocyte- and granulocyte-macrophage colony-stimulating factors), are inhibited by corticosteroids at these concentrations.1920,3435

The role of inhaled steroid therapy in chronic lung diseases caused by cigarette smoking remains to be clearly defined. Such a therapy appears plausible and can be promoted on the basis of in vitro findings; however, there is conflict among the few rigorously performed clinical studies that address this issue.3637 We chose to study subjects with symptoms of bronchitis and a normal FEV1. These subjects had an established smoking habit but no clinically significant impairment of airflow. As noted previously,38 many of the subjects had reduced midexpiratory flow rates; however, in our study, even this sensitive measure failed to improve with steroid treatment. In a previous report,33 a similar treatment with inhaled corticosteroids improved the midexpiratory flow rates and diminished the appearance of airways inflammation seen at bronchoscopy. In that study, the subjects had a greater smoking history, an established mild airflow obstruction (an FEV1/vital capacity ratio of < 75%), and midexpiratory flow rates that were approximately half of what was found in our group, respectively: 37 to 43% of predicted vs 75 to 80% of predicted. Although the treated group showed a spirometric improvement in FEV1 and FEF25–75%, as well as a minor reduction in the bronchitis index (the appearance of the mucosa at bronchoscopy), the changes in the inflammatory indexes were less convincing. In fact, had the placebo-treated group not shown a deterioration in the bronchial cell count and the lactoferrin, albumin, and lysozyme levels, the differences between the groups would not have been statistically significant. Thus, the laboratory measures of inflammation did not correlate at all with the functional or subjective assessments of bronchial inflammation, leaving open to question the mechanism of the observed improvements. Of note is that the primary outcome of our study (that there is no reduction in neutrophil counts in the airways in response to inhaled steroids) is similar to what was previously reported,33 using BAL samples.

Two recently published studies3940 of inhaled steroid treatment in established disease have yielded divergent conclusions. In a large multicenter study,39the administration of 500μ g of fluticasone propionate bid for 6 months led to modest improvements in symptoms, airflow, and exercise capacity when compared with placebo. The treated patients also had less severe exacerbations of their disease. In a study40 of patients with more advanced obstructive airways disease (a mean FEV1 of < 1,000 mL), the use of budesonide, 1,600 μg/d, for 6 months was not associated with an improvement in airflow or exercise capacity; 17 of 96 subjects were excluded from the study when they showed an improvement in airflow with oral prednisone.

The potential contribution of nonspecific bronchial hyperresponsiveness to the development of COPD has been considered for some time, initially as part of “the Dutch hypothesis”41; more recent epidemiologic studies42 have documented a negative correlation between airflow and the level of bronchial responsiveness. It is also possible that nonspecific bronchial hyperreactivity might result from smoking-induced airways inflammation; therefore, it would be expected to diminish if the inflammation is successfully treated, as has been shown with the appropriate management of asthma.32,43 We performed a bronchial challenge with methacholine at doses of up to 256 mg/mL. There was no appreciable change in either the number of subjects showing improvement or in the mean PC20 of the subjects receiving active treatment.

In inflammatory diseases of the pulmonary parenchyma, such as sarcoidosis and pulmonary fibrosis, steroid therapy is based on the concept that it can reduce inflammation, improve pulmonary function, and slow the progression of the disease. Lung epithelial permeability is typically increased in these conditions and is usually improved to some extent by steroid treatment, although it usually remains abnormal.4445 Also, we know from studies2829 of smokers that lung permeability is markedly increased but can return to normal over a 4-week period after smoking has ceased. However, our study failed to show any improvement in lung permeability after treatment with inhaled corticosteroids. This negative outcome is consistent with the lack of change we report in the other measures of airways inflammation.

The negative outcomes we observed may be explained in a number of ways. Perhaps the drug was ineffective because it was delivered mainly to the proximal airways, whereas the disease is present in the distal and smaller airways and in the alveoli. Imaging with radiolabeled BDP was not performed, but ventilation images obtained with 99mTc-DTPA, which has a smaller particle size than BDP, appeared to be uniform and were similar to normal scans from our laboratory.26 This suggests that the deposition of the inhaled drug should have been relatively unaffected by the differences in the host airway function. Perhaps the use of a BDP formulation having a smaller particle size would have led to a more effective intervention.46Alternatively, the stimulus provided by cigarette smoke in vivo is more potent than we expected, so that higher doses or the use of more potent agents such as fluticasone propionate are required to inhibit inflammatory responses. It is also possible that, despite encouraging data from in vitro studies, the inflammation induced by cigarette smoke in vivo has a different mechanism, so that it is resistant to inhibition by corticosteroids. We showed recently47 that neutrophil survival is increased by corticosteroid treatment. This effect is in marked contrast to our experience with other leukocytes, especially eosinophils,19 and it provides at least a partial explanation for the persistence of airway neutrophilia in spite of corticosteroid treatment. There are now a number of reports68,22,33,3637,3940,48 examining pulmonary inflammation in patients having a range of severity of lung disease caused by cigarette smoking. Despite some encouraging clinical experience showing modest improvements in airflow obstruction and reductions in the severity of exacerbations in a subgroup of subjects with mild or moderate airflow obstruction, the accumulated evidence indicates that corticosteroids are largely ineffective in reducing neutrophil-mediated inflammation. The relationship between inflammation and function remains to be clarified through careful studies of the mechanisms of effective treatments in these diseases.

Dr. Cox was supported by a Glaxo Wellcome research fellowship and is supported by the Fr. Sean O’Sullivan Research Center.

Table Graphic Jump Location
Table 1. Patient Characteristics*
* 

Data are presented as mean (± SD). For all subjects, FEV1 was > 70% of predicted and FVC was between 75% and 125% of predicted. None of the differences between the groups were statistically significant.

Table Graphic Jump Location
Table 2. Midexpiratory Flow Rates*
* 

Data are presented as mean (± SD) of the percent predicted FEF25–75%. The mean expiratory flow rates were reduced in these subjects, but there were no statistically significant differences between the groups at baseline or after treatment.

Table Graphic Jump Location
Table 3. Neutrophils in Spontaneous Sputum Samples*
* 

The proportion of neutrophils was measured in spontaneously produced samples obtained on 3 consecutive days before and at the end of the treatment period. The average of these three results was taken, and data are reported as mean ± SEM. The samples from two subjects in either group were unsuitable for interpretation because of excessive degradation of cells. In another subject in the active treatment group, the posttreatment sample was unusable. The difference between the groups at baseline was not statistically significant (p = 0.26), and there was no effect of active treatment on sputum neutrophilia.

Table Graphic Jump Location
Table 4. Clearance of DTPA in Minutes*
* 

The data are given for T1/2. The clearance of radiolabeled DTPA was measured on 2 separate days before treatment and at two visits after treatment. These baseline and posttreatment values were averaged and are reported as mean ± SEM. There was no difference between the groups at baseline, and while there was a slight improvement in both groups over the course of the study, this was not statistically significant (p = 0.67), and the degree of improvement was similar in both groups.

ACKNOWLEDGMENT: We are grateful for the technical assistance of Mona Sabry, Carole Chambers, and Michael Mazza. We appreciate the assistance of Dr. Charles Goldsmith and Eric Duku with data analysis.

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Kerstjens, HAM, Brand, PLP, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid for obstructive airways disease.N Engl J Med1992;327,1413-1419. [PubMed]
 
Keatings, VM, Jatakanon, A, Wordsell, M, et al Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD.Am J Respir Crit Care Med1997;155,542-548. [PubMed]
 
Seely, JE, Zuskin, E, Bouhuys, A Cigarette smoking: objective evidence for lung damage in teen-agers.Science1971;172,741-743. [PubMed]
 
Paggiaro, PL, Dahle, R, Bakran, I, et al Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease.Lancet1998;351,773-780. [PubMed]
 
Bourbeau, J, Rouleau, MY, Boucher, S Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease.Thorax1998;53,477-482. [PubMed]
 
Orie, NG, Sluiter, HJ, De Vries, K, et al The host factor in bronchitis. Orie, NG Sluiter, HJ eds.Bronchitis1961,43-59 Royal Vangorcum. Assen, the Netherlands:
 
Tashkin, DP, Altose, MG, Bleeker, ER, et al The Lung Health Study: airways responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation.Am Rev Respir Dis1992;145,301-310. [PubMed]
 
O’Connor, GT, Sparrow, D, Weiss, ST The role of allergy and nonspecific bronchial hyperresponsiveness in the pathogenesis of chronic obstructive pulmonary disease.Am Rev Respir Dis1989;140,225-252. [PubMed]
 
Rinderknecht, J, Shapiro, L, Krauthammer, M Accelerated clearance of small solutes from the lungs in interstitial lung disease.Am Rev Respir Dis1980;121,105-117. [PubMed]
 
Jacobs, MP, Baughman, RP, Hughes, J, et al Radioaerosol clearance in patients with active pulmonary sarcoidosis.Am Rev Respir Dis1985;131,687-689. [PubMed]
 
Leach, C Enhanced drug delivery through reformulating MDI’s with HFA propellants: drug deposition and its effects on preclinical and clinical programs. Dalby, RN Byron, PR Farr, ST eds.Respiratory drug delivery V1996,133-144 Interpharm Press. Buffalo Grove, IL:
 
Cox, G Glucocorticoid treatment inhibits apoptosis in human neutrophils: separation of survival and activation outcomes.J Immunol1995;154,4719-4725. [PubMed]
 
Renkema, TE, Schouten, JP, Koeter, GH, et al Effects of long-term treatment with corticosteroids in COPD.Chest1996;109,1156-1162. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Patient Characteristics*
* 

Data are presented as mean (± SD). For all subjects, FEV1 was > 70% of predicted and FVC was between 75% and 125% of predicted. None of the differences between the groups were statistically significant.

Table Graphic Jump Location
Table 2. Midexpiratory Flow Rates*
* 

Data are presented as mean (± SD) of the percent predicted FEF25–75%. The mean expiratory flow rates were reduced in these subjects, but there were no statistically significant differences between the groups at baseline or after treatment.

Table Graphic Jump Location
Table 3. Neutrophils in Spontaneous Sputum Samples*
* 

The proportion of neutrophils was measured in spontaneously produced samples obtained on 3 consecutive days before and at the end of the treatment period. The average of these three results was taken, and data are reported as mean ± SEM. The samples from two subjects in either group were unsuitable for interpretation because of excessive degradation of cells. In another subject in the active treatment group, the posttreatment sample was unusable. The difference between the groups at baseline was not statistically significant (p = 0.26), and there was no effect of active treatment on sputum neutrophilia.

Table Graphic Jump Location
Table 4. Clearance of DTPA in Minutes*
* 

The data are given for T1/2. The clearance of radiolabeled DTPA was measured on 2 separate days before treatment and at two visits after treatment. These baseline and posttreatment values were averaged and are reported as mean ± SEM. There was no difference between the groups at baseline, and while there was a slight improvement in both groups over the course of the study, this was not statistically significant (p = 0.67), and the degree of improvement was similar in both groups.

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Kerstjens, HAM, Brand, PLP, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid for obstructive airways disease.N Engl J Med1992;327,1413-1419. [PubMed]
 
Keatings, VM, Jatakanon, A, Wordsell, M, et al Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD.Am J Respir Crit Care Med1997;155,542-548. [PubMed]
 
Seely, JE, Zuskin, E, Bouhuys, A Cigarette smoking: objective evidence for lung damage in teen-agers.Science1971;172,741-743. [PubMed]
 
Paggiaro, PL, Dahle, R, Bakran, I, et al Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease.Lancet1998;351,773-780. [PubMed]
 
Bourbeau, J, Rouleau, MY, Boucher, S Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease.Thorax1998;53,477-482. [PubMed]
 
Orie, NG, Sluiter, HJ, De Vries, K, et al The host factor in bronchitis. Orie, NG Sluiter, HJ eds.Bronchitis1961,43-59 Royal Vangorcum. Assen, the Netherlands:
 
Tashkin, DP, Altose, MG, Bleeker, ER, et al The Lung Health Study: airways responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation.Am Rev Respir Dis1992;145,301-310. [PubMed]
 
O’Connor, GT, Sparrow, D, Weiss, ST The role of allergy and nonspecific bronchial hyperresponsiveness in the pathogenesis of chronic obstructive pulmonary disease.Am Rev Respir Dis1989;140,225-252. [PubMed]
 
Rinderknecht, J, Shapiro, L, Krauthammer, M Accelerated clearance of small solutes from the lungs in interstitial lung disease.Am Rev Respir Dis1980;121,105-117. [PubMed]
 
Jacobs, MP, Baughman, RP, Hughes, J, et al Radioaerosol clearance in patients with active pulmonary sarcoidosis.Am Rev Respir Dis1985;131,687-689. [PubMed]
 
Leach, C Enhanced drug delivery through reformulating MDI’s with HFA propellants: drug deposition and its effects on preclinical and clinical programs. Dalby, RN Byron, PR Farr, ST eds.Respiratory drug delivery V1996,133-144 Interpharm Press. Buffalo Grove, IL:
 
Cox, G Glucocorticoid treatment inhibits apoptosis in human neutrophils: separation of survival and activation outcomes.J Immunol1995;154,4719-4725. [PubMed]
 
Renkema, TE, Schouten, JP, Koeter, GH, et al Effects of long-term treatment with corticosteroids in COPD.Chest1996;109,1156-1162. [PubMed]
 
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