CLINICAL PHARMACODYNAMICS

Clin Drug Invest 2001; 21 (12): 835-842 1173-2563/01/0012-0835/$22.00/0 © Adis International Limited. All rights reserved.

Effect of Inhaled Corticosteroids on Respiratory Function Tests and Airway Inflammation in Stable Chronic Obstructive Pulmonary Disease A Randomised, Double-Blind, Placebo-Controlled Clinical Trial A. Mirici,1 Y. Bektas,1 G. Ozbakis2 and Z. Erman3 1 Chest Diseases Department, Faculty of Medicine, Atatürk University, Erzurum, Turkey 2 Pharmacology Department, Faculty of Medicine, Atatürk University, Erzurum, Turkey 3 Pathology Department, Faculty of Medicine, Atatürk University, Erzurum, Turkey

Abstract

Objective: To evaluate the efficacy of inhaled budesonide 400μg twice daily in the treatment of stable chronic obstructive pulmonary disease (COPD). Design and Setting: Randomised, placebo-controlled, double-blind, parallelgroup study. Patients: 40 patients with stable COPD. Interventions: The patients were randomised to receive either inhaled budesonide 400μg twice daily or placebo in the same form for 12 weeks. Spirometry and sputum cell analysis were performed both at baseline and post-treatment. Results: There were no significant differences between groups at baseline. At the end of the study, there was a trend to a decreased total sputum cell count in the group receiving budesonide, with a reduced proportion of neutrophils (p < 0.001) and an increased proportion of macrophages. The increase from baseline in the proportion of macrophages reached significance (p < 0.001) when compared with that in the placebo group [5.9% versus 0.4%, 95% confidence interval (CI) of difference 3.4 to 7.6%]. A significant increase compared with controls was also determined for forced vital capacity (9.0% versus 1.2%, p < 0.001, 95% CI of difference 4.6 to 10.9%) and forced expiratory volume in 1 second (7.4% versus 0.7%, p < 0.01, 95% CI of difference 2.1 to 11.2%). Conclusions: The efficacy of inhaled corticosteroids in COPD remains controversial. In this study, it was determined that inhaled budesonide improves airway inflammation and pulmonary function. Although these effects do not represent a clinically significant improvement, inhaled corticosteroids may be useful in COPD because of their superior adverse effect profile.

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Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease that is characterised by the presence of airflow obstruction resulting from chronic bronchitis and/or emphysema.[1,2] However, this definition explains only the functional mechanism of the disease. It has been stressed in the GOLD (Global Initiative for Chronic Obstructive Lung Disease) definition[3] that COPD originates from an abnormal inflammatory response to harmful agents. Although the presence of inflammation in COPD has been known for a long time, investigation of the details of this mechanism and its role in the pathogenesis of the disease has received increased attention in recent years. The three basic inflammatory cells are neutrophils, macrophages and T lymphocytes. It is known that in COPD inflammation on the surface epithelium of the lungs, in which neutrophils and macrophages on airways have a primary role, develops in response to irritating substances inhaled via the airways.[4,5] It has been shown that there are increased numbers of neutrophils in biopsy material from the bronchial walls in chronic bronchitis with or without the presence of obstructions. It has been reported that as airflow obstruction develops, T lymphocytes and neutrophils increase on the surface epithelium, and T lymphocytes and macrophages increase on the subepithelium.[5,6] Inflammation of the airways, remodelling of airways developing during the process of inflammatory repair and parenchymal destruction form the mechanisms of COPD pathology. Inflammation is the basis of functional loss. Continuing exposure to irritating substances is responsible for repeated inflammation-repair processes.[6,7] The use of anti-inflammatory therapy seems to be logical based on the clear evidence for the role of inflammation in COPD. Corticosteroids are the main anti-inflammatory agents used in the treatment of COPD and asthma. In fact, corticosteroids are known to increase peripheral neutrophil counts, but it is unclear whether this is true for neutrophils in lungs.[7] The observation that increased numbers of neutrophils and eosinophils are detected during © Adis International Limited. All rights reserved.

Mirici et al.

acute exacerbations of COPD and that acute exacerbations respond to corticosteroids suggest that corticosteroids are also effective on lung neutrophils. Moreover, it has also been reported that corticosteroids increase the β-adrenergic response and decrease pulmonary vascular resistance.[8] In this study, the effect of inhaled corticosteroid therapy on airway inflammation and lung function tests was investigated in patients with moderate-tosevere stable COPD. Patients and Methods Study Population

This study was performed in stable COPD patients admitted to the outpatient clinic of the Chest Diseases Department for routine follow-up. This double-blind, placebo-controlled, randomised parallel group trial was performed over the year from September 1999 to August 2000. Individuals with a forced expiratory volume in 1 second (FEV1) <70% of predicted with no selfreported asthma were referred to this study for further screening. Inclusion criteria were: FEV1 <70%, FEV1 reversibility after inhalation of terbutaline from a Turbuhaler® 1 of less than 15% of prebronchodilator FEV1. All patients were smokers who refused or failed a programme to quit smoking. The exclusion criteria were long-term treatment with oral or inhaled corticosteroids within 6 months of study entry, a respiratory tract infection in the previous 3 months, pregnancy or lactation, and the presence of other serious systemic diseases. The study protocol was approved by the local ethics committee at the Research Hospital of the Faculty of Medicine. Patients provided written informed consent before inclusion in the study. Study Design and Procedures

Lung function in all patients was measured by a 1 Trade name is used for identification purposes only and does not imply product endorsement. Clin Drug Invest 2001; 21 (12)

Inhaled Corticosteroids in Stable COPD

computerised spirometer. First airway obstruction was confirmed, then FEV1 reversibility in response to terbutaline was tested. Eligible patients were randomly allocated to either inhaled budesonide or placebo. Budesonide was given as 400μg in the morning and 400μg in the evening for 12 weeks. Medication was provided in a Turbuhaler® as budesonide powder for inhalation (200μg per dose, 200 doses). Placebo was administered in a Turbuhaler® as lactose powder for inhalation (200μg per dose, 200 doses). All inhalers had the same appearance and did not have drug labels. Randomisation was masked and case numbers were allocated in consecutive order. The randomisation sequence was computer-generated at the Research Centre of the Faculty of Medicine. The randomisation code was hidden by that centre and was not available to the researchers until the study had been completed. β2-Agonists of all kinds, theophylline and mucolytics were allowed. Inhaled corticosteroids other than study medication and oral or parenteral corticosteroids were not allowed. Patients were seen every 2 weeks. At each visit, measurements of spirometric indices and a physical examination were carried out. Patients who had an acute attack were withdrawn (an acute attack was defined as an unusual increase in cough and phlegm). Spirometry

Spirometric measurements were performed with a computerised spirometer (SensorMedics Vmax22) according to the American Thoracic Society specification and reference values were taken from the ECSC (European Coal and Steel Committee). The measurements of spirometric indices [vital capacity (VC), forced vital capacity (FVC), FEV1, and maximum mid-expiratory flow rate (FEF25-75)] were recorded as absolute units and as percentages of predicted values. Sputum Induction and Analysis

Sputum induction and analysis were done as previously described. [9] Briefly, sputum was induced by inhalation of an aerosol of 3% NaCl © Adis International Limited. All rights reserved.

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generated by an ultrasonic nebuliser. The aerosol was inhaled for 6 to 7 minutes. Before the procedure, patients were asked to rinse their mouths with water and attempt to cough sputum into a sterile container. Spirometric evaluations were done before and after the procedure. Before the procedure, inhaled terbutaline was given to subjects whose FEV1 was under 60%. After the procedure, FEV1 measurements were repeated. No complaints were noted from the patients either during or after the procedure. Sputum samples were examined within 1 hour. Sputum quality was assessed and selected under a microscope for the more viscous portions. Total cell counts were performed and 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 pathologists. These procedures were repeated on three consecutive days. The results were reported as the mean of all counts (two pathologists and three days). All spirometric indices and sputum cell analysis were performed at baseline and after treatment, blind to the clinical details. Data Analysis

Spirometric evaluation was recorded as a percentage of predicted and absolute values. Group data were expressed as mean ± standard deviation (SD). The effects of inhaled corticosteroids on functional and inflammatory indices and differences between the groups were evaluated by Student’s t-test, the chi-square test and by 95% confidence intervals (CI). Statistical significance was defined as p < 0.05. Results

Fifty individuals were included as a result of the initial screening. All patients were assigned to treatment as shown in figure 1. Ten patients withdrew from the trial, five from the budesonide group and five from the placebo group. Two patients in the study group and one patient in the placebo group were withdrawn because of acute attacks. In total, seven patients discontinued the study for Clin Drug Invest 2001; 21 (12)

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Mirici et al.

96 admitted and examined 15 without obstructive lung function

81 with obstructive lung function 11 excludeda

70 eligible for reversibility test 16 reversible

54 irreversible to β2-agonist 4 excludeda

50 recruited and randomised

25 assigned and received budesonide

25 assigned and received placebo

5 withdrew 2 acute attacks 1 not admitted 1 other

20 completed trial

5 withdrew 1 acute attack 3 not admitted 1 other

The proportion of neutrophils as a percentage of total cell count decreased in all patients. In the study group, there was a statistically significant decrease in the proportion of neutrophils and a statistically significant increase in the proportion of macrophages. The mean final percentage of sputum neutrophils was 69% in the treatment group and 70% in the control group. The mean final percentage of sputum macrophages was 24% in the treatment group and 21% in the control group. At the end of the study, the changes between groups for macrophages were significant (5.9% versus 0.4%, p < 0.001, 95% CI of difference 3.4 to 7.6%) and were not significant for neutrophils (−6.4% versus −3.6%, p > 0.05, 95% CI of difference −9.5 to 3.8%). A statistically significant increase was also determined in the spirometric values of the study group after treatment. However, these increases did not reach 10%. The increase in FVC was 9.0% (from 58.3% to 67.3%, 95% CI 6.3 to 11.6%) and the increase in FEV1 was 7.4% (from 64.1% to 71.5%, 95% CI 3.3 to 11.5%). However, when compared with the control group, increases in the rates of lung function were statistically significant for FEV1 (7.4% versus 0.7%, p < 0.01, 95% CI of difference 2.1 to 11.2%) and FVC (9.0% versus 1.2%, p < 0.001, 95% CI of difference 4.6 to 10.9%).

20 completed trial Table I. Patient characteristics at baseline. All differences between the groups were nonsignificant (p > 0.05)

a Patients excluded because they did not want to participate.

Fig. 1. Trial profile.

various reasons not related to COPD. Forty patients completed the study. There were no significant differences between the study and placebo groups at baseline (table I). The results of treatment are summarised as pre- and post-treatment values and changes between baseline and post-treatment values in table II, and differences between groups in table III. © Adis International Limited. All rights reserved.

Characteristic

Study group

Control group

Age (y)

51.8 ± 9.5

54.5 ± 10.3

Gender (male/female)

14/6

16/4

Smoking (packs/y)

21.7 ± 12.5

31.3 ± 19.1

Duration of symptoms (y)

8.8 ± 6.8

11.8 ± 6.7

FVC (% predicted)

58.3 ± 8.5

67.6 ± 17.0

FEV1 (% predicted)

64.1 ± 6.5

59.9 ± 8.2

Neutrophils (%)

75 ± 2.1

74 ± 2.2

Macrophages (%)

18 ± 0. 3

21 ± 0.3

Eosinophils (%)

0.8 ± 0.7

0.8 ± 0.4

Epithelial cells (%)

3.8 ± 0. 8

3.6 ± 0.1

Lymphocytes (%)

1.1 ± 0.9

0.5 ± 0.6

FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity.

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Inhaled Corticosteroids in Stable COPD

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Table II. Results of the two groups at baseline and at the end of study Parameter

Budesonide group before

after

VC (% predicted)

73.3 ± 14.2

79.9 ± 12.3

VC (L)

2.42 ± 0.54

3.11 ± 0.32

FVC (% predicted)

58.3 ± 8.5

67.3 ± 6.8

FVC (L)

2.18 ± 0.26

FEV1 (% predicted) FEV1 (L)

Placebo group mean difference from baseline

before

after

mean difference from baseline

6.7*

75.0 ± 18.1

75.5 ± 11.6

0.5

0.69*

2.88 ± 0.47

2.89 ± 0.5

0.01

9.0*

67.6 ± 5.0

68.8 ± 5.4

1.2

2.51 ± 0.23

0.33*

2.44 ± 0.39

2.49 ± 0.41

0.05

64.1 ± 6.5

71.5 ± 7.6

7.4*

59.9 ± 8.2

60.6 ± 7.1

0.7

1.94 ± 0.38

2.16 ± 0.37

0.22*

1.80 ± 0.28

1.83 ± 0.35

0.03

FEF25-75 (% predicted)

32.8 ± 15.5

41.4 ± 13.3

8.6*

29.9 ± 14.6

31.9 ± 13.9

2.0

FEF25-75 (L/sec)

0.99 ± 0.51

1.42 ± 0.56

0.43*

1.02 ± 0.49

1.08 ± 0.45

0.06

Total sputum cell count (cells/ml × 104)

204 ± 36

140 ± 59

−64

189 ± 32

186 ± 36

−3

Neutrophils (%)

75 ± 2.9

69 ± 1.5

−6.4*

74 ± 2.8

70 ± 1.5

−4

Eosinophils (%)

0.8 ± 0.7

1.1 ± 0.4

0.3

0.8 ± 0.4

0.6 ± 0.5

−0.2

Macrophages (%)

18 ± 3.4

24 ± 0.1

5.9**

21 ± 3.8

21 ± 2.6

0

Lymphocytes (%)

1.1 ± 0.9

1.1 ± 0.5

0.05

0.5 ± 0.6

0.8 ± 0.5

0.25

Epithelial cells (%)

3.8 ± 0.8

4 ± 0.7

0.15

3.6 ± 1.1

3.6 ± 1.1

0

FEF25-75 = forced expiratory flow from 25 to 75% of capacity; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; VC = vital capacity. * indicates statistically significant difference, p < 0.001; ** indicates statistically significant difference, p < 0.01. Table III. Differences between the groups Parameter

Mean differences from baseline budesonide group

Mean difference between groups

95% CI of difference

placebo group

VC (% predicted)

6.7

0.5

6.2**

1.73 to 10.76

FVC (% predicted)

9.0

1.2

7.8*

4.6 to 10.9

FEV1 (% predicted)

7.4

0.7

6.7**

2.1 to 11.2

FEF25-75 (% predicted)

8.6

2.0

6.6*

2.98 to 10.3

Neutrophils (%)

-6.4

−3.6

−2.8

−9.5 to 3.8

Eosinophils (%)

0.3

−0.2

0.5

0.1 to 1.0

Macrophages (%)

5.9

0.4

5.4*

3.4 to 7.6

Lymphocytes (%)

0.05

0.25

−0.2

−0.7 to 0.3

Epithelial cells (%)

0.15

0

0.1

−0.4 to 0.7

FEF25-75 = forced expiratory flow from 25 to 75% of capacity; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; VC = vital capacity. * indicates statistically significant difference, p < 0.001; ** indicates statistically significant difference, p < 0.01.

Discussion

We determined that inhaled budesonide affects airway inflammation and lung function to a limited extent. Although the responses in this study do not represent clinically significant improvements, they do suggest a role for inhaled corticosteroids in COPD. Although the sputum neutrophil count, as a percentage of total cell count, was reduced at © Adis International Limited. All rights reserved.

the end of the study in the budesonide group, the change was not significant when compared with the control group. However, pulmonary function improved in both the study and the placebo groups; these increases in the study group, especially for FEV1 and FVC, were significant when compared with controls. The study of Weiner et al.[10] was similar to our study in terms of dosage and duration of treatment. Clin Drug Invest 2001; 21 (12)

840

They detected mean changes of FEV 1 of 10% compared with initial values. Since our results were defined as the changes from baseline, expressed as percentages of predicted values, this may explain why the improvement of FEV1 in our study appears to be less. In another study by Confalonieri et al.,[11] no changes were found in FEV1 with beclomethasone dipropionate. However, the mean final value of sputum neutrophils was reduced, and the changes were significant when compared with the control group. The reasons for the difference from our results could be the strategy used for medication and the differences in the study population in severity of COPD. Some studies have investigated the effect of oral corticosteroids in stable COPD. In the meta-analysis performed by Callahan et al.,[7] it was found that approximately 10% of patients with stable COPD had 20% or greater improvement in baseline FEV1. However, oral corticosteroids do not change airway hyper-responsiveness and bronchodilator response.[7] It was reported that patients taking prednisolone at a dose of 10 mg/day or more for 20 years had a decline in FEV1 only after at least 6 to 24 months of therapy.[12,13] Since the long-term use of systemic corticosteroids might have adverse effects, the place of inhaled corticosteroids in the treatment of COPD has been investigated. There are ten randomised studies on the effect of the short-term use of inhaled corticosteroids in the treatment of stable COPD. All of these studies were placebo-controlled and investigated changes in FEV1 and bronchial hyper-reactivity. In these studies, 7 to 13% improvement was detected in FEV1.[7] In our country, studies investigating the effect of inhaled corticosteroids on COPD have also been performed. Güçlü and Sayiner[14] in 1992 studied whether inhaled beclomethasone dipropionate could be an alternative to oral corticosteroids, and observed that both forms of treatment led to similar spirometric changes. Yildiz et al.[15] studied the effect of fluticasone dipropionate 1500 μg/day on pulmonary functions, symptoms and sputum neutrophilia in COPD. Among the © Adis International Limited. All rights reserved.

Mirici et al.

parameters investigated, a significant positive effect was found only for sputum neutrophilia. The predicted percentage change in FEV1 was found to be between 1.7 and 6% in randomised, placebo-controlled studies investigating the longterm effects of inhaled corticosteroids in COPD.[7] In three long-term (36 months) multicentre studies on inhaled corticosteroids [European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP),[17] Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)[18] and Copenhagen City Lung Study[19]] an improvement in FEV1, decrease in the frequency of acute attacks and improvement in symptoms were reported.[16-18] In the ISOLDE trial[18] in patients with COPD, inhaled fluticasone dipropionate resulted in higher FEV1 values than placebo both at 3 months and at 3 years. This trial did not evaluate sputum analysis. Inflammation occurring in COPD and followed by remodelling forms the basis of functional impairment. Moreover, remodelling implies an irreversible component in COPD. When antiinflammatory approaches are being evaluated, lung function tests are usually used as outcome measures. Improvement in symptoms, a decrease in attack frequency, a decrease in bronchial hyperreactivity and bronchodilator response have been considered in recent studies, but most of those are functions or consequences of FEV1.[20] Evaluation of airway inflammation is more difficult to perform and interpret compared with lung function tests.[17] It is obvious that permanent and efficient improvement cannot occur in the absence of effective reduction of inflammation and/or its consequences. Accordingly, the effectiveness of anti-inflammatory therapy must be evaluated by inflammation parameters. It has been shown that analysis of induced sputum is a valid and reliable method for assessing airway inflammation.[9,21] It has been reported that inhaled corticosteroids are ineffective or have little effect on the increased interleukin-8 (IL-8) and tumour necrosis factor-α (TNFα) in bronchoalveolar lavage (BAL) fluid Clin Drug Invest 2001; 21 (12)

Inhaled Corticosteroids in Stable COPD

from patients with COPD,[22] possibly explaining why corticosteroids are ineffective in COPD.[23] It is documented that inhaled corticosteroids do not affect neutrophil count and the level of activation markers, but decrease the number of eosinophils and suppress eosinophilic markers.[22,24] This result is interpreted as indicating that corticosteroids affect eosinophilic inflammation, which is responsible for the reversible component of airway obstruction.[24] Our patients had irreversible obstruction and very little sputum eosinophil numbers. This difference might thus be a result of the baseline characteristics of the study population. Short-term oral corticosteroid therapy in COPD is recommended in situations where adequate bronchodilation is not reached in spite of optimum anticholinergic and β-agonist therapy. Long-term use of corticosteroids must take into account adverse effects; inhaled corticosteroids may thus be a more suitable choice in this situation as a result of their mild adverse effects. Long- and short-term studies of inhaled corticosteroid use in COPD generally reveal little effect in terms of lung function but evident effects in terms of attack frequency, quality of life and functional capacity (for example, exercise capacity). Thus, patients with positive responses to corticosteroids may use these agents for a longer duration. The use of corticosteroids in COPD for the purpose of anti-inflammatory therapy is not as effective as in asthma. This may be due to the ineffective inhibition of remodelling, neutrophil apoptosis and secretion of IL-8 and TNFα.[22] Therefore, the search for better anti-inflammatory therapy in COPD continues. Conclusion

Inhaled corticosteroids have limited effects on airway inflammation and lung function in COPD. Different investigations have produced conflicting results on reduction of neutrophil numbers in sputum, and studies with IL-8 and TNFα as activation markers have revealed that inhaled corticosteroids do not affect neutrophil function. When compared with placebo, the effects of inhaled corticosteroids © Adis International Limited. All rights reserved.

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on lung function, for example FEV1, in COPD do not appear to be of clinical significance. However, inhaled corticosteroids do appear to have positive effects on quality of life, attack frequency and functional capacity. Nevertheless, it remains unclear which COPD patients should receive inhaled corticosteroids. Further investigations are necessary to develop effective anti-inflammatory therapies in COPD and to determine which patients will benefit from corticosteroid treatment. References 1. ATS standards for the diagnosis and care of patients with chronic pulmonary disease. Am J Respir Crit Care Med 1995; 152: 77-120 2. Erdinç E, Erk M, Kocaba A, et al. , Turkish Thoracic Society COPD Study Group. Guideline for COPD [in Turkish]. Toraks Dergisi 2000; 1 (Suppl 2): 1-25 3. National Heart, Lung, and Blood Institute. Global initiative for chronic obstructive lung disease: global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO workshop report. 2000 4. Stockley RA. Cellular mechanisms in the pathogenesis of COPD. Eur Respir Rev 1996; 6: 264-9 5. Jeffery PK. Pathology of asthma and COPD: a synopsis. Eur Respir Rev 1997; 7 (43): 111-8 6. Cosio MG, Guerassimov A. Chronic obstructive pulmonary disease - inflammation of small airways and lung parenchyma. Am J Respir Crit Care Med 1999; 160: 21-5 7. Postma DS, Kerstjens HAM. Are inhaled glucocorticosteroids effective in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 1999; 160: 66-71 8. Rubini F, Rampulla C, Nava S. Acute effect of corticosteroids on respiratory mechanics in mechanically ventilated patients with chronic airflow obstruction and acute respiratory failure. Am J Respir Crit Care Med 1994; 149: 306-10 9. Quips JC, Fahy JV, Hargreave FE, et al. Methods for sputum induction and analysis of induced sputum: a method for assessing airway inflammation in asthma. Eur Respir J 1998; 11 Suppl 26: 9-11 10. Weiner P, Weiner M, Azgad Y, et al. Inhaled budesonide therapy for patients with stable COPD. Chest 1995; 108: 1568-71 11. Confalonieri M, Maniardi E, Della Porta R, et al. Inhaled steroids reduce neutrophilic inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998; 53: 583-5 12. Postma DS, Steenhuis EJ, Van der Weele LT, et al. Severe chronic airflow obstruction: can corticosteroids slow down progression ? Eur Respir J 1985; 67: 56-64 13. Postma DS, Peters I, Steenhuis J, et al. Moderately severe chronic airflow obstruction: can corticosteroids slow down obstruction? Eur Respir J 1988; 1: 22-6 14. Güçlü M, Saymer A. Beklametazon dipropionat inhalasyonu kortikosteroide yanit veren KOAH subgrubunda oral kortikosteroidin yerin alabilirmi?. [in Turkish]. Solunum 1992; 17: 155-61 15. Yildiz F, Kaur AC, Ilgazh A, et al. Inhaled corticosteroids may reduce neutrophilic inflammation in patients with stable

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chronic obstructive pulmonary disease. Respiration 2000; 67: 71-6 Pauwels RA, Löfdal CG, Laitinen L, et al. Long term treatment with inhaled budesonide in persons with chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999; 340: 1948-53 Burge PS. EUROSCOP, ISOLDE and Copenhagen City Lung Study. Thorax 1999; 54: 287-9 Burge PS, Calverley PMA, Jones PW, et al. Randomised, double-blind, placebo-controlled study of inhaler fluticasone dipropionate in patients with moderate and severe chronic obstructive pulmonary disease: The ISOLDE trial. BMJ 2000; 320: 1297-302 Vestbo J, Sorensen T, Lange P, et al. Long term effects of inhaler budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet; 353: 1819-23 Chanez P, Vignolo AM, Bousquet J. Remodelling of the airways in chronic obstructive pulmonary disease. Eur Respir Rev 1997; 43 (7): 142-5

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21. Popov TA, Pizzichini MMM, Pizzchini E, et al. Some technical factors influencing the induction of sputum for cell analysis. Eur Respir J 1995; 8: 559-5 22. Barnes PJ. Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160: 72-9 23. Keatings VM, Jatakanon A, Worsdell YM, et al. Effects of inhaler and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155: 542-8 24. Fujimoto K, Kubo K, Yamamoto H, et al. Eosinophilic inflammation in the airway is related glucocorticoid reversibility in patients with pulmonary emphysema. Chest 1999; 115: 697-702

Correspondence and offprints: Dr A. Mirici, Chest Diseases Department, Faculty of Medicine, Atatürk University, Erzurum, Turkey. E-mail: [email protected]

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