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(Chest. 2002;122:1966-1972.)
© 2002 American College of Chest Physicians

Effects of Varying Doses of Fluticasone Propionate on the Physiology and Bronchial Wall Immunopathology in Mild-to-Moderate Asthma*

Siobhán O’Sullivan, PhD; Liam Cormican, MB; Maeve Murphy, MB; Leonard W. Poulter, DSc and Conor M. Burke, MD, FCCP

* From the Department of Clinical Immunology (Drs. O’Sullivan and Poulter), Royal Free and University College Hospital Medical School, London, UK; and Department of Respiratory Medicine (Mr. Cormican, Ms. Murphy, and Dr. Burke), James Connolly Memorial Hospital, Dublin, Ireland.

Correspondence to: Siobhán O’Sullivan, PhD, Department of Clinical Immunology, Royal Free and University College School of Medicine, Pond St, NW3 2QG, London, UK; e-mail: sioosu{at}indigo.ie


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Inhaled corticosteroids (ICS) are typically associated with a flat dose-response curve when traditional efficacy values are examined (eg, FEV1). The aim of the present study was to investigate if a dose-response relationship exists for lung function and inflammatory cell numbers in bronchial biopsy specimens.

Methods: Bronchial biopsy specimens were obtained from 36 patients randomized to receive 100 µg, 500 µg, or 2,000 µg/d of fluticasone propionate (FP). Lung physiology and bronchial biopsies were performed at baseline and after 2 weeks of treatment.

Results: Improvement in lung function and suppression of airway inflammation were optimal at a dose of 500 µg/d of FP. Significant changes from baseline following treatment were documented in FEV1 (p = 0.02), forced expiratory flow (p = 0.002), FEV1/FVC (p = 0.007), provocative concentration of histamine causing a 20% fall in FEV1 (PC20) [p = 0.02], T-cell numbers (p = 0.0005), activated eosinophils (p = 0.01), and numbers of macrophages (p = 0.01) in the group treated with 500 µg/d of FP. Comparison between groups administered different doses of FP failed to demonstrate a dose-response relationship for change from baseline in PC20 (p = 0.43), any of the lung function parameters, T-cell numbers (p = 0.64), activated T cells (p = 0.46), eosinophils (p = 0.53), activated eosinophils (p = 0.48), or macrophage numbers (p = 0.68).

Conclusion: The apparent lack of a dose-response for ICS treatment in patients with asthma further validates the preferential use of add-on therapy over increasing the dose of ICS.

Key Words: dose-response • inflammation • inhaled corticosteroids


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
During the last number of years, inflammation has been recognized as an integral part of the pathophysiology of asthma, with inhaled corticosteroids (ICS) proving to be the most effective anti-inflammatory agents in asthma treatment.1 Improvements in lung function,2 3 symptom scores,4 5 attenuation of bronchial reactivity,2 6 and inflammatory cell recruitment7 8 are all hallmarks of ICS usage.

Due to the effectiveness of this class of drug in asthma management, ICS currently form the cornerstone of asthma treatment guidelines. The Global Initiative for Asthma directive recommends ICS therapy for all patients with persistent asthma,9 while the British guidelines advocate the introduction of ICS in patients requiring as-needed ß-agonists more than once per day.10 The aforementioned guidelines also recommend a step-down approach to asthma treatment, ie, starting at a high dose of ICS and tapering the dose progressively. This is in sharp contrast to earlier guidelines that promoted early intervention with a low dose of ICS, which should be increased until asthma control is achieved.11 Neither approach is based on clinical trial outcomes, since ICS are typically associated with a flat or shallow dose-response curve when traditional efficacy variables (FEV1, symptoms scores, and rescue bronchodilator use) are examined.4 12 13 14

Traditionally, asthma management has been based on control of clinical signs and symptoms; however, there is increasing evidence that an active inflammatory process can be present in the airways even when patients are asymptomatic.15 16 There are few studies that directly compare dose-response effects on physiologic and cellular markers in the same study.17 18 19 20 Inflammatory markers have been limited to eosinophil number,17 18 20 eosinophil cationic protein (ECP),18 19 tryptase,18 and nitric oxide (NO)17 19 measurements.

The aim of this study was to further explore if ICS can modulate airway inflammation and airway function in a dose-dependent manner. This information should prove valuable in devising guidelines that achieve optimum lung function and maximal suppression of airway inflammation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Thirty-six (28 men and 8 women; mean ± SE age, 32.8 ± 1.5 years; range, 21 to 51 years) non-smoking, atopic patients with mild-to-moderate asthma were recruited into the study (Table 1 ). Atopic status was established by a positive skin-prick test result to one or more of 10 routinely tested allergens (Dermatophagoides pteronyssinus, cat dander, dog dander, feather, five tree mix, grass mix, rye grass mix, milk, wheat, and yeast). Patients were required to have a FEV1 of >= 60% of the predicted value, a change in FEV1 >= 12% to salbutamol, and a provocative concentration of histamine to cause a 20% fall in FEV1 (PC20) of 4 mg/mL All of the subjects were steroid naive prior to enrollment and used ß-agonist on an as-needed basis. Exclusion criteria included a respiratory tract infection in the 6 weeks prior to the study, tobacco use within 6 months, or corticosteroid use (oral or inhaled) within 6 weeks of study commencement. The ethics committee of the hospital and the Irish Medicines Board approved the study, and all patients gave written informed consent prior to participation.


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  		Table 1.. Patient Characteristics

 
Study Design
This study involved five visits over a 4-week period to the asthma clinic. The study was a randomized, double-blind, parallel-group study with a 2-week run-in period to familiarize subjects with study procedures. At the end of the run-in period, the subjects were randomly assigned to one of three treatment groups (each n = 12), in a double-blinded manner to receive either 50, 250, or 1,000 µg of fluticasone propionate (FP) bid for 2 weeks. The parallel-group design avoided the issue of washout duration and possible confounding by carryover effects. Bronchoscopy, pulmonary function tests, and histamine provocation were performed on the last day of the run-in period and ± 2 days after the 2-week treatment period with FP.

Study Medication
During the 2-week, run-in period, the subjects were allocated two placebo inhalers, which they took on a twice-daily basis through a Volumatic device (Allen & Hanbury; Middlesex, UK). On completion, they were randomized to receive either 50, 250, or 1,000 µg of FP bid delivered by a pressurized canister through a Volumatic device. Subjects were also provided with a salbutamol, 100 µg/puff, pressurized rescue inhaler for use during the run-in and treatment periods for use on an as-needed basis for symptomatic relief.

Pulmonary Function Tests
Pulmonary function tests were performed at the same time in the morning, using a Gould 2400 spirometer (Gould Instruments; Cleveland, OH), and the best of three valid attempts were recorded. Bronchodilators were withheld for 8 h prior to testing. Spirometry and histamine provocation were performed as previously described.3 Peak flow measurements were made on a twice-daily basis following instruction by the supervising physician, with the subject recording the best of three attempts, prior to receiving any inhaled medication.

Symptom Scoring
Each patient was allocated a diary card on the first day of the run-in period, in which they documented a symptom score based on the previous 12 h. Subjects were asked to document asthma symptoms, nocturnal awakenings, peak flow measurements, and rescue salbutamol use.

Bronchoscopy
Endobronchial biopsy specimens (n = 3) were obtained from the second- to fourth-generation proximal bronchi on the right side under local anesthesia as previously described.3 Biopsy material was immediately snap frozen in iso-Pentane (BDH; Poole, UK), cooled to - 80°C, and then stored in liquid nitrogen. Sections 6 µm in thickness were subsequently cut from the specimens onto poly-L-lysine-coated glass slides (BDH). The integrity and architecture of the tissue was confirmed by staining with toluidine blue dye. Sections were then air dried for 1 h, fixed in chloroform:acetone 1:1 solution for 10 min, and re-air dried for a further 20 min prior to storage at - 20°C.

Immunocytochemistry
The absolute concentration of the following cells per unit area in the lamina propria was determined with an indirect immunoperoxidase method.3 The total T-cell concentration was determined by the use of a cocktail of mouse antihuman (IgM) anti CD-3+, anti CD-4+, and anti CD-8+ (monoclonal antibody raised in the Royal Free Hospital and School of Medicine [RFHSM]) at dilutions of 1:5 in phosphate-buffered saline solution (PBS), pH 7.2. The concentration of primed or memory T cells was determined by the use of mouse antihuman (IgG2{alpha}) anti-CD45RO (UCHL-1) at a dilution of 1:5 in PBS, pH 7.2. Activated eosinophils and total eosinophils were determined by a mouse antihuman IgG anti EG-2+, anti EG-1+ (RFHSM) at a dilution of 1:5 in PBS, pH 7.2, respectively. Macrophage concentrations were determined by the use of mouse antihuman (IgG) anti CD68+ (DAKO; Denmark) at a dilution of 1:10 in PBS, pH 7.2.

The CD4+:CD8+ ratio was determined within the lamina propria using an indirect double immunofluorescence technique.3 Mouse antihuman CD4+ IgG1 and CD8+IgM (DAKO; Glostrup, Denmark) were used at a concentration of 1:10 in PBS, pH 7.2. In order to determine the distribution of macrophage subsets, a combination of monoclonal antibodies, mouse antihuman IgM anti-RFD1 (D1), and mouse antihuman IgG anti-RFD7 (D7) [RFHSM] at dilutions of 1:5 in PBS, pH 7.2, were applied to biopsy sections. Negative controls were included for each section by omitting primary layer reagents (to identify endogenous peroxidase), and positive controls were concurrently performed on sections of human palatine tonsil.

The number of positive cells was quantified using an image-analysis system (Seescan; Cambridge, Cambs, UK), whereby the area of framed fields within the sections (minimum of five fields) were counted for positive cells.19 The number of cells counted was divided by the area of the frame, and this reduced each framed area to unity. Results are expressed as cells per 104 micrometers squared.

Data Analysis
Calculations of geometric mean PC20 values were performed on log-transformed data. Except where indicated, data were normally distributed and are expressed as mean and 95% confidence interval (CI) of the mean. Comparisons between baseline values for all three doses were performed by one-way analysis of variance and the Tukey test. Treatment effects from baseline for each group were analyzed using a paired Student t test or Wilcoxon signed-rank test, as appropriate. A linear regression analysis was performed to determine if a dose-response relationship existed for any of the parameters. In this analysis, the 2-week change was treated as the dependent variable and the dose received (coded as 1, 5, 20) was the independent variable. Thus, the slope coefficient from this model provided a test of a dose-response relationship with the 2-week change. In addition, an alternative model was also considered in which the doses were coded as 1, 2, 4 in order to assess the possibility of a nonlinear dose-response relationship. Similar results were obtained with this model (data not shown). A p value < 0.05 was considered significant. The statistical calculations were performed with the use of a validated statistical software package for personal computers (SigmaStat 2.0; Jandel Scientific; San Rafael, CA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All but 1 of the 36 subjects enrolled completed the study. One of the subjects in the FP, 100 µg/d, group acquired an upper respiratory tract infection during the last week of the 2-week treatment period and was withdrawn from the study. Baseline data on this subject were included in the analysis on an intent-to-treat basis. No other adverse events were reported for any of the treatment groups.

Lung Function and Asthma Symptoms
At baseline, there were no statistically significant differences in FEV1, forced expiratory flow (FEF), FEV1/FVC, peak expiratory flow, PC20, or symptom score between the three treatment groups. Treatment with FP, 100 µg, over 2 weeks failed to significantly improve any of the aforementioned parameters. Similarly, there was no significant change from baseline in any lung function measurement in the FP, 2,000 µg-treated group; however, there was a decrease in the number of asthma symptoms documented by the subjects in this group (p = 0.03). Significant changes from baseline in the group treated with FP, 500 µg/d, were documented in FEV1 (mean, 3.0 L [CI, 2.3 to 3.6 L] vs mean, 3.5 L [CI, 2.9 to 4.0]; p = 0.02), FEF (mean, 2.5 L [CI, 1.7 to 3.3 L] vs mean, 3.4 L [CI, 2.6 to 4.1]; p = 0.002), FEV1/FVC (mean, 0.72 [CI, 0.64 to 0.80] vs mean, 0.79 [CI, 0.72 to 0.87]; p = 0.007), PC20 (mean 0.55 mg/mL [CI, 0.1 to 1.0 mg/mL] vs mean, 1.26 mg/mL [CI, 0.3 to 2.2 mg/mL]; p = 0.02), and symptom score (mean, 7.8 [CI, 6.6 to 9.1] vs mean, 5.3 [CI, 3.7 to 7.0]; p = 0.005). Peak flow measurements in this group, however, remained unchanged after 2 weeks. Comparison of the changes from baseline between groups failed to demonstrate a dose-response relationship in PC20 (p = 0.43) [Fig 1 ] or any of the lung function parameters examined (Table 2 ).



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  		Figure 1.. Mean change from baseline in bronchial responsiveness following 2 weeks of FP, 100 µg/d (squares), 500 µg/d (circles), and 2,000 µg/d (triangles). A significant improvement in bronchial reactivity (p < 0.05) was observed in the group receiving 500 µg/d.

 

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  		Table 2.. Mean Change (CI) From Baseline After 2-Week Treatment Period*

 
Bronchial Biopsies
At baseline, there were no statistically significant differences in the number of eosinophils, T cells, or macrophages between the three treatment groups. T cells were significantly reduced following 2 weeks of treatment with FP, 100 µg (mean, 6.73 104 µm2 [CI, 5.6 to 7.9] vs mean, 5.06 104 µm2 [CI, 4.0 to 6.1]; p = 0.0009); FP, 500 µg (mean, 6.76 104 µm2 [CI, 5.5 to 8.0] vs mean, 4.44 104 µm2 [CI, 4.0 to 4.9]; p = 0.0005); and FP, 2,000 µg (mean, 7.09 104 µm2 [CI, 6.2 to 8.0] vs mean, 4.93 104 µm2 [4.1 to 5.8]; p = 0.0007). The CD4:CD8 ratio decreased in all three treatment groups but did not reach statistical significance. With respect to the activation status of the T cells, CD45RO expression was significantly reduced by treatment with the higher dose of FP, 2,000 µg (mean, 2.85 104 µm2 [CI, 2.0 to 3.7] vs mean, 1.63 104 µm2 [1.1 to 2.2]; p = 0.05).

The percentage of eosinophils decreased (not statistically significant) in all three treatment groups after 2 weeks of FP therapy. The number of activated eosinophils (EG2+) was found to be significantly decreased following treatment with FP, 500 µg (mean, 0.81 104 µm2 [CI, 0.5 to 1.1] vs mean, 0.50 104 µm2 [CI, 0.3 to 0.7]; p = 0.01).

The reduction from baseline in the number of macrophages (CD68+ cells) was significant in the FP, 500 µg (mean, 2.4 104 µm2 [1.4 to 3.3] vs mean, 3.4 104 µm2 [CI, 2.4 to 4.4]; p = 0.01) and FP, 2,000 µg (mean, 3.2 104 µm2 [CI, 2.0 to 4.4] vs mean, 0.51 104 µm2 [CI, 0.3 to 4.07]; p = 0.0003) groups. Furthermore, the D1/D7 ratio (inductive/suppressive macrophages) was decreased (not significantly) following 2 weeks of treatment with all three doses of FP.

Comparison of changes from baseline between the three treatment groups failed to demonstrate a dose-response relationship for change from baseline in T-cell numbers (p = 0.64) [Fig 2 ], activated T cells (p = 0.46) [Fig 2 ], eosinophils (p = 0.53) [Fig 3 ], activated eosinophils (p = 0.48) [Fig 3 ], or macrophage numbers (p = 0.68) [Fig 4 ].



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  		Figure 2.. Mean change from baseline in T-cell numbers (upper panel), CD4:CD8 ratio (middle panel), and expression of CD45RO on T cells (lower panel) in bronchial biopsy samples of patients treated with FP, 100 µg/d (squares); FP, 500 µg/d (circles); and FP, 2,000 µg/d (triangles). T cells were significantly decreased (p < 0.05) after 2 weeks of treatment in all three groups. A significant decrease in the number of activated T cells was only seen in the group treated with FP, 2,000 µg/d.

 


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  		Figure 3.. Mean change from baseline in eosinophil numbers (upper panel) and activated eosinophils (lower panel) in bronchial biopsy samples following 2 weeks of treatment with FP, 100 µg/d (squares), 500 µg/d (circles) and 2,000 µg/d (triangles). A significant decrease (p < 0.05) in the number of activated eosinophils was observed in the group treated with FP, 500 µg/d.

 


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  		Figure 4.. Mean change from baseline in macrophage numbers (upper panel) and the ratio of inductive (D1+) and suppressor (D7+) type macrophages (lower panel) following 2 weeks of treatment with FP, 100 µg/d (squares); FP, 500 µg/d (circles); and FP, 2000 µg/d (triangles). The reduction from baseline in the number of macrophages was significant (p < 0.05) in the groups receiving FP, 500 µg/d, and FP, 2,000 µg/d.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In patients with mild-to-moderate asthma treated with 100 µg, 500 µg, and 2,000 µg/d of FP, improvement in lung function and suppression of airway inflammation were optimal at a dose of 500 µg/d of FP. Our data are in agreement with a number of studies in the literature demonstrating significant improvements in lung function and bronchial responsiveness using a dose of 500 µg/d of FP.3 4 21 22 A recent meta-analysis23 of eight studies with 2,324 adolescents and adults with asthma determined that the maximum therapeutic benefit of inhaled FP was achieved with a dose of 500 µg/d. Indeed, most patients with moderate-to-severe asthma had achieved 90% of the maximum benefit at doses in the range of 150 to 250 µg/d.23 In the present study, a decrease in T cells and activated eosinophils was documented following treatment with FP, 500 µg/d. Bootsma et al24 showed a decrease in T-cell number and ECP levels in peripheral blood of asthmatics treated with a similar dose of FP (750 µg/d). Furthermore, Olivieri et al7 reported significant reductions in eosinophil and mast cell numbers in the bronchial submucosa following FP, 500 µg/d, over a 6-week period.

No further improvement over that observed with FP, 500 µg/d, could be documented in those subjects treated with FP, 2,000 µg/d, over a 2-week period. Treatment groups were well matched at baseline for lung function and inflammatory cell numbers, and maximal benefit appears to have been achieved at FP, 500 µg/d, leaving no room for further improvement with the higher dose of FP. We were unable to demonstrate any dose-response relationship with respect to lung function or bronchial inflammation with the three doses of FP used in this study.

A 2-week treatment regime was employed, as previous data from this laboratory have documented a significant improvement in pulmonary function, and a decrease in activated T cells, macrophage, and eosinophil numbers following a 2-week intervention with FP.8 In addition, Faul et al25 demonstrated that several parameters of airway inflammation become less reproducible with increased length of biopsy interval. The reproducibility of repeat measures of airway inflammatory cells is greater at 2 weeks than at 8 weeks.25

A lack of a dose-response relationship for FP in the current study could conceivably be due to small sample size, ie, 12 subjects in each treatment group. However, there was no evidence for a trend toward a dose-response relationship for either lung function or inflammatory cells. Several larger studies have also failed to document a dose-response relationship with ICS.14 20 26 27

Noonan et al28 demonstrated a dose-response relationship for FEV1 in patients receiving 750 µg or 1,000 µg of FP bid; these results are difficult to interpret since the subjects enrolled in this study were receiving concomitant prednisolone due to the severity of their asthma. The Formoterol and Corticosteroids Establishing Therapy study with 227 subjects allocated to 12 months of treatment with budesonide, 200 µg/d or 800 µg/d, could not document a dose-response relationship with respect to FEV1 or peak flow.20

There are few studies that have directly compared dose-response effects on physiologic and cellular markers in the same study. Wilson and Lipworth19 investigated the effect of treatment with 400 µg, 800 µg, or 1,600 µg of budesonide on both these parameters in an open, crossover study. Although a small but significant dose-response effect was noted for bronchial hyperresponsiveness to methacholine and serum ECP, no dose-response relationship could be established for FEV1, peak expiratory flow, or NO. In a group of 24 asthmatics of similar disease severity to the subjects in the current study, there was no difference in the reduction of tryptase or ECP in induced sputum with FP, 100 µg or 1,000 µg/d.18 The authors concluded that dose-response effects were difficult to establish due to the effectiveness of the low-dose treatment regime in gaining asthma control. Jatakanon et al,17 in a similar study in which patients received 100 µg, 400 µg, or 1,600 µg/d of budesonide, could show that 400 µg was more effective than 100 µg at decreasing NO levels, yet no further reduction was documented in subjects treated with 1,600 µg/d of budesonide.

These findings raise pertinent questions about our current approach to asthma treatment, in which patients are initiated at high doses of ICS, while tapering of the daily dose by 25 to 50% at 1- to 3-month intervals is recommended but not often achieved.10 The apparent lack of a dose-response for ICS treatment in asthma further validates the preferential use of add-on therapy over increasing the dose of ICS. There are now a number of studies that show that addition of a long-acting ß-agonist is more effective in terms of asthma control than doubling the dose of inhaled steroid.29 30 31 In addition, Lofdahl et al32 demonstrated the steroid-sparing effects of the leukotriene receptor antagonist montelukast in patients requiring moderate-to-high doses of ICS. Furthermore, during the run-in of the aforementioned study, patients successfully reduced their dose of ICS by 37% while maintaining asthma control, indicating that many patients are treated with higher-than-necessary doses of ICS. On the basis of these data, the use of several classes of drugs, each targeting different components of the pathologic process, appears to be a more justifiable approach to asthma treatment than increasing ICS doses.


   Acknowledgements
 
The authors thank Ms. Huda Al Doujaily, Ms. Suzanne Doyle, and Sister Mary Toole for technical assistance, and Dr. Caroline Sabine for advice on data analysis.


   Footnotes
 
Abbreviations: CI = confidence interval; ECP = eosinophil cationic protein; FEF = forced expiratory flow; FP = fluticasone propionate; ICS = inhaled corticosteroids; NO = nitric oxide; PBS = phosphate-buffered saline solution; PC20 = provocative concentration of histamine causing a 20% fall in FEV1; RFHSM = Royal Free Hospital and School of Medicine

Supported by GlaxoSmithKline R&D, UK (Protocol No. FLIFO3) and The Eastern Health Board, Ireland.

Received for publication February 21, 2002. Accepted for publication June 13, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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