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(Chest. 2005;128:1140-1145.)
© 2005 American College of Chest Physicians

Factors Influencing the Responsiveness to Inhaled Glucocorticoids of Patients With Moderate-to-Severe Asthma*

An-Soo Jang, MD; June-Hyuk Lee, MD; Sung Woo Park, MD; Young Mok Lee, MD; Soo Taek Uh, MD; Yong-Hoon Kim, MD and Choon-Sik Park, MD

* From the Asthma and Allergy Research Group (Drs. Jang, J.-H. Lee, S.W. Park, and C.-S. Park), Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Bucheon, Republic of Korea; and Asthma and Allergy Research Group (Drs. Y.M. Lee, Uh, and Kim), Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea.

Correspondence to: Choon-Sik Park, MD, Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Hospital, 1174, Jung-dong, Wonmi-gu, Bucheon-si, Gyeonggido 420–767, Republic of Korea; e-mail: schalr{at}schbc.ac.kr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Inhaled glucocorticoids (GCs) are the most effective control therapy for asthma. Although the clinical effects of inhaled GCs vary, there are few data on the differences in the responsiveness of individuals to inhaled GCs. The purpose of this study was to identify those factors that are associated with responsiveness to high-dose inhaled GCs in patients with moderate-to-severe asthma.

Design: This study was a prospective analysis.

Setting: Outpatient clinics of tertiary hospitals.

Patients: Eighty-six adult outpatients with moderate-to-severe asthma.

Methods: Eighty-six patients with asthma who had initial FEV1 values of < 80% predicted after they had received inhaled GCs (fluticasone propionate, 1,000 µg/d) for 4 weeks. The primary end points were FEV1, FEV1/FVC ratio, forced expiratory flow (midexpiratory phase), and the score at presentation in the asthma-related quality-of-life questionnaire (AQLQ).

Results: The inhalation of GCs for 4 weeks had significant improvements in the FEV1% predicted and in the AQLQ score compared with the baseline values. Asthmatic patients with responses of > 12% (n = 46, 53.4%) in the change in FEV1 ({Delta}FEV1 = [FEV1 at 4 weeks – baseline FEV1]/baseline FEV1 x 100) also had significantly higher proportions of blood eosinophils and lower FEV1 values (in liters) prior to treatment. The change in FEV1 values correlated with the number of sputum eosinophils prior to GC inhalation (r = 0.242; p < 0.05) and correlated inversely with the FEV1 percent predicted values prior to GC inhalation (r = –0.462; p < 0.001).

Conclusion: The FEV1 percent predicted and the blood and sputum eosinophil levels prior to GC inhalation are associated with the responsiveness to inhaled GCs in patients with moderate-to-severe asthma.

Key Words: asthma • FEV1 • glucocorticoid • inhalation • responsiveness


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled glucocorticoids (GCs) have revolutionized the treatment of asthma and have become the mainstay of therapy for patients with chronic asthma.123

Physiology, airway inflammation, and airway remodeling in asthma patients are interrelated and improved with GC therapy. Early and long-term intervention with GC therapy is needed, even in patients with relatively mild asthma.4 According to asthma management guidelines,3 patients with moderate persistent asthma should begin inhaled GC therapy with a dose of 400 to 800 µg of budesonide or its equivalent; treatment at this dosage should continue for ≥3 months, which is the amount of time required to obtain maximal benefit from the inhaled steroid. The dosage of inhaled GCs may then be reduced according to a simple step-down regimen. In some patients, the initial dose of steroid may be too low, making it necessary to increase the dose. In patients with severe persistent asthma, a budesonide dosage of ≥800 µg/d may be needed, or therapy with oral steroids may be required in order to obtain initial control of the asthma. A small percentage of asthmatic patients have symptoms that are severe enough to require high doses of GCs in order to establish maximal lung function.5 In a previous study, a change in the FEV1 became apparent by 4 weeks of treatment with inhaled GCs and peaked by 8 weeks of treatment.6 However, the data in that study were not based on the changes in FEV1 for individual patients but on averages of the overall FEV1 values. Although variable responses to inhaled GC therapy are expected among asthma patients, short-term cross-sectional data on their effects on factors that determine the outcome of inhaled GC treatment are rare.

Therefore, the aims of this study were as follows: (1) to estimate individual responsiveness in terms of pulmonary function and asthma symptoms after 4 weeks of treatment with the maximum recommended dose of an inhaled GCs (1,000 µg fluticasone propionate [FP]) in patients with moderate-to-severe asthma; (2) to classify each patient as a responder or nonresponder; and (3) to identify the factors that determine the outcome of inhaled GC treatment.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design
On the first day of the study (Fig 1 ), a clinical history was obtained for each patient using a physician-administered questionnaire. Chest posteroanterior radiography, allergy skin prick tests, and spirometry, including bronchodilator responses after the inhalation of two puffs of 100 µg aerosolized albuterol, were performed. The blood and sputum were sampled for differential cell counts. The asthma-related quality-of-life questionnaire (AQLQ) was evaluated at baseline and at 4 weeks of treatment. On the second day, airway hyperresponsiveness (AHR) was measured in patients with FEV1 values of ≥ 70% predicted. The patients were educated visually by a trained nurse as to the use of inhaled GCs until their accuracy scores reached 12 (maximal score, 14).7 GC inhalation therapy was maintained for 4 weeks. An inhaled GC dose of 1,000 µg/d FP was self-administered via a multidose dry-powder inhaler (Diskhaler; GlaxoSmithKline; Research Triangle Park, NC) [two puffs bid]. During the study period, the patients were asked to record their symptom scores and medication. The patients used short-acting bronchodilators as needed. During the study period, patients were switched to combination or add-on therapy in cases of exacerbations, that is, reductions of > 12% in AQLQ or FEV1, anytime that aggravating symptoms developed. The primary end points were changes in basal FEV1, the FEV1/FVC ratio, and the forced expiratory flow, midexpiratory phase (FEF25–75%) after active treatment with inhaled GCs. The change in the validated asthma control score was a secondary end point.



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  		Figure 1. Schematic diagram of study design.

 
Subjects
Patients with chronic asthma were recruited from the outpatient clinics of Soonchunhyang University Hospital. All of the patients exhibited one or more asthma symptoms, and their physical examinations were compatible with the American Thoracic Society definition of asthma.8 Each patient showed airway reversibility, as documented by a positive bronchodilator response of a > 15% increase in FEV1 and/or airway hyperreactivity to < 10 mg/mL methacholine.9 The exclusion criteria included duration of asthma of < 1 year, acute exacerbated asthma within 4 weeks, history of brittle asthma, atopy to pollens, parenchymal lung disease apparent on chest radiography, diffusing capacity of < 80%, previous inhaled steroid or systemic steroid use within the past 4 weeks, and maintenance therapy with theophylline or a leukotriene antagonist. Nineteen of the patients were current smokers, and 20 were ex-smokers who had given up smoking a median of 15 years prior to recruitment into the study. The prospective controlled trial involved 86 patients (mean age, 46 years) with moderate-to-severe persistent asthma according to the Global Initiative for Asthma guidelines.3 The clinical parameters are summarized in Table 1 . Thirty-seven percent of asthmatic patients showed a positive response to the skin test with common inhalant allergens. The change from day 1 to day 28 in FEV1 ({Delta}FEV1 = [FEV1 at 4 weeks – baseline FEV1]/baseline FEV1 x 100) following the inhalation of GCs was measured. Responders to the inhaled GC therapy were identified as those patients who demonstrated responses of ≥ 12% in {Delta}FEV1. During this period, seven asthmatic patients were moved to the combination or add-on therapy because of decreases of > 12% in FEV1 or AQLQ together with symptom aggravation. Those patients were included as nonresponders to the inhaled GC therapy. This study was performed with the approval of the Ethics Committee of the Soonchunhyang University Hospital, and informed written consent was obtained from all of the study subjects.


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  		Table 1. Characteristics in Patients With Asthma Prior to Treatment According to Responsiveness to Inhaled GCs*

 
Quality-of-Life Measurement
The AQLQ was evaluated at baseline and at 4 weeks of treatment using the Korean modification of the Juniper asthma quality-of-life questionnaire.10 The answers to each question were scored on a 5-point scale, with a score of 1 representing the greatest impairment and a score of 5 representing no impairment (lower AQLQ scores reflect increased impairment). Items were weighted equally and reported as the mean score for each domain (activity limitations, emotions, symptoms, and exposure to environmental stimuli), along with the overall score.

Lung Function Tests
Baseline measurements of FVC and FEV1 were obtained in the absence of recent use (ie, within 8 h) of a bronchodilator and were selected according to the American Thoracic Society criteria.8 Basal and postbronchodilator FEV1, FVC, and FEF25–75% were measured between 1:00 PM and 4:00 PM. AHR was measured by methacholine challenge and was expressed as the provocative concentration of a substance causing a 20% fall in FEV1 (PC20) in noncumulative units.11

Sputum Examination
Sputum was induced using an isotonic saline solution that contained a short-acting bronchodilator, as described by Norzila et al.12 Samples were treated within 2 h of collection using the method of Pizzichini et al13 with a minor modification. Briefly, all of the visible portions with greater solidity were carefully selected and placed in a preweighed Eppendorf tube. The samples were treated by adding eight volumes of 0.05% dithiothreitol (Sputolysin; Calbiochem Corp; San Diego, CA) in Dulbecco phosphate-buffered saline solution. One volume of protease inhibitors (0.1 mol/L ethylenediaminetetraacetic acid and 2 mg/mL phenylmethylsulfonylfluoride) was added to 100 volumes of the homogenized sputum, and the total cell count was determined with a hemocytometer. The homogenized sputum was spun in a cytocentrifuge, and 500 cells were read on each stained (Diff-Quick solution; American Scientific Products; Chicago, IL) sputum slide.

Allergy Skin Prick Tests
Allergy skin prick tests were performed using commercially available inhalant allergens, which included dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus; Bencard Co; Brentford, UK) and histamine (1 mg/mL). None of the subjects had received antihistamines orally in the 3 days preceding the study. All of the tests included positive controls (1 mg/mL histamine) and negative controls (diluent). After 15 min, the mean diameters of the wheals formed by the allergens were compared with those formed by histamine. If the former was the same or larger than the latter (allergen/histamine ratio, ≥ 1.0), the reaction was deemed to be positive. Atopy was determined by the presence of an immediate skin reaction to one or more aeroallergens, as described previously.14

Statistical Analysis
The data were double-entered into a statistical software package (SPSS, version 10.0; SPSS Inc; Chicago, IL). The data are expressed as the mean ± SD. Comparisons of continuous variables for responder and nonresponder patients with asthma were made using independent sample t testing. Differences in the proportions of patient populations were analyzed by {chi}2 testing with the Fisher exact test when low expected cell counts were encountered. Multivariate logistic regression analysis with a step-wise selection method at p < 0.05 for entry into the model was used to obtain the independent effects of factors showing significant associations with responsiveness to inhaled GC therapy. A p < 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 86 patients in the study, 79 patients (91.8%) were followed up at 4 weeks. Seven asthmatic patients who were included as nonresponders had moved to the combination or add-on therapy, owing to decreases of > 12% in FEV1 or AQLQ, with symptom aggravation. A total of 79 asthmatic patients finished the study by continuing the inhaled GC therapy for 4 weeks. The mean overall compliance and accuracy rates were 83.3 ± 2.57% and 12.69 ± 0.22%, respectively. During the study period, 46 patients (53.4%) with asthma showed a ≥ 12% increase in FEV1 in response to high-dose inhaled GC therapy, and 40 patients were nonresponders (Table 1). For 17 of the nonresponders, the FEV1 values were decreased compared with the baseline levels. There was no difference in mean baseline FEV1 levels between responders and the group receiving combination or add-on therapy with symptom aggravation (60.5 ± 12.4% vs 66.5 ± 7.64%, respectively) [Table 1]. The change in FEV1 ({Delta}FEV1 = [FEV1 at 4 weeks – baseline FEV1]/baseline FEV1 x 100) following the inhalation of GCs varied from – 21 to 126.8% (Fig 2 ). The change in FVC ({Delta}FVC = [FVC at 4 weeks – baseline FVC]/baseline FVC x 100) following the inhalation of GCs ranged from – 20 to 47%. The change in forced expiratory flow (FEF) [{Delta}FEF = (FEF at 4 weeks – baseline FEF)/baseline FEF x 100] following the inhalation of GCs ranged from –55.1 to 95%. The mean values for FEV1 percent predicted, FEF25–75%, FEV1/FVC ratio, and AQLQ score were significantly increased from baseline values after 4 weeks of GC inhalation therapy (FEV1, 63.9 ± 11.5% vs 78.2 ± 16.9% predicted, respectively; FEF25–75%, 43.7 ± 18.0% vs 68.7 ± 27.7%, respectively; FEV1/FVC ratio, 69.2 ± 11.9% vs 74.3 ± 12.1%, respectively; and AQLQ, 51.2 ± 13.8% vs 67.5 ± 12.5%, respectively; p < 0.01). The FEV1 percent predicted, FEF25–75%, FEV1/FVC ratio, and AQLQ score were also significantly increased after 4 weeks of inhaled GC therapy in patients who were classified as having moderate-to-severe asthma (Table 2 ). The pretreatment values for FEV1, FVC, FEV1/FVC, and FEF25–75% were significantly lower in responder patients than in nonresponder patients (Table 1). The responder patients exhibited higher response rates to inhaled, short-acting bronchodilators than did nonresponder patients with asthma (48.3% [15 of 31 patients] vs 26.4% [9 of 34 patients], respectively; p < 0.05). The responder asthmatic patients with {Delta}FEV1 values of > 12% had significantly higher proportions of blood eosinophils and lower baseline FEV1 values. The {Delta}FEV1 values correlated negatively with the FEV1 percent predicted and FEF25–75% values (r = –0.462 and p < 0.001 vs r = –0.265 and p < 0.05, respectively) and correlated positively with the proportions of sputum eosinophils (r = 0.242; p < 0.05) prior to the inhaled GC treatment. AHR prior to the inhaled GC treatment was not associated with responsiveness to inhaled GCs. In a multiple logistic regression model that included all of the patients and that was adjusted for age, sex, atopy, AQLQ score, asthma duration, number of cigarette pack-years smoked, blood eosinophil count, and sputum eosinophil count, the FEV1 percent predicted values prior to treatment were independently associated with responsiveness to inhaled GC therapy (odds ratio, 1.126; 95% confidence interval, 1.033 to 1.228; p = 0.007).



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  		Figure 2. Change in FEV1 following glucocorticoid inhalation therapy for 4 weeks.

 

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  		Table 2. Percentage of Change in AQLQ Score and Spirometry Following GC Inhalation Therapy for 4 Weeks Compared with Baseline Values Prior to Treatment*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our findings provide additional insight into the response of asthmatic patients to high-dose inhaled GC therapy. Among the patients with asthma, we found diverse associations with the FEV1 changes following 4 weeks of GC inhalation therapy. Higher blood and sputum eosinophil levels and lower FEV1 values prior to treatment play important roles in the responsiveness to inhaled GC therapy of patients with moderate-to-severe asthma.

GCs, which are usually administered by inhalation, are potent inhibitors of inflammatory responses and are currently considered to be the standard therapeutic regimen for the treatment of persistent asthma.8 GC therapy reduces the number of infiltrating eosinophils and lymphocytes in the airways of asthmatic patients, and decreases the production and release of proinflammatory mediators and cytokines. As a consequence, some of the structural abnormalities of asthmatic airways are normalized after GC treatment.15 In our study, asthmatic patients who were responders had higher levels of blood eosinophils and sputum eosinophils prior to GC inhalation, which indicates that asthmatic patients with eosinophilic airway inflammation are more responsive to inhaled GC therapy.

An earlier 5-month clinical study of inhaled beclomethasone propionate (BDP) examined 156 patients with asthma; despite increasing doses of inhaled BDP (from 400 to 1,600 µg), which were delivered via a pressurized, metered dose inhaler, no additional benefits in terms of FEV1 were derived from the treatment.16 However, later studies17181920 showed a good dose-response relationship. The control of asthma was superior in patients who received high doses of BDP (1,000 to 2,000 µg/d) to that in patients who received the lower dose (400 µg/d).21 Similar results were observed for patients who received FP.2223 However, these dose-response studies failed to show statistically significant differences between the clinical effects of adjacent doses within the dose-response curve. Normally, a difference of fourfold or more in dosage has been required to detect a statistically significant (and often small) difference in commonly measured outcomes, such as symptoms, peak expiratory flow, use of rescue ß2-agonist, and lung functions. Changes in the PC20 for methacholine, which is a more sensitive parameter, have shown the dose-response effects of budesonide (200 vs 800 µg/d, respectively).24 In the present study, we evaluated the effect of high-dose inhaled GC therapy in order to exclude the dose-dependent effect of GCs. We found significant increases in FEV1 at 4 weeks in asthmatic patients who had received high doses of inhaled GCs. Patient responsiveness to inhaled GC therapy varied widely, and we examined the factors associated with these variations. FEV1, sputum eosinophil numbers, blood eosinophil numbers, and the responses to bronchodilators prior to receiving inhaled GC therapy were associated with the responsiveness to inhaled GC therapy.

Despite the use of high-dose inhaled GC therapy, some patients are unable to dispense with oral GC therapy.25 However, high doses of inhaled steroids can effectively replace oral steroids in 70 to 90% of patients. It is now well-documented, in both adults and children, that long-term treatment with inhaled GC therapy suppresses the disease by affecting the underlying airway inflammation. As a result, the symptoms disappear and the lung function improves. The outcome parameter that responds most rapidly to the initiation of inhaled steroid therapy is that of symptoms; peak expiratory flow values improve gradually, whereas improvements in AHR may continue over many months or even years. Inhaled GC therapy may also modify the disease outcome if it is prescribed early enough and for a long enough period. However, if inhaled steroid therapy is stopped, most patients eventually reexperience the symptoms of asthma. The speed of relapse is probably related to patient age, length of symptom history, severity of symptoms, and duration of treatment.

In our study, FEV1 was significantly increased following 4 weeks of GC inhalation therapy, which underlines the importance of the number of blood eosinophils and sputum eosinophils over other factors, such as age, duration of asthma, atopy, and PC20 for methacholine. The long-term follow-up of AHR, such as with PC20 for methacholine measurements, is needed for verification. Nonresponders to inhaled GC therapy tended to be older and to have had asthma longer, which suggests that age and longer asthma duration may cause airway remodeling, thereby making the airways less responsive to inhaled GC therapy. The responder asthmatic patients had higher response rates to short-acting bronchodilators prior to the GC inhalation treatment, which indicates that the tone of the airway smooth muscles is a crucial factor in determining the effectiveness of inhaled GC therapy.

Active cigarette smoking is common in adult patients with asthma, with > 20% being current smokers.2627 Current smokers with asthma, compared with never-smokers, have more severe asthma symptoms. Cigarette smoking impairs the efficacy of corticosteroid therapy in subjects with asthma.28 In our study, although 19 patients with asthma were current smokers, and patients with severe asthma had a history of more pack-years of smoking, there were no differences in the therapeutic response to GCs.

An intriguing question that remains to be answered concerns the significance that should be attached to the lack of responsiveness to inhaled GC therapy. Changes in GC receptors, abnormalities in the binding to GC receptors, and alterations in the translocation to (transcription factor modulating and) GC-responsive genes are all known mechanisms of GC insensitivity.293031 A total of 15 missense, 3 nonsense, 3 frameshift, 1 splice site, and 2 alternative spliced mutations have been reported in the NR3C1 gene associated with GC resistance, as well as in 16 polymorphisms.32 Additional study will elucidate the association between genetic differences and variable responsiveness to inhaled steroids. In addition, studies that address the mechanisms of different airway responses to inhaled GC therapy will be important for establishing the best management strategies for asthma.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; AQLQ = asthma-related quality-of-life questionnaire; BDP = beclomethasone propionate; FEF = forced expiratory flow; FEF25–75% = forced expiratory flow midexpiratory phase; FP = fluticasone propionate; GC = glucocorticoid; PC20 = provocative concentration of a substance causing a 20% fall in FEV1

Supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6–01GN04–003).

Received for publication March 15, 2004. Accepted for publication December 1, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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