The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial

Article Outline

• Abstract
• Methods
  • Study population
  • Study design
  • Procedure
  • Statistical analysis
• Results
  • Study population
  • Six-week ICS period
  • Sixteen-week double-blind trial
    • Stratification by FEV1
    • Retrospective stratification by PC20
• Discussion
• Acknowledgment
• References
• Copyright

Background

Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled corticosteroids.

Objective

To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks).

Methods

Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV₁ and methacholine PC₂₀. After this, an additional 4-month trial evaluated asthma control.

Results

Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations (r ≥ ± 0.6) were albuterol reversibility (r = 0.83; P < .001), FEV₁/forced vital capacity (r = −0.75; P < .001), and FEV₁ % predicted (r = −0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV₁ improvement) and nonresponders (≤5%) determined the longer-term need for steroids. For the nonresponders, asthma control remained unchanged whether inhaled corticosteroids were continued or were substituted with a placebo (P = .99). The good short-term responders maintained asthma control longer-term only if maintained on inhaled steroids (P = .007).

Conclusion

The short-term response to inhaled corticosteroids with regard to FEV₁ improvement predicts long-term asthma control.

Clinical implications

The decision to use long-term inhaled steroids could be based on a short-term trial. Different therapeutic strategies would need to be established for nonresponders.

Key words: Inhaled corticosteroids, predicting response, therapy, characteristics, biomarkers

Abbreviations used: ACQ, Asthma Control Questionnaire, ACRN, Asthma Clinical Research Network, BHR, Bronchial hyperresponsiveness, FeNO, Fraction of exhaled nitric oxide, FVC, Forced vital capacity, ICS, Inhaled corticosteroid, NHLBI, National Heart, Lung, and Blood Institute, PEF, Peak expiratory flow

Inhaled corticosteroids (ICSs) are the preferred anti-inflammatory therapy for the treatment of persistent asthma as recommended by both national and international guidelines.¹, ², ³, ⁴ However, an increasing number of studies have demonstrated marked variability in response to ICS with 25% to 35% of subjects with asthma showing little improvement in FEV₁ and/or bronchial hyperresponsiveness (BHR).⁵, ⁶, ⁷ In the recent Gaining Optimal Asthma Control study, Bateman et al⁸ used increasing doses of combination therapy with an ICS and long-acting β₂-agonist for 1 year, which included a short oral corticosteroid trial. Although patients with asthma of different severities (defined by ICS dose at enrollment) showed a differential response to this treatment (a smaller proportion of the patients with more severe asthma responded than the patients with milder asthma), approximately 30% of the entire subject group enrolled did not achieve the study's standards for well controlled asthma.

Retrospective analysis of a previous Asthma Clinical Research Network (ACRN) study identified elevated fraction of exhaled nitric oxide (FeNO) and greater bronchodilator reversibility to a short-acting β₂-agonist as predictors of a positive FEV₁ response to ICS and higher sputum eosinophils and shorter duration of asthma (years since diagnosis) as predictors of improvement in BHR.⁷ This study did not examine, however, whether these responses in pulmonary function to short-term ICS treatment could predict the long-term response in the maintenance of asthma control with more prolonged treatment. Thus, the ACRN embarked on a larger prospective study to analyze biomarkers and characteristics of asthma as predictors of response to short-term (6-week) ICS treatment and then to examine the relationship of the short-term response to the importance of continued ICS treatment for maintenance of asthma control over a longer time (16 additional weeks).

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Methods 

Study population 

Inclusion criteria for study subjects were individuals with asthma between 18 and 55 years of age with a baseline FEV₁ 55% to 85% predicted and a methacholine PC₂₀ ≤12 mg/mL. Because FEV₁ reversibility was an outcome variable, this was not used as an inclusion criterion. No ICS or systemic corticosteroids were allowed for at least 4 weeks before enrollment. No smoking was allowed for 1 year before enrollment, and cumulative exposure was less than 10 pack-years. Other exclusion criteria included other respiratory disease or significant medical illness, respiratory infection within 6 weeks before screening, pregnancy, and previous enrollment in the aforementioned ACRN study.⁷ The lack of adherence to study procedures during the run-in period also mandated exclusion.

Protocol review was performed by a National Heart, Lung, and Blood Institute (NHLBI) Protocol Review Committee, and the study was monitored by an NHLBI Data Safety Monitoring Board. The protocol and consent were approved by each center's Institutional Review Board, and each subject gave informed, written consent.

Study design 

Eighty-three subjects were enrolled into this study. After a 2-week run-in characterization period, the subjects were begun on single-blind ICS, hydrofluoroalkane-beclomethasone proprionate at 160 μg twice daily (Fig 1). This period was used to evaluate biomarkers and characteristics prospectively that would predict ICS response (FEV₁ and PC₂₀ to methacholine). Biomarkers that were evaluated were β₂-agonist response, FeNO, induced sputum eosinophils, lung function, and BHR. Characteristics included duration of asthma diagnosis, age, sex, height, weight, and ethnicity. All biomarkers were obtained immediately before initiation of ICS and at the end of the 6-week trial.

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• Fig 1. 

  Protocol time line with the different interventions. Stratification is based on the 6-week ICS response: responders and nonresponders. Baseline and repeat measurements included the biomarkers of β₂-agonist response, FeNO, and induced sputum eosinophils. Duration of asthma diagnosis was initially obtained. The mini ACQ was measured prior to the 16-week trial and once every month during the 16 weeks. bid, Twice daily; D/C, discontinued.

After the single-blind period, subjects were stratified on the basis of the FEV₁ response to ICS. Responders were defined as those with a >5% FEV₁ improvement over the 6-week trial, whereas nonresponders had ≤5% change. At this point, the subjects were randomized to a double-blind, placebo-controlled 16-week trial (Fig 1) to evaluate asthma control by the primary outcome, the Asthma Control Questionnaire (ACQ).⁹ Secondary outcomes were morning peak expiratory flow (PEF) rates, symptom-free days and nights, rescue albuterol use, and exacerbations. We evaluated the PC₂₀ response as a determinant of ICS dependency for maintaining asthma control and other secondary outcomes by a retrospective stratification. PC₂₀ responders were defined as >1 doubling dilution over the 6-week ICS trial and nonresponders as ≤1 doubling dilution.

Procedure 

Spirometry, methacholine challenge, FeNO, and induced sputum were performed and analyzed as in previous ACRN studies.¹⁰, ¹¹ The maximum bronchodilator reversibility¹² used an initial 4 actuations (360 μg) of albuterol from a metered-dose inhaler. After 15 minutes, 3 repeat spirometric maneuvers were performed with the best FEV₁ selected. Then 2 additional albuterol actuations (180 μg) were administered, followed again by 15 minutes and repeat spirometry. If the difference in improvement between the 4 and 6 actuations was <5%, the test was terminated. If the FEV₁ rose by an additional ≥5% after these 2 additional actuations, a final 2 actuations were given. The greatest improvement from baseline was considered the maximum bronchodilator response.

Asthma control was defined by the mini ACQ, the set of 6 questions excluding FEV₁⁹; this was chosen because FEV₁ was an independent outcome measurement. A clinically significant change in the ACQ is considered to be 0.5 units. Asthma exacerbations were defined as an increase in symptoms of cough, sputum, chest tightness, wheezing, and/or shortness of breath in association with at least 1 of the following: ≥8 rescue albuterol inhalations over baseline for 48 hours or ≥16 per 24 hours; decrease in peak flow to ≤65% of baseline on 2 of 3 consecutive scheduled measurements; FEV₁ ≤ 80% of baseline; FEV₁ < 40% predicted; or need for systemic corticosteroids.¹⁰

Adherence monitoring was performed with a Doser device (Meditrak, Hudson, Mass) on the ICS metered-dose inhaler to record electronically the number and timing of an actuation. The Jaeger peak flow meter (Houston, Tex) was used for electronic recording of peak flow date and time. Subjects needed to have electronic documentation during the run-in phase of ≥85% compliance with required actuations from a placebo inhaler and ≥12 days of morning and evening peak flows to continue in the study.

Statistical analysis 

The precision to estimate whether certain biomarkers or asthma characteristics were associated with response to ICS based on FEV₁ (FeNO and bronchodilator response) and PC₂₀ (sputum eosinophils and duration of asthma) was determined on the basis of data from our previous study.⁷ We determined that a sample size of 80 subjects would allow us to estimate a 95% CI for the Kendall τ coefficient with width = 0.20 for each response (τ ± 0.10).¹³ This sample size assumed a SD of 0.4 and allowed a maximum of 20% dropouts.

For the 6-week ICS trial, the primary outcome variables were percent improvement in FEV₁ and the doubling dilution change in PC₂₀, which were both evaluated as continuous outcomes. The association between the baseline biomarkers/characteristics and the primary outcomes was evaluated by the Kendall τ coefficient for ordinal and nonnormally distributed baseline measures, and Pearson correlation coefficient for normally distributed baseline measures.

For the 4-month randomized study, asthma control was measured repeatedly throughout the duration of the trial for the 2 treatment arms stratified by the 6-week FEV₁ response/nonresponse. To incorporate appropriately all the repeated measurements from the 4-month study, a stratified repeated-measures analysis of covariance model was implemented to evaluate asthma control from the mini ACQ throughout the randomized phase of the trial. Secondary outcomes in the 4-month study (morning peak flow, rescue albuterol, FEV₁ % predicted, % symptom free days and nights) were also evaluated by stratified repeated-measures analysis of covariance models. Results are reported in terms of model-based average values adjusted for baseline values and visits. Time to exacerbation was analyzed by Kaplan-Meier curves for the 2 treatment arms stratified by FEV₁ response to ICS, and treatment arms were compared via the log-rank test within each level of stratification. Although the groups were stratified by the percent improvement in FEV₁ during the 4-month portion of the study, we were also able to examine retrospectively whether the change in PC₂₀ predicted protection against loss of asthma control. Therefore, repeated-measures analysis of covariance models evaluating asthma control and survival analysis methods evaluating time to exacerbation were also used to compare the 2 treatment arms stratified by PC₂₀ response.

The choice of >5% as the cut-point for ICS response is supported from our analysis of this study by noting that the 5% cut-point provides a better distinction of the trend that is seen in the ICS versus placebo comparison in the 4-month trial with respect to the asthma control outcomes. In other words, the asthma control outcomes for the ICS and placebo groups are more similar for the 5% nonresponders, and more different for the 5% responders, than for another corresponding classification, 7.5%. This can be determined by evaluating the stratified ICS versus placebo plots of the asthma control outcomes, as well as the stratified treatment comparisons from the repeated-measures analysis of covariance models. The treatment effect nested within FEV₁ stratification is more significant for the 5% cut-point (P = .026) than for the 7.5% cut-point (P = .052). The choice of 5% is also supported from our exacerbation analysis during the 4-month trial. Using the 5% cut-point showed a more significant reduction in exacerbation rates for the ICS versus placebo groups in the good responders defined by >5% (P = .028) than in the good responders defined by >7.5% (P = .059). This choice is also supported by the fact that it is a more conservative choice for the determination of continued ICS treatment. Using the 5% cut-point to determine who might benefit from continued ICS treatment will identify more subjects than using the 7.5% cut-point.

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Results 

Study population 

A total of 83 subjects were enrolled, with 36 men and 47 women. Thirty-eight minority (African American and Latino) individuals were enrolled. These subjects came from surrounding communities of the individual ACRN centers and not specifically from patients seen at these testing referral centers. Of the 83 enrolled subjects, 72 completed the initial 6-week trial. The reasons for dropout are described below. The baseline descriptive characteristics of the 72 subjects are shown in Table I. Because asthma is a variable disease, it is difficult to categorize severity at any given time. However, all these individuals had persistent asthma in the moderate severity range. As a group, 57% had previous oral corticosteroid use, 61% previous ICS use, with a mean FEV₁ of 72.5% predicted, 21% reversibility, ACQ score of 1.0, and methacholine PC₂₀ of 0.75 mg/mL. The exclusion criteria included no inhaled or systemic corticosteroids within 4 weeks of enrollment. The average (range) length of time off oral corticosteroids in 41 subjects who used this therapy was 33 (1-216) months. The length of time off ICS in 44 subjects with previous use was 27.4 (1.2-120) months.

Table I. Baseline descriptive characteristics for 6-week trial (n = 72)

Male/female	32/40
Minority, n (%)	32 (44.4)
Duration of asthma, n (%)
Less than 1 y	1 (1.4)
1-4 y	0 (0.0)
5-9 y	12 (16.7)
10-14 y	10 (13.9)
15 y or more	49 (68.1)
Oral corticosteroid use, n (%)	41 (56.9)
Mean time since use, mo (range)	33 (1-216)
ICS use, n (%)	44 (61)
Mean time since use mo (range)	27.4 (1.2-120)
	Mean ± SD
Age (y)	33.15 ± 9.14
FEV1 (L)	2.64 ± 0.65
FEV1 % predicted	72.63 ± 10.64
Maximum reversibility (%)	20.98 ± 16.85
Average ACQ score	1.00 ± 0.68
Nitric oxide (ppb)∗	13.9, 9.5, 25.8
Sputum eosinophils (%)∗	1.50, 0.40, 3.30
Methacholine PC20 (mg/mL)† (n = 69)	0.75, 1.22
IgE (IU)†	206.7, 1.38

Six-week ICS period 

Seventy-two subjects completed the 6-week trial. On ICS, 11 subjects did not complete the initial ICS 6-week study and were dropped for the following reasons: serious adverse events, 2; significant asthma exacerbation, 3; other exclusion criteria, 2; consent withdrawn, 1; and lost to follow-up, 3.

The FEV₁ increased from a baseline mean ± SE of 2.62 ± 0.07 L to 2.84 ± 0.07 L (P < .001). There were 39 subjects (54%) who were ICS responders and 33 subjects (46%) who were nonresponders. The distribution of responses can be seen in Fig 2. The responders had significantly lower % predicted FEV₁ and FEV₁/forced vital capacity (FVC) ratio at baseline than the nonresponse group (Table II). Sputum eosinophils and FeNO were not different between the groups (Table II).

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• Fig 2. 

  The FEV₁ distribution response to inhaled corticosteroid over the short-term 6-week trial. Bars represent 5% increments in FEV₁ response.

Table II. Baseline FEV₁ (% predicted) and FEV₁/FVC for ICS responders and nonresponders

IQR, Interquartile range.

The PC₂₀ geometric mean (coefficient of variation) at baseline was 0.76 mg/mL (1.22) and with ICS treatment was 1.11 mg/mL (1.25). The doubling dose increased by 0.60 ± 0.20 (P = .003). There were 28 subjects (39%) who were ICS responders (>1 doubling dilution), and 43 nonresponders (1 subject did not have the follow-up PC₂₀ because of technical problems).

Table III demonstrates the biomarkers and characteristics predicting the FEV₁ response. The predictors with strong correlation for ICS response were maximum albuterol reversibility with a correlation of r = 0.83 (P < .001). The initial 4 albuterol actuations were tightly linked to the maximal response (r = 0.93). The FEV₁/FVC ratio was also significantly correlated to the ICS FEV₁ response (r = −0.75; P < .001), as was the baseline FEV₁ % predicted (r = −0.71; P < .001).

Table III. Biomarkers and characteristics predicting ICS response

K, Kendall τ-b correlation coefficients reported for ordinal and skewed predictors; P, Pearson correlation coefficients reported for normally distributed predictors.

To separate the effect of a low baseline FEV₁ and maximum albuterol reversibility on FEV₁ response to an ICS, both predictors were included simultaneously in a regression model. The baseline FEV₁ was no longer a significant predictor (P = .21), whereas baseline maximum reversibility remained a significant predictor (P < .001).

The biomarkers and characteristics predicting BHR (PC₂₀; Table III) showed a poor correlation coefficient for sputum eosinophils of r = 0.04 (P = .59). Asthma duration was in the opposite direction of our initial study in that we found a longer duration of asthma predicted a greater change in PC₂₀ (r = 0.23; P = .008). No biomarker or characteristic approached a correlation coefficient of ≥± 0.6.

To determine whether previous use of either an ICS or systemic corticosteroid influenced the 6-week ICS response, no past use (n = 19) and past use (n = 52) were compared. For the percent change in FEV₁, the responses were 4.9% ± 16.2% and 10.9% ± 16.4%, respectively (P = .18). For PC₂₀ (log 2 scale), the responses were 0.53 ± 2.0 and 0.57 ± 1.5, respectively (P = .94).

Sixteen-week double-blind trial 

The characteristics that describe the responders and nonresponders at the start of the 16-week double blind trial are shown in Table IV. Induced sputum cell differential of responders and nonresponders to ICS at the start of the long-term trial is shown in Fig 3. There were no significant differences in cell differential between groups. There was a trend to increased percentage of eosinophils in the responder group.

Table IV. Baseline descriptive characteristics at the start of the 16-week trial

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• Fig 3. 

  Induced sputum characteristics stratified by inhaled corticosteroid response (post 6-week trial, before long-term trial). Horizontal lines represent 25th, 50th, and 75th percentiles.

Asthma control measured by the mini ACQ and stratified by FEV₁ response demonstrated the following (Fig 4; Table V). For subjects who were nonresponders to ICS during the 6-week trial, it did not matter whether they were maintained on ICS (ACQ, 0.80 ± 0.13) or switched to a placebo (0.81 ± 0.13) for the 16-week trial. The ACQ was not different over the period of the next 16 weeks (P = .99). Conversely, for the subjects who were ICS responders short-term, those maintained on ICS maintained their asthma control (0.74 ± 0.12), whereas those placed on a placebo had worse asthma control (1.23 ± 0.13; P = .007).

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• Fig 4. 

  Asthma control as measured by the ACQ over the 16-week ICS or placebo (PBO) continuation trial. The groups are categorized on the basis of the FEV₁ results of the previous 6-week ICS trial: nonresponders ≤5% improvement on ICS; responders >5% improvement on ICS. The only significant within-group difference occurred between PBO and ICS responder groups (P = .007).

Table V. Four-month ICS outcome measures, longitudinal analysis

Secondary outcomes are shown in Table V. Similar to the ACQ results, these secondary outcomes demonstrate that for the nonresponders to ICS in the short term, similar results were obtained independent of being maintained on the ICS for the next 4 months. However, if an ICS response was demonstrated in the short term, maintaining good overall asthma stability depended on the maintenance of ICS.

For the ICS nonresponders, with regard to PC₂₀ stratification, the ACQ was similar regardless of whether maintained on ICS or not (0.84 ± 0.12 vs 0.91 ± 0.13, respectively; P = .65). The secondary outcomes for the nonresponders were also similar and not significantly different. For the ICS responders, the ACQ was significantly better on ICS (0.68 ± 0.14) compared with placebo (1.16 ± 0.16; P = .02). The secondary outcomes also were improved with ICS maintenance.

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Discussion 

This ACRN protocol prospectively evaluated biomarkers and characteristics associated with ICS response and, in addition, determined whether a short-term response or lack of response to ICS predicted longer-term asthma control. With regard to biomarkers and characteristics as predictors of ICS response, only the response to a short-acting β₂-agonist (albuterol), low percentage predicted FEV₁, and FEV₁/FVC ratio had a strong (r ≥± 0.6) correlation with response. Of potential importance was the observation that a short-term nonresponse to ICS, 6 weeks with ≤5% FEV₁ improvement, indicated that these individuals may not need ICS in their treatment program. That is, whether they were maintained on or taken off ICS, asthma control and other secondary outcomes of response were maintained and similar. It is important to note that of the 33 poor short-term ICS responders, 17 were maintained on ICS long-term, and 3 of these improved their FEV₁ to the responder range after 4 additional months on ICS. The long-term ICS improvement in FEV₁ for these 3 subjects (16%, 14.5%, and 12.3%) did not necessarily coincide with the baseline maximal β₂-agonist reversibility (21.6%, 3.0%, and 11.7%, respectively). For the subjects with a short-term ICS response in FEV₁, defined as improvement >5%, who were subsequently taken off ICS, their asthma control worsened compared with subjects maintained on ICS (P = .007). Secondary response outcomes had similar findings.

Although the previous ACRN study retrospectively demonstrated that albuterol response, FEV₁/FVC, FeNO, sputum eosinophils, and shorter duration of asthma diagnosis predicted ICS response for FEV₁ or BHR,⁷ the present prospective study only showed the albuterol response, % predicted FEV₁, and FEV₁/FVC as strong predictive biomarkers. The inclusion and exclusion criteria were similar between the studies as well as the baseline lung function and BHR. For the current study compared with the previous study, the baseline FEV₁ was 73% versus 74% predicted and PC₂₀ 0.75 versus 0.52 mg/mL, respectively. However, the biomarkers appeared different between the current study and the previous report. The FeNO was slightly lower in the current study, 13 versus 16 ppb, respectively. The current study had a higher percentage of subjects with an asthma diagnosis greater than 15 years, 71% versus 64%, and sputum eosinophils, 1.5% versus 1.0%, respectively. A similar β₂-agonist response was seen between studies, 21% versus 20%. Thus, besides the important difference between prospective and retrospective study analyses, some differences in baseline biomarkers could also have added to the differing study results.

Other investigators have suggested that FeNO and sputum eosinophils are markers of corticosteroid response. Little et al¹⁴ reported that elevated levels of FeNO and sputum eosinophils before treatment were predictors of improvement in FEV₁ with a course of oral corticosteroids. Smith et al¹⁵ reported in 52 patients presenting with undiagnosed respiratory symptoms (27 asthmatic diagnoses) that the FeNO tertile of >47 ppb predicted the greatest ICS response for all endpoints that they measured. For the 27 subjects with asthma, the FeNO >47 ppb resulted in a 14.8% ± 6.4% increase in FEV₁ after 4 weeks of ICS (fluticasone 500 μg/d) therapy. In subjects with an FeNO 15 to 47 ppb, improvement in FEV₁ was only 7.3% ± 4.7%, and if <15 ppb, the improvement was 2.2% ± 4.9%. Our study, using different methodology for FeNO measurement, did not demonstrate a significant correlation between FeNO and ICS improvement in FEV₁. However, as with most reported studies, we had very few individuals with FeNO > 47 ppb. With respect to sputum eosinophils, Pavord et al¹⁶ demonstrated a significant positive correlation between sputum eosinophils and the improvement in PC₂₀ with ICS treatment. Bacci et al¹⁷ also demonstrated that improvement with ICS occurred in subjects with eosinophils >3% for FEV₁, BHR, and symptoms. However, long-term asthma control was not determined in either study. We also found a significant correlation between sputum eosinophils and FEV₁ improvement with ICS (P = .04), but the correlation was weak (r = 0.17). In addition, at the present time, induced sputum is not a practical clinical test.¹⁸

Szefler et al¹⁹ in children 6 to 17 years of age defined response to an ICS, fluticasone propionate, as an improvement of >7.5%. Only 40% of these subjects with asthma were responders to the ICS. Those that did respond had greater allergic inflammation (increased IgE, circulatory eosinophils, serum eosinophils cationic protein), increased FeNO, lower lung function, and decreased PC₂₀. We also found the lower FEV₁ relationship to exist in adults. Those subjects who were responders to ICS over the 6-week trial had a lower starting FEV₁ (68% predicted) compared with the nonresponders (77% predicted). Thus, airway caliber may play a role indicating ICS responsiveness to some extent, but not totally, because when low FEV₁ was combined with maximum albuterol reversibility in a regression model, the low FEV₁ was no longer a predictor of ICS response.

Deykin et al²⁰ demonstrated that the change in the percentage of induced sputum eosinophils during the first 2 weeks after ICS cessation was a useful predictor of subsequent deterioration of asthma control. Neither FeNO nor methacholine PC₂₀ was robust for being able to predict stability or deterioration on ICS withdrawal. Of interest, it was estimated that 48% of subjects with mild-to-moderate asthma could discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks. Either the previous ICS eliminated the inflammatory process or these subjects were poor responders to begin with. When prospective monitoring of either FeNO²¹ or sputum eosinophils²² has been used as a reference point to guide ICS dosing strategies, it has been found to be superior to standard care in maintaining control while minimizing ICS dosing burden over time. However, these trials answered different questions than those posed by the ACRN study.

Because it appears that predictive biomarkers and characteristics can give varying results, our observation suggests an intriguing possibility that the use of a simple short-term ICS trial (6 weeks) based on FEV₁ change appears to be a good indicator of longer-term asthma control in our study population. Of the short-term nonresponders to ICS, it did not matter whether they were maintained on or removed from this medication with regard to their long-term asthma control and other secondary outcome measures. Conversely, for short-term responders, long-term asthma control and secondary outcome measures were maintained with the continued use of ICS compared with removing this agent from the therapeutic regimen. Although the ICS-induced change in PC₂₀ to methacholine had some predictive value, these results were not as strong as for FEV₁. In addition, BHR testing is not as practical for office practice use as spirometry.

The duration of both the short-term (6-week) and long-term (4-month) trials can be critiqued for their relatively short time intervals. We chose a 6-week short-term interval because our previous study⁷ demonstrated that if a subject did not respond with regard to FEV₁ or PC₂₀ in 6 weeks, progressive increases in ICS dosing over the next 15 weeks did not produce a further change in the results. Furthermore, Szefler et al²³ analyzed 8 randomized, double-blind, placebo-controlled clinical trials with duration of at least 8 weeks and determined that the best observed effect with ICS occurred within 3 to 4 weeks for PEF, asthma symptoms, supplemental albuterol use, and FEV₁. As to long-term asthma control, no study has addressed the issue of the length of time ICSs are needed to be used to determine maximal benefit. However, for good to total asthma control, Bateman et al⁸ demonstrated that even when the dose of fluticasone-salmeterol combination was increased to 500/50 μg for 1 year and a 2-week oral corticosteroid burst was added, approximately 30% of subjects with asthma still were not well controlled depending on severity at enrollment.

In summary, the short-term response to ICS leading to FEV₁ improvement appears to predict long-term asthma control. With this relatively simple office procedure, spirometry, a determination of response can guide decision making in those patients who are ICS naive or have been off ICS for a time about the continued use of ICS or elimination of it from the therapeutic regimen. However, it must be stressed that these results need to be confirmed in larger, longer-term studies. If these follow-up studies indeed validate the results of our study, different therapeutic strategies would need to be established for the ICS nonresponders.

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We are indebted to Reuben Cherniack, MD (National Jewish Medical and Research Center, Denver), James P. Kiley, PhD, and Hector G. Ortega, MD, ScD (NHLBI, Bethesda, Md), for their valuable contributions to the design, conduct, and interpretation of this study. Additional thanks to the members of the Protocol Review Committee and the Data Safety Monitoring Board. Ivax Laboratories, Inc, supplied the study drug and placebo.

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