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Original Research: ASTHMA |

Sputum Eosinophils and the Response of Exercise-Induced Bronchoconstriction to Corticosteroid in Asthma* FREE TO VIEW

MyLinh Duong, MBBS; Padmaja Subbarao, MD, MSc; Ellinor Adelroth, MD, PhD; George Obminski, BSc; Tara Strinich, BSc; Mark Inman, MD, PhD; Soren Pedersen, MD, PhD; Paul M. O’Byrne, MB, FCCP
Author and Funding Information

*From the Department of Medicine (Drs. Duong, Inman, and O’Byrne, Mr. Obminski, and Ms. Strinich), McMaster University, Hamilton, ON, Canada; Hospital for Sick Children (Dr. Subbarao), University of Toronto, Toronto, ON, Canada; Umea University (Dr. Adelroth), Umea, Sweden; and the University of Southern Denmark (Dr. Pedersen), Kolding, Denmark.

Correspondence to: MyLinh Duong, MBBS, McMaster University, 1200 Main St West, Room 3U-24, Hamilton, ON, Canada L8N 3Z5; e-mail: duongmy@mcmaster.ca



Chest. 2008;133(2):404-411. doi:10.1378/chest.07-2048
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Background: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined.

Methods: Twenty-six steroid-naïve asthmatic patients with EIB were randomized to two parallel, double-blind, crossover study arms (13 subjects in each arm). Each arm compared two dose levels of inhaled ciclesonide that were administered for 3 weeks with a washout period of 3 to 8 weeks, as follows: (1) 40 vs 160 μg daily; and (2) 80 vs 320 μg daily. Baseline and weekly assessments with exercise challenge and sputum analysis were performed.

Results: Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia ≥ 5%. Only high-dose ICS therapy (ie, 160 and 320 μg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 μg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of < 5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time.

Conclusions: These results suggest that eosinophilic airway inflammation may be important in modifying the severity of EIB and the response to ICS therapy. Measurements of sputum eosinophil percentage may, therefore, be useful in predicting the magnitude and temporal response of EIB to different dose levels of ICSs.

Trial registration: clinicaltrial.gov; Identifier: NCT00525772

Figures in this Article

Eosinophils may be important in the pathophysiology of exercise-induced bronchoconstriction (EIB) and the response to therapy in patients with chronic asthma. In vitro studies1have demonstrated that eosinophils generate and release cysteinyl leukotrienes when subjected to a hyperosmolar stimulus, which is an important condition that provokes EIB. Cysteinyl leukotrienes are potent bronchoconstrictor mediators that are implicated in EIB.2Furthermore, the presence and severity of EIB is significantly correlated to eosinophil levels measured in the blood and sputum of asthmatic patients.36 Beyond these observations, the relationship between eosinophilic inflammation and EIB has not been fully explored.

In the present study, the relationship among sputum eosinophil levels, EIB, and the response to ICS therapy was examined. We previously reported on the heterogeneity of the response in EIB to four different doses of ciclesonide, as suggested by an increase in the coefficient of variability of the fall in FEV1 with exercise during treatment compared to baseline.7 From the same data, we now report on the secondary outcomes, examining the correlation between sputum eosinophil levels and EIB; and whether sputum eosinophil percentages predict the response of EIB to inhaled corticosteroid (ICS) therapy. We hypothesized that airway eosinophils contribute to the mechanisms underlying EIB and the therapeutic effect of ICS therapy. Therefore, high sputum eosinophil levels predict a greater severity in EIB and a response to ICS therapy that is mediated through the suppression of eosinophilic inflammation. In contrast, low eosinophil count is associated with relative ICS insensitivity, which cannot be overcome by increasing the dose or duration of ICS therapy.

Asthmatic subjects between 12 and 30 years of age and a baseline FEV1 of ≥ 70% predicted were enrolled into the study. All subjects demonstrated a maximum percentage fall in FEV1 from baseline after exercise challenge of ≥ 15% (%FEV1 fall) at screening and after a 1-week run-in period. Exclusion criteria included unstable asthma (≤ 6 weeks), regular medication use (except salbutamol), comorbidity, and current or ex-smokers with a history of ≥ 10 pack-years of smoking. Subjects were randomized to the following two parallel, double-blind, crossover arms, with each arm comparing two doses of ciclesonide: 40 vs 160 μg once daily and 80 vs 320 μg once daily for 3 weeks, with a washout period of 3 to 8 weeks. The data were pooled to give two dose levels of ICS therapy (low-dose therapy, 40 and 80 μg; high-dose therapy, 160 and 320 μg), based on previous findings that low doses (equivalent to budesonide, ≤ 100 μg daily) are ineffective in attenuating chronic sputum eosinophilia89; therefore, we anticipate ICS therapy having a limited effect on attenuating EIB. Each period comprised four visits, as follows: baseline; and weekly visits with an exercise challenge and sputum induction. The last dose of ciclesonide was administered 12 h prior to visits. Compliance was assessed by the weighing of canisters. The study was approved by the hospital research ethics board and informed consent was obtained from participants.

Spirometry was performed according to American Thoracic Society standards and reference values taken from Hankinson et al.10 Exercise challenge7 was performed on a treadmill for 8 min with continuous heart-rate monitoring and the patient breathing dry air (temperature, 21°C; relative humidity, < 10%). The treadmill was at a 10% incline, and the speed was adjusted to achieve 90% of the predicted maximum heart rate (210 − age) for the last 4 min of the test. After, the speed was reduced, and subjects walked while breathing dry air for another 2 min. FEV1 was measured at baseline, and at 2, 4, 6, 8, 10, 15, 20, and 30 min postexercise. The severity of EIB was expressed as the %FEV1 fall postchallenge (ie, preexercise FEV1 − lowest FEV1 postexercise/preexercise FEV1 × 100). Area under the curve for FEV1 fall up to 30 min postexercise (AUC0–30) was calculated using the trapezoidal rule.

Sputum induction and processing were performed as previously described11 with selected cell plugs treated with 0.1% dithiothreitol (Sputolysin; Calbiochem Corp; La Jolla, CA) and Dulbecco phosphate-buffered saline solution (Life Technologies Inc; Gaithersburg, MD). This sample was filtered and centrifuged, and the supernatant was separated. Total cell count (TCC) was determined using a Neubauer hemocytometer chamber (Hausser Scientific; Horsham, PA) and cytospins prepared on slides. Differential cell counts were performed manually (400 nonsquamous cells and metachromatic cells of a total of 1,500 cells). Results are expressed as the percentage of the TCC.

Statistical Analysis

This was a pilot study with 24 subjects as no data were available on the variability of the difference in EIB attenuation caused by ICS therapy. Subjects were divided into noneosinophilic and eosinophilic groups using a baseline sputum eosinophil cutoff of 5%.12 Sputum cell percentages were log-transformed. To compare the dose-time response of the %FEV1 fall, AUC0–30, and sputum cell percentage, a multiplicative analysis-of-variance model was used with the following factors: dose; visit; treatment sequence, and eosinophilic group. A mixed-effect regression model was used to examine the rate (slope) of improvement in %FEV1 fall over time by dose. The significance of eosinophil percentage as a predictor of severity and the response to ICS therapy was tested by its interactions with baseline %FEV1 fall and the rate of change in %FEV1 fall over time. A p value (two-sided) of ≤ 0.05 was accepted as significant. All analyses were performed using a statistical software package (SPSS, 12.0; SPSS, Inc; Chicago, IL).

Twenty-six subjects (16 male subject) were enrolled into the study. The ratio of enrolled to screened subjects was 1:3 (Fig 1 ). One subject was excluded from all analyses due to inadequate sputum sample production, one subject did not crossover due to insufficient %FEV1 fall after washout, and another subject missed one visit due to a musculoskeletal injury. All data were included up to the time of study withdrawal. Compliance with ciclesonide therapy was ≥ 90%.

Subject characteristics stratified by the baseline percentage of sputum eosinophils are shown in Table 1 . The correlation between %FEV1 fall and sputum eosinophil percentage was significant at baseline and for all subsequent visits (Fig 2 ).

Baseline sputum eosinophil percentage and %FEV1 fall were not significantly different between dose periods. Treatment with high doses (ie, 160 or 320 μg) resulted in a significant reduction in sputum eosinophil percentage for all treatment visits when compared to baseline (Table 2 ). No significant difference among treatment weeks 1, 2, and 3 was seen. Low doses (ie, 40 or 80 μg) provided no significant change from baseline in sputum eosinophil percentage. The comparison of the changes from baseline between dose levels was not significant. No treatment effect was observed for other sputum cell count percentages.

Baseline %FEV1 fall was consistently greater for the eosinophilic group compared to the noneosinophilic group (Fig 3 , Table 3 ). Treatment with low doses resulted in significant improvement in %FEV1 fall for all treatment weeks compared to baseline but not among treatment weeks 1, 2, and 3. The improvement in EIB was the same irrespective of baseline sputum eosinophil percentage during low-dose therapy; as the changes from baseline for all weeks were not significantly different between groups. In contrast, treatment with high doses resulted in an EIB response over time that was significantly different between inflammatory groups. Both groups demonstrated a reduction in %FEV1 fall that was significant for all treatment weeks. However, the improvement was significantly greater for the eosinophilic subject (vs noneosinophilic subjects) at weeks 2 and 3. Furthermore, eosinophilic subjects had a significantly greater response to high-dose ciclesonide compared to low-dose ciclesonide at weeks 2 and 3. Whereas noneosinophilic subjects demonstrated no difference in EIB response to the two dose levels. Similar results were found for the AUC0–30 response. Similar analysis was performed with a sputum eosinophil cutoff of 3% to ensure that the results were not sensitive to the cutoff threshold. The outcome remained unchanged, showing significant improvement from baseline for all weeks for both dose levels. The mean (± SE) magnitude of change in %FEV1 fall for the treatment weeks was not significantly different between the noneosinophilic group (n = 14; weeks 0, 21.5 ± 2.8%; week 1, 12.2 ± 1.8%; week 2, 12.8 ± 1.6%; week 3, 13.2 ± 1.7%) and the eosinophilic group (n = 8; week 0, 32.6 ± 3.5%; week 1, 24.8 ± 3.6%; week 2, 23.9 ± 3.8%; week 3, 24.7 ± 3.8%) during low-dose therapy (p > 0.05), but was significantly greater for eosinophilic subjects (week 0, 38.1 ± 5.6%; week 1, 32.1 ± 6.4%; week 2, 23.9 ± 6.5%; week 3, 17.7 ± 5.3%) vs noneosinophilic subjects (week 0, 24.2 ± 3%; week 1, 15.9 ± 3.7%; week 2, 12.6 ± 2.4%; week 3, 14.8 ± 2.4%) during high-dose therapy (p = 0.012).

Regression analysis showed that sputum eosinophil percentage was a significant predictor of baseline EIB severity. During high-dose therapy, sputum eosinophilia also predicted a slope of improvement in EIB that increased over time with no sign of leveling off at 3 weeks (Fig 2). Low eosinophil percentage predicted a significant initial slope of improvement, which then leveled off. In contrast, the percentage of sputum eosinophils had no effect on the slope of EIB improvement during low-dose treatment with an initial improvement at week 1 and leveling off thereafter in both inflammatory groups. No correlation was found between baseline %FEV1 fall and the slopes of improvement over time with treatment.

In steroid-naïve asthmatic subjects with EIB, we demonstrated that 40% had elevated (≥ 5%) baseline sputum eosinophil percentage counts. These subjects had a greater fall in FEV1 following a standardized exercise challenge. Sputum eosinophil percentage was significantly correlated to and was an independent predictor of EIB severity. Treatment with low and high doses of ciclesonide resulted in significant reduction in %FEV1 fall postexercise at 1 week. The subsequent temporal improvement in EIB was determined by the ICS dose and the presence of sputum eosinophils. Only high-dose ICS therapy significantly suppressed sputum eosinophil percentage counts.

Previous studies1315 have shown that sputum eosinophils are a marker for the response to ICS therapy in patients with nonexercise asthma. Our study is the first to show that sputum eosinophils also predicted a response in EIB and the temporal relationship of EIB response to different dose levels of ICSs. The potential implication of these findings is that sputum eosinophil percentage may be useful in predicting the response, the dose, and the duration of ICS therapy needed to treat EIB. This is relevant in patients who may require maintenance therapy for reasons of concurrent symptomatic chronic asthma or failure to use prophylactic therapies for EIB. In this case, sputum eosinophil percentage helps to predict the kinetics of the exercise response to ICS therapy and to assist in the choice of dosing and the expected time of maximal therapeutic response to ICS therapy. We observed that subjects with low sputum eosinophil percentages benefit to the same extent from low-dose and high-dose ICS therapy without any apparent dose-response effect. This response was time-independent, demonstrating a limited improvement (≤ 50% attenuation) in %FEV1 fall in the first week with little additional subsequent change. In contrast, subjects with high baseline sputum eosinophil levels showed a dose-dependent and time-dependent response to ICS therapy. Compared to low doses of ICSs, high doses provided a greater improvement at 2 weeks (%FEV1 fall attenuation, 26% vs 37%, respectively), and the difference was greater by 3 weeks (%FEV1 fall attenuation, 28% vs 51%, respectively). Indeed, at 3 weeks the eosinophilic group achieved a mean %FEV1 fall that was similar to the noneosinophilic counterpart (eosinophilic group, 19.1 ± 5.8%; noneosinophilic group, 14.3 ± 2.3%) with high-dose treatment, while the difference in %FEV1 fall between the two inflammatory groups remained significant throughout low-dose therapy. There was no correlation between baseline %FEV1 fall and the slopes of change with treatment in the regression model, indicating that the difference in the rate of improvement between the two inflammatory groups during high-dose ICS therapy was not related to differences in baseline EIB severity. This is in accordance with the findings from other studies.17 Similarly, this difference cannot be explained by regression to the mean; otherwise, we would expect the difference to be present during low-dose therapy. Furthermore, there was no difference in baseline sputum eosinophil percentage or %FEV1 fall between the two dose levels, making regression to the mean an unlikely cause for the difference in the exercise and eosinophilic response to high-dose therapy vs low-dose therapy.

Similar to previous studies,3,56 we found a significant but modest correlation between sputum eosinophils and EIB severity at baseline. Moreover, the correlation remained significant during ICS therapy, suggesting that both phenotypes may share common pathophysiologic mechanisms that are steroid-responsive. Like previous findings,89 we found therapy with low-dose ICSs (ie, ≤ 100 μg of budesonide equivalent) was ineffective in suppressing chronic sputum eosinophilia and was also limited in its effect on EIB; whereas, higher doses that significantly suppressed sputum eosinophil levels provided greater improvement in EIB. Together, it is conceivable that airway eosinophils may contribute to the mechanisms underlying EIB and that ICS therapy provides additional benefit to EIB in patients with sputum eosinophilia by attenuating eosinophilic inflammation. Also noteworthy is the slope of improvement in eosinophilic subjects who are receiving high-dose ICS therapy at 3 weeks, showing no sign of flattening out despite reaching a similar severity of %FEV1 fall as the noneosinophilic subjects. This difference in the response curves at similar degrees of EIB severity support the notion that these inflammatory groups are distinct; the former being dominated by mechanisms that are steroid-responsive and the latter by relative nonresponsive pathways. Otherwise, we would expect the response curve for the eosinophilic group to show signs of flattening out and resembling that of the noneosinophilic subjects, if both were pathophysiologically similar and differed only in the degree of severity.

There are limitations to our study. First, the sample size was small, and larger studies are needed to corroborate these findings. This was a pilot study designed to examine the utility of the exercise model to assess the relative potency of ICS therapy.7 Therefore, a larger sample size would make the use of an exercise methodology impracticable. Nonetheless, a retrospective power calculation showed that with 24 subjects, the power to detect a 50% attenuation in exercise response (p < 0.05) at 3 weeks for both dose levels was 70 to 75%. Second, combining the lower doses (ie, 40 and 80 μg) and the higher doses (ie, 160 and 320 μg) may have affected the study outcomes. If this was the case, we would expect the treatment effect to be diluted and the difference observed between the two dose levels to be reduced. Third, a cutoff of 5% for airway eosinophilia may be considered high compared to the previous cutoff of 3%.,18 Our threshold was based on local data in healthy control subjects from our center demonstrating that the absolute upper limit was 5%.12 This took into account local factors that might lead to a slight variation in the upper limit of normal range between populations. To ensure that our results were not sensitive to the threshold, we also performed the analyses using a 3% cutoff, which changed the classification of one subject from the noneosinophilic group to the eosinophilic group. The overall outcome or conclusions, however, remained unchanged. Last, we did not examine other markers of airway inflammation that may have served as better predictors of EIB response than sputum eosinophils. In this regard, a review of the literature supported our choice of sputum eosinophils, since previous studies35 have shown that blood eosinophils failed to consistently correlate with EIB severity, which is in keeping with nonexercise asthma where sputum eosinophils are more accurate in reflecting airway inflammation.19 Similarly, methacholine hyperresponsiveness has not been found to consistently correlate with EIB,6,2021 but instead to baseline FEV1, and to demonstrate a dose and temporal response to ICS therapy that is different than the EIB response.22 This suggests that the two phenotypes reflect different underlying pathophysiologic mechanisms. Finally, the correlation between exhaled nitric oxide and EIB severity is significant before ICS therapy2324 but not after ICS therapy,24 indicating that this marker may not be useful in the monitoring of the response during ICS therapy.

Despite these limitations, our findings provided useful insights into the heterogeneity of EIB and the response to ICS therapy. It draws attention to the potential interactions between the different pathways and the facets of asthma contributing to the variability in disease manifestations and response to therapy. As shown in the present study, sputum eosinophils as a marker of eosinophilic airway inflammation may modify the severity and response of EIB to ICS therapy at different dose levels. Future studies are needed to further examine the clinical utility of sputum eosinophil count in selecting the appropriate therapy, dose, and duration of treatment of EIB in patients with asthma.

Abbreviations: AUC0–30 = area under the curve for FEV1 fall up to 30 min postexercise; EIB = exercise-induced bronchoconstriction; %FEV1 fall = maximum percentage fall in FEV1 from baseline after exercise challenge; ICS = inhaled corticosteroid; TCC = total cell count

Some of the data from this article was presented in abstract form at the AAAAI Meeting, March 2005, San Antonio, TX; the American Thoracic Society Meeting, May 2005, San Diego, CA; and was published in the Journal of Allergy and Clinical Immunology.

The study was conducted at the Asthma Research Department, McMaster University, Hamilton, ON, Canada.

This study was funded in part by Altana Pharma AG.

Dr. O’Byrne has received consulting fees from Altana, AstraZeneca, Biolipox, GlaxoSmithKline, Resistentia, and Topigen, and honoraria for speaking from Altana, AstraZeneca, Chiesi, GlaxoSmithKline, and Ono Pharma. In addition, he has received grants-in-aid from Altana, AstraZeneca, Biolipox, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Medimmune, Merck, Pfizer, Topigen, and Wyeth. Dr. Pedersen has received lecture and consultancy fees from Altana, AstraZeneca, and GlaxoSmithKline. Dr. Inman has received research funding from Merck, GlaxoSmithKline, and AstraZeneca. Dr. Duong, Dr. Subbarao, Dr. Adelroth, Mr. Obminski, and Ms. Strinich have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Flow diagram of the number of subjects screened and randomized.Grahic Jump Location
Table Graphic Jump Location
Table 1. Subject Characteristics at Screening Stratified by Baseline Sputum Eosinophil Count*
* 

Values are given as the mean ± SE, unless otherwise indicated. ED = emergency department.

 

Symptoms and rescue medication use (including for exercise) averaged over 7 days. Daily symptoms were rated on a Likert scale from 0 to 4 (4, worse).

 

p < 0.05 (Student t test between eosinophilic groups).

§ 

p < 0.005 (Student t test between eosinophilic groups).

Figure Jump LinkFigure 2. %FEV1 fall and sputum eosinophil percentage for all visits.Grahic Jump Location
Table Graphic Jump Location
Table 2. Weekly Sputum Differential Cell Counts in Response to Ciclesonide Therapy*
* 

Values given as the geometric mean ± SE, unless otherwise indicated.

 

Values given as arithmetic mean ± SE.

 

p < 0.05 (vs week 0 on analysis of variance for sample size of 20).

§ 

p < 0.05 (vs week 0 on analysis of variance for sample size of 20).

Figure Jump LinkFigure 3. Exercise response to low-dose and high-dose ciclesonide therapy according to baseline sputum eosinophil counts. The data are presented as the mean ± SE. □, noneosinophilic group (< 5% eosinophils; n = 13); ▪, eosinophilic group (≥ 5% eosinophils; n = 10). Changes from baseline were compared within a group (*) and between groups (#) for each dose level at p < 0.05 (analysis of variance). The arrows indicate the effect was seen for both groups. Only the sputum eosinophilic group showed a significantly greater change from baseline to high ICS dose compared to low ICS dose (Ψ).Grahic Jump Location
Table Graphic Jump Location
Table 3. Weekly %FEV1 Fall in Response to Low-Dose and High-Dose Ciclesonide Therapy*
* 

Data are presented as mean ± SE, unless otherwise indicated.

 

Comparison of the change from baseline by week of treatment between noneosinophilic vs eosinophilic groups (within dose).

 

Comparison of the change from baseline by week of treatment between low-dose and high-dose therapy (within sputum group) [by analysis of variance].

§ 

Change from baseline significant at p < 0.05.

Moloney, ED, Griffin, S, Burke, CM, et al (2003) Release of inflammatory mediators from eosinophils following a hyperosmolar stimulus.Respir Med97,928-932. [PubMed] [CrossRef]
 
O’Byrne, PM Leukotriene bronchoconstriction induced by allergen and exercise.Am J Respir Crit Care Med2000;161,S68-S72. [PubMed]
 
Per Venge, P, Henriksen, J, Dahl, R Eosinophils in exercise-induced asthma.J Allergy Clin Immunol1991;88,699-704. [PubMed]
 
Koh, YI, Choi, IS Blood eosinophil counts for the prediction of the severity of exercise-induced bronchospasm in asthma.Respir Med2002;96,120-125. [PubMed]
 
Otani, K, Kanazawa, H, Fujiwara, H, et al Determinants of the severity of exercise-induced bronchoconstriction in patients with asthma.J Asthma2004;41,271-278. [PubMed]
 
Yoshikawa, T, Shoji, S, Fujii, T, et al Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma.Eur Respir J1998;12,879-884. [PubMed]
 
Subbarao, P, Duong, M, Adelroth, E, et al Effect of ciclesonide dose and duration of therapy on exercise-induced bronchoconstriction in patients with asthma.J Allergy Clin Immunol2006;117,1008-1013. [PubMed]
 
Jatakanon, A, Kharitonov, S, Lim, S, et al Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma.Thorax1999;54,108-114. [PubMed]
 
Taylor, DA, Jensen, MW, Kanabar, V, et al A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5-monophosphate in asthmatic patients.Am J Respir Crit Care Med1999;160,237-243. [PubMed]
 
Hankinson, J, Odencrantz, J, Fedan, KB Spirometric reference values from a sample of the general US population.Am J Respir Crit Care Med1999;157,179-187
 
Pizzichini, E, Pizzichini, M, Efthimiadis, A, et al Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements.Am J Respir Crit Care Med1996;154,308-317. [PubMed]
 
Belda, J, Leigh, R, Parameswaran, K, et al Induced sputum cells counts in healthy adults.Am J Respir Crit Care Med2000;161,475-478. [PubMed]
 
Hargreave, FE Induced sputum and responses to glucocorticoids.J Allergy Clin Immunol1998;102,S102-S105. [PubMed]
 
Szefler, SJ, Martin, RJ, King, TS, et al Significant variability in response to inhaled corticosteroids for persistent asthma.J Allergy Clin Immunol2002;109,466-469
 
Szefler, SJ, Phillips, BR, Martinez, FD, et al Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.J Allergy Clin Immunol2005;115,233-242. [PubMed]
 
Henriksen, JM, Dahl, R Effects of inhaled budesonide alone and in combination with low dose terbutaline in children with exercise-induced asthma.Am Rev Respir Dis1983;128,993-997. [PubMed]
 
Pederson, S, Hansen, O Budesonide treatment of moderate and severe asthma in children: a dose response study.J Allergy Clin Immunol1995;95,29-33. [PubMed]
 
Green, RH, Brightling, CE, McKenna, S, et al Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet2002;360,1715-1721. [PubMed]
 
Pizzichini, E, Pizzichini, M, Kidney, JC, et al Induced sputum, bronchoalveolar lavage and blood from mild asthmatics: inflammatory cells, lymphocyte subsets and soluble markers compared.Eur Respir J1998;11,828-834. [PubMed]
 
Bhagat, RG, Grunstein, MM Comparison of responsiveness to methacholine, histamine, and exercise in subgroups of asthmatic children.Rev Respir Dis1984;129,221-224
 
Sekerel, BE, Saraclar, Y, Cetinkaya, F, et al Comparison of four different measures of bronchial responsiveness in asthmatic children.Allergy1997;52,1106-1109. [PubMed]
 
Hofstra, WB, Neijens, HJ, Duiverman, EJ, et al Dose-response over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma.Pediatr Pulmonol2000;29,415-423. [PubMed]
 
Buchvald, F, Hermansen, MN, Nielsen, KG, et al Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children.Chest2005;128,1964-1967. [PubMed]
 
Petersen, R, Agertoft, L, Pedersen, S Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma.Eur Respir J2004;24,932-937. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Flow diagram of the number of subjects screened and randomized.Grahic Jump Location
Figure Jump LinkFigure 2. %FEV1 fall and sputum eosinophil percentage for all visits.Grahic Jump Location
Figure Jump LinkFigure 3. Exercise response to low-dose and high-dose ciclesonide therapy according to baseline sputum eosinophil counts. The data are presented as the mean ± SE. □, noneosinophilic group (< 5% eosinophils; n = 13); ▪, eosinophilic group (≥ 5% eosinophils; n = 10). Changes from baseline were compared within a group (*) and between groups (#) for each dose level at p < 0.05 (analysis of variance). The arrows indicate the effect was seen for both groups. Only the sputum eosinophilic group showed a significantly greater change from baseline to high ICS dose compared to low ICS dose (Ψ).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Subject Characteristics at Screening Stratified by Baseline Sputum Eosinophil Count*
* 

Values are given as the mean ± SE, unless otherwise indicated. ED = emergency department.

 

Symptoms and rescue medication use (including for exercise) averaged over 7 days. Daily symptoms were rated on a Likert scale from 0 to 4 (4, worse).

 

p < 0.05 (Student t test between eosinophilic groups).

§ 

p < 0.005 (Student t test between eosinophilic groups).

Table Graphic Jump Location
Table 2. Weekly Sputum Differential Cell Counts in Response to Ciclesonide Therapy*
* 

Values given as the geometric mean ± SE, unless otherwise indicated.

 

Values given as arithmetic mean ± SE.

 

p < 0.05 (vs week 0 on analysis of variance for sample size of 20).

§ 

p < 0.05 (vs week 0 on analysis of variance for sample size of 20).

Table Graphic Jump Location
Table 3. Weekly %FEV1 Fall in Response to Low-Dose and High-Dose Ciclesonide Therapy*
* 

Data are presented as mean ± SE, unless otherwise indicated.

 

Comparison of the change from baseline by week of treatment between noneosinophilic vs eosinophilic groups (within dose).

 

Comparison of the change from baseline by week of treatment between low-dose and high-dose therapy (within sputum group) [by analysis of variance].

§ 

Change from baseline significant at p < 0.05.

References

Moloney, ED, Griffin, S, Burke, CM, et al (2003) Release of inflammatory mediators from eosinophils following a hyperosmolar stimulus.Respir Med97,928-932. [PubMed] [CrossRef]
 
O’Byrne, PM Leukotriene bronchoconstriction induced by allergen and exercise.Am J Respir Crit Care Med2000;161,S68-S72. [PubMed]
 
Per Venge, P, Henriksen, J, Dahl, R Eosinophils in exercise-induced asthma.J Allergy Clin Immunol1991;88,699-704. [PubMed]
 
Koh, YI, Choi, IS Blood eosinophil counts for the prediction of the severity of exercise-induced bronchospasm in asthma.Respir Med2002;96,120-125. [PubMed]
 
Otani, K, Kanazawa, H, Fujiwara, H, et al Determinants of the severity of exercise-induced bronchoconstriction in patients with asthma.J Asthma2004;41,271-278. [PubMed]
 
Yoshikawa, T, Shoji, S, Fujii, T, et al Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma.Eur Respir J1998;12,879-884. [PubMed]
 
Subbarao, P, Duong, M, Adelroth, E, et al Effect of ciclesonide dose and duration of therapy on exercise-induced bronchoconstriction in patients with asthma.J Allergy Clin Immunol2006;117,1008-1013. [PubMed]
 
Jatakanon, A, Kharitonov, S, Lim, S, et al Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma.Thorax1999;54,108-114. [PubMed]
 
Taylor, DA, Jensen, MW, Kanabar, V, et al A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5-monophosphate in asthmatic patients.Am J Respir Crit Care Med1999;160,237-243. [PubMed]
 
Hankinson, J, Odencrantz, J, Fedan, KB Spirometric reference values from a sample of the general US population.Am J Respir Crit Care Med1999;157,179-187
 
Pizzichini, E, Pizzichini, M, Efthimiadis, A, et al Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements.Am J Respir Crit Care Med1996;154,308-317. [PubMed]
 
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