Introduction:Â Read more in previous publication “Corticosteroid in Asthma for Exercise-Induced Bronchoconstriction and Sputum Eosinophils“.
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 þV1 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 þV1 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 þV1 fall was consistently greater for the eosinophilic group compared to the noneosino-philic group (Fig 3, Table 3). Treatment with low doses resulted in significant improvement in þV1 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 þV1 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 AUCq_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 þV1 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 þV1 fall and the slopes of improvement over time with treatment.
Table 1—Subject Characteristics at Screening Stratified by Baseline Sputum Eosinophil Count
| Characteristics | Noneosinophilic Group (n = 15) | Eosinophilic Group (n = 10) |
| Sex, No. | ||
| Male | 8 | 7 |
| Female | 8 | 3 |
| Age, yr | 19.7 ± 3.6 | 19.7 ± 3.5 |
| Duration of asthma, yr | 13.5 ± 1.3 | 13.1 ± 5.8 |
| Positive results of allergy skin-prick test | 100% | 100% |
| Hospital/ED visits reported | ||
| < 5 episodes | 92% | 89% |
| > 5 episodes | 8% | 11% |
| Daytime symptoms! | 2.7 ± 0.7 | 4.6 ± 0.8 |
| Nighttime symptoms! | 1.3 ± 0.5 | 3.9 ± 1.5 |
| Rescue medication use! | 4.7 ± 1.3 | 9.8 ± 2.5 |
| FEV:, % predicted | 89.6 ± 12.3 | 95.7 ± 12.7 |
| FEV/FVC ratio, % | 80.3 ± 10.1 | 82.6 ± 6.0 |
| þV: fall | 22.5 ± 11 | ±.66.cr |
| AUC0_3q, % change X min | 442.7 ± 23.7 | .8±cc7 |
| Sputum TCC, 106 cells/mL | 4.2 ± 1.3 | 2.5 ± 0.8 |
| Neutrophils, % | 37.6 ± 6.3 | 28.1 ± 7.8 |
| Eosinophils, % | 1.6 ± 0.4 | 6.±.4£ |
| Lymphocytes, % | 0.2 ± 0.1 | 0.3 ± 0.1 |
| Metachromatic cells, % | 0.7 ± 0.2 | 0.7 ± 0.1 |
| Macrophages, % | 57.4 ± 6.1 | 36.5 ± 8.8 |
| Epithelial cells, % | 3.2 ± 1.8 | 3.8 ± 1.4 |
Table 2——Weekly Sputum Differential Cell Counts in Response to Ciclesonide Therapy
| Variables | 0 e e£ | Week 1 | Week 2 | Week 3 |
| Low-dose ciclesonide (40/80 g) | ||||
| TCC,| 106 cells/mL | c 1 cc | 4.6 ± 0.8 | 6.7 ± 1.8 | 2.7 ± 0.6 |
| Eosinophils, % | 2.5 ± 1.5 | 1.6 ± 1.5 | 1.6 ± 1.5 | 1.6 ± 1.5 |
| Neutrophils, % | 42.7 ± 1.2 | 41.1 ± 1.2 | 35.2 ± 1.2 | 46.5 ± 1.2 |
| Metachromatic cells, % | 0.64 ± 1.2 | 0.52 ± 1.1 | 0.47 ± 1.2 | 0.53 ± 1.2 |
| Lymphocytes, % | 0.22 ± 1.2 | 0.21 ± 1.2 | 0.20 ± 1.2 | 0.20 ± 1.2 |
| Macrophages, % | 33.7 ± 1.2 | 35.0 ± 1.2 | 28.8 ± 1.2 | 30.4 ± 1.2 |
| Epithelial cells, % | 0.6 ± 1.4 | 0.9 ± 1.5 | 1.0 ± 1.6 | 0.9 ± 1.4 |
| High-dose ciclesonide (160/320 mg) | ||||
| TCC,| 106 cells/mL | 2.7 ± 0.4 | 2.9 ± 0.5 | 3.2 ± 0.5 | 4.5 ± 1.3 |
| Eosinophils, % | 3.3 ± 1.5 | 1.5 ± 1.4 | 1.4 ± 1.4 | 1.2 ± 1.4 |
| Neutrophils, % | 28.0 ± 1.1 | 27.7 ± 1.2 | 37.8 ± 1.2 | 43.9 ± 1.2 |
| Metachromatic cells, % | 0.75 ± 1.1 | 0.72 ± 1.1 | 0.76 ± 1.2 | 0.66 ± 1.2 |
| Lymphocytes, % | 0.19 ± 1.2 | 0.19 ± 1.2 | 0.16 ± 1.2 | 0.16 ± 1.2 |
| Macrophages, % | 39.2 ± 1.1 | 43.3 ± 1.1 | 39.7 ± 1.1 | 30.8 ± 1.2 |
| Epithelial cells, % | 1.3 ± 1.5 | 1.6 ± 1.5 | 1.4 ± 1.4 | 1.6 ± 1.5 |
Table 3——Weekly þV1 Fall in Response to Low-Dose and High-Dose Ciclesonide Therapy
| Variables | Week | Noneosinophilic Group (n = 13) | Eosinophilic Group (n = 10) | p Value | |
| Between-Group Comparison | Between-Dose Comparison | ||||
| Noneosinophilic group | |||||
| Low-dose ciclesonide (40/80 g) | 0 | 20.8 ± 2.7 | 35.1 ± 3.3 | < 0.005 | > 0.05 |
| 1 | 12.7 ± 2.0 | 26.5 ± 3.8 | > 0.05 | > 0.05 | |
| 2 | 12.3 ± 1.4 | 26.1 ± 4.0 | > 0.05 | > 0.05 | |
| 3 | 14.9 ± 2.4 | 25.2 ± 4.2 | > 0.05 | > 0.05 | |
| Eosinophilic group | |||||
| High-dose ciclesonide (160/320 g) | 0 | 24.8 ± 2.9 | 38.7 ± 6.2 | < 0.005 | > 0.05 |
| 1 | 16.6 ± 3.5 | 32.7 ± 7.1 | > 0.05 | > 0.05 | |
| 2 | 13.2 ± 2.3 | 24.3 ± 7.4 | < 0.05 | < 0.05 | |
| 3 | 14.3 ± 2.3 | 19.1 ± 5.8 | < 0.005 | < 0.005 | |
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Figure 1. Flow diagram of the number of subjects screened and randomized.
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Figure 2. þV1 fall and sputum eosinophil percentage for all visits.
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Figure 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. □, noneosi-nophilic 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 (^).