Discussion about Corticosteroid in Asthma for Exercise-Induced Bronchoconstriction and Sputum Eosinophils Results

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In steroid-naive 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 V1 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 studies 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.

Inhaled Corticosteroid Therapy

This response was time-independent, demonstrating a limited improvement (< 50% attenuation) in V1 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 (V1 fall attenuation, 26% vs 37%, respectively), and the difference was greater by 3 weeks (V1 fall attenuation, 28% vs 51%, respectively). Indeed, at 3 weeks the eosinophilic group achieved a mean V1 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 V1 fall between the two inflammatory groups remained significant throughout low-dose therapy. There was no correlation between baseline V1 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. 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 V1 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.

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Similar to previous studies, 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, 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 V1 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.

Airway Eosinophilia

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. 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%. Our threshold was based on local data in healthy control subjects from our center demonstrating that the absolute upper limit was 5%. 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 stud-ies 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. Similarly, methacholine hyperresponsiveness has not been found to consistently correlate with EIB, but instead to baseline FEV1, and to demonstrate a dose and temporal response to ICS therapy that is different than the EIB response. 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 therapy (learn more) but not after ICS therapy, indicating that this marker may not be useful in the monitoring of the response during ICS therapy.

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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.

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