S11 The different mechanisms of inhaled and oral corticosteroids in T2-high asthma. For those established on inhaled steroids additional effects from oral steroids may lie in access to the small airways

Introduction Inhaled and oral corticosteroids are cornerstone treatments of eosinophilic asthma but their differential mechanisms of action are incompletely understood. Methods We conducted a prospective observational study to examine the effects of inhaled and oral corticosteroids [REC18/SC/0361]. Participants with FeNO >45 ppb and/or blood eosinophils >0.30x109/L were selected. Cohorts comprised: (i) inhaled corticosteroid-naïve patients before/after 8 weeks beclomethasone 200 mcg twice daily (ICS group, n=21); (ii) participants with confirmed adherence to ICS treatment (geomean daily BDP equivalent dose ±SEM 949±130mcg) and abstinent of oral corticosteroids for >3 months before/after 10 days of prednisolone 30 mg daily (OCS group, n=21); (iii) healthy controls (n=31). Outcomes included lung function, symptoms, blood and sputum cell counts and levels of 12 canonical markers of type-2 inflammation assayed via ELISA. Between and within group comparisons were made using mixed effects ANOVA. Results ICS and OCS groups were matched at baseline for age, gender, atopy, bronchodilator reversibility and FeNO. Both ICS and OCS treatments resulted in significant improvements in FEV1 (figure 1A) and reduction of symptom scores (mean ACQ5 difference 1.1 with OCS and 1.5 with ICS, both p<0.001). FeNO was reduced by both ICS (mean reduction 62%, p<0.0001) and OCS (mean reduction 42%, p<0.001) with no significant between-group treatment effect (figure 1B). Introducing OCS treatment resulted in a greater reduction of blood eosinophils (76%) than initiating ICS treatment (31%) (p<0.001) and OCS reduced sputum eosinophil% by a greater margin than ICS (28.5% points vs 6.8% points, p=0.02, figure 1D). ICS treatment had no significant effect on serum mediators while OCS treatment reduced serum IL-5 only (figure 1F). Both ICS and OCS treatment reduced sputum levels of IL-5, eotaxin-3 and TSLP (all p<0.01). Sputum eotaxin was reduced uniquely by ICS (p=0.02, figure 1G) while the addition of OCS uniquely reduced sputum levels of IL-4, IL-13 and LTE4 (all p<0.04). Conclusion Our findings are consistent with an important role for the small airways in FeNO non-suppression and a site of OCS treatment response in T2-high patients. This effect might result through greater tissue bioavailability of OCS and/or in providing enhanced access for inhaled therapies.

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