SYSTEMIC CORTICOSTEROID RAPIDLY REVERSES BRONCHODILATOR SUBSENSITIVITY INDUCED BY FORMOTEROL IN ASTHMATIC-PATIENTS

There is evidence that downregulation and desensitization of airway be ta(2)-adrenoceptors (beta(2)-AR> develops after continuous exposure te e long-acting beta(2)-agonists such as formoterol and salmeterol. To i nvestigate the facilitatory effects of acute administration of systema tic corticosteroid on bronchodilator subsensitivity, as might occur in the setting of acute asthma, 12 subjects with moderately severe asthm a, with a mean FEV1 of 66% predicted, of whom were all receiving inhal ed corticosteriod, were randomized to receive either inhaled placebo ( PL) or inhaled formoterol (FM) 24 mu g twice daily for 4 wk in a doubl e-blind crossover study. Subjects were also genotyped in terms of beta (2)-AR polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 188 mu g) was produced 1 h alter administration of placebo tablets and after injection at 3 wk and 1 h after administration of oral prednisolone, 50 mg, and intravenous hydr ocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for Delta FEV1 (as AUC, L.h): 2.51 versus 4.22 (95% CI: 0. 54 to 2.89; p = 0.01) and Delta FEF25-75 (as AUC, L x 10(3)): 11.30 ve rsus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly r eversed by steroid (S) for FEV1 (FM versus FM + S): 2.51 versus 3.57 ( 95% CI: (0.11 to 2.27; p = 0.03) and for FEF25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte beta(2)-AR density (log B-max; fmol/10(6) cells) showed significant upregulation 3 h after st eroid (FM + S versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivi ty with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.0 01), and this was reversed by steroid (FM + S versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic corticosteroid appears to be generally independent of beta(2)-AR polym orphism at loci 16 and 27. In conclusion, we have demonstrated that br onchodilator subsensitivity occurs after regular inhaled FM in asthmat ic patients, and is rapidly reversed by systemic corticosteroid, Thus, In acute asthma, systemic corticosteroid should be administered a soo n as possible, in order to restore normal ainway beta(2)-AR sensitivit y, particularly in patients who are receiving regular long-acting beta (2)-agonists.