Steroid-resistant asthma: Immunologic and pharmacologic features

Abstract

Glucocorticoids play an important role in asthma therapy; however, a subset of patients are poorly responsive. We evaluated immunologic and pharmacologic features of 17 patients with steroid-resistant (SR) asthma (six male and 11 female patients) between the ages of 16 and 69 years (mean age, 29 years). SR asthma was defined as failure to improve morning prebronchodilator FEV₁ >60% predicted after a 2-week course of oral prednisone (mean dose, 45 mg/day). These patients were compared to 24 steroid-sensitive (SS) patients, aged 5 to 70 years (mean age, 17 years; 17 male and seven female patients), and 47 healthy control subjects, aged 20 to 40 years. Mean prednisone dose in SS patients was 25 mg/day. Steroid pharmacokinetics were evaluated in six patients with SR asthma. All studies were within normal limits. Peripheral blood mononuclear cells (PBMCs) from all subjects were stimulated with 10 μg/ml of phytohemagglutinin and incubated for 72 hours with 10⁻⁵ to 10⁻⁹ mol/L of methylprednisolone (Mpn). The Mpn dose-response curve for PBMCs from patients with SR asthma demonstrated a significant (p < 0.05) increase in DNA synthesis, that is, more T cell proliferation than PBMCs stimulated with phytohemagglutinin in the presence of Mpn, as compared to SS patients and normal subjects. This augmentation of DNA synthesis was reversible with 10 μg/ml of troleandomycin in vitro. We conclude that PBMCs from patients with SR asthma demonstrate altered response to Mpn in the presence of a T cell mitogen. This abnormality in cellular response may contribute to persistent airway inflammation in patients with SR asthma despite glucocorticoid therapy. Furthermore, this immunologic abnormality appears to be reversible.