Effect of oral glucocorticoid treatment on serum inflammatory markers in acute asthma.

BACKGROUND: Acute asthma is associated with elevated serum concentrations of products of activated T cells and eosinophils. AIMS: To compare the changes in concentrations of these products with disease severity and changes in lung function following oral prednisolone treatment. METHODS: Twenty patients (mean age 8.7 years) were recruited on admission with acute asthma to a district general hospital. Disease severity was recorded before and after treatment with oral prednisolone using a validated pulmonary index score. Serum concentrations of interleukin (IL)-4, IL-5, soluble (s)CD25 (soluble IL-2 receptor), using a specific enzyme linked immunosorbent assay, and eosinophil cationic protein (ECP), using radioimmunoassay, were measured concomitantly. Non-asthmatic children (n = 6, mean age 9.2 years) undergoing elective surgery were recruited as controls, and serum samples were obtained on one occasion without treatment. Main outcome measures were changes in serum concentrations of cytokines and ECP, clinical asthma severity score, and peak expiratory flow rate. RESULTS: As expected, oral glucocorticoid treatment in the children with asthma was associated with clinical improvement and also with significant reductions in serum concentrations of IL-5 (mean 5.59 to 2.19 pg/ml, p = 0.0001), sCD25 (mean 2236 to 1772 pg/ml, p = 0.002), and ECP (mean 54.3 to 33. 1 pg/ml, p = 0.0001). Serum IL-4 concentrations, in most patients and all the controls, remained below the sensitivity of the assay. However, serum concentrations of IL-5, sCD25, and ECP remained significantly higher than in controls, even after treatment with oral glucocorticoids (p = 0.03). CONCLUSIONS: These data suggest that T cell mediated inflammation may persist in childhood asthma despite apparent clinical remission associated with conventional doses of prednisolone. The long term consequences of persistent inflammation after an apparently treated acute attack of asthma require clarification. Clinical assessment and pulmonary function are inadequate surrogates for airway inflammation.

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20 alpha-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate. Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20 alpha-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.