New insights into the pathogenesis and management of steroid-resistant asthma

A population of difficult-to-control asthmatics exists who, despite high-dose daily GC therapy, continue to display evidence for active disease. This group has been termed steroid resistant since they fail to adequately respond to aggressive courses of high-dose oral and inhaled GC therapy. Persistent immune activation and airway inflammation which to varying degrees is resistant to GC therapy appears to define the immunological abnormality underlying SR asthma. Recent studies utilizing molecular biological techniques have identified both ligand- and DNA-binding defects that could possibly account for steroid resistance at a molecular level. The evaluation of the SR asthmatic must be comprehensive in its scope as several confounding factors can contribute to this symptom complex. Among others, these include poor compliance, improper medication technique, inadequate anti-inflammatory therapy, unrecognized contributing diseases, incorrect diagnoses, environmental factors, and psychosocial disturbances. The management of the SR asthmatic is challenging, and every attempt should be made to maximize conventional therapy in these patients prior to embarking on alternative therapies as all of the alternative anti-inflammatory/immunomodulatory modalities are associated with significant toxicity or cost. Second-generation inhaled GC therapy, methotrexate, cyclosporine, IVIG, and leukotriene antagonists are potential alternative therapies, and although they remain viable options, they have been used in small numbers, and for short periods of time, and fail to result in long-term remissions. Although much insight into the pathogenesis of SR asthma has been gained, several issues remain unresolved. Ongoing airway inflammation is thought to contribute to steroid resistance, but at present, we have no standard method of determining the degree of inflammation. The incorporation of bronchoscopy with transbronchial biopsy has the potential to provide the greatest amount of information regarding the presence or absence of ongoing airway inflammation, but the invasive nature of the procedure precludes its use in pediatric patients and the most severe adult asthmatics. Large multicenter, placebo-controlled studies evaluating the available alternative therapies that incorporate markers of airway inflammation are needed, as are studies that evaluate these therapies over longer periods of time. It is hoped that by better understanding the mechanisms involved and the natural history of the SR asthmatic, specific treatment modalities will be developed for this challenging group of severe asthmatics.