The following information about steroid resistant asthma was originally developed for a healthcare professional audience and was published in Allergy, Rheumatology, Immunology and Asthma (ARIA), a journal produced by National Jewish Health and The Children's Hospital of Denver. An additional scientific article is available entitled Steroid Resistant Asthma, which was originally published in the National Jewish Health Medical Scientific Update.
Steroid Resistant Asthma: Definition and Mechanisms
By Donald Y.M. Leung, MD, PhD
Airway inflammation and immune activation plays an important role inchronic asthma. Current guidelines of asthma therapy have therefore focused on the use of anti-inflammatory therapy, particularly inhaled glucocorticoids (GCs). While the majority of patients respond toregular inhaled GC therapy, a subset of patients are poorly responsive even when treated with high doses of oral prednisone. This review will examine the mechanisms underlying steroid resistant (SR) asthma.
Definition of Steroid Resistant Asthma
At present there is no universally accepted definition of steroid resistant asthma. It is frequently defined by the failure to improve baseline AM pre-bronchodilator FEV1 by greater than 15% predicted following 7-14 days of 20 mg twice daily oral prednisone. Although most patients do not have an absolute resistance, but rather a glucocorticoid insensitivity, and some patients might respond to higher doses of prednisone or its equivalent given for longer periods of time, such doses would be undesirable because they are associated with marked adverse effects. Importantly, the diagnosis of steroid resistant asthma should only be made after an extensive evaluation to rule out other potential causes of wheezing or factors that contribute to the severity of asthma. Patients with steroid resistant asthma should fulfill the ATS criteria for diagnosis of asthma and have a bronchodilator response of greater than 15% improvement in FEV1.
Immune Responses to Glucocorticoids in Steroid Resistant Asthma
One of the major mechanisms by which glucocorticoids act in asthma is by reducing airway inflammation and immune activation. However, patients with steroid resistant asthma have higher levels of immune activation in their airways than do patients with steroid sensitive (SS) asthma. Furthermore, glucocorticoids do not reduce the eosinophilia or T cell activation found in steroid resistant asthmatics. This persistent immune activation is associated with high levels of IL-2, IL-4 and IL-5 in the airways of these patients.
Glucocorticoid Receptor (GCR) Abnormalities in Steroid Resistant Asthma
Two types of steroid resistant asthma have been described. One group with acquired steroid resistance (Type 1) and a second with primary steroid resistance (Type II). Patients with acquired steroid resistance have poor glucocorticoid receptor binding affinity for steroids and the DNA sites (GRE) recognized by the glucocorticoid receptor. Clinically they present as patients with steroid resistant asthma who develop severe side effects including adrenal gland suppression from chronic treatment with systemic steroids. Their defect is localized to the immune system, reversible in vitro and can be induced in their T cells by the combination of IL-2 and IL-4. In contrast, the primary form (Type II) of steroid resistant asthma is not associated with the development of steroid-induced side effects and the glucocorticoid receptor defect involves decreased GCR numbers. It may be analogous to patients with primary cortisol resistance, which has a genetic basis, as Type II steroid resistant asthma has an irreversible glucocorticoid receptor defect that involves all cell types. It should be noted that most patients who have a provisional diagnosis of primary steroid resistant asthma are simply NOT taking their medications. As a result, they develop no side effects after being prescribed oral prednisone and they obviously derive no therapeutic effects from the steroids. When patients present with a history of primary steroid resistant asthma, it is important to confirm they are taking the oral steroid under strict supervision by checking their AM serum cortisol after a course of steroid therapy. The acquired form (Type I) accounts for >95% of steroid resistant asthma. Therefore any patient presenting with primary steroid resistant asthma, should be suspected of poor adherence to therapy until proven otherwise.
Read more about the nine steps to success in managing steroid resistant asthma.
This information has been approved by Donald Leung, MD, PhD (August 2003) Original Publication August 2000; updated August 2003.
