Eur Respir J 1997; 10: 1640–1647 Copyright ERS Journals Ltd 1997 DOI: 10.1183/09031936.97.10071640 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 REVIEW Glucocorticoid-resistant asthma: pathogenesis and clinical implications for management S.J. Szefler, D.Y.M. Leung Glucocorticoid-resistant asthma: pathogenesis and clinical implications for manage- Divisions of Allergy & Immunology and ment. S.J. Szefler, D.Y.M. Leung. ©ERS Journals Ltd. 1997. Clinical Pharmacology, Dept of Pediatrics, ABSTRACT: At the present time, emphasis is placed on viewing asthma as a man- National Jewish Center for Immunology ifestation of chronic airway inflammation, possibly secondary to allergen hyper- and Respiratory Medicine, and Dept of Pediatrics, University of Colorado Health sensitivity. Consequently, one aspect of management is to institute measures of Sciences Center, Denver, Colorado, USA. environmental control to minimize the inflammatory response related to allergen stimulation, and to administer anti-inflammatory therapy to resolve inflammation Correspondence: S.J. Szefler and prevent progression of disease. National Jewish Center for Immunology Most patients respond very favourably to conventional therapy, as recommended and Respiratory Medicine in recent guidelines for asthma management. Some cases, however, remain very 1400 Jackson St difficult to control despite high-dose inhaled glucocorticoids, even combined with Dept of Pediatrics Goodman Bldg., Rm. 926 oral glucocorticoid therapy. Management of these patients raises questions about Denver the conditions that alter response to glucocorticoid therapy. Colorado 80206 The patient with difficult to control asthma not only presents a challenge to clin- USA ical management but raises new questions concerning our ability to control the progression of disease. Is difficult to control asthma secondary to overwhelming Keywords: Asthma, glucocorticoids or ongoing allergen exposure? Do anti-inflammatory medications, specifically inhaled Received: December 16 1996 glucocorticoids, really control the progression of the disease? Are these patients Accepted December 31 1996 destined to become severe asthmatics at birth due to the inherent characteristics of their airways, or is this indeed a consequence of progressive inflammation? Presented at the European Respiratory This review will summarize present concepts of glucocorticoid-resistant asthma, Society Meeting current knowledge of the mechanisms of persistent inflammation, and the impli- Barcelona, Spain, September 20, 1995. cations for management. The gaps in information will also be addressed in order Supported by USPHS grants HL-36577, to stimulate interest in further research that could lead to better understanding RR-00051, and AR-41256. S.J.S. holds the of the disease and potential windows for therapeutic intervention. Helen Wohlberg & Herman Lambert Chair Eur Respir J 1997; 10: 1640–1647. in Pharmacokinetics. Clinical presentation of glucocorticoid-resistant exacerbations; frequent nocturnal exacerbations; and asthma other concomitant medical disorders, such as sinusitis and gastro-oesophageal reflux. Although there is no sin- The condition of the majority of patients with asthma gle clinical definition of glucocorticoid-resistant asth- falls into the category of episodic, mild persistent, or ma, patients are usually recognized by their difficulty moderate persistent as recently defined in the Global in clinical management, frequent breakthrough symp- Initiative for Asthma [1]. Patients with severe persis- toms, compromised quality of life, or near death episodes. tent or "difficult to control" asthma are a small propor- Most of these patients also demonstrate significant ad- tion of those individuals with asthma. However, they are verse glucocorticoid effects secondary to high-dose and clearly the most challenging for management, account prolonged courses of treatment. Interestingly, some of for the majority of health care costs related to asthma these patients remain refractory to adverse glucocor- management, and most importantly, are the patients who ticoid effects [2]. This observation raises questions re- appear to be at high risk for asthma mortality. Asthma, garding a localized versus a systemic refractoriness to therefore, appears to be a spectrum varying from a very glucocorticoids. Perhaps the former may be acquired, mild, episodic, subclinical disease to one that is appar- whilst the latter is a primary genetic defect in gluco- ently "glucocorticoid (steroid) resistant (SR)", but re- corticoid response. mains responsive to bronchodilator therapy. Although Certain conditions can interfere with the appropriate not clearly documented, it appears that some patients in diagnosis and management of asthma. Conditions such the difficult to control category go on to develop severe as other respiratory disorders, environmental control, obstructive pulmonary disease, that is poorly reversible poor compliance, and inadequate therapy can be addres- even with bronchodilator therapy. sed by a careful medical evaluation and reorganization Patients who are "glucocorticoid-resistant" have some of the management plan (table 1). Patients who fail to or all of the following complicating features: exercise- respond prompt a more detailed evaluation and innov- induced asthma; spontaneous severe, life-threatening ative approaches to treatment. These patients are referred GLUCOCORTICOID-RESISTENT ASTHMA 1641 Table 1. – Potential mechanisms for poor response to Glucocorticoid pharmacokinetics glucocorticoid therapy Other respiratory disorder If a patient fails to respond or is unable to tolerate glu- Overwhelming allergen exposure cocorticoid doses lower than 20 mg every second day Irreversible airways hyperresponsiveness with either prednisone or methylprednisolone, we usu- Poor adherence to prescribed therapy ally evaluate glucocorticoid pharmacokinetics. The pur- Inadequate dose of anti-inflammatory medication pose of this evaluation is to determine whether there is Glucocorticoid pharmacokinetics incomplete glucocorticoid absorption, failure to convert Rapid elimination an inactive form (prednisone) to an active form (pred- Poor distribution to site of action nisolone), or rapid elimination. The evaluation is parti- Incomplete absorption of oral glucocorticoid Immunological mechanisms contributing to persistent airway cularly important in a patient who fails to demonstrate inflammation the anticipated adverse effects [5]. Measurements of plas- Glucocorticoid desensitization ma glucocorticoid concentrations can also be used in an Abnormal glucocorticoid receptor or postreceptor phenomenon assessment of compliance. Although the majority of pa- tients have normal absorption, conversion to the active form, and elimination, a proportion of these patients have to as "difficult to control" if they require high-dose in- pharmacokinetic abnormalities [6, 7]. The most frequ- haled and oral glucocorticoid therapy, >20 mg every -1 ent finding is rapid elimination, usually secondary to a second day or 10 mg·day oral prednisone, or "glucocor- drug-drug interaction, particularly the concomitant use ticoid-resistant" if they appear refractory to higher doses of anticonvulsants, such as phenytoin sodium, carbama- of oral glucocorticoid therapy. zepine or phenobarbitone. Occasional patients may show Our operational definition for this group of patients, poor absorption and, interestingly, substitution with an termed "glucocorticoid-resistant," includes those patients alternative glucocorticoid will show improved response [5]. who have a prebronchodilator morning forced expira- tory volume in one second (FEV1) <70% of predicted, and who fail to increase this pre-bronchodilator morn- Analysis of peripheral blood mononuclear cells ing FEV1 measurement by 15% after at least 1 week of an oral glucocorticoid course consisting of prednisone -1 Our own studies have confirmed that glucocorticoid 40 mg·day . They must also demonstrate a 15% improve- resistant asthmatics have a glucocorticoid dose response ment in FEV1 following a rapidly-acting bronchodilator curve shifted to the right using a functional measure of treatment. Other investigators differ in their operational glucocorticoid-response, specifically phytohaemaggluti- definition for glucocorticoid-resistant asthma. For exam- nin-induced inhibition of peripheral blood mononuclear ple, some will begin with a course of prednisolone, 20 -1 -1 cell (PBMC) proliferation [8]. Other investigators have mg·day for 1 week, and then increase it to 40 mg·day identified a similar alteration in the dose-response curve for a second week, before declaring the patient gluco- to a topical glucocorticoid with a skin blanching tech- corticoid-resistant [3]. Patients with "difficult to control" nique [9]. This prompted investigation of glucocorticoid asthma are not necessarily "glucocorticoid-resistant." A receptor-binding in these patients. proportion of patients who are identified as glucocorti- The importance of the glucocorticoid receptor (GCR) coid-resistant will improve their clinical response if ag- in determining clinical responsiveness to glucocorticoids gressive therapy is extended beyond 2 weeks, but this was reported previously as primary cortisol resistance course of treatment places the patient at risk for sig- in association with an endocrine abnormality [10]. These nificant adverse effects commonly associated with glu- patients presented with elevated total plasma cortisol cocorticoid