Addition of inhaled fluticasone propionate to systemic immunosuppression after lung transplantation: Cushing's syndrome in patients on itraconazole comedication.

Abstract

Bronchiolitis obliterans syndrome (BOS), the major cause of mortality after lung transplantation (LTx) (1), is difficult to prevent and treat, and the means to decrease its incidence are needed. We have read with interest the article by Whitford et al. (2) reporting the addition of inhaled fluticasone propionate (FP) to systemic immunosuppression after LTx. They found FP to be ineffective for the prevention of BOS (2). Four years ago, we also had started adding inhaled FP to systemic immunosuppression (including prednisone and cyclosporine) in our LTx recipients. Strikingly, four patients developed Cushing's syndrome (CS). CS was obvious by clinical signs, especially in skin appearance and fat distribution. We compared these patients with four patients receiving FP at the same time who did not develop CS (Table 1). Three males and one female developed CS a few weeks after they were on FP despite unchanged prednisone dosage. Groups were comparable in age, time since LTx, prednisone dosage, and presence of BOS. None of the patients developed BOS de novo.TABLE 1: Characteristics of eight lung-transplant recipients with and without Cushing's syndrome (CS) in response to inhaled fluticasone propionateThe development of CS while the patients were on inhaled FP was even more surprising because no such features were seen earlier postLTx under a higher prednisone dosage. The glucocorticoid balance in these patients seems to be rather complex (endogenous cortisol, oral prednisone, and inhaled fluticasone). CS patients showed higher serum cortisol and, particularly, dehydroepiandrosterone sulfate levels (Table 1). In contrast, as expected for patients treated with high-dose glucocorticoids, the adrenocorticotropic hormone axis was suppressed in patients without CS. All CS patients and two of the patients without CS were on itraconazole comedication, whereas none of the patients in Whitford's study was. Itraconazole may inhibit FP metabolism (especially CYP3A4 and possibly P-glycoprotein) and thereby increase its bioavailability. Recently, in a prospective study, we found increased circulating levels of FP in stable LTx patients on itraconazole (3). It is rather difficult to assign the CS phenotype to FP alone. Endogenous adrenocortical hormones would have been expected to be lower in CS patients. In healthy individuals, itraconazole increases plasma concentrations and elimination half-lives of dexamethasone (4) and methylprednisolone (5), thereby enhancing suppression of endogenous cortisol secretion. In our patients with pronounced systemic FP effects such as CS, the opposite seemed to be the case. Itraconazole appears to interfere much more with the metabolism of fluticasone, dexamethasone, and methylprednisolone than with prednisolone and cortisol (3–5). However, not all individuals on itraconazole and FP developed CS, suggesting additional important parameters such as other comedications or, possibly, polymorphisms in genes encoding peptide chains of the cytochrome P450 (CYP3A4), P-glycoprotein, or glucocorticoid receptors. CS resolved in all of the patients after discontinuation of FP, further suggesting that the inhaled FP caused this systemic side-effect. Our overall experience with FP is consistent with that of Whitford et al., but our findings strongly suggest that inhaled FP is far from being inactive but can become systemically available and have glucocorticoid effects, even to an unwanted extent. On the basis of our observations reported here and elsewhere (3), we strongly recommend that comedication be taken into consideration when inhaled FP is prescribed. Christoph Schmid Rahel Naef Rudolf Speich Annette Boehler 1Division of Endocrinology and Diabetes University Hospital Zurich Zurich, Switzerland 2Division of Pulmonary Medicine and Lung Transplant Program University Hospital Zurich Zurich, Switzerland