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Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation

King-Biggs, Melissa B.1; Dunitz, Jordan M.1; Park, Soon J.2; Kay Savik, S.3; Hertz, Marshall I.1 4

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Goal. The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients.

Methods. The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii.

Results. A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections.

Conclusions. We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Lung and heart-lung transplantation are viable therapeutic options for many patients with advanced cardiopulmonary disease. Although the early results after lung transplantation have improved, long-term survival still lags behind that observed after transplantation of other organs (1,2). Acute and chronic rejection are common problems, despite the fact that lung recipients receive triple-drug immune suppression with target dosages and levels among the highest of all organ transplants. In addition, medication toxicities from chronic immune suppression result in increased morbidity and mortality. Thus, more effective immune suppressive medications with tolerable side-effect profiles are needed to improve long-term lung-transplant outcomes.

Sirolimus (rapamycin, Rapamune) is a novel macrolide with potent immune suppressive and antiproliferative properties (3,4). Sirolimus is synergistic with cyclosporine A and tacrolimus in animal transplant chronic-rejection models, including models of obliterative bronchiolitis after lung transplantation (5,6). Studies in other human organ transplants demonstrate that sirolimus can control acute rejection and may reduce the need for corticosteroids and cyclosporine (7–9). Sirolimus has nonoverlapping toxicities with other immune-suppressive medications and does not cause significant renal impairment, which is a major problem with calcineurin inhibitors (10). These characteristics make sirolimus an appealing medication for lung transplantation; therefore, we performed an open-label pilot study to assess the efficacy of sirolimus in combination with prednisone and tacrolimus in lung-transplant recipients.

© 2003 Lippincott Williams & Wilkins, Inc.



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