Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans

Abstract

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival.The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database).Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls.Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone. The 3-yr survival after lung transplantation is 55% [1]. More than half of all lung transplant recipients who survive o1 yr develop chronic allograft rejection that is associated with bronchiolitis obliterans [2][3][4][5]. The development of bronchiolitis obliterans has a negative impact on long-term survival. No immunosuppressive regimen has been shown to prevent this complication or improve survival once it occurs [6][7][8].Bronchiolitis obliterans is thought to be a consequence of immunological lung injury [9][10][11]. An inflammatory cascade directed against allograft bronchiolar epithelial and endothelial cells is initiated by T-lymphocytes, as demonstrated in animals [12][13][14] and human subjects [15,16]. Alloreactive lymphocytes are found in bronchoalveolar lavage fluid, and selective T-cell clones are expanded during bronchiolitis obliterans [17]. Myriad cytokines and lymphocyte gene expression induce small airway inflammation, leading to myofibroblast-like cell proliferation and ingrowth of small airway granulation tissue, and resulting in occlusion of the airway lumen [18][19][20][21]. A cascade of injury and remodelling triggers a fibroproliferative process responsible for bronchiolar scarring and graft failure.Cyclosporin is one of the mainstays of maintenance immunosuppression after transplantation; however, it has a narrow therapeutic index when given systemically [22]. It blocks lymphocyte activation by inhibiting transcription of cytokine genes in a dose-dependent manner [22,23]. Cyclosporin also exerts an antifibrotic effect by inhibiting alveolar macrophage function and suppressing collagen deposition by lung fibroblasts [24,25].Previous inves...

Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT

“…Data in lung transplantation have shown that inhaled CsA improved survival by reducing chronic graft rejection (considered equivalent to BO in allo-SCT recipients) with very high local immunosuppression and little additional systemic toxicity. 23,24 Challenges to the progress of medical management of BO include nonavailability of effective therapy. Our data showed early encouraging results using ECP in advanced refractory BO.…”

Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery

“…[7][8][9] Local pulmonary delivery of CsA as nebulized liquid aerosols in lung transplant patients has been reported. 10,11 The improved response in a lung transplant patient by inhaled nebulized tacrolimus, another important immunosuppressant drug, for successful lung immunosuppression while significantly reducing systemic side effects and improving patient outcomes has been recently reported by the authors' group. 12 A metered-dose inhaler of CsA has been aerosolized in asthmatic patients.…”

The Effect of Cyclosporin A on Airway Cell Proinflammatory Signaling and Pneumonia

“…Excessive proinflammatory signaling is a major component of airway pathology in cystic fibrosis (CF) as well as many other respiratory diseases (16,17). The delivery of CsA by aerosol in lung transplantation is currently being studied, not only to avoid systemic toxicities of the drug, but to decrease local immunoproliferative responses and bronchiolitis obliterans, a major complication of lung transplantation (18). Because cyclosporin acts through inhibition of the Ca 2ϩ -dependent phosphatase calcineurin, which is expressed in the airway epithelium, it seemed likely that cyclosporin could affect epithelial signaling in response to bacterial ligands.…”