By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
January, 2016
Since the mid 1980’s, lung transplantation has become the treatment of choice for a variety of end-stage lung diseases. However, the long term outcomes today are only marginally better than they were 15 or 20 years ago. Surgical techniques have been perfected, and the post-operative management has been refined resulting in better outcomes in the first 30 days and first year after transplantation than 15 years ago. However, long term outcomes have not changed substantially because rejection remains as prevalent today as it was then. In fact, chronic rejection remains the leading cause of death after the first post-transplant year. Rejection represents the recipient’s immune response to the transplanted organ; the primary purpose of immunity is to detect and attack foreign substances, such as invading viruses or bacteria. In the setting of organ transplantation, the immune system recognizes the transplanted organ as foreign and attacks it. Two forms of rejection have been recognized after lung transplantation; acute rejection is common in the first year after transplantation and responds fairly well to treatment. On the other hand, chronic rejection results in inflammation and scarring of the small airways in the lungs and is less responsive to treatment. Tolerance, a state of immune unresponsiveness to the transplanted organ, has been called the “holy grail” of transplantation but despite significant advances in immunology and biology, it remains elusive in clinical practice. Thus, the mainstay of prevention and treatment of rejection remains immune suppression.
The advent of cyclosporine in the late 1970’s and early 1980’s improved the outcomes of all organ transplant recipients and allowed lung transplantation to become a clinical reality. The standard immunosuppressive regimen for most patients has been the triple drug combination of cyclosporine, azathioprine, and prednisone. Over the years, a few other drugs have been discovered and introduced into clinical practice including tacrolimus, mycophenolate mofetil, and sirolimus. Various combinations of these agents have been used, but approximately 95% of lung transplant recipients are treated with either cyclosporine or tacrolimus; 80% are treated with azathioprine or mycophenolate mofetil, and 10% are treated with sirolimus. In addition, 95% are maintained on prednisone lifelong. The various combinations have been evaluated in numerous clinical studies after lung transplantation, but differences in the incidence of rejection have not been substantial, and rejection remains prevalent despite treatment with the “best” regimen. In addition, enthusiasm over newer agents has often been tempered by unfavorable side effect profiles. Indeed, the side effects of most agents have been inauspicious including high blood pressure, diabetes, high cholesterol, kidney dysfunction, skin cancers, lymphoma, and infections. Obviously, these complications can have an ominous impact on the overall outcome after transplantation.
Since the lungs are in constant contact with the environment, they are susceptible to inhaled infectious agents, allergens, and irritants. This unique characteristic of the transplanted lung has been considered a potential explanation for the higher frequency of rejection compared to other transplanted organs, such as kidneys, hearts, and livers. It has been hypothesized that the inhalation of certain infectious or non-infectious substances in ambient air may potentially induce an immune response that might cross react with the transplanted lung and result in rejection. While this offers an intriguing explanation of the higher frequency of rejection after lung transplantation, it also presents an additional potential route of drug delivery. A number of medicines are aerosolized or nebulized to treat certain lung diseases; bronchodilators are inhaled or nebulized to treat patients with asthma and chronic obstructive pulmonary disease (COPD), antibiotics are nebulized to treat those with cystic fibrosis, and vasodilators can be aerosolized for those with pulmonary hypertension. So, why not nebulize immunosuppressants after transplantation? This offers a number of attractive advantages over the oral administration of immunosuppressants. Because the drug is delivered directly to the lung, the drug concentration in the lung may be substantially higher and systemic absorption and side effects can be reduced. Researchers at the University of Pittsburgh have developed an aerosolized cyclosporine preparation marketed by Chiron Corporation as Pulminiq that is currently being reviewed by the Food and Drug Administration (FDA). The FDA’s decision will likely be made based on the results of a pivotal trial comparing the efficacy of aerosolized cyclosporine to placebo after lung transplantation. In that study, the administration of aerosolized cyclosporine in addition to standard oral immunosuppressants resulted in a lower frequency of chronic rejection and improved survival. Only minimal side effects of aerosolized cyclosporine were reported and included airway irritation and bronchospasm. Unfortunately, the number of patients receiving aerosolized cyclosporine in the study was relatively small and possible rare but serious side effects may not have been detected. Ultimately, the FDA will decide whether the available data warrants approval of Pulminiq for use after lung transplantation and a decision is expected on June 6, 2005. If it is not approved, lung transplant recipients and their physicians will have to wait for other drugs that seem promising, which may be a year or two away from clinical use.