By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
April, 2007
The first human lung transplantation was performed in 1963, but the recipient died 18 days after the operation because of kidney failure and malnutrition. Nonetheless, this experience demonstrated that the transplanted lung could function physiologically and that rejection could be averted with the available immunosuppressants, at least for a short time. However, over the ensuing 15 years only 40 transplants were performed worldwide, and the majority of recipients died early after surgery because of complications at the airway anastomosis. The advent of cyclosporine in the late 1970s and refinement in surgical techniques improved airway healing and made lung transplantation a clinical reality. In 1981, the first combined heart-lung transplantation was performed for pulmonary hypertension, and in 1983 single lung transplantation was performed successfully for pulmonary fibrosis. The immunosuppressive regimen during this early era of lung transplantation consisted of cyclosporine, azathioprine, and prednisone, and remarkably relatively little has changed over the past 25 years. The next major breakthrough in immunosuppressive therapy was the introduction of tacrolimus in the 1990s. In addition, newer formulations of cyclosporine have been developed that result in more consistent absorption. Mycophenolate mofetil and sirolimus were then introduced in the late 1990s.
Currently, multiple combinations of immunosuppressants are possible. Cyclosporine or tacrolimus is the cornerstone of most regimens. The two drugs have the same mechanism of action; they both inhibit a key enzyme in immune cell activation called calcineurin. Thus, they are never used together at the same time. The consensus among most transplant physicians is that tacrolimus is probably more potent than cyclosporine. However, the difference in efficacy is not substantial and the two drugs have similar overall side-effect profiles. As immunosuppressants, both predispose to infections and cancer and both are toxic to the kidneys, but tacrolimus is more likely to cause diabetes. Conversely, cyclosporine can cause some unpleasant cosmetic side-effects including facial hair growth and gum hyperplasia. The second fundamental drug in the maintenance regimen is either azathioprine or mycophenolate mofetil. The two have similar mechanisms of action and inhibit immune cell proliferation. They also have similar side-effect profiles including low white blood cell counts and a predisposition to infections and cancer. However, mycophenolate mofetil is much more likely to cause gastrointestinal symptoms such as nausea, anorexia, and diarrhea. Again, the consensus among most transplant physicians is that mycophenolate mofetil may be more potent than azathioprine. Prednisone is the third agent in most regimens. Prednisone avoidance and withdrawal have been successful in many kidney and liver transplant protocols, but this is much less common after lung transplantation primarily because the transplanted lung is much more susceptible to rejection than kidneys or livers. Finally, the lung transplant community was enthusiastic about the introduction of sirolimus in the late 1990s because it had a distinct mechanism of action and could be used in combination with either cyclosporine or tacrolimus resulting in very potent immunosuppression. Indeed, lung transplant recipients treated with this combination have sometimes become overly susceptible to infections necessitating discontinuation of sirolimus. In addition, sirolimus cannot be used early after transplantation because it can inhibit wound healing. Furthermore, sirolimus has been reported to cause a lung injury in some kidney and heart transplant recipients. Obviously, this complicates its use in lung transplantation since it becomes very difficult to distinguish this lung injury from pneumonia and atypical manifestations of rejection.
In recent years, the most common maintenance immunosuppressive regimen among lung recipients reported to the International Society for Heart and Lung Transplantation Registry has consisted of tacrolimus, prednisone, and either mycophenolate mofetil or azathioprine. Fewer than 30% of recipients are managed with a cyclosporine based regimen. Transplant programs typically adhere to an immunosuppressive protocol for all patients and substitute alternate agents to manage complications or rejection. Because of the potential combinations, there is ongoing research to identify the optimal regime. In addition, recent studies suggest that a less potent maintenance immunosuppressive regimen can be used safely when coupled with very potent induction immunosuppression before the transplant. The rationale is that when the immune system is aggressively suppressed immediately before the transplant, it may be less likely to recognize the transplanted organ when it begins to recover. Obviously, this paradigm still needs to be investigated further to insure its safety and efficacy.