Inhaled Cyclosporine — A Breath of Fresh Air?
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《新英格兰医药杂志》
During the past two decades, lung transplantation has evolved from a new investigational intervention performed in fewer than 20 patients per year at one institution to an accepted, albeit complex, therapy for a wide variety of end-stage lung diseases that is performed in more than 1700 patients annually at nearly 150 centers worldwide.1 Early graft failures and deaths of patients were attributable to an amalgam of technical complications, opportunistic infections, and acute rejection. Refinements in surgical technique, enhanced graft preservation, and the routine use of contemporary monitoring and prophylactic and preemptive regimens for opportunistic viruses, fungi, and protozoan organisms have led to improved early survival after lung transplantation (Figure 1). Newer drugs for the induction and maintenance of immunosuppression have lessened the severity and frequency of acute rejection.2,3 However, beyond the first year after engraftment, the rate of death among lung-transplant recipients has essentially remained unchanged between the 1980s and the present. At the five-year follow-up, nearly 50 percent of recipients are dead.1,4
Figure 1. Differential Kaplan–Meier Analysis of Survival after Lung Transplantation, According to Era, 1988 through 2003.
Survival declines rapidly in the first year after transplantation. During the past 15 years, improved treatments for both donors and recipients have steadily driven the early-survival curves upward. In contrast, the rate of declining survival beyond the first year (slope of the curves) that is attributable mostly to chronic rejection (obliterative bronchiolitis) remains unchanged in each era. P=0.01 for a survival comparison of 1988–1994 with 1995–1999; P<0.001 for 1988–1994 as compared with 2000–2003; and P<0.001 for 1995–1999 as compared with 2000–2003. The median survival for 1988–1994 was 3.9 years, as compared with 4.5 years for 1995–1999. Data are from Trulock.1
Chronic rejection after lung transplantation is recognized histologically as obliterative bronchiolitis and has consistently been the leading cause of death among recipients who survive the first year.1,5 Whereas the mechanism of acute rejection in solid-organ transplantation is well understood as an inflammatory response to alloantigen stimulation mediated by T lymphocytes, neither the triggers nor the mechanisms of chronic rejection are known. Obliterative bronchiolitis is thought to be the consequence of some combination of immune, ischemic, and infectious injuries. Strategies to limit ischemia, minimize viral infections by matching the cytomegalovirus (CMV) serologic status between donor and recipient, and specific immune therapies to prevent obliterative bronchiolitis have been either impractical or unsuccessful.6 Moreover, therapeutic interventions short of retransplantation for established obliterative bronchiolitis have been disappointing.7 In this issue of the Journal, Iacono and colleagues provide the first efficacy data from a randomized, placebo-controlled trial of an intervention both to reduce chronic rejection and to enhance survival in lung-transplant recipients.8 As would be expected, there are some methodologic shortcomings in this small study of an intervention in a complex population of 58 patients, in which randomization cannot hope to balance equally all the confounding variables. Nevertheless, many of these variables would have been expected to negate any benefit of treatment, which makes the results all the more intriguing.
Lung transplantation lags behind other solid-organ transplantation in terms of medium-term and long-term survival. The explanation for this fact is both immunologic and physiological. Because the lung is in direct contact with the environment through respiration, it has a larger lymphocyte mass than do most other transplantable organs. Therefore, lung-transplant recipients usually require higher maintenance levels of immune suppression than do recipients of heart, liver, or kidney transplants.9,10 This demand produces a clinical conundrum for the lung-transplantation physician in the form of pulmonary infection, since this common consequence of chronic illness is even more common in an immunocompromised host. Unfortunately, dyspnea, cough, hypoxemia, fever, and pulmonary infiltrates are symptoms, signs, and findings associated with both pneumonia and rejection. Lung recipients are the only population of transplant recipients in which most of the serious infectious complications after transplantation occur in the graft itself.
Iacono and his colleagues from Pittsburgh exploited the unique interface of the lung with our world by delivering augmented immune therapy directly to the graft through the airways. They were able to do this without engendering an increase in pulmonary infection and without the risk of detectable systemic absorption and potential nephrotoxicity from larger amounts of calcineurin inhibitors. Previous attempts to achieve this effect with inhaled corticosteroids were unsuccessful.11 It would appear that inhaled cyclosporine might help in at least delaying the onset of obliterative bronchiolitis and pushing the late-survival curves of lung-transplant recipients upward toward those of heart, liver, and kidney recipients.
The clinical-trials purist will evaluate the study of Iacono and colleagues and see that with regard to the authors' primary end point (the rate of histologic acute rejection), the study must be considered a "negative" trial. Such a perspective, however, places a methodologic tree ahead of the forest. In addition, the trial fell far short of its prospectively defined accrual goal of 136 patients. Despite generating only 43 percent of the projected study sample, having only 50 percent treatment compliance, and having some substantial imbalances between treatment and placebo groups, there were very few complications of active treatment, and the clinical benefits of the inhaled drug remained statistically significant.
These results should be received enthusiastically by lung-transplant physicians and surgeons but need to be confirmed in a more broadly inclusive multicenter trial. Such trials have been woefully lacking in the lung-transplantation world, in which 78 percent of centers perform fewer than 20 transplantations per year.1 There is no consensus regionally, nationally, or internationally regarding such important treatment issues as the use of induction immunosuppression, the optimal maintenance combinations of immunosuppressive drugs, strategies for reducing the use of corticosteroids and limiting calcineurin renal toxicity, the question of when to schedule biopsies and when and how to treat acute rejection, and the optimal prophylactic regimen for CMV, pneumocystis, and fungal infections. Lung transplantation remains a low-volume, high-cost intervention. Without a mechanism for sharing experiences, studying new therapies and techniques, and critically analyzing pooled outcomes, the lung-transplantation community will never establish a set of best practices. Instead, it will be doomed to re-create a series of anecdotal experiences. Perhaps the inhaled-cyclosporine story will be that breath of fresh air that brings this community together.
Source Information
From the Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston.
References
Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report -- 2005. J Heart Lung Transplant 2005;24:956-967.
Palmer SM, Miralles AP, Lawrence CM, Gaynor JW, Davis RD, Tapson VF. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999;116:127-133.
McCurry KR, Iacono A, Zeevi A, et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg 2005;130:528-537.
Barr ML, Bourge RC, Orens JB, et al. Thoracic organ transplantation in the United States, 1994-2003. Am J Transplant 2005;5:934-949.
Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation: an analysis of risk factors and management. J Thorac Cardiovasc Surg 1995;110:4-14.
Scott AI, Sharples LD, Stewart S. Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies. Drugs 2005;65:761-771.
Date H, Lynch JP, Sundaresan S, Patterson GA, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998;17:869-875.
Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141-150.
Zhang JH, Dong ZJ, Zhou RB, Luo de M, Wei HM, Tian ZG. Isolation of lymphocytes and their innate immune characterizations from liver, intestine, lung and uterus. Cell Mol Immunol 2005;2:271-80.
Sester U, Gartner BC, Wilkens H, et al. Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant 2005;5:1483-1489.
Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002;73:1793-1799.(Malcolm M. DeCamp, Jr., M)
Figure 1. Differential Kaplan–Meier Analysis of Survival after Lung Transplantation, According to Era, 1988 through 2003.
Survival declines rapidly in the first year after transplantation. During the past 15 years, improved treatments for both donors and recipients have steadily driven the early-survival curves upward. In contrast, the rate of declining survival beyond the first year (slope of the curves) that is attributable mostly to chronic rejection (obliterative bronchiolitis) remains unchanged in each era. P=0.01 for a survival comparison of 1988–1994 with 1995–1999; P<0.001 for 1988–1994 as compared with 2000–2003; and P<0.001 for 1995–1999 as compared with 2000–2003. The median survival for 1988–1994 was 3.9 years, as compared with 4.5 years for 1995–1999. Data are from Trulock.1
Chronic rejection after lung transplantation is recognized histologically as obliterative bronchiolitis and has consistently been the leading cause of death among recipients who survive the first year.1,5 Whereas the mechanism of acute rejection in solid-organ transplantation is well understood as an inflammatory response to alloantigen stimulation mediated by T lymphocytes, neither the triggers nor the mechanisms of chronic rejection are known. Obliterative bronchiolitis is thought to be the consequence of some combination of immune, ischemic, and infectious injuries. Strategies to limit ischemia, minimize viral infections by matching the cytomegalovirus (CMV) serologic status between donor and recipient, and specific immune therapies to prevent obliterative bronchiolitis have been either impractical or unsuccessful.6 Moreover, therapeutic interventions short of retransplantation for established obliterative bronchiolitis have been disappointing.7 In this issue of the Journal, Iacono and colleagues provide the first efficacy data from a randomized, placebo-controlled trial of an intervention both to reduce chronic rejection and to enhance survival in lung-transplant recipients.8 As would be expected, there are some methodologic shortcomings in this small study of an intervention in a complex population of 58 patients, in which randomization cannot hope to balance equally all the confounding variables. Nevertheless, many of these variables would have been expected to negate any benefit of treatment, which makes the results all the more intriguing.
Lung transplantation lags behind other solid-organ transplantation in terms of medium-term and long-term survival. The explanation for this fact is both immunologic and physiological. Because the lung is in direct contact with the environment through respiration, it has a larger lymphocyte mass than do most other transplantable organs. Therefore, lung-transplant recipients usually require higher maintenance levels of immune suppression than do recipients of heart, liver, or kidney transplants.9,10 This demand produces a clinical conundrum for the lung-transplantation physician in the form of pulmonary infection, since this common consequence of chronic illness is even more common in an immunocompromised host. Unfortunately, dyspnea, cough, hypoxemia, fever, and pulmonary infiltrates are symptoms, signs, and findings associated with both pneumonia and rejection. Lung recipients are the only population of transplant recipients in which most of the serious infectious complications after transplantation occur in the graft itself.
Iacono and his colleagues from Pittsburgh exploited the unique interface of the lung with our world by delivering augmented immune therapy directly to the graft through the airways. They were able to do this without engendering an increase in pulmonary infection and without the risk of detectable systemic absorption and potential nephrotoxicity from larger amounts of calcineurin inhibitors. Previous attempts to achieve this effect with inhaled corticosteroids were unsuccessful.11 It would appear that inhaled cyclosporine might help in at least delaying the onset of obliterative bronchiolitis and pushing the late-survival curves of lung-transplant recipients upward toward those of heart, liver, and kidney recipients.
The clinical-trials purist will evaluate the study of Iacono and colleagues and see that with regard to the authors' primary end point (the rate of histologic acute rejection), the study must be considered a "negative" trial. Such a perspective, however, places a methodologic tree ahead of the forest. In addition, the trial fell far short of its prospectively defined accrual goal of 136 patients. Despite generating only 43 percent of the projected study sample, having only 50 percent treatment compliance, and having some substantial imbalances between treatment and placebo groups, there were very few complications of active treatment, and the clinical benefits of the inhaled drug remained statistically significant.
These results should be received enthusiastically by lung-transplant physicians and surgeons but need to be confirmed in a more broadly inclusive multicenter trial. Such trials have been woefully lacking in the lung-transplantation world, in which 78 percent of centers perform fewer than 20 transplantations per year.1 There is no consensus regionally, nationally, or internationally regarding such important treatment issues as the use of induction immunosuppression, the optimal maintenance combinations of immunosuppressive drugs, strategies for reducing the use of corticosteroids and limiting calcineurin renal toxicity, the question of when to schedule biopsies and when and how to treat acute rejection, and the optimal prophylactic regimen for CMV, pneumocystis, and fungal infections. Lung transplantation remains a low-volume, high-cost intervention. Without a mechanism for sharing experiences, studying new therapies and techniques, and critically analyzing pooled outcomes, the lung-transplantation community will never establish a set of best practices. Instead, it will be doomed to re-create a series of anecdotal experiences. Perhaps the inhaled-cyclosporine story will be that breath of fresh air that brings this community together.
Source Information
From the Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston.
References
Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report -- 2005. J Heart Lung Transplant 2005;24:956-967.
Palmer SM, Miralles AP, Lawrence CM, Gaynor JW, Davis RD, Tapson VF. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999;116:127-133.
McCurry KR, Iacono A, Zeevi A, et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg 2005;130:528-537.
Barr ML, Bourge RC, Orens JB, et al. Thoracic organ transplantation in the United States, 1994-2003. Am J Transplant 2005;5:934-949.
Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation: an analysis of risk factors and management. J Thorac Cardiovasc Surg 1995;110:4-14.
Scott AI, Sharples LD, Stewart S. Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies. Drugs 2005;65:761-771.
Date H, Lynch JP, Sundaresan S, Patterson GA, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998;17:869-875.
Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141-150.
Zhang JH, Dong ZJ, Zhou RB, Luo de M, Wei HM, Tian ZG. Isolation of lymphocytes and their innate immune characterizations from liver, intestine, lung and uterus. Cell Mol Immunol 2005;2:271-80.
Sester U, Gartner BC, Wilkens H, et al. Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant 2005;5:1483-1489.
Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002;73:1793-1799.(Malcolm M. DeCamp, Jr., M)