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The pathobiology of heart-lung transplantation
Human PATHOLOGY VOLUME 19
DECEMBER 1988
NUMBER 12
Editorial
The Pathobiology of Heart-Lung Transplantation Heart-lung transplantation has evolved over the past three decades from the experimental laboratory to an accepted means of treating patients with fatal pulmonary disease. From the first report by Demikhov in 1960,1 that combined heart and lung transplantation could provide cardiopulmonary support, to the first heart-lung transplant in a h u m a n in 1968 (a 2month-old infant with an atrioventricular canal defect who died 14 hours later), 2 the procedure is gaining clinical acceptance, and was performed on 177 patients worldwide in 1987. 3 Despite extensive investigation and experimental study, primarily at Stanford University, heart-lung transplantation did not assume the status of a viable treatment option until the introduction of cyclosporine. Actuarial survival curves for patients who received heart-lung transplants between 1981 and 1985 revealed a 52% survival rate at 1 year and a 44% survival rate at 2 years. Recent data from 1986 and 1987 have shown improvement, with a 62% survival rate at 1 year and a 61% survival rate at 2 years. 3 This can be attributed to better donorrecipient selection in addition to increased experience with the procedure and improved patient management. Nevertheless, clinical management continues to evolve, and the experience r e p o r t e d by Tazelaar and Yousem 4 in this issue of the Journal will greatly advance our understanding of the "natural" history and complications of heart-lung transplantation which, in turn, will improve clinical results. Primary pulmonary hypertension, congenital heart disease, and Eisenmenger's complex comprise the major indications for combined heart-lung transplantation today. The donor heart and lungs are removed en bloc without cardiopulmonary bypass and are cooled and/or autoperfused to maintain adequate preservation. The recipient organs are removed separately, beginning with the heart, and continuing with the left and right lungs. The recipient trachea is divided just above the carina, the donor heart and lungs are placed in the chest, and tracheal anastomosis is performed, followed by anastomosis of the right atria and, lastly, the aorta. The transplanted lungs do not have a bronchial arterial supply, pulmonary in-
nervation, or lymphatic drainage. While bronchial artery circulation and innervation do not appear to be important for survival of the graft, lack of lymphatic drainage requires careful monitoring of fluid balance and may contribute, in part, to the "reimplantation response" that can be seen in patients following surgery. An optimal immunosuppressive regimen is still under evaluation, although most centers are using cyclosporine, augmented by azathioprine and antithymocyte globulin, followed by the replacement of azathioprine with prednisone. (Corticosteroids are avoided in the early postoperative period to allow for tracheal healing.) The pathologist plays a critical role in the postoperative management of heart-lung recipients, enabling these patients to navigate a fine line between infection and rejection. The evaluation of lung allograft rejection is still primarily made on clinical grounds (appearance of infiltrates on chest radiographs, accompanied by fever, leukocytosis, and decreased oxygen tension). Surveillance of the transplanted heart by endomyocardial biopsy has not been found to be a reliable means to monitor for pulmonary rejection, since the lungs may reject without evidence of rejection in the myocardium. Thus, open lung biopsy may be performed in some patients to evaluate the degree of rejection. Data have also been published, primarily from Pittsburgh, suggesting that less invasive techniques, such as bronchioalveolar lavage, 5 may be useful in distinguishing between pulmonary rejection and infection. The pathologist will be pivotal in making this distinction if the preliminary observations by Hruban et al, 6 who used immunoperoxidase techniques to identify lymphocyte populations in transbronchial biopsy material, prove to be reproducible, although at our institution this technique has not been found to be of assistance thus far. Tazelaar and Yousem have shown that infection is a significant cause of death in patients who die within months following heart-lung transplantation. On the other hand, patients who survive longer than 2 to 9 months may develop significant bronchiolitis obliterans. The findings of bronchiolitis obliterans in
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HUMAN PATHOLOGY
Volume 19, No. 12 [December 1988]
long-term survivors at necropsy by Tazelaar and Yousem extend the previous observations made by the Stanford group. 7 Although it has been assumed that bronchiolitis obliterans is an immunologic (ie, rejection) phenomenon, Tazelaar and Yousem correctly point out that the role of infection cannot be ruled out. Before the publication of thearticle by Tazelaar and Yousem in this issue, descriptions of pathologic findings at necropsy in heart-lung recipients have been confined primarily to isolated reports. This work has particular importance to the practicing pathologist, in that, as in heart transplantation, attention is turning from the acute complications of the procedure to more long-term complications that compromise patient survival. Tazelaar and Yousem have shown that, aside from perioperative deaths related to recipient selection, infections (particularly cytomegalovirus and pneumocystis) and, in long-term patients, bronchiolitis obliterans are the major complications associated with death. Acute rejection is less of a problem. Of the four patients who have received combined heart-lung transplants at Vanderbilt University during the past year, two have died and in each case infection was a major complication. This article should have a major impact on the practicing pathologist in two ways. First, in no other area of practice does the pathologist potentially play a more direct and immediate role in clinical management than in the morphologic and immunologic evaluation of the heart or lungs in heart and heart-lung transplant recipients. A misleading diagnosis of rejection can result in over-immunosuppression and lead to fatal infection, while the failure to recognize acute rej.ection can result in death within hours if appropriate therapy is not promptly instituted. Second, the evaluation of these patients is not restricted to a few academic centers, but, as they leave the hospital, responsibility for patient management is transferred to the local level. Admittedly, the number of patients receiving heart-lung transplants remains small, particularly when compared with the number of patients receiving heart transplants. Nevertheless, given the lack of centers that are actively engaged in heart-lung transplantation, most patients must travel from relatively distant sites. The logistical problems involved in
having the patients return to the transplantation center when they develop a headache, low-grade fever, or dyspnea can be difficult. Thus, more of the burden of managing these patients will fall on local clinicians and pathologists. As more centers enter into the arena of heart-lung transplantation and gain experience, the greater the likelihood that the practicing pathologist will be called on to interpret a transbronchial or endomyocardial biopsy, bronchioalveolar lavage, or open lung biopsy. In our own experience, we have found the type of data provided by Tazelaar and Yousem to be invaluable as we attempt to sort out the sometimes confusing picture of chronic rejection, bronchilitis obliterans, and infection in individual clinical situations. Their data are also helpful in elucidating the natural history of the lung allograft, leading to improved diagnostic capabilities and clinical management of these patients. The findings reported in this study are an important extension of the valuable experience with the pathology of transplantation that has been provided by the Stanford group. JAMES B. ATKINSON, MD, PHD Vanderbilt University Nashville, TN REFERENCES 1. Demikhov VP: Some essential points of the techniques of transplantation of the heart, lungs and other organs, in Experimental Transplantation of Vital Organs. Moscow, Medgiz State Press for Medical Literature in Moscow, 1960, p 29 2. Cooley DA, Bloodwell RD, Hallman GL, et al: Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg 8:30, 1969 3. Fragomeni LS, Kaye MP: The Registry of the International Society for Heart Transplantation: Fifth Official Report--1988. J Heart Transplant 7:249, 1988 4. Tazelaar HD, Yousem SA: The pathology of combined heart-lung transplantation: An autopsy study. HUM PATHOL 19:1403-1416, 1988 5. Zeevi A, Rabinowich H, Paradis I, et al: Lymphocyte activation in bronchioalveolar lavages from heart-lung transplant recipients. Transplant Proc 20:189, 1988 6. Hruban RH, Beschorner WE, Gupta PK, et al: Diagnosis of rejection of lung allograft. N Engl J Med 318:1129, 1988 (letter) 7. Yousem SA, Burke CM, Billingham ME: Pathologic pulmonary alterations in long-term human heart-lung transplantation. HUM PATHOL16:911, 1985
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DECEMBER 1988
NUMBER 12
Editorial
The Pathobiology of Heart-Lung Transplantation Heart-lung transplantation has evolved over the past three decades from the experimental laboratory to an accepted means of treating patients with fatal pulmonary disease. From the first report by Demikhov in 1960,1 that combined heart and lung transplantation could provide cardiopulmonary support, to the first heart-lung transplant in a h u m a n in 1968 (a 2month-old infant with an atrioventricular canal defect who died 14 hours later), 2 the procedure is gaining clinical acceptance, and was performed on 177 patients worldwide in 1987. 3 Despite extensive investigation and experimental study, primarily at Stanford University, heart-lung transplantation did not assume the status of a viable treatment option until the introduction of cyclosporine. Actuarial survival curves for patients who received heart-lung transplants between 1981 and 1985 revealed a 52% survival rate at 1 year and a 44% survival rate at 2 years. Recent data from 1986 and 1987 have shown improvement, with a 62% survival rate at 1 year and a 61% survival rate at 2 years. 3 This can be attributed to better donorrecipient selection in addition to increased experience with the procedure and improved patient management. Nevertheless, clinical management continues to evolve, and the experience r e p o r t e d by Tazelaar and Yousem 4 in this issue of the Journal will greatly advance our understanding of the "natural" history and complications of heart-lung transplantation which, in turn, will improve clinical results. Primary pulmonary hypertension, congenital heart disease, and Eisenmenger's complex comprise the major indications for combined heart-lung transplantation today. The donor heart and lungs are removed en bloc without cardiopulmonary bypass and are cooled and/or autoperfused to maintain adequate preservation. The recipient organs are removed separately, beginning with the heart, and continuing with the left and right lungs. The recipient trachea is divided just above the carina, the donor heart and lungs are placed in the chest, and tracheal anastomosis is performed, followed by anastomosis of the right atria and, lastly, the aorta. The transplanted lungs do not have a bronchial arterial supply, pulmonary in-
nervation, or lymphatic drainage. While bronchial artery circulation and innervation do not appear to be important for survival of the graft, lack of lymphatic drainage requires careful monitoring of fluid balance and may contribute, in part, to the "reimplantation response" that can be seen in patients following surgery. An optimal immunosuppressive regimen is still under evaluation, although most centers are using cyclosporine, augmented by azathioprine and antithymocyte globulin, followed by the replacement of azathioprine with prednisone. (Corticosteroids are avoided in the early postoperative period to allow for tracheal healing.) The pathologist plays a critical role in the postoperative management of heart-lung recipients, enabling these patients to navigate a fine line between infection and rejection. The evaluation of lung allograft rejection is still primarily made on clinical grounds (appearance of infiltrates on chest radiographs, accompanied by fever, leukocytosis, and decreased oxygen tension). Surveillance of the transplanted heart by endomyocardial biopsy has not been found to be a reliable means to monitor for pulmonary rejection, since the lungs may reject without evidence of rejection in the myocardium. Thus, open lung biopsy may be performed in some patients to evaluate the degree of rejection. Data have also been published, primarily from Pittsburgh, suggesting that less invasive techniques, such as bronchioalveolar lavage, 5 may be useful in distinguishing between pulmonary rejection and infection. The pathologist will be pivotal in making this distinction if the preliminary observations by Hruban et al, 6 who used immunoperoxidase techniques to identify lymphocyte populations in transbronchial biopsy material, prove to be reproducible, although at our institution this technique has not been found to be of assistance thus far. Tazelaar and Yousem have shown that infection is a significant cause of death in patients who die within months following heart-lung transplantation. On the other hand, patients who survive longer than 2 to 9 months may develop significant bronchiolitis obliterans. The findings of bronchiolitis obliterans in
1367
HUMAN PATHOLOGY
Volume 19, No. 12 [December 1988]
long-term survivors at necropsy by Tazelaar and Yousem extend the previous observations made by the Stanford group. 7 Although it has been assumed that bronchiolitis obliterans is an immunologic (ie, rejection) phenomenon, Tazelaar and Yousem correctly point out that the role of infection cannot be ruled out. Before the publication of thearticle by Tazelaar and Yousem in this issue, descriptions of pathologic findings at necropsy in heart-lung recipients have been confined primarily to isolated reports. This work has particular importance to the practicing pathologist, in that, as in heart transplantation, attention is turning from the acute complications of the procedure to more long-term complications that compromise patient survival. Tazelaar and Yousem have shown that, aside from perioperative deaths related to recipient selection, infections (particularly cytomegalovirus and pneumocystis) and, in long-term patients, bronchiolitis obliterans are the major complications associated with death. Acute rejection is less of a problem. Of the four patients who have received combined heart-lung transplants at Vanderbilt University during the past year, two have died and in each case infection was a major complication. This article should have a major impact on the practicing pathologist in two ways. First, in no other area of practice does the pathologist potentially play a more direct and immediate role in clinical management than in the morphologic and immunologic evaluation of the heart or lungs in heart and heart-lung transplant recipients. A misleading diagnosis of rejection can result in over-immunosuppression and lead to fatal infection, while the failure to recognize acute rej.ection can result in death within hours if appropriate therapy is not promptly instituted. Second, the evaluation of these patients is not restricted to a few academic centers, but, as they leave the hospital, responsibility for patient management is transferred to the local level. Admittedly, the number of patients receiving heart-lung transplants remains small, particularly when compared with the number of patients receiving heart transplants. Nevertheless, given the lack of centers that are actively engaged in heart-lung transplantation, most patients must travel from relatively distant sites. The logistical problems involved in
having the patients return to the transplantation center when they develop a headache, low-grade fever, or dyspnea can be difficult. Thus, more of the burden of managing these patients will fall on local clinicians and pathologists. As more centers enter into the arena of heart-lung transplantation and gain experience, the greater the likelihood that the practicing pathologist will be called on to interpret a transbronchial or endomyocardial biopsy, bronchioalveolar lavage, or open lung biopsy. In our own experience, we have found the type of data provided by Tazelaar and Yousem to be invaluable as we attempt to sort out the sometimes confusing picture of chronic rejection, bronchilitis obliterans, and infection in individual clinical situations. Their data are also helpful in elucidating the natural history of the lung allograft, leading to improved diagnostic capabilities and clinical management of these patients. The findings reported in this study are an important extension of the valuable experience with the pathology of transplantation that has been provided by the Stanford group. JAMES B. ATKINSON, MD, PHD Vanderbilt University Nashville, TN REFERENCES 1. Demikhov VP: Some essential points of the techniques of transplantation of the heart, lungs and other organs, in Experimental Transplantation of Vital Organs. Moscow, Medgiz State Press for Medical Literature in Moscow, 1960, p 29 2. Cooley DA, Bloodwell RD, Hallman GL, et al: Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg 8:30, 1969 3. Fragomeni LS, Kaye MP: The Registry of the International Society for Heart Transplantation: Fifth Official Report--1988. J Heart Transplant 7:249, 1988 4. Tazelaar HD, Yousem SA: The pathology of combined heart-lung transplantation: An autopsy study. HUM PATHOL 19:1403-1416, 1988 5. Zeevi A, Rabinowich H, Paradis I, et al: Lymphocyte activation in bronchioalveolar lavages from heart-lung transplant recipients. Transplant Proc 20:189, 1988 6. Hruban RH, Beschorner WE, Gupta PK, et al: Diagnosis of rejection of lung allograft. N Engl J Med 318:1129, 1988 (letter) 7. Yousem SA, Burke CM, Billingham ME: Pathologic pulmonary alterations in long-term human heart-lung transplantation. HUM PATHOL16:911, 1985
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