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Isolated pulmonary rejection after combined heart-lung transplantation
J THoRAc CARDIOVASC SURG 90:623-630, 1985
Brief communications Isolated pulmonary rejection after combined heart-lung transplantation C. G. A. McGregor, ER.C.S., * J. C. Baldwin, M.D., S. W. Jamieson, F.R.C.S., M. E. Billingham, M.B., B.S., S. A. Yousem, M.D., C. M. Burke, M.R.C.P., P. E. Oyer, M.D., Ph.D., E. B. Stinson, M.D., and N. E. Shumway, M.D., Ph.D., Stanford. Calif. From the Departments of Cardiovascular Surgery and Pathology, Stanford University School of Medicine, Stanford Calif.
Severe plumonary rejection without cardiac rejection in a patient after combined heart-lung transplantation is presented with the clinical and pathological findings. Acute lung rejection after heart-lung trlllL'iplantation cannot be excluded by normal cardiac biopsy results.
The simultaneous appearance of cardiac and pulmonary rejection has been accepted as the working hypothesis in the management of patients after combined heart-lung transplantation. I·] This theory was based on experimental findings of a lymphocytic infiltrate of similar severity in both the heart and lungs following cardiopulmonary transplantation in dogs,' primates,' and in our early clinical experience. I·] The diagnosis of rejection in patients after heart-lung transplantation has therefore been dependent on the detection of cardiac allograft rejection by endomyocardial biopsy. As greater experience with this procedure has accumulated, several patients have presented with a syndrome of fevers, respiratory insufficiency, and diffuse opacification on the chest roentgenogram, occurring
after the tenth postoperative day. This appearance has often resolved in time with no specific therapy and was considered to represent the "reimplantation response" described previously.' In the laboratory, lethal pulmonary rejection after heart-lung transplantation has now been documented in primates with normal cardiac histology," One of our patients has now presented with severe pulmonary rejection in the absence of cardiac rejection. We present the clinical and pathological findings. Case report. A 40-year-old man with an aortopulmonary window and Eisenmenger physiology underwent combined heart and lung transplantation. The donor was a 19-year-old man who died after a motor vehicle accident. The recipient was extubated on the second postoperative day, and results of a cardiac biopsy on the fifth postoperative day were normal. On the sixth postoperative day a fever (380 C) and a right lower lobe infiltrate developed. Broad-spectrum antibiotic coverage was instituted. A thorough bacteriologic evaluation, including transtracheal aspirate, was unrevealing. Results of a second cardiac biopsy on the tenth postoperative day were normal.
Supported in part by Research Grant HLl3108-15 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Address for reprints: Dr. Stuart W. Jamieson, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. 'British Heart Foundation-American Heart Association Scholar. Present address: Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN, England.
Fig. 1. Chest radiograph on postoperative day 10 showing clear lung fields.
623
The Journal of
6 24 Brief communications
Thoracic and Cardiovascular Surgery
Fig. 4. By postoperative day 27 the lung fields had cleared. Fig. 2. Chest radiograph on postoperative day 22 showing a diffuse bilateral pulmonary infiltrate.
Fig. 3. Chest radiograph on postoperative day 23 showing complete opacification of the lung fields. The patient became afebrile and the radiographic abnormalities resolved (Fig. I). Antibiotics were discontinued. The patient remained clinically well until the twenty-second postoperative day, when he developed fever (38° C), leukocytosis (l7,OOO/mm2) , and a diffuse bilateral pulmonary infiltrate on the chest x-ray film (Fig. 2). Results of the cardiac biopsy on that day were normal. Over the next 24 hours, the patient's
temperature rose to 38.5° C and he experienced increasing respiratory distress with complete opacification of the lung fields on the chest x-ray film (Fig. 3). Pressor support and artificial ventilation were required, and oxygenation deteriorated progressivelywith an oxygen tension of 20 mm Hg on an inspired oxygen concentration of 100% and a peak endexpiratory pressure of 20 em H 20 . Antibiotic therapy (erythromycin, tobramycin, chloramphenicol, and cephamandol) was reinstituted. An open lung biopsy and a further cardiac biopsy were performed. The patient was treated with methylprednisolone I gm intravenously and rabbit antithymocyte globulin (RATG) 200 mg intramuscularly each day for 2 days. The circulating T-Iymphocyte count fell below 5% when measured on the third day. In the 24 hour period following initiation of this treatment, dramatic improvement occurred in the patient's condition so that the oxygen tension increased to 48 mm Hg on an inspired oxygen concentration of 40%. The patient became afebrile, the chest x-ray film cleared markedly, and inotropic support was discontinued. The chest x-ray film had cleared completely by postoperative day 27 (Fig. 4). The patient remained afebrile and was extubated on postoperative day 31. He was subsequently discharged from the hospital. At the time of his acute deterioration on the postoperative day 23, all cultures from lung tissue,blood, tracheal aspirate, urine, and feces failed to show any pathogenic organisms. Cytomegalovirus (CMV) was later isolated from lung tissue and CMV titers rose from 1:32 on postoperative day 28 to I:1024 on postoperative day 56. Results of cardiac biopsieson postoperative days 29 and 36 were again normal. Serum cyclosporine levels had been adequate throughout the postoperative period. Pathology. Multiple sections of the open lung biopsy specimen were reviewed. By far the most striking finding was a dense perivascular (particularly perivenular) cuff of plump pyroninophilic lymphoid cells, plasma cells, and occasional eosinophils (Fig. 5). This infiltrate percolated into the adjacent alveolar septa and was also associated with marked adventitial
Volume 90 Number 4
Brief communications 6 2 5
October, 1985
Fig. 5. Histopathologic appearance of acute pulmonary rejection in this patient. A marked perivascular infiltrate of mononuclear cellswas evidentat low-power examination (arrows). Transformedlymphocytes, plasma cells, and eosinophils compose the infiltrate (inset).
edema. The distal air spaces were distended by foamy macrophages, mixed with occasional neutrophils and fibrin, suggesting more proximal obstruction. Silver stains showed a single clusterof four pneumocystis cysts that were believed to be an incidental finding rather than the cause of any infection. No viral inclusions were noted and no bacteria were identified with special stains or cultures. The disproportionate perivascular infiltrate in relation to the alveolar inflammation was consistent with the diagnosis of acute pulmonary rejection. Discussion. The early development of new opacification on chest x-ray films in patients after heart-lung transplantation raises diagnostic difficulties. Potential causes of such changes, termed the "reimplantation responses," include the effects of donor lung ischemia, trauma, denervation, lymphatic interruption, or infection. The first four of these potential causes are commonly seen within days of operation and largely resolve by 21 days.' In the present case, there was no evidence of bacteriologic infection despite intensive investigation. CMV infection has been seen previously in heart-lung recipients, but the clinical and pathological presentation in this case is not consistent with a viral etiology? and would not have rapidly resolved with antirejection therapy. Similarly, a pneumocystis infection would not have responded to increased immunosuppression. Such isolated pneumocystis clusters can be found incidentally at autopsy in adults.' The diagnosis of pulmonary rejection in this case was
substantiated by the histopathological findings. In addition, the rapid resolution after treatment with steroids and RATG is in keeping with this diagnosis. Three endomyocardial biopsy specimens taken before this event, one during it, and four subsequent biopsy specimens were all normal. Endomyocardial biopsy is therefore not completely reliable for the surveillance of lung rejection after combined heart-lung transplantation. The development of fever, respiratory insufficiency, and diffuse pulmonary opacification on a chest roentgenogram in a patient after combined heart-lung transplantation raises the possibility of acute lung rejection whether or not the patient has abnormal results of cardiac biopsy. REFERENCES Baldwin JC, Jamieson SW, Stinson EB, Oyer PE, Shumway NE: Cardiopulmonary Transplantation. Cardiovasc Rev Rep 5:148-154, 1984 2 Reitz BA,Gaudiani VA, Hunt SA, WallworkJ, Billingham ME, Oyer PE, Baumgartner WA, Jamieson SW, Stinson EB, Shumway NE: Diagnosis and treatment of allograft rejection in heart-lung transplant recipients. J THoRAc CARDIOVASC SURG 85:354-361, 1983 3 Jamieson SW, Baldwin JC, Reitz BA, Stinson EB, Oyer PE, Hunt S, Billingham M, Theodore J, Modry D, Bieber CP, Shumway NE: Combined heart and lung transplantation. Lancet 1:1130-1132, 1983 4 Lower RR, Stofer RC, Hurley EJ, Shumway NE: Com-
.The Journal of
626
5
6
7 8
Brief communications
Thoracic and Cardiovascular Surgery
plete homograft replacement of the heart and both lungs. Surgery 50:842-845, 1961 Reitz BA, Burton NA, Jamieson SW, Bieber CP, Pennock JL, Stinson EB, Shumway NE: Heart and lung transplantation. Autotransplantation and allotransplantation in primates with extended survival. J THORAC CARDIOVASC SURG 80:360-372, 1980 Scott WC, Haverich A, Billingham ME, Dawkins KD, Jamieson SW: Lethal lung rejection without significant cardiac rejection in primate heart-lung allotransplants. Heart Transplant (in press) Craighead J: Cytomegalovirus pulmonary disease. Pathobioi Annu 5:197-220, 1975 Esterley JA: Pneumocystis carinii in lungs of adults at autopsy. Am Rev Respir Dis 97:935-937, 1968
New cannulation technique for the severely calcified ascending aorta Leonard A. R. Golding, M.D., Cleveland, Ohio From the Cleveland Clinic Foundation. Cleveland, Ohio.
Severe calcific atherosclerosis involving the femoral arteries, ascending aorta, right subclavian artery, and aortic arch precluded standard cannulation techniques for a patient requiring emergency revascularization. A cannula was passed from the apex of the left ventricle across the aortic valve to lie in the proximal ascending aorta, and successful cardiopulmonary bypass was achieved to aUow revascularization.
Severe diffuse atherosclerosis can produce difficulties in cannulation for cardiopulmonary bypass. In almost all cases, however, vascular access can be obtained to allow completion of the circuit for cardiopulmonary bypass. In this case the severity of the atherosclerotic process resulted in inability to use any of the standard techniques for cannulation because the vessels felt essentially like solid tubes. Case report. A 68-year-old woman was referred for coronary revascularization with Functional Class IV angina pectoris. Coronary arteriography showed an 80% left ostial obstruction with 80% obstruction in the dominant right coronary artery. Ventriculography showed normal ventricular function, but severe calcification was also noted throughout the whole ascending aorta extending into the arch. At operation this calcification involved the ascending aorta and continued into the arch with no evidence of any "soft spots." The calcification also extended into the right subclavian and carotid arteries. Exploration of both groins revealed severe diffuse atherosclerosis extending throughout the femorals and Address for reprints: Leonard A. R. Golding, M.D., The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44106.
Fig. 1. Transapical aortic cannulation. into the iliac arteries. Because of inability to construct the proximal end of a vein graft anastomosis to the ascending aorta, both internal mammary arteries were dissected from the chest wall, the patient was given heparin, and a two-stage venous cannula was inserted through the right atrial appendage. Aortic cannulation was achieved by passing a 20 Fr. end-hole armored venous cannula through the apex of the left ventricle and antegrade through the aortic valve to lie in the proximal portion of the ascending aorta. A small left ventricular vent was also positioned in the apex of the left ventricle to decompress this chamber (Fig. 1). Before the institution of cardiopulmonary bypass, no aortic regurgitation was noted on the arterial pressure record. The patient was placed on cardiopulmonary bypass and cooled systemically to 18° C. Bypass flows of 2.2 L/min/m' were achieved and the amount of drainage through the left ventricular vent did not exceed 300 ml/rnin. The left internal mammary artery was anastomosed to the left anterior descending coronary artery and the right internal mammary to the right coronary artery. The anastomoses were done with local occlusion only. The patient was rewarmed systemically to normothermia and then easily weaned from cardiopulmonary bypass. The postoperative course was uneventful with no alteration in the electrocardiogram or cardiac enzymes suggestive of myocardial infarction.
Discussion. In almost all cases cardiopulmonary bypass can be achieved with cannulation of the ascending aorta, femoral arteries, right subclavian artery, or the aortic arch. On a rare occasion the diffuse nature of atherosclerosis can preclude such techniques.
Brief communications Isolated pulmonary rejection after combined heart-lung transplantation C. G. A. McGregor, ER.C.S., * J. C. Baldwin, M.D., S. W. Jamieson, F.R.C.S., M. E. Billingham, M.B., B.S., S. A. Yousem, M.D., C. M. Burke, M.R.C.P., P. E. Oyer, M.D., Ph.D., E. B. Stinson, M.D., and N. E. Shumway, M.D., Ph.D., Stanford. Calif. From the Departments of Cardiovascular Surgery and Pathology, Stanford University School of Medicine, Stanford Calif.
Severe plumonary rejection without cardiac rejection in a patient after combined heart-lung transplantation is presented with the clinical and pathological findings. Acute lung rejection after heart-lung trlllL'iplantation cannot be excluded by normal cardiac biopsy results.
The simultaneous appearance of cardiac and pulmonary rejection has been accepted as the working hypothesis in the management of patients after combined heart-lung transplantation. I·] This theory was based on experimental findings of a lymphocytic infiltrate of similar severity in both the heart and lungs following cardiopulmonary transplantation in dogs,' primates,' and in our early clinical experience. I·] The diagnosis of rejection in patients after heart-lung transplantation has therefore been dependent on the detection of cardiac allograft rejection by endomyocardial biopsy. As greater experience with this procedure has accumulated, several patients have presented with a syndrome of fevers, respiratory insufficiency, and diffuse opacification on the chest roentgenogram, occurring
after the tenth postoperative day. This appearance has often resolved in time with no specific therapy and was considered to represent the "reimplantation response" described previously.' In the laboratory, lethal pulmonary rejection after heart-lung transplantation has now been documented in primates with normal cardiac histology," One of our patients has now presented with severe pulmonary rejection in the absence of cardiac rejection. We present the clinical and pathological findings. Case report. A 40-year-old man with an aortopulmonary window and Eisenmenger physiology underwent combined heart and lung transplantation. The donor was a 19-year-old man who died after a motor vehicle accident. The recipient was extubated on the second postoperative day, and results of a cardiac biopsy on the fifth postoperative day were normal. On the sixth postoperative day a fever (380 C) and a right lower lobe infiltrate developed. Broad-spectrum antibiotic coverage was instituted. A thorough bacteriologic evaluation, including transtracheal aspirate, was unrevealing. Results of a second cardiac biopsy on the tenth postoperative day were normal.
Supported in part by Research Grant HLl3108-15 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Address for reprints: Dr. Stuart W. Jamieson, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. 'British Heart Foundation-American Heart Association Scholar. Present address: Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN, England.
Fig. 1. Chest radiograph on postoperative day 10 showing clear lung fields.
623
The Journal of
6 24 Brief communications
Thoracic and Cardiovascular Surgery
Fig. 4. By postoperative day 27 the lung fields had cleared. Fig. 2. Chest radiograph on postoperative day 22 showing a diffuse bilateral pulmonary infiltrate.
Fig. 3. Chest radiograph on postoperative day 23 showing complete opacification of the lung fields. The patient became afebrile and the radiographic abnormalities resolved (Fig. I). Antibiotics were discontinued. The patient remained clinically well until the twenty-second postoperative day, when he developed fever (38° C), leukocytosis (l7,OOO/mm2) , and a diffuse bilateral pulmonary infiltrate on the chest x-ray film (Fig. 2). Results of the cardiac biopsy on that day were normal. Over the next 24 hours, the patient's
temperature rose to 38.5° C and he experienced increasing respiratory distress with complete opacification of the lung fields on the chest x-ray film (Fig. 3). Pressor support and artificial ventilation were required, and oxygenation deteriorated progressivelywith an oxygen tension of 20 mm Hg on an inspired oxygen concentration of 100% and a peak endexpiratory pressure of 20 em H 20 . Antibiotic therapy (erythromycin, tobramycin, chloramphenicol, and cephamandol) was reinstituted. An open lung biopsy and a further cardiac biopsy were performed. The patient was treated with methylprednisolone I gm intravenously and rabbit antithymocyte globulin (RATG) 200 mg intramuscularly each day for 2 days. The circulating T-Iymphocyte count fell below 5% when measured on the third day. In the 24 hour period following initiation of this treatment, dramatic improvement occurred in the patient's condition so that the oxygen tension increased to 48 mm Hg on an inspired oxygen concentration of 40%. The patient became afebrile, the chest x-ray film cleared markedly, and inotropic support was discontinued. The chest x-ray film had cleared completely by postoperative day 27 (Fig. 4). The patient remained afebrile and was extubated on postoperative day 31. He was subsequently discharged from the hospital. At the time of his acute deterioration on the postoperative day 23, all cultures from lung tissue,blood, tracheal aspirate, urine, and feces failed to show any pathogenic organisms. Cytomegalovirus (CMV) was later isolated from lung tissue and CMV titers rose from 1:32 on postoperative day 28 to I:1024 on postoperative day 56. Results of cardiac biopsieson postoperative days 29 and 36 were again normal. Serum cyclosporine levels had been adequate throughout the postoperative period. Pathology. Multiple sections of the open lung biopsy specimen were reviewed. By far the most striking finding was a dense perivascular (particularly perivenular) cuff of plump pyroninophilic lymphoid cells, plasma cells, and occasional eosinophils (Fig. 5). This infiltrate percolated into the adjacent alveolar septa and was also associated with marked adventitial
Volume 90 Number 4
Brief communications 6 2 5
October, 1985
Fig. 5. Histopathologic appearance of acute pulmonary rejection in this patient. A marked perivascular infiltrate of mononuclear cellswas evidentat low-power examination (arrows). Transformedlymphocytes, plasma cells, and eosinophils compose the infiltrate (inset).
edema. The distal air spaces were distended by foamy macrophages, mixed with occasional neutrophils and fibrin, suggesting more proximal obstruction. Silver stains showed a single clusterof four pneumocystis cysts that were believed to be an incidental finding rather than the cause of any infection. No viral inclusions were noted and no bacteria were identified with special stains or cultures. The disproportionate perivascular infiltrate in relation to the alveolar inflammation was consistent with the diagnosis of acute pulmonary rejection. Discussion. The early development of new opacification on chest x-ray films in patients after heart-lung transplantation raises diagnostic difficulties. Potential causes of such changes, termed the "reimplantation responses," include the effects of donor lung ischemia, trauma, denervation, lymphatic interruption, or infection. The first four of these potential causes are commonly seen within days of operation and largely resolve by 21 days.' In the present case, there was no evidence of bacteriologic infection despite intensive investigation. CMV infection has been seen previously in heart-lung recipients, but the clinical and pathological presentation in this case is not consistent with a viral etiology? and would not have rapidly resolved with antirejection therapy. Similarly, a pneumocystis infection would not have responded to increased immunosuppression. Such isolated pneumocystis clusters can be found incidentally at autopsy in adults.' The diagnosis of pulmonary rejection in this case was
substantiated by the histopathological findings. In addition, the rapid resolution after treatment with steroids and RATG is in keeping with this diagnosis. Three endomyocardial biopsy specimens taken before this event, one during it, and four subsequent biopsy specimens were all normal. Endomyocardial biopsy is therefore not completely reliable for the surveillance of lung rejection after combined heart-lung transplantation. The development of fever, respiratory insufficiency, and diffuse pulmonary opacification on a chest roentgenogram in a patient after combined heart-lung transplantation raises the possibility of acute lung rejection whether or not the patient has abnormal results of cardiac biopsy. REFERENCES Baldwin JC, Jamieson SW, Stinson EB, Oyer PE, Shumway NE: Cardiopulmonary Transplantation. Cardiovasc Rev Rep 5:148-154, 1984 2 Reitz BA,Gaudiani VA, Hunt SA, WallworkJ, Billingham ME, Oyer PE, Baumgartner WA, Jamieson SW, Stinson EB, Shumway NE: Diagnosis and treatment of allograft rejection in heart-lung transplant recipients. J THoRAc CARDIOVASC SURG 85:354-361, 1983 3 Jamieson SW, Baldwin JC, Reitz BA, Stinson EB, Oyer PE, Hunt S, Billingham M, Theodore J, Modry D, Bieber CP, Shumway NE: Combined heart and lung transplantation. Lancet 1:1130-1132, 1983 4 Lower RR, Stofer RC, Hurley EJ, Shumway NE: Com-
.The Journal of
626
5
6
7 8
Brief communications
Thoracic and Cardiovascular Surgery
plete homograft replacement of the heart and both lungs. Surgery 50:842-845, 1961 Reitz BA, Burton NA, Jamieson SW, Bieber CP, Pennock JL, Stinson EB, Shumway NE: Heart and lung transplantation. Autotransplantation and allotransplantation in primates with extended survival. J THORAC CARDIOVASC SURG 80:360-372, 1980 Scott WC, Haverich A, Billingham ME, Dawkins KD, Jamieson SW: Lethal lung rejection without significant cardiac rejection in primate heart-lung allotransplants. Heart Transplant (in press) Craighead J: Cytomegalovirus pulmonary disease. Pathobioi Annu 5:197-220, 1975 Esterley JA: Pneumocystis carinii in lungs of adults at autopsy. Am Rev Respir Dis 97:935-937, 1968
New cannulation technique for the severely calcified ascending aorta Leonard A. R. Golding, M.D., Cleveland, Ohio From the Cleveland Clinic Foundation. Cleveland, Ohio.
Severe calcific atherosclerosis involving the femoral arteries, ascending aorta, right subclavian artery, and aortic arch precluded standard cannulation techniques for a patient requiring emergency revascularization. A cannula was passed from the apex of the left ventricle across the aortic valve to lie in the proximal ascending aorta, and successful cardiopulmonary bypass was achieved to aUow revascularization.
Severe diffuse atherosclerosis can produce difficulties in cannulation for cardiopulmonary bypass. In almost all cases, however, vascular access can be obtained to allow completion of the circuit for cardiopulmonary bypass. In this case the severity of the atherosclerotic process resulted in inability to use any of the standard techniques for cannulation because the vessels felt essentially like solid tubes. Case report. A 68-year-old woman was referred for coronary revascularization with Functional Class IV angina pectoris. Coronary arteriography showed an 80% left ostial obstruction with 80% obstruction in the dominant right coronary artery. Ventriculography showed normal ventricular function, but severe calcification was also noted throughout the whole ascending aorta extending into the arch. At operation this calcification involved the ascending aorta and continued into the arch with no evidence of any "soft spots." The calcification also extended into the right subclavian and carotid arteries. Exploration of both groins revealed severe diffuse atherosclerosis extending throughout the femorals and Address for reprints: Leonard A. R. Golding, M.D., The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44106.
Fig. 1. Transapical aortic cannulation. into the iliac arteries. Because of inability to construct the proximal end of a vein graft anastomosis to the ascending aorta, both internal mammary arteries were dissected from the chest wall, the patient was given heparin, and a two-stage venous cannula was inserted through the right atrial appendage. Aortic cannulation was achieved by passing a 20 Fr. end-hole armored venous cannula through the apex of the left ventricle and antegrade through the aortic valve to lie in the proximal portion of the ascending aorta. A small left ventricular vent was also positioned in the apex of the left ventricle to decompress this chamber (Fig. 1). Before the institution of cardiopulmonary bypass, no aortic regurgitation was noted on the arterial pressure record. The patient was placed on cardiopulmonary bypass and cooled systemically to 18° C. Bypass flows of 2.2 L/min/m' were achieved and the amount of drainage through the left ventricular vent did not exceed 300 ml/rnin. The left internal mammary artery was anastomosed to the left anterior descending coronary artery and the right internal mammary to the right coronary artery. The anastomoses were done with local occlusion only. The patient was rewarmed systemically to normothermia and then easily weaned from cardiopulmonary bypass. The postoperative course was uneventful with no alteration in the electrocardiogram or cardiac enzymes suggestive of myocardial infarction.
Discussion. In almost all cases cardiopulmonary bypass can be achieved with cannulation of the ascending aorta, femoral arteries, right subclavian artery, or the aortic arch. On a rare occasion the diffuse nature of atherosclerosis can preclude such techniques.