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Graft-vs-Host Disease as a Complication of Lung Transplantation
CASE REPORT
Graft-vs-Host Disease as a Complication of Lung Transplantation Douglas M. Smith, MD, PhD,a Edward D. Agura, MD,a Ken Ausloos, MD,a W. Steves Ring, MD,b Rana Domiati-Saad, PhD,a and Goran B. Klintmalm, MD, PhDa We report a rare case of acute graft-vs-host disease (aGVHD) after a lung transplant. The patient presented with advanced disease manifested by skin rash, fever, diarrhea, liver dysfunction and severe pancytopenia. He went on to die of sepsis and multi-organ failure. aGVHD is a disease often confused with drug reactions or viral infection; therefore, it is important to have a high index of suspicion and to confirm the diagnosis early with tests for donor cell chimerism. Effective treatment is elusive but we are learning a great deal about the underlying mechanisms of this disease and hope to develop better treatment. J Heart Lung Transplant 2006;25:1175–7. Copyright © 2006 by the International Society for Heart and Lung Transplantation.
Acute graft-vs-host disease (aGVHD) is a rarely reported complication of lung transplantation. Six cases have been reported following combined heart–lung transplantation and a single case has been reported following an isolated lung transplant.1– 4 aGVHD is much more often reported as a complication of small bowel5,6 and liver transplantation7,8 and it is a well-documented but rare complication of blood transfusion.9 The early signs are often attributed to drug reactions or infections, such as skin rash, fever, diarrhea or liver dysfunction. Later, patients develop pancytopenia that predisposes them to infection and bleeding, which are the most frequent causes of death. All cases associated with heart–lung or single-lung transplants have been fatal. A similar high rate of mortality has been reported for aGVHD associated with other solid-organ transplants or blood transfusions, particularly if the patient is pancytopenic by the time the diagnosis is made. We present a case of aGVHD following a single-lung transplant, with clear evidence that the T lymphocytes were derived from the organ donor. We discuss methods to confirm the diagnosis early and possible approaches to treatments. CASE REPORT The patient was a 57-year-old white man, who had lung failure due to interstitial pneumonitis with pulmonary fibrosis. He had a history of diabetes and pulmonary
From the aDepartment of Pathology, Baylor University Medical Center, Dallas, Texas; and bUniversity of Texas Southwestern Medical Center, Dallas, Texas. Submitted December 21, 2005; revised March 28, 2006; accepted May 16, 2006. Reprint requests: Douglas M. Smith, MD, PhD, Transplant Immunology Laboratory, Department of Pathology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246. Telephone: 214-820-2119. Fax: 214-820-6384. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.05.008
embolus. He received a left single-lung transplant from a 31-year-old Asian man. The patient’s HLA type was HLA A2, 32 B7, 51 Bw4, 6 Cw07, 14 DR15 DQ6, and the donor’s type was HLA A24, 33 B58, 60 Bw4, 6 Cw03 DR4, 13 DQ6, DQ9. The lymphocyte crossmatch was negative against both T and B cells. The donor was cytomegalovirus (CMV) mismatched, and the patient was treated with Valcyte. His initial immunosuppressive drug regimen included cyclosporine, Imuran and corticosteroids. His initial post-operative course was uneventful, and he was discharged on post-operative day (POD) 11. He was re-admitted to the hospital on POD 39 with a 2-day history of joint and muscle pain, diarrhea and a pruritic rash on his face and thorax, which spread to his proximal extremities. He was found to have a low-grade fever, highly elevated liver function tests, and severe pancytopenia. This was initially thought to be a drug reaction. Bactrim and Imuran were discontinued and he was started on granulocyte– colony stimulating factor (G-CSF) for his neutropenia. He also had severe thrush, which was treated with oral medications and Diflucan. Bronchoscopy and biopsy were performed, which showed no evidence of rejection. His platelet count continued to drop and he was dependent on platelet and red blood cell (RBC) transfusions by POD 47. On POD 48, he had a bone marrow biopsy, which showed an aplastic marrow with ⬍5% cellularity. DNA tests for CMV, parvovirus and human herpesvirus 8 (HHV-8) were all negative. At this time, GVHD was suspected and the patient was re-typed for his HLA-A and -B antigens by serologic methods. This showed a mixture of patient and donor types with the stronger reactions being the donor’s HLA type. Engraftment tests using simple tandem repeat (STR) testing on POD 53 showed 25% donor CD3⫹ T cells, whereas the CD15⫹ granulocyte fraction was entirely recipient type. A bone marrow biopsy sample from POD 61 showed 22% donor CD3⫹ T cells and another blood sample from POD 64 showed 38% donor 1175
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Table 1. Clinical Course and Treatment of 7 Reported Cases of Graft-vs-Host Disease (GVHD) After Heart–Lung or Lung Transplantation Onset of signs of GVHD (PO day) Case no. 1 2a 3a 4
Ref. 3 2 4 1
Organ Heart–lung Heart–lung Heart–lung Heart–lung
Skin rash 18 12 39 33
Fever 15 12 20 33
Diarrhea 21
5 6 7 8
1 1 1
Heart–lung Heart–lung Single lung Single lung
30 180 81 37
30 180
30 180
39
37
39 34
Cytopenia 15 ⬎12 21 36
Hepatic dysfunction 21 ⬎12 21 40
30 180 113 39
30 180 81 39
PO, post-operative; RATG, rabbit anti-lymphocyte globulin; Aza, azathioprine; CNI, calcineurin inhibitor; G-CSF, granulocyte– colony-stimulating factor; GM-CSF, granulocyte–monocyte colony-stimulating factor; DIC, disseminated intravascular coagulation; CMV, cytomegalovirus; HSV, herpes simplex virus; MMF, mycophenolate mofetil. a Case 2 had a 5/6 HLA-antigen-matched donor and Case 3 had a 0/6 HLA-antigen-mismatched donor. b Case 8 was found at post-mortem to have a donor-derived lymphoma.
CD3⫹ T cells, 78% CD8⫹ T cells, 23% CD19⫹ B cells and 0% CD15 granulocytes. The patient developed chills and fever beginning on POD 46 and his blood cultures grew Candida krusei on multiple occasions after POD 52. He became more septic, with unstable blood pressures, renal azotemia and dyspnea. He died of sepsis and multi-organ failure on POD 64. No autopsy was performed. The recipient of the other lung from the same donor did not develop any signs of GVHD. DISCUSSION This is the second reported case of acute GVHD occurring after a lung transplant. Burton et al10 reported no cases of GVHD in a series of 348 lung transplants, thus the incidence of GVHD after lung transplantation is very low. More cases have been reported after heart–lung transplants (Table 1).1–3 GVHD is more common after the transplantation of organs that contain large numbers of passenger lymphocytes such as intestinal and liver transplants.5–7 Simultaneous infusion of donor bone marrow, to induce donor chimerism, has been associated with an increased incidence of aGVHD,11 and universal leukocyte depletion of blood transfusions has led to a decrease in transfusion-associated aGVHD.12 Another risk factor for GVHD is close HLA matching with the donor. Two of the cases reported in heart–lung transplant patients had close HLA matches (Table 1). Close HLA matching with the donor is the strongest risk factor for GVHD after liver transplantation.7 This is of particular importance when using a first-degree relative as a living donor. Three cases of GVHD have been reported after living donor liver transplantation from parents homozygous for a common HLA haplotype that they shared with the patient (a 1-way HLA match).13–15
Because living donors are sometimes used in lung transplantation it is likely to be risky to use a donor with a 1-way HLA match. The diagnosis of GVHD is often delayed because the symptoms are ascribed to more common complications such as drug reaction or viral infection. Patients typically present with fever along with a skin rash or diarrhea (Table 1), usually within 6 weeks after transplantation. This is followed by liver dysfunction and severe pancytopenia. The patient invariably dies as a result of bone marrow failure associated with sepsis or bleeding. The histopathology of skin or colonic biopsies can be very suggestive of GVHD, but may not rule out other diagnoses, such as drug reactions, or they may show evidence of viral infections that are the result of the profound immunosuppressive effect of GVHD rather than the principle diagnosis. Testing for donor lymphocyte chimerism is very important to diagnose or rule out GVHD. The fastest method to confirm donor cell chimerism is to repeat the patient’s HLA type using a polymerase chain reaction (PCR)-based method and DNA purified from isolated T cells (most HLA-typing laboratories use a magnetic bead method to isolate T cells). Our laboratory has shown that this will detect as few as 1% donor lymphocytes.16 Taylor et al8 showed that 0 of the 26 patients who had symptoms suggestive of aGVHD, but were negative for the donor HLA type by PCR-SSP testing, actually had aGVHD, whereas all 7 patients who had detectable donor cells were confirmed to have aGVHD. HLA typing is not quantitative and therefore the best method for monitoring the patient’s progress or response to treatment is to use engraftment testing using STR markers. There is no uniformly effective treatment for GVHD associated with solid-organ transplantation. In
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Table 1 continued Treatment Stop Aza or CNI Aza No Aza No No No Aza and MMF Aza
Anti-lymphocyte Rx RATG Basiliximab, alemtuzumab No RATG Basiliximab
Outcome Steroids Yes Yes Yes Yes Yes Yes Yes
G-CSF or GM-CSF Yes No No Yes
Death/ Recovery Death Death Death Death
PO day ⬎28 34 59 87
Yes Yes Yes Yes
Death Death Death Death
65 208 171 52
most cases, patients have been treated by increased immunosuppression and hematopoietic cytokines to support bone marrow function. However, this nearly always results in only temporary improvement. Some cases have recovered after a dramatic reduction in immunosuppression. This may be worth attempting if the diagnosis is made early, when the level of chimerism is relatively low, although the risk of acute graft rejection may make this approach difficult in lung or heart–lung transplants. Several attempts have been made to treat patients with an allogeneic bone marrow transplant, but such patients have generally been too ill by the time a donor could be found and died despite these attempts. In conclusion, we have reported the second case of aGVHD associated with a single-lung transplant. A high index of suspicion is needed to make the diagnosis early, and the best method to confirm the diagnosis is to confirm high levels of donor lymphocyte chimerism using HLA typing or engraftment testing using STR markers. The clinical course has so far been uniformly fatal and therefore more research is needed to develop effective methods for treatment or prevention. REFERENCES 1. Luckraz H, Zagolin M, McNeil K, Wallwork J. Graft-versushost disease in lung transplantation: 4 case reports and literature review. J Heart Lung Transplant 2003;22:691–7. 2. Pfitzmann R, Hummel M, Grauhan O, et al. Acute graftversus-host disease after human heart–lung transplantation: a case report. J Thorac Cardiovasc Surg 1997;114: 285–7. 3. Chau EM, Lee J, Yew WW, Chiu CS, Wang EP. Mediastinal irradiation for graft-versus-host disease in a heart–lung transplant recipient. J Heart Lung Transplant 1997;16: 974 –9. 4. Hunt B. Graft versus host disease in heart and/or lung transplantation, in Immunology of Heart and Lung Trans-
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8.
9.
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12.
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Cause of death Gastrointestinal bleeding, DIC, fungal sepsis Intracranial bleeding E coli sepsis and Aspergillis Pulmonary hemorrhage Multi-organ failure Pulmonary Aspergillis and Multi-organ failureb CMV and HSV Fungal sepsis and multi-organ failure
plantation, M. Rose and M. Yacoub, Editors. 1993, Arnold: London. p. 261–275. Frezza EE, Tzakis A, Fung JJ, Van Thiel DH. Small bowel transplantation: current progress and clinical application. Hepatogastroenterology 1996;43:363–76. Mazariegos GV, Abu-Elmagd K, Jaffe R, et al. Graft versus host disease in intestinal transplantation. Am J Transplant 2004;4:1459 – 65. Smith DM, Agura E, Netto G, et al. Liver transplantassociated graft-versus-host disease. Transplantation 2003;75:118 –26. Taylor AL, Gibbs P, Bradley JA. Acute graft versus host disease following liver transplantation: the enemy within. Am J Transplant 2004;4:466 –74. Williamson LM, Warwick RM. Transfusion-associated graft-versus-host disease and its prevention. Blood Rev 1995;9:251– 61. Burton CM, Milman N. Carlsen J, et al. The Copenhagen National Lung Transplant Group: survival after single lung, double lung, and heart–lung transplantation. J Heart Lung Transplant 2005;24:1834 – 43. Triulzi DJ, Nalesnik MA. Microchimerism, GVHD, and tolerance in solid organ transplantation. Transfusion 2001;41:419 –26. Stainsby D, Williamson L, Jones H, Cohen H. 6 years of shot reporting—its influence on UK blood safety. Transfus Apher Sci 2004;31:123–31. Hajeer AH, Issa S, Alaskar A, et al. Neutrophils and lymphoid chimerism after adult living-related liver transplantation from a homozygous donor. Transplant Proc 2005;37:4386 – 8. Nemoto T, Kubota K, Kita J, et al. Unusual onset of chronic graft-versus-host disease after adult living-related liver transplantation from a homozygous donor. Transplantation 2003;75:733– 6. Soejima Y, Shimada M, Suehiro T, et al. Graft-versus-host disease following living donor liver transplantation. Liver Transpl 2004;10:460 – 4. Domiati-Saad R, Klintmalm GB, Netto G, Agura ED, Chinnakotla S, Smith DM. Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism. Am J Transplant 2005;5:2968 –73.
Graft-vs-Host Disease as a Complication of Lung Transplantation Douglas M. Smith, MD, PhD,a Edward D. Agura, MD,a Ken Ausloos, MD,a W. Steves Ring, MD,b Rana Domiati-Saad, PhD,a and Goran B. Klintmalm, MD, PhDa We report a rare case of acute graft-vs-host disease (aGVHD) after a lung transplant. The patient presented with advanced disease manifested by skin rash, fever, diarrhea, liver dysfunction and severe pancytopenia. He went on to die of sepsis and multi-organ failure. aGVHD is a disease often confused with drug reactions or viral infection; therefore, it is important to have a high index of suspicion and to confirm the diagnosis early with tests for donor cell chimerism. Effective treatment is elusive but we are learning a great deal about the underlying mechanisms of this disease and hope to develop better treatment. J Heart Lung Transplant 2006;25:1175–7. Copyright © 2006 by the International Society for Heart and Lung Transplantation.
Acute graft-vs-host disease (aGVHD) is a rarely reported complication of lung transplantation. Six cases have been reported following combined heart–lung transplantation and a single case has been reported following an isolated lung transplant.1– 4 aGVHD is much more often reported as a complication of small bowel5,6 and liver transplantation7,8 and it is a well-documented but rare complication of blood transfusion.9 The early signs are often attributed to drug reactions or infections, such as skin rash, fever, diarrhea or liver dysfunction. Later, patients develop pancytopenia that predisposes them to infection and bleeding, which are the most frequent causes of death. All cases associated with heart–lung or single-lung transplants have been fatal. A similar high rate of mortality has been reported for aGVHD associated with other solid-organ transplants or blood transfusions, particularly if the patient is pancytopenic by the time the diagnosis is made. We present a case of aGVHD following a single-lung transplant, with clear evidence that the T lymphocytes were derived from the organ donor. We discuss methods to confirm the diagnosis early and possible approaches to treatments. CASE REPORT The patient was a 57-year-old white man, who had lung failure due to interstitial pneumonitis with pulmonary fibrosis. He had a history of diabetes and pulmonary
From the aDepartment of Pathology, Baylor University Medical Center, Dallas, Texas; and bUniversity of Texas Southwestern Medical Center, Dallas, Texas. Submitted December 21, 2005; revised March 28, 2006; accepted May 16, 2006. Reprint requests: Douglas M. Smith, MD, PhD, Transplant Immunology Laboratory, Department of Pathology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246. Telephone: 214-820-2119. Fax: 214-820-6384. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.05.008
embolus. He received a left single-lung transplant from a 31-year-old Asian man. The patient’s HLA type was HLA A2, 32 B7, 51 Bw4, 6 Cw07, 14 DR15 DQ6, and the donor’s type was HLA A24, 33 B58, 60 Bw4, 6 Cw03 DR4, 13 DQ6, DQ9. The lymphocyte crossmatch was negative against both T and B cells. The donor was cytomegalovirus (CMV) mismatched, and the patient was treated with Valcyte. His initial immunosuppressive drug regimen included cyclosporine, Imuran and corticosteroids. His initial post-operative course was uneventful, and he was discharged on post-operative day (POD) 11. He was re-admitted to the hospital on POD 39 with a 2-day history of joint and muscle pain, diarrhea and a pruritic rash on his face and thorax, which spread to his proximal extremities. He was found to have a low-grade fever, highly elevated liver function tests, and severe pancytopenia. This was initially thought to be a drug reaction. Bactrim and Imuran were discontinued and he was started on granulocyte– colony stimulating factor (G-CSF) for his neutropenia. He also had severe thrush, which was treated with oral medications and Diflucan. Bronchoscopy and biopsy were performed, which showed no evidence of rejection. His platelet count continued to drop and he was dependent on platelet and red blood cell (RBC) transfusions by POD 47. On POD 48, he had a bone marrow biopsy, which showed an aplastic marrow with ⬍5% cellularity. DNA tests for CMV, parvovirus and human herpesvirus 8 (HHV-8) were all negative. At this time, GVHD was suspected and the patient was re-typed for his HLA-A and -B antigens by serologic methods. This showed a mixture of patient and donor types with the stronger reactions being the donor’s HLA type. Engraftment tests using simple tandem repeat (STR) testing on POD 53 showed 25% donor CD3⫹ T cells, whereas the CD15⫹ granulocyte fraction was entirely recipient type. A bone marrow biopsy sample from POD 61 showed 22% donor CD3⫹ T cells and another blood sample from POD 64 showed 38% donor 1175
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Table 1. Clinical Course and Treatment of 7 Reported Cases of Graft-vs-Host Disease (GVHD) After Heart–Lung or Lung Transplantation Onset of signs of GVHD (PO day) Case no. 1 2a 3a 4
Ref. 3 2 4 1
Organ Heart–lung Heart–lung Heart–lung Heart–lung
Skin rash 18 12 39 33
Fever 15 12 20 33
Diarrhea 21
5 6 7 8
1 1 1
Heart–lung Heart–lung Single lung Single lung
30 180 81 37
30 180
30 180
39
37
39 34
Cytopenia 15 ⬎12 21 36
Hepatic dysfunction 21 ⬎12 21 40
30 180 113 39
30 180 81 39
PO, post-operative; RATG, rabbit anti-lymphocyte globulin; Aza, azathioprine; CNI, calcineurin inhibitor; G-CSF, granulocyte– colony-stimulating factor; GM-CSF, granulocyte–monocyte colony-stimulating factor; DIC, disseminated intravascular coagulation; CMV, cytomegalovirus; HSV, herpes simplex virus; MMF, mycophenolate mofetil. a Case 2 had a 5/6 HLA-antigen-matched donor and Case 3 had a 0/6 HLA-antigen-mismatched donor. b Case 8 was found at post-mortem to have a donor-derived lymphoma.
CD3⫹ T cells, 78% CD8⫹ T cells, 23% CD19⫹ B cells and 0% CD15 granulocytes. The patient developed chills and fever beginning on POD 46 and his blood cultures grew Candida krusei on multiple occasions after POD 52. He became more septic, with unstable blood pressures, renal azotemia and dyspnea. He died of sepsis and multi-organ failure on POD 64. No autopsy was performed. The recipient of the other lung from the same donor did not develop any signs of GVHD. DISCUSSION This is the second reported case of acute GVHD occurring after a lung transplant. Burton et al10 reported no cases of GVHD in a series of 348 lung transplants, thus the incidence of GVHD after lung transplantation is very low. More cases have been reported after heart–lung transplants (Table 1).1–3 GVHD is more common after the transplantation of organs that contain large numbers of passenger lymphocytes such as intestinal and liver transplants.5–7 Simultaneous infusion of donor bone marrow, to induce donor chimerism, has been associated with an increased incidence of aGVHD,11 and universal leukocyte depletion of blood transfusions has led to a decrease in transfusion-associated aGVHD.12 Another risk factor for GVHD is close HLA matching with the donor. Two of the cases reported in heart–lung transplant patients had close HLA matches (Table 1). Close HLA matching with the donor is the strongest risk factor for GVHD after liver transplantation.7 This is of particular importance when using a first-degree relative as a living donor. Three cases of GVHD have been reported after living donor liver transplantation from parents homozygous for a common HLA haplotype that they shared with the patient (a 1-way HLA match).13–15
Because living donors are sometimes used in lung transplantation it is likely to be risky to use a donor with a 1-way HLA match. The diagnosis of GVHD is often delayed because the symptoms are ascribed to more common complications such as drug reaction or viral infection. Patients typically present with fever along with a skin rash or diarrhea (Table 1), usually within 6 weeks after transplantation. This is followed by liver dysfunction and severe pancytopenia. The patient invariably dies as a result of bone marrow failure associated with sepsis or bleeding. The histopathology of skin or colonic biopsies can be very suggestive of GVHD, but may not rule out other diagnoses, such as drug reactions, or they may show evidence of viral infections that are the result of the profound immunosuppressive effect of GVHD rather than the principle diagnosis. Testing for donor lymphocyte chimerism is very important to diagnose or rule out GVHD. The fastest method to confirm donor cell chimerism is to repeat the patient’s HLA type using a polymerase chain reaction (PCR)-based method and DNA purified from isolated T cells (most HLA-typing laboratories use a magnetic bead method to isolate T cells). Our laboratory has shown that this will detect as few as 1% donor lymphocytes.16 Taylor et al8 showed that 0 of the 26 patients who had symptoms suggestive of aGVHD, but were negative for the donor HLA type by PCR-SSP testing, actually had aGVHD, whereas all 7 patients who had detectable donor cells were confirmed to have aGVHD. HLA typing is not quantitative and therefore the best method for monitoring the patient’s progress or response to treatment is to use engraftment testing using STR markers. There is no uniformly effective treatment for GVHD associated with solid-organ transplantation. In
The Journal of Heart and Lung Transplantation Volume 25, Number 9
Smith et al.
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Table 1 continued Treatment Stop Aza or CNI Aza No Aza No No No Aza and MMF Aza
Anti-lymphocyte Rx RATG Basiliximab, alemtuzumab No RATG Basiliximab
Outcome Steroids Yes Yes Yes Yes Yes Yes Yes
G-CSF or GM-CSF Yes No No Yes
Death/ Recovery Death Death Death Death
PO day ⬎28 34 59 87
Yes Yes Yes Yes
Death Death Death Death
65 208 171 52
most cases, patients have been treated by increased immunosuppression and hematopoietic cytokines to support bone marrow function. However, this nearly always results in only temporary improvement. Some cases have recovered after a dramatic reduction in immunosuppression. This may be worth attempting if the diagnosis is made early, when the level of chimerism is relatively low, although the risk of acute graft rejection may make this approach difficult in lung or heart–lung transplants. Several attempts have been made to treat patients with an allogeneic bone marrow transplant, but such patients have generally been too ill by the time a donor could be found and died despite these attempts. In conclusion, we have reported the second case of aGVHD associated with a single-lung transplant. A high index of suspicion is needed to make the diagnosis early, and the best method to confirm the diagnosis is to confirm high levels of donor lymphocyte chimerism using HLA typing or engraftment testing using STR markers. The clinical course has so far been uniformly fatal and therefore more research is needed to develop effective methods for treatment or prevention. REFERENCES 1. Luckraz H, Zagolin M, McNeil K, Wallwork J. Graft-versushost disease in lung transplantation: 4 case reports and literature review. J Heart Lung Transplant 2003;22:691–7. 2. Pfitzmann R, Hummel M, Grauhan O, et al. Acute graftversus-host disease after human heart–lung transplantation: a case report. J Thorac Cardiovasc Surg 1997;114: 285–7. 3. Chau EM, Lee J, Yew WW, Chiu CS, Wang EP. Mediastinal irradiation for graft-versus-host disease in a heart–lung transplant recipient. J Heart Lung Transplant 1997;16: 974 –9. 4. Hunt B. Graft versus host disease in heart and/or lung transplantation, in Immunology of Heart and Lung Trans-
5.
6.
7.
8.
9.
10.
11.
12.
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Cause of death Gastrointestinal bleeding, DIC, fungal sepsis Intracranial bleeding E coli sepsis and Aspergillis Pulmonary hemorrhage Multi-organ failure Pulmonary Aspergillis and Multi-organ failureb CMV and HSV Fungal sepsis and multi-organ failure
plantation, M. Rose and M. Yacoub, Editors. 1993, Arnold: London. p. 261–275. Frezza EE, Tzakis A, Fung JJ, Van Thiel DH. Small bowel transplantation: current progress and clinical application. Hepatogastroenterology 1996;43:363–76. Mazariegos GV, Abu-Elmagd K, Jaffe R, et al. Graft versus host disease in intestinal transplantation. Am J Transplant 2004;4:1459 – 65. Smith DM, Agura E, Netto G, et al. Liver transplantassociated graft-versus-host disease. Transplantation 2003;75:118 –26. Taylor AL, Gibbs P, Bradley JA. Acute graft versus host disease following liver transplantation: the enemy within. Am J Transplant 2004;4:466 –74. Williamson LM, Warwick RM. Transfusion-associated graft-versus-host disease and its prevention. Blood Rev 1995;9:251– 61. Burton CM, Milman N. Carlsen J, et al. The Copenhagen National Lung Transplant Group: survival after single lung, double lung, and heart–lung transplantation. J Heart Lung Transplant 2005;24:1834 – 43. Triulzi DJ, Nalesnik MA. Microchimerism, GVHD, and tolerance in solid organ transplantation. Transfusion 2001;41:419 –26. Stainsby D, Williamson L, Jones H, Cohen H. 6 years of shot reporting—its influence on UK blood safety. Transfus Apher Sci 2004;31:123–31. Hajeer AH, Issa S, Alaskar A, et al. Neutrophils and lymphoid chimerism after adult living-related liver transplantation from a homozygous donor. Transplant Proc 2005;37:4386 – 8. Nemoto T, Kubota K, Kita J, et al. Unusual onset of chronic graft-versus-host disease after adult living-related liver transplantation from a homozygous donor. Transplantation 2003;75:733– 6. Soejima Y, Shimada M, Suehiro T, et al. Graft-versus-host disease following living donor liver transplantation. Liver Transpl 2004;10:460 – 4. Domiati-Saad R, Klintmalm GB, Netto G, Agura ED, Chinnakotla S, Smith DM. Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism. Am J Transplant 2005;5:2968 –73.