© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 217–222 DOI: 10.1111/ctr.12300
Clinical Transplantation
Successful treatment for graft-versus-host disease after pancreas transplantation Chang JW, Sageshima J, Ciancio G, Mattiazzi A, Chen L, Tsai HL, Ruiz P, Burke III GW. Successful treatment for graft-versus-host disease after pancreas transplantation. Abstract: Graft-versus-host disease (GVHD) after pancreas transplantation is a rare but serious complication: All previously reported cases were fatal. We herein report three cases of GVHD after pancreas transplantation with favorable outcomes. Patients with a history of kidney (and pancreas) transplantation subsequently received a pancreas (and kidney) transplantation (i.e., pancreas retransplantation or pancreas after kidney transplantation) and developed acute GVHD. All of them responded to increased immunosuppression (e.g., steroid bolus, antithymocyte globulin) and retained normal graft function. Because the clinical manifestations are non-specific, vigilance is necessary to make an accurate diagnosis. We underscored the importance of a biopsy of involved organs and the clinicopathologic correlation in the early diagnosis of GVHD. Augmented immunosuppression to prevent progression from a self-limited disease to life-threatening pancytopenia or sepsis may be most critical to improve outcome.
Jei wen Changa,b, Junichiro Sageshimaa,e, Gaetano Ciancioa,e, Adela Mattiazzic, Linda Chena,e, Hsin-Lin Tsaib, Phillip Ruiza,d and George W. Burke IIIa,e a
Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, bDepartment of Pediatrics and Surgery, School of Medicine, Taipei Veterans General Hospital Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, cDivision of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, dDepartment of Pathology, University of Miami Miller School of Medicine and ethe Miami Transplant Institute, Lillian Jean Kaplan Renal Transplant Center, Miami, FL, USA Key words: graft-versus-host disease – pancreas transplantation – treatment Corresponding author: George W. Burke, III, MD, Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, 1801 NW 9th Avenue, Miami, FL 33136, USA. Tel.: 305 355 5111; fax: 305 355 5234; e-mail [email protected] Conflict of interest: The authors of this manuscript have no conflict of interests to disclose. Accepted for publication 21 November 2013
Graft-versus-host disease (GVHD) after solid organ transplantation is an uncommon but serious complication (1–8). It may occur when immunocompetent donor-derived T lymphocytes (transferred with the transplant graft or contained in blood products) are activated and respond against recipient tissue (9, 10). They commonly target skin, gastrointestinal tract, liver, and bone marrow, resulting in symptoms characterized by fever, skin rash, diarrhea, jaundice, and pancytopenia. Unlike GVHD after transplantation of hematopoietic
stem cells or hematopoietically rich organs (i.e., small bowel, liver, and spleen), GVHD after pancreas transplantation is rare, but still often lethal (1–6). We herein report three pancreas transplantassociated acute GVHD with favorable outcomes. Patients and methods
We retrospectively reviewed patients undergoing pancreas (and kidney) transplant from January 1999 to December 2012; patients who received a
217
Chang et al.
transplant in another institute and followed in our institute were also included. The pancreas graft was prepared on the back table before the transplantation to remove the spleen and the mesenteric and peripancreatic lymphoid tissue from the graft. The majority of patients who received simultaneous pancreas and kidney transplantation between September 2000 and December 2009 participated in the single-center prospective randomized trial comparing sirolimus and mycophenolate mofetil along with tacrolimus and steroid maintenance regimen (11). The patients in the study received dual induction therapy with rabbit antithymocyte globulin (rATG [thymoglobulin] 1 mg/kg 9 5 doses) and daclizumab (1 mg/kg 9 2 doses). Tacrolimus was started when the serum creatinine fell below 4 mg/dL with target trough levels of 5–7 ng/mL. Sirolimus (target trough levels: 5–7 ng/mL) or mycophenolate mofetil (target dose: 1 g twice a day) was started postoperative day 1 (POD). Corticosteroids were tapered progressively to reach methylprednisolone 4 mg daily by three months. Patients who did not participate in the study received similar immunosuppressive medication with minor discretionary changes by a treating physician. The baseline patient characteristics and the clinical outcome of the study patients were prospectively collected in the study database, and the outcomes of the nonstudy patients were reviewed in the hospital electronic medical record. The institutional review board approved the study. Results
We reviewed 170 patients who received a simultaneous pancreas and kidney transplantation between September 2000 and December 2009 and participated in the randomized study (11). In addition, we reviewed 46 patients who received a pancreas (and kidney) transplantation before or after the study. In a total of 216 patients from January 1999 to December 2012, we identified two patients (cases 1 and 2) who developed GVHD after the transplant; the incidence of GVHD was 0.9%. We also identified one patient (case 3) who originally underwent a kidney transplantation in our institute and subsequently received a pancreas transplantation in a different institute. The detailed clinical courses of these three patients are described below. Case 1
A 31-yr-old Caucasian male with type 1 diabetes and end-stage renal disease underwent a kidney– pancreas transplantation with rATG induction
218
and tacrolimus/mycophenolate/steroid maintenance immunosuppression. Because of the thrombotic complication, the pancreas graft was removed six d after transplantation. Seventeen months later, with the stable kidney graft function, he received an isolated second pancreas transplantation with two units of irradiated red blood cells. rATG and daclizumab were used as induction therapy: tacrolimus and steroids were continued, and mycophenolate was switched to sirolimus. Although he required a transient ventilator support for fluid overload, he was discharged home on POD 13 with excellent graft function. Three wk later, the patient was readmitted to the hospital complaining of sore throat, dry cough, and maculopapular rash in the face, chest, abdomen, and back. WBC count, glucose, creatinine, and liver enzymes were within normal limits on admission. He soon started spiking fevers. With the working diagnosis of viral/bacterial infection, he received intravenous ganciclovir and broad-spectrum antibiotics as well as intravenous immunoglobulin. His immunosuppression was reduced to low-dose steroids only. The rash became generalized and edematous. Skin biopsies from POD 42 demonstrated non-specific findings consistent with a drug or viral eruption. He remained negative for cytomegalovirus (CMV) and Epstein–Barr virus (EBV) by polymerase chain reaction. The patient developed respiratory distress and required ventilator support. He subsequently developed increased liver enzymes (total bilirubin 6.0 mg/dL, aspartate aminotransferase [AST] 2197 IU/L, and alanine aminotransferase [ALT] 3717 IU/L), and a liver biopsy on POD 47 was diagnostic of GVHD (Fig. 1A). Clinical grading of GVHD was Glucksberg grade III (12) and International Bone Marrow Transplant Registry (IBMTR) index C (13). He received high-dose corticosteroids along with a reinstitution of tacrolimus and mycophenolate: The skin rash and his general condition ameliorated significantly. Subsequent pseudomonas urosepsis and neutropenia were successfully treated, and the patient was discharged home on POD 79. Case 2
A Caucasian male received a pancreas transplantation for surgical diabetes after a staged total pancreatectomy for chronic pancreatitis. He subsequently received an human leukocyte antigen (HLA)-identical living donor kidney transplantation for diabetic nephropathy. Three yr later, he received his second pancreas transplant, but the graft was removed for thrombosis. The kidney
GVHD after pancreas transplantation A
lymphocytic infiltrate, which was compatible with GVHD grade II. The symptoms were limited to the skin: There was no change in liver enzymes or blood cell counts (Glucksberg grade I, IBMTR index B). He received corticosteroid bolus therapy and topical tacrolimus ointment, with amelioration of the skin rash within one wk. The patient was discharged on POD 60 and maintained a stable kidney (creatinine 1.1 mg/dL) and pancreas hemoglobin A1c (HbA1c 5.1%) graft function. Case 3
B
Fig. 1. (A) The liver biopsy taken from case 1 seven wk after transplantation demonstrated non-suppurative cholangitis, and endothelialitis of portal, vein, and central vein (arrow) tributaries contained a mixed inflammatory infiltrate (arrow heads), mild cholestasis, and a mixed portal inflammatory infiltrate with the diagnosis of graft-versus-host disease (GVHD) of cholangiohepatitic type. (B) The colon mucosa biopsy taken from case 3 revealed numerous confluent apoptotic bodies (arrow heads) and a moderate lymphoplasmacytic infiltrate.
graft function had gradually deteriorated due to chronic allograft injury, but he was still on tacrolimus/mycophenolate/steroids. At the age of 61, he received his second kidney and third pancreas transplantation with rATG/daclizumab induction and tacrolimus/sirolimus/steroid maintenance therapy. Perioperatively, six units of irradiated packed red blood cells were infused. His postoperative course was complicated by arrhythmia, respiratory distress, urinary tract, and line infection, and required exploratory laparotomy. On POD 43, he developed a maculopapular skin rash on the neck, chest, and upper extremities along with a buccal lesion and high fever. The skin rash had spread, and the skin biopsy of the lesion showed basal vacuolar degeneration, focal spongiosis, and a predominantly mononuclear and
A 46-yr-old African American male with type 1 diabetes for 25 yr and end-stage renal disease for two yr received a living donor kidney transplantation with rATG/daclizumab induction and tacrolimus/mycophenolate/steroid maintenance therapy. Two yr later, he received a pancreas transplantation with alemtuzumab induction and alemtuzumab/mycophenolate maintenance. Approximately 16 months after the pancreas transplantation, he presented with fever, malaise, and severe watery diarrhea. While his stool was negative for culture and Clostridium difficile toxin, he had abnormal blood chemistry values (creatinine 2.6 mg/dL, amylase 266 IU/L, lipase 1453 IU/L, total bilirubin 1.7 mg/dL, AST 134 IU/L, and ALT 390 IU/L). Empirical high-dose steroids were given, and mycophenolate was switched to sirolimus. The colon biopsy obtained four d after the admission revealed numerous apoptotic bodies and lymphoplasmacytic infiltrate consistent with GVHD grade II (Fig. 1B). He received high-dose steroids, rATG (16 mg/kg total), and one dose of daclizumab and rituximab. He responded well to the treatment clinically, and biological markers were normalized. He was discharged home 16 d after the admission. Discussion
Acute GVHD after pancreas transplantation is a rare but serious complication – all previously reported cases were fatal (Table 1) (1–6). We herein report three cases of GVHD after pancreas (and kidney) transplantation with full recovery responding to the treatment; not only did the recipients all survive, but also none of the grafts were lost. GVHD occurs when immunocompetent cells from the graft recognize the recipient as foreign and the recipient is incapable of rejecting them (9). The possible sources of immunocompetent cells include passenger lymphocytes transferred with transplanted organs and lymphocytes contained in non-irradiated blood products (10). All blood used
219
220
32M
61 M 49 M
DDP
DDKP DDP
14 M
DDP
P, K, I, P K
KP
No
No
K
No
No K
No
No
Previous transplant
ATG, IL-2/FK, SRL, CS ATG/FK, SRL, CS C1H/C1H, MMF
NA
ATG/FK. MMF. CS
ATG/FK, MMF, CS
ATG/FK, MMF, CS
NA ATG/FK, MMF, CS
NA
OKT3/CsA, AZ, CS
GI symptoms Fever, nausea, vomiting Fever
~60 25
43 470
37 Rash, fever Fever, malaise, diarrhea
Fever, malaise, neutropenia Liver dysfunction, hyperglycemia, hyperkalemia Fever, rash
~15 ~120
Fever
22
27
NA
Fever, cytopenia
Initial symptoms
NA
9
Onset (POD)
+ +
+ +
+
+
+
+
+
NA
+
NA +
NA +
+
+
+
+
+
+
+ +
NA
+
NA
+
+
+
Liver
Skin
Fever
Signs of GVHD
+
+
NA
+
+
+ +
+
GI
+
+
+
+
+
+ +
+
+
BM
Skin GI
Liver
BM
BM
Skin
Skin
GI. liver Skin
GI, skin
Skin
Sites
45 477
47
~130
NA
106
51
~80 60
~50
18
POD
Diagnostic biopsy
CS, FK/MMF reinstitution CS, topical FK CS, SRL
CS, stem cells
ATG, FK, CS
CS
ALG, CsA, CS
NA ALG, CsA, CS
NA
IS reduction
Treatment
Recovery Recovery
Recovery
Death, sepsis, bleeding Death, MOF, aspergillosis
Death, GI bleeding Death, MOF
Death, fungemia, BM failure Death, BM failure Death, MOF
Death, MOF
Outcome
~160
52
145
55
NA 73
~80
22
Time to death (POD)
K, kidney; P, pancreas; I, islet; DD, deceased donor; LD, living donor; ATG, antithymocyte globulin; AZ, azathioprine; C1H, alemtuzumab; CS, corticosteroids; CsA, cyclosporine; FK, tacrolimus; IL-2, interleukin-2 receptor antagonist; MMF, mycophenolate mofetil; SRL, sirolimus; BM, bone marrow; GI, gastrointestinal; MOF, multiorgan failure; NA, not available; POD, postoperative day; GVHD, graft-versus-host disease.
Current series
Weng et al. (4) Osband et al. (5) Sharma et al. (6)
45 M
LDK+DDP
DDKP
38 M
LDK+DDP DDP
54 M
32 NA 27 F
DDKP
DDP
58 NA
DDKP
Kimball et al. (1) Gulbahce et al. (2)
Weinstein et al. (3)
27 M
Type
Reference
Age Gender
Induction/ maintenance therapy
Table 1. Clinical characteristics of patients with graft-vs-host disease following pancreas transplantation
Chang et al.
GVHD after pancreas transplantation for these cases at our center was irradiated, although it is unclear whether non-irradiated blood was ever used outside our center. As lymphocytes in irradiated blood products have minimal capacity for proliferation, it is unlikely to be the source in our cases. As compared with lymphocyte-rich organ transplants (e.g., liver and small bowel), kidney and pancreas (without spleen) contain relatively small amounts of lymphoid tissue, explaining the paucity of reported GVHD in kidney and pancreas transplantation. Nevertheless, venous effluents of the kidney graft after perfusion may contain enough lymphocytes to cause an immunological response within the recipient (14): Peripancreatic lymph nodes may be able to modulate the immune response of the recipient as well (15). It would thus be reasonable to presume that even this amount of lymphatic tissue could cause GVHD when the recipient is immunocompromised and allows donor lymphocytes to proliferate. Our recipients expressed three, five, and three HLA antigens not present in the donor, allowing donor lymphocytes to recognize the recipient tissue as foreign. Unlike the immune system of preconditioned stem cell transplant recipients, that of solid organ transplant recipients is relatively intact – another explanation of the paucity of GVHD in solid organ transplantation (9). However, similar to the previous reports of pancreas after kidney transplantation (3, 4) and liver retransplantation (16), all three patients in this report had previous transplants and were on immunosuppression, which could hinder the recipients rejecting donor lymphocytes. Clinical manifestations of GVHD vary from skin rash to systemic involvement, including liver, intestine, and bone marrow (Table 1) (1–8). Ambiguous skin rash and fever may resemble a drug reaction or viral infection, while skin and other tissue biopsies may be non-pathognomonic (2). Previous reports indicate that even multiple biopsies, especially taken in the early stage of the disease, can be non-diagnostic and otherwise misleading (2–4). Furthermore, an actual drug reaction or viral infection can precede or coexist with GVHD (2, 4). Our first case was also initially treated as a viral infection. Some medications commonly used after transplantation can cause a skin reaction; liver, gastrointestinal, or bone marrow dysfunction; and overlapping symptoms with GVHD; and any suspicious medications (e.g., sulfa and mycophenolate) should be switched to alternative medications. Although historical examinations of involved organs (e.g., skin, liver, intestine, and bone marrow) are often diagnostic of GVHD, no donor DNA confirma-
tory tests were performed in our cases. Because of the limitations of the retrospective case review, we are unable to provide the evidence of donor cell presence in the recipient tissue, and there is a remote possibility that these were not truly cases of GVHD that have donor cell involvements in the affected organs. Optimal treatment for GVHD after solid organ transplantation has yet to be determined (16–19). In our cases, the judicious use of corticosteroids and the reinstitution of other immunosuppressants at a relatively early stage after the onset of symptoms led to successful results for GVHD after pancreas transplantation. Because of the high mortality with systemic involvement, prevention of the progression from self-limited disease to a fatal disorder may be most critical to improve outcome. A high level of suspicion leading to early recognition and treatment for GVHD before life-threatening pancytopenia or sepsis is required. Acknowledgement The authors would like to express their appreciation to Ms. Erna Stoddart for her assistance in the preparation of this manuscript.
Disclosure
The manuscript was not prepared or funded in any part by a commercial organization. Authors’ contributions
JC, JS, GC, AM, LC, HLT, PR, and GWB analyzed and interpreted the clinical data and wrote the paper. References 1. KIMBALL P, HAM J, EISENBERG M et al. Lethal graft-versus-host disease after simultaneous kidney-pancreas transplantation. Transplantation 1997: 63: 1685. 2. GULBAHCE HE, BROWN CA, WICK M, SEGALL M, JESSURUN J. Graft-vs-host disease after solid organ transplant. Am J Clin Pathol 2003: 119: 568. 3. WEINSTEIN A, DEXTER D, KUKURUGA DL, PHILOSOPHE B, HESS J, KLASSEN D. Acute graft-versus-host disease in pancreas transplantation: a comparison of two case presentations and a review of the literature. Transplantation 2006: 82: 127. 4. WENG FL, PANCOSKA C, PATEL AM. Fatal graft-versushost disease presenting as fever of unknown origin in a pancreas-after-kidney transplant recipient. Am J Transplant 2008: 8: 881. 5. OSBAND AJ, LASKOW DA, MANN RA. Treatment of acute graft-vs-host disease after simultaneous pancreas-kidney transplantation: a case report. Transplant Proc 2010: 42: 3894.
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Chang et al. 6. SHARMA A, ARMSTRONG AE, POSNER MP et al. Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature. Ann Transplant 2012: 17: 133. 7. CORRY RJ, NGHIEM DD, SCHULAK JA, BEUTEL WD, GONWA TA. Surgical treatment of diabetic nephropathy with simultaneous pancreatic duodenal and renal transplantation. Surg Gynecol Obstet 1986: 162: 547. 8. DEIERHOI MH, SOLLINGER HW, BOZDECH MJ, BELZER FO. Lethal graft-versus-host disease in a recipient of a pancreas-spleen transplant. Transplantation 1986: 41: 544. 9. BILLINGHAM RE. The Biology of graft-versus-host reactions. Harvey Lect 1966: 62: 21. 10. WISECARVER JL, CATTRAL MS, LANGNAS AN et al. Transfusion-induced graft-versus-host disease after liver transplantation. Documentation using polymerase chain reaction with HLA-DR sequence-specific primers. Transplantation 1994: 58: 269. 11. CIANCIO G, SAGESHIMA J, CHEN L et al. Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single-center trial at 10 years. Am J Transplant 2012: 12: 3363. 12. GLUCKSBERG H, STORB R, FEFER A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974: 18: 295.
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13. ROWLINGS PA, PRZEPIORKA D, KLEIN JP et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997: 97: 855. 14. VAN SCHILFGAARDE R, HERMANS P, TERPSTRA JL, VAN BREDA VRIESMAN PJ. Role of mobile passenger lymphocytes in the rejection of renal and cardiac allografts in the rat. A passenger lymphocyte-mediated graft-versus-host reaction amplifies the host response. Transplantation 1980: 29: 209. 15. BARTLETT ST, CHIN T, DIRDEN B, QUERESHI A, HADLEY G. Inclusion of peripancreatic lymph node cells prevents recurrent autoimmune destruction of islet transplants: evidence of donor chimerism. Surgery 1995: 118: 392. 16. LEHNER F, BECKER T, SYBRECHT L et al. Successful outcome of acute graft-versus-host disease in a liver allograft recipient by withdrawal of immunosuppression. Transplantation 2002: 73: 307. 17. IWASAKI T. Recent advances in the treatment of graft-versus-host disease. Clin Med Res 2004: 2: 243. 18. LE BLANC K, FRASSONI F, BALL L et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graftversus-host disease: a phase II study. Lancet 2008: 371: 1579. 19. VARADI G, OR R, SLAVIN S, NAGLER A. In vivo CAMPATH-1 monoclonal antibodies: a novel mode of therapy for acute graft-versus-host disease. Am J Hematol 1996: 52: 236.
Clin Transplant 2014: 28: 217–222 DOI: 10.1111/ctr.12300
Clinical Transplantation
Successful treatment for graft-versus-host disease after pancreas transplantation Chang JW, Sageshima J, Ciancio G, Mattiazzi A, Chen L, Tsai HL, Ruiz P, Burke III GW. Successful treatment for graft-versus-host disease after pancreas transplantation. Abstract: Graft-versus-host disease (GVHD) after pancreas transplantation is a rare but serious complication: All previously reported cases were fatal. We herein report three cases of GVHD after pancreas transplantation with favorable outcomes. Patients with a history of kidney (and pancreas) transplantation subsequently received a pancreas (and kidney) transplantation (i.e., pancreas retransplantation or pancreas after kidney transplantation) and developed acute GVHD. All of them responded to increased immunosuppression (e.g., steroid bolus, antithymocyte globulin) and retained normal graft function. Because the clinical manifestations are non-specific, vigilance is necessary to make an accurate diagnosis. We underscored the importance of a biopsy of involved organs and the clinicopathologic correlation in the early diagnosis of GVHD. Augmented immunosuppression to prevent progression from a self-limited disease to life-threatening pancytopenia or sepsis may be most critical to improve outcome.
Jei wen Changa,b, Junichiro Sageshimaa,e, Gaetano Ciancioa,e, Adela Mattiazzic, Linda Chena,e, Hsin-Lin Tsaib, Phillip Ruiza,d and George W. Burke IIIa,e a
Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, bDepartment of Pediatrics and Surgery, School of Medicine, Taipei Veterans General Hospital Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, cDivision of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, dDepartment of Pathology, University of Miami Miller School of Medicine and ethe Miami Transplant Institute, Lillian Jean Kaplan Renal Transplant Center, Miami, FL, USA Key words: graft-versus-host disease – pancreas transplantation – treatment Corresponding author: George W. Burke, III, MD, Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, 1801 NW 9th Avenue, Miami, FL 33136, USA. Tel.: 305 355 5111; fax: 305 355 5234; e-mail [email protected] Conflict of interest: The authors of this manuscript have no conflict of interests to disclose. Accepted for publication 21 November 2013
Graft-versus-host disease (GVHD) after solid organ transplantation is an uncommon but serious complication (1–8). It may occur when immunocompetent donor-derived T lymphocytes (transferred with the transplant graft or contained in blood products) are activated and respond against recipient tissue (9, 10). They commonly target skin, gastrointestinal tract, liver, and bone marrow, resulting in symptoms characterized by fever, skin rash, diarrhea, jaundice, and pancytopenia. Unlike GVHD after transplantation of hematopoietic
stem cells or hematopoietically rich organs (i.e., small bowel, liver, and spleen), GVHD after pancreas transplantation is rare, but still often lethal (1–6). We herein report three pancreas transplantassociated acute GVHD with favorable outcomes. Patients and methods
We retrospectively reviewed patients undergoing pancreas (and kidney) transplant from January 1999 to December 2012; patients who received a
217
Chang et al.
transplant in another institute and followed in our institute were also included. The pancreas graft was prepared on the back table before the transplantation to remove the spleen and the mesenteric and peripancreatic lymphoid tissue from the graft. The majority of patients who received simultaneous pancreas and kidney transplantation between September 2000 and December 2009 participated in the single-center prospective randomized trial comparing sirolimus and mycophenolate mofetil along with tacrolimus and steroid maintenance regimen (11). The patients in the study received dual induction therapy with rabbit antithymocyte globulin (rATG [thymoglobulin] 1 mg/kg 9 5 doses) and daclizumab (1 mg/kg 9 2 doses). Tacrolimus was started when the serum creatinine fell below 4 mg/dL with target trough levels of 5–7 ng/mL. Sirolimus (target trough levels: 5–7 ng/mL) or mycophenolate mofetil (target dose: 1 g twice a day) was started postoperative day 1 (POD). Corticosteroids were tapered progressively to reach methylprednisolone 4 mg daily by three months. Patients who did not participate in the study received similar immunosuppressive medication with minor discretionary changes by a treating physician. The baseline patient characteristics and the clinical outcome of the study patients were prospectively collected in the study database, and the outcomes of the nonstudy patients were reviewed in the hospital electronic medical record. The institutional review board approved the study. Results
We reviewed 170 patients who received a simultaneous pancreas and kidney transplantation between September 2000 and December 2009 and participated in the randomized study (11). In addition, we reviewed 46 patients who received a pancreas (and kidney) transplantation before or after the study. In a total of 216 patients from January 1999 to December 2012, we identified two patients (cases 1 and 2) who developed GVHD after the transplant; the incidence of GVHD was 0.9%. We also identified one patient (case 3) who originally underwent a kidney transplantation in our institute and subsequently received a pancreas transplantation in a different institute. The detailed clinical courses of these three patients are described below. Case 1
A 31-yr-old Caucasian male with type 1 diabetes and end-stage renal disease underwent a kidney– pancreas transplantation with rATG induction
218
and tacrolimus/mycophenolate/steroid maintenance immunosuppression. Because of the thrombotic complication, the pancreas graft was removed six d after transplantation. Seventeen months later, with the stable kidney graft function, he received an isolated second pancreas transplantation with two units of irradiated red blood cells. rATG and daclizumab were used as induction therapy: tacrolimus and steroids were continued, and mycophenolate was switched to sirolimus. Although he required a transient ventilator support for fluid overload, he was discharged home on POD 13 with excellent graft function. Three wk later, the patient was readmitted to the hospital complaining of sore throat, dry cough, and maculopapular rash in the face, chest, abdomen, and back. WBC count, glucose, creatinine, and liver enzymes were within normal limits on admission. He soon started spiking fevers. With the working diagnosis of viral/bacterial infection, he received intravenous ganciclovir and broad-spectrum antibiotics as well as intravenous immunoglobulin. His immunosuppression was reduced to low-dose steroids only. The rash became generalized and edematous. Skin biopsies from POD 42 demonstrated non-specific findings consistent with a drug or viral eruption. He remained negative for cytomegalovirus (CMV) and Epstein–Barr virus (EBV) by polymerase chain reaction. The patient developed respiratory distress and required ventilator support. He subsequently developed increased liver enzymes (total bilirubin 6.0 mg/dL, aspartate aminotransferase [AST] 2197 IU/L, and alanine aminotransferase [ALT] 3717 IU/L), and a liver biopsy on POD 47 was diagnostic of GVHD (Fig. 1A). Clinical grading of GVHD was Glucksberg grade III (12) and International Bone Marrow Transplant Registry (IBMTR) index C (13). He received high-dose corticosteroids along with a reinstitution of tacrolimus and mycophenolate: The skin rash and his general condition ameliorated significantly. Subsequent pseudomonas urosepsis and neutropenia were successfully treated, and the patient was discharged home on POD 79. Case 2
A Caucasian male received a pancreas transplantation for surgical diabetes after a staged total pancreatectomy for chronic pancreatitis. He subsequently received an human leukocyte antigen (HLA)-identical living donor kidney transplantation for diabetic nephropathy. Three yr later, he received his second pancreas transplant, but the graft was removed for thrombosis. The kidney
GVHD after pancreas transplantation A
lymphocytic infiltrate, which was compatible with GVHD grade II. The symptoms were limited to the skin: There was no change in liver enzymes or blood cell counts (Glucksberg grade I, IBMTR index B). He received corticosteroid bolus therapy and topical tacrolimus ointment, with amelioration of the skin rash within one wk. The patient was discharged on POD 60 and maintained a stable kidney (creatinine 1.1 mg/dL) and pancreas hemoglobin A1c (HbA1c 5.1%) graft function. Case 3
B
Fig. 1. (A) The liver biopsy taken from case 1 seven wk after transplantation demonstrated non-suppurative cholangitis, and endothelialitis of portal, vein, and central vein (arrow) tributaries contained a mixed inflammatory infiltrate (arrow heads), mild cholestasis, and a mixed portal inflammatory infiltrate with the diagnosis of graft-versus-host disease (GVHD) of cholangiohepatitic type. (B) The colon mucosa biopsy taken from case 3 revealed numerous confluent apoptotic bodies (arrow heads) and a moderate lymphoplasmacytic infiltrate.
graft function had gradually deteriorated due to chronic allograft injury, but he was still on tacrolimus/mycophenolate/steroids. At the age of 61, he received his second kidney and third pancreas transplantation with rATG/daclizumab induction and tacrolimus/sirolimus/steroid maintenance therapy. Perioperatively, six units of irradiated packed red blood cells were infused. His postoperative course was complicated by arrhythmia, respiratory distress, urinary tract, and line infection, and required exploratory laparotomy. On POD 43, he developed a maculopapular skin rash on the neck, chest, and upper extremities along with a buccal lesion and high fever. The skin rash had spread, and the skin biopsy of the lesion showed basal vacuolar degeneration, focal spongiosis, and a predominantly mononuclear and
A 46-yr-old African American male with type 1 diabetes for 25 yr and end-stage renal disease for two yr received a living donor kidney transplantation with rATG/daclizumab induction and tacrolimus/mycophenolate/steroid maintenance therapy. Two yr later, he received a pancreas transplantation with alemtuzumab induction and alemtuzumab/mycophenolate maintenance. Approximately 16 months after the pancreas transplantation, he presented with fever, malaise, and severe watery diarrhea. While his stool was negative for culture and Clostridium difficile toxin, he had abnormal blood chemistry values (creatinine 2.6 mg/dL, amylase 266 IU/L, lipase 1453 IU/L, total bilirubin 1.7 mg/dL, AST 134 IU/L, and ALT 390 IU/L). Empirical high-dose steroids were given, and mycophenolate was switched to sirolimus. The colon biopsy obtained four d after the admission revealed numerous apoptotic bodies and lymphoplasmacytic infiltrate consistent with GVHD grade II (Fig. 1B). He received high-dose steroids, rATG (16 mg/kg total), and one dose of daclizumab and rituximab. He responded well to the treatment clinically, and biological markers were normalized. He was discharged home 16 d after the admission. Discussion
Acute GVHD after pancreas transplantation is a rare but serious complication – all previously reported cases were fatal (Table 1) (1–6). We herein report three cases of GVHD after pancreas (and kidney) transplantation with full recovery responding to the treatment; not only did the recipients all survive, but also none of the grafts were lost. GVHD occurs when immunocompetent cells from the graft recognize the recipient as foreign and the recipient is incapable of rejecting them (9). The possible sources of immunocompetent cells include passenger lymphocytes transferred with transplanted organs and lymphocytes contained in non-irradiated blood products (10). All blood used
219
220
32M
61 M 49 M
DDP
DDKP DDP
14 M
DDP
P, K, I, P K
KP
No
No
K
No
No K
No
No
Previous transplant
ATG, IL-2/FK, SRL, CS ATG/FK, SRL, CS C1H/C1H, MMF
NA
ATG/FK. MMF. CS
ATG/FK, MMF, CS
ATG/FK, MMF, CS
NA ATG/FK, MMF, CS
NA
OKT3/CsA, AZ, CS
GI symptoms Fever, nausea, vomiting Fever
~60 25
43 470
37 Rash, fever Fever, malaise, diarrhea
Fever, malaise, neutropenia Liver dysfunction, hyperglycemia, hyperkalemia Fever, rash
~15 ~120
Fever
22
27
NA
Fever, cytopenia
Initial symptoms
NA
9
Onset (POD)
+ +
+ +
+
+
+
+
+
NA
+
NA +
NA +
+
+
+
+
+
+
+ +
NA
+
NA
+
+
+
Liver
Skin
Fever
Signs of GVHD
+
+
NA
+
+
+ +
+
GI
+
+
+
+
+
+ +
+
+
BM
Skin GI
Liver
BM
BM
Skin
Skin
GI. liver Skin
GI, skin
Skin
Sites
45 477
47
~130
NA
106
51
~80 60
~50
18
POD
Diagnostic biopsy
CS, FK/MMF reinstitution CS, topical FK CS, SRL
CS, stem cells
ATG, FK, CS
CS
ALG, CsA, CS
NA ALG, CsA, CS
NA
IS reduction
Treatment
Recovery Recovery
Recovery
Death, sepsis, bleeding Death, MOF, aspergillosis
Death, GI bleeding Death, MOF
Death, fungemia, BM failure Death, BM failure Death, MOF
Death, MOF
Outcome
~160
52
145
55
NA 73
~80
22
Time to death (POD)
K, kidney; P, pancreas; I, islet; DD, deceased donor; LD, living donor; ATG, antithymocyte globulin; AZ, azathioprine; C1H, alemtuzumab; CS, corticosteroids; CsA, cyclosporine; FK, tacrolimus; IL-2, interleukin-2 receptor antagonist; MMF, mycophenolate mofetil; SRL, sirolimus; BM, bone marrow; GI, gastrointestinal; MOF, multiorgan failure; NA, not available; POD, postoperative day; GVHD, graft-versus-host disease.
Current series
Weng et al. (4) Osband et al. (5) Sharma et al. (6)
45 M
LDK+DDP
DDKP
38 M
LDK+DDP DDP
54 M
32 NA 27 F
DDKP
DDP
58 NA
DDKP
Kimball et al. (1) Gulbahce et al. (2)
Weinstein et al. (3)
27 M
Type
Reference
Age Gender
Induction/ maintenance therapy
Table 1. Clinical characteristics of patients with graft-vs-host disease following pancreas transplantation
Chang et al.
GVHD after pancreas transplantation for these cases at our center was irradiated, although it is unclear whether non-irradiated blood was ever used outside our center. As lymphocytes in irradiated blood products have minimal capacity for proliferation, it is unlikely to be the source in our cases. As compared with lymphocyte-rich organ transplants (e.g., liver and small bowel), kidney and pancreas (without spleen) contain relatively small amounts of lymphoid tissue, explaining the paucity of reported GVHD in kidney and pancreas transplantation. Nevertheless, venous effluents of the kidney graft after perfusion may contain enough lymphocytes to cause an immunological response within the recipient (14): Peripancreatic lymph nodes may be able to modulate the immune response of the recipient as well (15). It would thus be reasonable to presume that even this amount of lymphatic tissue could cause GVHD when the recipient is immunocompromised and allows donor lymphocytes to proliferate. Our recipients expressed three, five, and three HLA antigens not present in the donor, allowing donor lymphocytes to recognize the recipient tissue as foreign. Unlike the immune system of preconditioned stem cell transplant recipients, that of solid organ transplant recipients is relatively intact – another explanation of the paucity of GVHD in solid organ transplantation (9). However, similar to the previous reports of pancreas after kidney transplantation (3, 4) and liver retransplantation (16), all three patients in this report had previous transplants and were on immunosuppression, which could hinder the recipients rejecting donor lymphocytes. Clinical manifestations of GVHD vary from skin rash to systemic involvement, including liver, intestine, and bone marrow (Table 1) (1–8). Ambiguous skin rash and fever may resemble a drug reaction or viral infection, while skin and other tissue biopsies may be non-pathognomonic (2). Previous reports indicate that even multiple biopsies, especially taken in the early stage of the disease, can be non-diagnostic and otherwise misleading (2–4). Furthermore, an actual drug reaction or viral infection can precede or coexist with GVHD (2, 4). Our first case was also initially treated as a viral infection. Some medications commonly used after transplantation can cause a skin reaction; liver, gastrointestinal, or bone marrow dysfunction; and overlapping symptoms with GVHD; and any suspicious medications (e.g., sulfa and mycophenolate) should be switched to alternative medications. Although historical examinations of involved organs (e.g., skin, liver, intestine, and bone marrow) are often diagnostic of GVHD, no donor DNA confirma-
tory tests were performed in our cases. Because of the limitations of the retrospective case review, we are unable to provide the evidence of donor cell presence in the recipient tissue, and there is a remote possibility that these were not truly cases of GVHD that have donor cell involvements in the affected organs. Optimal treatment for GVHD after solid organ transplantation has yet to be determined (16–19). In our cases, the judicious use of corticosteroids and the reinstitution of other immunosuppressants at a relatively early stage after the onset of symptoms led to successful results for GVHD after pancreas transplantation. Because of the high mortality with systemic involvement, prevention of the progression from self-limited disease to a fatal disorder may be most critical to improve outcome. A high level of suspicion leading to early recognition and treatment for GVHD before life-threatening pancytopenia or sepsis is required. Acknowledgement The authors would like to express their appreciation to Ms. Erna Stoddart for her assistance in the preparation of this manuscript.
Disclosure
The manuscript was not prepared or funded in any part by a commercial organization. Authors’ contributions
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