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• W2025538804 abstract "Acute graft-versus-host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54-year-old male with type 1 diabetes who received a zero-antigen mismatched pancreas-after-kidney transplant from a pancreas donor who was homozygous at the HLA-B, -Cw, -DR, and -DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low-grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants. Acute graft-versus-host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54-year-old male with type 1 diabetes who received a zero-antigen mismatched pancreas-after-kidney transplant from a pancreas donor who was homozygous at the HLA-B, -Cw, -DR, and -DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low-grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants. Acute graft-versus-host disease (GVHD) has rarely been reported as a complication of pancreas transplantation. To our knowledge, documented acute GVHD after pancreas transplantation has occurred in only five other reported instances (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar, 2Kimball P Ham J Eisenberg M et al.Lethal graft-versus-host disease after simultaneous kidney-pancreas transplantation.Transplantation. 1997; 63: 1685-1688Crossref PubMed Scopus (32) Google Scholar, 3Gulbahce HE Brown CA Wick M Segall M Jessurun J Graft-versus-host disease after solid organ transplant.Am J Clin Pathol. 2003; 119: 568-573Crossref PubMed Scopus (54) Google Scholar), with an additional three cases when the spleen was transplanted together with the pancreas (4Gonwa TA Goeken NE Schulak JA Nghiem DD Corry RJ Failure of cyclosporine to prevent in vivo T cell priming in man. Studies in allogeneic spleen transplantation.Transplantation. 1985; 40: 299-304Crossref PubMed Scopus (19) Google Scholar,5Deierhoi MH Sollinger HW Bozdech MJ Belzer FO Lethal graft-versus-host disease in a recipient of a pancreas-spleen transplant.Transplantation. 1986; 41: 544-546Crossref PubMed Scopus (49) Google Scholar). We describe a recipient of a pancreas-after-kidney transplant whose GVHD initially presented as prolonged fevers of unknown origin. The patient was a 54-year-old white male with end-stage renal disease due to insulin-dependent diabetes mellitus, with a peak historical panel reactive antibody of 89%. He had received a six-antigen mismatched, deceased donor kidney transplant, with 6 mg/kg of rabbit antithymocyte globulin as induction therapy. He was maintained on prednisone, tacrolimus and mycophenolate mofetil, with a baseline serum creatinine of 1.0–1.2 mg/dL. Eleven months following the kidney transplant, the patient received a zero-antigen mismatched, enterically drained pancreas transplant from a cytomegalovirus (CMV)-negative 33-year-old white male, with an additional 6 mg/kg of rabbit antithymocyte globulin. Table 1 shows the HLA typing of the patient and his pancreas and kidney donors. Except for perioperative bleeding requiring three units of leuko-reduced red blood cell transfusions, his initial course was uneventful, with immediate pancreatic function. He was discharged home on postoperative day (POD) #9 on a prednisone taper, tacrolimus and mycophenolate mofetil.Table 1HLA-A, -B, -Cw, -DR and -DQ antigens for the patient and his pancreas and kidney donorsABCwDRDQRecipient1, 248 (Bw6), 62 (Bw6)7, 94 (53), 17(52)2, 8Pancreas donor1, 248 (Bw6)717 (52)2Kidney donor34, 7453 (Bw4), 71 (Bw6)6, 1018 (52), 9 (53)2, 4 Open table in a new tab On POD #22, the patient was readmitted with fevers and night sweats. Plasma polymerase chain reaction (PCR) for CMV showed 300 DNA copies/mL (ViraCor Laboratories, Lee’s Summit, MO). Despite treatment with oral valganciclovir (900 mg twice daily) (6Asberg A Humar A Rollag H et al.Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients.Am J Transplant. 2007; 7: 2106-2113Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar) and mycophenolate dose reduction, the fevers and low-grade CMV viremia persisted. Other evaluation was unrevealing and included blood cultures, urine cultures, plasma PCR for other viruses, stool studies, bone marrow biopsy (POD #57, normal marrow cellularity with all marrow elements present), transthoracic echocardiography and upper and lower endoscopy. Small bowel biopsy from the upper endoscopy showed an intracytoplasmic inclusion consistent with invasive CMV disease. Radiologic imaging (including magnetic resonance imaging, computed tomography scans, ultrasounds and hepatobiliary scintigraphy) was also nondiagnostic. Exploratory laparotomy was performed on POD #49, with open biopsies of the liver (normal histology) and transplant pancreas (nonspecific inflammation of undetermined significance). The patient was anticoagulated for bilateral lower extremity deep vein thromboses diagnosed by Doppler (POD #60). The fevers gradually abated, and the patient was discharged home on POD #64, afebrile with a white blood cell count (WBC) of 4300 per mm3. At home, he continued treatment for possible CMV disease with high-dose valganciclovir and then intravenous (i.v.) ganciclovir. During an office visit on POD #106, the patient was noted to have a diffuse rash sparing the palms and soles, consisting of erythematous macules with almond-shaped plaques as well as macular patches of erythema. A skin biopsy performed that day was consistent with GVHD, showing hyperkeratosis, sparse superficial perivascular lymphocytic infiltrate and exocytosis with necrotic keratinocytes. Peripheral blood was drawn on POD #120 to perform short tandem repeat (STR) DNA chimerism studies (7Domiati-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: 2968-2973Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). One hundred percent of the circulating CD8+ lymphocytes were of pancreas donor origin (Table 2), confirming the histological diagnosis of GVHD.Table 2Results of peripheral blood single-tandem repeat testing for chimerismPOD #120POD #140CD3100% recipient100% pancreas donorCD8100% pancreas donor100% pancreas donorCD15100% recipient58% recipient, 42% pancreas donorCD19100% recipient52% recipient, 48% pancreas donor Open table in a new tab Skin biopsy specimens from POD #106 were also sent for STR DNA analysis (University of Maryland Medical Center, Immunogenetics Laboratory, Baltimore, MD) (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar). The skin biopsy also demonstrated chimerism, with an average of 21% pancreas donor DNA. No DNA from the kidney donor was present in the skin biopsy specimen. Possible treatment options for GVHD, including transplant pancreatectomy and changes in immunosuppression, were discussed with the patient. Prior to any initiation of therapy, the patient was readmitted on POD #131, acutely ill-appearing with fevers, severe pancytopenia and abnormal liver function tests (total bilirubin 2.0 mg/dL, alkaline phosphatase 605 IU/L). Despite i.v. antibiotics, platelet transfusions, red blood cell transfusions, injections of granulocyte colony-stimulating factor and high-dose corticosteroids for several days to try to treat his GVHD, the patient steadily deteriorated. Repeat peripheral blood STR chimerism studies on POD #140 showed increasing amounts of donor lymphocytes, consistent with the patient’s deteriorating clinical condition (Table 2). The patient expired on POD #145 due to multiorgan failure. The patient’s HLA typing was performed by a reverse sequence-specific oligonucleotide probe (rSSOP) method using LABType SSO (One Lambda, Inc., Canoga Park, CA). This HLA typing was performed at the time of the recipient’s original pretransplant evaluation using a peripheral blood specimen. Peripheral blood from the kidney and pancreas donors was typed using a sequence-specific primer (SSP) method (MicroSSP I and II; One Lambda, Inc.). After GVHD was suspected, the recipient’s postpancreas transplant peripheral blood, the recipient’s archived pretransplant DNA, the kidney donor’s archived DNA and the pancreas donor’s archived donor DNA were all retested simultaneously with the same reagents under the same conditions using rSSOP. These were the same DNA specimens as used for the STR analyses. A comparison of the rSSOP HLA typing between the two recipient specimens (pretransplant and postpancreas transplant) showed no differences at any locus. The rSSOP typing of the pancreas donor DNA confirmed homozygosity at the HLA-B, -Cw, -DRB1*, -DRB3* and -DQ loci. STR DNA chimerism studies were performed on the patient’s peripheral blood as follows (7Domiati-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: 2968-2973Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). CD3+, CD8+, CD15+ and CD19+ lymphocytes were isolated from peripheral blood using immunomagnetic beads (Dynal Biotech, Brown Deer, WI). Cells were eluted from the beads, and DNA was isolated using a GenoM-6 robot isolation system (Qiagen, Inc., Valencia, CA). The patient’s postpancreas transplant DNA and frozen, archived pretransplant DNA from the patient, the kidney donor and the pancreas donor were amplified using AmpFLSTR Identifiler PCR amplification kit (Applied Biosystems, Foster City, CA). The amplified DNA was analyzed for STRs using the ABI 3100-Avant Genetic Analyzer (Applied Biosystems). The STR profile of the patient’s postpancreas transplant specimens (POD #120 and POD #140) were compared with the STR profiles for the two donors. The major and minor contributors were calculated for informative markers. GVHD is a rare cause of fevers following transplantation of the pancreas and/or kidney (8Assi MA Pulido JS Peters SG McCannel CA Razonable RR Graft-versus-host disease in lung and other solid organ transplant recipients.Clin Transplant. 2007; 21: 1-6Crossref PubMed Scopus (42) Google Scholar). Among recipients of pancreas and/or kidney transplants, fevers usually stem from an infection, drug reaction or allograft rejection (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar). When these and other causes of fevers have been excluded, GVHD should be considered as a possible, although admittedly obscure, diagnosis. After months of delay, frustration and diagnostic testing, we diagnosed our patient with GVHD when he developed a skin rash. Use of peripheral blood STR analysis may permit earlier diagnosis of GVHD and earlier initiation of possibly life-saving therapies. In our patient, as well as in other cases of GVHD after pancreas transplant (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar,2Kimball P Ham J Eisenberg M et al.Lethal graft-versus-host disease after simultaneous kidney-pancreas transplantation.Transplantation. 1997; 63: 1685-1688Crossref PubMed Scopus (32) Google Scholar), the diagnosis of GVHD was not considered or suspected until the appearance of a rash and subsequent biopsy of the affected skin. Earlier testing for chimerism, when our patient was febrile but before onset of the rash, may have permitted earlier treatment of GVHD. STR analysis has already been used to quantify donor T cells in peripheral blood of recipients after liver transplantation (7Domiati-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: 2968-2973Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,9Taylor AL Gibbs P Sudhindran S et al.Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation.Transplantation. 2004; 77: 441-446Crossref PubMed Scopus (87) Google Scholar) and to help confirm or rule out GVHD after solid organ transplant (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar,10Schrager JJ Vnencak-Jones CL Graber SE et al.Use of short tandem repeats for DNA fingerprinting to rapidly diagnose graft-versus-host disease in solid organ transplant patients.Transplantation. 2006; 81: 21-25Crossref PubMed Scopus (39) Google Scholar). For some histocompatibility laboratories, STR analysis of peripheral blood may be easier and quicker to perform than STR analysis of tissue specimens such as skin. Our patient had several risk factors associated with GVHD after solid organ transplantation. Most notably, our patient’s pancreas transplant was a zero-antigen mismatch. Other studies have associated close HLA matching between the donor and recipient with subsequent GVHD. In particular, the pancreas donor’s homozygosity in the setting of a zero-mismatch (a so-called ‘one-way’ zero-mismatch) may predispose to GVHD (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar,11Smith DM Agura ED Levy MF Melton LB Domiati-Saad R Klintmalm G Graft versus host disease following kidney transplantation using an ‘0 HLA antigen mismatched’ donor.Nephrol Dial Transplant. 2006; 21: 2656-2659Crossref PubMed Scopus (12) Google Scholar). Our patient’s severely immunocompromised state, a result of receiving two short courses of rabbit antithymocyte globulin induction therapy, also likely contributed to his development of GVHD. The presence of such risk factors should alert clinicians to the possibility of GVHD. The prognosis of GVHD after pancreas transplantation is dismal. To our knowledge, the five other reported cases of GVHD in recipients of pancreas transplants (without concomitant splenic transplantation) were fatal (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar, 2Kimball P Ham J Eisenberg M et al.Lethal graft-versus-host disease after simultaneous kidney-pancreas transplantation.Transplantation. 1997; 63: 1685-1688Crossref PubMed Scopus (32) Google Scholar, 3Gulbahce HE Brown CA Wick M Segall M Jessurun J Graft-versus-host disease after solid organ transplant.Am J Clin Pathol. 2003; 119: 568-573Crossref PubMed Scopus (54) Google Scholar). Patients died from bone marrow failure and its associated complications, such as infection and multiorgan failure (1Weinstein 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: 127-131Crossref PubMed Scopus (24) Google Scholar, 2Kimball P Ham J Eisenberg M et al.Lethal graft-versus-host disease after simultaneous kidney-pancreas transplantation.Transplantation. 1997; 63: 1685-1688Crossref PubMed Scopus (32) Google Scholar, 3Gulbahce HE Brown CA Wick M Segall M Jessurun J Graft-versus-host disease after solid organ transplant.Am J Clin Pathol. 2003; 119: 568-573Crossref PubMed Scopus (54) Google Scholar). These poor outcomes are consistent with the high mortality of GVHD after other solid organ transplants (8Assi MA Pulido JS Peters SG McCannel CA Razonable RR Graft-versus-host disease in lung and other solid organ transplant recipients.Clin Transplant. 2007; 21: 1-6Crossref PubMed Scopus (42) Google Scholar), most notably liver transplants (12Smith DM Agura E Netto G et al.Liver transplant-associated graft-versus-host disease.Transplantation. 2003; 75: 118-126Crossref PubMed Scopus (162) Google Scholar). Intensified and reduced immunosuppression have each been proposed as treatments for GVHD after solid organ transplant (13Taylor AL Gibbs P Bradley JA Acute graft versus host disease following liver transplantation: The enemy within.Am J Transplant. 2004; 4: 466-474Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 14Lehner 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: 307-310Crossref PubMed Scopus (58) Google Scholar, 15Chinnakotla S Smith DM Domiati-Saad R et al.Acute graft-versus-host disease after liver transplantation: Role of withdrawal of immunosuppression in therapeutic management.Liver Transpl. 2007; 13: 157-161Crossref PubMed Scopus (38) Google Scholar). Transplant pancreatectomy is another treatment option, albeit unproven, for GVHD after pancreas transplant. In conclusion, transplant physicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants. Increased awareness of this unusual disorder may permit earlier interventions, such as transplant pancreatectomy and changes in immunosuppression, that may improve the prognosis of this almost uniformly fatal condition. Early testing for chimerism, especially using STRs, may permit earlier diagnosis and allow treatment even prior to the development of any skin rash. We thank Dr. Stephanie Silos-Badalamenti (Saint Barnabas Medical Center, Department of Dermatology), Dr. Marc E. Uknis (Saint Barnabas Medical Center, Renal and Pancreas Transplant Division), Dr. Douglas M. Smith (University of Michigan, Department of Pathology) and Dr. Debra KuKuruga (University of Maryland Medical Center, Immunogenetics Laboratory) for their assistance in diagnosing the patient with acute graft-versus-host disease. We also thank Patricia Bowe and Helen LaCarrubba (New Jersey Organ & Tissue Sharing Network) for their assistance in performing the STR chimerism studies and follow-up rSSOP typing of the donors and recipient." @default.
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• W2025538804 title "Fatal Graft-Versus-Host Disease Presenting as Fever of Unknown Origin in a Pancreas-After-Kidney Transplant Recipient" @default.
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