A 45-year-old man with type 1 diabetes mellitus for 20 years and end-stage renal disease on hemodialysis therapy for 3 years underwent simultaneous pancreas-kidney transplantation from an ABO blood group–, 1A-, 1DR-matched 16-year-old female donor. Both donor and recipient were cytomegalovirus (CMV) positive. Cold ischemic times were 8 hours for the pancreas and 10 hours for the kidney. No perioperative transfusion was required. Induction immunosuppression consisted of thymoglobulin, methylprednisolone, and mycophenolate mofetil. The hospital course was uneventful, and he was discharged to home on postoperative day 8 on an immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and prednisone. One week after discharge, he was readmitted with fever, hypotension, and generalized malaise and weakness. Physical examination showed a temperature of 102.4°F and no evidence of rash, adenopathy, focal tenderness, or splenomegaly. Function of both the kidney and pancreas allografts was good (serum creatinine, 1.5 mg/dL [133 μmol/L]; estimated glomerular filtration rate > 60 mL/min/1.73 m2 [>1.00 mL/s/1.73 m2]; glucose, 107 mg/dL [5.93 mmol/L]; amylase, 58 U/L; and lipase, 17 U/L), and the remainder of his laboratory results were within normal limits (white blood cells, 4.7 × 103/μL [4.7 × 109/L]; hemoglobin, 9.9 g/dL [99 g/L]; and platelets, 308 × 103/μL [308 × 109/L]). During the next few days, his white blood cell count decreased to 0.2 × 103/μL despite withholding mycophenolate mofetil and valganciclovir and initiating treatment with filgrastim (Neupogen).
■ What is the differential diagnosis of neutropenia in a recent transplant recipient?
■ What evaluation should be included in this workup?
■ What is your diagnosis? How would you confirm this?
Discussion
What is the differential diagnosis of fever and neutropenia in a recent transplant recipient?
Fever and neutropenia in the early posttransplantation period could be caused by drugs, infections, rejection, or bone marrow injury. Infection may be viral, bacterial, or fungal, with CMV the most common. The most commonly implicated medications are mycophenolate mofetil, trimethoprim-sulfamethoxazole, and valganciclovir, as well as such induction agents as thymoglobulin and campath. Another usual cause is cellular or humoral acute rejection.
What evaluation should be included in this workup?
Patients should have a full physical examination, searching for infectious causes, rashes, or other physical findings. A complete blood count with differential should be checked to distinguish leukopenia from pancytopenia, in addition to a pan-culture and serological testing for CMV. Withdrawing potentially causative medications may be undertaken. Response to Neupogen should be assessed, and if neutropenia persists, a bone marrow biopsy should be undertaken.
What is your diagnosis? How would you confirm this?
The bone marrow biopsy specimen showed lymphocytes of both male and female karyotypes (Fig 1A and B), providing the diagnosis of graft-versus-host disease (GVHD). The patient was treated with a course of thymoglobulin, an increase in tacrolimus dose, and methylprednisolone. Repeated blood specimens were sent to the HLA typing laboratory for short tandem repeat analysis, which first showed eradication of all graft female T cells and then showed repopulation of the recipient's CD3, CD8, and CD15 cell lines. The pathological course of GVHD involves donor T-cell activation and attack of the recipient.1 By increasing our patient's immunosuppression, especially that directed toward the T-cell population, we succeeded in eliminating the donor T cells. Unfortunately, the patient developed bleeding and an enterocutaneous fistula at the pancreas allograft site, as well as persistent bacteremia and fungemia. He eventually died of sepsis.
Figure 1. Karyotype analysis of a single bone marrow sample shows 2 different karyotypes: (A) male karyotype (note the presence of a Y chromosome) from cells of the transplant recipient, and (B) female karyotype (note the paired X chromosomes) from cells derived from the donor.
Although uncommon, GVHD frequently is lethal in solid-organ transplant recipients.1, 2 The burden of donor lymphocytes transplanted with an organ is associated with the risk of GVHD3; thus, there is a greater incidence in liver and multiorgan transplantation. All reported cases of GVHD after pancreas transplantation resulted in death of the recipient, with or without transplant pancreatectomy. The usual presentation involves fever, neutropenia, skin rash, and increased liver transaminase levels.4 A high degree of clinical suspicion usually is required to make the diagnosis because posttransplantation fever and neutropenia have many possible causes.5 Diagnosis is made based on rash histological characteristics, bone marrow biopsy, or short tandem repeats showing circulating donor lymphocytes.6
Final diagnosis
Graft-versus-host disease.
Acknowledgements
Support: None.
Financial Disclosure: None.
References
1. 1Taylor AL, Gibbs P, Bradley JA. Acute graft versus host disease following liver transplantation: The enemy within. Am J Transplant. 2004;4:466–474. MEDLINE |
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2. 2Assi MA, Pulido JS, Peters SG, McCannel CA, Razonable RR. Graft-vs.-host disease in lung and other solid organ transplant recipients. Clin Transplant. 2007;21:1–6. MEDLINE |
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3. 3Triulzi DJ, Nalesnik MA. Microchimerism, GVHD, and tolerance in solid organ transplantation. Transfusion. 2001;41:419–426. MEDLINE |
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4. 4Reddy P, Ferrara JLM. Graft-versus-host disease. In: Hoffman R, Benz E, Shattil S, Furie B, Cohen H editor. Hematology: Basic Principles and Practice. (ed 4). Philadelphia, PA: Elsevier; 2005;p. 1784–1792.
5. 5Weng FL, Pancoska C, Patel AM. Fatal graft-versus-host disease presenting as fever of unknown origin in a pancreas-after-kidney transplant recipient. Am J Transplant. 2008;8:881–883.
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6. 6Schrager 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;81:21–25. MEDLINE |
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Case provided and authored byAdena J. Osband, MD, David A. Laskow, MD, Teresa Berkowicz, PharmD, and Richard A. Mann, MD, Robert Wood Johnson Medical School, New Brunswick, NJ.
Address correspondence to Adena J. Osband, MD, Kidney/Pancreas Transplant, CAB 2160, 125 Paterson St, New Brunswick, NJ 08901.E-mail: adena.osband@rwjuh.edu
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