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Volume: 20 Issue: 5 May 2022 - Supplement - 3


A Fatal Complication of Liver Transplant: Posttransplant Lymphoproliferative Disease

Immunosuppressive therapy is a double-edged sword and causes a risk for some complications, such as opportunistic infections and posttransplant lymphoproliferative disease. The most likely risk factors for posttransplant lymphoproliferative disease are Epstein-Barr virus serology mismatch, prolonged and high viral load for Epstein-Barr virus, higher doses of immunosuppressive therapy, and cytomegalovirus infection. Transplant recipients who are seropositive for Epstein-Barr virus show a lower risk for posttransplant lymphoproliferative disease than seronegative recipients. Here, we present a 3.5-year-old boy who was seropositive for Epstein-Barr virus and developed posttransplant lymphoproliferative disease 18 months after liver transplant with a previous history of cytomegalovirus-related pneumatosis intestinalis.

Key words : Cytomegalovirus, Epstein-Barr virus, Lymphoma, Tacrolimus

Liver transplant (LT) is a life-saving therapy but carries risk of opportunistic infections. Posttransplant lymphoproliferative disease (PTLD) is a rare but potentially fatal complication of solid-organ transplant and includes a group of disorders from benign lymphoid hyperplasia to high-grade malignant lymphoma and is highly associated with Epstein-Barr virus (EBV). The risk factors for PTLD are not absolutely defined, but EBV serology mismatch (recipient negative, donor positive), prolonged and high EBV viral load, exaggerated immunosuppressive therapy, and associated cytomegalovirus (CMV) infection are likely factors.1 Transplant recipients seropositive for EBV are at moderate risk for PTLD. Despite the weak recommendation for children, routine close monitoring for EBV viral load in EBV-seropositive pediatric patients to prevent PTLD is not recommended.2 Here, we present an EBV-seropositive child who developed PTLD 18 months after LT with a previous history of CMV-related pneumatosis intestinalis.

Case Report
A 20-month-old boy born from a nonconsanguineous marriage received a diagnosis of citrullinemia type 1, and he was referred for LT to treat frequent metabolic decompensations despite dietary modifications. Living donor LT was planned, and his father was prepared as a donor. The recipient and the donor were seropositive for CMV and EBV. Before scheduled LT, the recipient presented with elevated liver enzymes and high levels for international normalized ratio at 2 years of age. Fifteen hours after hospitalization, he showed rapid deterioration of consciousness, and an emergent living donor LT was performed. Steroids and tacrolimus were given, along with a prophylaxis of valganciclovir, trimethoprim-sulfamethoxazole, and fluconazole. Subcapsular seroma was determined on day 24, but this resolved after percutaneous biliary drainage; liver biopsy showed no rejection, and staining was negative for EBV and CMV. By the end of month 3 after LT, valganciclovir and trimethoprim-sulfamethoxazole were stopped.

At month 4 after LT, mild rejection occurred (rejection activity index, 3/9; fibrosis, 1/6). In addition to steroid induction, mycophenolate mofetil was added and rejection was resolved. In month 6 after LT, he was hospitalized to treat emesis and anemia, high levels of C-reactive protein, hypoalbuminemia, and CMV viremia (CMV, 90?499 copies/mL; EBV, 2220 copies/mL). Intravenous ganciclovir was given for 31 days and was then switched to oral valganciclovir as the viral load decreased; valganciclovir treatment was ceased after 16 days because of drug interactions. Abdominal ultrasonography results were normal. Endoscopic evaluation was planned but was canceled because the parents would not provide consent during the COVID-19 pandemic. Tacrolimus levels were 6 to 12 ng/mL despite dose adjustment.

On day 32 of hospitalization, fever and tachypnea occurred. Results from COVID-19 polymerase chain reaction (PCR) tests and tuberculosis screening were negative. He had prerenal azotemia and showed elevated liver enzymes and tacrolimus levels (CMV, 161 copies/mL; EBV, 1022 copies/mL). Abdominal computed tomography showed pneumatosis along the colonic mucosa, edema of the small bowel wall and mesentery, and periportal edema in the transplanted liver. Tacrolimus was paused. In addition to antibiotherapy, parenteral nutrition was given for 14 days and switched to amino acid formula. One month later, during the investigation of prolonged fever, PCR tests for EBV and CMV were 11?889 and 1331 copies/mL, respectively, and acyclovir treatment was added. Tacrolimus dosage was reduced because the levels were generally between 5 and 9.1 ng/mL, except for some high peak levels. Albumin level increased after bowel rest and protein-rich feeding protocol. He was discharged with liver enzymes within the reference range and with low serum levels of EBV (1377 copies/mL) and mildly elevated CMV levels (2392 copies/mL).

Two weeks after discharge, the patient experienced a 10-fold increase in CMV viral load, so treatment with intravenous ganciclovir was planned, but valganciclovir was provided instead. In response to CMV levels, valganciclovir treatment was stopped after 3 months. His PCR tests showed 95 copies/mL for CMV and 2314 copies/mL for EBV. Tacrolimus levels were between 8.3 and 9.3 ng/mL, and drug dosage was reduced. In month 15 after LT, acute gastroenteritis resulted in acute renal damage and fluctuation of tacrolimus levels up to 10.2 ng/mL. Dose reduction to 1 dose of 1 mg of tacrolimus was implemented.

In month 18 after LT, the patient was admitted to emergency service with emesis, abdominal pain, and cough. Auscultation revealed reduced breath sounds in the left hemithorax and tachycardia, and a chest radiograph showed a mass in the left hemithorax that was pushing against the trachea. Thorax computed tomography showed a solid mass with calcifications located in the upper front mediastinum and the left paracardial area that was pressing against the pulmonary conus, the left pulmonary artery, and the left main bronchus. Mediastinal vascular structures, trachea, and esophagus were mildly pushed to the right-hand side and mild pericardial fluid was detected. Abdominal computerized tomography showed normal liver parenchyma, but a solid mass between the abdominal bifurcation of the aorta and pelvis. Measurements of complete blood count, liver enzymes, and alpha-fetoprotein were within reference limits despite high levels of C-reactive protein. The level of EBV was 611?027 copies/mL; PTLD was suspected, so immunosuppressive treatment was stopped. Corticosteroid was given with suspicion of lymphoma. Biopsy with a Tru-Cut biopsy device revealed CD20+ high-grade B-cell lymphoma. Unfortunately, the tumor was aggressive despite chemotherapy, and the patient died of systemic inflammatory response syndrome.

One of the most devastating complications of LT is PTLD,2 and this is the most common reason for posttransplant malignancy in pediatric LT recipients.3 Mismatched EBV serology and high viral load caused by treatment with high-dose immunosuppressives are very often the cause of PTLD. However, PTLD does not occur in all patients with high EBV viral load, and not all PTLD tumors are seropositive for EBV. Hence, the prediction for PTLD occurrence and behavior of the tumor is very challenging.3 Here, we described an LT recipient who developed a fulminant presentation of PTLD that was resistant to chemotherapy despite several attempts of immunosuppressive dose reduction and antiviral treatments.

Liver transplant recipients develop PTLD less often than do transplant recipients of intestine, lung, and heart. On the other hand, PTLD is more common in pediatric LT than in adult LT because most pediatric recipients have EBV-negative serology but often receive a liver from an adult with EBV-positive serology.1 Generally, the pathophysiology of PTLD derives from the ability of EBV to infect and immortalize B cells as well as prevent their apoptosis.2

Active CMV infection is assumed to contribute to PTLD, with an immune senescence effect and suppressed cellular immunity3 despite contradictions.2 Our patient developed pneumatosis intestinalis related to CMV infection only 1 month after cessation of valganciclovir prophylaxis, and CMV infection may be a facilitator for EBV-related PTLD. Pneumatosis intestinalis is characterized by gas-filled intramural cysts in the submucosa or serosa of the colonic or intestinal wall. It has been asserted that pneumatosis intestinalis is induced by immunosuppressive therapies (mostly caused by corticosteroid-induced atrophy of gastrointestinal lymphoid tissue that results in mucosal defects and finally dissection of the intestinal wall), opportunistic intestinal infections (such as CMV), and reaction to the inflamed transplanted organ. The therapeutic management includes bowel rest, antibiotherapy, and dose reduction of immunosuppressives.4 In our patient, the abdominal imaging showed no mass or lymphadenopathy, but pneumatosis was present, and these results excluded the possibility of slowly progressing PTLD.

Posttransplant lymphoproliferative disease may present in nondestructive form or with polymorphic or monomorphic features. The immunosuppressive therapies are implemented to inhibit cell-mediated immune response after LT. On the other hand, the immunosuppressive therapies that directly inhibit T-cell activation, such as calcineurin inhibitors (tacrolimus) and antithymocyte globulin, can cause loss of T-cell control of B-cell proliferation; therefore, these therapies become risk factors for PTLD. Prolonged and high cumulative doses of corticosteroids have been shown to inhibit T-cell function and activation and therefore may also be risk factors for PTLD.1

The principal strategy for prevention of PTLD is avoidance of higher doses of immunosuppressive and maintenance of tacrolimus levels under 5 to 7 ng/mL after 1 year of LT.1 Close monitoring for EBV and CMV viral load1,2 may guide the reduction of immunosuppressive dosage,1 but an evidence-based preemptive approach does not yet exist.2 Antiviral agents (acyclovir, ganciclovir) inhibit the active replication phase of EBV but show no effect on latent infection. Antiviral agents and intravenous immunoglobulin are sometimes used preemptively, but the benefit of such treatments remains controversial, with insufficient evidence to support routine implementation of this therapy as a sole preemptive intervention for PTLD. There are still no evidence-based recommendations for or against a switch to inhibitors of the mechanistic target of rapamycin or an addition of rituximab (with antiviral agents or as a salvage therapy for patients who remain unresponsive to immunosuppressive reduction).2

Immunosuppressive therapy is a double-edged sword. Ful-minant PTLD is one of the most devastating complications of LT, and dose reduction of immunosuppressives remains the single most effective treatment known to date. A previous severe CMV infection may facilitate a fulminant course of EBV-related PTLD.


  1. Simakachorn L, Tanpowpong P, Lertudomphonwanit C, et al. Various initial presentations of Epstein-Barr virus infection-associated post-transplant lymphoproliferative disorder in pediatric liver transplantation recipients: case series and literature review. Pediatr Transplant. 2019;23(2):e13357. doi:10.1111/petr.13357
    CrossRef - PubMed
  2. Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13652. doi:10.1111/ctr.13652
    CrossRef - PubMed
  3. Baker A, Frauca Remacha E, Torres Canizales J, et al. Current practices on diagnosis, prevention and treatment of post-transplant lymphoproliferative disorder in pediatric patients after solid organ transplantation: Results of ERN TransplantChild Healthcare Working Group Survey. Children (Basel). 2021;8(8)661. doi:10.3390/children8080661
    CrossRef - PubMed
  4. Park CS, Hwang S, Jung DH, et al. Pneumatosis intestinalis after adult living donor liver transplantation: report of three cases and collective literature review. Korean J Hepatobiliary Pancreat Surg. 2015;19(1):25-29. doi:10.14701/kjhbps.2015.19.1.25
    CrossRef - PubMed

Volume : 20
Issue : 5
Pages : 102 - 104
DOI : 10.6002/ect.PediatricSymp2022.O33


From the 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, the 2Department of Pediatric Oncology, and the 3Department of General Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Hayriye Hizarcioglu-Gulsen, Hacettepe University Faculty of Medicine, Department of Pediatric Gastroenterology, Hepatology and Nutrition, 06100, Sihhiye, Ankara, Turkey
Phone: +90 532 5903570