Graft-vs-host disease (GVHD) is a rare complication after liver transplant (LT), occurring in <2% of recipients. Unfortunately, mortality is >85% and diagnosis and management remain challenging.1–3 Burdick et al first described the incidence of GVHD after LT in 1988, but much is still not known about the risk factors and mechanism of the disease process.1 The diagnosis is challenging, and recognition of a patient with preserved graft function, fever, skin rash, and leukopenia should lead to a high index of suspicion.2 We present a case of a 49-year-old woman who developed GVHD during a coronavirus disease 2019 (COVID-19) infection 3 months after receiving a LT. To the best of our knowledge, there is no other case associated with GVHD after LT and COVID-19 infection. We found only 1 other case in the literature describing a patient who developed GVHD after LT after being only exposed to COVID-19 but had negative confirmatory testing.3
Our patient had a history of alcohol-associated cirrhosis and received a LT from a 23-year-old male brain-dead donor. Her postoperative course was complicated by rising liver enzymes and a return to the operating room later that day for exploratory laparotomy resulting in temporary abdominal closure and a liver biopsy negative for acute rejection. Her immunosuppression regimen included basiliximab induction in the setting of preoperative renal impairment, tacrolimus, mycophenolate mofetil, and prednisone. Three months after transplant, she came in with worsening abdominal pain, nausea, vomiting, and diarrhea. She underwent an esophagogastroduodenoscopy with normal-appearing mucosa and biopsies. At this time, she was treated with antibiotics for a urinary tract infection. One week later, she returned for ongoing abdominal pain. A computed tomography scan showed portal vein stenosis, and interventional radiology performed a venoplasty, which improved the portal vein flow. On this admission, she tested negative for a rapid COVID-19 test, but 2 days later, before her interventional radiology procedure, she was positive for COVID-19 on a polymerase chain reaction. At the time of diagnosis, she was afebrile and on room air. She received 5 days of remdesivir, and monoclonal antibody treatment was deferred because sotrovimab was not available at our institution and other monoclonal antibodies were discouraged given high levels of resistance by the Omicron variant at the time. Her liver enzymes remained normal, and her ongoing gastrointestinal symptoms were attributed to COVID-19 given her normal esophagogastroduodenoscopy and resolution of her portal vein stenosis. However, during her prolonged hospitalization, she became progressively more neutropenic and developed a diffuse rash of multiple hyperpigmented patches as shown in Figure 1. Diagnosis of GVHD was suspected.
Peripheral blood chimerism progressively increased to >99% donor CD3 lymphocytes. Skin biopsy of the rash showed discernible dyskeratotic cells mostly at the dermal-epidermal junction. The dermis demonstrated lymphohistiocytic infiltrate with rare eosinophils and numerous melanophages in the papillary dermis. A diagnosis of GVHD after LT in the setting of COVID-19 infection was established.
Step-up treatment included high-dose steroids, followed by abatacept; rabbit antithymocyte globulin; and ATGAM, a sterile solution containing lymphocyte immune globulin and equine antithymocyte globulin. Two months into hospitalization, she became hypoxic and continued to test positive for COVID-19. Her cycle threshold values increased over the third month of her stay, and she received sotrovimab, 2 additional rounds of remdesivir, and 2 units of convalescent plasma. The choice for immunosuppressive therapy for GVHD was very difficult given the patient's ongoing pancytopenia, COVID-19 infection, and development of C. difficile colitis. Unfortunately, the patient died from acute respiratory distress syndrome.
GVHD occurs as an immune response from the donor graft against the host. The donor cells recognize the host cells as foreign, which leads to clonal expansion of the donor T lymphocytes and thus an immune response against the host. Proposed risk factors for the rare occurrence of GVHD after LT include older age, human leukocyte antigen class I mismatch, and patients with hepatocellular carcinoma.4,5 In addition, one study by Elfeki et al6 demonstrated that an age difference of >20 years among the donor and recipient is an additional risk factor for developing GVHD after LT with an estimated risk of 6% per 1 year of age difference. Our patient was 26 years older than her donor, which could have increased her risk of developing GVHD. There are not enough data to determine whether COVID-19 correlates with a risk of developing GVHD, but we believe it definitely worsened the course.
We present this case to raise awareness of the constellation of overlapping symptoms (postviral illness, ongoing GI symptoms, neutropenia, fever, hyperpigmented rash) when suspecting GVHD after solid organ transplant. It is important to suspect GVHD in LT recipients when there is unexplained leukopenia and rash. Contrary to other solid organ transplants, in cases of GVHD in LT, liver enzyme elevations are uncommon. The function of the graft liver remains unaffected because the graft is mounting the immune reaction against the host.7 Early diagnosis is essential to begin prompt immunosuppressive therapy and improve outcomes. A multidisciplinary approach with input from hematology is important to determine a treatment plan. This case is unique because of the development of GVHD during COVID-19 infection, which has not yet been documented in the literature.
Author contributions: S. Kiparizoska was responsible for acquisition of data; drafted the manuscript; reviewed the literature; and is the article guarantor. V. Nguyen was responsible for acquisition of data; drafted the manuscript; and revised it critically for important intellectual content. AS Rangnekar was responsible for acquisition of data and interpretation of data; revised it critically for important intellectual content; and provided the final approval of the version to be published.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
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