Increased Incidence Rate of Post-Transplant Lymphoproliferative Disorders (PTLD) Following the COVID-19 Pandemic: A Single Center Experience

Background:

The post-transplant lymphoproliferative disorders (PTLD) are a spectrum of disorders involving a proliferation of lymphoid elements as a result of immunosuppression following solid organ or allogeneic hematopoietic stem cell transplantation (HSCT). It is one of the most serious post-transplant complications, contributing to a significant increase in the rates of graft failure and mortality. Among the recognized risk factors for PTLD, the most established one is Epstein-Barr virus (EBV) infection or reactivation in the setting of decreased cytotoxic T-cell immune surveillance. EBV-driven PTLD usually demonstrates EBV-encoded RNA using in-situ hybridization (EBER ISH) on pathology specimens. Nevertheless, the pathophysiology of PTLD remains poorly understood, particularly the EBV-negative type which represents up to 30% of cases. There has been a notable increase in the incidence rate of PTLD cases diagnosed in our institution, prompting a further investigation in light of the most significant recent medical event, the COVID-19 pandemic.

Methods:

A retrospective review of the electronic medical records of patients diagnosed with PTLD at Stony Brook University Hospital between 1/1/2009 and 6/12/2022 was performed, with a data cutoff date of 7/30/2022. The study was approved by the local institutional review board. The incidence rate of PTLD during the period from 1/1/2009 to 12/31/2019 was compared to that during the period from 1/1/2020 to 6/12/2022. Data of PTLD cases diagnosed after 1/1/2020, which was considered the starting point of the COVID-19 pandemic, was collected with a focus on the clinicopathological features of PTLD and the time of diagnosis in relation to transplant, COVID-19 infection, and/or COVID-19 vaccination.

Results:

Thirty-five cases of PTLD were diagnosed during that period between 1/1/2009 and 6/12/2022. Twenty-five cases were diagnosed before 1/1/2020 at a rate of 2.3 cases per year. Ten cases, the characteristics of which are summarized in Table 1, were diagnosed between 1/1/2020 and 6/12/2022 at a rate of 4.1 cases per year. All patients were kidney transplant recipients diagnosed with monomorphic PTLD, including B cell lymphomas (n=8), T cell lymphoma (n=1), and plasmacytoma (n=1). EBER ISH was negative on the pathology specimens of 7 patients, positive in 1 patient, and not done in 2 patients. The median age was 52 years (range 25-77). Apart from one patient diagnosed with PTLD within one year from the time of transplant, the time from transplant to PTLD diagnosis in the other 9 patients ranged from 5 to 26 years. Eight patients were EBV-seropositive at the time of transplant. COVID-19 infection preceded PTLD diagnosis in one patient, while six patients had received at least one dose of a COVID-19 vaccine prior to PTLD diagnosis. All vaccinated patients in our series had received the BNT162b2 mRNA vaccine. With an estimated median follow-up of 6.5 months from the date of PTLD diagnosis, the overall survival rate was 70%.

Conclusion:

The annual incidence rate of PTLD at our institution has nearly doubled since the start of the COVID-19 pandemic and appears higher than previously reported rates in kidney transplant recipients (0.3-3%). A notable finding in our case series is that the vast majority of patients were diagnosed with PTLD five or more years after transplant, in contrast to previous reports estimating 80% of PTLD cases occur in the first year. Additionally, most patients were EBV-seropositive at the time of transplant but had negative EBER ISH at the time of PTLD diagnosis. Interestingly, there has been emerging evidence suggesting a potential relation between mRNA COVID-19 vaccination and increased reactivation of latent herpesviruses like EBV and varicella zoster virus (VZV) in both transplant recipients and older adults. One proposal is that post-vaccination polarization of the T-cell response could alter the balance between T-cell subsets, leading to the reactivation of latent viruses. Our study findings warrant further investigation into the immunomodulatory responses to COVID-19 infection and vaccination, particularly in immunocompromised patients.

No relevant conflicts of interest to declare.