key: cord-0818030-w4m9agd0 authors: Tang, Wen-Ruei; Hsu, Che-Wei; Lee, Chia-Chi; Huang, Wei-Li; Lin, Chia-Ying; Hsu, Ya-Ting; Chang, Chen; Tsai, Meng-Ta; Hu, Yu‐Ning; Hsu, Chih-Hsin; Chen, Po-Lin; Chow, Nan-Haw; Roan, Jun-Neng title: A Case Report of Post-transplant lymphoproliferative disorder following AstraZeneca COVID-19 vaccine in a heart transplant recipient date: 2021-09-30 journal: Transplant Proc DOI: 10.1016/j.transproceed.2021.09.006 sha: 9b828beb9779eecb0bae5202e345462581922835 doc_id: 818030 cord_uid: w4m9agd0 We report a case of a heart transplant recipient who presented with a rapidly growing Epstein-Barr virus (EBV)-positive, diffuse large B-cell lymphoma seven days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. Because of the atypical radiological presentation, the initial tentative diagnosis was a mediastinal abscess. This observation indicates a potential risk of EBV reactivation after COVID-19 vaccination, which might lead to or aggravate the presentation of post-transplant lymphoproliferative disorder in transplantation patients. Transplant surgeons should be aware of the potential immunomodulatory effects of COVID-19 vaccination. A case report of post-transplant lymphoproliferative disorder following AstraZeneca During the coronavirus disease 2019 (COVID-19) pandemic, vaccination is recommended for immunocompromised patients, including those who have received solid organ transplantation [1] . The most common adverse reactions include pain at the injection site, headache, fatigue, myalgia, fever, and joint pain [2] . Less common side effects include lymphadenopathy or lymphadenitis in the ipsilateral axillary region [3] . Additionally, reactivation of the Gammaherpesvirinae subfamily, such as Epstein-Barr virus (EBV), and herpesvirus have been reported in case studies [4] [5] [6] . However, information on COVID-19 vaccines among immunocompromised patients (solid organ transplant recipients, blood and solid organ cancers, etc.) is limited, and further investigation is required regarding efficacy and safety [7] . A 51-year-old man was admitted with a chief complaint of fever up to 38°C and generalized soreness at one week after the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) in the right deltoid muscle. The symptoms lasted for three days. He had been diagnosed with idiopathic dilated cardiomyopathy and received an orthotopic heart transplantation on February 6, 2014. He developed end-stage renal disease and required hemodialysis in December 2018. His recent immunosuppressant regimen included tacrolimus (1 mg twice a day) and mycophenolate mofetil (1.25 g per day). Chest radiography showed a new mass in the right upper mediastinum, which had not been seen on the chest film one month before admission ( Figure 1 ). Physical examination was unremarkable, and there was no palpable axillary or supraclavicular lymphadenopathy. Nasopharyngeal swab severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) (Cobas 6800 system) testing was negative. Laboratory tests revealed normal white blood cell count (4.0 × 10^3/uL), platelet count (2.76 x 10^5/uL), and C-reactive protein level (9.4 mg/L). The whole blood trough concentration of tacrolimus was 6.5 ng/mL. Contrast-enhanced computed tomography (CT) of the chest revealed a ring-enhancing mass of approximately 52 × 50 × 42 mm in the right upper mediastinum ( Figure 2 ). CT-guided drainage was performed under the impression of a mediastinal abscess, which failed to drain any contents. Therefore, he underwent debulking surgery for the mass lesion using video-assisted thoracoscopy. Pathology examination revealed EBV-positive diffuse large B-cell lymphoma (Figure 3 ), which was consistent with a diagnosis of monomorphic post-transplant lymphoproliferative disorder (PTLD). Blood, sputum, and excisional specimens were sent for bacterial, fungal, and mycobacterial cultures, and real-time PCR (Xpert® MTB/RIF assay) analyses. Abbott real-time PCR was used to detect viremia, and data on CMV, EBV, and SARS-CoV-2, and HSV1, HSV2, HBV, and HCV serology were obtained. In addition, DNA microarray technology was used for mold, fungus, and mycobacterium detection, and 16S ribosomal RNA gene PCR was used to detect bacterial pathogens. All studies evaluating the infectious etiology were negative. Even Abbott real-time EBV PCR of serum was negative two months before and one month after admission. The patient was treated with a 50% reduction in immunosuppressant dosages in conjunction with rituximab once a week for four weeks as an inpatient. PTLD refers to a group of lymphoid disorders with heterogeneous presentations ranging from indolent to aggressive disease [8, 9] . The highest incidence is in cases of multi-visceral transplants, followed by lung transplants and heart transplants [8] . The risk contribution of specific immunosuppressive agents varies in reports, but greater impact of higher intensity and longer duration of immunosuppression (i.e., total immunosuppressive burden) have been reported [8, 9] . The pathogenesis of PTLD is closely associated with infection or reactivation of EBV in the context of chronic immunosuppression as the main predisposing factor [8] [9] [10] . In the classic model, most EBV-positive PTLD results from EBV-infected B cells with a latency III pattern that proliferates only under conditions of reduced cytotoxic T-cells [8, 10] . Additionally, different EBV life phases are associated with different immune conditions [8] . Therefore, cell-mediated immunity is crucial for quiescent coexistence with EBV, especially for organ recipients who have made great efforts to strike an optimal risk balance between infection and immunosuppression. Nonetheless, EBV-positive PTLD only develops in a minority of solid organ transplant recipients receiving immunosuppression [8] . This suggests that the key step towards lymphomagenesis is multifactorial and extends beyond the scope of chronic immunosuppression. In a population-based study conducted in Nebraska, the risk of non-Hodgkin lymphoma was positively associated with receiving influenza vaccination (OR=1.53, CI=1.14-2.06) [11] . In particular, follicular lymphoma (OR=1.23, CI=1.23-3.18) and diffuse large B-cell lymphoma (OR=1.88, CI=1.13-3.12) were among the most common forms of lymphoma. Alteration of T helper 1 and Th2 cell balance after vaccination is inferred to be the cause of this increased risk. Accordingly, vaccination for SARS-CoV-2 may be an external stimulus and may temporarily alter this fragile balance [6] , based on the experience gained from various vaccines [4] [5] [6] 11] . As a result, tissue EBV reactivation may occur after COVID-19 vaccination [3] . Although it is far-fetched to establish a straightforward relationship between the COVID-19 vaccine and PTLD, two in vitro studies have implicated it in oncogenesis. Chen et al. [12] reported that transfection of SARS-CoV-2 spike protein S vectors led to a significant increase in representative lytic gene expression in the iSLK.219 cell line harboring recombinant Kaposi's sarcoma-associated herpesvirus.219 (rKSHV.219). This indicates that protein S, one of SARS-CoV-2 major structural proteins and the target antigen encoded by the COVID-19 vaccine [2] , has the potential to induce lytic reactivation of KSHV in chronically infected cells. EBV and KSHV are members of the Gammaherpesvirinae subfamily, which have a biphasic life cycle comprising lytic and latent phases and can cause a variety of cancers in humans [13] . In recent years, the role of the lytic cycle in tumorigenesis and tumor progression of both viruses have been elucidated and are well recognized as the main contributors to genomic instability and the necessary anti-apoptotic and immunomodulatory signals [10, 12, 13] . Chiang et al. [14] demonstrated the ability of SARS-CoV-1 spike protein to transform B cells in vitro, and proposed that devastating viral ligands may accelerate abnormal conversion of lymphocytes under a dampened immune system. Although SARS-CoV-2 and SARS-CoV-1 have different S sequences and bind angiotensin-converting enzyme 2 via distinct regions in the S protein receptor-binding motif [15] , the B-cell conversion ability of coronavirus S protein is indirectly implied. In summary, we hypothesize that the vaccine may contribute to B lymphocyte tumorigenesis via the reactivation of latent EBV. However, it has been acknowledged that chronically EBV-infected B cells accumulate pro-oncogenic aberrations (e.g., A20, BCL2, BCL6, MYC, PAX5, and TP53) under impaired immune surveillance and can transform into lymphoma by themselves at some point in time [8, 9] . In this reported case, PTLD occurred seven years after transplantation, which falls within the range of the second peak [9] . The patient received a heart transplant and was maintained on tacrolimus, both of which are associated with a higher risk of PTLD [9] . Nevertheless, the blood concentration of tacrolimus was kept within low limits of the therapeutic range and EBV viral load in the serum was undetectable for five years, even four weeks after diagnosis of EBV-positive PTLD. Additionally, although serum EBV DNA kinetics have been demonstrated to be important in the highest-risk hematopoietic stem cell transplantation group with a median of seven days from EBV DNAema onset to EBV-related lymphoproliferative disorders, evidence in solid organ transplant is less compelling because of the lack of sensitivity to localized EBV-positive PTLD and EBV-negative PTLD [8] . We report a case of PTLD following COVID-19 vaccination in a heart transplant recipient, which might show a possible pathogenic link. Although we are not able to exclude the coincidence of COVID-19 vaccination and the development of PTLD in this case, transplant surgeons should be aware of the immunomodulatory effect following COVID-19 vaccination and always think the worst until proven otherwise. Guidance from the International Society of Heart and Lung Transplantation regarding the SARS CoV-2 pandemic 2021 Vaxzevria (previously COVID-19 Vaccine AstraZeneca): EPAR -Product information Association of COVID-19 mRNA vaccine with ipsilateral axillary lymph node reactivity on imaging Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: A case series Herpes zoster emergence following mRNA COVID-19 vaccine Reactivation of varicella zoster virus after vaccination for SARS-CoV-2 COVID-19 vaccination in our transplant recipients: The time is now Post-transplant lymphoproliferative disorders Post-Transplantation lymphoproliferative disorders in adults Latency and lytic replication in Epstein-Barr virus-associated oncogenesis Vaccination history and risk of non-Hodgkin lymphoma: A population-based, case-control study SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus Contribution of the KSHV and EBV lytic cycles to tumourigenesis SARS spike protein induces phenotypic conversion of human B cells to macrophage-like cells Comprehensive structural and molecular comparison of spike proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and their interactions with ACE2 We thank Wiley Editing Services for enhancing our writing. There is no conflict. This study was approved by the institutional review board of the National Cheng Kung University Hospital (IRB No. B-EC-110-024, 08/01/2021). Written informed consent for the publication of details and images was obtained from the patient.