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1
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Wu HL, Weber WC, Waytashek CM, Boyle CD, Reed JS, Bateman KB, Fisher HK, Chen Y, Armantrout K, Swanson T, Shriver-Munsch C, Northrup M, Fischer M, Biswas S, Templon J, Panoskaltsis-Mortari A, Burwitz BJ, Johnson AL, Colgin L, Lewis AD, Smedley JV, Axthelm MK, Skalsky R, Meyers G, Maziarz RT, Mittra E, Berg M, Stanton JJ, Sacha JB. A model of lymphocryptovirus-associated post-transplant lymphoproliferative disorder in immunosuppressed Mauritian cynomolgus macaques. PLoS Pathog 2024; 20:e1012644. [PMID: 39527641 PMCID: PMC11581395 DOI: 10.1371/journal.ppat.1012644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 11/21/2024] [Accepted: 10/06/2024] [Indexed: 11/16/2024] Open
Abstract
Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT. Five simian immunodeficiency virus (SIV)-infected, CD8α+ cell-depleted MCMs received an infusion of autologous B-lymphoblastoid cells transformed with CyLCV, followed by varying degrees of immunosuppression. Four of five infused macaques developed masses coincident with increasing CyLCV plasma viremia, and necropsies confirmed the presence of multicentric lymphomas, which most commonly manifested in lymph nodes, gastrointestinal tract, adrenal glands, and pancreas. Affected tissues harbored neoplastic lymphocytes double-positive for CD20 and CyLCV EBNA2 antigen, large frequencies of proliferating B cells, and high levels of cell-associated CyLCV DNA. In addition, longitudinal 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) of one MCM successfully detected lymphoproliferative disease in the adrenal glands prior to clinical signs of disease. These data demonstrate successful induction of lymphocryptovirus-associated PTLD-like disease in 4 of 5 MCMs, and thus support the use of MCMs as a preclinical NHP model of EBV-associated lymphoproliferative disease that could be employed to test novel diagnostic and therapeutic modalities.
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Affiliation(s)
- Helen L. Wu
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Whitney C. Weber
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Courtney M. Waytashek
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Carla D. Boyle
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Jason S. Reed
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Katherine B. Bateman
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Hannah K. Fisher
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Yan Chen
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Kimberly Armantrout
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Tonya Swanson
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Christine Shriver-Munsch
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Mina Northrup
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Miranda Fischer
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Sreya Biswas
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - John Templon
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Angela Panoskaltsis-Mortari
- Division of Blood and Marrow Transplantation, Department of Pediatrics; University of Minnesota; Minneapolis, Minnesota, United States of America
| | - Benjamin J. Burwitz
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Amanda L. Johnson
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Lois Colgin
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Anne D. Lewis
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Jeremy V. Smedley
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Michael K. Axthelm
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Rebecca Skalsky
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Gabrielle Meyers
- Blood and Marrow Transplant Program, Knight Cancer Institute; Oregon Health & Science University; Portland, Oregon, United States of America
| | - Richard T. Maziarz
- Blood and Marrow Transplant Program, Knight Cancer Institute; Oregon Health & Science University; Portland, Oregon, United States of America
| | - Erik Mittra
- Division of Nuclear Medicine and Molecular Imaging; Oregon Health & Science University; Portland, Oregon, United States of America
| | - Melissa Berg
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Jeffrey J. Stanton
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
| | - Jonah B. Sacha
- Oregon National Primate Research Center; Oregon Health & Science University; Beaverton, Oregon, United States of America
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Robinson WH, Younis S, Love ZZ, Steinman L, Lanz TV. Epstein-Barr virus as a potentiator of autoimmune diseases. Nat Rev Rheumatol 2024; 20:729-740. [PMID: 39390260 DOI: 10.1038/s41584-024-01167-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/12/2024]
Abstract
The Epstein-Barr virus (EBV) is epidemiologically associated with development of autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. Although there is well-established evidence for this association, the underlying mechanistic basis remains incompletely defined. In this Review, we discuss the role of EBV infection as a potentiator of autoimmune rheumatic diseases. We review the EBV life cycle, viral transcription programmes, serological profiles and lytic reactivation. We discuss the epidemiological and mechanistic associations of EBV with systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. We describe the potential mechanisms by which EBV might promote autoimmunity, including EBV nuclear antigen 1-mediated molecular mimicry of human autoantigens; EBV-mediated B cell reprogramming, including EBV nuclear antigen 2-mediated dysregulation of autoimmune susceptibility genes; EBV and host genetic factors, including the potential for autoimmunity-promoting strains of EBV; EBV immune evasion and insufficient host responses to control infection; lytic reactivation; and other mechanisms. Finally, we discuss the therapeutic implications and potential therapeutic approaches to targeting EBV for the treatment of autoimmune disease.
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Affiliation(s)
- William H Robinson
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
- VA Palo Alto Health Care System, Palo Alto, CA, USA.
| | - Shady Younis
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Zelda Z Love
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Lawrence Steinman
- Department of Neurology and Neurological Sciences and Paediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Tobias V Lanz
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
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3
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Furlano PL, Böhmig GA, Puchhammer-Stöckl E, Vietzen H. Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation. Transplantation 2024; 108:1867-1881. [PMID: 39166902 DOI: 10.1097/tp.0000000000004919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.
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Affiliation(s)
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
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Law N, Logan C, Taplitz R. EBV Reactivation and Disease in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients and Its Impact on HSCT Outcomes. Viruses 2024; 16:1294. [PMID: 39205268 PMCID: PMC11359191 DOI: 10.3390/v16081294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/02/2024] [Accepted: 08/10/2024] [Indexed: 09/04/2024] Open
Abstract
The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.
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Affiliation(s)
- Nancy Law
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, La Jolla, CA 92093, USA
| | - Cathy Logan
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, La Jolla, CA 92093, USA
| | - Randy Taplitz
- Division of Infectious Diseases, Department of Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA;
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Ghanbari Sevari F, Mehdizadeh A, Abbasi K, Hejazian SS, Raisii M. Cytokine-induced killer cells: new insights for therapy of hematologic malignancies. Stem Cell Res Ther 2024; 15:254. [PMID: 39135188 PMCID: PMC11321231 DOI: 10.1186/s13287-024-03869-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 07/30/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Cytokine-induced killer (CIK) cells are a novel subgroup of immune effectors, classified as one of the modified T cell-mediated arms for immunotherapy. These cells exert MHC-unrestricted cytotoxicity against both hematological and solid malignancies with low incidence of treatment-related severe complications. This study reviews the application of CIK cells in treating cases with hematologic malignancies. MAIN BODY CIK cells consist of CD3+/CD56+ natural killer (NK) T cells, CD3-/CD56+ NK cells, and CD3+/CD56- cytotoxic T cells. In this regard, the CD3+/CD56+ NK T cells are the primary effectors. Compared with the previously reported antitumor immune cells, CIK cells are characterized by improved in vitro proliferation and amplification, enhanced migration and invasive capacity to tumor region, more significant antitumor activity, and a broader antitumor spectrum. CIK cells can also induce death in tumor cells via numerous pathways and mechanisms. Hence, CIKs-based therapy has been used in various clinical trials and has shown efficacy with a very low graft versus host disease (GVHD) against several cancers, such as hematologic malignancies, even in relapsing cases, or cases not responding to other therapies. Despite the high content of T cells, CIK cells induce low alloreactivity and, thus, pose a restricted threat of GVHD induction even in MHC-mismatched transplantation cases. Phase 1 and 2 clinical trials of CIK cell therapy have also highlighted satisfactory therapeutic advantages against hematologic cancers, indicating the safety of CIK cells even in haploidentical transplantation settings. CONCLUSION CIK cells have shown promising results in the treatment of hematologic malignancies, especially in combination with other antitumor strategies. However, the existing controversies in achieving desired clinical responses underscore the importance of future studies.
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Affiliation(s)
- Faezeh Ghanbari Sevari
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khadijeh Abbasi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyed Sina Hejazian
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mortaza Raisii
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Lee C, Lim Y, Saintine D, Babady NE. Analytical and clinical evaluation of the cobas Epstein-Barr virus test at a tertiary care cancer hospital. J Clin Virol 2024; 173:105680. [PMID: 38728796 PMCID: PMC11938105 DOI: 10.1016/j.jcv.2024.105680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/18/2024] [Accepted: 04/28/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Epstein-Barr Virus (EBV) viral loads in hematopoietic stem cell transplant (HSCT) recipients are typically monitored using quantitative molecular assays. The Cobas EBV test (Roche Molecular, Pleasanton, CA) has recently been FDA-cleared for the monitoring of EBV viral loads in plasma samples of transplant patients. In this study, we compared the viral loads obtained by a laboratory-developed test (EBV LDT) using Altona Analyte specific reagents (ASR) to those obtained on the Cobas EBV test. METHODS The analytical performance of the assay was established using the EBV verification panel from Exact Diagnostics and the EBV ATCC strain B95-8. The clinical evaluation was performed using 343 plasma samples initially tested on the EBV LDT. RESULTS The analytical sensitivity (<18.8 IU/mL), precision (SD < 0.17 log) and linear range (35.0 IU/mL to 1E + 08 IU/mL) of the Cobas EBV assay established by the manufacturers were confirmed. The strength of the qualitative agreement was substantial between the cobas EBV and the EBV LDT (85.6 %; κ = 0.71) and almost perfect when discordant results were resolved (96.4 %; κ = 0.93). The quantitative agreement was moderate (82.9 %; κ = 0.53) with the viral load obtained on the Cobas EBV test being lower across the linear range of the two tests (mean log difference of 1.0). While the absolute values of the viral loads were markedly different, the overall trends observed in patients with multiple consecutive results were similar between the two tests. CONCLUSIONS The Cobas EBV test provides an accurate and valid, in vitro diagnostic (IVD) option for monitoring of EBV viral loads in transplant patients and should provide an opportunity for increased standardization and commutability of tests results across laboratories.
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Affiliation(s)
- Cindy Lee
- Department of Pathology and Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Younmin Lim
- Department of Pathology and Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Deborah Saintine
- Department of Pathology and Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - N Esther Babady
- Department of Pathology and Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
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7
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Wang XN, Hong J, Xu YG, Zhang P, Li YY, Dou HL, Li HP. Epstein-Barr virus-positive iris diffuse large B-cell lymphoma detected by metagenomic next-generation sequencing. BMC Ophthalmol 2024; 24:99. [PMID: 38438866 PMCID: PMC10913400 DOI: 10.1186/s12886-024-03334-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/31/2024] [Indexed: 03/06/2024] Open
Abstract
PURPOSE Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a relatively rare subtype of DLBCL. Herein, we report a case of a patient with EBV-positive iris DLBCL after undergoing penetrating keratoplasty and discuss its possible pathogenesis. METHODS A 72-year-old male patient presented to our hospital with progressive blurring of vision in the left eye for the past 4 months. Small white nodular lesions were observed on the iris and retinal surface of the left eye, with a white cloud-like opacity in the vitreous cavity. RESULTS The patient was eventually diagnosed with EBV-positive iris DLBCL after undergoing pathological and metagenomic tests. After injecting methotrexate in the left vitreous cavity and administering systemic and local antiviral treatments, the ocular lesions disappeared. CONCLUSION EBV infection, drug immunosuppression, and aging-related immune deterioration may play significant roles in the pathogenesis of EBV-positive iris DLBCL. SYNOPSIS Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a new subtype of DLBCL, which rarely occurs. Herein, we report a case of a patient with EBV-positive iris DLBCL after undergoing penetrating keratoplasty and discuss its possible pathogenesis.
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Affiliation(s)
- Xiao-Na Wang
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China
| | - Jing Hong
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China
| | - Yong-Gen Xu
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China
| | - Pei Zhang
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China
| | - Ying-Yu Li
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China
| | - Hong-Liang Dou
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China.
| | - Hai-Ping Li
- Department of Ophthalmology, Beijing Key Laboratory of Restoration of Damage Ocular Nerve, Peking University Third Hospital, 100191, Beijing, China.
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8
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Socié G, Barba P, Barlev A, Sanz J, García-Cadenas I, Chevallier P, Fagioli F, Guzman-Becerra N, Kumar D, Ljungman P, Pigneux A, Sadetsky N, Yáñez San Segundo L, Shadman M, Storek J, Thirumalai D, Xing B, Mohty M. Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy. Bone Marrow Transplant 2024; 59:52-58. [PMID: 37865719 PMCID: PMC10781634 DOI: 10.1038/s41409-023-02127-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/27/2023] [Accepted: 10/11/2023] [Indexed: 10/23/2023]
Abstract
Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.
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Affiliation(s)
| | - Pere Barba
- Hospital Universitari Vall Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Arie Barlev
- Atara Biotherapeutics, Thousand Oaks, CA, USA.
| | - Jaime Sanz
- Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | | | | | - Franca Fagioli
- Regina Margherita Children's Hospital, AOU Città della Salute e della Scienza, Turin, Italy
- University of Turin, Turin, Italy
| | | | - Deepali Kumar
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Per Ljungman
- Karolinska Institutet Huddinge, Stockholm, Sweden
- Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
| | - Arnaud Pigneux
- CHU Bordeaux, Service d'Hématologie Clinique et de Thérapie Cellulaire, Bordeaux, France
| | | | | | - Mazyar Shadman
- University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Jan Storek
- University of Calgary, Calgary, AB, Canada
| | | | | | - Mohamad Mohty
- Sorbonne University, Saint-Antoine Hospital, Paris, France
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9
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Kinzel M, Kalra A, Tripathi G, Dharmani-Khan P, Khan F, Storek J. Lack of both donor and recipient anti-EBV T cells in EBV seronegative recipients of grafts from seropositive donors. Bone Marrow Transplant 2023; 58:332-333. [PMID: 36450829 DOI: 10.1038/s41409-022-01884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/16/2022] [Accepted: 11/21/2022] [Indexed: 12/03/2022]
Affiliation(s)
- Megan Kinzel
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| | - Amit Kalra
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Gaurav Tripathi
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Poonam Dharmani-Khan
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Alberta Precision Labs, Calgary, AB, Canada
| | - Faisal Khan
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Alberta Precision Labs, Calgary, AB, Canada
| | - Jan Storek
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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10
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Kinzel M, Kalra A, Khanolkar RA, Williamson TS, Li N, Khan F, Puckrin R, Duggan PR, Shafey M, Storek J. Rituximab Toxicity after Preemptive or Therapeutic Administration for Post-Transplant Lymphoproliferative Disorder. Transplant Cell Ther 2023; 29:43.e1-43.e8. [PMID: 36273783 DOI: 10.1016/j.jtct.2022.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
Abstract
Rituximab is commonly used as prevention, preemption, or therapeutically for post-transplant lymphoproliferative disorder (PTLD) after hematopoietic cell transplantation (HCT). Although it is generally assumed that rituximab toxicity (ie, infections resulting from hypogammaglobulinemia and neutropenia) is negligible in relation to mortality due to PTLD, limited evidence supports the validity of this assumption. We sought to determine the impact of rituximab on immunoglobulin levels, neutrophil count, infection density, and mortality outcomes. This study retrospectively analyzed 349 HCT recipients, 289 of whom did not receive rituximab and 60 of whom received rituximab preemptively or therapeutically at a median of 55 days post-transplantation. IgM, IgG, and IgA levels at 6 months and 12 months post-transplantation were lower in patients who received rituximab compared with those who did not (significant at P < .05 for IgM and IgA at 6 months and for IgM and IgG at 12 months). Rituximab recipients also had a higher incidence of severe neutropenia (<.5/nl) between 3 and 24 months (subhazard ratio [SHR], 2.3; P = .020). Regarding non-Epstein-Barr viral infections/PTLD, the rituximab group had a higher infection density between 3 and 24 months compared with the no-rituximab group (3.8 versus 1.6 infections per 365 days at risk; incidence rate ratio, 2.2; P < .001). The rituximab group also had a higher incidence of fatal infections (SHR, 3.1; P = .026), higher nonrelapse mortality (SHR, 2.4; P = .006), and higher overall mortality (hazard ratio, 1.7; P = .033). There were no significant between-group differences in the incidence of clinically significant graft-versus-host disease, graft failure, or relapse. Based on this study, rituximab given for PTLD is associated with substantial morbidity and mortality. Whether the benefit of preemptive rituximab outweighs the risk remains to be determined. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Affiliation(s)
- Megan Kinzel
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - Amit Kalra
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Rutvij A Khanolkar
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tyler S Williamson
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Na Li
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Faisal Khan
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Precision Labs, Calgary, Alberta, Canada
| | - Robert Puckrin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Precision Labs, Calgary, Alberta, Canada
| | - Peter R Duggan
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Precision Labs, Calgary, Alberta, Canada
| | - Mona Shafey
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Precision Labs, Calgary, Alberta, Canada
| | - Jan Storek
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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11
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Markouli M, Ullah F, Omar N, Apostolopoulou A, Dhillon P, Diamantopoulos P, Dower J, Gurnari C, Ahmed S, Dima D. Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder. Cancers (Basel) 2022; 14:cancers14235949. [PMID: 36497432 PMCID: PMC9740763 DOI: 10.3390/cancers14235949] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.
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Affiliation(s)
- Mariam Markouli
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Anna Apostolopoulou
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Puneet Dhillon
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Panagiotis Diamantopoulos
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Joshua Dower
- Department of Hematology and Medical Oncology, Tufts Medical Center, Boston, MA 02111, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Sairah Ahmed
- Department of Lymphoma-Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
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12
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Zhou X, Lu X, He J, Xu Z, Li Q, Ye P, Zhong Z, Shi W, Yan H, You Y, Hu Y, Wang H. Clinical value of plasma and peripheral blood mononuclear cells Epstein–Barr Virus DNA dynamics on prognosis of allogeneic stem cell transplantation. Front Cell Infect Microbiol 2022; 12:980113. [PMID: 36189344 PMCID: PMC9524571 DOI: 10.3389/fcimb.2022.980113] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
The application of intracellular and extracellular Epstein–Barr virus (EBV) DNA in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been poorly characterized. We conducted a combined prospective-retrospective study of 300 patients who underwent allo-HSCT between 2016 to 2019 in our center and monitored for EBV DNA within the first year after HSCT. Combining the optimal cut-off value of EBV DNA load (7.3×104 copies/106 cells) in peripheral blood mononuclear cells (PBMCs) and qualitative detection in plasma (400 copies/mL) allowed for the better differentiation of EBV-related posttransplant lymphoproliferative disorders (EBV-PTLD), with increased sensitivity (100%) and specificity (86%), and provided the effective risk stratification of EBV DNA level according to their impact on transplant outcomes. By multivariate analysis, patients with intermediate-level of EBV DNA load (low EBV DNA load in PBMCs or high load in PBMCs but negative in plasma) was associated with superior overall survival (HR 1.92, 95% CI 1.03-3.57, p=0.039) and lower transplant-related mortality (HR 3.35, 95% CI 1.31-8.58, p=0.012) compared to those with high-level (high load in PBMCs and positive in plasma). Notably, high EBV-level group had poor reconstitution of CD4+ and CD8+T cells, and both low and high EBV-level groups showed abnormally increase in IL-10 level within one year. Additionally, patients with peak EBV DNA load in PBMCs during 3-12 months had a higher incidence of chronic graft versus host disease (GVHD) than those within 3 months post transplantation (17.4% vs 13.7%, p=0.029). Collectively, EBV DNA in PBMCs can synergistically predict the risk of EBV-PTLD and GVHD. The intermediate-level of EBV DNA presented in plasma and PBMCs might contribute to a better reconstitution of T cells associated with favorable prognosis of allo-HSCT.
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Affiliation(s)
- Xi Zhou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Lu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing He
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziwei Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pian Ye
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaodong Zhong
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Shi
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Yan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong You
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huafang Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Huafang Wang,
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13
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Epstein-Barr virus-associated posttransplant lymphoproliferative disorders: new insights in pathogenesis, classification and treatment. Curr Opin Oncol 2022; 34:413-421. [PMID: 35900750 DOI: 10.1097/cco.0000000000000885] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following transplantation from an allogeneic donor. Epstein-Barr Virus (EBV) is involved in a substantial number of cases. In this review, we aim to summarize recent knowledge on pathogenesis, classification and treatment of EBV + PTLD. RECENT FINDINGS New insights in the complex oncogenic properties of EBV antigens noncoding Ribonucleic acids (RNAs), especially EBV MicroRNA (miRNAs), have increased our knowledge of the pathogenesis of EBV + PTLD. In addition the potential influence of EBV on the tumor microenvironment is becoming clearer, paving the way for new types of immunotherapy. Currently PTLD is classified according to the World Health Organization classification together with other lymphoproliferative disorders, based on the specific immunosuppression. However, a new framework integrating all types of lymphoproliferative disorders in all different settings of immune deficiency and dysregulation is needed. Although treatment of EBV + and EBV - PTLD was largely similar in the past, EBV-directed therapies are currently increasingly used. SUMMARY The use of EBV-directed therapies and new agents, based on better understanding of pathogenesis and classification of PTLD, will change the treatment landscape of EBV + PTLD in the next era.
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14
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Third-party CMV- and EBV-specific T cells for first viral reactivation after allogeneic stem cell transplant. Blood Adv 2022; 6:4949-4966. [PMID: 35819448 PMCID: PMC9631614 DOI: 10.1182/bloodadvances.2022007103] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/01/2022] [Indexed: 11/20/2022] Open
Abstract
Early use of third-party virus-specific T-cells is safe and leads to high rates of viral control and excellent outcomes in HSCT. Virological clearance is associated with recovery of virus-specific immunity, in particular CD8+ effector memory T-cells. Virus-specific T-cells (VSTs) from third-party donors mediate short- and long-term antiviral effects in allogeneic hematopoietic stem cell transplant (HSCT) recipients with relapsed or refractory viral infections. We investigated early administration of third-party VSTs, together with antiviral therapy in patients requiring treatment for first cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Thirty HSCT patients were treated with 1 to 4 VST infusions (2 × 107 cells/m2; CMV n=27, EBV n=3) at a median of 4 days after initiation of antiviral treatment. The overall viral response rate was 100%, with a complete response (CR) rate of 94%. Of the 28 patients who achieved a CR, 23 remained virus PCR negative (n=9) or below quantitation limit (n=14) for the duration of follow-up. Four patients had brief episodes of quantifiable reactivation not requiring additional therapy, and one required a second infusion after initial CR, remaining PCR negative thereafter. All 3 patients treated for EBV post-transplant lymphoproliferative disorder achieved sustained CR. Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively. There were no serious infusion-related adverse events. VST infusion was associated with rapid recovery of CD8+CD45RA−CD62L− and a slower recovery of CD4+CD45RA−CD62L− effector memory T-cells; CMV-specific T-cells comprised up to 13% of CD8+ cells. At 1 year post-transplant, non-relapse mortality was 10%, cumulative incidence of relapse was 7%, overall survival was 88% and 25 of 27 patients had ECOG status of 0 or 1. Early administration of third-party VSTs in conjunction with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes. Registered on Australian New Zealand Clinical Trials Registry as #ACTRN12618000343202.
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15
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Worku D, Chang LH, Blyth I. An Unusual Presentation of Glandular Fever. Case Rep Infect Dis 2022; 2022:5981070. [PMID: 35340747 PMCID: PMC8956444 DOI: 10.1155/2022/5981070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/10/2022] [Accepted: 03/02/2022] [Indexed: 11/24/2022] Open
Abstract
Epstein-Barr virus (EBV) is an ubiquitous DNA herpesvirus with >90% of adults >40 years of age showing a serological response. While in their youth, primary EBV infection may pass unnoticed, young adults have a high incidence of infectious mononucleosis (IM). This is characterized by a triad of pharyngitis, cervical lymphadenopathy, and fever because of a self-limiting lymphoproliferative disease. Common complications include but are not limited to hepatitis, splenomegaly, encephalitis, and haemophagocytic lymphohistiocytosis (HLH) with evidence that Caucasian males and smokers are more likely to suffer severe disease. Here we present a 21-year-old male who presented with a 2-week history of fever, dry cough, and a 4-week history of pharyngitis. He had no exposure to unwell contacts and denied any new sexual partners. Examination revealed general pallor with tender bilateral cervical lymphadenopathy and pharyngeal erythema. Admission bloods revealed pancytopenia (WCC 1.5 × 109/L, Plt 84 × 109/L, and Hb 82 g/L) with normal reticulocyte count and raised mean corpuscular volume (114 fL). Serum vitamin B12 and folate were low with serum ferritin raised (1027 µg/L) suggesting a proinflammatory state. Admission liver function tests, coeliac serology, autoimmune panel (ANA, ANCA, and anti-dsDNA), hepatitic (hepatitis A, B, and E), human immunodeficiency virus (HIV), toxoplasmosis, parvovirus, and CMV serology were normal. The monospot test on day 1 of the presentation was negative. Ultrasound (US) of the abdomen on day 3 of the presentation revealed isolated splenomegaly (16.8 cm). Day 4 EBV serology (VCA IgM, VCA IgG, and EBNA IgG) was negative as such haematological investigations including JAK2, serum free light chains, and BCR-ABL were undertaken alongside cervical lymph node core biopsy. Repeat Monospot testing on day 7 came back positive. Repeat EBV serology now showed equivocal EBV VCA IgG (0.77 OD) and positive VCA IgM (9.04 OD) with concurrent new hepatitis. Histopathology of the core biopsy revealed Sternberg-reed cells and a mixed immunoblastic reaction in keeping with resolving IM. This case highlights the need for physicians to have a strong clinical suspicion of IM and understand the multiple ways in which IM may be present as well as the time lag to positivity in serological testing.
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Affiliation(s)
- Dominic Worku
- Infectious Diseases, Morriston Hospital, Swansea, UK
- Public Health Wales, Cardiff, UK
| | - Li Hui Chang
- Gastroenterology, Morriston Hospital, Swansea, UK
| | - Ian Blyth
- Infectious Diseases, Morriston Hospital, Swansea, UK
- Public Health Wales, Cardiff, UK
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16
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Blinatumomab Induces Complete Response in Refractory PTLD after Hematopoietic Cell Transplantation. Blood Adv 2022; 6:3058-3061. [PMID: 35078207 PMCID: PMC9131924 DOI: 10.1182/bloodadvances.2021006535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/10/2022] [Indexed: 11/20/2022] Open
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17
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Guo Y, Zhou SH, Cao ZZ, Bao YY, Shen LF, Yao HT. Epstein-Barr Virus-Positive Langerhans Cell Sarcoma: Is There a Link? A Case Report. Front Oncol 2022; 11:769310. [PMID: 35117987 PMCID: PMC8803631 DOI: 10.3389/fonc.2021.769310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Langerhans cell sarcoma (LCS) is an extremely rare, malignant neoplasm that originates from Langerhans cells (LCs). Fewer than 70 cases have been reported in the English-language literature. LCS typically involves multiple organs, including the skin, lymph nodes, lungs, bone, bone marrow, liver, spleen, and soft tissues. Several etiological factors for LCS have been proposed, including immunosuppression, virus infection, and prior hematological disease. We report a rare case of LCS with Epstein-Barr virus (EBV) infection; bilateral cervical giant cysts were the initial manifestation. To our knowledge, this is the first report of LCS with EBV infection. The case information was complete, and the relevant literature was reviewed to gain insight into LCS. The case raises new questions on the oncogenic character of EBV.
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Affiliation(s)
- Yu Guo
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shui-Hong Zhou
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zai-Zai Cao
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yang-Yang Bao
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Li-Fang Shen
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hong-Tian Yao
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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18
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Munting A, Manuel O. Viral infections in lung transplantation. J Thorac Dis 2022; 13:6673-6694. [PMID: 34992844 PMCID: PMC8662465 DOI: 10.21037/jtd-2021-24] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Viral infections account for up to 30% of all infectious complications in lung transplant recipients, remaining a significant cause of morbidity and even mortality. Impact of viral infections is not only due to the direct effects of viral replication, but also to immunologically-mediated lung injury that may lead to acute rejection and chronic lung allograft dysfunction. This has particularly been seen in infections caused by herpesviruses and respiratory viruses. The implementation of universal preventive measures against cytomegalovirus (CMV) and influenza (by means of antiviral prophylaxis and vaccination, respectively) and administration of early antiviral treatment have reduced the burden of these diseases and potentially their role in affecting allograft outcomes. New antivirals against CMV for prophylaxis and for treatment of antiviral-resistant CMV infection are currently being evaluated in transplant recipients, and may continue to improve the management of CMV in lung transplant recipients. However, new therapeutic and preventive strategies are highly needed for other viruses such as respiratory syncytial virus (RSV) or parainfluenza virus (PIV), including new antivirals and vaccines. This is particularly important in the advent of the COVID-19 pandemic, for which several unanswered questions remain, in particular on the best antiviral and immunomodulatory regimen for decreasing mortality specifically in lung transplant recipients. In conclusion, the appropriate management of viral complications after transplantation remain an essential step to continue improving survival and quality of life of lung transplant recipients.
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Affiliation(s)
- Aline Munting
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland.,Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
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19
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Enok Bonong PR, Buteau C, Duval M, Lacroix J, Laporte L, Tucci M, Robitaille N, Spinella PC, Cuvelier GDE, Lewis V, Vercauteren S, Alfieri C, Trottier H. Risk factors for post-transplant Epstein-Barr virus events in pediatric recipients of hematopoietic stem cell transplants. Pediatr Transplant 2021; 25:e14052. [PMID: 34076939 DOI: 10.1111/petr.14052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients. METHODS We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice-Williams-Petersen models were used to analyze risk factors for post-transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV-VL), and preemptive use of rituximab, an effective therapy against PTLD. RESULTS Females were at higher risk for increasing EBV-VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33-6.03]) and rituximab use (HR = 3.08 [1.14-8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74-1.99]) and recurrence risks (HR=1.05 [0.70-1.58]) compared to males. EBV DNAemia was associated with recipient pre-transplant EBV seropositivity (HR = 2.47 [1.17-5.21]) and with graft from an EBV-positive donor (HR = 3.53 [1.95-6.38]). Anti-thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47-19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03-0.63]). CONCLUSION This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV-VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV-VL and the use of rituximab) include female sex and ATG use.
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Affiliation(s)
- Pascal R Enok Bonong
- Department of Social and Preventive Medicine, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Chantal Buteau
- Division of Infectious Diseases, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Michel Duval
- Division of Hematology-Oncology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Jacques Lacroix
- Division of Pediatric Intensive Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Louise Laporte
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada
| | - Marisa Tucci
- Division of Pediatric Intensive Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Nancy Robitaille
- Division of Hematology-Oncology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Héma-Québec, Montreal, QC, Canada
| | - Philip C Spinella
- St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplant, Department of Pediatric Hematology-Oncology-BMT, Department of Pediatrics and Child Health, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Victor Lewis
- Department of Pediatrics and Department of Oncology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada
| | - Suzanne Vercauteren
- Department of Pathology and Laboratory Medicine, BC Children's Hospital, University of British Colombia, Vancouver, BC, Canada
| | - Caroline Alfieri
- Department of Microbiology, Infectiology and Immunology, Centre de recherche du CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Helen Trottier
- Department of Social and Preventive Medicine, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
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20
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Kinzel M, Dowhan M, Kalra A, Williamson TS, Dabas R, Jamani K, Chaudhry A, Shafey M, Jimenez-Zepeda V, Duggan P, Daly A, Dharmani-Khan P, Khan F, Storek J. Risk Factors for the Incidence of and the Mortality due to Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation. Transplant Cell Ther 2021; 28:53.e1-53.e10. [PMID: 34607072 DOI: 10.1016/j.jtct.2021.09.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/17/2021] [Accepted: 09/26/2021] [Indexed: 11/17/2022]
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a potentially serious complication that occurs following hematopoietic cell transplantation (HCT), in which B cells transformed by Epstein-Barr virus (EBV) proliferate uncontrollably. It is unknown whether risk factors for the incidence of PTLD are identical to those for mortality due to PTLD, a clinically more important outcome. We sought to determine the risk factors influencing the incidence of PTLD and those influencing mortality due to PTLD in a cohort of 1184 allogenic HCT recipients. All patients were predisposed to PTLD, because their graft-versus-host disease (GVHD) prophylaxis included antithymocyte globulin. The overall PTLD incidence was 9.0%, and mortality due to PTLD was 1.1%. In multivariate analysis, risk factors for PTLD incidence include donor+/recipient- (D+/R-) EBV serostatus (subhazard ratio [SHR], 3.3; P = .002), use of a donor other than an HLA-matched sibling donor (non-MSD) (SHR, 1.7; P = .029), receipt of total body irradiation (TBI; SHR, 3.3; P = .008), and the absence of GVHD (SHR, 3.3; P < .001). The sole risk factor for mortality due to PTLD among all patients was D+/R- serostatus (SHR, 5.8; P = .022). Risk factors for mortality due to PTLD among patients who developed PTLD were use of a bone marrow (BM) graft (compared with peripheral blood stem cells [PBSCs]; SHR, 22.8; P < .001) and extralymphatic involvement (SHR, 14.6; P < .001). Interestingly, whereas the absence of GVHD was a risk factor for PTLD incidence, there was a trend toward the presence of GVHD as a risk factor for PTLD mortality (SHR, 4.2; P = .093). Likewise, whereas use of a BM graft was a risk factor for PTLD mortality, there was a trend toward use of a PBSC graft as a risk factor for PTLD incidence (SHR, 0.44; P = .179). Some risk factors for the incidence of PTLD are identical to the risk factors for mortality due to PTLD (ie, D+/R- serostatus), whereas other risk factors are disparate. Specifically, TBI was identified as a risk factor for PTLD incidence but not for PTLD mortality; the absence of GVHD was a risk factor for PTLD incidence, whereas the presence of GVHD was possibly a risk factor for PTLD mortality; and receipt of a PBSC graft was possibly a risk factor for PTLD incidence, whereas receipt of a BM graft was a risk factor for PTLD mortality.
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Affiliation(s)
- Megan Kinzel
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | | | - Amit Kalra
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tyler S Williamson
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Rosy Dabas
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kareem Jamani
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Ahsan Chaudhry
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Mona Shafey
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Victor Jimenez-Zepeda
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Peter Duggan
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Andrew Daly
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
| | - Poonam Dharmani-Khan
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada; Alberta Precision Laboratories, Calgary, Alberta, Canada
| | - Faisal Khan
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada; Alberta Precision Laboratories, Calgary, Alberta, Canada
| | - Jan Storek
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Calgary, Alberta, Canada
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21
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Lee CC, Hsu TC, Kuo CC, Liu MA, Abdelfattah AM, Chang CN, Yao M, Li CC, Wu KH, Chen TC, Gau JP, Wang PN, Liu YC, Chiou LW, Lee MY, Li SS, Chao TY, Jou ST, Chang HH. Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database. Oncologist 2021; 26:e2034-e2041. [PMID: 34506688 DOI: 10.1002/onco.13969] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. MATERIALS AND METHODS Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. RESULTS We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). CONCLUSION Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. IMPLICATIONS FOR PRACTICE This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.
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Affiliation(s)
- Chien-Chang Lee
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Center of Intelligent Healthcare, National Taiwan University Hospital, Taipei, Taiwan
| | - Tzu-Chun Hsu
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Chih Kuo
- Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Michael A Liu
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Ahmed M Abdelfattah
- Information Services Department, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Chia-Na Chang
- Department of Radiation Oncology, Taipei Municipal Wanfang Hospital, Taipei, Taiwan
| | - Ming Yao
- Division of Hematology and Oncology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Cheng Li
- Division of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, Taiwan
| | - Kang-Hsi Wu
- Division of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, Taiwan
| | - Tsung-Chih Chen
- Division of Hematology and Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jyh-Pyng Gau
- Division of Hematology and Oncology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Po-Nan Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Medical Foundation, Linkou Branch, Taoyuan, Taiwan
| | - Yi-Chang Liu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lun-Wei Chiou
- Department of Hematology and Medical Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan
| | - Ming-Yang Lee
- Division of Hematology and Oncology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Sin-Syue Li
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Tsu-Yi Chao
- Division of Hemato-Oncology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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22
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Yang X, Li D, Xie Y. Anti-Thymocyte Globulin Prophylaxis in Patients With Hematological Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: An Updated Meta-Analysis. Front Oncol 2021; 11:717678. [PMID: 34490116 PMCID: PMC8417733 DOI: 10.3389/fonc.2021.717678] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/29/2021] [Indexed: 11/13/2022] Open
Abstract
Background Anti-thymocyte globulin (ATG) prophylaxis reduces graft-versus-host disease (GVHD) incidence. This meta-analysis aimed to explore the long-term efficacy of ATG and the influencing factors in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods PubMed, Embase, and Cochrane databases were searched for the relevant studies published up to August 2020. Data from randomized controlled trials (RCTs) on ATG prophylaxis for GVHD prevention in allo-HSCT patients were extracted. Results A total of eight relevant RCTs (1,348 patients) were included. ATG significantly reduced the incidence of grade III–IV aGVHD (P = 0.001) and cGVHD (P < 0.001). ATG significantly improved the GVHD relapse-free survival (GRFS) (P < 0.001). The immunosuppressive regimen (number and dose of immunosuppressants) was significantly reduced when using ATG (P = 0.005). Epstein-Barr virus (EBV) reactivation was high in patients receiving ATG (P = 0.003). No significant differences were detected in relapses, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) between the ATG and no ATG groups. Subgroup analyses revealed that the donor type and ATG formulation might be the possible sources of heterogeneity among the included studies. Meta-regression analysis showed that the cumulative dose of ATG did not affect GVHD, OS, relapse, RFS, and NRM. Conclusion Although ATG had no significant effect on relapse, RFS, and NRM, it significantly reduced the occurrence and severity of GVHD, improved the GRFS, and reduced the number and dose of immunosuppressants in patients undergoing allo-HSCT.
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Affiliation(s)
- Xue Yang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Dongjun Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Yao Xie
- Department of Obstetrics and Gynaecology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
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23
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Marzolini MAV, Wilson AJ, Sanchez E, Carpenter B, Chakraverty R, Hough R, Kottaridis P, Morris EC, Thomson KJ, Peggs KS. Natural History of Epstein-Barr Virus Replication and Viral Load Dynamics after Alemtuzumab-Based Allogeneic Stem Cell Transplantation. Transplant Cell Ther 2021; 27:682.e1-682.e12. [PMID: 33962069 DOI: 10.1016/j.jtct.2021.04.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 04/02/2021] [Accepted: 04/25/2021] [Indexed: 01/27/2023]
Abstract
Epstein-Barr virus (EBV) load monitoring after allogeneic hematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and often serves as a trigger for preemptive therapies aimed at reducing EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene based solely on viral load. This affords an opportunity to study the natural history of EBV replication and to assess whether our strategy reduces overtreatment without compromising outcomes. The objectives of the present study were to assess the natural history of untreated EBV replication in patients who underwent an alemtuzumab-based allogeneic HSCT and to examine whether our clinical strategy reduced overtreatment without compromising patient outcomes. In this retrospective single-center observational study of 515 consecutive patients (age ≥18 years) undergoing T cell-depleted allogeneic HSCT incorporating alemtuzumab, patients underwent surveillance monitoring for EBV by quantitative PCR in the peripheral blood at least weekly up to 100 days post-transplantation and longer if they remained on immunosuppressive therapy. The cumulative incidence of EBV detection and EBV-related disease were assessed. Among the 515 patients, 192 had EBV DNA detectable on ≥1 occasion, with a cumulative incidence of 35.8% (31.8% to 40.4%), although this remained below the limit of quantification in 93 patients. The median time to first detection was 89.5 days (range, 0 to 2254 days). The incidence was higher in recipients of sibling donor transplants (45.4% versus 30%; P = .00021) compared with recipients of unrelated donor transplants. Twenty patients developed EBV-related disease (cumulative incidence, 3.9%). Two patients had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died from post-transplantation lymphoproliferative disorder, all of whom had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1% to 72.7%). The cumulative incidence of EBV-related disease in our study (3.9%) is comparable to that reported in other studies incorporating alemtuzumab, and our clinical strategy reduced overtreatment in this patient population. PCR-based surveillance strategies have limitations, as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value, which may influence the potential choice of a threshold for preemptive intervention. We conclude that it remains unclear whether treatment based on a rising EBV viral load alone provides superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.
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Affiliation(s)
- Maria A V Marzolini
- Department of Haematology, UCL Cancer Institute, University College London, London, Uinted Kingdom; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
| | - Andrew J Wilson
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Emilie Sanchez
- Department of Virology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Ben Carpenter
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Ronjon Chakraverty
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Rachael Hough
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Panos Kottaridis
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Emma C Morris
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Kirsty J Thomson
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Karl S Peggs
- Department of Haematology, UCL Cancer Institute, University College London, London, Uinted Kingdom; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
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24
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Dutta R, Miao SY, Phan P, Fernandez-Pol S, Shiraz P, Ho D, Mannis GN, Zhang TY. Epstein-Barr virus-positive lymphoproliferative disorder manifesting as pulmonary disease in a patient with acute myeloid leukemia: a case report. J Med Case Rep 2021; 15:170. [PMID: 33773605 PMCID: PMC8005240 DOI: 10.1186/s13256-021-02744-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/15/2021] [Indexed: 11/21/2022] Open
Abstract
Background Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5 months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients. Case presentation Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein–Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient’s condition rapidly deteriorated, and he passed away prior to treatment initiation. Conclusions To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings.
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Affiliation(s)
- Ritika Dutta
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.,Stanford University School of Medicine, Stanford, CA, USA
| | - Susanna Y Miao
- Department of Medicine, Stanford University, Stanford, CA, USA
| | - Paul Phan
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | | | - Parveen Shiraz
- Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA, USA
| | - Dora Ho
- Department of Medicine, Division of Infectious Diseases & Geographic Medicine, Stanford University, Stanford, CA, USA
| | - Gabriel N Mannis
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Tian Y Zhang
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. .,Stanford University School of Medicine, Stanford, CA, USA.
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25
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Enok Bonong PR, Zahreddine M, Buteau C, Duval M, Laporte L, Lacroix J, Alfieri C, Trottier H. Factors Associated with Post-Transplant Active Epstein-Barr Virus Infection and Lymphoproliferative Disease in Hematopoietic Stem Cell Transplant Recipients: A Systematic Review and Meta-Analysis. Vaccines (Basel) 2021; 9:288. [PMID: 33808928 PMCID: PMC8003684 DOI: 10.3390/vaccines9030288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/15/2021] [Accepted: 03/15/2021] [Indexed: 12/29/2022] Open
Abstract
This systematic review was undertaken to identify risk factors associated with post-transplant Epstein-Barr virus (EBV) active infection and post-transplant lymphoproliferative disease (PTLD) in pediatric and adult recipients of hematopoietic stem cell transplants (HSCT). A literature search was conducted in PubMed and EMBASE to identify studies published until 30 June 2020. Descriptive information was extracted for each individual study, and data were compiled for individual risk factors, including, when possible, relative risks with 95% confidence intervals and/or p-values. Meta-analyses were planned when possible. The methodological quality and potential for bias of included studies were also evaluated. Of the 3362 titles retrieved, 77 were included (62 for EBV infection and 22 for PTLD). The overall quality of the studies was strong. Several risk factors were explored in these studies, but few statistically significant associations were identified. The use of anti-thymocyte globulin (ATG) was identified as the most important risk factor positively associated with post-transplant active EBV infection and with PTLD. The pooled relative risks obtained using the random-effect model were 5.26 (95% CI: 2.92-9.45) and 4.17 (95% CI: 2.61-6.68) for the association between ATG and post-transplant EBV infection and PTLD, respectively. Other risk factors for EBV and PTLD were found in the included studies, such as graft-versus-host disease, type of conditioning regimen or type of donor, but results are conflicting. In conclusion, the results of this systematic review indicate that ATG increases the risk of EBV infection and PTLD, but the link with all other factors is either nonexistent or much less convincing.
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Affiliation(s)
- Pascal Roland Enok Bonong
- Department of Social and Preventive Medicine, Université de Montréal, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada; (P.R.E.B.); (M.Z.)
| | - Monica Zahreddine
- Department of Social and Preventive Medicine, Université de Montréal, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada; (P.R.E.B.); (M.Z.)
| | - Chantal Buteau
- Department of Pediatrics, Division of Infectious Diseases, CHU Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada;
| | - Michel Duval
- Department of Pediatrics, Division of Hematology-Oncology, CHU Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada;
| | - Louise Laporte
- Research Center of CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada;
| | - Jacques Lacroix
- Department of Pediatrics, Division of Pediatric Intensive Care Medicine, CHU Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada;
| | - Caroline Alfieri
- Departement of Microbiology, Infectiology and Immunology, Université de Montréal, CHU Sainte-Justine Research Center, Montréal, QC H3T 1C5, Canada;
| | - Helen Trottier
- Department of Social and Preventive Medicine, Université de Montréal, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada; (P.R.E.B.); (M.Z.)
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26
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EBV-PTLD in a patient after haploidentical stem-cell transplantation with post-transplant cyclophosphamide. Int J Hematol 2021; 114:136-140. [PMID: 33675520 DOI: 10.1007/s12185-021-03111-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/12/2021] [Accepted: 02/18/2021] [Indexed: 12/18/2022]
Abstract
Here, we describe the case of a male patient with Epstein-Barr virus post-transplantation lymphoproliferative disorder (EBV-PTLD), which developed 18 months after a haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and the administration of post-transplant cyclophosphamide (PTCy). Of note, no anti-thymoglobulin was used in the entire clinical course. Prior to the onset of EBV-PTLD, the patient had pulmonary chronic graft-versus-host disease and was treated with prednisolone and tacrolimus. After stopping immunosuppressive therapy, he was diagnosed with EBV-positive infectious mononucleosis PTLD, and EBV-associated hemophagocytic syndrome; therefore, dexamethasone and rituximab monotherapies were administered. After four courses of rituximab, EBV-DNA was no longer detected in the peripheral blood, and the patient's laboratory data improved. Overall, this study highlights the need to predict the risk factors associated with the development of EBV-PTLD in transplanted patients after haplo-HSCT with PTCy.
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27
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Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) and its association with Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis: a case report. BMC Neurol 2021; 21:80. [PMID: 33602163 PMCID: PMC7890986 DOI: 10.1186/s12883-021-02110-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/10/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood. CASE PRESENTATION We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients. CONCLUSIONS Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
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28
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Post-transplantation lymphoproliferative disorder after haematopoietic stem cell transplantation. Ann Hematol 2021; 100:865-878. [PMID: 33547921 DOI: 10.1007/s00277-021-04433-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 01/18/2021] [Indexed: 12/19/2022]
Abstract
Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of haematopoietic stem cell transplantation (HSCT), occurring in a setting of immune suppression and dysregulation. The disease is in most cases driven by the reactivation of the Epstein-Barr virus (EBV), which induces B cell proliferation through different pathomechanisms. Beyond EBV, many factors, variably dependent on HSCT-related immunosuppression, contribute to the disease development. PTLDs share several features with primary lymphomas, though clinical manifestations may be different, frequently depending on extranodal involvement. According to the WHO classification, histologic examination is required for diagnosis, allowing also to distinguish among PTLD subtypes. However, in cases of severe and abrupt presentation, a diagnosis based on a combination of imaging studies and EBV-load determination is accepted. Therapies include prophylactic and pre-emptive interventions, aimed at eradicating EBV proliferation before symptoms onset, and targeted treatments. Among them, rituximab has emerged as first-line option, possibly combined with a reduction of immunosuppression, while EBV-specific cytotoxic T lymphocytes are effective and safe alternatives. Though prognosis remains poor, survival has markedly improved following the adoption of the aforementioned treatments. The validation of innovative, combined approaches is the future challenge.
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29
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Silcock R, Mitchell K, Fraser C, Clark J. Epidemiology and outcome for viremia in children undergoing bone marrow transplant: A retrospective cohort study. Transpl Infect Dis 2021; 23:e13580. [PMID: 33533068 DOI: 10.1111/tid.13580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 12/23/2020] [Accepted: 01/10/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Viral infections pose a serious risk for children undergoing hematopoietic stem cell transplant (HSCT). There are few published case series of prevalence, risk factors, and outcomes examining multiple viruses simultaneously, and no pediatric Australasian data published to date. We describe the real-life experience of viremia in pediatric HSCT in a single tertiary center. METHODS All episodes of viremia in children undergoing HSCT between 2000 and 2018 were identified by matching HSCT patients' unique identification numbers with positive blood polymerase chain reaction (PCR) results for human adenovirus (HAdV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus 6 (HHV-6). Paper or electronic charts and electronic pathology results were used to extract the study variables. RESULTS Viremia was detected in 177/445 (39.8%) HSCT episodes, of which 46% were allogeneic and 19% autologous transplants. Viremia was disseminated in 96 (21.6%) episodes, with 80 (18%) having more than one virus. HAdV was detected in 108 (24.3% of total episodes) and frequently in autologous transplants, CMV in 71 (16.0%), EBV in 60 (13.5%), and HHV-6 in 38 (8.5%). Of 174 children, 19 (10.9%) died of a viral-associated cause, with viral mortality highest in CMV (18.3%), lowest in HHV-6 (2.6%) with HAdV and EBV similar (6.6% and 6.7%). Adenoviral (but not other virus) dissemination was significantly associated with lower lymphocyte count at time of first detection. CMV dissemination and death were significantly associated with initial and highest CMV viral loads (copies/mL). CONCLUSION This study presents the first pediatric-specific Australasian data for viremia in HSCT. Findings may help guide clinicians in prophylaxis and treatment decisions.
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Affiliation(s)
- Robyn Silcock
- Queensland Children's Hospital, Brisbane, Qld, Australia.,University of Queensland, Brisbane, Qld, Australia
| | | | - Chris Fraser
- Queensland Children's Hospital, Brisbane, Qld, Australia
| | - Julia Clark
- Queensland Children's Hospital, Brisbane, Qld, Australia.,University of Queensland, Brisbane, Qld, Australia
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30
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Song H, Guja KE, Iagaru A. 18F-FDG PET/CT for Evaluation of Post-Transplant Lymphoproliferative Disorder (PTLD). Semin Nucl Med 2021; 51:392-403. [PMID: 33455722 DOI: 10.1053/j.semnuclmed.2020.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) are a spectrum of heterogeneous lymphoproliferative conditions that are serious and possibly fatal complications after solid organ or allogenic hematopoietic stem cell transplantation. Most PTLD are attributed to Epstein-Barr virus reactivation in B-cells in the setting of immunosuppression after transplantation. Early diagnosis, accurate staging, and timely treatment are of vital importance to reduce morbidity and mortality. Given the often nonspecific clinical presentation and disease heterogeneity of PTLD, tissue biopsy and histopathological analysis are essential to establish diagnosis and most importantly, determine the subtype of PTLD, which guides treatment options. Advanced imaging modalities such as 18F-FDG PET/CT have played an increasingly important role and have shown high sensitivity and specificity in detection, staging, and assessing treatment response in multiple clinical studies over the last two decades. However, larger multicenter prospective validation is still needed to further establish the clinical utility of PET imaging in the management of PTLD. Significantly, new hybrid imaging modalities such as PET/MR may help reduce radiation exposure, which is especially important in pediatric transplant patients.
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Affiliation(s)
- Hong Song
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA
| | - Kip E Guja
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA
| | - Andrei Iagaru
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA.
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Characteristics of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation in patients with chronic active Epstein-Barr virus disease: favorable responses to rituximab. Bone Marrow Transplant 2021; 56:1449-1451. [PMID: 33420394 PMCID: PMC8189911 DOI: 10.1038/s41409-020-01193-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 11/23/2022]
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Wu HL, Weber WC, Shriver-Munsch C, Swanson T, Northrup M, Price H, Armantrout K, Robertson-LeVay M, Reed JS, Bateman KB, Mahyari E, Thomas A, Junell SL, Hobbs TR, Martin LD, MacAllister R, Bimber BN, Slifka MK, Legasse AW, Moats C, Axthelm MK, Smedley J, Lewis AD, Colgin L, Meyers G, Maziarz RT, Burwitz BJ, Stanton JJ, Sacha JB. Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications. Xenotransplantation 2020; 27:e12578. [PMID: 31930750 PMCID: PMC7354885 DOI: 10.1111/xen.12578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/11/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.
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Affiliation(s)
- Helen L. Wu
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Whitney C. Weber
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | | | - Tonya Swanson
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Mina Northrup
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Heidi Price
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Kimberly Armantrout
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | | | - Jason S. Reed
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Katherine B. Bateman
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Eisa Mahyari
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Archana Thomas
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Stephanie L. Junell
- Divison of Medical Physics, Department of Radiation Medicine, Oregon Health & Science University, Portland, OR Vaccine and Gene Therapy Institute, Oregon Health
| | - Theodore R. Hobbs
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Lauren D. Martin
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Rhonda MacAllister
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Benjamin N. Bimber
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Mark K. Slifka
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Alfred W. Legasse
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Cassandra Moats
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Michael K. Axthelm
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Jeremy Smedley
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Anne D. Lewis
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Lois Colgin
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Gabrielle Meyers
- Divison of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Richard T. Maziarz
- Divison of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Benjamin J. Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Jeffrey J. Stanton
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Jonah B. Sacha
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
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Nowak J, Gwozdowicz S, Graczyk-Pol E, Mika-Witkowska R, Rogatko-Koros M, Nestorowicz K, Szlendak U, Malinowska A, Kaczmarek B, Nasilowska-Adamska B, Tormanowska M, Szczurowska N, Szypnicki J, Witkowska A, Lasota M, Malinowska E, Halaburda K. Epstein-Barr virus infections are strongly dependent on activating and inhibitory KIR-HLA pairs after T-cell replate unrelated hematopoietic stem cell transplantation, the principles, and method of pairing analysis. HLA 2020; 94 Suppl 2:40-48. [PMID: 31758851 DOI: 10.1111/tan.13770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 12/26/2022]
Abstract
Viral infections are the main cause of increased morbidity and mortality among recipients in allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells fight virally infected cells provided directional activation of cytotoxicity. In this study, we analyzed the role of receptor-ligand pairs that include inhibitory or activating killer cell immunoglobulin-like receptors (KIRs) with their HLA class I ligands in the course of viral infections. The paper also presents an algorithm that allows performing automated inhibitory (i) KIR:HLA pairing and rechecking in the clinical setting. The obtained results indicate a significant adverse roles of reduced number of iKIR:HLA pairs (40% vs 9%; odds ratio [OR] = 6.67; P = .0057; 95% confidence interval [CI] 1.74-25.62) and the presence of activating KIR:HLA pairs (15% vs 5%, OR = 3.58, P = .028, 95% CI 1.19-10.73) in EBV infections post HSCT.
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Affiliation(s)
- Jacek Nowak
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Sławomir Gwozdowicz
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Elżbieta Graczyk-Pol
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Renata Mika-Witkowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marta Rogatko-Koros
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Klaudia Nestorowicz
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Urszula Szlendak
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Agnieszka Malinowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Beata Kaczmarek
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Barbara Nasilowska-Adamska
- Department of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Magdalena Tormanowska
- Department of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Natalia Szczurowska
- Department of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Jeremi Szypnicki
- Department of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Agnieszka Witkowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marta Lasota
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Ewelina Malinowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Kazimierz Halaburda
- Department of Hematopoietic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
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Luo XY, Mo XD, Xu LP, Zhang XH, Wang Y, Liu KY, Chang YJ, Zhao XY, Huang XJ. A retrospective analysis on anti-CD20 antibody-treated Epstein-Barr virus-related posttransplantation lymphoproliferative disorder following ATG-based haploidentical T-replete hematopoietic stem cell transplantation. Ann Hematol 2020; 99:2649-2657. [PMID: 32206854 DOI: 10.1007/s00277-020-04003-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 03/12/2020] [Indexed: 11/26/2022]
Abstract
Posttransplantation lymphoproliferation disorder (PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). Anti-CD20 antibody is the most widely used antibody to eliminate infected B cells. Few studies have focused on prognostic factors predicting the outcome of EBV (Epstein-Barr virus)-PTLD. We conducted a retrospective analysis of 2571 haplo-HSCTs performed between 2010 and 2017 at the Peking University Institute of Hematology; seventy patients who had been treated with rituximab for PTLD were enrolled. The overall EBV-related PTLD frequency was 3.1%. With a median follow-up time of 365 days (range, 54-2659), the overall survival rate was 51.43% (36/70). The cumulative incidence of EBV-PTLD complete remission with anti-CD20 antibody monotherapy was 68.57% (48/70). EBV-PTLD-related mortality was 11.43% (8/70), while the transplantation-related mortality was 38.57% (27/70). Multivariate analysis showed that a decrease in EBV viral load 1 week after therapy was associated with high response rate of EBV-PTLD (p = 0.007, 0.106 (0.021-0.549)), low PTLD-related mortality (p = 0.010, HR 0.058 (0.007-0.503)), and transplantation-related mortality (p = 0.051, HR 0.441 (0.194-1.003)). For EBV-PTLD patients after haplo-HSCT who received rituximab as first-line therapy, non-decreased EBV viral load 1 week after anti-CD20 therapy could be high risk factor for poor outcomes.
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Affiliation(s)
- Xue-Yi Luo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiao-Dong Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Ying-Jun Chang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiang-Yu Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
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Santos CAQ, Rhee Y, Czapka MT, Kazi AS, Proia LA. Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients. J Clin Med 2020; 9:jcm9030865. [PMID: 32245201 PMCID: PMC7141503 DOI: 10.3390/jcm9030865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/11/2022] Open
Abstract
Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key “safety net” in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible “safety net” for these immunocompromised hosts.
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Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant 2020; 10:29-46. [PMID: 32226769 PMCID: PMC7093305 DOI: 10.5500/wjt.v10.i2.29] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/21/2019] [Accepted: 12/14/2019] [Indexed: 02/05/2023] Open
Abstract
Transplant recipients are vulnerable to a higher risk of malignancy after solid organ transplantation and allogeneic hematopoietic stem-cell transplant. Post-transplant lymphoproliferative disorders (PTLD) include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior. Two main risk factors of PTLD are: Firstly, the cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The latter is a key pathognomonic driver of PTLD evolution. Over the last two decades, a considerable progress has been made in diagnosis and therapy of PTLD. The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy. In this review we shall discuss the prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies of this devastating disorder.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Ihab Sakr Shaheen
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Paediatric Nephrology, Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplant Surgery, Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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37
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Latour S, Fischer A. Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases. Immunol Rev 2020; 291:174-189. [PMID: 31402499 DOI: 10.1111/imr.12791] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 12/13/2022]
Abstract
Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV - notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T- and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions.
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Affiliation(s)
- Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Paris, France.,University Paris Descartes Sorbonne Paris Cité, Imagine Institut, Paris, France
| | - Alain Fischer
- University Paris Descartes Sorbonne Paris Cité, Imagine Institut, Paris, France.,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,Collège de France, Paris, France.,Inserm UMR 1163, Paris, France
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38
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Successful treatment of Hodgkin lymphoma-like EBV-associated post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation with nivolumab. Ann Hematol 2020; 99:887-889. [PMID: 32052134 DOI: 10.1007/s00277-020-03960-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 02/06/2020] [Indexed: 01/22/2023]
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39
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Fujimoto A, Suzuki R. Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders after Hematopoietic Stem Cell Transplantation: Pathogenesis, Risk Factors and Clinical Outcomes. Cancers (Basel) 2020; 12:cancers12020328. [PMID: 32024048 PMCID: PMC7072403 DOI: 10.3390/cancers12020328] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/27/2020] [Accepted: 01/30/2020] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous virus belonging to the human γ-herpes virus subfamily. After primary infection, EBV maintains a life-long latent infection. A major concern is that EBV can cause a diverse range of neoplasms and autoimmune diseases. In addition, patients undergoing hematopoietic stem cell transplantation or solid organ transplantation can experience post-transplant lymphoproliferative disorders (PTLDs) due to dysfunction or suppression of host’s immune system, or uncontrolled proliferation of EBV-infected cells. In recent years, the number of EBV-associated PTLD cases has increased. This review focuses on the current understandings of EBV-associated PTLD pathogenesis, as well as the risk factors and clinical outcomes for patients after allogeneic stem cell transplantation.
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Affiliation(s)
| | - Ritsuro Suzuki
- Correspondence: ; Tel.: +81-853-20-2517; Fax: +81-853-20-2525
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40
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Ayee R, Ofori MEO, Wright E, Quaye O. Epstein Barr Virus Associated Lymphomas and Epithelia Cancers in Humans. J Cancer 2020; 11:1737-1750. [PMID: 32194785 PMCID: PMC7052849 DOI: 10.7150/jca.37282] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 12/01/2019] [Indexed: 02/06/2023] Open
Abstract
Epstein Barr virus (EBV) is a cosmopolitan oncogenic virus, infecting about 90% of the world's population and it is associated to tumors originating from both epithelia and hematopoietic cells. Transmission of the virus is mainly through oral secretions; however, transmission through organ transplantation and blood transfusion has been reported. In order to evade immune recognition, EBV establishes latent infection in B lymphocytes where it expresses limited sets of proteins called EBV transcription programs (ETPs), including six nuclear antigens (EBNAs), three latent membrane proteins (LMP), and untranslated RNA called EBV encoded RNA (EBER), shown to efficiently transform B cells into lymphoblastic cells. These programs undergo different patterns of expression which determine the occurrence of distinct types of latency in the pathogenesis of a particular tumor. Hematopoietic cell derived tumors include but not limited to Burkitt's lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and natural killer (NK)/T cell lymphoma. EBV undergoes lytic infection in epithelia cells for amplification of the viral particle for transmission where it expresses lytic stage genes. However, for reasons yet to be unveiled, EBV switches from the expression of lytic stage genes to the expression of ETPs in epithelia cells. The expression of the ETPs lead to the transformation of epithelia cells into permanently proliferating cells, resulting in epithelia cell derived malignancies such as nasopharyngeal cancer, gastric cancer, and breast cancer. In this review, we have summarized the current updates on EBV associated epithelial and B cell-derived malignancies, and the role of EBV latency gene products in the pathogenesis of the cancers, and have suggested areas for future studies when considering therapeutic measures.
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Affiliation(s)
- Richmond Ayee
- Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra, Ghana
| | | | - Edward Wright
- Department of Biochemistry, University of Sussex, Brighton, U.K
| | - Osbourne Quaye
- Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra, Ghana
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41
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Alterations in NKG2A and NKG2C Subsets of Natural Killer Cells Following Epstein–Barr Virus Reactivation in CTLA4Ig-based Haploidentical Transplantation Is Associated With Increased Chronic Graft-Versus-Host Disease. Transplantation 2020; 104:e23-e30. [DOI: 10.1097/tp.0000000000002941] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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42
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Althubaiti S, Ali S, Renzi S, Krueger J, Chiang KY, Schechter T, Punnett A, Ali M. Lymphocyte subset at time of Epstein-Barr viremia post-allogeneic hematopoietic stem cell transplantation in children may predict development of post-transplant lymphoproliferative disease: CD8:CD20 ratio as a sensitive predictor. Pediatr Transplant 2019; 23:e13574. [PMID: 31496046 DOI: 10.1111/petr.13574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 07/31/2019] [Accepted: 08/05/2019] [Indexed: 11/27/2022]
Abstract
EBV-associated PTLD following allogeneic HSCT is a serious complication associated with significant mortality. In this retrospective study, we evaluated whether lymphocyte subset numbers and CD8:CD20 ratio at time of EBV viremia in children undergoing allogeneic HSCT could predict development of PTLD. Absolute lymphocyte count, lymphocyte subsets, and CD8:CD20 ratio at the time of EBV viremia were analyzed. Patients who were treated preemptively with rituximab for high blood EBV viral load were excluded. Out of 266 patients transplanted during the study period, 26 patients were included in the analysis. Patients were divided into two cohorts; cohort 1 included patients with EBV-associated PTLD (n = 5; four with proven, one with probable PTLD). Cohort 2 included patients with EBV viremia without PTLD (n = 21). Lymphocyte recovery was slower in the PTLD group. CD8:CD20 ratio was significantly lower in the PTLD group (median 0.15) compared to the non-PTLD group (median 2.4, P = .012). Using the ROC curve and 1 as the cutoff value, CD8:CD20 ratios were analyzed. In the PTLD group, 4/5 patients (80%) had a ratio <1 whereas in the non-PTLD group, all 21 patients had a ratio >1. Sensitivity and specificity were 80% and 100%, respectively. Negative and PPVs were 95% and 100%, respectively. Profoundly low T-cell count and CD8:CD20 ratio may be used to predict development of PTLD in the context of EBV viremia in children post-allogeneic HSCT. Further studies are needed to validate this finding.
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Affiliation(s)
- Sami Althubaiti
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,King Abdulaziz Medical City, Ministry of National Guard, Jeddah, Saudi Arabia
| | - Salah Ali
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Samuele Renzi
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Joerg Krueger
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,University of Toronto, Toronto, ON, Canada
| | - Kuang-Yueh Chiang
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,University of Toronto, Toronto, ON, Canada
| | - Tal Schechter
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,University of Toronto, Toronto, ON, Canada
| | - Angela Punnett
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,University of Toronto, Toronto, ON, Canada
| | - Muhammad Ali
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,University of Toronto, Toronto, ON, Canada
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Strunz PP, Schmalzing M, Heidemeier A, Rasche L, Einsele H, Kortüm KM. Response to daratumumab in rituximab-resistant EBV-associated PTLD following allogenic stem cell transplantation from an EBV seronegative donor. Leuk Lymphoma 2019; 60:3573-3576. [DOI: 10.1080/10428194.2019.1636981] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Patrick-Pascal Strunz
- Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany
| | - Marc Schmalzing
- Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany
| | - Anke Heidemeier
- Universitatsklinikum Würzburg, Radiologie, Wurzburg, Germany
| | - Leo Rasche
- Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany
| | - Hermann Einsele
- Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany
| | - K. Martin Kortüm
- Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany
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Li X, Huang J, Zhu Z, Li N. Refractory autoimmune haemolytic anaemia following allogenic haematopoietic stem cell transplantation: successful treatment of rituximab. J Int Med Res 2019; 47:3320-3331. [PMID: 31280646 PMCID: PMC6683942 DOI: 10.1177/0300060519855593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate the effectiveness and safety of rituximab in treating autoimmune haemolytic anaemia (AIHA) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Methods Patients with refractory AIHA following allo-HSCT were treated once-weekly with rituximab 375 mg/m2 for a total of four doses. In an animal study, recipient CB6F1 mice were conditioned with busulfan/fludarabine and transplanted with splenocytes and T-cell-depleted bone marrow from C57Bl/6 mice. In this animal model, anti-CD20 monoclonal antibody (mAb) was evaluated to see if it could prevent graft versus host disease (GVHD). GVHD was monitored by body weight loss, GVHD clinical scores and the survival of each group of mice. Histopathological analyses of the skin, intestine, liver and lung were used to analyse the severity of GVHD. Results After rituximab therapy, refractory AIHA was resolved in all four patients as shown by increased haemoglobin levels. B-cell proportions were reduced with a relative increase of the proportions of T-cells following rituximab treatment. None of the four patients experienced chronic GVHD. In the animal model, anti-CD20 mAb treatment reduced GVHD. Conclusions Rituximab therapy deserves consideration for the treatment of post-HSCT patients with refractory AIHA. Further studies are needed to define the therapeutic role of this anti-CD20 mAb.
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Affiliation(s)
- Xiaofan Li
- Haemopoietic Stem Cell Transplantation Centre, Department of Haematology, Fujian Institute of Haematology, Fujian Provincial Key Laboratory on Haematology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Jiafu Huang
- Haemopoietic Stem Cell Transplantation Centre, Department of Haematology, Fujian Institute of Haematology, Fujian Provincial Key Laboratory on Haematology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Zhijuan Zhu
- Haemopoietic Stem Cell Transplantation Centre, Department of Haematology, Fujian Institute of Haematology, Fujian Provincial Key Laboratory on Haematology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Nainong Li
- Haemopoietic Stem Cell Transplantation Centre, Department of Haematology, Fujian Institute of Haematology, Fujian Provincial Key Laboratory on Haematology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
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45
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Risk Factors and Predictive Scoring System For Post-Transplant Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2019; 25:1441-1449. [DOI: 10.1016/j.bbmt.2019.02.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 02/12/2019] [Indexed: 11/24/2022]
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46
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Epstein-Barr virus-related post-transplant lymphoproliferative disease (EBV-PTLD) in the setting of allogeneic stem cell transplantation: a comprehensive review from pathogenesis to forthcoming treatment modalities. Bone Marrow Transplant 2019; 55:25-39. [DOI: 10.1038/s41409-019-0548-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/10/2019] [Accepted: 04/15/2019] [Indexed: 12/17/2022]
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47
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Ali S, AlThubaiti S, Renzi S, Krueger J, Chiang KY, Naqvi A, Schechter T, Punnett A, Ali M. Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein-Barr virus-associated post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Pediatr Transplant 2019; 23:e13319. [PMID: 30417487 DOI: 10.1111/petr.13319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/11/2018] [Accepted: 10/15/2018] [Indexed: 12/01/2022]
Abstract
EBV-related PTLD developing after HSCT is a potentially life-threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV-PTLD with a median age at HSCT of 5.9 years (range: 2.3-17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV-PTLD within the first 100-day post-HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV-PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV-PTLD seems imperative to control the disease, especially if signs of HLH are evolving.
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Affiliation(s)
- Salah Ali
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Sami AlThubaiti
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Samuele Renzi
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Joerg Krueger
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - K Y Chiang
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Ahmed Naqvi
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Tal Schechter
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Angela Punnett
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Muhammad Ali
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
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Adoptive T Cell Therapy Strategies for Viral Infections in Patients Receiving Haematopoietic Stem Cell Transplantation. Cells 2019; 8:cells8010047. [PMID: 30646564 PMCID: PMC6356262 DOI: 10.3390/cells8010047] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/08/2019] [Accepted: 01/11/2019] [Indexed: 01/18/2023] Open
Abstract
Adverse outcomes following virus-associated disease in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) have encouraged strategies to control viral reactivation in immunosuppressed patients. However, despite timely treatment with antiviral medication, some viral infections remain refractory to treatment, which hampers outcomes after HSCT, and are responsible for a high proportion of transplant-related morbidity and mortality. Adoptive transfer of donor-derived lymphocytes aims to improve cellular immunity and to prevent or treat viral diseases after HSCT. Early reports described the feasibility of transferring nonspecific lymphocytes from donors, which led to the development of cell therapy approaches based on virus-specific T cells, allowing a targeted treatment of infections, while limiting adverse events such as graft versus host disease (GvHD). Both expansion and direct selection techniques have yielded comparable results in terms of efficacy (around 70–80%), but efficacy is difficult to predict for individual cases. Generating bespoke products for each donor–recipient pair can be expensive, and there remains the major obstacle of generating products from seronegative or poorly responsive donors. More recent studies have focused on the feasibility of collecting and infusing partially matched third-party virus-specific T cells, reporting response rates of 60–70%. Future development of this approach will involve the broadening of applicability to multiple viruses, the optimization and cost-control of manufacturing, larger multicentred efficacy trials, and finally the creation of cell banks that can provide prompt access to virus-specific cellular product. The aim of this review is to summarise present knowledge on adoptive T cell manufacturing, efficacy and potential future developments.
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Velvet AJJ, Bhutani S, Papachristos S, Dwivedi R, Picton M, Augustine T, Morton M. A single-center experience of post-transplant lymphomas involving the central nervous system with a review of current literature. Oncotarget 2019; 10:437-448. [PMID: 30728897 PMCID: PMC6355190 DOI: 10.18632/oncotarget.26522] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 12/13/2018] [Indexed: 12/13/2022] Open
Abstract
Background Central Nervous System (CNS) lymphoma is a rare presentation of post-transplantation lymphoproliferative disorder (PTLD). Methods This single center retrospective study reviewed presentations, management and outcomes of CNS lymphomas in kidney transplant patients transplanted 1968 to 2015, and reviews relevant current literature. Results We identified 5773 adult kidney transplant recipients of who 90 had a PTLD diagnosis confirmed. CNS disease was diagnosed in 6/90 (7%). Median age at presentation was 60 years and time from transplant 4.5 years. Immunosuppression at diagnosis included mycophenolate mofetil and prednisolone without calcineurin inhibitor in 5/6 patients. Histological analysis diagnosed monomorphic disease in 5/6, and one polymorphic case with tissue positive for Epstein-barr virus (EBV) in 5/6 cases. Despite this 2/4 EBV positive cases had no detectable EBV in peripheral blood or CSF at diagnosis. Treatment strategies included reduction in immunosuppression in all, chemotherapy (n=5), radiotherapy (n=3), Cytotoxic T-Lymphocytes and Craniotomy (n=2). Patient survival was 40% at 1 year with CTL treated patients surviving beyond three years from diagnosis. Conclusion This study supports observational data suggesting MMF treated patients without CNI may have increased risk of disease. Peripheral blood screening for EBV DNAemia does not seem helpful in early identification of those at risk.
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Affiliation(s)
- Anju John John Velvet
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Shiv Bhutani
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Stavros Papachristos
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Reena Dwivedi
- Department of Radiology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Michael Picton
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Titus Augustine
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.,Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Muir Morton
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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50
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Treatment of Epstein-Barr virus associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation with intrathecal donor lymphocyte infusion. Bone Marrow Transplant 2018; 54:821-827. [PMID: 30518982 DOI: 10.1038/s41409-018-0409-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 11/15/2018] [Accepted: 11/17/2018] [Indexed: 11/08/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective measure for the treatment of hematological disease. With the progress and widespread use of allo-HSCT, Epstein-Barr virus (EBV) related central nervous system (CNS) diseases have gotten more and more attention because of its poor prognosis and overall survival. Since currently there is no standard treatment for patients with EBV-associated CNS diseases and reported therapies are heterogeneous with mixed results, we attempted to develop a novel therapeutic method. We applied a regimen of intrathecal donor lymphocyte infusion (IDLI) in three patients with EBV-associated CNS diseases after allo-HSCT in addition to immunosuppressants reduction and combined antiviral therapy. All of three patients were responsive to this therapy: all clinical symptoms and EBV load in CSF were resolved 10, 17, and 12 days after initial IDLI, respectively, and magnetic resonance imaging (MRI) showed that lesions of case 1 and 2 disappeared 15 and 19 days after initial IDLI, respectively. Even more appealing, there were no acute or chronic adverse reactions during the infusion and up to 23 months of follow-up. In conclusion, IDLI seems to be an effective and safe method for EBV-associated CNS diseases in allo-HSCT recipients. We recommend this treatment modality for further investigation.
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