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Post-transplant lymphoproliferative disease and other Epstein-Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. (Barnonkologisk forskning/Lönnerholm)
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2007 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 39, no 3, 235-244 p.Article in journal (Refereed) Published
Abstract [en]

The clinical value of monitoring of Epstein-Barr virus (EBV) viraemia by quantitative polymerase chain reaction during 1 y was evaluated. 39 recipients of allogeneic hematopoietic stem cell transplantation (SCT) were followed. More than 100 EBV genome equivalents (gEq)/ml in blood or plasma were found in 16/39 patients (41%) at 34 d (range 1-139) post-transplant. Seven of these 16 patients developed EBV disease; 3 post-transplant lymphoproliferative disease (PTLD), 1 myelitis, 1 encephalitis and 2 reactivations with fever. EBV diseases were only found in the high-risk group among recipients of mismatched related or unrelated donor grafts or in patients who underwent reduced-intensity conditioning. In this group, 3/20 (15%) developed PTLD. Conditioning with antithymocyte globulin was significantly associated with EBV disease (p<0.01). EBV load in plasma was more strongly associated with EBV disease than viral load in blood. A cut-off level of 1000 gEq/ml plasma distinguished EBV disease from asymptomatic viraemia, but not PTLD from other EBV diseases. Weekly monitoring of EBV load in plasma in high-risk patients in the first 3 months following SCT seems to be of value for prediction of EBV disease. Therapy for PTLD including rituximab was evaluated during 2 y and showed response in 4/6 cases.

Place, publisher, year, edition, pages
2007. Vol. 39, no 3, 235-244 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-14286DOI: 10.1080/00365540600978906ISI: 000245235300008PubMedID: 17366054OAI: oai:DiVA.org:uu-14286DiVA: diva2:42056
Available from: 2008-06-03 Created: 2008-06-03 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
Open this publication in new window or tab >>Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epstein-Barr virus (EBV) infects almost all humans and establishes lifelong latency in B cells. Posttransplant lymphoproliferative disorder (PTLD) is a rare but serious complication after transplantation triggered by immunosuppression and often related to EBV infection. The aim of this thesis was to study the role of EBV in relation to clinical and histological features of PTLD, regulatory T cells (Tregs), and donor or recipient origin of PTLD.

EBV surveillance after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed that EBV reactivations were common, but that symptomatic EBV disease (including PTLD) only occurred in the high-risk group (unrelated or mismatched related grafts, reduced-intensity conditioning). A threshold of 1000 copies/ml plasma distinguished EBV disease from asymptomatic reactivations.

In a population-based cohort of 135 PTLDs/lymphomas after solid organ transplantation (SOT) almost half were EBV. EBV+ PTLDs were associated with B cell phenotype, non-germinal center subtype of diffuse large B cell lymphoma (DLBCL), early-onset, graft involvement, antithymocyte globulin treatment, and younger age. EBV PTLDs were associated with T cell phenotype, bone marrow involvement, and hepatitis C. Most PTLDs displayed few or no intratumoral Tregs with the marker FoxP3, possibly due to heavy immuno­suppres­sion. Half of both FoxP3+ and FoxP3PTLDs were EBV+. FoxP3+ PTLDs were associated with B cell phenotype and hepatitis C. All PTLDs for which tumor origin could be determined were recipient-derived and half of them were EBV+. Eight of twelve recipient-derived graft PTLDs were disseminated outside the graft. T cell PTLD and hepatitis C were independently associated with inferior overall survival, whereas subtype of DLBCL, FoxP3-expression, and EBV-status did not influence survival.

In conclusion, monitoring of EBV DNAemia in high-risk patients after allo-HSCT and pre-emptive therapy is valuable for prevention of PTLD. Use of anti­thymocyte globulin increases the risk for EBV+ PTLDs after allo-HSCT and SOT. With long follow-up time, a large proportion of PLTDs after SOT are EBVwith a different clinical presentation. Tregs are rare in PTLD and do not affect survival. The vast majority of PTLDs after SOT is of recipient origin. Graft PTLDs are more likely recipient-derived if disseminated. EBV-status is not associated with intratumoral Tregs or PTLD of recipient origin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 107 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1043
Keyword
PTLD, Lymphoma, Epstein-Barr Virus, EBV DNAemia, FoxP3, Treg, Microenvironment, Cell of Origin, Recipient, Transplantation, Immunosuppression, Hepatitis C, Survival
National Category
Cancer and Oncology Infectious Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-234130 (URN)978-91-554-9074-4 (ISBN)
Public defence
2014-11-29, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (Swedish)
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Available from: 2014-11-05 Created: 2014-10-14 Last updated: 2015-02-03

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Kinch, AmelieArvidson, JohanPauksens, Karlis

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