Determining the type of cell infected with Epstein-Barr virus (EBV) in peripheral blood mononuclear cells (PBMCs) proves to be a valuable tool for improving the differential diagnosis of hematologic disease with concurrent EBV infection, according to study results published in Open Forum Infectious Diseases.

EBV is a herpesvirus that infects approximately 90% of the population and is strongly linked to a variety of diseases ranging from asymptomatic infections to a number of hematologic and nonhematologic cancers. However, without detailed clinical information it is difficult to differentiate these diseases, highlighting the need for a uniform approach to an aggressive analysis of EBV status and pathologic consequences in the routine diagnosis of diseases with concurrent EBV infection.

Currently, the measurement of EBV DNA has an important role in the diagnosis and management of EBV-positive diseases, and whole blood, plasma, and PBMCs are used to quantify the DNA. However, although measurement of EBV loads from PMBCs represents the viral load in circulating cells, measurements from plasma provide information that is distinct from circulating cells. Since different lymphoproliferative diseases are associated with different EBV-infected lymphocyte cells types, diagnosis of differential EBV-positive lymphoproliferative diseases could be improved by determining this cell type. However, the relationship between EBV-infected cell type in PBMCs and disease entity has not been investigated comprehensively. Therefore, this retrospective study determined the relative utility of determining EBV-infected lymphocyte cell types in PBMCs as a tool for discriminating EBV-positive hematologic diseases.

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EBV-infected cell types in PBMCs were investigated in 291 patients with high EBV loads to determine the EBV-infected lymphocyte. Based on the identified EBV-infected cell types, clinical features and prognoses of 93 patients with EBV-positive T-cell/natural killer-cell (NK-cell) lymphoproliferative diseases were investigated over a 5-year period.

B-cell-type infection was observed in immunocompromised patients and in immunocompetent patients with asymptomatic high EBV carriage, infectious mononucleosis, EBV-positive B-cell lymphoproliferative diseases, and EBV-positive B-cell lymphomas. Most B-cell-type diseases reflected the self-limited reactivation of EBV infection related to the EBV life cycle, with the exception of EBV-positive B-cell lymphomas and post-transplantation lymphoproliferative disorder. Most of these B-cell-type diseases included the clinical treatment of increased surveillance and steroid and/or antiviral therapies.

Conversely, in immunocompetent hosts, T-cell, NK-cell, and multiple-cell-type EBV infections require immediate diagnosis and prompt treatment. Results showed that EBV levels in PBMCs are higher in patients with T-cell, NK-cell, and multiple-cell-type EBV infections compared with patients with B-cell infections. This suggests that patients who have PBMCs with high levels of EBV are more likely to have non-B-cell infection. Therefore, the first step in the differential diagnosis of EBV-positive hematologic diseases should be the examination of dominant EBV-infected lymphocyte cells in PBMCs.

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Further, when examining the 93 patients with EBV-positive T-cell/NK-lymphoproliferative disorders, NK cells were found to be the dominant EBV infection target in 54.8% of the adult cohort, while EBV-positive T-cell/NK-lymphoproliferative disorders were mainly related to EBV-infected T cells in children in Japan. Further, only 10% of Chinese pediatric patients with EBV-positive hemophagocytic lymphohistiocytosis had genetic defects with 47.8% of patients in the study cohort having genetic defects.

The differences seen in infected cell types and a higher rate of genetic mutations in adult patients suggests that the pathogenesis of adult EBV-positive T-cell/NK-lymphoproliferative disorders is significantly different from that in children. This suggests that the EBV infection of T/NK cells in immunocompetent hosts is a more valuable marker than a targeted sequencing panel that only covers a limited number of genes.

Overall, the study investigators concluded that, “Based on the EBV-infected lymphocyte cell types and the host’s immune state (immunocompetent or immunocompromised, EBV[-positive] hematological disease can be feasibly subclassified for further differential diagnosis.”


Zhang P, Zeng C, Cheng J, et al. Determination of Epstein-Barr virus-infected lymphocyte cell types in peripheral blood mononuclear cells as a valuable diagnostic tool in hematological disease.Open Forum Infectious Diseases. 2019;6(5):ofz171

This article originally appeared on Infectious Disease Advisor