The superiority of Epstein‐Barr virus DNA in plasma over in peripheral blood mononuclear cells for monitoring EBV‐positive NK‐cell lymphoproliferative diseases

Abstract

Epstein‐Barr virus (EBV), characterized as an omnipresent virus, has been found able to infect NK cells and leads to NK‐cell type EBV‐positive lymphoproliferative diseases (EBV‐NK‐LPDs). We retrospective analyzed 202 EBV‐NK‐LPDs (including 64 CAEBV‐NK, 27 aggressive natural killer‐cell leukemia (ANKL), and 111 extranodal NK/T‐cell lymphoma (ENKTL)) patients' relationships between EBV DNA copies laboratory test results and clinical features. In CAEBV‐NK cohort, EBV DNA loads in either plasma or PBMCs had significant differences between the active state and the inactive state. Receiver operating characteristic curves were used to measure the diagnosis accuracy of EBV DNA copies. After comparing the area under the curve, EBV DNA loads in plasma had significantly higher accuracy in distinguishing disease activation than in PBMCs. Therefore, we propose redefining CAEBV‐NK diagnosis criteria as increased EBV DNA copies in plasma (over 7.1 × 102 copies/ml) instead of in peripheral blood. In ANKL and ENKTL cohorts, patients who received effective therapy had significantly lower EBV DNA copies in plasma & PBMCs than in those with ineffective therapy. The significant and consistent decline indicated EBV DNA loads in plasma being a more sensitive biomarker in monitoring EBV‐NK‐LPDs therapy responses. Hemophagocytic lymphohistiocytosis (HLH) can occur secondary to EBV‐NK‐LPDs, mostly associated with a poor prognosis, so we try to estimate the combination of HLH by monitoring EBV DNA copies. When comparing the Receiver operating characteristic curves of EBV DNA copies, EBV DNA loads in plasma had higher diagnosis accuracy. When the copies level over 4.16 × 103 copies/ml, it might indicate combining with HLH.

Comparison of plasma proteomic profiles of patients with Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis and infectious mononucleosis

“…Based on EBV‐specific antibody titers, three of the four patients with EBV‐HLH were considered to have a primary EBV infection (EBV‐viral capsid antigen‐IgM and ‐IgG positive, and EBV‐nuclear antigen negative), whereas one patient was thought to experience reactivation of EBV. EBV DNA loads in four patients with EBV‐HLH (median; 93,556 IU/mL) were comparable to those of previous reports of EBV‐HLH 8,9 . Other conditions that can cause HLH, such as malignancies, rheumatic diseases, and immune deficiencies, were deemed unlikely from the laboratory data and clinical courses 10,11 …”

The Clinical Significance and Prognostic Role of Whole-Blood Epstein-Barr Virus DNA in Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

“…The treatments used in our cohort are not uniform and could be a confounding factor in determining the prognostic factors for lymphoma-associated HLH. The study by Zheng et al has demonstrated that plasma EBV DNA was superior to EBV DNA from peripheral blood mononuclear cells in monitoring EBV-associated HLH (19). However, in our study, only the whole-blood EBV DNA was determined and whether plasma EBV DNA is a better prognostic factor remains to be explored.…”

“…For EBV-positive lymphomas, a higher EBV load may trigger or aggravate HLH. For instance, in patients with EBV-positive NK-cell lymphoid tumors including ANKL and ENKL, a higher EBV load was signi cantly associated with the presence of HLH (19). However, it should be noted that factors other than EBV are also very important in the pathogenesis of HLH in these NK-cell lymphoid malignancies, as HLH is also frequently present in patients with EBV-negative ANKL (20).…”

Virological Markers in Epstein–Barr Virus-Associated Diseases

“…In ENKTL patients at diagnosis, EBV DNA is more frequently detected in plasma than in peripheral blood mononuclear cells, thus making plasma a more appropriate specimen for monitoring the therapeutic responses of EBV-NK/T lymphoproliferative diseases [ 99 , 100 ]. In patients with NKTL, plasma EBV DNA is a useful tumor marker for diagnosis, disease monitoring, and prognosis [ 101 ].…”