Limited Utility of Serology and Heterophile Test in the Early Diagnosis of Epstein–Barr Virus Mononucleosis in a Child after Renal Transplantation

Abstract

Background: Epstein–Barr virus (EBV) infection is associated with significant morbidity and mortality in renal transplant (RT) recipients. The spectrum of illness ranges from infectious mononucleosis (IM) to post-transplant lymphoproliferative disorder (PTLD). In association with clinical signs and symptoms, virus-specific serology and heterophile antibody tests are widely used in confirming the diagnosis of IM in the general population. However, these tests may have a limited role in immunosuppressed RT recipients from seropositive donor, especially in children who were EBV-seronegative prior to the transplant. The aim of this study is to evaluate the utility of these tests in the early diagnosis of IM in this subset of patients. Methods: This is a case study with a review of literature. Results: Here, we present a 14-year-old male with hemophilia B who presented with fever, fatigue, sore throat, palatal petechial rash, exudative tonsillitis and cervical lymphadenopathy 3 months post-RT. He was EBV seronegative prior to RT and received a deceased donor kidney transplant from a seropositive donor. Induction was done with Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. Initial heterophile antibody test (monospot) was negative, but became positive at 5 months and remained positive at 9 months follow-up post-RT. EBV viral capsid antigens (VCA) IgM and IgG, early antigen (EA) and nuclear antigen (EBNA) were all negative at the time of presentation. VCA IgM and IgG both became positive at 5 months and peaked at 9 months follow-up, however the EA and EBNA remained negative. EBV viral load as measured by polymerase chain reaction (PCR) was negative for the first 3 months post-RT but became positive at presentation, peaked at 6 months and started declining thereafter. Peripheral blood smear examination showed no absolute and atypical lymphocytosis. Cytomegalovirus PCR in the blood and throat culture for streptococcus were negative. There was no splenomegaly. He was managed conservatively with intravenous fluids, bed rest, antipyretics and reduction of immunosuppression. Conclusions: EBV serological markers have a limited role in the early diagnosis of EBV-IM following RT in prior seronegative children. Initial heterophile antibody test may also be negative, and hence a repeat test may be necessary. Once becoming positive, the VCA IgM may remain persistently elevated for prolonged duration. In addition to the suppressed cellular immunity secondary to immunosuppression, humoral response to viral infections is also delayed in transplant recipients, especially in the early transplant period. Hence, routine monitoring with PCR is superior to serology in diagnosing IM early and monitoring the EBV infection post-RT for timely evaluation and management.

Analysis of two laboratory tests for determination of EBV‐IM in children

“…Low-affinity EBV-CA IgG can be detected at the early stage of infection, but its level gradually decreases as the infection progresses; peripheral blood EBV-DNA generally starts to decline rapidly after 2 weeks of EBV infection and may not be detectable after fever reduction, but EBV-CA IgM levels gradually increase instead. 27 Recently, in a study reported for timely assessment and management. 27 The current study still has some limitations.…”

“…27 Recently, in a study reported for timely assessment and management. 27 The current study still has some limitations. First, the number of EBV-IM cases was relatively small.…”

“…Thus, combined testing of low‐affinity EBV‐CA IgG, EBV‐CA IgM, and peripheral blood EBV‐DNA can improve the diagnostic rate of EBV‐IM. Moreover, in some groups with specific immune responses, such as children after renal transplantation, routine monitoring using PCR is superior to serology for the early diagnosis of IM and for monitoring EBV infection after radiotherapy for timely assessment and management 27 …”

“…Serological testing is an effective method for diagnosing EBV infection, but it can only be used as an index of viral infection and does not accurately reflect the replication of EBV infection in the body, whereas quantitative PCR analysis can accurately determine the viral load. Low‐affinity EBV‐CA IgG can be detected at the early stage of infection, but its level gradually decreases as the infection progresses; peripheral blood EBV‐DNA generally starts to decline rapidly after 2 weeks of EBV infection and may not be detectable after fever reduction, but EBV‐CA IgM levels gradually increase instead 27 . Recently, in a study reported that clinical samples were analyzed by serological and molecular methods (real‐time PCR), and the results of the patients were evaluated together.…”

Comparison between Serological and Molecular Diagnosis of Epstein Barr Virus Infection among Egyptian Renal Transplant Recipients

“…They were subjected to pre-and posttransplantation evaluation as follows: I) Pretransplant evaluations: age, sex, previous blood transfusion, pretransplant hemodialysis, associated comorbidities as diabetes mellitus, the degree of matching between recipient and donor, and history of CMV and HCV infections. ,and classified according to their DU value as negative (<9 DU), grey zone (9)(10)(11), or positive (⩾11).…”