Ask the Experts - Management of Epstein-Barr Virus Infection?
My patient is a 14-year-old liver transplant recipient (12/98), currently on tacrolimus 2 mg bid and prednisone 7.5 mg qd. The patient developed an Epstein-Barr virus (EBV), mononucleosis-like illness. The EBV polymerase chain reaction (PCR) titer was 50,000. The patient received 6 weeks of ganciclovir 450 mg bid. The symptoms resolved, but the viral load is now 4000. Liver function is normal. What should I do now -- continue ganciclovir (intravenous or oral), discontinue ganciclovir and monitor viral load, try intravenous immunoglobulin (IVIG)?
Paul J. Alessi, MD
The presented case describes a 14-year-old child status post orthotopic liver transplantation (OLT) who developed a mononucleosis-like picture associated with an elevated EBV viral load to 50,000. The patient was treated with 6 weeks of ganciclovir. Clinical symptoms appeared to have resolved, but the viral load is still 4000. A question of the meaning and management of this patient's EBV viral load at this time persists.
The above scenario illustrates several key components in interpreting EBV viral loads in transplant recipients. A critical point to consider is that we have not been told the units with which the EBV viral load is being reported. Depending on whether the viral load is described in genome copies/10 peripheral blood lymphocytes, genome copies/mcg DNA, or genome copies/mL of whole blood, the meaning of the values may be different.
If we assume that 50,000 is elevated, it is likely that the patient's clinical picture was truly an EBV-associated illness. Although the patient has become asymptomatic, he/she still has an elevated EBV viral load to 4000. In our experience, resolution of an EBV clinical syndrome is typically initially associated with a drop in the EBV viral load. As we don't know the units of this test, the value of 4000 may be consistent with our experience. It would be interesting to know whether the value of the viral load was ever documented to have fallen further and hence, whether or not the current value of 4000 may represent a "rebound" in viral load. In our experience, intermittent or persistent rebound in EBV viral load in patients who have recovered from EBV disease and who are asymptomatic is very common.
It is so common, in fact, that given the fact that recurrence of PTLD is an infrequent event (5% to 10%), the finding of an elevated viral load post EBV/posttransplant lymphoproliferative disorder (PTLD) by itself may have no clinical significance. Research efforts by our group are currently attempting to identify "secondary markers" that might determine which (if any) of these patients may be at risk of developing recurrent disease.
Our current strategy (developed by David Rowe Graduate School of Public Health, University of Pittsburgh) is to look at mRNA transcription from several gene products by RT-PCR to attempt to identify "ominous" patterns. In general, patients like the one currently described have a "relatively benign" phenotype.
I will now attempt to address the question of therapy and the potential role of ganciclovir. Most experts would agree that the initial management of this patient should have included "temporarily" discontinuing or significantly reducing his/her immunosuppressants as part of the therapeutic regimen. The role of the antiviral agent, ganciclovir, is less clear. Ganciclovir is only active against EBV-infected cells that are undergoing lytic replication. We know that as many as 90% of EBV-infected cells within "PTLD" lesions are transformed cells that do not undergo lytic replication. Rather, the virus is replicated through EBV-driven proliferation of the transformed B cells. This mechanism is dependent on human DNA replication enzymes, which are not susceptible to ganciclovir. Accordingly, the use of this agent does not limit the majority of the infected cells from replicating. There is a theoretical possibility that the use of ganciclovir will serve as a "fire wall" to keep the 5% to 10% of affected B cells undergoing lytic replication from producing new virus, which could infect new B cells and produce new clones.
Recent data evaluating the state of viral infection in EBV-infected B cells in the peripheral blood (which are what we measure in the viral load) are also suggestive of the fact that the vast majority of these cells are transformed and not in the lytic state. Work from the laboratory of David Rowe identified the presence of lytic virus in the peripheral blood in patients with elevated viral load on only rare occasions; this was true of patients who had active disease (including PTLD) and also of patients with a prior history of EBV/PTLD who were now asymptomatic with elevated viral loads, as in the current patient. Clearly, for this patient the viral load has persisted (or rebounded) despite the use of 6 weeks of ganciclovir therapy. Further, published experience has shown that viral loads can develop and climb to extremely high levels in patients despite continuous use of intravenous ganciclovir from the time of transplant for the first 100 days.
The observation that viral loads are not "driven" to nondetectable amounts by the use of ganciclovir alone, the absence of a high frequency of lytic EBV infection in the peripheral blood in patients with elevated loads post EBV/PTLD, and the high frequency of persistent elevations in EBV viral load after EBV/PTLD, all strongly suggest that there is no role for the continued use of ganciclovir (or other nucleoside analogues) in patients like this. In general, our current recommendations would be to "ignore" viral loads after resolution from PTLD unless the follow-up is part of a clinical protocol aimed at further understanding the natural history of the EBV viral load after EBV disease. Such efforts should be coupled with attempts to identify secondary markers, and results of these follow-up tests should not prompt clinical intervention in asymptomatic patients. Outside of such systematic efforts, we would discourage even ordering the test once clinical symptoms resolve.
Guest Expert Michael Green, MD, Division of Allergy, Immunology and Infectious Diseases, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pennsylvania