Is an ounce of prevention worth a pound of cure?

I n general, preventing disease is preferred to treatment. However, this implies that morbidity and/or mortality is less in the entire cohort when prevention is applied to many compared to that of the few treated for the disease. An example of this is latent herpesvirus infection following hematopoietic stem cell transplant (HSCT). Great advances have been made in reducing morbidity/mortality due to cytomegalovirus (CMV). Prophylactic use of antiviral therapy, such as ganciclovir, definitely reduces complications due to CMV, but does not reduce overall mortality due to complications associated with ganciclovir, e.g., infections and graft failure, due to marrow suppression [1]. The use of regular screening for CMV reactivation and early (pre-emptive) therapy with antiviral therapy has been demonstrated to be equally effective in reducing CMV disease and reducing overall mortality by placing only the patients at greatest risk to the risks of therapy [2]. Post-transplant lymphoproliferative disease (PTLD) is a well known complication of Epstein–Barr virus (EBV) following HSCT. PTLD occurs almost exclusively in the first 3–6 months post-HSCT, the time when EBV specific cytotoxic T-cell (EBVCTL) immunity is lowest [3]. Patients at highest risk for PTLD have been well described and are basically any patient where either B-cell proliferation is enhanced and/or T-cell immunity is suppressed post-HSCT [4]. Antiviral therapy has been shown to have little benefit in prophylaxis or treatment of PTLD, since the problem is proliferation of latently infected B-cells. It has been demonstrated that infusion of ex-vivo expanded EBV-CTL is very effective in treating and preventing PTLD [5]. However, this technology is available only at few transplant centers and is not cost effective in that PTLD occurs in about 2% of patients overall post-HSCT and 25% in the highest risk patients [4]. It has been shown that the majority of patients with PTLD at time of diagnosis have high amounts of EBVDNAdetectable by polymerase chain reaction (PCR) in the peripheral blood. Therefore, people have used quantitativePCR forEBVDNAas a method of screening patients at risk of developing PTLD. There ismuch confusion in the literature aboutwhat level of EBVDNA is to be used to predict patients at risk for PTLD. This confusion stems largely from the utilization of different PCR methodologies and specimens assayed (peripheral blood mononuclear cells vs. whole blood vs. serum/plasma) [6]. The use of serum or plasma for EBV PCR quantitation has been reported to be both sensitive and predictive of PTLD [7]. But it is unclear why this is the case, since PTLD is not due to EBV replication and it has been demonstrated that the increased EBVDNA levels in whole blood of PTLD patients correlate with the number of EBV infected B-cells [8]. For pre-emptive therapy to be effective the method of detection, i.e., EBV PCR screening, needs to be very sensitive, but also specific if the therapeutic intervention has a significant toxicity. Studies, mostly in adult patients receiving HSCT, show that EBV PCR screening is quite sensitive for detecting patients who go on to develop PTLD, but generally lacks specificity. The sensitivity of EBV PCR screening depends greatly on the interval of testing because PTLDcan develop very rapidly. Since EBV reactivation appears to occur in the majority of patients post-HSCT, the predictive value of EBV DNA screening has been low, except for patients receiving T-cell depleted (TCD) grafts [7]. The low specificitywould be acceptable if the cost and toxicity profile of the pre-emptive therapy is low. Currently, the options of pre-emptive therapy for PTLD post-HSCT are: (1) donor lymphocyte infusion carrying a significant risk of graftversus-host disease, and this is sometimes not readily available using unrelated donors, (2) EBV-CTL therapy takes four or more weeks to produce and is unavailable at most centers, or (3) rituximab. There are no randomized, controlled trials using rituximab as pre-emptive therapy, but it appears to be effective in preventing PTLD in patients with EBV reactivation compared to historical controls. In the post-HSCT patient, rituximab therapy delays B-cell recovery often for 6–9 months following therapy, often requiring supplemental IVIG [9]. Taking into account these issues, Greenfield et al., in this issue of Pediatric Blood & Cancer report a retrospective review of 28 children sequentially receiving allogeneic HSCT and monitored by EBV DNA by PCR screening of whole blood [10]. Patients were tested every week while hospitalized and ‘‘regularly’’ as outpatients. They found that the majority of children (68%) developed EBV reactivation. They further subdivided these patients into low (log10 4.5 copies/ml of EBV). Two patients (7%) developed PTLD, both with >log10 6 copies/ml EBV. These patients received rituximab and resolved the PTLD. Of the remaining seven high level (>log10 4.5) EBV reactivation patients, three received rituximab, and four did not and none developed PTLD. Based on these data, the authors prospectively have raised the treatment threshold to >log10 6. The results in this pediatric cohort are similar to what has been reported in series of adult post-HSCT patients. However, caution must be taken in extrapolating these results to other pediatric cohorts. As