Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients.
BACKGROUND
We have previously reported a 10% incidence of posttransplant lymphoproliferative disease (PTLD) in pediatric patients receiving first liver grafts and primarily immunosuppressed with tacrolimus. To decrease the incidence of PTLD, we developed a protocol utilizing preemptive intravenous ganciclovir in high-risk recipients (i.e., donor (D)+, recipient (R)-), combined with serial monitoring of peripheral blood for Epstein Barr virus (EBV) by polymerase chain reaction (PCR).


METHODS
Consecutive pediatric recipients of a first liver graft were immunosuppressed with oral tacrolimus (both induction and maintenance), and low-dose prednisone. EBV serologies were obtained at the time of orthotopic liver transplant in recipients and donors. Recipients were divided into groups: group 1, high-risk (D+R-), and group 2, low-risk (D+R+; D-R-; D-R+). In group 1 (high-risk), all patients received a minimum of 100 days of intravenous ganciclovir (6-10 mg/kg/day), while, in group 2 (low-risk), patients received intravenous ganciclovir during their initial hospitalization and then were converted to oral acyclovir (40 mg/kg/day) at discharge. Semiquantitative EBV-PCR determinations were made at 1-2-month intervals. In both groups, patients with an increasing viral copy number by EBV-PCR had tacrolimus levels decreased to 2-5 ng/ml. Tacrolimus was stopped, and intravenous ganciclovir reinstituted for PTLD. A positive EBV-PCR with symptoms, but negative histology, was defined as EBV disease; PTLD was defined as histologic evidence of polyclonal or monoclonal B cell proliferation.


RESULTS
Forty children who had survived greater than 2 months were enrolled. There were 18 children in group 1 (high-risk; mean age of 14+/-15 months and mean follow-up time of 243+/-149 days) and 22 children in group 2 (low-risk; mean age of 64+/-65 months and follow-up time of 275+/-130 days). In group 1 (high-risk), there was no PTLD and one case of EBV disease (mononucleosis-like syndrome), which resolved. In group 2 (low-risk), there were two cases of PTLD; both resolved when tacrolimus was stopped. Both children were 8 months old at time of transplant. Neither received OKT3, and they had one and two episodes of steroid-sensitive rejection, respectively. One child had EBV disease (mild hepatitis), which resolved.


CONCLUSIONS
Since instituting this protocol, the overall incidence of PTLD has fallen from 10% to 5% for children receiving primary tacrolimus therapy after OLT. No high-risk pediatric liver recipient treated preemptively with intravenous ganciclovir developed PTLD. Both children with PTLD were less than 1 year at OLT and considered low-risk. However, their positive EBV antibody titers may have been maternal in origin and not have offered long-term protection. Serial monitoring of EBV-PCR after pediatric OLT is recommended to decrease the risk of PTLD by allowing early detection of EBV infection, which is then managed by decreasing immunosuppression and continuing intravenous ganciclovir.
McDiarmid
S V
SV
Department of Surgery, UCLA Medical Center, Los Angeles, California, USA.
Jordan
S
S
Kim
G S
GS
Toyoda
M
M
Goss
J A
JA
Vargas
J H
JH
Martín
M G
MG
Bahar
R
R
Maxfield
A L
AL
Ament
M E
ME
Busuttil
R W
RW
Lee
G S
GS
D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015774:Ganciclovir / Q000627:therapeutic use*; D006566:Herpesviridae Infections / Q000517:prevention & control*; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016031:Liver Transplantation / Q000009:adverse effects*; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D014412:Tumor Virus Infections / Q000517:prevention & control*
D000998:Antiviral Agents; D015774:Ganciclovir