The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children

Abstract

Twenty cases of Epstein-Barr virus (EBV)-associated lymphoproliferative syndrome (LPS), defined by the presence of EBV nuclear antigen and/or EBV DNA in tissues, were diagnosed in 1467 transplant recipients in Pittsburgh from 1981-1985. The frequency of occurrence in pediatric transplant recipients was 4% (10/253), while in adults it was 0.8% (10/1214) (P less than .0005). The frequency of LPS in adults declined after 1983 coincidental with the introduction of cyclosporine monitoring. However there was no apparent decline of LPS in children. We describe these ten pediatric cases and one additional case of LPS in a child who received her transplant before 1981. The frequency of EBV infection in 92 pediatric liver recipients was 63%. Of these subjects, 49% were seronegative and 77% of those acquired primary infection. Of 11 cases of pediatric EBV-associated LPS, 10 were in children who had primary infection shortly before or after transplantation. These results reinforce the importance of primary EBV infection in producing LPS, which was previously shown in adults. Children are at greater risk because they are more likely to be seronegative for EBV and to acquire primary infection. Three clinical types of LPS were recognized in children. The first (5 cases) was a self-limited mononucleosislike syndrome. The second syndrome (4 cases) began similarly, but then progressed over the next two months to widespread lymphoproliferation in internal organs and death. The third type (2 cases) was an extranodal intestinal monoclonal B cell lymphoma, occurring late after primary infection.

Figure 1

Southern blot showing the presence of EBV DNA in tissue samples from 7 children with lymphoproliferative syndromes following liver transplantation. Cellular DNA was digested with Bam HI and probed with the EcoRI B fragment of EBV DNA cloned in pACYC184. The Bam HI subfragments found in EcoRI B are shown at the left and right margins. The terminal Bam HI fragments (Bam HI Ef and Bam HI Gf) are different size in the probe (lane 13) since they contain EcoRI sites. Tissue samples from patients in group 1 (nonfatal lymphoproliferative disease) are found in lane 4 (K.H. tonsil), lanes 6 and 8 (C.C. tonsil and axillary node), and lane 7 (K.L. cervical node). Samples from patients with fatal lymphoproliferative disease, group 2, are seen in lane 2 (M.M. mesenteric node) lane 5 (J.C. mesenteric node), and lane 11 (K.E. tonsil). The sample in lane 9 is the gut lymphoma from J.M. The signal in lane 13 with plasmid DNA is equivalent to about 18 copies of the EBV genome per cell.

Figure 2

Tonsil from K.H. The polymorphous nature of the proliferation is readily apparent. Small lymphocytes, plasma cells, and histiocytes are among the cell types seen. Mitoses are present.

Figure 3

Abdominal lymph node from autopsy of M.M. The monomorphous large cell population, with prominent nucleoli, most closely resembles an immunoblastic sarcoma. In this instance only some B cell markers, but not immunoglobulins, were demonstrable on the cells.