Mary Kay Breinig

THE FREQUENCY OF EPSTEIN-BARR VIRUS INFECTION AND ASSOCIATED LYMPHOPROLIFERATIVE SYNDROME AFTER TRANSPLANTATION AND ITS MANIFESTATIONS IN CHILDREN

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 < .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 mononucleo-sislike 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.

INFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS IN THE PITTSBURGH TRANSPLANT POPULATION: A Study of 583 Donors and 1043 Recipients, 1981–1986

We performed a retrospective serologic survey of 583 organ donors and 1043 transplant recipients for antibodies to human immunodeficiency virus type 1 (HIV-1). Two (0.34%) of the 583 donors and 18 (1.7%) of the 1043 recipients had HIV-1 antibodies by enzyme immunoassay and by Western blot. Two of 5 seropositive recipients tested also had blood cultures positive for HIV-1. Seven (0.7%) of the 1043 transplant recipients had antibodies to HIV-1 before transplantation; 2 of these had hemophilia A, and 5 had previous transfusions. Eleven (1.3%) of 860 recipients followed for 45 days or more seroconverted to HIV-1 a mean of 96 days after transplantation. Likely sources of HIV-1 infection for 3 of these 11 recipients included a seropositive organ donor in 1 patient and high-risk blood donors in 2 patients. A definite source of HIV-1 infection was not found for the other 8 recipients, 3 of whom seroconverted to HIV-1 after institution of blood donor screening for HIV-1 antibodies. Seroconversion to HIV-1 was less common in kidney recipients than in liver, heart, or multiple-organ recipients (P less than 0.02). Nine (50%) of the 18 HIV-1 seropositive transplant recipients died a mean of 6 months after transplant surgery, and 9 (50%) are still alive a mean of 43 months after transplantation. AIDS-like illnesses occurred in 3 of the dead and 1 of the living patients and included pneumocystis pneumonia (3 cases), miliary tuberculosis (1 case), and recurrent cytomegalovirus infection (1 case). These data suggest that the course of HIV-1 infection is not more severe in transplant recipients receiving cyclosporine than in other hosts and that, despite screening of blood and organ donors, a small number of transplant recipients will become infected with HIV-1.

Tolerance to the Induction of Interferons by Endotoxin and Virus Role of a Humoral Factor.

Summary The intravenous inoculation of either endotoxin or Sindbis virus rendered a rabbit tolerant to the interferon-inducing action of endotoxin or virus. There was crossed tolerance in the sense that animals first inoculated with endotoxin became tolerant to virus. By 6 hours after receiving an inoculation of endotoxin, the animals became tolerant to endotoxin and remained so for at least 3 days, but by the 6th day, sensitivity to endotoxin had been regained. Concurrent with the development of tolerance to endotoxin, a serum humoral factor which could inactivate or decrease the interferon-inducing capacity of endotoxin was found. It is suggested that this factor may play a role in producing tolerance to endotoxin.

METABOLIC DETERMINANTS OF INTERFERON FORMATION.

Abstract Three antimetabolites were used to study interferon production induced in chick cell monolayers by infectious Sindbis virus and by UV-irradiated Newcastle disease virus (NDV). Interferon production was inhibited by intermediate doses of mitomycin C, by actinomycin D, and by puromycin; while only puromycin inhibited virus replication. Maximal inhibition of interferon production by actinomycin D occurred within 2 hours after inoculation of interferon inducer, suggesting that the formation of DNA dependent RNA required for interferon synthesis is largely completed in that time. Inhibition by puromycin suggests that interferon formation requires new protein synthesis.

Leukocyte Interferon for Treating First Episodes of Genital Herpes in Women

Abstract Women experiencing their first episodes of genital herpes were treated, beginning within three days of the onset of lesions, with 5 × 104 units of human leukocyte interferon/kg of body weight for 12 doses over 14 days (total, ∼3.6 × 107 units) or with placebo in equivalent volumes. Life-table analysis revealed quicker healing and significant reductions in the duration of shedding of virus in interferon-treated patients. Maximum daily geometric mean titers of virus and total area of unhealed lesions also decreased more quickly. No statistically significant difference in resolution of pain was seen between the two groups. Interferon had no effect on onset or frequency of subsequent recurrences recorded over one year of follow-up. Moderate, transient neutropenia occurred in 13 of 34 interferon-treated patients. A therapeutic effect of human leukocyte interferon on initial genital herpes was documented, but the clinical usefulness of interferon treatment of genital herpes is limited at this time.

Factors associated with the development of post-transplant lymphoproliferative disease (PTLD) in Epstein-Barr virus (EBV) - seronegative adult liver transplant recipients

Abstract Epstein‐Barr virus (EBV) infection is recognized as the principal aetiological factor in the pathogenesis of post‐transplant lymphoproliferative disease (PTLD), particularly when primary EBV infection occurs after transplantation. We analysed, using a time‐dependent proportional hazards model, the factors associated with development of PTLD in 40 adult liver transplant recipients who were seronegative for EBV prior to transplantation. Of 40 patients, 13 (33%) had a tissue diagnosis of PTLD at a median time of 126 days after transplantation. The multivariate analysis showed that prior CMV disease, the number of steroid boluses given and the number of units of RBC and FFP transfused were significant risk factors for development of PTLD.

Effects of cortisol and adrenalectomy on induction of interferon by endotoxin.

Summary The administration of 1 to 5 mg of cortisol to 1 kg rabbits markedly suppressed interferon production by E. coli endo-toxin. Single doses of cortisol, up to 25 mg, did not decrease circulating interferon levels following inoculations with Newcastle disease virus. This type of interferon was only partially suppressed with multiple injections of 250 mg. Thus, administered cortisol inhibited more readily the production of endotoxin-in-duced interferon than the virus-induced counterpart. Adrenalectomy markedly potentiated the production of interferon by endotoxin. Adrenalectomized rabbits inoculated with endotoxin produced serum interferon to a mean titer of 1:388, while the mean titer in control animals was 1:28, suggesting that endogenous steroids suppress the interferon esponse to endotoxin. Mrs. Linda Carcione offered excellent technical assistance. One of us (Miss Catherine DeAngelis) was a recipient of a summer research fellowship under NIH grant 5416-05.