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.

Fourteen patients who developed B cell lymphomas or lymphoproliferative lesions after kidney, liver, heart, or heart-lung transplantation in Pittsburgh during [1981][1982][1983] had active infection with Epstein-Barr virus (EBV) of the primary (six patients), reactivated (seven patients), or chronic (one patient) type. In transplant patients without tumors, the incidence of EBV infection was 30% (39 of 128). Only three of these patients had primary infections. Thus the frequency of active infection was significantly higher in patients with tumors, and patients with primary infections were at greater risk of developing tumors. Five of 13 tumors tested contained EBV nuclear antigen (EBNA) and nine of 11 contained EBV genomes detected by DNA-DNA hybridization with BamHI K, BamHI W, or EcoRI B cloned probes. All EBNA-positive tumors, except one, were also positive by hybridization. Only one tumor was negative for both EBNA and EBV DNA. These data suggest that EBV plays an etiologic role in the development of these lesions.Epstein-Barr virus (EBV) is a human herpesvirus associated with an array of conditions that range from inapparent infection and infectious mononucleosis to lethal lymphoproliferative syndromes, nasopharyngeal carcinoma, Burkitt's lymphoma, and B cell lymphomas in immunocompromised patients [1]. The precise role of the virus in carcinogenesis is unclear, although in Burkitt's lymphoma the importance of viral transformation of infected B lymphocytes and chromosomal translocations has been emphasized [2]. It is even less clear in lymphomas and lymphoproliferative lesions arising in immuno-compromised patients, where the immunopathology may not be uniform and where chromosomal studies are largely lacking.Recently, we reported on the reversibility of lymphomas and lymphoproliferative lesions in a series of 17 transplant patients after reduction of cyclosporine and steroid immunosuppression [3]. In that preliminary report we noted that seven of these patients had evidence of primary EBV infections and eight had evidence of reactivated infection. Six tumors had evidence of EBV nuclear antigen (EBNA) and seven had evidence of EBV DNA by nucleic acid hybridization. [6] reported the results of studies on 19 renal transplant patients who developed lymphoproliferative disorders and lymphomas after transplantation. All the patients except one were receiving azathioprine, prednisone, and antithymocyte globulin. Two of their patients developed primary EBV infection, in six the infection reactivated, and 12 had evidence of EBV DNA in their tumors by hybridization studies. Bieber et al. [7] reported that five of 39 heart transplant recipients receiving cyclosporine, prednisone, and antithymocyte globulin developed lymphomas. Four tumors were positive for EBV DNA by cRNA-DNA filter hybridization, and three patients had serological evidence of EBV infection.We report here evidence for active EBV infection in all of our patients with tumors and a significantly higher frequency of primary infection than found i...

One hundred twenty-one adult liver transplant recipients were studied for the incidence, risk factors, and morbidity associated with herpesviruses infections after transplantation. The overall incidence of infection was 59% for cytomegalovirus (CMV), 35% for herpes simplex virus (HSV), 25% for Epstein-Barr virus (EBV), and 7% for varicella-zoster virus (VZV). Primary CMV infection occurred in 46% and reactivation CMV infection in 67% of the susceptible recipients. Symptomatic and disseminated CMV diseases were more common when patients developed primary infection (P less than .01, for both comparisons). The donor organ appeared to be the only important source of CMV infection in seronegative recipients. The use of OKT3 antibodies was associated with disseminated CMV disease in patients with primary infection (P = .04) but not with reactivation infection (P greater than .10). Although most HSV infections were oral or genital reactivations, three cases of HSV hepatitis occurred--one was a primary infection. Symptomatic reactivations of HSV were observed in 53% of HSV-seropositive recipients who received OKT3, versus 31% of seropositive recipients who did not receive OKT3 (P = .05).

Twelve patients developed herpes simplex (HSV) hepatitis a median of 18 days after solid organ transplantation. This is earlier than cytomegalovirus hepatitis, which usually occurs 30-40 days after transplantation. Eight recipients (67%) died, and in seven, the diagnosis was made at autopsy or <48 h before death. Clinical manifestations associated with mortality were hypotension, disseminated intravascular coagulation (DIC), metabolic acidosis, gastrointestinal bleeding, and bacteremia. Laboratory abnormalities at diagnosis associated with mortality were high creatinine, low platelet counts, prolonged partial thromboplastin time, and a high percentage of band forms on the blood smear. Disseminated HSV disease was noted in four of six patients who had an autopsy and included involvement of lungs in three and the gastrointestinal tract in three. Five recipients developed DIC and all died. Pathologically, HSV hepatitis has two forms, focal and diffuse. All three patients with diffuse liver pathology died. However, three of seven with focal liver pathology survived with antiviral therapy, which suggests that early diagnosis and treatment may be lifesaving. None of these patients had received prophylactic acyclovir. It is possible that acyclovir prophylaxis may be able to prevent this disease.Herpes simplex virus (HSV) hepatitis is considered rare [1]. It has been observed most frequently as part of disseminated HSV in immunologically compromised patients or during pregnancy. Sporadic cases have been reported from this institution in renal transplant recipients and have ended fatally [2,3], as have most cases reported in the literature. Here we report 12 cases that occurred after solid organ transplantation over a 9-year period (1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987)(1988). This series is large enough to allow us to determine the approximate frequency of HSV hepatitis in our transplantation population; to present the effect of viral dissemination, the nature of the liver pathology, and the range of clinical and laboratory characteristics of the disease; and to investigate prognostic factors. Materials and Methods DefinitionsCases of HSV hepatitis were diagnosed by laboratory, histologic, and clinical findings of one or more of the following in liver tissue from a biopsy or autopsy: isolation of HSV, positive immunoperoxidase staining for HSV antigen, or histology showing intranuclear inclusion bodies and pathology consistent with HSV lesions. In one case there was no liver tissue to examine, and the diagnosis was made by isolation of HSV from multiple sites outside the liver, including buffy coat, and clinical evidence of fulminant hepatitis. The histologic pattern of Laboratory methodsTissue specimens obtained by biopsy or at autopsy were examined after routine staining and processing for detection of HSV antigen by immunoperoxidase staining and, on occasion, processed for isolation of HSV. Other specimens obtained from transplant recipients for viral isolation included throat wash, urine, buffy co...

We studied 51 consecutive pediatric patients for the frequency and morbidity of viral infections after liver transplantation. The incidence of primary (67fT/o) and reactivation (480/0) Epstein-Barr virus (EBV) infections and reactivation (88fT/o) cytomegalovirus (CMV) infection was comparable to that seen in adult transplant recipients. However, fewer pediatric than adult transplant recipients experienced primary CMV infection (P < .01). Five (38%) of 13 CMV infections were symptomatic and included hepatitis, pneumonitis, enteritis, and mononucleosis. Two of 14 patients with primary EBV infection subsequently developed, at two months and two years after initial infection, an EBV-associated lymphoproliferative syndrome, and one of 10 patients with reactivated EBV infection developed a possible EBV-associated febrile encephalopathy. Other viruses causing infection in these children included herpes simplex virus, varicella-zoster virus, adenovirus, parainfluenza virus, respiratory syncytial virus, and rotavirus.Both Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are notable for their ubiquity, latency, and tendency to reactivate in the immunosuppressed host. Reports on the frequency and morbidity of EBV and CMV infections in adult transplant recipients from this center are available [1][2][3]. Comparable data in children have not been reported because, until recently, they had not undergone transplantations in large numbers. The behavior of EBV and CMV in pediatric transplant recipients is of interest not only because children may respond differently, but unlike adults, a large proportion of children have not been infected by these viruses before transplantation. Hence, a smaller number of children are at risk of developing reactivation infections; however, a greater number may be susceptible to primary infections and their consequent morbidity.

IL-6, a multifunctional cytokine produced by monocytes, fibro-

Women attending family planning clinics in western Pennsylvania were enrolled into a prospective epidemiologic study of herpes simplex virus (HSV) infection. Detection of antibodies to HSV-1 and HSV-2 was based on an immunodot assay using type-specific glycoproteins gG-1 and gG-2. Serologic and historical data at enrollment were analyzed for 4527 subjects; the seroprevalence of HSV-2 was 21.6%. By multivariate analysis, HSV-2 infection as determined by seroprevalence was significantly and independently associated with age, years of sexual activity, race, one or more episodes of other genital infections, lower annual family income, and multiple sexual partners. The presence of antibody to HSV-1 was associated with a lower frequency of antibody to HSV-2, suggesting that developed immunity to HSV-1 protected against HSV-2 infection. Of 926 participants who had antibody to HSV-2, only 117 (12.6%) reported a history of genital herpes. Hence the vast majority of HSV-2 infections were inapparent. Although seroprevalence of HSV-2 was higher among black (35.4%) than white (18.5%) women, black women appeared to have significantly less symptomatic genital herpes than white women (7.7% vs. 14.7%, P less than .01).

We investigated the association between human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) infections in 593 homosexual men. The status of EBV infection in this group was evaluated based on serological evidence of EBV-specific antibody responses. The geometric mean titers (GMT) of antibody to EBV capsid antigen (EBV-VCA) (1:154) and EBV early antigen (EA) (1:16) in 141 HIV-seropositive men were significantly higher than respective titers in 452 HIV seronegative men (1:95 and 1:12). Antibody titers to EBV were higher in HIV-infected men with lymphadenopathy than in asymptomatic HIV-seropositive men. However, these correlation were less evident in patients with AIDS-related complex. Elevated antibody titers to EBV were found to be independent of levels of total serum IgG. Cytomegalovirus (CMV) antibody titers were also found to be significantly increased among HIV-seropositive men, independent of total IgG. Antibody titers to EBV were not correlated with those to CMV in either HIV-seronegative or HIV-seropositive men. Subjects without evidence of HIV infection, but who had high antibody titers to EBV-VCA and EBV-EA, had elevated mean numbers of CD3+, CD4+, and CD8+ cells, and lower levels of CD4+/CD8+ cell ratios compared to subjects with low EBV-antibody titers. This study suggests that the elevated levels of circulating antibodies against EBV in homosexual men are associated with loss of control of latent EBV due to HIV infection.