Seroepidemiology of Helicobacter pylori infection in heart transplant recipients.

We analyzed serum samples obtained from 100 heart transplant recipients before and after transplantation for the presence of IgG antibodies to Helicobacter pylori. Enzyme-linked immunosorbent assay revealed that 35 patients were seropositive before the procedure. Seropositive patients were older than seronegative patients, but the two groups did not differ in terms of cardiac diagnosis, gender, survival, or the number of admissions or rejection episodes. In addition, seropositive patients did not have more-frequent episodes of gastritis, ulcer disease, or gastrointestinal bleeding. Over a mean serological follow-up of 3.4 years, only one of 65 seronegative patients seroconverted. Of the 35 seropositive patients, 14 became seronegative for H. pylori a median of 194 days (range, 47-2,657 days) after transplantation. Seroreverters, as compared with serofast patients, had received more intravenous and total antibiotics during follow-up (P = .01), were more likely to have received a combination of antibiotics active against H. pylori (P < .025), and had received more antirejection treatment (P = .01). The incidence of H. pylori infection is not increased after heart transplantation, and many seropositive patients serorevert after transplantation when antibacterial and immunosuppressive agents are administered.

Investigation of cytomegalovirus infection as a risk factor for coronary atherosclerosis in the explanted hearts of patients undergoing heart transplantation.

Infection with a human herpes virus, particularly cytomegalovirus (CMV), has been hypothesized to be a cofactor in the development of atherosclerosis in humans. We investigated the association of prior CMV infection with the presence of atherosclerosis in the coronary arteries of the native heart of 314 individuals undergoing heart transplantation. Age, male gender, race, tobacco use, and previous general and cardiac surgery were also studied as covariables. Factors associated with the presence of coronary atherosclerosis by univariate analysis were age greater than the median of 48 years (odds ratio [OR] = 5.9, 95% confidence intervals [CI] 3.0-11.6; P < 0.0001), tobacco use (OR = 3.8, 95% CI 2.1-7.0; P < 0.005), CMV seropositivity (OR = 3.1, 95% CI 1.8-5.5; P < 0.001), and male gender (OR = 3.0, 95% CI 1.6-5.4; P < 0.0005). When patients were divided into quartiles based on age, coronary atherosclerosis was shown to be associated with CMV seropositive status only in the youngest quartile of patients (OR = 3.6, 95% CI 1.4-8.9; P < 0.01) but not in the older three quartiles of patients (OR = 0.9, 95% CI = 0.3-2.4; P > 0.5). In multiple logistic regression analyses, CMV seropositivity was not a significant independent variable in the whole group of patients (P = 0.13) but remained a significant variable in the youngest quartile of patients (P = 0.01). However, 43% of these younger patients and 29% of all patients with coronary atherosclerosis were seronegative for CMV.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.

Interleukin-6 production in posttransplant lymphoproliferative disease.

IL-6, a multifunctional cytokine produced by monocytes, fibroblasts, and endothelial cells, promotes the growth of EBV-immortalized B cells in vitro and renders these cells tumorigenic in athymic mice. In the present study, serum/plasma IL-6 bioactivity was found to be abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients with posttransplant lymphoproliferative disease (PTLD), with a mean maximal level of 196.7 U/ml. This represents a 16.4 increase above the normal mean (11.3 U/ml). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (mean maximal level 41.4 U/ml, P = 0.0007). When transferred to single cell culture, the 11 PTLD tissues produced 640 to 1.25 x 10(6) IL-6 U/ml in the culture supernatant, with a mean maximal level of 35,025 IL-6 U/ml. Cell separation experiments demonstrated that the adherent cells, identified as non-B cells, were the principal source of IL-6 production in vitro by PTLD tissue. Control cultures of inflammatory lymphoid tissue negative for lymphoproliferative disease as well as of PBL from patients with acute EBV-induced infectious mononucleosis consistently produced < 10 IL-6 U/ml. Thus, IL-6 is produced at high levels by PTLD tissues and may play a critical role in the pathogenesis of PTLD.

Herpes simplex virus hepatitis after solid organ transplantation in adults.

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 less than 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.

Epidemiology of genital herpes in Pittsburgh: serologic, sexual, and racial correlates of apparent and inapparent herpes simplex infections.

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).

Enhanced antibody responses to Epstein-Barr virus in HIV-infected homosexual men.

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.

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.

Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies.

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).

Occurrence of cytomegalovirus hepatitis in liver transplant patients.

The differential diagnosis of liver dysfunction after orthotopic liver transplantation can be difficult. Cytomegalovirus (CMV) hepatitis is one possibility. This report reviews our experience with 17 cases of pathologically proven CMV hepatitis following liver transplantation and demonstrates the need for percutaneous liver biopsies to establish the diagnosis. There were seven pediatric patients (ages 2-11 years, five males, two females) and ten adult patients (ages 17-53 years, eight males, two females). The most common symptoms were prolonged fever (15 patients, with a mean duration of 22 +/- 5.5 days), elevation in total bilirubin (14 patients), and elevation in liver enzymes (15 patients); all symptoms were also found in rejection. Leukopenia and thrombocytopenia, reported to frequently occur with CMV infection, were found in only three and five patients, respectively. Twelve patients with the above symptoms underwent percutaneous biopsy on one or more occasions to differentiate CMV hepatitis from rejection. The diagnosis was made at retransplantation in five patients. CMV hepatitis followed treatment for acute rejection in 14 patients and occurred without additional immunosuppression in three patients. All patients were maintained on cyclosporine and prednisone. Acute rejection episodes were treated with a 5-day tapering dose of steroids (17 courses in 12 patients), OKT3 monoclonal antibody [Ortho (4 patients)] antithymocyte globulin [Upjohn (2 patients)], and azathioprine (1 patient). CMV was isolated from urine (nine patients), blood (nine patients), throat (seven patients), lungs (two patients), and other organs (two patients). CMV was cultured from the liver biopsy specimens in five of the seven attempts in pediatric patients. When the diagnosis was confirmed in the absence of rejection, immunosuppression was routinely lowered. When rejection occurred concomitantly with CMV hepatitis, therapy had to be individualized. Retrospectively, three patients treated for rejection were noted at retransplantation to have only CMV hepatitis, and all three patients died. A high index of suspicion and the judicious use of liver biopsies is essential in order to differentiate CMV hepatitis from other causes of posttransplant liver dysfunction.

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 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.

Leukocyte interferon for treating first episodes of genital herpes in women.

Women experiencing their first episodes of genital herpes were treated, beginning within three days of the onset of lesions, with 5 X 10(4) units of human leukocyte interferon/kg of body weight for 12 doses over 14 days (total, approximately 3.6 X 10(7) 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.

Epstein-Barr virus, cytomegalovirus, and other viral infections in children after liver transplantation.

We studied 51 consecutive pediatric patients for the frequency and morbidity of viral infections after liver transplantation. The incidence of primary (67%) and reactivation (48%) Epstein-Barr virus (EBV) infections and reactivation (88%) cytomegalovirus (CMV) infection was comparable to that seen in adult transplant recipients. However, fewer pediatric than adult transplant recipients experienced primary CMV infection (P less than .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.

Pediatric liver transplantation: patient evaluation and selection, infectious complications, and life-style after transplantation.

Liver transplantation is an increasingly accepted treatment for children with end-stage liver disease. Evaluation of the patient and appropriate patient selection for transplantation will become increasingly important issues as more and more children come to transplantation and compete for available organs. Numerous complications occur after transplantation, including infections. We have summarized our experience with bacterial, fungal, and viral infections in these patients and emphasize the need for continued improvement in immune suppressive drugs and regimens to minimize such complications. And finally, information presented on 65 pediatric patients followed 2 to 5 years suggests that, despite numerous complications and often prolonged hospitalization for transplantation, life-style after transplantation appears to be significantly improved.

Epstein-Barr virus infections and DNA hybridization studies in posttransplantation lymphoma and lymphoproliferative lesions: the role of primary infection.

Fourteen patients who developed B cell lymphomas or lymphoproliferative lesions after kidney, liver, heart, or heart-lung transplantation in Pittsburgh during 1981-1983 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.

Interferon susceptibility of herpes simplex virus strains isolated from patients enrolled in clinical trials.

Herpes simplex virus type 1 strains isolated from patients who had received interferon in a clinical trial were not more resistant to human leukocyte interferon than strains derived from recipients of a placebo. The susceptibility of herpes simplex virus type 2 strains isolated from herpes genitalis was slightly less than that of herpes simplex virus type 1 strains causing herpes genitalis.

Response of cloned progeny of clinical isolates of herpes simplex virus to human leukocyte interferon.

First- and third-generation cloned progeny viruses were derived from clinical isolates of herpes simplex virus and examined for their sensitivities to human interferon by inhibition of plaque formation in Vero cells. The dose-response curves obtained with the first- and third-generation clones were similar to those obtained with the parental isolates, and both the parent and the clones showed similar sensitivities to interferon. These results suggest that clinical isolates of herpes simplex virus consist of a homogeneous population of virus particles with respect to interferon sensitivity. The dose-response curves obtained with herpes simplex virus demonstrated a shallower slope than those obtained with vesicular stomatitis virus. Vesicular stomatitis virus plaque formation as completely inhibited at high concentrations of interferon, whereas complete inhibition of plaque formation by herpes simplex virus did not occur at the highest concentration of interferon used. Cloned progeny were derived from plaques appearing in the presence of high concentrations of interferon. The dose-response curves and interferon sensitivities of these clones were similar to those of the parent and third-generation clone from which they were derived. There was no evidence for genetic heterogeneity with respect to interferon sensitivity.

Antiviral effect of pyran against systemic infection of mice with herpes simplex virus type 2.

The immunomodulator pyran markedly protected 5-week-old mice from lethal intravenous infection with herpes simplex virus type 2. The 50% lethal dose was increased almost 100-fold in pyran-treated mice as compared with controls. Although the protection was not as marked in older mice (10 and 16 weeks old), there was a significant increase in mean survival time. When the pathogenesis of herpesvirus disease was monitored in control and drug-treated mice, the effect of pyran was most evident in the spinal cord, where virus was recovered from 20 of 25 control mice and from only 6 of 25 pyran-treated mice. There was also a significant reduction in the titer of virus present, and virus appeared later in the spinal cord of pyran-treated mice than in control mice. The protective effect of pyran was observed only when the drug was administered 24 h before viral challenge, was seen after both intraperitoneal and intravenous injection, and was not due to direct inactivation of the virus.