Hepatitis C status of heart transplant recipients.

The records of 155 consecutive patients who underwent successful heart transplantation (HTx) were reviewed to document the incidence of hepatitis C (HCV) infection. One patient was HCV RNA positive pre-HTx, and 12 patients (8%) developed transient or permanent HCV positivity post-HTx. HCV RNA positivity was associated with biochemical features of liver injury. Liver biopsy was performed in 8, and demonstrated features of chronic hepatitis in all. Two patients died of chronic liver failure at 50 and 56 months post-HTx, respectively. Interferon therapy was given to three patients, two of whom converted to HCV negativity. This study suggests that HCV infection is more common than previously anticipated in HTx patients, and varies from a mild transient condition to a fatal chronic liver failure.

Primary bronchogenic carcinoma in recipients of heart transplants.

With the exception of carcinomas of the skin and lip, carcinoma of the bronchus is the most common carcinoma that afflicts recipients of solid organ grafts. Of 859 tumors occurring in 830 recipients of thoracic organs reported to the Cincinnati Tumor Transplant Registry, 242 were carcinomas and 68 of these were bronchogenic carcinomas, which therefore made up 8% of the overall total. There are, however, relatively few reports of heart transplant patients with bronchogenic carcinoma in the literature. We present details of four patients who developed this malignancy out of a total of 196 patients who survived and have been followed up for more than 3 months at our center, an incidence of 2%. The mean period from the time of transplant to diagnosis of malignancy was 58 months (range 11-82 months). The histology was squamous or anaplastic in three cases, and adenocarcinoma in one. Immunosuppressive therapy was reduced in all cases. Resection was carried out in two patients (both of whom died 6 and 11 months later, respectively), resection was combined with chemotherapy and radiation in one patient (alive 15 months later), and therapy consisting of radiation alone was given to one patient (died within 1 month). We conclude that bronchogenic carcinoma is relatively common in patients with heart transplants and that it has a poor prognosis.

Cardiac transplantation in patients aged 60 years or older.

One hundred eighty-four consecutive patients who underwent heart transplantation from January 1987 to December 1994 have been reviewed. Patients who were 60 years of age or older at the time of transplant (Group A, n = 50) showed improved overall survival when compared with younger patients (Group B, n = 134), though this was not statistically significant. Survivals in groups A and B were 94% and 90%, respectively, at 1 year; 86% and 80% at 5 years; and 86% and 78% at 8 years. Overall survival of older patients in the U.S. and worldwide is inferior when compared with younger patients. More thorough pretransplant evaluation of the older patient and improved compliance post-transplantation may be factors in the good results obtained in this group at our own center.

How many endomyocardial biopsies are necessary in the first year after heart transplantation?

Since 1989, the immunosuppressive regimen used in all heart transplant (HTx) patients at our center has consisted of a combination of cyclosporin, azathioprine, and prednisone. No prophylactic cytolytic agents have been given. One hundred consecutive patients were followed for periods of 4-56 months (mean 27 months). The incidence of rejection was so low in the initial 18 patients that we felt confident about reducing the number of routine endomyocardial biopsies (EMBs) that were performed. The mean number of EMBs in this subgroup was 10 (median 11). In the next 20 patients, EMB was performed routinely on only three occasions during the 1st post-transplant year (at 2, 4, and 8 weeks). In the subsequent 62 patients, EMB was performed on post-transplant days 10, 20, 30, and 60. Further EMBs were performed after acute rejection episodes had been treated. No noninvasive methods of diagnosing rejection were employed. In 82 consecutive patients, therefore, the mean number of EMBs within the 1st year was five per patient (median four), with 58% undergoing fewer than five EMBs and 25% requiring more than five EMBs. In the entire group of 100 patients, the mean number of EMBs was 5.9. The incidence of acute rejection requiring increased therapy was 24%. Only 7% required i.v. steroids, two of whom (2%) also required ALG and/or OKT3, with 17% requiring increased oral immunosuppression alone. Actuarial survival was 98% at 30 days, 94% at 1 year, and 92% at 2 years. It is possible that we may have missed acute rejection episodes that resolved spontaneously. However, the excellent medium-term results would suggest that any such rejection episode did not progress to become hemodynamically significant. It may be, therefore, that when an effective immunosuppressive regimen is utilized, the number of EMBs performed at many centers is excessive.

Interferon alpha treatment of chronic hepatitis C in patients with evidence for co-existent autoimmune dysregulation.

BACKGROUND/AIMS: We performed a prospective nonrandomized clinical trial to demonstrate that Interferon (IFN) treatment of individuals with chronic hepatitis C virus (HCV) positive hepatitis (CH-C) and serologic and/or histologic evidence of autoimmune dysregulation is feasible and whether the benefits of successfully treating CH-C are outweighed by the risk of exacerbating Autoimmune Chronic Active Hepatitis (ACAH). PATIENTS AND METHODS: 23 patients with positive autoimmune dysregulation markers underwent a 6 month course of IFN treatment for chronic HCV hepatitis and were followed for a total of 12 months. Patients were treated with 5 MU of a2b IFN administered subcutaneously 7 days a week for 6 months. Complete blood counts and a panel of liver enzymes were monitored weekly for 4 weeks and then monthly for an additional 11 months (6 months of therapy and 6 months of follow-up). Serum auto-antibodies titers were determined prior to treatment, at the end of the treatment and again after 6 months of follow-up. A liver biopsy was performed prior to, and at the end of treatment and again at 12 months. RESULTS: Using the standard ALT criteria for defining a response to IFN therapy, 14 (61%) patients experienced a full response and 3 (13%) experienced a partial response. Forty-three percent of the full responders and 33% of the partial responders experienced a relapse during the follow-up. The titer of each of the previously positive autoantibodies either remained unchanged or increased by 1 or 2 dilutions. No clinical exacerbations of a co-existent ACAH were observed. CONCLUSIONS: Individuals with combined CH-C and one or more markers of autoimmune dysregulation can be treated successfully with IFN. Such treatment does not necessarily increase or exacerbate co-existent ACAH and elevate the serum ALT level. In those who clear HCV-RNA as a result of IFN, the liver histology shifts from one consistent with CH-C to resembling ACAH.

Induction therapy with cyclosporine without cytolytic agents results in a low incidence of acute rejection without significant renal impairment in heart transplant patients.

Since 1989, the immunosuppressive regimen used in all heart transplant patients at our center has consisted of (i) cyclosporine induction therapy (pretransplant p.o. 2-6 mg/kg depending on serum creatinine level, with immediate post-transplant i.v. therapy at 1-3 mg/h until p.o. therapy alone maintains a whole blood trough level of 300 ng/ml by RIA); (ii) azathioprine (2.5 mg/kg/d i.v./p.o.); (iii) methylprednisolone i.v. for 24 h and then prednisone p.o. at 1 mg/kg/d, tapering to 0.1 mg/kg/d at 1 yr. No prophylactic cytolytic agents (ALG, OKT3) were given. One hundred consecutive patients have been followed for periods of 4-56 months (mean 27 months). The incidence of acute rejection requiring increased therapy was 24%, with only 7% requiring i.v. steroids, 2 of whom (2%) also required ALG and/or OKT3, and with 17% requiring increased oral immunosuppression alone. Mean creatinine levels (mg/dl) were 1.3 pretransplant, 1.4 on d 7, 1.5 at 30 d, and 1.8 after 2 yr. Only 1 patient required temporary hemodialysis. Survival was 98% at 30 d, 94% at 1 yr, and 92% at 2 yr. We conclude that cyclosporine induction therapy with steroids and azathioprine without any cytolytic agent results in a low incidence of acute rejection without jeopardizing renal function.

Cryoglobulinemia: a cause for false negative polymerase chain reaction results in patients with hepatitis C virus positive chronic liver disease.

With the introduction of interferon therapy for liver disease due to chronic viral hepatitis, it has become important to test individuals thought to have hepatitis C virus disease for the presence of the virus. Moreover, the current goal of therapy for hepatitis C virus-positive liver disease is to render the individual patient HCV-RNA negative. Recently, it has been reported that as many as one-third of the patients with hepatitis C virus liver disease test positive for the presence of mixed cryoglobulins. Few of these cryoglobulin-positive patients have overt disease manifestations of cryoglobulinemia, such as nephropathy, peripheral neuropathy and vasculitis. Because the cryoglobulins in patients with hepatitis C virus-positive disease are directed at hepatitis C virus epitopes, the precipitation of cryoglobulins from serum samples also effectively removes virus. When the viral carriage rate is low in terms of the number of genomes/unit serum, as occurs in cases that are partially treated, the serum can test negative for hepatitis C virus even by polymerase chain reaction, despite the presence of persistent viremia, if precautions preventing the precipitation of cryoglobulins prior to the removal of the sample for polymerase chain reaction testing are taken. From a group of 75 patients with hepatitis C virus-positive hepatitis seen at our institution in the last year (all HCV-RNA positive), 35% were found to test positive for the presence of cryoglobulins. Importantly, in all cases, the cryoglobulins collected tested strongly positive for HCV-RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival following organ transplantation in an Oklahoma institution, 1985-1993.

Since 1985, a total of 413 patients have undergone 439 solid organ transplants at the authors' institution. The current actuarial one-year survival rate of patients undergoing heart, kidney, lung, or liver transplantation at our center is 94%, 90%, 87%, and 91%, respectively. Five-year survival of heart and kidney recipients is 80% and 75%, respectively. In view of these excellent results and the excellent quality of life that successful organ transplants provide patients with end-stage organ failure, every possible effort should be made to increase organ donation.

Study of the relative incidences of psychosocial factors before and after heart transplantation and the influence of posttransplantation psychosocial factors on heart transplantation outcome.

Psychosocial factors substance abuse, noncompliance, psychiatric problems, and obesity in relation to the outcome of heart transplantation have been investigated. Data were gathered at the time of initial assessment, and patients (n = 53) were monitored during the follow-up after heart transplantation (mean 18 months). Noncompliance, psychiatric problems, or excessive weight before heart transplantation continued after heart transplantation. Significantly fewer substance abusers exhibited similar behavior after heart transplantation (p < 0.01), although in many cases this exposed other psychiatric or compliance problems. Patients with psychiatric problems after heart transplantation had a higher risk of infection (p < 0.01). Both these patients and those who were noncompliant had higher incidences of hospital readmission (p < 0.01) which were reflected in higher medical costs (p < 0.01) during the second year after heart transplantation in both subgroups. We conclude that (1) heart transplant recipients do not alter previous behavior after heart transplantation except with regard to substance abuse, (2) patients exhibiting substance abuse before heart transplantation and abstaining after heart transplantation have other psychosocial problems, (3) psychosocial problems after heart transplantation do not increase the risk for medical complications in the early posttransplantation period except with regard to infection, and (4) the presence of noncompliance and psychiatric problems after heart transplantation is related to increased readmissions and higher total medical costs.

Cardiac allotransplantation across the ABO-blood group barrier by the neutralization of preformed antibodies: the baboon as a model for the human.

The baboon, like the human, expresses A and/or B blood group antigens on its tissues. Anti-A and anti-B antibodies are directed against these antigens, the epitopes of which are carbohydrate structures. Portions of these carbohydrates have been synthesized (trisaccharides A and B, respectively). When infused intravenously, the synthetic trisaccharides form a complex with the specific antibodies and neutralize their activity preventing them from binding to the antigen targets on a transplanted organ. In nonimmunosuppressed, hyperimmunized baboons, the continuous intravenous infusion of the specific trisaccharide alone (for 6 days) inhibited rejection of ABO-incompatible cardiac allografts, extending survival from a mean of 19 min (n = 3) to 8 days (n = 2), at which time the grafts failed from cellular (not vascular) rejection. The combination of long-term pharmacologic immunosuppression plus trisaccharide infusion (for periods of 8 to 19 days) extended survival to a mean of > 28 days (n = 4) with one heart functioning > 52 days. Accommodation clearly occurred in three of the four cases. This form of therapy may permit cadaveric organ allotransplantation across the ABO blood-group barrier in the human.

Specific intravenous carbohydrate therapy. A new concept in inhibiting antibody-mediated rejection--experience with ABO-incompatible cardiac allografting in the baboon.

Heterotopic allografting of ABO-incompatible donor hearts in recipient baboons "hyperimmunized" against the incompatible A or B antigen (n = 3) was followed by hyperacute antibody-mediated vascular rejection within a mean of 19 min. The A and B epitopes against which these antibodies are directed are carbohydrates that can be synthesized. The continuous i.v. infusion of the specific synthetic A or B trisaccharide, beginning immediately pre-transplant and continued posttransplant for several days, prolonged allograft survival to a mean of 8 days (n = 2) and prevented antibody-mediated rejection, graft failure resulting from acute cellular rejection. The addition of triple pharmacologic immunosuppressive therapy (n = 4) resulted in prolongation of graft survival to a mean of > 28 days, with one heart still beating at 52 days; all grafts showed features of cellular rejection. "Accommodation" would appear to have developed in several baboons as graft function continued for periods of up to 39 days after discontinuation of carbohydrate therapy. Specific i.v. carbohydrate therapy should allow organ allografting to be performed across the ABO blood group barrier in humans. Furthermore, if the carbohydrate epitopes on the organs of discordant animals (e.g., the pig) against which human xenoreactive antibodies are directed can be confirmed, then this form of therapy might allow successful discordant organ xenotransplantation in man.