Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of long-term morbidity and mortality after heart transplantation (HTx), whose relationship with CMV infection is uncertain. This study evaluated the influence of CMV infection in the development of CAV. METHODS: We enrolled 166 consecutive HTx recipients who underwent their first transplant from January 1995 to July 2002. All patients received 14 days of intravenous ganciclovir and were prospectively monitored for CMV infection during the first year after HTx. CAV was diagnosed by coronary angiography performed at 1, 5, and 10 years after HTx, following the new criteria of the International Society for Heart and Lung Transplantation. We collected all variables potentially related with the development of CAV. Risk factors were studied using a complementary log-log model. RESULTS: After a median follow-up of 11 years (range, 1-17 years), 72 patients (43%) developed CAV (63.8% CAV(1), 15.2% CAV(2), 20.8% CAV(3)). Symptoms secondary to CAV were present in 32% of these patients, and 8% died because of it. In the regression multivariate analysis, independent variables associated with the development of CAV were donor age (hazard ratio [HR], 1.028; 95% confidence interval [CI], 1.002-1.053; p < 0.028), presence of cellular acute rejection ≥ 2R (HR, 1.764; 95% CI, 1.011-3.078; p < 0.0414), CMV infection (HR, 2.334; 95% CI, 1.043-5.225; p < 0.0354), and not having been treated with a calcium channel blocker (HR, 0.472; 95% CI, 0.275-0.811; p < 0.0055). CONCLUSIONS: Standardized angiographic criteria show CMV infection is associated with the development of CAV.

The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs.

New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC(50) of 0.5muM. Yield reduction assays demonstrated an ED(90) and ED(99) of 0.4 and 0.6muM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7mg/ml (n=6; range, 17.8-35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs (p<0.05, Mann-Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals (p<0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.

Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation.

In this multicenter, randomized study, cytomegalovirus (CMV)-seropositive patients who received an allogeneic bone marrow transplant were provided high-dose intravenous acyclovir (500 mg/m(2) q8h) from the day of transplantation until engraftment. The patients were then randomly assigned to receive either oral valacyclovir, 2 g q.i.d. (n=83), or intravenous ganciclovir, 5 mg/kg q12h for 1 week, then 6 mg/kg once daily for 5 days per week (n=85), until day 100 after transplantation. CMV infection occurred in 12% of the patients who received valacyclovir and in 19% of the patients who received ganciclovir (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.391-2.778; P=.934). CMV disease developed in only 2 patients who received valacyclovir and in 1 patient who received ganciclovir (HR, 1.943; 95% CI, 0.176-21.44; P=.588). Oral valacyclovir can be an effective alternative to intravenous ganciclovir for prophylaxis of CMV disease after bone marrow transplantation.

Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients.

BACKGROUND: Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution. METHODS: Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. RESULTS: The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence. CONCLUSIONS: Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

Subependymal caudothalamic groove hyperechogenicity and neonatal chronic lung disease.

Chronic lung disease is associated with several poorly defined risk factors for impaired cerebral development. Late neonatal onset of subependymal hyperechogenic areas in the caudothalamic groove has been reported in association with dexamethasone treatment and postnatal cytomegalovirus infection. We reviewed charts of 18 patients who developed subependymal hyperechogenicity beyond the first week of life, as well as charts of 79 patients belonging to a prospective surfactant study group. Thirteen of the 18 patients with subependymal hyperdensities had been treated with surfactant and were all found in the subgroup with chronic lung disease. In the surfactant-treated patients who did not develop chronic lung disease, we could not find any patient with subependymal hyperdensities. From the remaining five patients with ultrasound lesions, but who were not treated with surfactant, three had developed chronic lung disease. There was no evident association with dexamethasone treatment or cytomegalovirus infection. Our results support the idea of an association between chronic lung disease and the described echographic lesions in the caudothalamic groove, but the nature of the link between them is still unclear.

Neurologic complications of liver transplantation.

Nineteen adult patients underwent 21 orthotopic liver transplants at the Cleveland Clinic between November 1984, and August 1986. Eight of 19 (42%) patients developed seizures. One patient suffered a single seizure, and seven patients had multiple, generalized seizures. Two of these seven patients became comatose after several days of seizure activity. Over several weeks, both of these patients regained consciousness--however, they exhibited a cerebellar-type syndrome, manifested as severe ataxia, weakness, and dysarthria. Both patients have improved, but remain neurologically impaired. Laboratory evaluation included serum electrolytes, magnesium, osmolality, and cyclosporine levels. Neurologic testing consisted of cerebrospinal fluid (CSF) analysis, computed tomographic (CT) scanning, and electroencephalography (EEG). Although the CSF protein was mildly elevated in two patients, all cultures remained sterile. None of the CT scans demonstrated any abnormalities. In five patients, the EEG showed generalized slowing consistent with diffuse encephalopathy. Other factors associated with seizures in transplant patients were analyzed, including fluid retention, hypertension, high-dose steroids, hypomagnesemia, graft dysfunction, and demyelinization. Many of our patients had the first three of these factors, since all but one developed their seizures within the first ten postoperative days. Only one patient had mild hypomagnesemia. Trough cyclosporine levels (whole blood, HPLC) were not in the toxic range (greater than 500 ng/mL). The serum osmolality was elevated in all four patients in whom it was measured, ranging from 309 to 341 mOsm/kg. Only three patients exhibited graft dysfunction--two moderate and one severe. The cause of neurologic toxicity following transplantation is unclear. Although many factors have been implicated, no common denominator has emerged. Several reports have linked cyclosporine with seizures and other neurologic problems, such as the cerebellar-type syndrome exhibited in two of our patients. Future studies should include magnetic resonance (MR) imaging of the head and measuring osmolality and cyclosporine levels in the blood and CSF.