F. Jay Fricker

Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study

BACKGROUND Post-transplant lymphoproliferative disorders (PTLD) are an important cause of morbidity and mortality after organ transplantation. We sought to better define the prevalence, pathology, current therapeutic approaches, and outcomes of PTLD in a large group of children who had received heart transplants. METHODS We assessed data on patients followed up at 19 centres in the Pediatric Heart Transplant Study (PHTS) from 1993 to 2002. Probability of freedom from PTLD was assessed along with details of presentation, pathology, treatment, and outcomes. Risk factors for survival and event-free survival were investigated. FINDINGS Of 1184 primary transplant recipients, 56 (5%) developed PTLD. Probability of freedom from PTLD was 98% at 1 year, 94% at 3 years, and 92% at 5 years. Mean time to PTLD was 23.8 months. Most common sites of disease were gastrointestinal tract (n=22, 39%) and respiratory system (n=14, 25%). Histology was polymorphic in 35 (65%) and monomorphic in 19 (35%). 47 of 48 cases were of B-cell origin, 39 of 45 (87%) were Epstein-Barr virus positive. Probability of survival was 75% at 1 year, 68% at 3 years, and 67% at 5 years after diagnosis. Death from graft loss was as frequent as death from PTLD. INTERPRETATION About 5% of paediatric heart-transplant recipients develop PTLD, almost always of B-cell lineage and driven by Epstein-Barr virus. Although many achieve satisfactory outcomes, mortality remains substantial with death due to progressive disease and allograft loss. Advances in management should focus on strategies to protect the allograft as well as improved therapies for PTLD.

A six-minute walk test for assessing exercise tolerance in severely ill children

OBJECTIVES The primary objective of this study was to compare exercise tolerance, heart rate, and oxyhemoglobin saturation (Sao2) between a traditional progressive maximal exercise test and a self-paced, 6-minute walk test in severely ill children. STUDY DESIGN Seventeen patients (9 to 19 years of age) performed a progressive maximal exercise test on a cycle ergometer and a self-paced, 6-minute walk test as part of the evaluation for possible heart, lung, or combined heart and lung transplantation. Physical work capacity and peak oxygen uptake were measured during the progressive cycle test. The walk test was performed in a hospital corridor, with patients trying to cover as much distance as possible in 6 minutes at their own pace. Oxyhemoglobin saturation and heart rate were monitored continuously by pulse oximetry and compared between the two tests. RESULTS The distance walked in 6 minutes correlated with peak oxygen uptake (r = 0.70, p < 0.01) and physical work capacity (r = 0.64, p < 0.005). The minimum (Min) Sao2 on the bike test correlated significantly with Min Sao2 on the walk test (r = 0.82, p < 0.001), with 11 of 17 patients having a lower Min Sao2 on the walk test than the bike test (mean Min Sao2, 84% and 86%, respectively). The peak heart rate did not correlate significantly between the bike and walk tests (r = 0.25), although significantly lower (p < 0.01) values were observed on the walk (148 beats/min) than bike (169 beats/min) test. CONCLUSIONS The results suggest that the 6-minute self-paced walk test may provide an alternative method for assessing functional capacity in severely ill children, and that Sao2 measured during progressive exercise testing on a cycle ergometer may not reflect the degree of oxyhemoglobin desaturation during self-paced walking in some patients with severe cardiopulmonary disease.

Absent right superior vena cava with persistent left superior vena cava: implications and management.

Seven cases of absent right superior vena cava with persistent left superior vena cava and normal situs were diagnosed at Childrens Hospital of Pittsburgh. All patients had associated cardiac defects. In two cases the diagnosis was made at autopsy, the first in 1957 and in a 26 day old infant with multiple cogenital defects and the second in 1965 in a 22 day old infant who had pulmonary atresia with ventricular septal defect and patent ductus arteriosus. Since 1966 absent right superior vena cava has been diagnosed at cardiac catheterization in five children. Three of these children have had surgery, two for subaortic stenosis and one for an atrial septal defect. One has an insignificant atrial septal defect and the fifth has a ventricular septal defect. The electrocardiogram of four reveals s short P-R interval and a leftward frontal plane axis of the P wave, suggesting a low atrial focus. None has had any significant conduction problem. All five children are living and well, the oldest has survived 13 years postoperatively. Certain precautions are necessary should corrective cardiac surgery or transvenous pacemaker insertion be necessary.

Coronary arteriosclerosis in pediatric heart transplant survivors: Limitation of long-term survival

Because coronary atherosclerosis after heart transplantation has been a limiting problem in long-term survival of adults, we reviewed the coronary angiograms, and autopsy data when available, from 21 of 30 children who underwent orthotopic heart transplantation and survived the perioperative period. Six patients had coronary atherosclerosis, and five of these patients died 6 months to 3 years after heart transplantation. The late deaths were sudden and unexpected. Coronary angiography demonstrated several types of lesions, including concentric narrowing, tubular segmental lesions, and abrupt obliteration of major coronary vessels. Risk factors assessed included hypertension, hyperlipidemia, cytomegalovirus infection, type of immunosuppressive regimen, number of rejection episodes, and major histocompatibility antigen mismatches. Only the frequency and duration of rejection episodes seemed to be more prevalent in the patients in whom coronary atherosclerosis developed. Despite the benefits of heart transplantation in treating children with end-stage heart disease, coronary atherosclerosis may limit long-term survival. We suggest that these children should undergo serial coronary angiography to identify those at risk for subsequent events related to coronary artery disease.

Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy

OBJECTIVE Structural changes in human mitochondrial DNA (mtDNA) have been implicated in a number of clinical conditions with dysfunctions in oxidative phosphorylation called OX-PHOS diseases, some of which have cardiac involvement. The objective of this study was to assess the frequency and extent of specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. METHODS DNA extracted from tissue derived from the left ventricle of 41 patients with idiopathic dilated cardiomyopathy and 17 controls was amplified by polymerase chain reaction using specific primers to assess the incidence and proportion of 5-kb and 7.4-kb deletions in mitochondrial DNA. RESULTS In reactions using primers to detect the 5-kb deletion, an amplified product of 593 bp was found in low abundance relative to undeleted mitochondrial DNA but with high frequency in a number of controls and patients. A second deletion of 7.4 kb in size was also frequently present in controls and patients. In contrast to previous reports, these deletions were found to be present in both controls and in cardiomyopathic patients, 18 years and younger, including several infants. The 7.4-kb deletion was prominently increased in both frequency and in its proportion relative to undeleted mitochondrial DNA in patients 40 years and older with idiopathic dilated cardiomyopathy. CONCLUSIONS At variance with current literature our study reports a significant presence of both 5 and 7.4-kb deletions in the young and a higher frequency and quantity of the 7.4-kb deletion in the older cardiomyopathic patients in comparison with controls. The increased accumulation of the 7.4-kb deletion as both a function of aging and cardiomyopathy is suggestive that this specific mitochondrial DNA deletion arises more likely as an effect of heart dysfunction rather than as a primary cause of cardiomyopathy.

Experience with Heart Transplantation in Children

Between March 1981 and March 1986, 200 orthotopic heart transplantations were performed at the University of Pittsburgh. Fourteen of those procedures were carried out in children 2 to 16 years of age. Two children received combined liver and heart transplants; one because of familial hypercholesterolemia with associated ischemic heart disease, and the other because of dilated cardiomyopathy associated with intrahepatic biliary atresia. Eight patients had dilated cardiomyopathy, and two had myocarditis. Two had heart transplantations for congenital heart disease: one had multiple muscular ventricular septal defects repaired in infancy and had an associated cardiomyopathy, and the other developed a cardiomyopathic ventricle from a congenital right coronary artery to right atrial fistula. Chronic immune suppression consisted 0.2 to 0.5 mg/kg/d of prednisone and 5 to 50 mg/kg/d cyclosporine, with the addition of antithymocyte globulin for unresolved moderate or severe acute rejection. There were three early postoperative deaths: one from intracranial bleeding, one from Pseudomonas mediastinitis, and one from ischemic injury to transplanted organs. Early postoperative complications included reversible renal failure, hypertension, and seizures. Late problems were related to allograft rejection and side effects of cyclosporine and corticosteroids. Significant rejection episodes occurred in all patients surviving longer than 2 weeks, with seven requiring antithymocyte globulin. Two patients died 8 months following transplantation of severe acute and chronic rejection; another patient required retransplantation for ischemic cardiomyopathy resulting from chronic rejection but subsequently died of recurring rejection 3 months after the second transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of formalin-fixed and frozen myocardial autopsy samples for viral genome in childhood myocarditis and dilated cardiomyopathy with endocardial fibroelastosis using polymerase chain reaction (PCR)

Viral infection of the myocardium is implicated in the pathogenesis of myocarditis and dilated cardiomyopathy (DCM). Enteroviruses have been considered the most common viral etiologic agents, based on peripheral culture and serologic methods. Recently, polymerase chain reaction (PCR) has been shown to be useful in the detection of viral genomes from various infected organs and body fluids. In this study, myocardial samples from autopsy specimens (formalin fixed and fresh frozen) were examined for enteroviral and DNA viral (adenovirus, herpes simplex virus [HSV], and cytomegalovirus (CMV]) genome by PCR. The specimens studied were from 58 patients with myocarditis, 28 patients with DCM and endocardial fibroelastosis [EFE], and 22 controls. Viral genome was detectable in 34 of the 58 (59%) autopsy-proven myocarditis samples (18 adenovirus, 12 enterovirus, 2 CMV, 2 HSV) and 6 of the 28 samples from patients with DCM and EFE (6 adenovirus). We conclude that PCR is effective in the rapid amplification of virus from frozen and formalin-fixed myocardial samples and that adenovirus is an important etiologic agent in viral myocarditis as well as DCM with EFE.

Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients

BACKGROUND Hyperlipidemia is common after cardiac transplantation and it is a risk factor for post-transplantation coronary artery disease. Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia. Pravastatin, a HMG-CoA reductase inhibitor, has been shown to be effective and safe for cholesterol reduction in adult heart transplant recipients. To our knowledge the safety and efficacy of pravastatin therapy in pediatric and adolescent heart transplant populations have not been previously analyzed. Therefore, we evaluated lipid profiles, liver transaminases, rejection data, and possible side effects in pediatric and adolescent cardiac transplant recipients treated with pravastatin. METHODS The study group consisted of 40 cardiac transplant recipients 10 to 21 years old (mean age 16.9 years). Twenty-two patients received pravastatin in addition to an immunosuppressive regimen of either cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Serial determinations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides were available for all pravastatin-treated patients. Pre-treatment lipid values and hepatic transaminases were compared with those measured after therapy with pravastatin. Comparison of pravastatin-induced lipid reduction between groups treated with cyclosporine vs tacrolimus was also made. RESULTS Patients receiving pravastatin experienced a mean 32 mg/dl decrease in TC (p < 0.005) and a mean 31 mg/dl decrease in LDL (p < 0.005), regardless of their immunosuppressive regimen. No statistical differences occurred in the magnitude of mean lipid reduction induced by pravastatin between the groups treated with cyclosporine vs tacrolimus. No significant changes in hepatic transaminase levels were noted, and no clinical evidence of pravastatin-induced myositis occurred in any subjects. CONCLUSION Pravastatin therapy is effective and safe when used in pediatric and adolescent cardiac transplant recipients. Although the pravastatin-induced reduction in TC and LDL was more pronounced in patients receiving cyclosporine, the reduction was not statistically different from that in the tacrolimus group. No evidence of hepatic dysfunction or rhabdomyolysis in patients treated with pravastatin was noted. Long-term studies are required to evaluate the effect of pravastatin therapy on the incidence of accelerated coronary atherosclerosis in this population.

Immunosuppression switch in pediatric heart transplant recipients: Cyclosporine to FK 506

OBJECTIVES We studied rejection, allograft function and side effects, such as hypertension, renal dysfunction and hypercholesterolemia, in seven patients switched from cyclosporine-based triple-drug immunosuppression to FK 506. BACKGROUND A subset of pediatric heart transplant recipients treated with triple-drug immunosuppression consisting of cyclosporine, azathioprine and prednisone experience either persistent rejection when attempts are made to taper corticosteroids or morbidity from cyclosporine and corticosteroids. Experience with the new immunosuppressive agent FK 506 has demonstrated its effectiveness as a single agent in heart transplant recipients, and anecdotal evidence has shown that side effects such as hypertension and hypercholesterolemia may be lower. METHODS Seven patients whom we deemed corticosteroid dependent were switched to FK 506-based therapy. Allograft function, episodes of rejection, need for corticosteroids and incidence of side effects from FK 506 were monitored. The switch to FK 506 was performed using an established protocol. Follow-up time has ranged from 15 to 41 months. Serial right heart catheterizations and endomyocardial biopsies were performed after each reduction of corticosteroid dosing. RESULTS Catheterization data showed no significant change in pulmonary wedge pressure, mean right atrial pressure or cardiac index, indicating no decline in allograft function. Serial echocardiographic variables of allograft function were also stable. At present, all seven patients are free of the corticosteroid portion of their immune suppression. There have been only two episodes of significant acute rejection requiring treatment with intravenous corticosteroids. Antihypertensive medications have been discontinued in five of six patients previously treated with these drugs. Plasma cholesterol, low density lipoprotein and triglyceride levels were decreased, and renal function was stable. CONCLUSIONS Preliminary studies suggest that FK 506 may be an alternative immunosuppressive agent for pediatric and adolescent patients experiencing ongoing rejection or significant morbidity from cyclosporine and corticosteroids and in those patients dependent on corticosteroids for immune suppression.

Orthotopic heart transplantation in children with congenital heart disease.

The early experience (February 1982 to June 1988) with transplantation for the treatment of congenital heart disease at the University of Pittsburgh was disappointing due to an excessively high perioperative mortality. From July 1988 to June 1992, a further 21 children with congenital heart disease underwent orthotopic transplantation. Thirteen had undergone multiple prior palliative procedures (mean, 2.8 per patient). In 12 of these patients, prior procedures involved the pulmonary arteries on one or more occasions. In contrast to our earlier experience, there were no deaths stemming from inadequate surgical reconstruction or pulmonary hypertension. The actuarial survival was 71% at both 1 and 3 years. This did not differ significantly from the survival among 18 patients who underwent transplantation for the management of cardiomyopathy over the same period (1-year and 3-year survival, 83%). The perioperative mortality and short-term survival are now similar for children undergoing transplantation for the treatment of either congenital heart disease or cardiomyopathy. These improved results probably reflect more careful patient selection and an increasing surgical experience with complex reconstructive procedures.