Gerard J. Boyle

Posttransplantation lymphoproliferative disorders in pediatric thoracic organ recipients

OBJECTIVEnTo determine the frequency, predisposing factors, clinical presentation, and outcome of posttransplantation lymphoproliferative disorders (PTLDs) in pediatric thoracic organ transplant recipients.nnnMETHODSnRetrospective review of the medical records of all 120 children who survived longer than 1 month after thoracic organ transplantation at our center.nnnRESULTSnPTLD was diagnosed in 14 patients (11.7%), including 7.7% of heart and 19.5% of heart-lung/lung recipients. Presentation of PTLD was variable, ranging from asymptomatic lung nodules on chest radiograph to diffuse multiorgan failure. Treatment with a reduction of immunosuppression and antiviral therapy resulted in resolution of PTLD in eight patients. Eight patients died. PTLD contributed to death in five. No patient seropositive for Epstein-Barr virus (EBV) before transplantation had PTLD. There was a significant association between primary EBV infection after transplantation and the presence of PTLD.nnnCONCLUSIONSnPTLD occurs with greater frequency in pediatric thoracic organ transplant recipients than in the adult transplant population. Primary EBV infection after transplantation is the major risk factor for the development of PTLD. Patients in whom primary EBV infection develops after transplantation should be managed with a reduction in immunosuppression and with heightened surveillance for the development of PTLD.

Long-term survivors of pediatric heart transplantation: A multicenter report of sixty-eight children who have survived longer than five years

OBJECTIVEnShort-term survival after pediatric heart transplantation is now excellent, but ultimately the efficacy of this procedure will depend on duration and quality of survival. We sought to evaluate the clinical course of long-term survivors of heart transplantation in childhood.nnnMETHODSnPatients who had undergone heart transplantation at the university hospitals of Stanford, Columbia, and Pittsburgh between 1975 and 1989 and survived longer than 5 years from transplantation were identified and their clinical courses retrospectively reviewed.nnnRESULTSnSixty eight children have survived more than 5 years from transplantation, and 60 (88%) are currently alive with a median follow-up of 6.8 years (5 to 17.9 years). Thirteen have survived more than 10 years from transplantation. Renal dysfunction caused by immunosuppressive agents was common, and two patients required late renal transplantation. Lymphoproliferative disease or other neoplasm occurred in 12 patients, but none resulted in death. Coronary artery disease was diagnosed in 13 patients (19%), leading to retransplantation in eight. Death after 5 years was related to acute or chronic rejection in 5 of 8 cases. Two of the deaths were directly related to noncompliance with immunosuppressive medication. All survivors are in New York Heart Association class 1.nnnCONCLUSIONSnLong-term survival with good quality of life can be achieved after heart transplantation in childhood, though complications of immunosuppression remain common. Posttransplantation coronary artery disease is emerging as the main factor limiting long term graft and patient survival.

Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression

Background. Posttransplantationdiabetes mellitus (PTDM) is a well-known complication of tacrolimus-based immunosuppression in both adult and pediatric solid organ recipients. The “natural history” of diabetes in the pediatric thoracic transplant population has not yet been described. Methods. We identified all pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression who developed PTDM. Medical records were reviewed, with a particular focus on the clinical course of PTDM and its relationship to drug weaning. Results. Diabetes developed in 24 of 143 (17%) 30-day survivors of heart (12/96, 13%) and heart-lung/lung (12/47, 26%) transplantation. In 17 (71%) patients, the immunosuppressive regimen at the onset of PTDM also included maintenance corticosteroids. Seventeen patients demonstrated glucose intolerance before the onset of diabetes. Nine patients (38%) developed diabetes during pulsed corticosteroid therapy. Median time of onset after transplantation was 9.0 months. All patients required s.c. insulin for glucose control. The median follow-up from transplant was 49.9 months. There was a significant decrease in mean tacrolimus dosage (P <0.01), tacrolimus level (P <0.04), and steroid dosage (P <0.02) from onset of PTDM to most recent follow-up. Despite this significant reduction in immunosuppression, only 3/24 (13%) patients were successfully weaned off insulin. Conclusions. Diabetes mellitus is a common complication in pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression. Insulin dependence in our population rarely resolved, even after lowering tacrolimus and steroid doses. Discontinuation of steroids did not guarantee resolution of diabetes.

Endomyocardial biopsy in pediatric heart transplant recipients: A useful exercise? (Analysis of 1169 biopsies)

Abstract: The objective of this study was to define the diagnostic yield for endomyocardial biopsy (EMB) procedures performed for various indications in a large pediatric heart transplant population. Endomyocardial biopsy procedure has been employed as the ‘gold standard’ for rejection surveillance. Previous studies have questioned the value of surveillance EMB beyond the early post‐transplant period. We retrospectively reviewed data on 82 pediatric heart transplant recipients with serial EMB. A total of 1169 EMB were performed during a follow‐up period of 2–149u2003months (median 41u2003months). EMB were classified by age at transplantation, time from transplant, immunosuppressive regimen used [tacrolimus vs. cyclosporin A (CsA)] and indication, i.e. surveillance, follow‐up after rejection or lowering of immunosuppression, non‐specific clinical symptoms and graft dysfunction. During the first year after heart transplantation, surveillance EMB demonstrated significant rejection [International Society for Heart and Lung Transplantation (ISHLT) grade ≥u20033A] in 18% of biopsies with the yield being 14–43% for all other indications. Surveillance EMB 1–5u2003yr post‐transplantation were found to have a lower diagnostic yield in infants (4% vs. 13% in children) and in patients with favorable first‐year rejection history (9% vs. 17% in ‘frequent rejectors’). Tacrolimus‐based immunosuppression was associated with significantly less rejection, but only in the first year post‐transplantation (14% in tacrolimus vs. 24% in CsA surveillance EMB, p =u20030.035). Surveillance EMB remains an important diagnostic tool for rejection surveillance during the first 5 years after pediatric heart transplantation. Endomyocardial biopsy is particularly warranted after reduction of immunosuppression and for monitoring for ongoing rejection after treatment of acute rejection episodes.

Tacrolimus dosage requirements after initiation of azole antifungal therapy in pediatric thoracic organ transplantation

Abstract:u2002 Azole antifungals inhibit the metabolism of tacrolimus mediated by CYP3A4. Upon initiation of azole therapy, the required dose reduction of tacrolimus is unknown. We reviewed our experience with azole antifungals in our pediatric thoracic transplant population receiving tacrolimus. Tacrolimus levels and dosage requirements were compared before and during azole therapy. Thirty‐one patients received both tacrolimus and an azole antifungal (fluconazoleu2003=u20039, itraconazoleu2003=u200322). The tacrolimus dose was empirically reduced by approximately one‐third when azole therapy was initiated. Mean tacrolimus dose requirements decreased by 68% within the first month of therapy (pre‐azole: 0.27u2003±u20030.14u2003mg/kg/day; 30u2003day post‐azole: 0.087u2003±u20030.069u2003mg/kg/day; pu2003<u20030.001). Despite a mean decrease in tacrolimus dose from baseline of 33, 42, and 55% on day 1, 2, and 4 of azole therapy, respectively, there was still an unintended 38% increase in tacrolimus levels during the first month of azole therapy. A calculated dose‐reduction protocol of 50% on day of azole initiation, 70% on day 3, and 75% on day 14 should result in minimal mean changes in the tacrolimus levels. There was no difference in tacrolimus dose reduction between fluconazole and itraconazole groups. Azole antifungals markedly decrease tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one‐third is insufficient, and dose reduction of at least 50% upon azole initiation seems warranted. Once azole antifungal therapy is initiated, frequent therapeutic drug monitoring is required.

CONNECTION GEOMETRY AFFECTS RESISTANCE TO FLOW IN FONTAN CONNECTIONS: IN VITRO STUDIES † 174

Recent modifications to the original Fontan procedure have placed emphasis on the nature of the connection between the cavae and the pulmonary arteries. Since there is no ventricle acting as a pump to drive blood through the pulmonary circulation, a critical determinant of outcome is the overall resistance to flow across the surgical connection and pulmonary circuit. This study addressed the hypothesis that Fontan connection geometry significantly affects resistance to flow. Methods: Connections of the following three types were performed on explanted canine hearts; (1) atriopulmonary connection (APC), (2) lateral tunnel total cavopulmonary connection (TCPC) and(3) partial cavopulmonary connection (intra-atrial baffle with posterior cavo-atriopulmonary connection) (PCPC). Anatomically correct transparent urethane flow models were constructed using injection molding and casting procedures. The models were perfused using a blood analog fluid at flow rates ranging from 2-7 L/min. A variable voltage pumping system allowed input voltage, which can be related to the rate of energy expenditure, to be recorded for each flow condition. Results: Resistances at constant flow differed for each geometry (p<.01). The TCPC had the lowest values of resistance for equivalent flows through each model followed by the PCPC and the APC. Resistance differentials increased with flow rate for each model(p<.05). Conclusions: Based on these experiments, we conclude that a lateral tunnel TCPC offers the least resistance flow among these commonly used connections. The observed increase in resistance differentials with flow may have implications regarding exercise capacity and suggests that minimizing resistance in the Fontan circuit may have significant implications for postoperative morbidity and survival. Figure

PROPAGATION OF ACTIVATED LYMPHOCYTES UNDER DIFFERING CULTURE CONDITIONS FROM ENDOMYOCARDIAL BIOPSY SAMPLES OF HEART TRANSPLANT RECIPIENTS. • 222

PROPAGATION OF ACTIVATED LYMPHOCYTES UNDER DIFFERING CULTURE CONDITIONS FROM ENDOMYOCARDIAL BIOPSY SAMPLES OF HEART TRANSPLANT RECIPIENTS. • 222