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

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 1,169 EMB were performed during a follow-up period of 2-149 months (median 41 months). 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 > or = 3A] in 18% of biopsies with the yield being 14-43% for all other indications. Surveillance EMB 1-5 yr 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 = 0.035). 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.     

Hemodynamic support of a 15-year-old waiting for a heart transplant: Is there a role for levosimendan in pediatric heart failure?

Decompensated heart failure in children requires rapid and aggressive support. In refractory cases, invasive supportive care is essential to ensure cardiac output. This results in lengthy pediatric intensive care unit (PICU) stays, secondary morbidity, and high cost. Levosimendan may help palliate the pitfalls encountered with the usual treatment. It has been shown to improve hemodynamics and decrease morbidity and mortality from heart failure in adult trials and pediatric cohorts. We report the case of a 15-year-old boy with dilated cardiomyopathy and refractory ventricular dysfunction who was weaned from continuous inotropes and discharged from the PICU with levosimendan while waiting for heart transplantation.     

Infectious risk in pediatric organ transplant recipients: Is it increased with the new immunosuppressive agents?

The risk of infection in pediatric organ transplant recipients is determined by several factors, including age, the types of organ transplanted and the immunosuppressive treatment which has dramatically changed over the past 10 yr. Little information has been reported regarding the infectious complications related to the current immunosuppressive protocols used in these children. This paper reviews (i) the immunosuppressive agents, focusing on their mechanisms of action and on the new regimens, (ii) the infections related to excessive immunosuppression and also anti-infectious properties or infectious adverse reactions associated with specific immunosuppressive agents. With the new immunosuppressive protocols, the advances in immunologic monitoring, microbiological diagnosis, anti-infectious prophylactic and preemptive treatments, strategies to minimize the risk of infection related to the immunosuppressive therapy are proposed.     

A multicenter survey on post‐transplant lymphoproliferative disorders in pediatric heart transplant recipients: A case for development of consensus guidelines for screening,surveillance, and treatment?

Post‐transplant lymphoproliferative disorders (PTLD) are the main malignancy seen after pediatric heart transplant and are a significant cause of morbidity and mortality. Prior to the development of detailed guidelines, we sought to identify trends in screening, diagnosis, and treatment of pediatric PTLD. All Pediatric Heart Transplant Society (PHTS) institutions were surveyed. No identifiable patient information was shared. From 56 PHTS centers, 22 responses were received (39.3%). 100% agree PTLD cannot be diagnosed solely based on elevated Epstein‐Barr virus (EBV) load. All respondents routinely screen for EBV by blood PCR, but frequency of screening varies. There was intermediate consensus regarding the use of computed tomography (CT) and/or positron emission tomography (PET) in surveillance management for PTLD. Most centers require a diagnostic biopsy before initiating new treatment for PTLD (14 of 18, 77.8%), but many reduce immune suppression based on elevated EBV without pathologic PTLD (16 of 22, 72.7%). Beyond immune modulation, rituximab is most commonly used (9 of 13, 69.2%). Consultation with oncology is common (17 of 17, 100%), but timing varies widely. Our survey highlights significant elements of agreement and significant practice variation among PHTS institutions regarding pediatric PTLD. Reduction of immune suppression prior to pathologic diagnosis of PTLD is a common management strategy. When this fails, rituximab is used, but is most often reserved until after confirmation of the diagnosis. Oncology subspecialists are commonly involved in these cases. Our findings highlight the need to develop improved guidelines for evaluation and treatment of pediatric PTLD.     

Long‐term surveillance biopsy: Is it necessary after pediatric heart transplant?

Due to limited and conflicting data in pediatric patients, long‐term routine surveillance endomyocardial biopsy (RSB) in pediatric heart transplant (HT) remains controversial. We sought to characterize the rate of positive RSB and determine factors associated with RSB‐detected rejection. Records of patients transplanted at a single institution from 1995 to 2015 with >2 year of post‐HT biopsy data were reviewed for RSB‐detected rejections occurring >2 year post‐HT. We illustrated the trajectory of significant rejections (ISHLT Grade ≥3A/2R) among total RSB performed over time and used multivariable logistic regression to model the association between time and risk of rejection. We estimated Kaplan‐Meier freedom from rejection rates by patient characteristics and used the log‐rank test to assess differences in rejection probabilities. We identified the best‐fitting Cox proportional hazards regression model. In 140 patients, 86% did not have any episodes of significant RSB‐detected rejection >2 year post‐HT. The overall empirical rate of RSB‐detected rejection >2 year post‐HT was 2.9/100 patient‐years. The percentage of rejection among 815 RSB was 2.6% and remained stable over time. Years since transplant remained unassociated with rejection risk after adjusting for patient characteristics (OR = 0.98; 95% CI 0.78‐1.23; P = 0.86). Older age at HT was the only factor that remained significantly associated with risk of RSB‐detected rejection under multivariable Cox analysis (P = 0.008). Most pediatric patients did not have RSB‐detected rejection beyond 2 years post‐HT, and the majority of those who did were older at time of HT. Indiscriminate long‐term RSB in pediatric heart transplant should be reconsidered given the low rate of detected rejection.     

C0 or C2 driven cyclosporine monitoring in long-term pediatric kidney transplant recipients: Is there any threat for chronic rejection development?

The clinical management of cyclosporine has evolved greatly during the last decade thanks to the use of pharmacokinetic (PK) studies which confirmed the dose relationship between drug exposure and its biological effects. Therefore, cyclosporine PK monitoring during the early phase of the post-transplant period became essential to avoid over or underexposure to the drug thus preventing the risk of nephrotoxicity or acute rejection episodes. More recently, a simple PK determination based on cyclosporine blood concentration measured 2 h after the morning dose, has proven to be very effective for monitoring cyclosporine exposure in the early postoperative period. In this paper, the authors present a set of PK profiles obtained from a stable, long-term pediatric kidney transplant population and correlate these parameters with the risk of chronic rejection development. The study shows how cyclosporine monitoring based on the sole trough level determination misled a correct therapeutic behavior, as revealed by the PK parameters that were constantly below the therapeutic threshold in a small patient cohort who eventually developed chronic rejection. The C2 determination should be considered as the gold standard for cyclosporine monitoring in long-term pediatric recipients.     

Regional variation in the use of 1A status exceptions for pediatric heart transplant candidates: is this equitable?

The use of status exceptions (SE) was recently publicized as a strategy to reduce waitlist times for children awaiting heart transplant (HTx). The aim of this study was to assess SE use across UNOS regions and compare survival in patients listed using a SE to those listed by standard criteria. The OPTN database was queried for all pediatric patients listed for HTx (2000–2014). SE use was compared across UNOS regions. Survival curves were generated and compared using the log‐rank test. 1A SE use is uncommon, being utilized in 108 of 4587 pediatric 1A listings (2.4%). There is significant variability in SE use across UNOS regions (0.7%–16.4% of 1A listings, P < .001). Waitlist survival is significantly higher in candidates listed using a 1A SE compared to those listed by standard criteria (P = .001) and is similar to 1B listings. Regional variation in 1A SE use has the potential to introduce bias into a system designed to be equitable. Waitlist survival in patients listed using a SE is similar to those listed status 1B, suggesting these patients may not require 1A status. Careful review of pediatric heart allocation policies is needed to optimize patient outcomes and ensure a fair and unbiased allocation system.     

Is ABPM clinically useful after pediatric solid organ transplantation?

When ambulatory blood pressure monitoring (ABPM) is performed in populations with a high risk for secondary hypertension, such as solid organ transplant recipients, hypertension or abnormalities in circadian blood pressure variability are often discovered even in patients with normal office blood pressure (BP). To discuss whether ABPM should be routinely assessed in pediatric solid organ recipients, the available information on pathological findings, association of ABPM abnormalities with outcome parameters, and treatment options is reviewed. ABPM is a useful tool to optimize therapy in the large proportion of transplant recipients with confirmed hypertension. Whether the use of ABPM on a routine basis should be recommended for pediatric transplantation patients without office hypertension remains to be determined.