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.     

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.     

Is Doppler echocardiography useful for estimating left ventricular filling pressures in pediatric heart transplant recipients?

LV E/E′ ratio obtained using Doppler echocardiography is considered a surrogate for LV filling pressure in adults but has performed poorly in children. We hypothesized that LV E/E′ ratio Z‐score, adjusted for age, will relate more strongly to LV filling pressures than LV E/E′ ratio in pediatric HT recipients. We analyzed 751 echocardiograms performed within 24 hours of a heart catheterization in 122 pediatric HT recipients (median age at HT 13 years, median 6 studies per patient). The primary end‐point was PCWP, assessed both as a continuous and a binary variable. Associations with LV E/E′ ratios and z‐scores were assessed using generalized estimating equations models. PCWP, LV E/E′ ratios (using E′ from LV free wall, septum, and their average), and LV E/E′ ratio Z‐scores, all declined over time after HT. LV E/E′ ratios and their Z‐scores were significantly associated with PCWP assessed as a continuous variable (P < 0.001 for all); however, the relationship was weak (R² range, 0.083 to 0.121). LV E/E′ ratios and their Z‐scores were also significantly associated with PCWP as a binary variable (P < 0.001 for all) but with only modest ability to discriminate PCWP ≥15 mm Hg (c‐statistic range, 0.660 to 0.695). The association between LV E/E′ ratio and PCWP in pediatric HT recipients is modest. Using a LV E/E′ ratio Z‐score did not result in significantly improved association with PCWP. Current Doppler echocardiographic methods are unreliable for estimating LV filling pressures in pediatric HT recipients.     

Can severity‐of‐illness indices for neonatal intensive care predict outcome at 4 years of age?

Aim: To test four neonatal severity-of-illness indices (CRIB, NTISS, SNAP, SNAP-PE) for their ability to predict short- and long-term outcome in very low-birthweight infants receiving neonatal intensive care.

Methods: Data on 240 newborns with birthweights below 1500 g from two Swedish neonatal units were collected. The predictive values of the indices for an adverse outcome in the neonatal period and at 4 y of age were compared with those of gestational age and birthweight.

Results: An early adverse outcome (in-hospital death, severe haemorrhagic-ischaemic brain lesion, retinopathy, chronic lung disease) was better predicted with CRIB (area under ROC curve (Az) = 0.87) and SNAP-PE (Az = 0.86), while SNAP-PE was best for predicting late problems (deviations in growth and psychomotor development, neurosensory impairment, difficulties in concentration, and impairment in vision, and hearing,) (Az = 0.63). All indices predicted the early outcome better than the outcome at the 4-y follow-up. Severity-of-illness indices can be used as instruments to follow and improve the level of neonatal intensive care, but unfortunately seem to be of little value in long-term follow-up.

Conclusion: CRIB and SNAP-PE indices are better in predicting hospital mortality than birthweight. None of the systems can predict adverse outcome at 4 y of age.     

Variability index of tacrolimus serum levels in pediatric liver transplant recipients younger than 12 years: Non‐adherence or risk of non‐adherence?

MLVI has been used to assess adherence. To determine the MLVI in children <12 years of age at transplantation and to identify demographic correlates and consequences for the graft. This is a retrospective study of 50 outpatients (4.0 ± 3.5 years), at least 13‐month post‐liver transplantation. The outcomes evaluated were MLVI, ALT > 60 IU/L, ACR, death, and graft loss. We analyzed demographic and socioeconomic characteristics, indication for transplantation, and type of donor. Student's t test and the chi‐square test were used. Statistical significance was set at P ≤ .05. Seventy‐two percent were infants or preschoolers, 62% biliary atresia. Seventy‐four percent of the mothers had middle‐school education, and 54% of the families had an income ≤3632.4 US$/y. Twenty‐two (44%) patients had a MLVI ≥ 2 SD; this was more prevalent in families with higher incomes (P = .045). ALT levels > 60 IU/L were more common in MLVI ≥ 2 SD group (P = .035). ACR episodes were similar between groups (P = 1.000). No patient died or lost the graft. MLVI ≥ 2 SD may be an indicator of the risk of medication non‐adherence.