Outcomes of fetal listed patients awaiting heart transplantation

HTx in neonates is mainstay therapy for those with severe cardiomyopathies and congenital heart disease. Fetal listing for HTx has been proposed as a way to increase the potential window for a donor with outcomes predicted to be similar to the neonatal population. Data from the PHTS, a prospective multicenter study, were used to examine the outcomes of fetuses listed between 1993 and 2009. Four thousand three hundred and sixty‐five children were listed for HTx during this period. Fetuses comprised 1% and neonates 19.8% of listed patients. In those patients listed as fetus and transplanted, the median wait time from listing to HTx was 55 days (range 4–255), with a median of 25 days (range 0–233) after birth. By six months post‐listing, a higher proportion of fetal listed patients had undergone HTx with a lower waitlist mortality when compared with neonate. There was no significant difference in survival following HTx between the two group (p = 0.4). While the results of this study may be less applicable to current practice due to changes in referrals for fetal listing, they do indicate that fetal listing can be a reasonable option. These results are of particular interest at the present time given the ongoing public discourse on the proposed elimination of fetal listing within UNOS.     

Impact of mechanical circulatory support on survival in pediatric heart transplantation

Evidence on the impact of MCS on pediatric heart transplant survival is still scarce related to congenital heart disease patients including univentricular physiology as well as the risk factors for complications. We performed a retrospective review of all urgent pediatric (aged ≤16 years) HT from 2004 to 2014 in the Spanish Pediatric Heart Transplant Registry Group. Patients were stratified into two groups: urgent 0 (MCS at HT) and urgent 1 (non‐MCS at HT). The primary outcome measure was post‐transplant survival; secondary outcome measures were complications and absence of infections and rejection during the first post‐transplant year. One hundred twenty‐one pediatric patients underwent urgent HT, 58 (47.9%) urgent 0 and 63 (52%) urgent 1. There were 30 (24.8%) deaths: 12 in the urgent 0 group and 18 in the urgent 1 group, P = n.s. Regarding the type of MCS, patients on ECMO had the highest rate of complications (80%) and mortality (40%). Patients in the urgent 1 group showed a higher risk of hospital re‐admission for infection during the first year after transplantation (OR 2.31 [1.1‐4.82]), P = .025. We did not identify a risk factor for mortality. MCS does not impact negatively on survival after HT. However, there is a significant increase in 30‐day and 1‐year mortality and complications in ECMO patients compared with VAD patients. Infants, congenital heart disease, and PediMACS were not found to be risk factors for mortality.     

Chronic diarrhea, ascites, and protein-losing enteropathy in an infant with hepatic venous outflow obstruction after liver transplantation

Hourigan SK, Anders RA, Mitchell SE, Schwarz KB, Lau H, Karnsakul W. Chronic diarrhea, ascites, and protein‐losing enteropathy in an infant with hepatic venous outflow obstruction after liver transplantation. Abstract: An 18‐month‐old female status post‐orthotopic liver transplant for biliary atresia presented nine months after transplant with severe diarrhea and intolerance of feeds. She was found to have a PLE as evidenced by a low serum albumin and a persistent elevation of fecal A1AT. Investigation eventually revealed that the cause of the PLE was a stricture at the anastomosis site between the hepatic vein and inferior cava, supported by resolution of the PLE after venoplasty of the stricture. The patient has subsequently required several repeat venoplasties for recurrence of her symptoms correlating with recurrence of the stricture. This is a very rare presentation of hepatic venous outflow obstruction. Moreover, normal duplex ultrasound imaging of liver vasculature and her unusual presentation led to a delay in her diagnosis highlighting the need for an increased index of suspicion.     

Heart transplantation in an infant with Williams‐Beuren syndrome and rapidly progressive ischemic cardiomyopathy

Ischemic cardiomyopathy with resultant refractory HF may occur in patients with WBS, often as the result of coronary involvement with SVAS. The rapid development of arteriopathy at a young age raises concerns regarding transplant candidacy due to progressive stenoses at other arterial sites with potential detrimental impact on long‐term heart graft function. We report a 2‐month‐old male infant diagnosed with mild aortic stenosis during the neonatal period, but subsequently developed rapidly progressive supravalvar and coronary artery stenoses leading to cardiogenic shock due to myocardial ischemia. The presentation led to the diagnosis of WBS. He required prolonged CPR including ECMO therapy. He subsequently underwent LVAD implantation as bridge to transplant and 4 days later heart transplantation. His post‐operative course was complicated by prolonged mechanical ventilation and extended intensive care unit and hospital stays. However, at follow‐up 18 months post‐transplant he continues to have normal graft function with mild, non‐progressive residual coarctation of aorta and non‐progressive moderately hypoplastic pulmonary arteries.     

Outcome of heart transplantation in pediatric cancer survivors

The aim of this study is to evaluate the outcome of heart transplantation in children surviving malignancies. Pediatric heart transplant recipients were identified using the UNOS database. Follow‐up data including survival and rate of malignancy were analyzed. A total of 7169 children received heart transplants between 1987 and 2011. Of these, 107 (1.5%) survived previous malignancy treatment (group I) and 7062 (98.5%) did not have prior malignancy (group II). Survival after transplant was 92.5%, 90.6%, 80.3%, and 65% at three months, one, five, and 10 yr in group I, similar to the rate in group II (90.1%, 84.4%, 73.8%, and 57.7%). Survival after transplantation was similar between group I and children who underwent OHT secondary to cardiomyopathy in group II. The rate of post‐OHT malignancy in group I was higher than that in group II (14/107(13%) vs. 386/7062 (5.4%), p = 0.001). Children who developed malignancy in group I had similar survival as children who developed malignancy in group II. Post‐transplant survival is similar in children with and without pretransplant malignancy in spite of higher rate of malignancy in children with pretransplant malignancy. OHT appears to be a reasonable treatment option in children who develop end‐stage heart disease after malignancy treatment.     

The history of pediatric heart and lung transplantation

As is the case with other forms of solid organ transplantation, success with heart and lung transplantation in the pediatric population was a natural extension of success with these procedures in adults. As a result, to review the history of pediatric heart and lung transplantation, one must by necessity review the landmarks in research and the events that gave way to successful heart and lung transplantation in adults.     

Risk factors for the development of donor‐specific antibodies after pediatric heart transplantation

DSA after HTx may have adverse effects on patient survival. The aim of this study was to assess risk factors for the development of DSA after pediatric HTx. All HTx recipients at our center with serial monitoring of DSA were identified. Cox proportional hazards model was used to estimate donor and recipient characteristics associated with the development of DSA. De novo DSA were detected in 40 (33%) of 121 HTx recipients. Characteristics associated with de novo DSA included older age, African American race, prior operations, prior ECMO, PRA > 10%, longer bypass time, mechanical support at transplant, and donor death from GSW. In a multivariable model, mechanical support (HR 3.23, 95% CI [1.02, 8.87]), African American race (HR 3.36, 95% CI [1.68, 7.32]), and donor death from GSW (HR 4.76, 95% CI [1.62, 14.01]) were significantly associated with DSA. Multiple factors appear to play a role in the development of DSA, knowledge of which may guide the frequency of post‐transplant monitoring. DSA develop more frequently in those with prior sensitizing events, suggesting the possibility that these exposures predispose the immune system to respond to donor antigens, even in the presence of a negative cross‐match.     

Strain and strain rate imaging using speckle tracking in acute allograft rejection in children with heart transplantation

Acute allograft rejection is a major cause of morbidity and mortality following heart transplantation. There is no reliable noninvasive test to diagnose rejection. We aimed to investigate the accuracy of strain by speckle tracking echocardiography in the detection of acute rejection. We identified acute rejection episodes in patients followed at a single transplant center. Data were collected at baseline, during rejection and two follow‐up points. Peak systolic radial and circumferential strain at the level of papillary muscles and peak systolic longitudinal strain from apical four‐chamber view were analyzed offline. ANOVA was used for comparison between groups. p value ≤0.05 was considered significant. Fifteen rejection episodes were identified. There were no differences in the fractional shortening, LV posterior wall thickness, E/A, septal E/E’, septal S’, lateral E/E’, lateral S’, or MPI during rejection, compared to baseline. There was a significant increase in the LV mass during a rejection episode (47.5 vs. 34.4 g/ht^2.7 [p = 0.03]). The peak systolic radial strain (18.3 vs. 26.5; p = 0.03), longitudinal strain (?11.7 vs. ?14.6; p = 0.05), and circumferential strain (?14.4 vs. ?21.7; p = 0.05) declined significantly during rejection. In conclusion, peak systolic radial, longitudinal and circumferential strain decline and LV mass increases during an episode of rejection.     

Psychosocial predictors of medication adherence in pediatric heart and lung organ transplantation

Few studies have identified the psychosocial characteristics of those children and their families associated with future non‐adherence to immunosuppressive medications following a heart or lung transplant. UNOS data and medical records information were used to test the association between patient and family psychosocial characteristics and medication adherence. Medication adherence outcomes were obtained using the physician assessments in the UNOS data and measured through patient‐level standard deviation scores of immunosuppressive medication blood levels. Complete data were collected on 105 pediatric heart and lung transplant recipients and their families. Multivariate, stepwise analyses were conducted with each adherence outcome. Physician reports of adherence were associated with age of the child at transplantation, parental education, two‐parent families, significant psychosocial problems, and the pretransplant life support status of the child. The resulting model (χ²=28.146, df=5, P<.001) explained approximately 39.5% of the variance in physician reports of adherence (Nagelkerke r²=.395). Blood level standard deviation scores were predicted by age at transplant (F=5.624, P=.02, r²=.05). Results point to the difficulties experienced by children and families when undergoing a heart or lung transplantation. Efforts to develop standardized and evidence‐based pretransplant psychosocial assessments in pediatric populations are suggested, especially those surrounding familial risk factors.     

Ten yr of pediatric heart transplantation: A report from the Pediatric Heart Transplant Study

The PHTS was founded in 1991 as a not‐for‐profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2000–December 31, 2009) and summarize the changes, trends, outcomes, and lessons learned.     

Transplant‐related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant‐related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high‐risk group (P = .006). High‐risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.     

Comparison of inhospital outcomes of pediatric heart transplantation between single ventricle congenital heart disease and cardiomyopathy

Data investigating the impact of household income and other factors on SV patient status‐post‐Fontan palliation after heart transplantation are lacking. We aim to evaluate factors affecting outcomes after OHT in this population. The PHIS database was interrogated for either SV or myocarditis/primary CM who were 4 years or older who underwent a single OHT. There were 1599 patients with a median age of 13.2 years (IQR: 9.3‐16.1). Total hospital costs were significantly higher in the SV group ($408 000 vs $294 000, P < 0.0001), but as median household income increased, the risk of inhospital mortality, post‐transplant LOS, and LOS‐adjusted total hospital costs all decreased. The risk of inhospital mortality increased 6.5% per 1 year of age increase at the time of transplant. Patients in the SV group had significantly more diagnoses than those in the CM group (21 vs 15, P < 0.0001) and had longer total hospital LOSs as a result of longer post‐transplant courses (25 days vs 15, P < 0.0001). Increased median household income and younger age are associated with decreased resource utilization and improved inhospital mortality in SV CHD patients who undergo OHT. In conclusion, earlier consideration of OHT in this population, coupled with improved selection criteria, may increase survival in this population.     

Multiple listing for pediatric heart transplantation in the USA: Analysis of OPTN registry data from 1995 through 2009

Multiple listing is associated with shorter waitlist durations and increased likelihood of transplantation for renal candidates. Little is known about multiple listing in pediatric heart transplantation. We examined the prevalence and outcomes of multiple listing using OPTN data from 1995 through 2009. Characteristics and waitlist outcomes of propensity‐score‐matched single‐ and multiple‐listed patients were compared. Multiple listing occurred in 23 of 6290 listings (0.4%). Median days between listings was 35 (0–1015) and median duration of multiple listings was 32 days (3–363). Among multiple‐listed patients, there were trends toward less ECMO use (0% vs. 11%, p = 0.1) and more frequent requirement for a prospective cross‐match (17% vs. 8%, p = 0.08). Multiple‐listed patients more commonly had private insurance (78% vs. 56%; p = 0.03). Urgency status at listing was similar between groups (1/1A: 61% vs. 64%, 1B/2: 39 vs. 36%; p = 0.45) as were weight, age, diagnosis, ventilator/inotrope use, and median income (each p ≥ 0.17). There was a trend toward increased incidence of heart transplantation for multiple‐listed patients at three, six, and 24 months (50%, 65%, 80%) vs. single‐listed patients (40%, 54%, 64%; p = 0.11). Multiple listing for pediatric heart transplantation in the USA occurs infrequently and is more common in patients with private insurance.     

Impact of routine surveillance biopsy intensity on the diagnosis of moderate to severe cellular rejection and survival after pediatric heart transplantation

Data are lacking on RSB intensity and outcomes after pediatric heart transplantation. PHTS centers received a survey on RSB practices from 2005 to present. PHTS data were obtained for 2010‐2013 and integrated with center‐matched survey responses for analysis. Survey response rate was 82.6% (38/46). Centers were classified as low‐, moderate‐, and high‐intensity programs based on RSB frequency (0—more than 8 RSB/y). RSB intensity decreased with increasing time from HT. Age at HT impacted RSB intensity mostly in year 1, with little to no impact in later years. Most centers have not replaced RSB with non‐invasive methods, but many added ECHO and biomarker monitoring. Higher RSB intensity was not associated with decreased 4‐year mortality (P=.63) or earlier detection of moderate to severe (ISHLT grade 2R/3R) cellular rejection (RSBMSR) in the first year (P=.87). First‐year RSBMSR incidence did not differ with intensity or age at HT. Significant variability exists in RSB intensity, but with no impact on timing and incidence of RSBMSR or 4‐year mortality. Reduction in RSB frequency may be safe in certain patients after pediatric HT.     

Prevalence and outcomes of heart transplantation in children with intellectual disability

Heart transplantation in children with intellectual disability is a controversial issue. We sought to describe the prevalence and outcomes of heart transplantation in children with intellectual disability and hypothesized that recipients with intellectual disability have comparable short‐term outcomes compared to recipients without intellectual disability. We performed a retrospective cohort analysis of children receiving a first heart‐alone transplant in the UNOS STAR database from 2008 to 2013. Recipients with intellectual disability were compared to those without using chi‐square tests. Kaplan‐Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between intellectual disability and graft failure and patient survival. Over the study period, 107 children with intellectual disability underwent initial heart transplantation, accounting for 8.9% of first pediatric heart transplants (total=1204). There was no difference in the incidence of acute rejection between groups in the first year after transplant. Mean functional status scores at follow‐up improved in both groups after transplantation, but tended to be lower among children with intellectual disability than children without. Log‐rank tests did not suggest significant differences in graft survival between those with and without intellectual disability during the first 4 years following transplantation. Children with intellectual disability constitute a significant portion of total heart transplants with short‐term outcomes comparable to children without intellectual disability.     

Renal glomerular size in infants with congenital heart disease and in cases of sudden infant death syndrome

Recurrent apnoea and chronic hypoventilation have been implicated in the pathogenesis of the sudden infant death syndrome (SIDS) and markers of chronic hypoxaemia have been reported in such infants at post mortem examination. Markers of chronic hypoxaemia are common in cyanotic congenital heart disease. Glomerular enlargement in congenital heart disease is said to be related to hypoxaemia although the precise mechanism whereby this occurs is not clear.We have established a normal range of glomerular size for the postperinatal period and confirmed glomerular enlargement to be a common finding in children with congenital heart disease of similar age. In contrast glomerular size in SIDS is not different from controls. The results question the role of significant chronic hypoxaemia being involved in these deaths.Abbreviations SIDS sudden infant death syndrome - VSD ventricular septal defect - ASD atrial septal defect     

Risk factors for specific causes of death following pediatric heart transplant: An analysis of the registry of the International Society of Heart and Lung Transplantation

We sought to determine temporal changes in COD and identify COD‐specific risk factors in pediatric primary HTx recipients. Using the ISHLT registry, time‐dependent hazard of death after pediatric HTx, stratified by COD, was analyzed by multiphasic parametric hazard modeling with multivariable regression models for risk factor analysis. The proportion of pediatric HTx deaths from each of cardiovascular cause, allograft vasculopathy, and malignancy increased over time, while all other COD decreased post‐HTx. Pre‐HTx ECMO was associated with increased risk of death from graft failure (HR 2.43; p < 0.001), infection (HR 2.85; p < 0.001), and MOF (HR 2.22; p = 0.001), while post‐HTx ECMO was associated with death from cerebrovascular events/bleed (HR 2.55; p = 0.001). CHD was associated with deaths due to pulmonary causes (HR 1.78; p = 0.007) or infection (HR 1.72; p < 0.001). Non‐adherence was a significant risk factor for all cardiac COD, notably graft failure (HR 1.66; p = 0.001) and rejection (HR 1.89; p < 0.001). Risk factors related to specific COD are varied across different temporal phases post‐HTx. Increased understanding of these factors will assist in risk stratification, guide anticipatory clinical decisions, and potentially improve patient survival.     

Subclinical atherosclerosis after heart and heart-lung transplantation in childhood

Abstract:  Children after heart transplantation are considered as at-risk patients for extracardiac atherosclerotic complications. Noninvasive ultrasound measurement of the common carotid artery (IMT) provides valid information about the endothelial structure of the vascular system. Twenty-two patients (17 male, mean age 12.4 ± 4.5 yr) after heart and (5.7 ± 4.5 yr) heart–lung transplantation were enrolled. The mean IMT was measured and compared with a control group (18 children, 10 male, mean age 11.8 ± 1.8 yr) and to normative data. Transplanted children had a higher IMT than controls (0.453 ± 0.003 vs. 0.424 ± 0.002 mm, p < 0.001). IMT-SDS was increased as well (1.6 ± 0.1 vs. 0.8 ± 0, p < 0.001). Transplanted children had a higher LDL/HDL-ratio (2.2 ± 0.2 vs. 1.2 ± 0.1, p < 0.001). Time after transplantation, age at the time of transplantation, or medical therapy did not influence the findings. We found evidence for subclinical atherosclerosis in children after heart and heart–lung transplantation. Even if single atherosclerotic risk factors could not be identified, transplanted children seem to be at risk for atherosclerosis. Our findings support the recently published statement of the AHA-Expert panel: after heart transplantation atherosclerotic complications may occur with increased incidence. We propose the IMT-measurement in these patients as an easy method to assess the vascular status and to guide preventive measures.     

Elevated pretransplant pulmonary vascular resistance index does not predict mortality after isolated orthotopic heart transplantation in children: A retrospective analysis of the UNOS database

OHT is the definitive therapy in end‐stage heart failure. Elevated PVRI is considered a relative contraindication to isolated OHT; this assumption is re‐evaluated using data from the UNOS database. A retrospective review of de‐identified data from the UNOS dataset was performed. There were 1943 pediatric OHT recipients between 10/87 and 12/11 with sufficient data for analysis. Cox regression was performed to examine the effect of baseline characteristics on post‐transplant survival. Patients were propensity matched, and Kaplan–Meier survival analysis was performed comparing cohorts of patients using thresholds of 6 and 9 WU × m². PVRI was not a significant predictor of post‐transplant outcomes in either univariate or multivariate Cox regression. Kaplan–Meier analysis revealed no difference in survival between both unmatched and propensity‐matched OHT recipients. In conclusion, elevated PVRI was not associated with post‐transplant mortality in pediatric OHT recipients. A prospective study assessing the current use of PVRI ≥6 as a threshold to contraindicate isolated OHT should be undertaken. Removing this potentially unnecessary restriction on transplant candidacy may make this life‐saving therapy available to a greater number of patients.